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Optimising therapy with 131I-MIBG for neuroblastoma patients and for neuroblastoma patients with intraspinal extension
Kraal, K.C.J.M.
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Citation for published version (APA): Kraal, K. C. J. M. (2017). Optimising therapy with 131I-MIBG for neuroblastoma patients and for neuroblastoma patients with intraspinal extension.
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Download date:23 Sep 2021 I-MIBG I-MIBG 131 Kathelijne Kraal intraspinal extension. intraspinal for neuroblastoma patients and and patients for neuroblastoma for neuroblastoma patients with patients for neuroblastoma Optimising therapy with with therapy Optimising
Optimising therapy with 131I-MIBG for neuroblastoma patients Kathelijne Kraal and for neuroblastoma patients with intraspinal extension.
OPTIMISING THERAPY WITH 131I-MIBG FOR NEUROBLASTOMA PATIENTS AND FOR NEUROBLASTOMA PATIENTS WITH INTRASPINAL EXTENSION. The research described in this thesis was financially supported by KiKa, Tom Voute Fonds (also known as SKK) and Stichting zeldzame ziekten fonds (ZZF).
Printing of this thesis was financially supported by Academic medical Center (University of Amsterdam) and this is gratefully acknowledged.
ISBN: 978-94-6233-520-2 Cover design: Merel en Lotte Koenecke. Layout: Annelies Wisse. Printing: Gildeprint. OPTIMISING THERAPY WITH 131I-MIBG FOR NEUROBLASTOMA PATIENTS AND FOR NEUROBLASTOMA PATIENTS WITH INTRASPINAL EXTENSION
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op vrijdag 10 februari 2017, te 13 uur
door
door Kathelijne Catherina Jeanette Maria Kraal geboren te Zaandam Promotie commissie Promotores Prof. dr. H.N. Caron Universiteit van Amsterdam
Copromotor Dr. G.A.M. Tytgat Universiteit van Amsterdam Dr. M.M. van Noesel Universiteit van Utrecht
Overige leden Dr. P. Brock Great Ormond Street Hospital Prof. dr. J Booij Universiteit van Amsterdam Prof. dr. J.B. van Goudoever Universiteit van Amsterdam Prof. dr. P.M. Hoogerbrugge Prinses Máxima Centrum, Radboud Universiteit Nijmegen Prof dr. T. Simon Universität zu Köln Prof. dr. C.E van der Schoot Universiteit van Amsterdam
Faculteit der Geneeskunde Aan mijn dochters, Merel en Lotte Koenecke en mijn ouders. Table of Contents
Chapter 1 9 General introduction and scope of the thesis.
Part A 25 Optimising therapy with 131I-MIBG for neuroblastoma patients.
Chapter 2 27 131I-metaiodobenzylguanidine (MIBG), hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients.
Chapter 3 43 Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan.
Chapter 4 61 Feasibility, toxicity and response of upfront 131I-MIBG therapy followed by GPOH NB 2004 protocol in newly diagnosed stage 4 neuroblastoma patients.
Chapter 5 79 131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma, a Cochrane review.
Chapter 6 127 Autologous stem cell transplantation harvesting and hematological reconstitution in high-risk neuroblastoma patients treated with 131Iodine- metaiodobenzylguanidine.
Part B 149 Neuroblastoma patients with intraspinal extension
Chapter 7 151 Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors.
Chapter 8 179 Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review.
Chapter 9 223 General discussion and implications for clinical practice and future research. Appendix 242 English summary
246 Nederlandse samenvatting (Dutch summary)
252 List of co-authors and their contribution to the manuscript
256 List of publications
258 PhD portfolio
261 Acknowledgements
268 Curriculum Vitae
269 Abbreviations
Chapter 1 General introduction and scope of the thesis
Partly adapted from: Nieuwe behandelingen voor pediatrische (HR) NBL patiënten. Ned Tijdschr Oncol 2013;10:11-9. KCJM Kraal, BLF van Eck-Smit, MM van Noesel, HN Caron en GAM Tytgat Neuroblastoma Epidemiology and pathogenesis Neuroblastoma (NBL) is the most common extra cranial solid tumor of childhood, derived from the sympathetic nervous system (1). NBL accounts for 8-10% of all childhood cancers, but is responsible for more than 15% of childhood cancer deaths (2). The median age at diagnosis is 18 months (3). In the Netherlands approximately 20-25 children per year are diagnosed with neuroblastoma. The neuroblastoma can arise anywhere along the sympathetic side chain (cervical, thoracic, abdominal and pelvic cavity), but mainly from the adrenal gland.
Clinical presentation and classification The International Neuroblastoma Staging System (INSS), is a post-surgical staging system, and classifies NBL into five stages, 1 to 4 and 4S, a special stage (4). Children with stage 4 NBL present with metastatic disease at diagnosis, mainly involving the bone marrow (BM) and lymph nodes (LN). The defining charac- teristics of high-risk (HR) NBL include an age of more than one year, with metastatic disease, unfavourable Shimada histology or amplification of MYCN (NMA) (5-7). More recently, the International Neuroblastoma Risk Group Staging System was developed, since the INSS classification is a post-surgical staging system (Table I) (8).
The combination of stage and other prognostic factors results in the INRG classification system, defining 3 risk groups: low risk (LR), medium risk (MR) and high risk (HR). At diagnosis 50% of NBL patients have metastatic disease, classifying them as HR.
Diagnosis Catecholamines (CME) are produced mainly by the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. They can be divided into dopaminergic, adrena-
Stage Description L1 Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment L2 Locoregional tumor with presence of one or more image- defined risk factors M Distant metastatic disease (except stage MS) MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow
Table I: International Neuroblastoma Risk Group Staging System
10 Chapter 1 Response Primary tumor Metastatic sites CR (1) No tumor No tumor; CME normal. VGPR (2) Decreased by 90-99% No tumor; CME normal; residual 99Tc bone changes allowed. PR (3) Decreased by > 50% All measurable sites decreased by > 50%. Bones and BM: number of positive bone sites decreased by > 50%; no more than 1 positive BM site allowed.* MR (4) No new lesions; > 50% reduction of any measurable lesion (primary or metastases) with < 50% reduction in any other; < 25% increase in any existing lesion. NR (5) No new lesions; < 50% reduction but < 25% increase in any existing lesion. PD (6) Any new lesion; increase of any measurable lesion by > 25%; previous negative BM positive for tumor.
* One positive BM aspirate or trephine biopsy allowed for PR if this represents a decrease from the number of positive sites at diagnosis. Figure 1. International Neuroblastoma Response Criteria (INRC) (4)
linergic and noradrenalinergic. CME are metabolised and eventually degraded into “metanephrines” and their acidic metabolites (homovanillic acid (HVA), vanylmandylic acid (VMA) and 3-Methoxytyramine (3-MT)). They can be elevated and measured in the urine of NBL patients. Other investigations performed at diagnosis are MRI/ CT or ultrasound of the primary tumor, 123I-metaiodobenzylguanidine scan (123I-MIBG) and BM investigation for NBL infiltration (using BM aspirate or trephine biopsy and cytology staining).
Response The response has been scored according to the revised International Neuroblastoma Response Criteria (INRC), taking into account the volume of the primary tumor (using MRI/ CT or ultrasound), metastatic sites using urinary CME, 123I-MIBG scans and BM examination (4). Response categories are complete response (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progressive disease (PD).
Therapy and prognosis Internationally the treatment for HR NBL consists of different treatment modalities: • 131I-metaiodobenzylguanidine (131I-MIBG),
General introduction and scope of this thesis 11 • Induction chemotherapy, • Myeloablative chemotherapy (MAT) with autologous stem cell transplantation (ASCT)), • Surgery, • Radiotherapy, • Maintenance therapy (anti-disialoganglioside (GD2) therapy, granulocyte-macrophage colony stimulating-factor (GM-CSF) and interleukine-2 (IL-2) and cis-retinoic acid (cis-RA).
Patients with HR NBL have a 5-year survival rate of only 30-40%, even if there is a favourable response to initial therapy(9). Relapse remains common, despite the achievement of a complete clinical remission (CR) with myeloablative therapy and ASCT, suggesting that minimal residual disease (MRD) is an important cause of recurrence. A few years ago, the Children’s Oncology group (COG) have reported that the addition of immunotherapy (IT) with ch14.18 (anti-GD2 antibody), GM-CSF, interleukine-2 (IL-2) to the maintenance therapy with cis-RA has improved the outcome by 20% (10). The IT has now become “standard of care” and has been incorporated into many of the HR NBL treatment regimens.
Induction chemotherapy The leading international groups are: the German “Gesellschaft fur Padiatrische Onkologie und Hematologie” (GPOH), the American “Children’s Oncology Group” (COG) and the European consortium “International Society of Pediatric Oncology European Neuroblastoma” (SIOPEN). The induction chemotherapy for HR NBL protocols is (dose-) intensive (short interval between chemotherapy courses) and uses different cytostatic drug combinations. In the SIOPEN Pearson et al. have randomised giving chemotherapy “rapid” (21 days) versus “standard” (10 days), 3 year- event free survival (EFS) (24,2% standard group and 31.0% rapid group, p=0.30), however the 5-year EFS was statistically significantly different (18.2% in the standard group and 30.2% inthe rapid group) (p=0.022). There was no difference in toxicity. Based on these findings, a rapid treatment “Rapid-COJEC” combined with prophylactic G-CSF, is used as an induction regimen. This rapid regimen
DCOG Dx 2*MIBG N5/N6 N5/N6 N5/N6 ASCT 13-cis-RA
Dx N5/N6 N5/N6 N5/N6 ASCT 13-cis-RA
GPOH R
Dx 2*N8 N5/N6 N5/N6 N5/N6 ASCT 13-cis-RA
12 Chapter 1 (also known as “dose intense”), aimed to prevent development of resistance forming of the tumor, produces a rapid response in patients with HR NBL with no long interval between the induction chemotherapy and MAT ASCT (11). The current treatment in the Netherlands consists of the Dutch Childhood Oncology Group (DCOG)- NBL-2009 protocol, this protocol is based on the GPOH 2004 treatment protocol (12). GPOH: The “dose intense” induction chemotherapy consists of N5/ N6 chemotherapy, N5: cisplatinum, etoposide and vindesine; N6: vincristine, dacarbazine, ifosfamide and doxorubicine. The GPOH randomise two cycles N8 (Cyclophosphamide, Etoposide and Topotecan) chemotherapy courses upfront, followed by the backbone of N5/N6 chemotherapy compared with no N8 courses upfront. The Dutch group use the N8 courses as a salvage regimen, in case of no CR or VGPR (before MAT and ASCT). In order to qualify for MAT ASCT your response needs to be at least PR.
123I-Meta-iodobenzylguanidine (123I-MIBG)
(A)123I-mIBG scoring method 1: method 1 divides the skeleton into nine segments to view osteomedullary involvement, and adds a tenth sector that counts any soft tissue involvement to the score. The extension score for method 1 is graded as: 0, no sites per segment; 1, one site per segment; 2, more than one site per segment; and 3, diffuse involvement (>50% of the segment). (B) 123I-mIBG scoring Frappaz-method 2: method 2 divides the skeleton into seven segments. The intensity score for method 2 is graded as: 0, no uptake; 1, doubtful uptake; 2, obvious but mild uptake; 3, strong uptake, with a maximum score of 21. Soft tissue involvement is noted separately from the score. (C) 123I-mIBG scoring SIOPEN-method 3: method 3 divides the skeleton into 12 anatomic segments. The extension score for method 3 is graded as: 0, no sites per segment, 1, one discrete site per segment; 2, two discrete lesions; 3, three discrete lesions; 4, >3 discrete foci or a single diffuse lesions involving <50% of a bone; 5, diffuse involvement of >50–95% whole bone; 6, diffuse involvement of the entire bone. Figure 2: Three different 123I-MIBG scorings methods
General introduction and scope of this thesis 13 About 95% of NBL take up 123I-Meta-Iodobenzylguanidine (123I-MIBG). The uptake is specific for NBL, ganglioneuroma and pheochromocytoma. Furthermore, 123I MIBG releases only gamma irradiation, which can be detected on MIBG scan and has no therapeutic properties, making it an important tool for diagnosis and follow-up of NBL. The 123I-MIBG scans can be scored using different scorings methods, in our studies we have used the Curie scoring method (13) and there are also the Frappaz and SIOPEN scorings methods (14).
Recent studies have shown that a Curie score ≤ 2 and a SIOPEN score ≤ 4 (best cutoff) at diagnosis were correlated to significantly better EFS and OS compared with higher scores. After four cyclesof chemotherapy (German Neuroblastoma Trial NB97), OS was significantly better for MIBG-negative patients compared with those with any residual MIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between MIBG-negative patients and patients with residual MIBG-positive metastases. Patients without MIBG-positive metastases after four and six cycles of chemotherapy had a better OS, but late clearance of MIBG-positive metastases did not improve outcome. Data from the German group demonstrate that MIBG scoring is a valuable diagnostic tool and is prognostic at diagnosis and during therapy. The Curie and the SIOPEN scores are highly correlated and equally reliable and predictive (15;16).
¹³¹I-Meta-Iodobenzylguanidine (131I-MIBG) therapy ¹³¹I-Meta-Iodobenzylguanidine (131I-MIBG) therapy provides a means of specific tumor localization for radionuclide delivery and targeted therapy to NBL (17). When 131I-MIBG is produced for clinical application, Iodine is bound for approximately 98% to MIBG; and the remaining two percent is free, which can cause harm, when it accumulates in the thyroid gland. Therefore, prophylaxis is indicated to prevent uptake in the thyroid gland, using dilute (Potassium Iodide)-block (Strumazol) and replace (Euthyrox) principle (18). The half-life of 131I is eight days, post therapy scans are performed to test for adequate uptake and retention. In 1985 Voûte et al. reported the value of 131I-MIBG in the detection of NBL. In the next years it became clear that there was also a role for therapeutic use of MIBG. Initially 131I-MIBG therapy was given to patients with recurrent NBL. After some time, a second group of patients was included, namely those with residual disease after chemotherapy and surgery. From these studies it became clear that the most prominent response was obtained in patients with a large bulky tumor at the time of treatment with 131I-MIBG. In these patients, studies have demonstrated response rates between 20 and 60% (19;20). A review by Wilson et al. on 131I-MIBG therapy has reported that the objective tumour response rate reported in 25 studies ranged from 0% to 75%, with a mean of 32%. They concluded that 131I-MIBG therapy is an active treatment for NBL, but its place in the management of NBL remains unclear. Prospective randomised trials are essential to strengthen the evidence for the efficacy and tolerability of 131I-MIBG therapy (21). In the GPOH and COG, 131I-MIBG therapy combined with MAT ASCT is reserved for HR NBL patients with residual tumor tissue (primary or metastasis) and clear strong MIBG uptake at the end of induction (22). Patients with MIBG-non
14 Chapter 1 avid tumors at initial diagnosis will not undergo 131I-MIBG therapy.
Simon et al. recently analysed their national database (abstract #85 at ANR 2016) including 232 stage 4 NBL patients, age ≥ 18 months at diagnosis, N5/N6 induction chemotherapy, non- progressing residual MIBG positive metastatic disease after induction chemotherapy prior to MAT ASCT and diagnosed between 1997-2012. 131I-MIBG therapy was scheduled for non- progressing residual MIBG positive lesions. The EFS was similar for patients who underwent 131I-MIBG therapy compared to no 131I-MIBG therapy. In contrast, a trend for better OS was found after 131I-MIBG therapy compared to no 131I-MIBG therapy (5yr-OS 58.1 +/- 7.6% vs. 38.9 +/- 7.5%, p=0.086). Multivariate analysis including MYCN, 131I-MIBG therapy, local RT, and immunotherapy with ch14.18 treatment revealed an independent impact of MNA, ch14.18 treatment and 131I-MIBG therapy (p=0.047, hazard ratio 0.426) on OS.
Matthay et al. reported in 2009 the results of a phase I study in refractory-/ relapsed HR NBL patients at the end of induction, it showed that closely spaced tandem (double) infusions of 131I-MIBG (with a 2- week interval) followed by MAT ASCT, can be administered safely without dose-limiting non-hematological toxicity and with rapid and reliable reconstitution of hematopoiesis. (23) Side effects that can be seen using 131I-MIBG therapy are nausea and thrombocytopenia.
In The Netherlands, 131I-MIBG therapy has been given to newly diagnosed NBL patients in the “upfront setting” with an objective response rate of 66% (12). Until recently, all eligible HR NBL patients received 2 cycles of upfront 131I-MIBG at the beginning of the HR NBL the DCOG NBL2009 treatment protocol before high-intensity (dose intense) chemotherapy treatment followed by MAT and ASCT. To reduce bone marrow toxicity, the 131I-MIBG dose regimen was aimed at a whole body exposure of 4 Gy for the combined 2 cycles of 131I-MIBG (20;24).
Recently, the treatment protocol was amended, the 2 cycles of upfront 131I-MIBG stopped, as it was not found to be not logistically feasible to be administered in large number of cases. Approximately, 66% of the HR NBL patients had a poor clinical condition at diagnosis (mainly hypertension) or did not have MIBG uptake, which meant that many patients were not eligible for upfront 131I-MIBG therapy. Secondly, the low
DCOG Dx 2*MIBG N5/N6 N5/N6 N5/N6 ASCT 13-cis-RA Evaluation
Excluded patients for 131I-MIBG therapy: Poor clinical conditions, hypertension, no/ insufficient MIGB uptake Figure 3: Dutch Childhood Oncology Group (DCOG) HR treatment protocol
General introduction and scope of this thesis 15 power of the study required an extreme long inclusion period, which was considered not feasible, to answer the study questions: how does the toxicity, tolerability and response of upfront 131I-MIBG therapy compare to induction chemotherapy.
In summary, despite the feasibility problems in some patients, 131I-MIBG therapy seems to have a high response rate at induction of HR NBL patients and the toxicity profile allows combination with induction chemotherapy followed by mega therapy (MAT) and ASCT.
131I-MIBG therapy and radio-sensitizers 131I-MIBG therapy have been combined with radio-sensitizers in various studies and consortia with promising results. Cisplatin (25), Vorinostat (New Approaches to Neuroblastoma Therapy (NANT)), Topotecan in several phase II trials (26;27), Vincristine/Irinotecan (NANT (28;29)) and MIBG therapy combined with Gemcitabine.
MAT with ASCT Since Matthay et al. have shown that myeloablative therapy (MAT) and autologous hematopoietic cell rescue (ASCT) result in significantly better 5-year EFS (30% +/- 4% versus 19% +/- 3%, respectively (p = 0.04) than non myeloablative chemotherapy this has become incorporated into the HR NBL treatment protocols (30). The GPOH and DCOG use Carboplatin, Etoposide and Melphalan (CEM) as their myeloablative chemotherapy. The SIOPEN group use Busulphan and melphalan (BuMel). From the COG group, Park et al. recently showed data at ANR 2016 (abstract #90) on 652 eligible patients with newly diagnosed HR NBL patients, randomizing at the end of induction to single ASCT with Carboplatin, Etoposide and Melphalan (CEM) or “tandem” ASCT with thiotepa and Cyclophosphamide (TC) ASCT followed by a modified CEM. Tandem myeloablative consolidation therapy improves survival probability, especially in the setting of post consolidative immunotherapy (3-yr EFS CEM 55.4± 4.6% vs. TC:CEM 73.7± 4.4%; p= 0.0009) and 3-yr OS CEM 75.7± 3.9% vs. 86.3 ± 3.4%; p= 0.0158).
Neuroblastoma patients with intraspinal extension Background Neuroblastoma patients with intraspinal extension (IE), make up a special category of NBL patients and are rare (approximately 10-15% of all NBL patients). In these patients, NBL can grow through the neuroforamina into the spinal canal, causing severe neurological problems such as paraplegia, paraparesis and incontinence problems. Approximately 60% of NBL patients with intraspinal extension present with neurological deficit (symptomatic patients), some patients can present without neurological deficit. These asymptomatic patients, can be found by coincidence, i.e. a routine chest X-ray or due to neuro-muscular symptoms (i.e. scoliosis). The survival of these patients is superior to other NBL patient categories (31).
16 Chapter 1
Treatment Neurological conditions of NBL patients with IE may progress to irreversible paraplegia, or other neurological deficit, so early diagnosis and prompt treatment is of critical importance. The treatment options include chemotherapy, neurosurgical decompression, corticosteroids and radiotherapy. They are all effective for a rapid relief of spinal cord compression, the optimal treatment strategy for these patients has yet to be established. Most studies reported on small number of patients in retrospective studies. In the past, emergency (neuro-) surgical decompression such as laminectomy was quite often performed. However, this can cause long term health problems such as scoliosis. Currently, we would prefer to give chemotherapy in first instance, however in some cases acute surgical intervention might still be needed. Patients that present with severe neurological deficit (i.e. paraplegia), could still benefit from neurosurgery, the optimal treatment strategy for these patients, still remains to be elucidated.
Health problems With increasing numbers of children surviving cancer, attention must focus on long term health problems. The development of optimal treatment strategies in NBL patients with intraspinal extension, are important in the perspective of reducing the number of early and late health problems. The longer the neurological problems exists, the harder it is for the symptoms to disappear and the more treatment interventions that are needed, to resolve the symptoms. Quite often, the neurological deficit will remain (albeit to a lesser degree). Few studies have reported health problems in this group of patients (32). More well-designed studies, that register health problems uniformly and according to common toxicity criteria are needed.
Scope of this thesis The prognosis of patients with high risk NBL is still poor, there is need for new and innovative treatment strategies. Clinical data from studies incorporating 131I-MIBG for NBL patients are promising. However, the optimal timing, dosing of 131I-MIBG and the optimal combination with chemotherapy and MAT ASCT for the administration of this therapy remains to be debated. The research presented in this thesis focused on optimizing therapy with 131I-MIBG for NBL patients in various phase II studies in both relapsed/ refractory and newly diagnosed NBL patients. Furthermore, a Cochrane review of the literature was performed on 131I-MIBG therapy in newly diagnosed high-risk NBL patients. As patients with high-risk NBL receive many treatment modalities (especially 131I-MIBG) that can cause myelosuppression, an additional study was performed, collecting retrospective data on two cohorts of high-risk NBL patients looking specifically at autologous stem cell harvesting and hematological reconstitution following MAT ASCT. The hematological toxicity, causes mainly thrombocytopenia, we analyzed the stored autologous stem cell harvests looking at the CD34+/41+ megakaryocyte precursors in the transplant. The second topic of this thesis concentrates on characterizing NBL patients with intraspinal extension
General introduction and scope of this thesis 17 and their treatment- and associated health problems. These patients have a relatively high survival rate compared to other NBL patients. The optimal treatment strategy for this group of patients has yet to be deciphered. In light of this, we have analyzed the frequency and severity of long term health problems in these patients and have performed a review of the literature.
In part A, the research focusses on optimising therapy with 131I-MIBG for NBL patients. Chapter 2 reports on the results of a phase I/II study combining 131I-metaiodobenzylguanidine (MIBG), hyperbaric oxygen and vitamin C in relapsed/ refractory HR NBL patients. Chapter 3 focusses on the efficacy of the combination of Topotecan and MIBG in newly diagnosed HR NBL patients in a prospective, window phase II study. Chapter 4 results are shown of the feasibility, toxicity and response of upfront 131I-MIBG therapy followed by GPOH NB 2004 protocol in newly diagnosed stage 4 NBL patients. Chapter 5 is a Cochrane review on the literature of 131I-MIBG therapy for patients with newly diagnosed HR NBL to assess the efficacy and adverse effects. Chapter 6 describes the yield of the autologous stem cell harvests (quantity and quality) and hematological reconstitution following MAT ASCT, in newly diagnosed HR NBL patients treated with and without upfront 131I-MIBG therapy.
In part B, the research focusses on NBL patients with intraspinal extension and their treatment and associated health problems. Chapter 7 reports on the NBL patients with Intraspinal Extension: Health Problems in Long-Term Survivors. Chapter 8 is a systematic review of the literature of Treatment and outcome of NBL patients with intraspinal extension.
Chapter 9 comprises the summary, general discussion and future perspectives.
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General introduction and scope of this thesis 19 March;44(4):551-6. 17. Hattner RS, Huberty JP, Engelstad BL, Gooding CA, Ablin AR. Localization 13. Matthay KK, Shulkin B, Ladenstein R, of m-iodo(131I)benzylguanidine in Michon J, Giammarile F, Lewington V neuroblastoma. AJR Am J Roentgenol 1984 et al. Criteria for evaluation of disease August;143(2):373-4. extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the 18. van Santen HM, de KJ, van Eck BL, de International Neuroblastoma Risk Group Vijlder JJ, Vulsma T. Improved radiation (INRG) Task Force. Br J Cancer 2010 April protection of the thyroid gland with thyroxine, 27;102(9):1319-26. methimazole, and potassium iodide during diagnostic and therapeutic use of 14. Frappaz D, Bonneu A, Chauvot P, radiolabeled metaiodobenzylguanidine in Edeline V, Giammarile F, Siles S et al. children with neuroblastoma. Cancer 2003 Metaiodobenzylguanidine assessment July 15;98(2):389-96. of metastatic neuroblastoma: observer dependency and chemosensitivity evaluation. 19. Klingebiel T, Berthold F, Treuner J, The SFOP Group. Med Pediatr Oncol 2000 Schwabe D, Fischer M, Feine U et al. April;34(4):237-41. Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma: 15. Decarolis B, Schneider C, Hero B, Simon results of the German Neuroblastoma Trial. T, Volland R, Roels F et al. Iodine-123 Med Pediatr Oncol 1991;19(2):84-8. metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in 20. Matthay KK, Yanik G, Messina J, Quach patients with stage 4 neuroblastoma: results A, Huberty J, Cheng SC et al. Phase II of the Cologne interscore comparison study. study on the effect of disease sites, age, J Clin Oncol 2013 March 1;31(7):944-51. and prior therapy on response to iodine- 131-metaiodobenzylguanidine therapy in 16. Criteria for evaluation of disease extent by refractory neuroblastoma. J Clin Oncol 2007 (123)I-metaiodobenzylguanidine scans in March 20;25(9):1054-60. neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task 21. Wilson JS, Gains JE, Moroz V, Wheatley K, Force. Matthay KK, Shulkin B, Ladenstein Gaze MN. A systematic review of 131I-meta R, Michon J, Giammarile F, Lewington V, iodobenzylguanidine molecular radiotherapy Pearson AD, Cohn SL. Br J Cancer. 2010 Apr for neuroblastoma. Eur J Cancer 2014 27;102(9):1319-26. March;50(4):801-15.
20 Chapter 1 22. Schmidt M, Simon T, Hero B, Eschner W, high-dose 131I-meta-iodobenzylguanidine with Dietlein M, Sudbrock F et al. Is there a benefit topotecan as a radiosensitizer in children with of 131 I-MIBG therapy in the treatment of metastatic neuroblastoma. Cancer Biother children with stage 4 neuroblastoma? A Radiopharm 2005 April;20(2):195-9. retrospective evaluation of The German Neuroblastoma Trial NB97 and implications 27. McCluskey AG, Boyd M, Ross SC, Cosimo for The German Neuroblastoma Trial NB2004. E, Clark AM, Angerson WJ et al. [131I] Nuklearmedizin 2006;45(4):145-51. meta-iodobenzylguanidine and topotecan combination treatment of tumors expressing 23. Matthay KK, Quach A, Huberty J, Franc the noradrenaline transporter. Clin Cancer Res BL, Hawkins RA, Jackson H et al. Iodine- 2005 November 1;11(21):7929-37. 131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue 28. DuBois SG, Chesler L, Groshen S, Hawkins for neuroblastoma: a new approaches to R, Goodarzian F, Shimada H et al. Phase I neuroblastoma therapy phase I study. J Clin study of vincristine, irinotecan, and (1)(3)(1) Oncol 2009 March 1;27(7):1020-5. I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new 24. Goldberg SS, DeSantes K, Huberty JP, approaches to neuroblastoma therapy trial. Price D, Hasegawa BH, Reynolds CP et al. Clin Cancer Res 2012 May 1;18(9):2679-86. Engraftment after myeloablative doses of 131I-metaiodobenzylguanidine followed by 29. DuBois SG, Allen S, Bent M, Hilton JF, autologous bone marrow transplantation for Hollinger F, Hawkins R et al. Phase I/II study treatment of refractory neuroblastoma. Med of (131)I-MIBG with vincristine and 5 days of Pediatr Oncol 1998 June;30(6):339-46. irinotecan for advanced neuroblastoma. Br J Cancer 2015 February 17;112(4):644-9. 25. Mastrangelo S, Rufini V, Ruggiero A, Di GA, Riccardi R. Treatment of advanced 30. Matthay KK, Reynolds CP, Seeger RC, neuroblastoma in children over 1 Shimada H, Adkins ES, Haas-Kogan D et year of age: The critical role of (131) al. Long-Term Results for Children With I-metaiodobenzylguanidine combined High-Risk Neuroblastoma Treated on a with chemotherapy in a rapid induction Randomized Trial of Myeloablative Therapy regimen. Pediatr Blood Cancer 2011 July Followed by 13-cis-Retinoic Acid: A Children’s 1;56(7):1032-40. Oncology Group Study. J Clin Oncol 2009 January 26. 26. Gaze MN, Chang YC, Flux GD, Mairs RJ, Saran FH, Meller ST. Feasibility of dosimetry-based 31. De BB, Pianca C, Pistamiglio P, Veneselli E,
General introduction and scope of this thesis 21 Viscardi E, Pession A et al. Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 2001 January 1;19(1):183-90.
32. Simon T, Niemann CA, Hero B, Henze G, Suttorp M, Schilling FH et al. Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 2012 February 13.
22 Chapter 1 General introduction and scope of this thesis 23
Part A
Optimising therapy with 131I-MIBG for neuroblastoma patients.
When you understand all about the sun and all about the atmosphere and all about the rotation of the earth, you may still miss the radiance of the sunset.
Siegfried Kracaver. Op een briefje in huis Frankrijk gevonden mei 2011, door Roos Jones geschreven. 1. Department of Pediatric Oncology, Academic Medical Centre (AMC), Amsterdam, the Netherlands. 2. Princess Maxima center for Pediatric Oncology, Utrecht, the Netherlands. 3. Laboratory Genetic Metabolic Diseases, AMC, Amsterdam, the Netherlands. 4. Department of Nuclear medicine, AMC, Amsterdam, The Netherlands. 5. University Medical Centre Utrecht, Utrecht, The Netherlands. Chapter 2 A phase I/II study of 131I-Meta- Iodobenzylguanidine (MIBG), hyperbaric oxygen (HBO) and vitamin C in patients with recurrent neuroblastoma (NBL).
K.C.J.M. Kraal1,2, N.G. Abeling3, B.L.F. van Eck-Smit4, M.M. van Noesel2,5, H.N. Caron1 and G.A.M. Tytgat1,2.
Submitted for publication Abstract Aim of the study Targeted-radiotherapy with 131I-Meta-Iodobenzylguanidine (131I-MIBG) has demonstrated antitumor activity in patients with recurrent neuroblastoma (NBL). Hyperbaric oxygen-therapy (HBO) increases the effectiveness of 131I-MIBG, and vitamin C, cytotoxic for NBL, can act as a pro-oxidant. In a multi-centre, prospective, dose-escalating, phase I/II study we studied the safety, pharmacokinetics (PK)/ -dynamics (PD) and preliminary efficacy of vitamin C in combination with 131I-MIBG-HBO.
Methods Patients with MIBG-accumulating recurrent NBL tumors were eligible for two treatment courses. After 131I-MIBG, HBO combined with oral vitamin C, was given and evaluated after 2 courses. The vitamin C dose (100 mg/kg/day) was escalated per patient with 50 mg/kg/day with each course, as well as the starting dose (+ 50 mg/kg/day) for the next cohort (n=3).
Results Twenty-two patients (median age 5.6 years; range 1.0 – 17 years) received 1 (n= 8), 2 (n=14) cycles of therapy. The 131I-MIBG-HBO-vitamin C combination was well tolerated, aside from the expected trombo- cytopenia, no toxicity was observed. No dose limiting toxicity was observed, the maximum achievable dose of vitamin C was 250 mg/kg/day because of patient compliance with drug intake (too large volume for oral intake). Objective responses occurred in 7 (4 very good partial responses and 3 partial responses) of 22 patients (ORR: 32%). The PD marker 8-hydroxydeoxy-guanosine was increased in 15/22 patients after the first course; reflecting vitamin C induced hydroxyl radical mediated DNA double-strand breaks.
Conclusion 131I-MIBG-HBO and vitamin C therapy is clinically feasible, safe and effective (ORR 32%) with clear signs of biological efficacy
28 Chapter 2 Introduction
131I-MIBG therapy leads to objective responses, both in newly diagnosed HR NBL patients as in patients with recurrent NBL (1, 2). 131I-MIBG treatment considerably improves the quality of life (pain reduction), usually within days, and has limited side effects besides prolonged thrombocytopenia (2-5). Since it is known that hypoxia is common in solid tumours, with oxygen levels ranging from 5% to anoxia and one-third of tumour areas contain less than 0.5% oxygen (6). A combination of 131I-MIBG and hyperbaric oxygen (HBO) for patients with recurrent HR-NBL was studied in 1989 in a phase II study, comparing 131I-MIBG with and without a combination of 131I-MIBG and HBO, and demonstrated the feasibility with a cumulative probability of survival of 32% versus 12% (7).
Oxygen, of all radio-sensitizers, possesses the highest enhancement ratio, defined as enhancement of therapeutic effect of ionizing radiation due to the presence of the radiosensitizer, 2,7 to 3,0 (8). A Cochrane review of trials adding HBO to radiotherapy, showed a reduction in mortality for head and neck cancers at both one year and five years after therapy (9).
Vitamin C is cytotoxic for NBL cells in vitro and NBL cells actively accumulate vitamin C (10;11). In NBL cells, vitamin C can have a pro-oxidant effect by increased hydroxyl (OH·) radical production based on two biochemical effects; 1. increased catecholamine production and 2. increased intracellular release of Fe2+ from ferritin (12;13). The formed catecholamines are auto-oxidised by monoamine oxidase, leading to an increased production of hydrogen peroxide (H2O2), (11;14) and combination of H2O2 and Fe2+ will lead to OH·, which are highly reactive and cause double-strand (ds)-DNA breaks (15;16) (Figure 1).
Recurrent NBL form an ideal target for the pro-oxidative effect of vitamin C as they have high intra-cellular ferritin content and an active catecholamine metabolism. 8-hydroxydeoxy-guanosine (8OHDG), a specific hydroxyl radical-mediated end product, can be measured in urine and serum to quantify the amount of ds-DNA breaks (17). The fact that tissue-damage by radiation and the cytotoxic effect of vitamin C both rely on ds-DNA breaks, led us to the hypothesis that the simultaneous use of 131I-MIBG, HBO and vitamin C can have additive anti-tumor effect. In earlier studies, very few side effects were reported of vitamin C in the dose-range (500-2000 mg) (18;19). Therefore, the present study evaluated the application of vitamin C together with 131I-MIBG and HBO for relapsed stage 4 NBL patients in a dose escalation phase I/II trial. In a time, where chemotherapy in combination with radio-sensitizers is of increasing importance, this paper is of interest for treating physicians in the field of NBL.
Methods Study design Multi-Centre (Table I) prospective, dose-escalating, phase I/II study, November 1998- May 2002. The study was approved by the Medical Ethical Committee of the Academic Medical Centre (AMC). Patients
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 29 Radiolabelled MIBG therapy under Hyperbaric oxygen (HBO) conditions results in saturation of hypoxic (tumour) tissues enhancing the effect radiotherapy. Vitamin C is actively accumulated in neuroblastoma, where it (1.) induces the rate limiting enzymes TH (tyro- sine Hydroxylase) and DBH (Dopamin-beta-Hydroxylase), and increases CME (Catecholamine) production. The degradation of CME mediated by monoamine oxidase (MAO) leads to increased production of H2O2. Neuroblastoma tumors are Ferritin rich, e.g. contai- ning high levels of bound iron (Fe3+) (2.), Vitamin C can act as pro-oxydant, releasing iron as free Fe2+. In the Fenton reaction (3.), this highly reactive Fe2+ , reacts with the H2O2, formed from degradation of the CME, producing the highly reactive hydroxyl radicals: OH•, causing DNA-ds breaks (4), which can be detected as end product (5): 8OHDG= 8-hydroxydeoxy-guanosine.
NBL= neuroblastoma, H2O2= hydrogen peroxide, Fe2+= iron (oxidation status +2), Fe3+= iron (oxidation status +3), OH·= hydroxyl radical, 8OHDG= 8-hydroxydeoxy-guanosine, ds-DNA= double strand DNA breaks, CME= catecholamines, vitamin C= ascorbic acid.
= cytotoxic, = active uptake, TH= tyrosine hydroxylase, DBH= dopamine-b-hydroxylase, 131I-MIBG= 131radio-isotope meta-iodobenzylguanidine, HBO= hyperbaric oxygen.
Figure 1: Rationale of combined 131I-MIBG therapy, hyperbaric oxygen and vitamin C for recurrent neuroblastoma.
up to 18 years with relapsed (histology proven) NBL, were eligible if they had MIBG-avid disease, were judged to undergo at least two treatment courses in the presence of a non-pregnant caretaker. Patients had to be adequately recovered from previous treatment, and written informed consent given. Exclusion criteria, because of potential toxicity with vitamin C, were a positive family history for Glucose-6-phosphate dehydrogenase (G6PD) deficiency and/ or kidney concrements (20). At study entrance disease status, (MycN-amplification (MNA), loss of heterozygosity chromosome 1p (LOH1p)) was documented and ferritin
30 Chapter 2 N/ %
Number of patients 22 Gender Male 16 (73)/ female 6 (27) Median age and range (y) 5.6 (1.0 – 17) Tumor stage 22 relapsed NBL stage 4 Tumor genetics MNA 6 (28) LOH1p 5 (23) Serum ferritin (mcg/L): Normal 4 (20) Elevated 16 (80) Unknown 2 (10) Prior chemotherapy 22 (100) Prior 131I-MIBG therapy 10 (45) Prior MAT/ ASCT 14 (64) Referring centre: Amsterdam (AMC) 5 (22) Groningen (UMCG) 1 (5) Nijmegen (UMCN) 1 (5) Rotterdam (EMC) 3 (13) Utrecht (UMCU) 1 (5) Abroad 11 (50) Number of combined 131I-MIBG with HBO and vitamin C * treatments: 1 8/22 (36) 2 14/22 (64) Cumulative 131I-MIBG dosis Median and range mCi/ 275 (100- 400) GBq 10.2 (3.7- 14.8) mCi/kg 15.9 (6.3- 25.0)
MycN amplification= MNA, Loss of heterozygosity chromosome 1 p= LOH1p Myeloablative therapy= MAT, Autologous stem cell transplantation= ASCT mCi= milliCurie, GBq= Giga Becquerel, kg= kilogram.
* If possible patients were evaluated after 2 courses of combined therapy. Patients that went on to receive more than 2 courses of combined therapy did so because they responded with stable disease (SD) or better (partial response (PR) or very good partial response (VGPR)) or they tolerated the treatment well. Table I: Patient characteristics
levels were measured in the blood. Diagnostic 123I-MIBG scans, additional radiological examinations MRI, CT or ultrasound (3 dimensional measurements) of the primary tumor, bone marrow (BM), urinary catecholamine excretion, were performed.
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 31 Blood samples: *1: Full blood count, creatinine, liver function tests, ferritin, FT4, TSH, G6PD enzyme level (if family history positive), 8-OH-deoxy-guanosine (8OHDG), vitamin C level. *2: vitamin C level, 8OHDG, SGOT, SGPT. *3: *2 + platelet count, creatinine, capillary blood gas *4: *3 + ferritin, LDH, FT4, TSH, Hb + ery-indices (add vit.B12, if macrocytic anaemia) 12h Urine samples: #1: catecholamine metabolites, creatinine, pH, 8OHDG, oxalate and uric acid #2: 8OHDG @: 123I-MIBG, CT/ ultrasound, BM, urine catecholamines (INRC) B1= before 1st MIBG, B2= before 2nd MIBG, A1= after 1st MIBG, A2= after 2nd MIBG HBO= hyperbaric oxygen, 131I-MIBG= 131Iodine- metaiodobenzylguanidine, MIBG I= 5.6- 7.4 GBq (150- 200 mCi), MIBG II= 3.7GBq (100 mCi) BM= bone marrow, INRC= International Neuroblastoma Response Criteria (24). Figure 2: Scheme of treatment and evaluation
The study consisted of 2 treatment courses of 131I-MIBG followed by oral vitamin C in combination with HBO (Figure 2), with an evaluation 4 weeks after the 2nd course. If possible patients were evaluated after 2 courses of combined therapy. Patients that went on to receive more than 2 courses of combined therapy did so because they responded with stable disease (SD) or better (partial response (PR) or very good partial response (VGPR)) or they tolerated the treatment well. 131I-MIBG therapy was given a first dose 7.4 GBq (200 mCi) and second dose 3.7 GBq (100 mCi), administered
32 Chapter 2 in 3.7 (100 mCi)/hr i.v. (2;5;21), as previously described. The platelets needed to be > 100 x 109/L for the first course, and when > 50 and <100 x 109/L, the MIBG dose for the 2nd course was reduced by half, or stopped when < 50 x 109/L, for longer than four weeks. Thyroid protection for patient and caretaker was prescribed as previously described (22). The day of discharge from radio-protective-isolation, vitamin C and HBO were started and the vitamin C continued till the 2nd MIBG therapy, or till evaluation (Figure 2). HBO was delivered twice daily for 4 consecutive days according to standardized protocol.
Phase I study The primary endpoints of the dose-escalation portion of the study were safety and pharmacokinetics (PK). Dose limiting toxicities (DLTs) were defined as: any grade 4 toxicity (according to common toxicity criteria for adverse events version 3.0) or liver function test abnormalities (SGOT/SGPT >500 U/L; not normalized before the next treatment course); or urinary oxalate/uric acid kidney stones; or macrocytic anemia, due to vitamin B12 deficiency, unresponsive to oral suppletion. In case of a DLT, the dose escalation of vitamin C was stopped and the treatment would then be continued for all patients at the next lower dose level. As potential protective effect of vitamin C on thrombocytopenia, the nadir of the platelets after 131I-MIBG therapy was compared to that of a cohort, treated without Vitamin C (7). Toxicity was monitored before and after the 131I-MIBG treatment.
Pharmacokinetics The vitamin C starting dose was 100 mg/kg/day orally, and was escalated per patient with 50mg/kg/day per course and per cohort (n=3) + 50 mg/kg as starting dose. The caretakers of the patients were interviewed, by questionnaires, concerning the intake of the vitamin C, dose level and the problems encountered. Vitamin C plasma levels were measured the last day of hyperbaric oxygen treatment, 2-4 hours after ingestion.
Phase II part The primary end points tumor response and biochemical response (pharmacodynamics) (PD) after 131I-MIBG treatment. Tumor response was evaluated 4 weeks after two courses of combined therapy according to the International Neuroblastoma response Criteria (INRC) (23). These investigations included assessment of clinical condition (use of pain medication), weight gain or loss, ultra-sound or CT-scans for tumor measurements, 123I-MIBG scan, and urinary catecholamines. Objective response rate (ORR) was defined as complete response (CR), very good partial response (VGPR) and/ or partial response (PR). If patients were not evaluable for response, e.g. due to prolonged thrombocytopenia, lost to follow-up or clinically evident tumor progression (PD) before this time point, the patient best clinical response, respectively PD was scored. Biochemical efficacy of the combined therapy was investigated by measuring serum 8OHDG. Normalised 8OHDG urine levels/ mmol creatinine are given, with 0.3-3.6 nmol/mmol creatinine being normal values, and 1= 3.6 nmol/mmol creatinine.
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 33 10 8OHDG
8
6
8OHDG 4
2
0
B1 A 1 B2 A2
E valuation Tim e point
8OHDG= 8-OH-deoxy-guanosine, 8OHDG urine levels is x times normal (whereas 1= 3.6 nmol/mmol creatinine). Normal levels 8OHDG = 0.3-3.6 nmol/mmol creatinine. B1= before 1st MIBG, A1= after 1st MIBG, B2 = before 2nd MIBG and A2 = after 2nd MIBG Boxplots (mean and standard deviation (SD) error bars) Figure 3: Time points of evaluations and corresponding 8OHDG.
Values were obtained before and after 4 - 5 days of combined 131I-MIBG-HBO- vitamin C therapy. To prevent oxidation, blood was collected in dichlorodiphenyltrichloroethane (DDT) containing tubes. The protocol aimed to give at least 2 cycles of combination therapy; in case of good tolerability and clinical effect (stable disease (SD), PR and VGPR) the patients could receive additional cycles as palliative therapy (range 1-5
With vitamin C Without vitamin C
(n=22) (n=16)
Mean duration thrombocytopenia* 7.2/ 50,4 6.8/ 47.6 (weeks/ days) Nadir thrombocytopenia (x 109/ L) 13 8 Mean N (range) 131I-MIBG therapy 2 (1- 5) 2.43(1-6)
*WHO grade 3 (CTCAE version 3.0 platelets < 50 x 109/ L) Table II: The effect of combined therapy vs. 131I-MIBG therapy with HBO without vitamin C on thrombocytopenia.
34 Chapter 2 cycles). The study endpoint was after 2 courses of the 131I-MIBG-HBO-vitamin C combination.
Results We report on 22 patients; median age 5.6 years (1.0 – 17.0), sixteen (73%) males and 6 (27%) females with a recurrent stage 4 NBL, referred from 5 Dutch centres and from abroad. Ferritin levels in the blood were elevated in 16/20 (80%), MNA in 6/22 (28%), LOH1p in 5/22 (23%). All patients had received prior chemotherapy, 10/ 22 (45%) had received prior 131I-MIBG therapy and 64% had previously undergone myeloablative therapy (Table 1). Eight patients (8/22 (36%) received one MIBG-HBO vitamin C therapy; 14/22 (64%) at least 2 courses. Seven out of 22 patients (32%) went on to receive further 131I-MIBG-HBO- vitamin C combination therapies; courses: three 3/ 22, four 3/22 and five 1/22, on a compassionate use basis. Median (and range) of delivered 131I-MIBG dose were: course I 150 mCi (milliCurie)/ 5.6 GBq (Giga Becquerel) (100- 200 mCi/ 3.7- 7.4 GBq); course II (median and range): 125 mCi/ 4.6 GBq (100- 200 mCi/3.7- 7.4 GBq). Cumulative 131I-MIBG dosis (median and range) 275 mCi/ 10.2 GBq (100- 400 mCi/ 3.7- 14.8GBq) and cumulative MIBG mCi/ kg 15.9 (6.3- 25.0).
Safety and Pharmacokinetics Toxicity: Besides the expected thrombocytopenia, no toxicity was observed. There was no protective effect of the addition of vitamin C on the nadir and/ or duration of the thrombocytopenia (Table II). In particular, we observed no increase of hepatic enzymes, no increase in creatinin, or anemia (data not shown). Kidney stones were not observed and the urinary oxalate was only occasionally moderately increased. No dose limiting toxicities were observed and the MTD was not reached. The maximum achievable dose of vitamin C was 250 mg/kg/day, as at this dose, the quantity of vitamin C became too large for oral intake.
Dose level vitamin C: The median (range) vitamin C dose for the first course was 200 mg (100-250) and for the second course 200 mg (150- 250). One patient received vitamin C as an intravenous administration (due to inability of oral intake). We observed a gradual rise in plasma levels with increasing doses of vitamin C. In patients with 150 mg/kg vitamin C, the measured plasma concentration was 33 (± 30) mol/l, with 200 mg/kg 40 (± 26) mol/l and for 250 mg/kg 108 (± 49) mol/l. Normal levels Vitamin C = 11-51 μmol/l. The increased vitamin C level at the onset of treatment (30.5 (± 26) µmol/L was suggestive that some patients had started oral intake of vitamin C before the first blood sampling, against protocol guidelines.
Efficacy Tumor response: Ten patients underwent evaluation after the 2nd course of MIBG, for twelve patients only the best clinical response was reported because they had progressive disease (PD) n=9, lost to FU n=1, and 2 patients
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 35 (VGPR, PR) had returned abroad with prolonged thrombocytopenia. The best clinical response was: 4/22 (18%) VGPR, 3/22 (14%) PR, 5/22 (23 %) SD, 9/22 (41%) PD and 1 patient was lost to FU. The ORR for the 22 patients was 7/22 (32%). For the patients that showed a response, the quality of life improved considerably with limited side effects, resulting in relief of pain, cessation of pain medication and weight gain.
Pharmacodynamics (biochemical response) Eight-hydroxydeoxy-guanosine (8OHDG): 8OHDG levels were most pronounced after the first course 3.02 (± 5.11) nmol/mmol creatinine (normal levels 8OHDG = 0.3-3.6 nmol/mmol creatinine). This is 2.4 times elevated compared to before start treatment (1.22 (± 1.26) nmol/mmol creatinine). 8OHDG level was increased in 15/22 patients, 7 had missing values (data not shown). At evaluation the 8OHDG levels were still raised compared to normal (Figure 3). There was no correlation between vitamin C and 8OHDG levels.
Discussion We have studied the effect of combining high levels of Vitamin C, with 131I-MIBG and hyperbaric oxygen in patients with recurrent high-risk neuroblastoma. We have demonstrated, aside from the expected thrombo- cytopenia, no other toxicity. We have also demonstrated a correlation between vitamin C dose and plasma levels, in contrast to other authors, that did not find this correlation, possibly due to fast metabolism of vitamin C (18;19; 24). We speculated that addition of the radical scavenging molecule, vitamin C, could diminish the toxicity, but this was not found, as the addition of vitamin C to 131I-MIBG and hyperbaric oxygen did not influence the nadir or the duration of thrombocytopenia in patients with relapsed NBL. Despite the fact that the median (range) cumulative dose of 131I-MIBG during this study was 15.9 (6.3- 25.0) mCi/ kg, no stem cell rescue was needed, although our heavily pre-treated patients did suffer from prolonged thrombocytopenia. Two phase I/II study of Vincristine, Irinotecan (IRN) and 131I-MIBG by Dubois et al, with 15 mCi/kg or 18mCi/kg 131I- MIBG and PBSC described no DLT and recommended 18 mCi/kg. Grade 4 thrombocytopenia was seen in 17% (15 mCi/kg) and 58% of patients (18 mCi/kg). All patients with grade 4 thrombocytopenia engrafted within 56 days (median 14 days for patients who received 18 mCi/kg) (25). In a study by Bleeker et. al in patients with newly diagnosed HR NBL receiving upfront 131I-MIBG, the main grade 4 reported toxicity was hematological, occurring only in stage 4 patients with BM involvement. Thrombocytopenia was seen after the first and second131 I-MIBG therapies in 2% and 4%, needing no stem cell rescue (26). Our study, in newly diagnosed NBL patients who received 131I-MIBG therapy in combination with Topotecan, with a median cumulative MIBG dose 29.4 mCi/kg showed after the first course, 25% grade 4 platelet toxicity; after second course 33% (27).
This study shows that the addition of vitamin C to 131I-MIBG and HBO, did not lead to any DLT. However, the intake of large amounts of vitamin C became dose limiting at a level of 250 mg/kg/day. This combination
36 Chapter 2 therapy of HBO-MIBG- vitamin C, was feasible with an objective response rate of 32% and relieve of pain symptoms, in a group of heavily pre-treated patients (albeit in a small group) with a poor life expectancy, this is promising. We have detected elevated levels of 8OHDG, indicating increased DNA ds-breaks, demonstrating effect of 131I-MIBG, HBO and vitamin C, especially after the first treatment course. At evaluation the 8OHDG levels were still raised compared to normal, although 131I-MIBG and HBO therapy had been terminated four weeks before. This is possibly combined effect of 131I-MIBG retention in the tumor a vitamin C effect, because the patients were still using vitamin C. This is the first paper to report on the use of 8OHDG as a biological marker to investigate for the in vivo formation of ds-DNA breaks by targeted therapy.
Surprisingly, overall levels were elevated, probably due to the fact that the formation and degradation of catecholamines gives rise to H2O2. This can further react to produce OH·, especially in NBL tumors that have reduced levels of gluthation peroxidase, which normally breaks down H2O2. The main question that remains is if these changes are purely attributable to the addition of vitamin C or HBO, since we did not measure the urine of these patients before and directly after only 131I-MIBG treatment. Combining radiolabeled therapy with hyperbaric oxygen, significantly increases the oxygen radicals in the tumors (28). Hypoxic conditions have been detected in several human malignancies (6). Oxygen and reactive oxygen species (ROS) also play a role in in-vitro neuronal differentiation. Therefore, manipulating hypoxia and ROS production represents a useful therapeutic to enhance or to modulate neuronal differen- tiation (29). NBL cells have 2 defective endogenous defence systems against oxygen-derived free radicals: a reduced catalase activity, causing an intracellular accumulation of H2O2 and a 2-3 times elevated ferritin content (30;31). By combining 131I-MIBG with HBO, the cytotoxic effect of radiation is enhanced by two mechanisms: firstly, especially in the hypoxic/ anoxic areas of the tumor, which are known to be relatively radio-resistant, have increased oxygen pressure. Secondly, more oxygen-derived free OH· is produced, which will lead to irradiation-induced cytotoxicity. Although the logistics of HBO therapy in combination with 131I-MIBG is difficult, this study shows that the addition of radio-sensitizers to MIBG treatment is feasible, safe, with an objective response rate of 32% and should be studied more intensely. Conflict of interest statement: nothing to disclose.
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 37 Reference List outcome. Cancer Metastasis Rev 2007 June;26(2):225-39. 1. de KJ, Hoefnagel KA, Verschuur AC, van EB, van Santen HM, Caron HN. Iodine-131- 7. Voute PA, van der Kleij AJ, de KJ, Hoefnagel metaiodobenzylguanidine as initial induction CA, Tiel-van Buul MM, Van GH. Clinical therapy in stage 4 neuroblastoma patients experience with radiation enhancement by over 1 year of age. Eur J Cancer 2008 hyperbaric oxygen in children with recurrent March;44(4):551-6. neuroblastoma stage IV. Eur J Cancer 1995;31A(4):596-600. 2. Hoefnagel CA, Voute PA, de KJ, Valdes Olmos RA. [131I]metaiodobenzylguanidine therapy 8. Vaupel P, Schlenger K, Knoop C, Hockel M. after conventional therapy for neuroblastoma. Oxygenation of human tumors: evaluation of J Nucl Biol Med 1991 October;35(4):202-6. tissue oxygen distribution in breast cancers by computerized O2 tension measurements. 3. de KJ, Hoefnagel CA, Caron H, Valdes Olmos Cancer Res 1991 June 15;51(12):3316-22. RA, Zsiros J, Heij HA et al. First line targeted radiotherapy, a new concept in the treatment 9. Conere TJ, Brock A, Nias AH. of advanced stage neuroblastoma. Eur J Radiosensitization by 17 atmospheres Cancer 1995;31A(4):600-2. pressure of air. Br J Radiol 1991 September;64(765):871. 4. Matthay KK, DeSantes K, Hasegawa B, Huberty J, Hattner RS, Ablin A 10. Baader SL, Bruchelt G, Trautner MC, Boschert et al. Phase I dose escalation of H, Niethammer D. Uptake and cytotoxicity 131I-metaiodobenzylguanidine with of ascorbic acid and dehydroascorbic autologous bone marrow support in acid in neuroblastoma (SK-N-SH) and refractory neuroblastoma. J Clin Oncol 1998 neuroectodermal (SK-N-LO) cells. Anticancer January;16(1):229-36. Res 1994 January;14(1A):221-7.
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38 Chapter 2 dopamine beta-monooxygenase activity in evidence for a recommended dietary resting and stimulated chromaffin cells. J Biol allowance. Proc Natl Acad Sci U S A 1996 Chem 1986 June 5;261(16):7347-56. April 16;93(8):3704-9.
13. Menniti FS, Knoth J, Diliberto EJ, Jr. Role of 20. Abdul-Razzak KK, Almomany EM, Nusier MK, ascorbic acid in dopamine beta-hydroxylation. Obediat AD, Salim AM. Antioxidant vitamins The endogenous enzyme cofactor and and glucose-6-phosphate dehydrogenase putative electron donor for cofactor deficiency in full-term neonates. Ger Med Sci regeneration. J Biol Chem 1986 December 2008;6:Doc10. 25;261(36):16901-8. 21. Hoefnagel CA, Voute PA, de KJ, Marcuse 14. Bruchelt G. [Clinical significance of reactive HR. Radionuclide diagnosis and therapy oxygen species]. Immun Infekt 1995 of neural crest tumors using iodine-131 October;23(5):174-8. metaiodobenzylguanidine. J Nucl Med 1987 March;28(3):308-14. 15. Baader SL, Bill E, Trautwein AX, Bruchelt G, Matzanke BF. Mobilization of iron 22. van Santen HM, de KJ, van Eck BL, de from cellular ferritin by ascorbic acid in Vijlder JJ, Vulsma T. High incidence of neuroblastoma SK-N-SH cells: an EPR study. thyroid dysfunction despite prophylaxis FEBS Lett 1996 February 26;381(1-2):131-4. with potassium iodide during (131)I-meta- iodobenzylguanidine treatment in children 16. Medina MA, Garcia d, V, Schweigerer L. with neuroblastoma. Cancer 2002 April Ascorbic acid is cytotoxic for pediatric tumor 1;94(7):2081-9. cells cultured in vitro. Biochem Mol Biol Int 1994 November;34(5):871-4. 23. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP et al. 17. Lunec J. Free radicals: their involvement in Revisions of the international criteria for disease processes. Ann Clin Biochem 1990 neuroblastoma diagnosis, staging, and May;27 ( Pt 3):173-82. response to treatment. J Clin Oncol 1993 August;11(8):1466-77. 18. Cameron E. Protocol for the use of vitamin C in the treatment of cancer. Med Hypotheses 24. Levine M, Dhariwal KR, Welch RW, Wang Y, 1991 November;36(3):190-4 Park JB. Determination of optimal vitamin C . requirements in humans. Am J Clin Nutr 1995 19. Levine M, Conry-Cantilena C, Wang Y, Welch December;62(6 Suppl):1347S-56S. RW, Washko PW, Dhariwal KR et al. Vitamin C pharmacokinetics in healthy volunteers: 25. DuBois SG, Allen S, Bent M, Hilton JF,
131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 39 Hollinger F, Hawkins R et al. Phase I/II study contain iron-rich ferritin. Cancer 1988 June of (131)I-MIBG with vincristine and 5 days of 15;61(12):2497-502. irinotecan for advanced neuroblastoma. Br J Cancer 2015 February 17;112(4):644-9.
26. Bleeker G, Schoot RA, Caron HN, de KJ, Hoefnagel CA, van Eck BL et al. Toxicity of upfront (1)(3)(1)I-metaiodobenzylguanidine ((1)(3)(1)I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis. Eur J Nucl Med Mol Imaging 2013 October;40(11):1711-7.
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31. Iancu TC, Shiloh H, Kedar A. Neuroblastomas
40 Chapter 2 131I-MIBG, hyperbaric oxygen and Vitamin C in relapsed/ refractory high risk neuroblastoma patients. 41 1. Department of Pediatric Oncology, Amsterdam Medical Centre (AMC), Amsterdam, the Netherlands. 2. Department of Nuclear Medicine, AMC, Amsterdam, the Netherlands. 3. Department of Nuclear medicine, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands. 4. Department of pediatric oncology/hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands. 5. Princess Máxima centre for pediatric oncology, Utrecht, the Netherlands. Chapter 3 Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan.
KCJM Kraal1,5, GAM Tytgat1, BLF van Eck-Smit2, B Kam3, HN Caron1 and MM van Noesel4,5
Pediatric Blood and Cancer 2015 Nov;62(11):1886-91. ABSTRACT Background 131I- metaiodobenzylguanidine (131I-MIBG) has a significant anti-tumor effect against neuroblastoma (NBL). Topotecan (TPT) can act as a radio-sensitizer and can up-regulate 131I-MIBG uptake in vitro in NBL. Aim: Determine the efficacy of the combination of 131I-MIBG with topotecan in newly diagnosed high-risk (HR) NBL patients.
Methods In a prospective, window phase II study, patients with newly diagnosed high-risk neuroblastoma were treated at diagnosis with 2 courses of 131I-MIBG directly followed by topotecan (0.7 mg/m² for 5 days). After these 2 courses, standard induction treatment (4 courses of VECI), surgery and myeloablative therapy (MAT) with autologous stem cell transplantation (ASCT) was given. Response was measured after 2 courses of 131I-MIBG-topotecan and post MAT and ASCT. Hematologic toxicity and harvesting of stem cells were analysed. Topoisomerase-1 activity levels were analysed in primary tumor material.
Results Sixteen patients were included in the study; median age was 2.8 years. MIBG administered activity (AA) (median and range) of the first course was 0.5 (0.4-0.6) GBq/kg (giga Becquerel/ kilogram)and ofthe second course 0.4 (0.3-0.5) GBq/kg. The overall objective response rate (ORR) after 2 x MIBG/TPT was 57%, the primary tumor RR was 94%, and bone marrow RR was 43%. The ORR post MAT and ASCT was 57%. Hematologic grade 4 toxicity: after first and second 131I-MIBG (platelets 25/ 33%, neutrophils 13/ 33% and hemoglobin 25/ 7%). Topoisomerase-1 activity levels were increased in 10/10 (100%) measured tumors.
Conclusions Combination therapy with MIBG-topotecan is an effective window treatment in newly diagnosed high-risk neuroblastoma patients.
44 Chapter 3 Introduction High-risk neuroblastoma remains an aggressive pediatric tumor for which the standard treatment is an intense, multi-modality program. The 3-year overall survival rate is 30-40%.(1,2) High-risk disease includes patients with metastatic disease (stage 4) and all patients with MYCN amplification (MNA).(3) Post-in- duction treatment with anti-disialoganglioside (GD2) directed immunotherapy (4) can increase the survival significantly. 131I- metaiodobenzylguanidine (131I-MIBG) therapy has been proven to be effective in the upfront treatment of high-risk neuroblastoma with an objective response rate (ORR) 66% and a mild toxicity profile .(5,6)
Topotecan (TPT) is a topoisomerase I inhibitor and an effective drug in the treatment of NBL.
Topoisomerase I is a nuclear enzyme involved in the relaxation of supercoiled DNA during replication, transcription and DNA repair. TPT is highly active in the synthesis (S) -phase of the cell cycle and important in enabling increased cell proliferation. Various in vitro and in vivo studies have shown that TPT can enhance radiation effects (to act as a radio-sensitizer in vitro) in various cell lines (melanoma and human carcinoma); it is drug dose- and timing–dependent.(7,8)
Vassal et al. showed the in vivo effect of topotecan and irinotecan in nude mice with neuroblastoma xenografts, where there was a clear antitumor activity of both drugs. They also determined the levels of topoisomerase activity in immature neuroblastoma, in vitro, and compared this to normal adrenal gland tissue and ganglioneuroblastoma. Topoisomerase-I activity reference levels ranged from 69-1304 arbitrary units/mg of protein, and were significantly higher in immature neuroblastoma than in ganglioneuro- blastoma and adrenal gland cells.(9)
In vitro data suggest that topotecan can increase the uptake of 131I-MIBG by increasing the expression of the noradrenaline transporter.(10) In several neuroblastoma cell lines it has been demonstrated that 131I-MIBG combined with topotecan resulted in synergistic inhibition of tumor cell growth, particularly when topotecan was given simultaneously with 131I-MIBG. Cells treated with topotecan either simultaneously or 24 hours after 131I-MIBG showed a reduction in DNA repair mechanisms.(11,12)
Phase 1 clinical studies, combining topotecan with cyclophosphamide, in pediatric recurrent tumors, show mainly myelosupression as toxicity with some response.(13-15) Phase II studies with topotecan have been performed in refractory/ relapsed solid tumors showing limited toxicity and some tumor response. (16,17). Other phase II studies have combined dose-intensive topotecan with other chemotherapy in newly diagnosed/ refractory high-risk neuroblastoma patients, showing similar toxicities and promising response. (18,19)
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 45 Topotecan has been combined with 131I-MIBG (MATIN) in a pilot, feasibility study. This combination was well-tolerated without significant hematologic toxicity or unexpected side effects.(20) Following from this study, this schedule was used in a European multi-centre study for patients with refractory or relapsed neuroblastoma. The MATIN schedule has an acceptable morbidity profile in a group of patients with a very poor prognosis; this will be further evaluated in a randomised trial by the Societé International Oncologie et Pediatrie (SIOPEN) group. Dubois et al. used an alternative topoisomerase inhibitor, irinotecan, with vincristine and 131I-MIBG in a phase I study for patients with relapsed/refractory neuroblastoma. 131I-MIBG was found to be tolerable; myelosupression and diarrhoea were the most common toxicities found. Significant antitumor activity was seen, with responses occurring in 6/24 (25%) (2 CR and 4 PR) evaluable patients.(21) Here we describe a phase II window study, with the combination of 131I-MIBG and topotecan for newly-diagnosed high-risk neuroblastoma patients.
Materials and methods Between March 2000 and August 2003 we conducted a prospective, window phase II study with 131I-MIBG in combination with topotecan in every consecutive eligible newly-diagnosed high-risk neuroblastoma patient in two pediatric oncology centres, in Amsterdam (AMC) and Rotterdam (Erasmus MC-Sophia Children’s Hospital), the Netherlands. No patients were lost to follow-up. Eligibility criteria included: histolo- gically confirmed high-risk neuroblastoma, no prior cancer treatment, a non-complicated clinical condition which allowed for 5-day radioprotective isolation for 131I-MIBG treatment, age 0-16 years at diagnosis, and a signed and dated informed consent. The study was approved by the local ethical committees of the two pediatric oncology centres.
MNA and loss of heterozygosity chromosome 1p (LOH1p) were assessed using fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) microarray techniques in the Dutch
Abbreviations: 131I-MIBG-TPT: 131I- Meta-Iodobenzylguanidine; TPT: Topotecan: 0.7 mg/m2 d 1-5 i.v. MIBG/TPT I: 7.4 GBq/ 200 mCi 131I-MIBG; MIBG/TPT II: 5.6 GBq/150 mCi 131I-MIBG. VECI: Vincristine 1.5 mg/m2 i.v. 1 day, Teniposide 150 mg/m2 i.v. 1 day, Carboplatin 400 mg/m2 i.v. 1 day and Ifosfamide 3000 mg/m2 i.v. 2 days. MAT and ASCT: Myeloablative therapy Carboplatin 800 mg/m2 i.v. (day -3) and Melphalan 180 mg/m2 i.v. (day -1) and autologous stem cell transplantation. 13-cis-RA: cis-retinoic acid 160 mg/m2/dag in 2 doses for 2 weeks followed by 2 weeks rest (6 cycles). Figure 1: A phase II pilot window study (AMRO-NB-HR-2000/01).
46 Chapter 3 reference laboratory for neuroblastoma biology (Department Oncogenomics, AMC).
Treatment consisted of two upfront cycles of 131I-MIBG (fixed administered activity (AA) treatment): 1st AA 7,4 gigabecquerel (GBq)/ 200 milliCurie (mCi), second AA 5,6 GBq/ 150 mCi with an interval of 4 weeks. As soon as the patient was allowed to leave the nuclear medicine ward (patients remained in radiation protective isolation until the exposure rate was less than 20 µSv/h, measured with a counter at a distance of 1 m from the patient), this treatment was followed by a daily 1-hour infusion of topotecan 0.7 mg/m2 i.v. for 5 days (see Figure 1). This combination therapy was followed by 4 courses of VECI (vincristine 1,5 mg/ m2 i.v. day 1, carboplatin 400 mg/m2 i.v. day 3, teniposide 150 mg/m2 i.v. day 4 and ifosfamide 3000 mg/m2 i.v. day 1-2), at 4 week intervals, the standard induction treatment at that time. Hematologic criteria for proceeding to the next VECI course were white cells > 2 x 109/L and platelets > 50 x 109/L. Stem cells were collected using an apheresis procedure or by bone marrow (BM) harvesting. Peripheral blood stem cell harvesting took place after the first VECI course, if the BM was clear. If the stem cell harvest was not successful this was repeated after the next course.
Optimal timing for surgery was discussed when the distant metastases were inactive (BM and 123I-MIBG scan clear) and the tumor operable. The myeloablative therapy (MAT) consisted of carboplatin 800 mg/m2 (day -3) and melphalan 180 mg/m2 i.v. (day -1), followed by autologous stem cell transplantation (ASCT) on day 0.
Criteria for proceeding to MAT and ASCT were: response (according to the revised International Neuroblastoma Response Criteria [INRC]) at least very good partial response (VGPR), white blood cells > 2 x 109/L, and platelets > 50 x 109/L. Response to treatment was scored according to the revised INRC, taking into account the volume of the primary tumor (using MRI/ CT or ultrasound), urinary catecholamines, 123I-MIBG diagnostic scans and BM examination (using BM aspirate and trephine biopsy with conventional cytology and histology). Definition of BM response was: clearance of BM invasion using conventional cytology and histology on BM aspirate and/or trephine biopsy.
The Curie method was used for scoring of the 123I-MIBG scans and this was independently scored by 3 blinded experts.(22) The absolute value of the extension score of the Curie scorings method for each patient were noted at diagnosis, after 2 cycles of MIBG/topotecan and post MAT and ASCT. From these values, median and range were calculated at each time point. The relative extension scores (post therapy Curie score divided by pre therapy Curie score) were calculated at the same time points.
Response categories were complete response (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progressive disease (PD).(23) Objective response rate
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 47 (ORR) was defined as the extent of patients whose best overall response was CR, VGPR or PR (according to INRC).
The primary aim of the study was to assess the ORR after 2 courses of 131I-MIBG/topotecan.
Hematologic toxicity was measured by scoring the number of patients with grade 3 and 4 toxicities according to the definition of the common terminology criteria for adverse events (CTCAE) version 3.0 for platelets, hemoglobin (Hb) and neutrophils at diagnosis and after each cycle of MIBG/ TPT. Feasibility to harvest sufficient number of stem cells was analysed, aiming for a yield of > 2 x 106 CD34 positive stem cells/kg body weight. Hematologic recovery (median and range) post MAT and ASCT of neutrophils (> 0,5 x 109/L) and platelets (> 25 x 109/L) were analysed. Topoisomerase-1 activity was measured in the primary tumor samples from which material was available. DNA was isolated according to standard protocols. Topoisomerase 1 was measured using the TPT assay (topoisomerase I assay kit, TopoGEN, Columbus, Ohio). For each tumor, 10 serially diluted extracts were performed in buffer. Supercoiled DNA was incubated with each diluted extract. DNA topoisomers were separated by gel electrophoresis. One arbitrary unit (AU) of topoisomerase 1 activity was the amount of topoisomerase 1 that was needed to relax 0.25 mcg of DNA. The value was compared to references level as described by Vassal.(9) Topoisomerase-1 activity levels were correlated with the response (INRC) after 2 cycles of 131I-MIBG/topotecan.
Results Patient characteristics: Sixteen newly-diagnosed high-risk neuroblastoma patients (10 male) were included in the study. The primary tumor was localised in the abdomen in 15/16 (94%) and thoraco-abdominal in 1/16 (6%). All patients had BM disease at diagnosis (16/16; 100%), other metastatic sites were lymph node (LN) 4/16 (25%) and pleura 1/16 (6%). 123I- MIBG scans at diagnosis were all positive for primary and metastatic sites; the median Curie score was 16,5 (range 1-27). MNA was found in 8/14 (57%), LOH1p in 6/15 (40%) and in 6/14 (43%) tumors both MNA and LOH1p was found (Table I).
Therapy: The first and second131 I-MIBG administered activities (AA) were fixed (7.4 GBq/ 200 mCi), and 5.6 GBq/ 150 mCi, respective), but to evaluate effect, the AA/kg are reported here. For all 16 patients, the median (range) of the first131 I-MIBG AA was 0.5 (0.4- 0.6) GBq/kg/ 14,5 (10,1- 16,8) mCi/kg. One patient developed PD after the first course of MIBG/topotecan and did not receive the second course. Fifteen patients received the second course of MIBG/topotecan with a median (range) 131I-MIBG AA of 0.4 (0.3- 0.5) GBq/kg/ 10,6 (6,9- 12,6) mCi/kg. The cumulative 131I-MIBG AA of the 2 infusions had a median (range) of 0.9 (0.5- 1.1) GBq/
48 Chapter 3 Patients (n= 16) N Sex (M: F) 10 : 6 Age at diagnosis* 2.8 (1.6-8.3) Localisation primary tumour: Abdomen 15 (94%) Thoraco-abdominal 1 (6%) Metastases at diagnosis: Bone marrow biopsy/ aspirate 16 (100%) LN 4 ( 25%) Pleura 1 ( 6%) Curie score (median and range) 16,5 (1-27) Genetic status primary tumour: MNA 8/14 (57%) LOH1p 6/15 (40%) Combination MNA and LOH1p 6/14 (43%) MIBG-TPT 1st course 16/16 (100%) 2nd course 15/16 ( 94%) Surgery 12 (75%) MAT and ASCT 9 (56%) Stem cells harvest (CD34 positive) 13 (100%) Yield PBSC ** 2.2 (0-6.9) Yield BM ** 3.4 (1.0- 9.1)
Abbreviations: M= male, F= female; Age at diagnosis* *(median and range) years, BM= bone marrow; LN= lymph node, N= number, MNA= MYCN amplification (> 8 copies); LOH1p = Loss of Heterozygosity chromoso- me 1p, MAT and ASCT= Myeloablative therapy and autologous stem cell transplantation PBSC= Peripheral Blood Stem Cells; Yield PBSC ** and Yield BM: **(mean and range) x 106/ kg. Table I: Patient characteristics of study cohort
kg/ 25 (14,3- 29,4) mCi/kg (Table II). Median interval (median and range in days) times between 131I-MIBG and administration of topotecan for the first cycle were 5 (3-8 days) and for the second cycle 4 (3-5) days.
Subsequent treatment consisted of VECI chemotherapy in 15 patients; surgery was performed in 12/16 (75%) of the patients and MAT and ASCT in 9/16 (56%) (Table I).
Response and outcome: After 2 courses of 131I-MIBG/topotecan, the overall objective response rate (ORR) was 9/16 (57%), for the primary tumor the RR was 15/16 (94%), and the BM RR was 6/14 (43%). Post MAT and ASCT the ORR was 9/16 (57%), for the primary tumor the RR was 9/16 (57%), and the BM RR was 7/15 (47%) (Table II and III).
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 49 Pat.No. Interval 131I-MIBG-TPT 131I-MIBG therapy 123I-MIBG scan1 Rel. extension score Topo-1 activity Response (INRC) levels MIBG TPT I MIBG TPT II MIBG/TPT I GBq/ MIBG/TPT II Cum. GBq/ kg/ DX After 2x Post MAT After 2x Post MAT After 2x Post MAT kg/(mCi/kg) GBq/ kg/(mCi/kg) (mCi/kg) MIBG/TPT ASCT MIBG/TPT ASCT MIBG/TPT ASCT 1 6 5 0.5 (13.9) 0.4 (10.4) 0.9 (24.3 20 14 0 0,7 0 15385 MR PR 2 5 - 0.5 (14.3) - 0.5 (14.3) 14 15 - 1,1 - ND PD - 3 5 4 0.4 (10.2) 0.3 (7.7) 0.7 (17.9) 8 1 0 0,1 0 33333 PR CR 4 8 5 0.6 (16.5) 0.5 (12.4) 1.1 (28.9) 27 14 3 0,52 0,1 ND MR PR 5 4 4 0.6 (16.8) 0.5 (12.6) 1.1 (29.4) 8 0 # (2) 0 - 11111 PR PD# 6 6 4 0.5 (14.7) 0.4 (11.0) 1.0 (25.7) 20 5 0 0,3 0 17391 PR CR 7 UK 4 0.6 (16.7) 0.4 (11.7) 1.1 (28.4) 11 1 - 0,1 - 20000 PR -^ 8 4 4 0.6 (16.4) 0.5 (12.3) 1.1 (28.7) 7 2 # (4) 0,3 - 12766 PR PD# 9 4 4 0.4 (10.5) 0.3 (7.9) 0.7 (18.4) 25 23 9 0,9 0,4 ND MR PR 10 UK UK 0.6 (15.7) 0.4 (11.8) 1.0 (27.5) 2 0 0 0 0 ND PR CR 11 5 4 0.5 (13.4) 0.4 (10.1) 0.9 (23.5) 1 0 0 0 0 50000 VGPR CR 12 7 4 0.5 (13.8) 0.3 (6.9) 0.8 (20.7) 24 1 # (3) 0 - 8219 PR PD# 13 5 5 0.4 (10.1) 0.3 (7.6) 0.7 (17.7) 22 13 0 0,6 0 ND MR CR 14 6 4 0.6 (15.4) 0.4 (10.8) 1.0 (26.2) 26 14 0 0,54 0 4444 MR PR 15 5 3 0.4 (10.5) 0.3 (7.9) 0.7 (18.4) 19 5 - 0,2 - 60000 PR -^ 16 3 3 0.6 (15.4) 0.4 (11.5) 1.0 (26.9) 7 6 - 0,9 - ND MR -^
Median 5 4 0.5 (14.5) 0.4 (10.6) 0.9 (25) 16,5 5 0 0,3 0 (range) (3-8) (3-5) (0.4- 0.6) (0.3- 0.5) (0.5- 1.1) (1- 27) (0- 23) (3-9) (0- 1,1) (0- 0,4) (10.1- 16.8) (6.9- 12.6) (14.3- 29.4)
Reported are: Pat. No: patient number. Interval 131I-MIBG therapy-TPT: MIBG-TPT I: first cycle of 131I-MIBG and Topotecan; MIBG-TPT II: second cycle of 131I-MIBG and Topotecan (days). 131I-MIBG therapy dose: MIBG/TPT I mCi/kg: first cycle of 131I-MIBG and Topotecan milliCurie/ kilogram; MIBG/TPT II mCi/kg: second cycle of 131I-MIBG and Topotecan milliCurie/ kilogram; Cum. mCi/kg: cumulative dose milliCurie/ kilogram. GBq/kg: gigabequerel/ kilogram. 1 mCi= 0.037 GBq. 123I-MIBG scan1: The 1Curie score (22) measured on 123I-MIBG scan: DX: at diagnosis; after 2x MIBG/TPT: after the 2 courses 131I-MIBG-topotecan; post MAT and ASCT: After myeloablative therapy and autologous stem cell transplantation. Rel. extension score: post therapy Curie score divided by pre therapy Curie score. Topo-1 activity levels: topoisomerase-1 activity levels measured in primary tumor at diagnosis (reference levels ranged from 69-1304 arbitrary units/mg of protein) (9). Response (INRC): INRC*: Response measured per patient according to International Neuroblastoma Response Criteria (INRC) (23). CR: complete response; VGPR: very good partial response; PR: partial response; MR: mixed response; PD: progressive disease; ORR: objective response rate; RR: response rate. ^: PD during VECI (N=2 VECI 3 and N=1 VECI 4) #: PD pre MAT and ASCT (N= 3). ND: not done. UK: unknown. Table II. 131I-MIBG doses and responses
50 Chapter 3 Pat.No. Interval 131I-MIBG-TPT 131I-MIBG therapy 123I-MIBG scan1 Rel. extension score Topo-1 activity Response (INRC) levels MIBG TPT I MIBG TPT II MIBG/TPT I GBq/ MIBG/TPT II Cum. GBq/ kg/ DX After 2x Post MAT After 2x Post MAT After 2x Post MAT kg/(mCi/kg) GBq/ kg/(mCi/kg) (mCi/kg) MIBG/TPT ASCT MIBG/TPT ASCT MIBG/TPT ASCT 1 6 5 0.5 (13.9) 0.4 (10.4) 0.9 (24.3 20 14 0 0,7 0 15385 MR PR 2 5 - 0.5 (14.3) - 0.5 (14.3) 14 15 - 1,1 - ND PD - 3 5 4 0.4 (10.2) 0.3 (7.7) 0.7 (17.9) 8 1 0 0,1 0 33333 PR CR 4 8 5 0.6 (16.5) 0.5 (12.4) 1.1 (28.9) 27 14 3 0,52 0,1 ND MR PR 5 4 4 0.6 (16.8) 0.5 (12.6) 1.1 (29.4) 8 0 # (2) 0 - 11111 PR PD# 6 6 4 0.5 (14.7) 0.4 (11.0) 1.0 (25.7) 20 5 0 0,3 0 17391 PR CR 7 UK 4 0.6 (16.7) 0.4 (11.7) 1.1 (28.4) 11 1 - 0,1 - 20000 PR -^ 8 4 4 0.6 (16.4) 0.5 (12.3) 1.1 (28.7) 7 2 # (4) 0,3 - 12766 PR PD# 9 4 4 0.4 (10.5) 0.3 (7.9) 0.7 (18.4) 25 23 9 0,9 0,4 ND MR PR 10 UK UK 0.6 (15.7) 0.4 (11.8) 1.0 (27.5) 2 0 0 0 0 ND PR CR 11 5 4 0.5 (13.4) 0.4 (10.1) 0.9 (23.5) 1 0 0 0 0 50000 VGPR CR 12 7 4 0.5 (13.8) 0.3 (6.9) 0.8 (20.7) 24 1 # (3) 0 - 8219 PR PD# 13 5 5 0.4 (10.1) 0.3 (7.6) 0.7 (17.7) 22 13 0 0,6 0 ND MR CR 14 6 4 0.6 (15.4) 0.4 (10.8) 1.0 (26.2) 26 14 0 0,54 0 4444 MR PR 15 5 3 0.4 (10.5) 0.3 (7.9) 0.7 (18.4) 19 5 - 0,2 - 60000 PR -^ 16 3 3 0.6 (15.4) 0.4 (11.5) 1.0 (26.9) 7 6 - 0,9 - ND MR -^
Median 5 4 0.5 (14.5) 0.4 (10.6) 0.9 (25) 16,5 5 0 0,3 0 (range) (3-8) (3-5) (0.4- 0.6) (0.3- 0.5) (0.5- 1.1) (1- 27) (0- 23) (3-9) (0- 1,1) (0- 0,4) (10.1- 16.8) (6.9- 12.6) (14.3- 29.4)
Reported are: Pat. No: patient number. Interval 131I-MIBG therapy-TPT: MIBG-TPT I: first cycle of 131I-MIBG and Topotecan; MIBG-TPT II: second cycle of 131I-MIBG and Topotecan (days). 131I-MIBG therapy dose: MIBG/TPT I mCi/kg: first cycle of 131I-MIBG and Topotecan milliCurie/ kilogram; MIBG/TPT II mCi/kg: second cycle of 131I-MIBG and Topotecan milliCurie/ kilogram; Cum. mCi/kg: cumulative dose milliCurie/ kilogram. GBq/kg: gigabequerel/ kilogram. 1 mCi= 0.037 GBq. 123I-MIBG scan1: The 1Curie score (22) measured on 123I-MIBG scan: DX: at diagnosis; after 2x MIBG/TPT: after the 2 courses 131I-MIBG-topotecan; post MAT and ASCT: After myeloablative therapy and autologous stem cell transplantation. Rel. extension score: post therapy Curie score divided by pre therapy Curie score. Topo-1 activity levels: topoisomerase-1 activity levels measured in primary tumor at diagnosis (reference levels ranged from 69-1304 arbitrary units/mg of protein) (9). Response (INRC): INRC*: Response measured per patient according to International Neuroblastoma Response Criteria (INRC) (23). CR: complete response; VGPR: very good partial response; PR: partial response; MR: mixed response; PD: progressive disease; ORR: objective response rate; RR: response rate. ^: PD during VECI (N=2 VECI 3 and N=1 VECI 4) #: PD pre MAT and ASCT (N= 3). ND: not done. UK: unknown. Table II. 131I-MIBG doses and responses
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 51 "N=16
After 2x MIBG/TPT" CR VGPR PR MR PD ORR INRC* 0 1 8 6 1 9 (57%) Primary tumour RR** 0 1 14 1 0 15 (94%) BM RR*** (2 unknown) 6 6 (43%)
"N=9
Post MAT + ASCT" CR VGPR PR MR PD ORR INRC* 5 0 4 0 0 9 (57%) Primary tumour RR** 8 1 0 0 0 9 (57%) BM RR*** (1 unknown) 7 7 (47%)
INRC*: Response measured per patient according to International Neuroblastoma Response Criteria (INRC) (23). CR: complete response; VGPR: very good partial response; PR: partial response; MR: mixed response; PD: progressive disease; ORR: objective response rate; RR: response rate. MIBG/TPT: 131I- Meta-Iodobenzylguanidine and Topotecan. MAT + ASCT: myeloablative therapy and autologous stem cell transplantation. ** Response rate for the primary tumour determined by primary tumour volume (3-dimensions), see material and methods. BM RR*** : Bone marrow RR (clearance of bone marrow invasion: conventional cytology and histology on aspirate and trephine biopsy). Table III: Response after 2x 131I-MIBG/topotecan and post MAT and ASCT.
The median Curie score at diagnosis was 16.5 (range 1-27), after 2 courses of MIBG/topotecan the median score was 5 (range 0-23), post MAT and ASCT the median score was 0 (range 3-9). This is a decrease of 70% between diagnosis and the end of 2 cycles of MIBG/topotecan and 100% between diagnosis and post MAT and ASCT. The median (range) values of the relative extension score after 2 courses of MIBG/ topotecan was 0.3 (0- 1.1) and post MAT and ASCT 0 (0- 0.4) (Table II). After 2 courses of MIBG/topotecan 9/16 (56%) and post MAT and ASCT, 9/9 (100%) of the patients had a relative extension score of 0.5 or less. The mean cumulative AA in our study was 12.4 GBq (335 mCi) , the mean AA/kg was 0.9 GBq/kg (24.3 mCi/kg), with a percentage responders 9/16 (57%) post MAT and ASCT. After 10 years of follow-up only one patient has survived (10-year OS 6%); he was recently seen in a long term survivor out-patient clinic and is in complete remission, without any events.
Topoisomerase-1 activity: The topoisomerase-1 activity levels were measured in 10 primary tumors. The levels were increased in all tumors, compared to reference levels reported by Vassal et al. (9), with a median value of 16388 AU/mg of protein (4444-60000). Out of the 10 measured topoisomerase-1 activity levels, the tumor samples with the 5 highest topoisomerase-1 activity levels showed responses of 4 PR and 1 VGPR, compared to the 5 lowest topoisomerase-1 activity levels showing responses of 3 PR and 2 MR. In the 6 patients with unknown topoisomerase-1 activity levels we observed 1 PR, 4 MR and 1 PD (Table II).
52 Chapter 3 Platelets Neutrophils Hemoglobin
Time point: Grade 3* (N) Grade 4** (N) Grade 3# (N) Grade 4## (N) Grade 3^ (N) Grade 4^^ (N) Diagnosis (N=16) 0 0 0 0 5 2 Post MIBG-TPT I (N=16) 2 4 6 2 7 4 Post MIBG-TPT II (N=15) 4 5 4 5 7 1
Abbreviations: CTCAE= Common Terminology Criteria for Adverse Events * Grade 3 platelets < 50- 25 x 109/L; ** Grade 4 platelets < 25 x 109/L # Grade 3 neutrophils < 1.0- 0.5 x 109/L; ## Grade 4 neutrophils < 0.5 x 109/L. ^ Grade 3 Hemoglobin < 4.9- 4.0 mmol/L; ^^ Grade 4 Hemoglobin < 4.0 mmol/L. N: number of patients. Table IV: Hematological results at diagnosis and nadir after MIBG/topotecan courses I and II according to CTCAE version 3.0.
Dosing intervals: We aimed to give the MIBG/topotecan at 4-week intervals; the mean interval time (range) between the first and second MIBG/topotecan was 33 days (27-41) and 30 days (20-47) between the second MIBG/ topotecan and the first VECI chemotherapy course. The mean interval time (range) for the subsequent VECI chemotherapy courses was 30 days (18-40) for the first course, 31 days (28-38) for the second course and 29 days (21-46) between the third and fourth course.
Hematologic toxicity and stem cell harvesting: We measured the hematologic toxicity, and report the grade 3 and 4 toxicity, after the first and second courses of MIBG/topotecan (Table IV). After the first course, grade 4 platelet toxicity occurred in 4/16 (25%); after the second course, in 5/15 (33%). After the first course, grade 4 neutrophil toxicity occurred in 2/16 (13%); after the second course, in 5/15 (33%). Grade 4 hemoglobin toxicity occurred at diagnosis in 2/16 (13%), and in 4/16 (25%) after the first, and 1/15 (7%) after the second therapy course, respectively.
Harvesting of stem cells was performed in 13/16 (79%) patients; 3/16 (21%) patients were not harvested due to PD. Peripheral blood stem cell (PBSC) apheresis was successful in 6/13 (46%) patients. Six patients underwent further BM harvesting. The mean yield of PBSC harvest was 2.2 (0-6.9) x 106/kg CD34+ stem cells and of BM harvest the mean yield was 3.4 (1.0-9.1) x 106/kg CD 34+ stem cells (Table I). After MAT and ASCT, median (range) platelet recovery times (> 25x 109/L) were 37 (14-74) days and neutrophil recovery (> 0.5x 109/L) was 21 (12-62) days.
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 53 Discussion Our data show that the combination 2 courses of 131I-MIBG with topotecan in newly-diagnosed high-risk neuroblastoma patients leads to an overall ORR of 57%, and a response of 94% in the primary tumor, thus being an effective treatment option for these patients. Historically, 131I-MIBG therapy alone as upfront treatment in high-risk neuroblastoma patients resulted in an ORR of 66%.(6) The response rates of this 131I-MIBG /topotecan combination study are comparable and not superior, although both series have limited numbers of patients and limited statistical power.
In our study, after 2 courses of 131I-MIBG/topotecan the BM was cleared in 43%, at the same time the median Curie score reduced with 70%. The high response rates of BM and metastatic disease on 123I- MIBG scan in our study is in contrast to the study reported by Dubois and colleagues.(21) In their study in recurrent/ refractory patients, there were 13/24 (54%) patients with positive BM on study entry and all 123I- MIBG scans were positive in these patients. After therapy the BM response was 9 SD, 2 PD, 1 not done, and 1 CR unconfirmed. MIBG scans were only negative in 2/13 (15%) patients and 5 had improved Curie scores. In the refractory/ relapsed setting the tumor load in the BM is relatively low, contrary to the upfront, newly-diagnosed situation, suggesting that the higher tumor load would explain the better BM and metastatic response in our study. Another explanation is that the patients in the refractory/ relapsed setting have received more treatment and that their tumors may have become resistant to therapy.
A review by Wilson et al. including studies with neuroblastoma and 131I-MIBG reported an objective tumor RR ranging 0%-75%, mean 32%. In the multivariate analysis of cumulative AA (measured in GBq) there was a positive association between RR and cumulative AA (p= 0.001); there was no clear relationship between response and AA/kilogram (kg) (p= 0.16).(24)
We calculated the cumulative AA and mean AA/kg of the 131I-MIBG cycles, but found no association with response. The mean cumulative AA and the mean AA/kg of the 2 infusions of 131I-MIBG in our study is high compared to the data reported by the Wilson review. Our ORR of 57% after MAT and ASCT is acceptable compared to the other reported responses.(24) Unfortunately, in our study the radiation dosimetry data (whole body or tumor) were not collected, as this would have been of additional value.
A study reported by Bleeker et al. reported a low incidence of grade 4 platelet and hemoglobin toxicity in newly diagnosed NBL patients with upfront 131I-MIBG therapy alone, specifically in patients with BM disease. (25) In our study reporting on the combination of 131I-MIBG and topotecan, the hematologic grade 4 toxicity was more frequently seen, however all patients had BM disease at diagnosis and it did not cause delay in induction chemotherapy thereafter. Also, these percentages were considerably lower than seen in patients receiving standard induction chemotherapy. A study by Dubois et al., in a group of refractory/ relapsed NBL patients receiving 18 mCi/kg (0.7 GBq/kg) 131I-MIBG on a phase I/II protocol, reported considerably higher
54 Chapter 3 haematological toxicities.(26) It was feasible to harvest sufficient numbers of stem cells (PBSC). At this time we were still optimizing our apheresis procedure in this group of patients, making it necessary to perform BM harvest in 6 of our patients. In our current practice this is never performed. The median (range) recovery times after MAT and ASCT, for platelets (> 25x109/L) was 37 (14-74) days and for neutrophil recovery (> 0,.5x 109/L), was 21 (12-62) days. These recovery times are similar to those reported in the literature.(26,27)
Topoisomerase-1 activity levels were measured in 10 of our patient tumor samples. The high expression of topoisomerase-1 suggests that topotecan can be an effective drug in neuroblastoma. However, after 2 cycles of 131I-MIBG/topotecan, no conclusions concerning topoisomerase 1 activity levels and response could be drawn from these data due to small numbers and missing data in 6/16 samples. Limitations of this study are the relatively small number of patients included and the less intense VECI chemotherapy that followed combination MIBG/topotecan therapy. Furthermore, in this small cohort, an unusual high number of patients with NMYC amplified tumors were included. However, these data are still valuable considering the growing interest in both efficacy of 131I-MIBG in newly diagnosed high-risk neuroblastoma and interest in optimising 131I-MIBG treatment by using radio-sensitizers. This study has shown that the combination MIBG/topotecan therapy is effective in patients with upfront newly-diagnosed high-risk neuroblastoma. Whether this combination therapy has additional benefits compared to the use of single agent 131I-MIBG therapy is not clear and will need to be addressed in future studies. Ultimately, a randomized trial will be needed to determine whether topotecan adds clinical benefit.
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24. Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy
58 Chapter 3 Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. 59 The first two authors have contributed equally to this article (joint first authorship).
1. Department of Pediatric Oncology, Emma Children’s Hospital, Amsterdam, the Netherlands. 2. Department of Radiology/ Nuclear Medicine, NWZ Alkmaar, Alkmaar, The Netherlands. 3. Department of Nuclear Medicine, Academic Medical Centre (AMC), Amsterdam, the Netherlands. 4. Department of Pediatric Oncology and Hematology, University Children’s Hospital, and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. 5. Department of Pediatric Oncology/Hematology, Erasmus MC (EMC)-Sophia Children’s Hospital, Rotterdam, the Netherlands. 6. Princess Máxima centre for Pediatric Oncology, Utrecht, the Netherlands. Chapter 4 Feasibility, toxicity and response of upfront 131I-MIBG therapy followed by GPOH NB 2004 protocol in newly diagnosed stage 4 neuroblastoma patients
KCJM Kraal1,6, GM Bleeker2, BLF van Eck-Smit3, NKA van Eijkelenburg6, F Berthold4, MM van Noesel5,6, HN Caron1 and GAM Tytgat1,6 .
Submitted for publication Abstract
Aim of the study Radiolabelled meta-iodobenzylguanidine (MIBG) is an effective option in treatment of patients with neuroblastoma (NBL) tumours. We studied feasibility, toxicity and efficacy of upfront 131I-MIBG and induction treatment in stage 4 NBL patients.
Patients and Methods Retrospective, multi-centre (AMC and EMC) pilot regimen (1/1/2005- 2011). Newly diagnosed stage 4 NBL patients, were treated with 2 courses of 131I-MIBG, GPOH 2004 NBL protocol, myeloablative therapy (MAT) and autologous stem cell rescue (ASCT). 131I-MIBG was administered in a fixed dose. Response rate (RR) was defined as complete remission, very good partial response and partial response.
Results Thirty-two patients, (median age (range) 2.9 (0- 11.4) years), 21 received 131I-MIBG therapy, 11 did not because of: MIBG non-avid (N=5) and poor clinical condition (N=6). In 95% of eligible patients 131I-MIBG treatment was feasible within 2 weeks from diagnosis. Interval between chemotherapy courses was 25 days (131I-MIBG group) vs. 22 days (chemotherapy group). No stem cell support was needed after 131I-MIBG therapy. Stem cell harvest in both groups was feasible, neutrophil recovery was comparable, but platelet recovery post MAT ASCT was slower for 131I-MIBG treated patients. RR post 131I-MIBG was 38%, post MAT + ASCT: 71% (131I-MIBG group), 36% (chemotherapy group) and overall 59%.
Conclusions Induction therapy with 131I-MIBG prior to the HR GPOH NB 2004 protocol is feasible, tolerable and effective in newly diagnosed stage 4 NBL patients. 131I-MIBG upfront therapy induces early responses.
62 Chapter 4 Introduction
Neuroblastoma (NBL) is the most common extra cranial solid tumour in childhood, derived from the sympathetic nervous system (1). The prognosis for patients with HR NBL, was less than 40% for a long time, but this has improved over the last decades (2;3). A study performed by Yu et al. showed a 20% survival (overall survival (OS) and event free survival (EFS)) benefit of addition of immunotherapy after myeloablative therapy (MAT), followed by autologous stem cell transplantation (ASCT) in HR NBL patients (4). The 3-year EFS of HR NBL patients, treated according to the German Pediatric Oncology Group (GPOH) NB97 protocol with ASCT has been shown to be 47% (5).
Imaging with 123I-Meta-Iodobenzylguanidine (123I-(MIBG) is a reliable and reproducible method for staging and response evaluation in NBL (6-8). For targeted treatment, MIBG labelled with 131I has been used successfully (9). 131I-MIBG has a significant antitumor efficacy against NBL, with response rates (RR) between 20-60% (10-16). Tandem 131I-MIBG therapy can be given to patients with relapsed/ refractory NBL with tumor response or stable disease (SD), and available stem cells. Early second 131I-MIBG therapy safely reduces disease burden in patients with relapsed NBL (17).
Systematic review of studies with 131I-MIBG in NBL by Wilson et. al, revealed an objective tumour RR ranging from 0%- 75%. Multivariate analysis of cumulative administered activity ((AA) measured in GBq) show that there was a positive association between response rate and cumulative AA (p= 0.001), but no clear relationship between response and AA/kilogram (kg) (p= 0.16) (18). The primary aim of the study was feasibility/ toxicity and secondary outcomes were: interval between chemo courses, feasibility to harvest stem cells, hematological reconstitution post ASCT and response of 2 courses of upfront 131I-MIBG therapy, followed by the standard arm of the HR GPOH 2004 protocol.
Patients and Methods We performed a retrospective, multi-centre (Emma Children’s Hospital (AMC), Amsterdam and the Erasmus MC (EMC) Sophia Children’s Hospital, Rotterdam, the Netherlands), analysis of cohort pilot regimen (1/1/2005- 2011), including consecutive all newly diagnosed stage 4 NBL patients, age 0- 19 years, including <12 months with stage 4/M and MycN amplification (MNA) tumors, after oral informed consent from the parents (19;20). Patients were excluded from 131I-MIBG therapy if 123I-MIBG uptake was insufficient, or there was a poor clinical condition (uncontrollable hypertension, orbital masses, pleural effusion). Insufficient MIBG uptake was defined as: insufficient MIBG uptake in the primary tumor and/or metastasis.
131I-MIBG therapy was indicated in patients with a higher MIBG uptake level in the primary tumor than the physiological liver activity combined with MIBG uptake in known metastases, confirmed by diagnostic 123I-MIBG imaging.
Feasibility, toxicity and response of upfront 131I-MIBG therapy 63 Fixed dose 131I-MIBG therapy: 1st cycle 7400 MBq (200 mCi), 2nd cycle 5500 MBq (150 mCi). N5= Vindesine, etoposide and cisplatin N6= Vincristine, dacarbacine, ifosfamide and doxorubicine MAT + ASCT= myeloablative therapy and autologous stem cell transplantation CEM= Carboplatin, etoposide and melfalan Cis-RA= cis retinoic acid * Stem cell harvest when BM in MRD ** Radiotherapy BM= bone marrow, MRD= minimal residual disease S= surgery (was performed after N5/ N6 courses, optimal timing of surgery was discussed). Figure 1: Treatment overview
Data were collected from patient medical files, census date for analysis was 1/1/2012. The protocol consisted of two courses of upfront 131I-MIBG therapy, followed by the standard high risk arm of the GPOH NB 2004 protocol (registered in clinical trials. gov; identifier NCT00526318). The standard arm of the HR GPOH NB2004 protocol consists of induction chemotherapy 6 courses (alternate N5/ N6 courses, interval aimed at 21 days), followed by surgery. Patients that reached complete response (CR), very good partial response (VGPR) and partial response (PR) proceeded to MAT ASCT (one mixed response (MR) patient by exemption), followed by radiotherapy (RT) to the primary tumour site and retinoic acid (Figure 1). The first course of 131I-MIBG was aimed to start within 2 weeks from diagnosis. The scheduled interval between the two 131I-MIBG courses was 4 weeks. If the platelet count was below 50 x 109/L, the second course was postponed, or, if platelet counts allowed, a 3 week interval was permitted. Patients were admitted to a special nuclear medicine ward and thyroid prophylaxis was prescribed (21). Patients remained in radiation protective isolation until the exposure rate was less than 20 microsieverts per hour (µSv/h), at 1 m distance. At day 3 and 7 post therapy, a scan was performed to study the 131I-MIBG retention in the tumor and its metastases. In case of inadequate MIBG retention on these post-therapy scans, no second course was given.
64 Chapter 4 Fixed doses of 131I-MIBG were given; AA was 7400 MBq (megabecquerel)/ 200 mCi (millicurie) (first course) and 5500 MBq/ 150 mCi (second course). The AA of each 131I-MIBG course- and the cumulative dose/kg body weight were calculated in GBq/kg (mCi/kg), for the group as a whole and per patient. Hematological toxicity (nadir and range of platelets) at diagnosis, after the first and second 131I-MIBG course and between two induction chemotherapy courses (corrected for surgery) was noted. Patients were eligible for stem cell harvest as soon as the BM was clear of tumour cells. The yield of collected autologous peripheral stem cells, the number of harvest sessions, time to neutrophil (> 0.5 x 109/L) and platelet (>20 x 109/L) recovery post MAT and ASCT were noted. Response was scored according to the revised INRC criteria (20). We used the Curie MIBG scoring system for scoring metastasis on a diagnostic 123I-MIBG scan (22). Response rate (RR) was defined as CR, VGPR and partial response (PR). The response to induction treatment was measured post 2 courses of 131I-MIBG, post chemotherapy induction and post MAT and ASCT. The relative extension scores (post therapy Curie score divided by pre therapy Curie score) were calculated at the same time points (7).
Statistics Differences between 131I-MIBG group and chemotherapy group were tested with Chi Square and Mann Whitney U test with a significance level of p=0.05 was used. However, since this was not a randomized study, all comparisons should be considered with caution. OS and EFS Kaplan Meier curves were calculated for the entire cohort. OS was measured as the time from start of treatment to death by any cause. EFS was defined as the time from start of treatment to a first event (progression, relapse or death).
Results Patient and tumour characteristics Thirty two patients with stage 4 NBL were enrolled in this study, 21/ 32 patients received upfront 131I-MIBG treatment, 11/32 were not eligible: MIBG non-avid on the 123I-MIBG-scan (N = 5; 4 primary tumor non-avid, 1 MIBG non-avid skeletal lesions); poor clinical condition (N = 6). The patient characteristics are shown in Table I. The median age (range) of the overall study cohort was 2.9 (0- 11.4) years, in the 131I-MIBG group this was 3.1 years (0-6.2) and 2.2 years (1.2- 11.4) in the chemotherapy group. Overall, the percentage MNA and 1p loss of heterozygosity (LOH1p) in the NBL tumours was 37% and 36 %, respectively. Twenty-seven out of 32 patients had BM disease at diagnosis and in 29/31 the diagnostic 123I-MIBG scans indicated MIBG avid metastatic disease.
Therapy: Twenty-one patients were treated with a first course of 131I-MIBG, 16 with a second. Reasons for not giving a second course of 131I-MIBG therapy were: insufficient MIBG retention (N = 2), thrombocytopenia
Feasibility, toxicity and response of upfront 131I-MIBG therapy 65 Overall 131I-MIBG treatment No 131I-MIBG treatment
Total Number 32 21 11 Sex N: Male 19 (59%) 13 (62%) 6 (55%) Female 13 (41%) 8 (38%) 5 (45%) Age at diagnosis Median (range) years: 2.9 (0- 11.4) 3.1 (0-6.2) 2.2 (1.2- 11.4) Genetic aberrations N: MNA 11 (37%) 7 (35%) 4 (40%) Unknown 2 1 1 LOH1p 9 (36%) 6 (35%) 3 (38%) Unknown 7 4 3 Primary tumor N: Abdominal 31 (97%) 20 (95%) 11 (100%) Thoracic 1 ( 3%) 1 (5%) 0 (0%) Metastases N: BM 27 (84%) 17 ( 81%) 10 (91%) 123I-MIBG 28 (90%) 20 (100%) 8 (73%) Unknown 1 1 0 Urine catecholamines 29 (100%) 19 (100%) 10 (100%) Unknown 3 2 1 Therapy N: 131I-MIBG therapy I - 21 N/A 131I-MIBG therapy II - 16 N/A Induction chemo 31 20 11 Surgery 21 (66%) 16 (76%) 5 (45%) MAT+ ASCT 21 (66%) 16 (76%) 5 (45%)
MNA: MYCN amplification; LOH1p: 1p loss of heterozygosity. MAT + ASCT= myeloablative therapy and autologous stem cell transplantation N/A= not applicable, N= number, BM= bone marrow, EFS: event free survival OS: overall survival. Table I: Patient characteristics
combined with clinical deterioration (N = 1), and PD (N = 2) of which 1 patient died during MIBG I therapy. Twenty-one out of 32 (66%) patients underwent surgery and MAT + ASCT, 76% in the 131I-MIBG group and 45% in the chemotherapy group. Two patients in the chemotherapy group died of toxicity; 1 patient died due to multi-organ failure and another due to surgical complications (see flowchart (Figure 2).
66 Chapter 4 Treatment 131I-MIBG Interval (N)** No 131I-MIBG Interval (N)** Overall* modalities treatment* treatment* <21 21-28 >28 <21 21-28 >28 N5 I – N6 I 27 (21-34) (20) 4 10 6 21 (20-32) (10) 7 0 3 25 (20-34) N6 I – N5 II 24 (20-49) (18) 8 8 2 21 (20-32) (10) 7 0 3 21 (20-49) N5 II – N6 II 23 (21-41) (19) 7 9 3 20 (19-34) (8) 6 0 2 22 (19-41) N6 II – N5 III 27 (20-44) (19) 3 8 8 23 (14-30) (8) 2 5 1 24 (14-44) N5 III – N6 III 26 (21-40) (18) 5 6 7 26 (21-31) (6) 2 3 1 26 (21-40) N6III – MAT+ ASCT 33 (20-44) (15) 2 1 12 30 (28-34) (4) 0 1 3 32 (20-44) Overall time per course:* N5I- MAT+ ASCT 26 23 25 N5I- N6III 25 22 24
* Interval time in days (median and range) ** Interval time in days (N= number) Table III: Interval between two induction chemotherapy courses (corrected for surgery)
Figure 2: Flowchart
Feasibility, toxicity and response of upfront 131I-MIBG therapy 67 Pat. No. Interval 131I-MIBG (days) 131I-MIBG therapy Response (INRC) Curie score Dx/-MIBG I MIBG I-MIBG II MIBG II-N5 I MIBG I GBq/ kg/ MIBG II GBq/ kg/ Cum. MIBG GBq/ Post 2x Post N6III "Post MAT Dx/ Post 2x Post N6III "Post MAT (mCi/kg) (mCi/kg) kg/(mCi/kg) MIBG MIBG 1 12 28 28 0,46 (12,5) 0,46 (12,5) 0,92 (25,0) VGPR VGPR CR 5 0 0 0 2 12 28 30 0,46 (12,4) 0,24 (6,6) 0,70 (19,0) MR CR PR 17 0 - 0 3 8 27 30 0,56 (15,2) 0,42 (11,4) 0,98 (26,6) MR CR CR 21 14 0 0 4 3 28 29 0,41 (11,3) 0,41 (11,3) 0,82 (22,6) - PR CR 4 - 0 - 5 1 27 35 0,38 (10,3) 0,53 (14,3) 0,91 (24,6) VGPR CR CR 22 1 0 0 6 11 32 24 0,53 (14,3) 0,39 (10,7) 0,92 (25,0) VGPR VGPR PR 17 2 2 2 7 2 25 0,45 (11,3) 0,41 (11,1) 0,86 (22,4) MR CR CR 2 0 0 0 8 13 # # 0,41 (11,1) - 0,41 (11,1) MR CR PD 20 2 0 0 9 11 # # 0,17 (4,7) - 0,17 (4,7) PD PR PD 6 0 - - 10 14 # # 0,53 (14,3) - 0,53 (14,3) PR PR PR 12 12 7 7 11 9 # # 0,34 (9,1) - 0,34 (9,1) PR CR CR 1 2 0 0 12 2 19 23 0,49 (13,3) 0,37 (10,0) 0,86 (23,3) NR PR PR 8 8 - 2 13 9 21 21 0,39 (10,6) 0,29 (7,9) 0,68 (18,5) PD PR VGPR 6 6 - 0 14 5 27 29 0,53 (14,4) 0,36 (9,6) 0,89 (24,0) NR PR PR 25 16 1 2 15 15 35 26 0,47 (12,8) 0,36 (9,6) 0,83 (22,4) PD MR PD 24 25 25 - 16 6 21 31 0,44 (12,0) 0,33 (9,0) 0,77 (21,0) MR PR VGPR 20 20 4 1 17 9 28 22 0,40 (10,7) 0,29 (8,0) 0,69 (18,7) PR PD - 21 8 - - 18 11 43 28 0,34 (8,7) 0,25 (6,8) 0,59 (15,5) PD PR PD 16 17 12 - 19 6 28 49 0,52 (14,1) 0,52 (14,1) 1,04 (28,2) PR PR CR 15 2 0 0 20 8 42 21 0,36 (9,8) 0,27 (7,3) 0,63 (17,1) PR CR CR 21 5 0 0 21 7 # # 0,56 (15,2) - 0,56 (15,2) PD (death) - - -
Median 9 (1-15) 28 (19-43) 29 (21- 49) 0,45 (12,0) 0,37 (9,8) 0,77 (21,0) 16,5 5 0 0 (range) (0,17-0,56) (0,25- 0,53) (0,17-1,04) (1- 25) (0-25) (0-25) (0-7) (4,7-15,2) (6,6- 14,3) (4,7- 28,2)
# No second MIBG: PD death N=1, PD N=1, non-MIBG avid N=2, thrombocytopenia N=1
Table II: Interval times 131I-MIBG, dose of 131I-MIBG and response (INRC)
68 Chapter 4 Pat. No. Interval 131I-MIBG (days) 131I-MIBG therapy Response (INRC) Curie score Dx/-MIBG I MIBG I-MIBG II MIBG II-N5 I MIBG I GBq/ kg/ MIBG II GBq/ kg/ Cum. MIBG GBq/ Post 2x Post N6III "Post MAT Dx/ Post 2x Post N6III "Post MAT (mCi/kg) (mCi/kg) kg/(mCi/kg) MIBG MIBG 1 12 28 28 0,46 (12,5) 0,46 (12,5) 0,92 (25,0) VGPR VGPR CR 5 0 0 0 2 12 28 30 0,46 (12,4) 0,24 (6,6) 0,70 (19,0) MR CR PR 17 0 - 0 3 8 27 30 0,56 (15,2) 0,42 (11,4) 0,98 (26,6) MR CR CR 21 14 0 0 4 3 28 29 0,41 (11,3) 0,41 (11,3) 0,82 (22,6) - PR CR 4 - 0 - 5 1 27 35 0,38 (10,3) 0,53 (14,3) 0,91 (24,6) VGPR CR CR 22 1 0 0 6 11 32 24 0,53 (14,3) 0,39 (10,7) 0,92 (25,0) VGPR VGPR PR 17 2 2 2 7 2 25 0,45 (11,3) 0,41 (11,1) 0,86 (22,4) MR CR CR 2 0 0 0 8 13 # # 0,41 (11,1) - 0,41 (11,1) MR CR PD 20 2 0 0 9 11 # # 0,17 (4,7) - 0,17 (4,7) PD PR PD 6 0 - - 10 14 # # 0,53 (14,3) - 0,53 (14,3) PR PR PR 12 12 7 7 11 9 # # 0,34 (9,1) - 0,34 (9,1) PR CR CR 1 2 0 0 12 2 19 23 0,49 (13,3) 0,37 (10,0) 0,86 (23,3) NR PR PR 8 8 - 2 13 9 21 21 0,39 (10,6) 0,29 (7,9) 0,68 (18,5) PD PR VGPR 6 6 - 0 14 5 27 29 0,53 (14,4) 0,36 (9,6) 0,89 (24,0) NR PR PR 25 16 1 2 15 15 35 26 0,47 (12,8) 0,36 (9,6) 0,83 (22,4) PD MR PD 24 25 25 - 16 6 21 31 0,44 (12,0) 0,33 (9,0) 0,77 (21,0) MR PR VGPR 20 20 4 1 17 9 28 22 0,40 (10,7) 0,29 (8,0) 0,69 (18,7) PR PD - 21 8 - - 18 11 43 28 0,34 (8,7) 0,25 (6,8) 0,59 (15,5) PD PR PD 16 17 12 - 19 6 28 49 0,52 (14,1) 0,52 (14,1) 1,04 (28,2) PR PR CR 15 2 0 0 20 8 42 21 0,36 (9,8) 0,27 (7,3) 0,63 (17,1) PR CR CR 21 5 0 0 21 7 # # 0,56 (15,2) - 0,56 (15,2) PD (death) - - -
Median 9 (1-15) 28 (19-43) 29 (21- 49) 0,45 (12,0) 0,37 (9,8) 0,77 (21,0) 16,5 5 0 0 (range) (0,17-0,56) (0,25- 0,53) (0,17-1,04) (1- 25) (0-25) (0-25) (0-7) (4,7-15,2) (6,6- 14,3) (4,7- 28,2)
# No second MIBG: PD death N=1, PD N=1, non-MIBG avid N=2, thrombocytopenia N=1
Table II: Interval times 131I-MIBG, dose of 131I-MIBG and response (INRC)
Feasibility, toxicity and response of upfront 131I-MIBG therapy 69 Overall
INRC response
CR VGPR PR MR NR PD TD NE N
Post Induction 8 2 10 1 0 9 2 0 32 Post MAT + ASCT 9 5 5 0 0 11 2 0 32 131I-MIBG treatment
INRC response
CR VGPR PR MR NR PD TD NE N
Post MIBG 0 3 5 5 2 5 0 1 21 Post Induction 7 2 7 0 0 5 0 0 21 Post MAT +ASCT 8 2 5 0 0 6 0 0 21 no 131I-MIBG treatment
INRC response
CR VGPR PR MR NR PD TD NE N
Post Induction 1 0 3 1 0 4 2 0 11 Post MAT + ASCT 1 3 0 0 0 5 2 0 11
INRC: International Neuroblastoma Response Criteria (23) CR= complete response, VGPR= very good partial reponse, PR= partial response, MR= mixed response, NR= no response, DOD= died of progressive disease (PD), NE= not evaluable, TD= toxic death RR: response rate (CR, VGPR and PR), MIBG= Metaiodo-benzylguanidine therapy, ASCT= autologous stem cell transplantation Table IV: Response according to the INRC criteria (ITT)
131I-MIBG treatment The median (range) interval from diagnosis to MIBG-I was 9 (1-15) days (Table II). Twenty out of 21 patients received MIBG within 14 days. Due to logistic reasons for 1 patient, it took 15 days before MIBG treatment could be started. The median (range) interval of MIBG-I to MIBG-II was 28 (median) (with a range of 19-43) days (N=16), 14/16 patients received 131I-MIBG-II (<28- 35 days). The interval MIBG-II to N5I was 29 (21-49) days. The median (range) AA of MIBG-I was 0.45 (0.17-0.56) GBq/kg (12.0 (4.7-15.2) mCi/kg); -MIBG-II was 0.37 (0.25-0.53) GBq/kg (9.8 (6.6- 14.3) mCi/kg). For the patients receiving 2 courses of 131I-MIBG, the cumulative AA 131I-MIBG was 0.85 (0.63-1.04) GBq/kg and 23.0 (17.1-28.2) mCi/kg), for the patients receiving only 1 course of 131I-MIBG the median AA was 0.41 (0.17-0.56) GBq/kg and 11.1 (4.7- 15.2) mCi/ kg.
Chemotherapy courses: The median (range) interval between courses of chemotherapy (N5I- N6III) was 25 (23- 27) days in the 131I-MIBG group, 22 (20- 26) days in the chemotherapy group, and overall 24 (21- 26). The interval between
70 Chapter 4 131I-MIBG treatment No 131I-MIBG treatment Overall
Harvest: (N) 17 8 25 Number of harvest sessions 1 (1-3) 1.5 (1-2) 1 (1-3) Type of harvest: PBSC 16 7 23 BM 2* 1 3 Yield of harvest: (CD34+ x 106/kg) PBSC 5,5 (0,8 - 32.3) 3,5 (1.2-7,1) 4,4 ( 0,8-32,3) BM 15,9 (0,3-31.4) 6,6 6,6 (0,3-31,4) ASCT: Reinfusions 16 5 21 No reinfusions 1 3 4
N= number, PBSC: peripheral blood stem cell; BM: bone marrow; ASCT: autologous stem cell transfusion. Yield of harvest: median (range) x106/kg CD34+. *: poor PBSC harvest Table V: Harvest yield and reinfusion
N5-I to MAT ASCT was 26 (23- 33) days in the 131I-MIBG group and 23 (20- 30) days in the chemotherapy group, and overall 25 (21- 32) days (Table III).
Response The RR post induction was 20/ 32 (63%) and post MAT ASCT 19/32 (59%). The progression rate was 11/32 (34%). In the 131I-MIBG group the RR post 131I-MIBG was 8/21 (38%), post induction 16/21 (76%) and post MAT ASCT 15/21 (71%) (Table IV).
The median Curie score for the 131I-MIBG group at diagnosis was 16,5 (median) with a range of 1-25, after 2 courses of MIBG 5 (0-25), post induction 0 (0-25), post MAT ASCT 0 (0-7), respectively. This is a decrease of 70% between diagnosis and the end of two courses of MIBG and 100% between diagnosis and post MAT and ASCT (Table II). The relative extension score was 0.5 or less, after 2 courses of MIBG in 10/21 patients (48%) and post MAT and ASCT in 14/16 patients (88%). For the chemotherapy group, the median Curie score was at diagnosis 8 (range 0-24), post induction 4 (0-16), post MAT ASCT 2 (0-14). This is a decrease of 75% between diagnosis and post MAT ASCT. The relative extension score post MAT and ASCT was 0.5 or less in 4/6 patients (66%) (data not shown).
Following MIBG-II, 5 patients developed PD, of which 4 continued with chemotherapy and showed response, 1 patient died. Furthermore, 4 patients had PD during induction (N=1 post N6-I and N=3 post N6-III). Sixteen
Feasibility, toxicity and response of upfront 131I-MIBG therapy 71 EFS and OS whole cohort
100 EFS 80 OS
60
40
Percent survival Percent 20
0 0 2 4 6 8 time from diagnosis (years)
3 yrs EFS= 40%, 3yrs OS= 57% EFS= event free survival, OS= overall survival (n=32). Analysed till 1-1-2012 Figure 3: EFS and OS whole cohort
patients proceeded to MAT ASCT. One other patient developed PD post MAT ASCT. The overall progression rate was 6/ 21 patients (29%) from diagnosis to MAT ASCT. In the chemotherapy group the RR post induction and -MAT ASCT was 4/11 (36%). There were 4 patients that developed PD during induction (N=1 post N6-I, N=1 post N5-II and N=2 post N6-III), two patients died due to toxicity. Five patients went on to MAT ASCT. The progression rate was 5/11 (45%).
Hematological toxicity At diagnosis, the median (range) overall platelet count was 346 (64-746), comparable in the 2 groups. The nadir (range) of the platelets post MIBG I was 112 (17-393) and post MIBG II was 111 (20-206). In the 131I-MIBG group, the nadir of the platelet counts were lower compared to the chemotherapy group in between chemotherapy courses (data not shown). The planned interval between two chemotherapy courses, shown in Table III, is more informative. Especially, since this interval (median) was slightly longer (25 days) in the MIBG group than in the chemotherapy group (22 days) and overall 24 days.
72 Chapter 4 Stem cell harvest yield and reinfusion In the 131I-MIBG group, in 17 of 21 patients (81%), stem cells were harvested in 1 (median, range 1-3) session (Table V). Two patients had a yield of peripheral stem cell harvest of < 2.0 x 106/kg CD34+ and needed an additional BM harvest. The yield of PBSC harvested stem cells was 5.5 (0.8-32.3), median (range), and BM harvest 15.9 (0.3-31.4) x 106/kg CD34+. Sixteen out of 17 (94%) patients proceeded to MAT with reinfusion of their stem cells. In the chemotherapy group, 8 out 11 patients (73%) stem cells were successfully harvested, with a median (range) number of harvest sessions of 1.5 (1-2) and one patient had a yield of PBSC harvest < 2.0 x 106/kg CD34+, and also underwent an additional BM harvest. The yield of PBSC harvested stem cells was 3.5 (1.2- 7.1), median (range), and BM harvest 6.6 x 106/kg CD34+. Five out of 8 (63%) of the patients proceeded to MAT + ASCT. Overall, harvest was performed in 25/32 (78%) patients, failure to harvest PBSC occurred in 3/25 (12%) of the patients. There was no significant difference in harvest results between the 2 groups of patients (Table V).
The platelet recovery (> 20 x 109/L) post MAT + ASCT in median (range) days was: 25 (12-194) in the 131I-MIBG group and 14 (14-48) days for chemotherapy group. The neutrophil recovery (neutrophils > 0.5 x 109/L) post MAT + ASCT in median (range) days was comparable: 131I-MIBG group 11 (8-34); chemotherapy group 11 (10-18) days (Table V).
Outcome The 3 year OS in our patient cohort was 57% and the 3 year EFS was 40% (Figure 3). The 3 year OS/ EFS in patients having received 131I-MIBG therapy was 63/ 47% vs. chemotherapy group 46/ 27%.
Discussion This pilot study shows that it is feasible to start upfront 131I-MIBG therapy within 2 weeks after diagnosis of NBL. The cumulative administered 131I-MIBG dose of 0.85 (0.637-1.04) GBq/ kg (23.0 (17.1-28.2) mCi/ kg), is high compared to doses reported in other 131I-MIBG studies (18). This high cumulative administered 131I-MIBG therapy dose, could be given to newly diagnosed stage 4 neuroblastoma patients (being chemo-naïve). The median interval between chemotherapy courses was 25 days. In the patients receiving 131I-MIBG the median intervals were slightly longer. Our interval of 25 days is in concordance with the GPOH NB 97 (27 days)/ -04 (22 days) studies (personal communication F Berthold).
Our study shows a post induction RR of 63% and post MAT and ASCT of 59%. This RR as a whole is comparable, but not superior to RR reported in other 131I-MIBG therapy studies in newly diagnosed patients(3;23-24). The SIOPEN group reports 21% not in CR after induction. The COG group describes RR
Feasibility, toxicity and response of upfront 131I-MIBG therapy 73 between 69-73% (CR, VGPR and PR). In consecutive GPOH studies, after 6-8 courses of chemotherapy (end of induction), RR 69-87% (CR, VGPR and PR) are reported. In the 131I-MIBG group the RR post 131I-MIBG was 38%, post induction 76% and post MAT ASCT 71%. In the chemotherapy group the RR post induction and -MAT ASCT was 36%. Overall, the patients in the 131I-MIBG group had a better RR and survival than patients in the chemotherapy group. We think that the chemotherapy group patients were sicker compared to 131I-MIBG group, with a higher median Curie score at diagnosis, this is a potential selection bias. Furthermore, this being a non-randomized study, any comparison should be interpreted carefully. Also, both groups had a high percentage of MNA, however other studies by Pearson and Kreisman et. al. have reported similar percentages (33-44%) (23;25).
Several studies have reported that approximately one third of patients treated with administered activity > 12 mCi/kg 131I-MIBG, require support with ASCT to prevent for prolonged myelosupression, especially thrombocytopenia (11;15;26;27). In our study, despite the high doses of administered 131I-MIBG, no stem cell support was needed. The platelet toxicity (median nadir) after each 131I-MIBG course was very mild, in the 131I-MIBG group, the nadir of the platelet counts were lower compared to the chemotherapy group in between chemotherapy courses, but without delay in recovery. The addition of MIBG therapy did not result in a substantial delay in chemotherapy intervals. Over time, the intervals between chemotherapy courses have decreased due to a learning curve. In our study it was feasible to harvest stem cells in 78% of the patients, and there was no difference between the 2 groups. The yield of the stem cells was comparable to data reported in the literature (28). The platelet recovery post MAT + ASCT took longer in the 131I-MIBG group than in the chemotherapy group, but was similar to the recovery times reported in the literature (28;29).
A limitation of this pilot study is the small number and selection bias of patients receiving upfront 131I-MIBG therapy, since patients in poor clinical condition at diagnosis did not receive upfront 131I-MIBG therapy. Strength of this study is, that patients have been treated in only 2 centres, making the set of data very uniform and complete.
The optimal time point for the incorporation of 131I-MIBG therapy in stage 4 NBL treatment protocols is still not defined. Even if patients are in CR, prior to MAT ASCT, post 131I-MIBG scans can reveal MIBG avid lesions (not avid on 123I-MIBG), suggesting that there is (minimal) residual NBL disease (17). For future studies, we consider giving 131I-MIBG before MAT + ASCT, in order to intensify this therapy.
Conclusion Induction therapy with 131I-MIBG prior to the HR GPOH NB 2004 protocol is feasible, tolerable and effective in newly diagnosed stage 4 neuroblastoma patients.
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2. Simon T, Berthold F, Borkhardt A, Kremens 7. Messina JA, Cheng SC, Franc BL, B, De CB, Hero B. Treatment and outcomes Charron M, Shulkin B, To B et al. of patients with relapsed, high-risk Evaluation of semi-quantitative scoring neuroblastoma: results of German trials. system for metaiodobenzylguanidine Pediatr Blood Cancer 2011 April;56(4):578-83. (mIBG) scans in patients with relapsed neuroblastoma. Pediatr Blood Cancer 2006 3. Matthay KK, Villablanca JG, Seeger RC, Stram December;47(7):865-74. DO, Harris RE, Ramsay NK et al. Treatment of high-risk neuroblastoma with intensive 8. Matthay KK, Edeline V, Lumbroso J, chemotherapy, radiotherapy, autologous bone Tanguy ML, Asselain B, Zucker JM et al. marrow transplantation, and 13-cis-retinoic Correlation of early metastatic response by acid. Children’s Cancer Group. N Engl J Med 123I-metaiodobenzylguanidine scintigraphy 1999 October 14;341(16):1165-73. with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol 2003 4. Yu AL, Gilman AL, Ozkaynak MF, London July 1;21(13):2486-91. WB, Kreissman SG, Chen HX et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and 9. Hattner RS, Huberty JP, Engelstad BL, isotretinoin for neuroblastoma. N Engl J Med Gooding CA, Ablin AR. Localization 2010 September 30;363(14):1324-34. of m-iodo(131I)benzylguanidine in neuroblastoma. AJR Am J Roentgenol 1984 5. Berthold F, Boos J, Burdach S, Erttmann R, August;143(2):373-4. Henze G, Hermann J et al. Myeloablative megatherapy with autologous stem-cell 10. Klingebiel T, Berthold F, Treuner J, rescue versus oral maintenance Schwabe D, Fischer M, Feine U et al. chemotherapy as consolidation treatment Metaiodobenzylguanidine (mIBG) in in patients with high-risk neuroblastoma: a treatment of 47 patients with neuroblastoma: randomised controlled trial. Lancet Oncol results of the German Neuroblastoma Trial. 2005 September;6(9):649-58. Med Pediatr Oncol 1991;19(2):84-8.
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Feasibility, toxicity and response of upfront 131I-MIBG therapy 75 A, Huberty J, Cheng SC et al. Phase II January;16(1):229-36. study on the effect of disease sites, age, and prior therapy on response to iodine- 16. Voute PA, Hoefnagel CA, de KJ, Valdes 131-metaiodobenzylguanidine therapy in OR, Bakker DJ, van de Kleij AJ. Results of refractory neuroblastoma. J Clin Oncol 2007 treatment with 131 I-metaiodobenzylguanidine March 20;25(9):1054-60. (131 I-MIBG) in patients with neuroblastoma. Future prospects of zetotherapy. Prog Clin 12. Hutchinson RJ, Sisson JC, Miser JS, Zasadny Biol Res 1991;366:439-45. KR, Normolle DP, Shulkin BL et al. Long-term results of [131I]metaiodobenzylguanidine 17. Johnson K, McGlynn B, Saggio J, Baniewicz D, treatment of refractory advanced Zhuang H, Maris JM et al. Safety and efficacy neuroblastoma. J Nucl Biol Med 1991 of tandem 131I-metaiodobenzylguanidine October;35(4):237-40. infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 2011 13. Lashford LS, Lewis IJ, Fielding SL, Flower December 15;57(7):1124-9. MA, Meller S, Kemshead JT et al. Phase I/II study of iodine 131 metaiodobenzylguanidine 18. Wilson JS, Gains JE, Moroz V, Wheatley K, in chemoresistant neuroblastoma: a Gaze MN. A systematic review of 131I-meta United Kingdom Children’s Cancer Study iodobenzylguanidine molecular radiotherapy Group investigation. J Clin Oncol 1992 for neuroblastoma. Eur J Cancer 2014 December;10(12):1889-96. March;50(4):801-15.
14. Lumbroso J, Hartmann O, Schlumberger 19. Brodeur GM, Seeger RC, Barrett A, Berthold F, M. Therapeutic use of [131I] Castleberry RP, D’Angio G et al. International metaiodobenzylguanidine in neuroblastoma: criteria for diagnosis, staging, and response a phase II study in 26 patients. “Societe to treatment in patients with neuroblastoma. Francaise d’Oncologie Pediatrique” and J Clin Oncol 1988 December;6(12):1874-81. Nuclear Medicine Co-investigators. J Nucl Biol Med 1991 October;35(4):220-3. 20. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP et al. 15. Matthay KK, DeSantes K, Hasegawa Revisions of the international criteria for B, Huberty J, Hattner RS, Ablin A neuroblastoma diagnosis, staging, and et al. Phase I dose escalation of response to treatment. J Clin Oncol 1993 131I-metaiodobenzylguanidine with August;11(8):1466-77. autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 1998 21. van Santen HM, de KJ, van Eck BL, de
76 Chapter 4 Vijlder JJ, Vulsma T. High incidence of Lancet Oncology, 2013 July;14(10):999–1008. thyroid dysfunction despite prophylaxis with potassium iodide during (131)I-meta- 26. DuBois SG, Messina J, Maris JM, iodobenzylguanidine treatment in children Huberty J, Glidden DV, Veatch J et al. with neuroblastoma. Cancer 2002 April Hematologic toxicity of high-dose iodine- 1;94(7):2081-9. 131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol 2004 22. Matthay KK, Shulkin B, Ladenstein R, June 15;22(12):2452-60. Michon J, Giammarile F, Lewington V et al. Criteria for evaluation of disease 27. Goldberg SS, DeSantes K, Huberty JP, extent by (123)I-metaiodobenzylguanidine Price D, Hasegawa BH, Reynolds CP et al. scans in neuroblastoma: a report for the Engraftment after myeloablative doses of International Neuroblastoma Risk Group 131I-metaiodobenzylguanidine followed by (INRG) Task Force. Br J Cancer 2010 April autologous bone marrow transplantation for 27;102(9):1319-26. treatment of refractory neuroblastoma. Med Pediatr Oncol 1998 June;30(6):339-46. 23. Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D. High-dose rapid and 28. Yanik GA, Levine JE, Matthay KK, Sisson standard induction chemotherapy for patients JC, Shulkin BL, Shapiro B et al. Pilot study aged over 1 year with stage 4 neuroblastoma: of iodine-131-metaiodobenzylguanidine a randomised trial.; European Neuroblastoma in combination with myeloablative Study Group; Children’s Cancer and chemotherapy and autologous stem-cell Leukaemia Group (CCLG formerly United support for the treatment of neuroblastoma. Kingdom Children’s Cancer Study Group). J Clin Oncol 2002 April 15;20(8):2142-9. Lancet Oncol. 2008 Mar;9(3):247-56 29. Pradhan KR, Johnson CS, Vik TA, Sender LS, 24. Simon T, Hero B, Faldrum A, Handgretinger R, Kreissman SG. A novel intensive induction Schrappe M, Klingebiel T and Berthold F. Long therapy for high-risk neuroblastoma utilizing term outcome of high-risk neuroblastoma sequential peripheral blood stem cell patients after immunotherapy with antibody collection and infusion as hematopoietic ch14.18 or oral metronomic chemotherapy. support. Pediatr Blood Cancer 2006 June;46(7):793-802. 25. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. The
Feasibility, toxicity and response of upfront 131I-MIBG therapy 77
Chapter 5 Iodine-131-meta-iodobenzyl- guanidine therapy for patients with high risk neuroblastoma (Cochrane)
Kraal KCJM, van Dalen EC, Tytgat GAM, van Eck-Smit BLF, Caron HC. Cochrane protocol: “Iodine-131-meta-iodobenzylguanidine therapy for patients with high risk neuroblastoma”.
The Cochrane Library 2013, Issue 2.
Full review Kraal KCJM, van Dalen EC, Tytgat GAM, van Eck-Smit BLF. Cochrane protocol: “Iodine-131-meta-iodobenzylguanidine therapy for patients with high risk neuroblastoma”.
Submitted for publication Abstract Background Newly diagnosed high risk (HR) neuroblastoma (NBL) patients still have a poor outcome, despite multi-mo- dality intensive therapy. This poor outcome necessitates the search for new therapies, such as treatment with 131I-MIBG.
Objectives To assess the efficacy and adverse effects of131 I-MIBG therapy in patients with newly diagnosed high-risk NBL.
Search methods We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 3), MEDLINE (PubMed) (1945 to 25 April 2016) and EMBASE (Ovid) (1980 to 25 April 2016). In addition, we hand searched reference lists of relevant articles and reviews. We also assessed the conference proceedings of the International Society for Paediatric Oncology, Advances in Neuroblastoma Research and the American Society of Clinical Oncology; all from 2010 up to and including 2015. We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institutes of Health Register for ongoing trials (https://www.clinical- trials.gov); both registers were searched on 13 April 2016.
Selection criteria Randomised controlled trials (RCTs), clinically controlled trials (CCTs), non-randomised single-arm trials with historical controls and cohort studies including 10 patients or more examining the efficacy of131 I-MIBG therapy in patients with newly diagnosed high-risk NBL.
Data collection and analysis Two review authors independently performed the study selection, risk of bias assessment and data extraction.
Main results We identified 2 eligible cohort studies including 60 newly diagnosed HR NBL patients. All studieshad methodological limitations, with regard to both internal (risk of bias) and external validity. As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. In one study the objective response rate (ORR) was 73% after surgery; the median overall survival was 15 months (95% CI 7 to 23 months); 5-year overall survival was 14.6%; median event-free survival was 10 months (95% CI 7 to 13 months); 5-year event-free survival was 12.2%. In the other study the ORR was 56% after myeloablative therapy and autologous stem cell
80 Chapter 5 transplant; the 10-year overall survival was 6.25%; event-free survival was not reported. With regard to short-term adverse effects one study showed a prevalence of 2% (95% CI 0 to 13%; best case scenario) for death due to myelosuppression. After the first cycle of 131I-MIBG therapy in one study platelet toxicity was found in 38% (95% CI 18 to 61%), neutrophil toxicity in 50% (95% CI 28 to 72%) and Hb toxicity in 69% (95% CI 44 to 86%); after the second cycle this was 60% (95% CI 36 to 80%) for platelets and 53% (95% CI 30 to 75%) for neutrophils and Hb. In one study the prevalence of hepatic toxicity during or within 4 weeks after last the MIBG treatment was 0% (95% CI 0 to 9%; best case scenario). Both studies did not report on cardiovascular toxicity and sialoadenitis. One study assessed long-term adverse events in part of the patients: elevated plasma TSH was found in 45% (95% CI 27 to 65%); in all patients the free T4 was within the age related normal range (0%, 95% CI 0 to 15%). No secondary malignancies were observed (0%, 95% CI 0 to 9%), but only 5 patients survived more than 4 years.
Authors’ conclusions No RCTs or CCTs comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in newly diagnosed HR NBL patients were identified. Two small observational studies were identified, but, besides the associated high risk of bias, not for all relevant outcomes results were available. Also, it should be kept in mind that recently the age cut-off for high-risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate risk disease were included in the high risk groups. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in newly diagnosed high-risk neuroblastoma patients in clinical practice. More high quality research is needed.
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 81 Plain language summary Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high-risk neuroblastoma
Review question We reviewed the evidence of the efficacy and adverse effects of 131I-MIBG therapy in patients with newly diagnosed high-risk (HR) neuroblastoma (NBL).
Background Newly diagnosed HR NBL patients still have a poor outcome, despite intensive treatments. This poor outcome makes it necessary to search for new therapies, such as treatment with 131I-MIBG, which is a type of targeted radiotherapy.
Study characteristics The evidence is current to April 2016. We found 2 cohort studies (60 patients) addressing 131I-MIBG treatment in patients with newly diagnosed HR NBL.
Key results As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), it was not possible to combine the results. Not for all relevant outcomes results were available. Response rates were 56% and 73%, but survival is still poor: the median overall survival duration is 15 months, the median event-free survival duration is 10 months. The 5-year overall survival is 14.6%, 10-year overall survival 12.2%. With regard to short-term adverse effects, hematological toxicity (low blood counts) did occur. Liver toxicity was not identified (best case scenario). The studies did not report on cardiovascular toxicity and sialoadenitis. One study assessed long-term adverse events in part of the patients: thyroid toxicity occurred, but no secondary malignancies were observed. It should be kept in mind that recently the age cut-off for HR disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease were included in the HR groups. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in newly diagnosed HR NBL patients in clinical practice. More high quality research is needed before definite conclusions can be made.
Quality of the evidence All studies had problems relating to quality of the evidence.
82 Chapter 5 Background Description of the condition Neuroblastoma (NBL) is the most common extra cranial solid tumour of childhood, derived from the sympathetic nervous system (Gurney 1996). The median age of diagnosis is 18 months. According to the International NBL Staging System (INSS), NBL is classified in four stages, 1 to 4, with a special stage termed 4S. Children with stage 4 NBL present with metastatic disease at diagnosis, mainly involving lymph nodes and bone marrow. Traditionally, the defining characteristics of high-risk NBL included an age of more than one year, metastatic disease, unfavourable Shimada histology and MYCN amplification (Bernstein 1992; Shimada 1995; Shimada 1999). In recent years an age cut-off of 18 months is discovered and implemented for pre-treatment risk stratification, as opposed to the traditional cut-off of one year (Cohn 2009). However, most currently published studies use the old definition. Current high-risk treatment consists of intensive multi-agent chemotherapy induction (Peinemann 2015b), extensive surgical resection of the primary tumour, external beam irradiation of residual primary tumour, myelo-ablative chemotherapy (Yalcin 2015) and maintenance with differentiation and immunotherapy (Peinemann 2015a). Despite this very intensive treatment, children with advanced-stage high-risk NBL still have a poor prognosis; the long-term survival is less than 40%. This poor outcome necessitates the search for new therapies (Matthay 1999; Simon 2011).
Description of the intervention The majority of NBL tumours accumulate meta-iodobenzylguanidine (MIBG). When radiolabeled with 123I-, MIBG can be used for imaging and when labelled with 131I- it can be used as a form of targeted radiotherapy (Bleeker 2015; Hattner 1984; Suc 1996). In various studies around the world, the radiopharmaceutical 131I-MIBG has shown to have a significant antitumour effect against NBL (Hutchinson 1991; Klingebiel 1991a; Klingebiel 1991b; Lashford 1992; Lumbroso 1991; Matthay 1998; Matthay 2007; Simon 2011; Voute 1991). More than 95% of NBL tumours are able to accumulate 131I-MIBG actively (Leung 1997). Given the unsatisfactory results of high-intensity induction chemotherapy it is rational to add 131I-MIBG, as ‘targeted radiotherapy’, to the treatment of high-risk NBL.
Extensive experience exists with 131I-MIBG treatment of children with NBL. Hoefnagel et al reported the value of 131I-MIBG in the detection of NBL (Hoefnagel 1985). In the following years it became clear that there was also a role for therapeutic use of 131I-MIBG. Initially 131I-MIBG therapy was given to patients with recurrent NBL (Matthay 1998; Matthay 2001). After some time, a second group of patients was included, patients with residual disease after chemotherapy and surgery. From these studies it became clear that the most prominent response was obtained in patients with a large tumour burden at the time of 131I-MIBG treatment (Matthay 1998; Matthay 2001). This finding has served as the basis for a study performed in Amsterdam, with the objectives to document response in untreated children with stage IV or non-operable stage III disease, and to further characterise the side-effects of 131I-MIBG treatment. The study was closed in 1999. In summary, 131I-MIBG therapy has a very high response rate at induction of
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 83 high-risk NBL patients and can be combined with induction chemotherapy followed by mega-therapy and autologous stem cell transplantation. In this study, the chemotherapy was not dose intense and since then we have learned that dose intense chemotherapy results in better outcome (De Kraker 2008). The current Dutch Childhood Oncology group high-risk NBL 2009 treatment protocol combines upfront 131I-MIBG with induction chemotherapy followed by mega-therapy and ASCT.¬Matthay et al. reported in 2009 the results of a phase I study in refractory or relapsed high-risk NBL patients. It showed that closely spaced infusions of 131I-MIBG can be administered safely using autologous stem cell transplantation without dose-limiting non-haematological toxicity and with rapid and reliable reconstitution of haematopoiesis (Matthay 2009-2).
How the intervention might work 131I-MIBG is a radiopharmaceutical; it is a radio labelled molecule similar to noradrenalin which can be taken up by NBL tissue (Hattner 1984). When NBL has taken up the 131I-MIBG (gamma and beta emitting isotope), its beta particles will irradiate neighbouring tissue with a median range of 1 cm causing cell death by double strand DNA breaks and damage to lipid bilayer (Hutchinson 1991; Matthay 2007).
Why it is important to do this review At the moment the prognosis for high-risk NBL patients is still very poor. Relapses remain common, despite the achievement of a complete clinical remission after induction therapy. The place of 131I-MIBG¬in newly diagnosed high-risk treatment is not yet well established.
Objectives To assess the efficacy and adverse effects of131 I-MIBG therapy in patients with newly diagnosed high-risk NBL.
Methods Criteria for considering studies for this review Types of studies We included all randomised controlled trials (RCTs), clinically controlled trials (CCTs), non-randomised single-arm trials with historical controls and cohort studies examining the efficacy of 131I-MIBG therapy in patients with newly diagnosed high-risk NBL. Cross-sectional studies, case-reports and case series (i.e. a series of non-consecutive patients) were excluded. A cohort study was defined as a study in which a group of consecutive patients treated for high-risk NBL was followed from diagnosis onwards. The described study could be the original cohort or a subgroup of the original cohort based on well defined inclusion criteria. We excluded studies including less than 10 patients.
84 Chapter 5 Types of participants Patients with newly diagnosed high-risk NBL. The defining characteristics of high-risk NBL include an age of more than one year, regional or metastatic disease, unfavourable Shimada histology or MYCN amplification. Patients with esthesioneuroblastoma and/or newly diagnosed patients who received prior chemotherapy were excluded. If studies included both eligible and non-eligible patients the results of eligible patients should have been seperately available in order to be included in the review.
Types of interventions 131I-MIBG therapy.
Types of outcome measures Primary outcomes • Response as measured by the International Neuroblastoma Response Criteria (Brodeur 1993) • Overall survival (as defined in the original study) • Event-free survival, defined as the time span that follows therapy during which there are no objective signs of recurrence or other events (as defined in the original study) • Adverse events, as defined in the original studies. We particularly looked at haematological, cardiovascular, hepatic problems and sialoadenitis as short-term events. Long-term events were thyroid dysfunction and secondary malignancies
Secondary outcomes • Dose intensity after 131I-MIBG treatment: the actual administered amount of 131I-MIBG in mega Becquerel/micro Curie (MBq/mCi) • Time span of delivering chemotherapy induction treatment after 131I-MIBG therapy • Yield of peripheral stem cell collection during harvest sessions (defined as the mean number of collected autologous haematopoeitic stem cells) • Number of successful peripheral stem cell harvests (defined as more than 2x106/kg autologous haematopoeitic stem cells) • Number of peripheral stem cell harvest sessions necessary to obtain a sufficient amount of autologous haematopoeitic stem cells (i.e. more than 2x106/kg autologous haematopoeitic stem cells) • Percentage of patients in which bone marrow harvest is performed • Stem cell engraftment defined as the time to haematopoeitic recovery after myeloablative chemotherapy and autologous stem cell transplantation were measured for each of the haematopoeitic cell lineages • Stem cell harvest could have taken place at any stage of the treatment protocols (i.e. before or after 131I-MIBG therapy).
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 85 Search methods for identification of studies We did not impose language restrictions.
Electronic searches We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 3 2016), MEDLINE in PubMed (from 1945 to 25 April 2016) and EMBASE in Ovid (from 1980 to 25 April 2016).The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in the appendices (Appendix 1; Appendix 2; Appendix 3).
Searching other resources We located information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We handsearched the conference proceedings of the International Society for Paediatric Oncology, Advances in Neuroblastoma Research and the American Society of Clinical Oncology published from 2010 up to and including 2015. We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn. com) and the National Institute of Health Register for ongoing trials (https://www.clinicaltrials.gov); both registers were searched on 13 April 2016 using this search strategy: (131I-MIBG OR 131I-meta-iodobenzyl- guanidine) AND neuroblastoma.
Data collection and analysis Selection of studies After performing the search strategy described previously, two authors independently selected studies meeting the inclusion criteria. All discrepancies between reviewers were resolved by consensus. If this was not possible, final resolution was achieved by using a third-party arbitrator. We obtained in fulltext any study which seems to meet the inclusion criteria based on the title and/or abstract for closer inspection. We clearly stated details of reasons for exclusion of any study considered for this review. We have included a flow chart of the selection of studies in the review.
Data extraction and management Two authors independently performed data extraction using standardised data extraction forms. Discrepancies between authors were resolved by discussion. Data was extracted on the following items.
• Study characteristics, including: • design; • number of patients enrolled in the study;
86 Chapter 5 • number of patients fulfilling the pre-defined inclusion criteria. • Participants characteristics, including: • gender • age at time of diagnosis (range, mean and/or median); • stage of disease according to the INSS; • tumour biology and genetic aberrations (MYCN amplified and loss of heterozygosity chromosome 1P); • tumour localisation (primary and metastasis). • Interventions, including: • schedule of 131I-MIBG treatment and total amount of 131I-MIBG administered (MBq/mCi); • additive (radio-sensitizing) therapeutics (dose and schedule) during 131I-MIBG treatment and chemotherapy schedules thereafter. • Outcome measures (as described above) • Length of follow-up
Assessment of risk of bias in included studies Two authors independently performed the assessment of risk of bias of the included studies. If RCTs and CCTs would have been identified we would have used the risk of bias items as described in the module of Cochrane Childhood Cancer (Kremer 2012), which are based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The assessment of risk of bias in observational studies was based on previously described checklists according to Evidence-Based Medicine Criteria (Grimes 2002; Laupacis 2004). See Table 1 for the definitions of the different risk of bias criteria. For attrition bias, detection bias and outcome reporting bias (i.e. biases that can be assessed for each outcome separately) we only assessed the risk of bias for the primary outcomes. The risk of bias in included studies was taken into account in the interpretation of the review’s results. We resolved discrepancies between reviewers by consensus.
Measures of treatment effect If a control group would have been available dichotomous variables would have been analysed using risk ratios (RRs); continuous outcomes would have been analysed using mean differences (MDs); survival would have been analysed using hazard ratios (HRs). We would have used the Parmar’s method if HRs had not been explicitly presented in the study (Parmar 1998). However, as all included studies did not have a control group we used the prevalence (and corresponding 95% confidence intervals (CI)) to analyse tumour response and adverse effects; other outcomes were summarised descriptively.
Dealing with missing data When relevant data regarding study selection were missing, we contacted the study authors to retrieve the missing data. If RCTs or CCTs would have been included we would have extracted data by the allocated
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 87 intervention, irrespective of compliance with the allocated intervention, in order to allow an intention-to-treat analysis. If this was not possible, we would have stated this and we would have performed an ‘as treated’ analysis.
Assessment of heterogeneity As pooling of results was not possible assessment of heterogeneity was not applicable. Otherwise we would have assessed heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, that is the I2 statistic. In the absence of significant heterogeneity (I2 < 50%) (Higgins 2011), we would have used a fixed-effect model for the estimation of treatment effects. Otherwise, we would have explored possible reasons for the occurrence of heterogeneity and we would have taken appropriate measures.
Assessment of reporting biases In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we would have assessed reporting bias by constructing a funnel plot when there would have been a sufficient number of included studies (that is at least 10 studies included in a meta-analysis). When there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011). As pooling of results was not possible this was not applicable.
Data synthesis We entered data into Cochrane’s statistical software, Review Manager (Review Manager 2014), and undertook analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We included outcome measures only if it was the intention of the study to perform the necessary assessments in all patients (that is, not only optional or only performed in some centres). We performed pooling of results only if studies were comparable with regard to important prognostic factors [i.e. age, stage according to INSS (bone marrow involvement), mycN amplification and loss of chromosome 1P], treatment and used outcome definitions. Different study designs were taken into account in the analyses. Studies for which pooling of results was not possible were summarised descriptively. We used the Wilson method to calculate the corresponding 95% CIs of the prevalences. As this was not possible in RevMan we used the following tool: http://epitools.ausvet.com.au/content.php?pa- ge=CIProportion&SampleSize=375&Positive=3&Conf=0.95&Digits=4.
Sensitivity analysis For all outcomes for which pooling was possible we would have performed sensitivity analyses for all risk of bias criteria separately. We would have excluded studies with a high risk of bias and studies for which the risk of bias was unclear and compared the results of studies with a low risk of bias with the results of all available studies. As pooling of results was not possible this was not applicable.
88 Chapter 5 Results
Description of studies Results of the search Running the searches in the electronic databases of CENTRAL, MEDLINE (PubMed) and EMBASE (Ovid) yielded a total of 3366 references. Following initial screening of the titles, abstracts, or both, we excluded 3304 references which clearly did not meet all criteria required for considering studies for this review. The 62 remaining references were assessed in full, of which 2 fulfilled all the criteria for considering studies for this review and were thus eligible for inclusion. Three articles are awaiting classification (see Characte- ristics of studies awaiting classification table) and the other 57 references were excluded for the reasons described in the Characteristics of excluded studies table.
Scanning the reference lists of the included articles and reviews did not identify any additional eligible studies. By scanning the conference proceedings we identified 3 additional studies (see Characteristics of studies awaiting classification) and by scanning the ongoing trials databases we identified 1 possible ongoing study (see Characteristics of ongoing studies table).
In summary, 2 studies were eligible for inclusion in the review; six studies are awaiting classification, 57 were excluded and 1 is ongoing. See Figure 1 1 for a flow diagram of the selection of studies for this systematic review.
Included studies The characteristics of the included studies are summarised below. For more detailed information see the Characteristics of included studies table. We identified a single-center prospective cohort study (De Kraker 2008) and a multi-center prospective phase II windows study (Kraal 2015), both conducted in the Netherlands. The total number of patients with newly diagnosed high risk neuroblastoma included in these studies was 60; in both studies (De Kraker 2008, Kraal 2015) it was described that the patients had metastatic disease, i.e. INSS stage 4. Patients were aged between 1 and 15.4 years at diagnosis. In one study patients received 131I-MIBG single agent therapy (De Kraker 2008), while in the other study patients received 131I-MIBG in combination with topotecan (Kraal 2015). For complete detailed treatment information see the Characteristics of included studies table. None of the studies reported the length of follow-up.
Risk of bias in included studies See the risk of bias section of the Characteristics of included studies table and Figure 2 for the exact scores per study and the support for the judgements made. We have looked both at internal and external validity. Internal validity Selection bias
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 89 Figure 1: Flow diagram of study selection
For evaluating selection bias we have assessed if there was a representative study group. In both studies the risk of selection bias was low.
Attrition bias For evaluating attrition bias we have assessed the completeness of follow-up for the different primary outcomes. Both studies assessed response, overall survival and hematological toxicity; for the first
90 Chapter 5 Representative study group (selection bias) study group Representative Complete follow-up assessment (attrition bias): response survival Complete follow-up assessment (attrition bias): event-free survival Complete follow-up assessment (attrition bias): overall toxicity Complete follow-up assessment (attrition bias): hematological Complete follow-up assessment (attrition bias): hepatic toxicity dysfunction Complete follow-up assessment (attrition bias): thyroid Complete follow-up assessment (attrition bias): secondary malignancies survival Blinded outcome assessor (detection bias): overall Blinded outcome assessor (detection bias): all other primary outcomes (reporting study group bias) Well-defined follow-up (reportingWell-defined bias) survival outcome (reportingoverall response and Well-defined bias): outcome (reportingtoxicity Well-defined bias): hematological outcome (reporting primaryWell-defined evaluated bias): all other outcomes
De Kraker 2008 + + + + ? ? - + + ? + ? + ? ? Kraal 2015 + + + + + ? + ? + +
Figure 2: Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.
2 outcomes the risk of attrition bias was low in both studies, for hematological toxicity the risk of bias was low in one study (Kraal 2015) and unclear in the other study (De Kraker 2008). De Kraker 2008 also assessed event-free survival (low risk of attrition bias), hepatic toxicity (unclear risk of attrition bias), thyroid disfunction (high risk of attrition bias) and secondary malignancies (low risk of attrition bias).
Detection bias For evaluating detection bias we have assessed if the outcome assessors were blinded to the investigated determinant for the different primary outcomes. For overall survival this was not applicable and therefore the risk of detection bias was judged to be low in both studies. For all other outcomes that were assessed in both studies the risk of detection bias was unclear.
External validity Reporting bias In both studies the study group was well-defined and the risk of reporting bias thus low. In both studies the length of follow-up was not mentioned, so the risk of reporting bias was unclear.
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 91 For overall survival the outcome is well-defined by default, so the risk of reporting bias was low in both studies assessing this outcome. Both studies also assessed response (low risk of reporting bias in both studies) and hematological toxicity (low risk of reporting bias in Kraal 2015, unclear risk of reporting bias in De Kraker 2008). For all other primary outcomes that were assessed in both studies the risk of reporting bias was unclear. Overall, neither of the 2 included studies scored good on all applicable reporting bias items.
Effects of interventions Not all articles allowed data extraction for all endpoints (see the Characteristics of included studies table for a more detailed description of the extractable endpoints from each article). As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. For response and adverse effects (both short-term and long-term) we used the Wilson method to calculate the prevalence and 95% CI; for all other outcomes we present results as described in the publications.
Response De Kraker 2008 used the International Neuroblastoma Response Criteria (Brodeur 1993) to define response. The objective response rate (ORR, i.e. complete response (CR), very good partial response (VGPR) or partial response (PR)) was evaluated at two different time points. After 2 cycles of 131I-MIBG therapy the ORR was 66% (95% CI 51 to 78%); 1 of the 41 patients had a CR and 26 had a PR. After surgery the ORR was 73% (95% CI 58 to 84%); 16 out of 41 patients had a CR, 1 a VGPR and 13 a PR. For the ORRs in 131I-MIBG only patients and 131I-MIBG + chemotherapy patients separately see Table 2. Kraal 2015 also used the International Neuroblastoma Response Criteria (Brodeur 1993) to define response. The ORR was evaluated at two different time points. After 2 cycles of 131I-MIBG therapy with topotecan the ORR was 56% (95% CI 33 to 77%); 1 of the 16 patients had a VGPR and 8 had a PR. After myeloablative therapy and autologous stem cell transplantation the ORR was also 56% (95% CI 33 to 77%); 5 of the 16 patients had a CR and 4 a PR.
Overall survival De Kraker 2008 provided no definition for overall survival. The median overall survival for all 41 patients was 15 months (95% CI 7 to 23 months); 5-year overall survival was 14.6%. Kraal 2015 also provided no definition for overall survival. The 10-year overall survival was 6.25%.
Event-free survival De Kraker 2008 provided no definition for this outcome. The median event-free survival for all 41 patients was 10 months (95% CI 7 to 13 months); 5-year event-free survival was 12.2%. Kraal 2015 did not report this outcome.
92 Chapter 5 Short-term adverse events Haematological adverse events De Kraker 2008 defined haematological adverse events as death due to myelosuppression. One patient died 43 days after stem cell reinfusion of a cerebral bleeding while still thrombocytopenic (no definition provided); the patient had received a cumulative dose of 800 mCi of MIBG. A toxic myelosuppression is highly suspective for the death. It was not clear if all patients were assessed for this outcome, but the best case scenario shows a prevalence of 2% (95% CI 0 to 13%). Kraal 2015 defined haematological adverse events as grade 3 or 4 according to the CTCAEv3 criteria. They assessed platelets, neutrophils and haemoglobin (Hb) at two different time points. After the first cycle of 131I-MIBG therapy with topotecan 6 out of 16 patients had grade 3 or 4 platelets (38%; 95% CI 18 to 61%), 8 out of 16 had grade 3 or 4 neutrophils (50%; 95% CI 28 to 72%) and 11 out of 16 had grade 3 or 4 Hb (69%; 95% CI 44 to 86%). After the second cycle of 131I-MIBG therapy with topotecan 9 out of 15 patients had grade 3 or 4 platelets (60%; 95% CI 36 to 80%), the same result was found for grade 3 or 4 neutrophils and 8 out of 15 patients had grade 3 or 4 Hb (53%; 95% CI 30 to 75%).
Cardiovascular adverse events Both De Kraker 2008 and Kraal 2015 did not report this outcome. Hepatic adverse events De Kraker 2008 defined hepatic adverse events as > grade 1, but no definition was provided. It was assessed during or within 4 weeks after last the MIBG treatment. It was not clear if all patients were assessed for this outcome, but the best case scenario shows a prevalence of 0% (95% CI 0 to 9%). Kraal 2015 did not report this outcome. Sialoadenitis Both De Kraker 2008 and Kraal 2015 did not report this outcome.
Long-term adverse events Thyroid dysfunction De Kraker 2008 tested thyroid function in 22 of the 41 patients (54%) before or after MIBG treatment. They looked at TSH (>4.5mU/l) and T4 (no cutoff point provided). Patients were measured at a median follow-up of 19 months (range 0.7 - 129 months). Ten out of 22 patients had an elevated plasma TSH (45%, 95% CI 27 to 65%), which was transient in 3 patients. It remained elevated in 7 patients of which 5 were prescribed thyroxine. In all 22 patients, the free T4 was within the age related normal range (0%, 95% CI 0 to 15%). Kraal 2015 did not report this outcome.
Secondary malignancies De Kraker 2008 provided no definition for secondary malignancies. None were observed (0%, 95% CI 0 to 9%), but only 5 patients survived more than 4 years.
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 93 Kraal 2015 did not report this outcome.
Dose intensity after 131I-MIBG treatment: the actual administered amount of 131I-MIBG mega Becquerel/ micro Curie (MBq/mCi) In De Kraker 2008 patients received a cumulative dose of 350–950 mCi (13–35GBq) 131I-MIBG (median 500 miC) as induction therapy. In Kraal 2015 the administered activity (AA) was median 0.5 (0.4-0.6) GBq/kg and 14.5 (10.1-16.8) mCi/ kg in the first cycle and median 0.4 (0.3-0.5) GBq/kg and 10.6 (6.9 12.6) mCi/kg in the second cycle. The cumulative administered activity was median 0.9 (0.5-1.1) GBq/kg and median 25 (14.3-29.4) mCi/kg.
Time span of delivering chemotherapy induction treatment after 131I-MIBG therapy De Kraker 2008 did not report this outcome. In Kraal 2015 the researchers aimed to give treatment at 4 week intervals. The actual mean interval time (range) between the second MIBG/topotecan and the first VECI chemotherapy course was 30 days (20-47). The mean interval time (range) for the subsequent VECI chemotherapy courses was 30 days (18-40) for the first course, 31 days (28-38) for the second course and 29 days (21-46) between the third and fourth course.
Stem cells Yield of peripheral stem cell collection during harvest sessions De Kraker 2008 did not report the mean number of collected autologous haematopeoitic stem cells, but they did report the median value for the 17 patients that underwent a stem cell harvest. In the first 8 patients it was 11.6x104/kg CFU-C colonies (range 2.9 to 31.6), while in the subsequent 9 patients the median was 4.9x106/kg CD34+ cells (range 1.2 to 17). Kraal 2015 did report the mean number of collected stem cells for the 13 patients that underwent a stem cell harvest: the mean yield of peripheral blood stem cells harvest was 2.2 (0 to 6.9)x106/kg CD34+ stem cells. For the bone marrow harvest this was 3.4 (1.0 to 9.1)x106/kg CD34+ stem cells.
Number of successful peripheral stem cell harvests De Kraker 2008 did not report this outcome. Kraal 2015 did not provide a definition for a succesful peripheral stem cell harvest, so we cannot be certain it was according our pre-specified definition of 2x106/kg autologous haematopoeitic stem cells. They reported that peripheral blood stem cell apheresis was succesful in 6 out of 13 patients (46%).
Number of peripheral stem cell harvest sessions necessary to obtain a sufficient amount of autologous haematopoeitic stem cells Both De Kraker 2008 and Kraal 2015 did not report this outcome.
94 Chapter 5 Percentage of patients in which bone marrow harvest is performed De Kraker 2008 did not report this outcome. In Kraal 2015 6 out of 13 patients (46%) underwent further bone marrow harvesting.
Stem cell engraftment defined as the time to haematopoeitic recovery after myeloablative chemotherapy and autologous stem cell transplantation for each of the haematopoeitic cell lineages De Kraker 2008 assessed this outcome for platelets and neutrophils, but not for haemoglobin (Hb). The median time to platelet engraftment (>50x103/ul) was 47 days. The median time to neutrophil engraftment (>1x10³/ul) was 23 days. Kraal 2015 also assessed this outcome for platelets and neutrophils, but not for Hb. The median time to platelet engrafment (>25x109/l) was 37 days (range 14-74 days). For neutrophil engraftment (>0.5x109/l) this was 21 days (range 12-62 days).
Discussion Summary of main results Newly diagnosed high risk (HR) neuroblastoma (NBL) patients still has a poor outcome, despite multi-mo- dality intensive therapy. This poor outcome necessitates the search for new therapies, such as treatment with 131I-MIBG. In this systematic review, we assessed the efficacy and adverse effects of131 I-MIBG therapy in patients with newly diagnosed high-risk NBL. We identified 2 prospective (cohort) studies investigating efficacy and toxicity of upfront131 I-MIBG therapy in newly diagnosed HR NBL patients. The first study included 44 patients (De Kraker 2008), the second study included 16 patients (Kraal 2015). As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. Response according to the INRC was assessed in both studies. In De Kraker 2008 the ORR was 73% after surgery. In Kraal 2015 the ORR was 56% after MAT and ASCT.
In De Kraker 2008 the median overall survival was 15 months (95% CI 7 to 23 months); 5-year overall survival was 14.6%. The median event-free survival was 10 months (95% CI 7 to 13 months); 5-year event-free survival was 12.2%. In Kraal 2015 the 10-year overall survival was 6.25%; event-free survival was not reported.
With regard to short-term adverse effects De Kraker 2008 looked at death due to myelosuppression. It was not clear if all patients were assessed for this outcome, but the best case scenario shows a prevalence of 2% (95% CI 0 to 13%). Kraal 2015 assessed platelets, neutrophils and Hb grade 3 or 4 according to the CTCAEv3 criteria. After the first cycle of 131I-MIBG therapy with topotecan platelet toxicity was found in 38% (95% CI 18 to 61%), neutrophil toxicity in 50% (95% CI 28 to 72%) and Hb toxicity in 69% (95% CI 44
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 95 to 86%). After the second cycle this was 60% (95% CI 36 to 80%) for platelets and 53% (95% CI 30 to 75%) for neutrophils and Hb. Hepatic toxicity was only reported by De Kraker 2008: it was assessed during or within 4 weeks after last the MIBG treatment (> grade 1). It was not clear if all patients were assessed for this outcome, but the best case scenario shows a prevalence of 0% (95% CI 0 to 9%). Both studies did not report on cardiovascular toxicity and sialoadenitis. Kraal 2015 did not look at long-term adverse events, but De Kraker 2008 reported elevated plasma TSH in 45% of the 22 assessed patients (95% CI 27 to 65%); in all 22 patients the free T4 was within the age related normal range (0%, 95% CI 0 to 15%). No secondary malignancies were observed (0%, 95% CI 0 to 9%), but only 5 patients survived more than 4 years.
With regard to dose intensity after 131I-MIBG treatment, patients in De Kraker 2008 received a cumulative dose of 350–950 mCi (13–35GBq) 131I-MIBG (median 500 miC) as induction therapy, while in Kraal 2015 the administered activity (AA) was median 0.5 (0.4-0.6) GBq/kg and 14.5 (10.1-16.8) mCi/kg in the first cycle and median 0.4 (0.3-0.5) GBq/kg and 10.6 (6.9 12.6) mCi/kg in the second cycle. The cumulative administered activity was median 0.9 (0.5-1.1) GBq/kg and median 25 (14.3-29.4) mCi/kg.
Time span of delivering chemotherapy induction treatment after 131I-MIBG therapy was reported only by Kraal 2015, who aimed to give treatment at 4 week intervals. The actual mean interval time (range) between the second MIBG/topotecan and the first VECI chemotherapy course was 30 days (20-47). The mean interval time (range) for the subsequent VECI chemotherapy courses was 30 days (18-40) for the first course, 31 days (28-38) for the second course and 29 days (21-46) between the third and fourth course.
We also collected information on stem cells. De Kraker 2008 did report the median number of collected autologous haematopeoitic stem cells during harvest sessions for the 17 patients that underwent a stem cell harvest. In the first 8 patients it was 11.6x104/kg CFU-C colonies (range 2.9 to 31.6), while in the subsequent 9 patients the median was 4.9x106/kg CD34+ cells (range 1.2 to 17). Kraal 2015 did report the mean number of collected stem cells for the 13 patients that underwent a stem cell harvest: the mean yield of peripheral blood stem cells harvest was 2.2 (0 to 6.9)x106/kg CD34+ stem cells. For the bone marrow harvest this was 3.4 (1.0 to 9.1)x106/kg CD34+ stem cells. De Kraker 2008 did not provide information on the number of successful stem cell harvests; Kraal 2015 reported that peripheral blood stem cell apheresis was succesful in 46% of the patients, but no definition was provided. Both studies did not provide information on the number of peripheral stem cell harvest sessions necessary to obtain a sufficient amount of autologous haematopoeitic stem cells. In Kraal 2015 46% underwent bone marrow harvesting; De Kraker 2008 provided no information. Both studies reported on stem cell engraftment for platelets and neutrophils, but not for Hb. In De Kraker 2008 the median time to platelet engraftment (>50x10³/ul) was 47 days; the median time to neutrophil engraftment (>1x10³/ul) was 23 days. In Kraal 2015 the median time to platelet engrafment (>25x109/l) was 37 days (range 14-74 days); for neutrophil engraftment (>0.5x109/l) this was 21 days (range 12-62 days).
96 Chapter 5 Overall completeness and applicability of evidence The external validity of a study indicates how well its results can be extrapolated to individual patients with newly-diagnosed high-risk neuroblastoma treated with 131I-MIBG therapy. It includes the following items: well defined study group, well-defined follow-up and well-defined outcome. If important information is missing, it is difficult to correctly interpret the results and extrapolate them to individual patients. In both studies the study group was well-defined and the risk of reporting bias thus low. In both studies the length of follow-up was not mentioned, so the risk of reporting bias was unclear. Follow-up could have been too short for patients to develop for example long-term adverse effects. For overall survival the outcome is well-defined by default, so the risk of reporting bias was low in both studies assessing this outcome. Both studies also assessed response (low risk of reporting bias in both studies) and hematological toxicity (low risk of reporting bias in Kraal 2015; unclear risk of reporting bias in De Kraker 2008). For all other primary outcomes assessed by the included studies the risk of reporting bias was unclear. Overall, none of the 2 included studies scored good on all applicable reporting bias items, on many occasions due to a lack of reporting.
Also, the studies were performed in different treatment era (1989-2003). Supportive care, like antibiotic use, and anti-cancer treatments have changed substantially within this period, so consequently, the results may not all be applicable to patients who are treated today. It should be kept in mind that the time span of delivering chemotherapy induction treatment after 131I-MIBG therapy does not only depend on the effects of 131I-MIBG therapy, but for example also on adverse effects after chemotherapy.
Despite all patients were diagnosed as newly diagnosed high risk neuroblasoma, in this review we used the old definition of HR NBL. Recently, the age cut-off has been changed from one year to 18 months. As a result some included patients might now be classified as intermediate risk disease. As far as we know, there are no studies that compare stage 4 NBL patients with age at diagnosis 12 months vs. 18 months, therefore the implications are unknown.
Even though RCT’s are the highest level of evidence, it should be recognised that data from non-randomised studies on the efficacy of 131I-MIBG therapy in newly diagnosed NBL patients are available (Kraal 2015; De Kraker 2008). The overall response rate after two courses of 131I-MIBG therapy was 66% (De Kraker 2008) and 56% (Kraal 2015). Although the results of these studies are promising they should be interpreted with caution due to the biases associated with non-randomised study designs, in these cases two retrospective cohort studies. A study by Park et al decribes for example a lower response rate to chemotherapy of 39% after 2 cycles of Topotecan/ cyclofosfamide in HR NBL patients (Park 2011), but it should be kept in mind that treatment and timing of response assessment was different than that in the included studies and no
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 97 definitive conclusions can be made. Unfortunately, other studies in HR NBL report response rates after 4 or 6 courses of chemotherapy, which are therefore not useful for comparison (Matthay 1999; Berthold F 2005) Finally, data were not available for all outcomes of interest. As a result we cannot draw conclusions regarding those outcomes, but they are ofcourse important for clinical practice.
Quality of the evidence In order to adequately assess the efficacy and adverse effects of 131I-MIBG therapy in patients with newly diagnosed high-risk NBL, the best study design- provided that the design and execution are correct- is an RCT in which the only difference between the intervention and control group is use of 131I-MIBG therapy. CCTs can also provide reliable information, keeping in mind their limitations, but these were not found. Other study designs were included in this review, but they are associated with a high risk of bias.
The internal validity gives an indication of the bias present in a study and thus how valid the results of a certain study are. It includes the following issues: selection bias, attrition bias, and detection bias. In both studies selection bias could be ruled out. The risk of attrition bias was low for response, event-free survival, overall survival, secondary malignant disease, stem cells and in one study (Kraal 2015) also for hematological toxicity. In the other study the risk of attrition bias was unclear for hematological toxicity and hepatic toxicity, and high for thyroid dysfunction (De Kraker 2008). Attrition bias can lead to an over- or underestimation of the risk of these adverse effects. The risk of detection bias was low for overall survival, but it could not be ruled out for all other assessed primary outcomes. Knowledge of prognostic factors can increase the possibility of classifying a patient as having a certain outcome.
Potential biases in the review process This systematic review used a very broad search strategy for identifying eligible studies. However, although it is unlikely that eligible studies were missed, it is never possible to completely rule out reporting bias.
Authors’ conclusions Implications for practice No RCTs or CCTs comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in newly diagnosed HR NBL patients were identified. Two observational studies were identified, but, besides the associated high risk of bias, not for all relevant outcomes results were available. Also, it should be kept in mind that recently the age cut-off for high-risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermedi- ate-risk disease were included in the high-risk groups. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in newly diagnosed high-risk neuroblastoma patients in clinical practice.
98 Chapter 5 Implications for research Prospective randomised controlled trials are essential to strengthen the evidence base on the use of 131I-MIBG therapy in newly diagnosed high-risk neuroblastoma patients. The studies should be performed in homogeneous study populations (e.g. stage of disease; using the most recent definitions for high risk patients) and have a long-term follow-up. Dosimetry for 131I-MIBG therapy should be incorporated into the treatment protocol. The number of included patients should be sufficient to obtain the power needed for the results to be reliable. Accurate and transparent reporting of findings will make it possible for readers to critically appraise the results of these studies.
Acknowledgements Huib Caron was a co-author of the protocol for this systematic review and we thank him for his valuable input. We would like to acknowledge the Editorial Base of Cochrane Childhood Cancer for their advice and support. The Editorial Base of Cochrane Childhood Cancer is funded by ‘Stichting Kinderen Kankervrij’ (KiKa), the Netherlands.
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131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 109 Characteristics of studies Characteristics of included studies
De Kraker 2008 Methods Prospective cohort study. Single-centre study performed in the Netherlands. Start and end date: April 1989 and October 1999.
Participants 44 patients (median age at diagnosis 2.6 years (range 1-15.4); 21 females and 23 males) with newly diagnosed high-risk neuroblastoma (INSS stage not explicitely mentioned, but based on the metastatic disease, deduced that this is stage 4). Only 41 patients were evaluable (age range at start treatment 1.2-15.5 years; 20 females and 21 males; n=24 received MIBG and n=17 received MIBG and chemotherapy): in 2 patients it was not feasible to start 131I-MIBG therapy (n=1 early progression requiring immediate treatment; n=1 sepsis and too unstable for MIBG treatment); in 1 patient with progressive disease parents refused further therapy after 1 MIBG infusion. Two other patients with only 1 MIBG infusion remain in the study. Tumor biology: neuroblastoma. Genetics: 10/44 (23%) MYCN amplification (4/24 (16%) MIBG and 6/17 (35%) MIBG and chemotherapy group), 20/43 (47%; value for 1 patient not available) loss of heterozygosity chromosome1p (LOH1p) (12 (50%) MIBG and 8 (47%) MIBG and chemotherapy). Tumor localisation primary tumor and metastasis: primary tumor not mentioned; bone marrow metastasis (all patients). Previous treatment received: not mentioned (but see exclusion criteria for further information). Inclusion criteria: patients 1-18 years of age at diagnosis with high-risk, MIBG positive neuroblastoma. Exclusion criteria: previous chemotherapy. Initial surgery as the only treatment modality was allowed.
Interventions 2 cycles of 131I-MIBG single agent therapy → if objective response third MIBG treatment (n=24); if stable disease or progression pre-operative VECI chemotherapy (n=17) → surgery (as soon as the surgeon felt that a greater than 95% resection was feasible) → 4 courses of VECI chemotherapy at 4-weekly intervals → consolidation therapy 4 weeks after last VECI: HDCT/ASCT → retinoic acid. VECI: vincristine (1.5 mg/m² intravenous on day 1), ifosfamide (3000 mg/m2 intravenous over 1 hour on days 1 and 2), carboplatin (400 mg/m2 intravenous in a 24 hour infusion on day 3), etoposide (150 mg/m2 intravenous over 4 hours on day 4). Consolidation therapy: carboplatin (800 mg/m2 intravenous over 6 hours on day 1), melfalan (180 mg/m2
110 Chapter 5 intravenous on day 3), reinfusion of bone marrow or peripheral blood stem cells on day 5. Harvest of stem cells: during postoperative VECI courses as soon as the patient was in VGPR or CR with a clear BM. After stem cell reinfusion 13-cis-retinoic acid in a dose of 160 mg per square meter per day administered orally in two divided doses for 14 consecutive days in a 28-day cycle, was given for 6 months, beginning 4 weeks after stem-cell re-infusion, in 14-day cycles. 131I-MIBG: first infusion fixed dose of 200 mCi (7.4 GBq), 2nd and all subsequent infusions 100-150 mCi (3.7- 5.6 GBq) by intravenous 4 hour infusion. Interval between MIBG infusions was 4 weeks. MIBG dosimetry not performed. Thyroid blocking: potassium iodide 100 mg for 14 days, beginning on day before MIBG infusion. N=14 no surgery; n=2 only 1 MIBG infusion; n=17 stem cell transplant. No control patients.
Outcomes Response (according to INRC (Brodeur 1993)). Overall survival (no definition provided). Event-free survival (no definition provided). Toxicity: • Haematological toxicity (i.e. death due to myelosuppression; no definition provided) • Hepatic (> grade 1, but no definition provided) • Thyroid (based on TSH (>4.5mU/l) and T4 (no cutoff point provided)) • Secondary malignancies
Dose intensity after 131I-MIBG treatment (the actual administered amount of 131I-MIBG mega Becquerel/ micro Curie (MBq/mCi)) Stem cells: • Yield of PBSC collection (median number of collected stem cells, either CFU-C colonies or CD34+ cells) • Stem cell engraftment (platelets >50x10³/ul) • Stem cell engraftment (neutrophils >1x10³/ul)
Notes Follow-up: not mentioned, but the maximal follow-up according to the survival curves was approximately 175 months; thyroid dysfunction was assessed after a mean follow-up of 19 months (range 0.7-129 months). Influence of funders not reported.
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 111 Risk of bias table
Bias Authors' Support for judgement judgement Representative study group (selection bias) Low risk >90% of the original cohort Complete follow-up assessment (attrition bias): Low risk Response was assessed for > 90% of the study group response of interest Complete follow-up assessment (attrition bias): Low risk Event-free survival was assessed for > 90% of the event-free survival study group of interest Complete follow-up assessment (attrition bias): Low risk Overall survival was assessed for > 90% of the study overall survival group of interest Complete follow-up assessment (attrition bias): Unclear risk Not mentioned hematological toxicity Complete follow-up assessment (attrition bias): Unclear risk Not mentioned hepatic toxicity Complete follow-up assessment (attrition bias): High risk Thyroid dysfunction was only assessed in 50% of the thyroid dysfunction study group of interest Complete follow-up assessment (attrition bias): Low risk Secondary malignancies were assessed in > 90% of secondary malignancies the study group of interest Blinded outcome assessor (detection bias): Low risk Blinding of outcome assessor not applicable for overall survival overall survival Blinded outcome assessor (detection bias): all Unclear risk Not mentioned other primary outcomes Well-defined study group (reporting bias) Low risk All necessary items (see Table 1) were provided Well-defined follow-up (reporting bias) Unclear risk Length of follow-up was not mentioned Well-defined outcome (reporting bias): Low risk Outcome definition provided for response, not response and overall survival applicable for overall survival Well-defined outcome (reporting bias): Unclear risk No outcome definition provided hematological toxicity Well-defined outcome (reporting bias): all other Unclear risk No outcome definition provided evaluated primary outcomes
Kraal 2015 Methods Prospective phase II windows study. Multi-centre study performed in the Netherlands (2 centers). Start and end date: March 2000 and August 2003.
Participants 16 patients (median age at diagnosis 2.8 years (range 1.6-8.3); age at start treatment not mentioned; 10
112 Chapter 5 male and 6 females) with newly diagnosed HR NBL (INSS stage not explicitely mentioned, but based on the metastatic disease, deduced that this is stage 4). Tumor biology: neuroblastoma. Genetics: 8/14 (57%; value for 2 patients not available) MYCN amplification, 6/15 (40%; value for 1 patient not available) loss of heterozygosity chromosome1p (LOH1p), MYCN amplification and LOH1p 6/14 (43%; value for 2 patients not available). Tumor localisation primary tumor and metastasis: 15/16 (94%) abdominal and 1/16 (6%) thoraco- abdominal; tumor metastasis: 16/16 (100%) BM, 4/16 (25%) lymph node and 1/16 (6%) pleura. Previous treatment received: none (no prior cancer treatment was allowed). Inclusion criteria: histologically confirmed HR NBL, no prior cancer treatment, a non-complicated clinical condition which allowed for a 5-day radioprotective isolation for 131I-MIBG treatment, age 0-16 years at diagnosis, signed and dated informed consent. Exclusion criteria: not confirm inclusion criteria stated above.
Interventions 2 cycles of 131I-MIBG therapy and topotecan (n=16) → 4 courses of VECI chemotherapy at 4 week intervals (n=15) → surgery (n=12; optimal timing of surgery was discussed when the distant metastases were inactive and the tumor operable) → myeloablative therapy/ASCT (n=9) → 13 cis retinoic acid (n=13). Topotecan: daily 1 hour infusion of topotecan 0.7 mg/m2 iv for 5 days after MIBG therapy. VECI: vincristine (1.5 mg/m2 intravenous on day 1), ifosfamide (3000 mg/m2 intravenous on days 1 and 2), carboplatin (400 mg/m² intravenous on day 3), etoposide (150 mg/m² intravenous on day 4). Harvest of stem cells: peripheral blood stem cell harvesting took place after the first VECI course if the BM was clear; if not successful this was repeated after the next course. Myeloablative therapy: carboplatin (800 mg/m² on day -3) and melphalan (180 mg/m²intravenous on day -1), ASCT on day 0. 13-cis-retinoic acid 160 mg/m² in 2 doses for 2 weeks followed by 2 weeks rest (6 cycles). 131I-MIBG therapy: first dose 7.4 GBq/200 mCi and second dose 5.6 GBq/150 mCi. Interval between MIBG infusions was 4 weeks. MIBG dosimetry not performed. Thyroid blocking: not reported. N=4 no surgery; n=1 only 1 MIBG infusion; n=9 stem cell transplant. No control patients.
Outcomes Response (according to INRC (Brodeur 1993)). Overall survival (no definition provided). Toxicity:
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 113 • Haematological toxicity: platelets, Hb, neutrophils (grade 3 and 4 according to CTCAEversion 3.0). Dose intensity after 131I-MIBG treatment (defined as the actual administered amount of 131I-MIBG mega Becquerel/micro Curie (MBq/mCi)) Time span of delivering chemotherapy induction treatment after 131I-MIBG therapy Stem cells: • Yield of PBSC collection (mean number of collected CD34+ stem cells) • Number of successful PBSC harvest (no definition provided) • Percentage of patients in which bone marrow harvest is performed • Stem cell engraftment (platelets >25x109/l) • Stem cell engraftment (neutrophils >0.5x109/l)
Notes Follow-up: not mentioned, but maximal length of follow-up 10 years. Influence of funders not reported.
Risk of bias table
Bias Authors' Support for judgement judgement Representative study group (selection bias) Low risk All eligible consecutive patients Complete follow-up assessment (attrition bias): Low risk Response was assessed for > 90% of the study group response of interest Complete follow-up assessment (attrition bias): Unclear risk event-free survival Complete follow-up assessment (attrition bias): Low risk Overall survival was assessed for > 90% of the study overall survival group of interest Complete follow-up assessment (attrition bias): Low risk Hematological toxicity was assessed for > 90% of the hematological toxicity study group of interest Complete follow-up assessment (attrition bias): Unclear risk hepatic toxicity Complete follow-up assessment (attrition bias): Unclear risk thyroid dysfunction Complete follow-up assessment (attrition bias): Unclear risk secondary malignancies Blinded outcome assessor (detection bias): Low risk Blinding of outcome assessor not applicable for overall survival overall survival Blinded outcome assessor (detection bias): all Unclear risk Not mentioned other primary outcomes Well-defined study group (reporting bias) Low risk All necessary items (see Table 1) were provided Well-defined follow-up (reporting bias) Unclear risk Length of follow-up was not mentioned
114 Chapter 5 Well-defined outcome (reporting bias): Low risk Outcome definition provided for response, not response and overall survival applicable for overall survival Well-defined outcome (reporting bias): Low risk Outcome definition provided hematological toxicity Well-defined outcome (reporting bias): all other Unclear risk evaluated primary outcomes
Footnotes CTCAE- Common Terminology Criteria for Adverse Events v3.0 (CTCAE); publication date: August 9, 2006. AA= administered activity, NBL= neuroblastoma, MIBG= meta-iodobenzylguanidine, HD ASCT= high dose autologous stem cell transplantation, PBSC= peripheral blood stem cells, INRC= International Neuroblastoma Response Criteria, Hb= hemoglobin, TPT= Topotecan, ORR= objective response rate, ANC= absolute neutrophil count, LOH1p= loss of heterozygosity chromosome 1p, MNA= mycN amplification, TSH= thyroid stimulating hormone, VECI= Vincristine, etoposide, Carboplatin and Ifosfamide.
Characteristics of excluded studies
Bleeker 2009 Reason for exclusion: Unclear number of HR NBL patients. Bleeker 2013 Reason for exclusion: Unclear number of HR NBL patients. Brans 2002 Reason for exclusion: Less than 10 HR NBL patients. Brendel 1989 Reason for exclusion: Case reports. Claudiani 1988 Reason for exclusion: Less than 10 MIBG therapy patients. Clement 2013 Reason for exclusion: Unclear if they are newly diagnosed and/or HR NBL patients. Clement 2015 Reason for exclusion: Unclear if they are newly diagnosed and/or HR NBL patients. Corbett 1991 Reason for exclusion: Less than 10 HR NBL patients. De Kraker 1995 Reason for exclusion: Includes all stages, no separate analysis for HR NBL patients. Edeling 1986 Reason for exclusion: Less than 10 HR NBL patients. El-Sabban 2013 Reason for exclusion: Unclear number of HR NBL patients. Garaventa 1995 Reason for exclusion: Unclear number of patients. Garaventa 2003 Reason for exclusion: Unclear if they are HR NBL patients. Gerrard 1987 Reason for exclusion: Case report. Hartmann 1988 Reason for exclusion: Not MIBG therapy. Hoefnagel 1987 Reason for exclusion: Unclear number of HR NBL patients. Hoefnagel 1988 Reason for exclusion: Unclear number of HR NBL patients. Hoefnagel 1991 Reason for exclusion: Less than 10 HR NBL patients. Hoefnagel 1994 Reason for exclusion: Unclear if they are HR NBL patients. Hoefnagel 1995 Reason for exclusion: Includes all stages, no separate analysis for HR NBL patients.
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 115 Klingebiel 1991 Reason for exclusion: Unclear number of HR NBL patients. Klingebiel 1994 Reason for exclusion: Less than 10 HR NBL patients. Klingebiel 1998 Reason for exclusion: Prior chemotherapy before MIBG therapy. Kosmin 2012 Reason for exclusion: Unclear if they are HR NBL patients. Lashford 1990 Reason for exclusion: Unclear if they are HR NBL patients. Mastrangelo 1987 Reason for exclusion: Editorial, no primary data. Mastrangelo 1991 Reason for exclusion: Case report. Mastrangelo 2001 Reason for exclusion: Unclear if they are HR NBL patients. Mastrangelo 2011 Reason for exclusion: No separate analysis for HR NBL patients; prior chemotherapy before MIBG therapy. Matthay 2009 Reason for exclusion: Relapsed/ refractory patients. McEwan 1986 Reason for exclusion: No patient data, biochemical analysis. Mitjavila 1989 Reason for exclusion: Less than 10 HR NBL patients. Monsieurs 2001 Reason for exclusion: Unclear if they are HR NBL patients. Mussa 1987 Reason for exclusion: Diagnostic MIBG scan. O’Donoghue 1991 Reason for exclusion: Less than 10 HR NBL patients. Picco 1995 Reason for exclusion: Unclear if they are HR NBL patients. Racch 2011 Reason for exclusion: Less than 10 HR NBL patients. Schoot 2009 Reason for exclusion: Less than 10 HR NBL patients. Schoot 2009-2 Reason for exclusion: Less than 10 HR NBL patients. Shapiro 1991 Reason for exclusion: Unclear number of HR NBL patients. Sudbrock 2010 Reason for exclusion: Unclear number of HR NBL patients. Sutton 1982 Reason for exclusion: Unclear number of HR NBL patients. Sze 2013 Reason for exclusion: Less than 10 HR NBL patients. Teszler 2013 Reason for exclusion: Editorial. Van Hasselt 1996 Reason for exclusion: Includes all stages, no seperate analysis for HR NBL patients. Van Santen 2002 Reason for exclusion: No outcome parameters mentioned as included in the eligibility criteria of this review. Van Santen 2005 Reason for exclusion: Includes all stages, no seperate analysis for HR NBL patients Van Santen 2012 Reason for exclusion: Unclear if they are newly diagnosed and/or HR NBL patients. Van Santen 2013 Reason for exclusion: Includes all stages, no seperate analysis for HR NBL patients. Vitale 2012 Reason for exclusion: Includes all stages, no seperate analysis for HR NBL patients Voute 1985 Reason for exclusion: Unclear number of HR NBL patients. Voute 1987 Reason for exclusion: Unclear number of HR NBL patients. Voute 1987-2 Reason for exclusion: Unclear number of HR NBL patients Voute 1988 Reason for exclusion: Unclear number of HR NBL patients. Voute 1988-2 Reason for exclusion: Unclear number of HR NBL patients. Voute 1991 Reason for exclusion: Includes all stages, no seperate analysis for HR NBL patients. Wong 2013 Reason for exclusion: Refractory NBL patients.
Footnotes HR NBL= high risk neuroblastoma, MIBG= meta-iodobenzylguanidine.
116 Chapter 5 Characteristics of studies awaiting classification Hamidieh 2014 Methods: Single center study Participants: 13 patients (mean age at diagnosis was 42.5 months (range 17-65) and mean age at transplan- tation was 60.2 +/- 21.3 months (range 34-92)) with HR NBL and MIBG avid lesions. Interventions: Therapeutic 131I- MIBG therapy (12 mCi/kg) followed by myeloablative therapy (etoposide 1200 mg/m², carboplatin 1500 mg/m² and melpahaln 210 mg/m²) and autologous stem cell transplan- tation. After autologous stem cell transplantation all patients received cis-retinoic acid. Outcomes: The median time to neutrophil engraftment after autologous stem cell transplantation was 10 days (range 9-13) and median platelet engraftment was 13 days (range 10- 20). None of the patients failed to engraft after autologous stem cell transplantation. In studied patients, 3 year OS was 66% +/- 21% while 3 year EFS was 53% +/- 20%. Notes: This study has not been published in full text (16-05-2016), but has been published as an abstract for bone marrow transplantation (BMT) meeting.
Kraal 2012 Methods: Multi-center pilot study Participants: HR NBL patients Interventions: 2 cycles of upfront 131I-MIBG therapy. Of the 33 evaluable patients, 16 (48%) received 2 cycles of upfront 131I-MIBG therapy (group A), 17 (51%) patients were treated without upfront 131I-MIBG therapy (group B; insufficient MIBG uptake, weak clinical condition and hypertension) and 2 patients were excluded (they received prior chemotherapy). Outcomes: 131I-MIBG therapy within 2 weeks from diagnosis was feasible in all patients eligible for 131I-MIBG therapy. Interval between subsequent N5/N6 chemotherapy courses was similar in both groups (22- 30 days). There was no serious haematological toxicity. Stem cell harvest after 131I-MIBG therapy was undisturbed and did not compromise HD chemotherapy with ASCT treatment. Response analysis (FU 1/1/2005- 1/1/2012) showed an effect of 2 131I-MIBG courses in 10/15 (67%) patients (1 missing) after 3 times N5/N6 of 15/16 (94%) and at FU of 13/16 (81%). Notes: This study has not been published in full text (16-05-2016), but has been presented at the ANR conference 2012.
Leung 2011 Methods: Retrospective chart review Participants: 15 children (median age 3.6 years) with stage 4 (high-risk) disease with 131I-MIBG-avid lesions at initial diagnosis. Interventions: All patients received 131I-MIBG therapy (14 one infusion; 1 two infusions). Fourteen 131I-MIBG-therapies were administered as part of the conditioning regimen for haematopoietic
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 117 stem cell transplantation (HSCT).Lugols solution was given for thyroid protection. For 131I-MIBG therapy administered as curative treatment, the dose ranged from 9 to 12.9 mCi/kg, with median dose of 12 mCi/ kg. Carboplatin, etoposide and melphalan was given 7 to 10 days after MIBG treatment as conditioning for HSCT. Outcomes: At a median follow up of 1.2 years (range 0 to 7 years), 5 out of 14 patients receiving therapeutic 131I-MIBG treatment relapsed (36%) and 4 of them died (7%). The estimated 2-year overall and event-free survival was 12.8% and 15.3% respectively. Six patients (43%) developed primary hypothyroidism with elevation of TSH at 5 months to 1 year after treatment and 3 required thyroxine replacement. No patient experienced liver derangement immediately after 131I-MIBG treatment. Notes: Overlap in patients with Leung 2013 is very likely. This study has not been published in full text (16-05-2016), but has been presented at the SIOP conference 2011.
Leung 2013 Methods: Retrospective chart review Participants: 22 children (median age 2.9 years) with stage 4 (high-risk) neuroblastoma with MIBG avid lesions at diagnosis Interventions: All patients received 131I-MIBG therapy. Twenty-one 131I-MIBG-therapies were administered as part of the conditioning regimen for haematopoietic stem cell transplantation. The median dose of 131I-MIBG administered for curative treatment was 12mCi/kg (range 5.8 to 12.9mCi/ kg). Lugol’s solution was given for thyroid protection. Outcomes: At a median follow up of 1.2 years (range 0 to 9 years), 12 out of 21 (57%) patients receiving therapeutic 131IMIBG treatment relapsed and 8 of them died (38%). The estimated 2-years OS was 66.1 [+/-]12.5%. Among 15 patients who had evaluable thyroid function result, 9 (60%) developed primary hypothy- roidism with elevation of TSH at 0.3 to 2.9 years post-treatment and 4 required thyroxine replacement. No patient experienced liver derangement. Notes: Overlap in patients with Leung 2011 is very likely. This study has not been published in full text (16-05-2016), but has been presented at the SIOP conference 2013. Lopez-Aguilar 2003 Methods: Cohort study Participants: Children with newly diagnosed neuroblastoma stage III and IV; not mentioned if this were all high-risk patients. Interventions: Chemotherapy (cisplation, epirubicin, etoposide, ifosfamide), massive doses of 131I-MIBG and surgical ablation of the remaining tumor were possible.
118 Chapter 5 Outcomes: Not reported for the MIBG treated patients only. Notes: We are currently awaiting the translation of this article in Spanish. Based on the currently available information it is unclear whether this study fullfills the inclusion criteria for this review.
Nakajo 1987 Methods: Unclear Participants: Patients with pheochromocytoma and neuroblastoma; no further information available Interventions: 131I-MIBG; no further information available. Outcomes: Unclear Notes: Article in Japanese. We were unable to obtain a copy of this article. Based on the currently available information it is unclear whether this study fullfills the inclusion criteria for this review.
Footnotes HR NBL= high-risk neuroblastoma, MIBG= meta-iodobenzylguanidine, EFS= event free survival, OS= overall survival, FU= follow-up, TSH= thyroid stimulating hormone, SIOP= Societe International Oncologie et Pediatrie, HSCT= hematopeotic stem cell transplantation, ASCT= autologous stem cell transplantation.
Characteristics of ongoing studies NCT01175356 Study name: Induction therapy including 131I-MIBG and chemotherapy in treating patients with newly diagnosed high-risk neuroblastoma undergoing stem cell transplant, radiation therapy, and maintenance therapy with isotretinoin Methods: Interventional study Participants: Patients with newly diagnosed neuroblastoma or ganglioneuroblastoma stage 4 disease according to International Neuroblastoma Staging System (INSS) Interventions: 131I-MIBG therapy followed by myeloablative busulfan/melphalan Outcomes: Response, event-free survival and adverse effects Starting date: October 2010 Contact information: Children’s Oncology Group; principal investigator: Brian Weiss, MD Notes: No full text publication as per 22 May 2016
Footnotes EFS= event free survival, Bu/ Mel= Busulphan/ Melfalan, MIBG= meta=iodobenzylguanidine,
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 119 Data and analyses This review has no analyses.
Additional tables
Internal validity External validity Study group Selection bias (representative: yes/no): Reporting bias (well defined: yes/no): If the described study group consisted of more If the mean, median or range of the 131 than 90% of the high-risk NBL patients treated cumulative I-MIBG dose was mentioned with 131I-MIBG included in the original cohort Or And If it was a random sample of these patients When it was described what other treatment with respect to important prognostic factors (including the received doses) was given (i.e. age, stage according to INSS (bone marrow involvement), MYCN amplification and loss of chromosome 1p), type of disease (i.e. newly diagnosed, relapsed, refractory) and cancer treatment Follow-up Attrition bias (adequate: yes/no): Reporting bias (well-defined: yes/no): If the outcome was assessed for more than 90% If the length of follow-up was mentioned of the study group of interest (++) Or If the outcome was assessed for 60-90% of the study group of interest (+) Outcome Detection bias (blind: yes/no): Reporting bias (well-defined: yes/no): If the outcome assessors were blinded to the If the outcome definition was provided investigated determinant
MIBG: meta-iodobenzylguanidine; NBL: neuroblastoma Table 1. Risk of bias criteria for observational studies
Treatment ORR (95% CI) before surgery ORR (95% CI) after surgery 131I-MIBG only (n=24) 79% (60 to 91%) 92% (74 to 98%) 131I-MIBG and chemotherapy (n=17) 35% (17 to 59%) 47% (26 to 69%)
ORR=objective response rate; CI=confidence interval Table 2. Objective response rate for 131I-MIBG only patients and 131I-MIBG + chemotherapy patients
120 Chapter 5 Appendices 1 Search strategy for CENTRAL (The Cochrane Library) 1. For 'Neuroblastoma' the following text words were used: neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR neuroepitheliomas OR Peripheral Primitive Neuroectodermal Tumors OR Peripheral Primitive Neuroectodermal Neoplasm OR Primitive Neuroectodermal Tumor, Extracranial OR Neuroecto- dermal Tumor, Peripheral OR Neuroectodermal Tumors, Peripheral OR Peripheral Neuroectodermal Tumor OR Peripheral Neuroectodermal Tumors OR Tumor, Peripheral Neuroectodermal OR Tumors, Peripheral Neuroectodermal OR pPNET OR PNET OR PNET* OR Peripheral Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumors OR Neuroectodermal Neoplasm, Peripheral Primitive OR Neuroectodermal Tumor, Peripheral Primitive
2. For '131I-meta-iodobenzylguanidine' the following text words were used: 131I-Meta-iodobenzylguanidine or 131I-MIBG or 131I-metaiodobenzylguanidine or Iodine-131 Metaiodobenzylguanidine or Iobenguane (131I) or (3-Iodo- (131I) benzyl) guanidine OR iodine-131-me- taiodobenzylguanidine or 131I-MIBG therapy or I-metaiodobenzylguanidine or I-131-MIBG or I-131-Metaiodobenzylguanidine or (131) I-MIBG or (131) I-metaiodobenzylguanidine or (MIBG and (treatment or therapy)) OR 3-Iodobenzylguanidine Final search 1 AND 2 The search was performed in title, abstract or keywords [* = zero or more characters]
2 Search strategy for MEDLINE (PubMed) 1. For 'Neuroblastoma' the following MeSH headings and text words were used: neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR neuroepitheliomas OR (Peripheral Primitive Neuroectodermal Tumors OR Peripheral Primitive Neuroectodermal Neoplasm OR Primitive Neuroectodermal Tumor, Extracranial OR Neuroectodermal Tumor, Peripheral OR Neuroectodermal Tumors, Peripheral OR Peripheral Neuroecto- dermal Tumor OR Peripheral Neuroectodermal Tumors OR Tumor, Peripheral Neuroectodermal OR Tumors, Peripheral Neuroectodermal) OR (pPNET OR PNET OR PNET*) OR Peripheral Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumors OR Neuroectodermal Neoplasm, Peripheral Primitive OR Neuroectodermal Tumor, Peripheral Primitive
2. For '131I-meta-iodobenzylguanidine' the following MeSH headings and text words were used: (131I-Meta-iodobenzylguanidine OR 131I-MIBG OR 131I-metaiodobenzylguanidine OR Iodine-131 Metaio- dobenzylguanidine OR Iobenguane (131I) OR (3-Iodo-(131I)benzyl)guanidine OR Iodine Radioisotopes/
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 121 therapeutic use OR 3-Iodobenzylguanidine/therapeutic use) OR (iodine-131-metaiodobenzylguanidine OR 131I-MIBG therapy OR I-metaiodobenzylguanidine OR I-131-MIBG OR I-131-Metaiodobenzylguanidine OR (131) I-MIBG OR 3-Iodobenzylguanidine[mh] OR (131) I-metaiodobenzylguanidine OR (MIBG AND (treatment OR therapy))) Final search 1 AND 2 [* = zero or more characters]
3 Search strategy for EMBASE (Ovid) 1. For 'Neuroblastoma' the following Emtree terms and text words were used: 1. exp neuroblastoma/ 2. (neuroblastoma or neuroblastomas or neuroblast$).mp. 3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp. 4. (neuroepithelioma or neuroepitheliomas or neuroepitheliom$).mp. 5. exp neuroectoderm tumor/ or (peripheral primitive neuroectodermal tumors or peripheral primitive neuroectodermal tumours).mp. 6. (peripheral primitive neuroectodermal neoplasm or peripheral primitive neuroectodermal neoplasms).mp. 7. (peripheral neuroectodermal tumor or peripheral neuroectodermal tumors or peripheral neuroectodermal tumour or peripheral neuroectodermal tumours).mp. 8. (pPNET or PNET or PNET$).mp. 9. (peripheral primitive neuroectodermal tumor or peripheral primitive neuroectodermal tumour).mp. 10. (extracranial primitive neuroectodermal tumor or extracranial primitive neuroectodermal tumors or extracranial primitive neuroectodermal tumour or extracranial primitive neuroectodermal tumours). mp. 11. or/1-10
2. For '131I-meta-iodobenzylguanidine' the following Emtree terms and text words were used: 1. exp "(3 iodobenzyl)guanidine i 131"/ or 131I-Meta-iodobenzylguanidine.mp. 2. 131I-MIBG.mp. 3. 131I-metaiodobenzylguanidine.mp. 4. Iodine-131 Metaiodobenzylguanidine.mp. 5. Iobenguane 131I.mp. 6. "(3 iodobenzyl)guanidine"/ 7. Iodine Radioisotopes.mp. or exp radioactive iodine/ 8. radiopharmaceutical agent/ad, dt 9. 131I-MIBG therapy.mp.
122 Chapter 5 10. I-metaiodobenzylguanidine.mp. 11. (I-131-MIBG or I-131-Metaiodobenzylguanidine or 131-I-MIBG).mp. 12. 3-Iodobenzylguanidine.mp. 13. 131-I-metaiodobenzylguanidine.mp. 14. (MIBG and (treatment or therapy)).mp. 15. or/1-14 Final search 1 AND 2 [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; / = Emtree term; $=zero or more characters; ad=drug administration; dt=drug therapy]
Contributions of authors Kathelijne Kraal designed the study and wrote the protocol. She identified the studies meeting the inclusion criteria (both by initial screening and thereafter). She searched for unpublished and ongoing studies. She performed the data extraction and risk of bias assesment of the included studies and interpreted the results. She wrote and revised the manuscript.
Elvira van Dalen designed the study and critically reviewd the protocol. She identified studies meeting the inclusion criteria and searched for ongoing studies. She acted as a third party arbitrator for study selection. She performed the data extraction and risk of bias assessment of the included studies. She analysed the data and contributed to the interpretation of the results. She wrote the manuscript. critically reviewed the manuscript.
Godelieve Tytgat critically reviewed the protocol. She identified studies meeting the inclusion criteria and contributed to the interpretation of the results. She critically reviewed the manuscript. Berthe van Eck-Smit critically reviewed the protocol. She identified studies meeting the inclusion criteria and contributed to the interpretation of the results. She critically reviewed the manuscript.
Declarations of interest Some of the authors of this systematic review were also authors of the included studies: KC Kraal, BLF van Eck-Smit and GAM Tytgat are authors of Kraal 2015 and BLF van Eck-Smit is also an author of De Kraker 2008.
Sources of support Internal sources • Cochrane Netherlands, Netherlands. Training
131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 123 External sources • Stichting Kinderen Kankervrij (KiKa), Netherlands. • Koningin Wilhelmina Fonds (KWF), Netherlands
Differences between protocol and review The protocol was written for newly diagnosed, relapsed and refractory high-risk NBL (Kraal 2013). Since then it was decided that it would be preferable to prepare separate reviews for newly diagnosed and relapsed/refractory disease. This review focussed on newly diagnosed disease.
As recommeded by Cochrane Childhood Cancer we have classified the outcome “Toxicity and adverse effects” as a primary outcome instead of a secondary outcome in order to comply with the MECIR standards. In the protocol it was stated that when relevant data regarding data extraction and risk of bias assessment were missing, we would attempt to contact the study authors to retrieve the missing data. This has not been done. Also, in consultation with Cochrane Childhood Cancer, we restricted the risk of bias assessment of observational studies to the primary outcomes for attrition bias, detection bias and outcome reporting bias (i.e. biases that can be assessed for each outcome separately).
Data synthesis: after the publication of our protocol Cochrane Childhood Cancer changed its policy regarding the calculation of prevalences and the corresponding 95% CIs. So instead of using the generic inverse variance function of RevMan to calculate the 95% CIs we were advised to use the Wilson method. As this was not possible in RevMan we used the following tool: http://epitools.ausvet.com.au/content. php?page=CIProportion&SampleSize=375&Positive=3&Conf=0.95&Digits=4.
124 Chapter 5 131I-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma 125 1. Princess Máxima centre for Pediatric Oncology (PMC), Utrecht, the Netherlands 2. Department of Pediatric Oncology, Emma Children’s Hospital (EKZ/ AMC), Amsterdam, the Netherlands. 3. Department of hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam, the Netherlands. 4. Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands 5. Department of Pediatric Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands 6. Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam, the Netherlands 7. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands 8. Mathematical institute, Leiden University, Leiden, The Netherlands Chapter 6 Autologous stem cell transplantation harvesting and hematological reconstitution in high-risk neuroblastoma patients treated with 131Iodine-metaiodobenzylguanidine.
KCJM Kraal1,2, HM Kansen¹, I Timmerman3, C vd Bos², J Zsiros1,2, H van den Berg², S Somers², E Braakman4, AML Peek5, MM van Noesel¹, CE van der Schoot6, M Fiocco7,8, HN Caron², C Voermans³, GAM Tytgat1,2
Manuscript in preparation Abstract Aim To evaluate feasibility of stem cell apheresis and haematological reconstitution after autologous stem cell transplantation (ASCT) in high-risk neuroblastoma (HR NBL) patients treated with upfront 131Iodine- meta-iodobenzylguanidine (131I-MIBG) therapy.
Methods In two prospective, multi-centre cohort studies newly diagnosed HR-NBL patients, were treated with 2 courses 131I-MIBG therapy, followed by HR-NBL protocol. Stem cell harvest yield, number of sessions needed and time to neutrophil (>0.5x109/L) and platelet reconstitution (>20x109/L) after ASCT were analysed. Viability and clonogenic capacity (CFU-GM) of CD34+ cells pre-freezing and post-thawing were tested.
Results Thirty-eight (46%) patients were treated with 131I-MIBG therapy, forty-four (54%) received chemothera- py-only. Median cumulative 131I-MIBG dose/kg was 0.81 GBq (22.1 mCi). Median peripheral blood stem cell (PBSC) apheresis yield was comparable in both groups; 5.4 x106/kg in 131I-MIBG (n=34) and 5.6 x106/kg in chemotherapy-only (n=37) patients. Median cumulative apheresis days were also comparable between the groups. Failure to harvest PBSC: 131I-MIBG therapy one and chemotherapy group two patients. A multivariate regression model for PBSC harvest yield showed, adjusted for age/gender/MYCN-amplification/LOH1p/ Cisplatin dose, a significant association with bone marrow infiltration at diagnosis (p=0.004). Delayed platelet recovery (29 (compared to 15 days, (p=0.037), and comparable neutrophil recovery (11and 10days) was seen for 131I-MIBG and chemotherapy-only group, respectively. There was no impact of 131I-MIBG therapy on clonogenic capacity, recovery and CD33 expression of cryopreserved CD34+ cells, but viability of CD34+ cells after cryopreservation and expression of CD34+/CD62L was lower in 131I-MIBG- compared to chemotherapy- treated patients.
Conclusion Harvesting of PBSC is feasible after 131I-MIBG in HR-NBL patients, however, it resulted after ASCT, in delayed platelet recovery while comparable neutrophil recovery was observed. Possibly caused by a lower percentage of viable CD34+ cells and a lower expression of CD62L in 131I-MIBG treated patients.
128 Chapter 6 Introduction Neuroblastoma (NBL) is the most common extra cranial solid tumour in children, accounting for 7% to 10% of all childhood malignancies.(1,2) Outcome of high risk (HR) cases is still poor with 5-year event free survival rates of less than 50% and long-term overall survival in less than one-third of patients, despite multi-modality treatment.(2-4) The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue in consolidation has resulted in improvements of survival. (2;4-5;6) Radiolabelled meta-iodo- benzylguanidine (MIBG) selectively concentrates in 90% of NBL. (1) When labelled with 131I- it is used as targeted therapy and as upfront induction therapy in newly diagnosed HR NBL patients, has an objective response rate of 70% or more.(7,8) Currently, the optimal place for 131I-MIBG in newly diagnosed NBL HR patients is being investigated. The dose limiting toxicity of 131I-MIBG therapy is myelosuppression. Several studies have reported that many patients treated with more than 12 mCi/kg 131I-MIBG, require support with autologous stem cell transplantation (ASCT) to prevent for prolonged myelosupression, especially thrombocytopenia. (9) Therefore it has been hypothesized that 131I-MIBG therapy might influence the microenvironment of the bone marrow (BM) and stem cells (CD34+ cells), impairing the ability to harvest peripheral blood stem cells (PBSC). Our objectives were to investigate the feasibility to harvest PBSC and study the haematological recovery after ASCT in HR NBL patients treated with upfront 131I-MIBG therapy.
Patients and methods Data were collected from two prospective, multi-centre (Emma Children´s Hospital-Academic Medical Centre (AMC) Amsterdam, Sophia Children’s Hospital-Erasmus Medical Centre (EMC) Rotterdam, University Medical Centre Groningen (UMCG), Princess Máxima Centre (PMC) Utrecht, the Netherlands) cohort studies: the pilot HR NBL (1/1/2005-2011) and the HR Dutch Childhood Oncology Group (HR DCOG) NBL-2009 (2011-Oktober 2015). All newly diagnosed HR NBL patients, ≥1-19 years with stage 4 NBL or MYCN-amplification (any age and stage, according to INSS) were included. Twenty-four patients were included in a previously published report.(10) Patients with MIBG-avid disease and good clinical condition, were treated with two courses of upfront 131I-MIBG therapy followed by the standard HR arm of the German Paediatric Oncology and Haematology (HR GPOH) NBL protocol. In the pilot study, the 131I-MIBG adminis- tration was based on a fixed dose: 1st 7.4 GBq (200 mCi) and 2nd 5.5 GBq (150 mCi). In the NBL 2009 study, the dosage regimen was aimed to limit whole body dose to 4 Gy for the combined series of two consecutive 131I-MIBG administrations. The first administration was based on a fixed dose/kg (444 MBq/ kg). The second dose was based on the total body radiation dose calculated from the first therapeutic administration. Induction-chemotherapy for both studies consisted of 3 times N5/ N6 courses (N5: 160 mg/m2 cisplatinum, 400 mg/m2 etoposide and 3mg/m2 vindesine; N6: 2x 1.5 mg/m2 vincristine, 1000mg/ m2 dacarbazine, 7500 mg/m2 ifosphamide and 60 mg/m2 doxorubicine), followed by surgery, myeloablative chemotherapy (MAT) (180 mg/m2 melphalan, 40 mg/kg etoposide and 1500 mg/m2 carboplatin) with autologous stem cell reinfusion (ASCT) and radiotherapy to the primary tumour site. (as was described previously: (4). Maintenance treatment consisted of immunotherapy (anti-disialoganglioside (GD2),
Autologous stem cell transplantation harvesting and hematological reconstitution 129 interleukin (IL-) 2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and 13-cis-retinoic acid.
Stem cell harvest and myeloablative therapy Autologous peripheral blood stem cells (PBSC) were harvested as soon as the bone marrow (BM) was negative, tested with immunocytology. After the chemotherapy course, patients were treated with 10ugr/ kg filgastrim and when pre-collection peripheral blood count of CD34+ cells were (>20 CD34/microliter) an apheresis catheter was inserted and stem cells were collected, aimed at ≥ 2 x 106/kg body weight CD34 positive stem cells. We noted the number of day’s needed to collect the stem cells. If the harvest yield was not sufficient, after the next course of chemotherapy, a second session was attempted, noted as number of sessions. In no adequate number of stem cells could be collected, in the earlier day’s in three cases, BM harvest was performed.
Only patients with good response to induction therapy (complete response, VGPR or PR), were allowed to proceed to MAT, followed by ASCT. Haematological reconstitution was defined as a platelet count >20 x 109/L and neutrophil as >0.5 x 106/L.
Processing stem cells Colony-forming units granulocyte-macrophage (CFU-GM) assay Progenitor capacity of PBSCs was assessed using a clonogenic assay of granulocyte/macrophage progenitors, which was performed before cryopreservation (n= 81samples of 45 patients) and only in one institution tested post-thawing (n=19). Nucleated cells were plated in duplicate in 35 mm tissue culture plates at concentrations of 1.0, 0.5 and 0.25*10 5 cells/ml, respectively, in MethoCult GF 4534 (StemCell Technologies, Vancouver, BC, Canada). Cultures were incubated for 12-14 days at 37°C at 5% CO2. CFU-GM colonies, defined as containing at least 40 translucent cells, were scored in triplicate by microscopy (Leica, Solms, Germany). CFU-GM recovery was calculated as the number of colonies formed after thawing divided by the number of colonies before cryopreservation.
Cell viability To determine the viability of the harvested cells, we analyzed cryopreserved reference ampoules of PBSC transplants of nine 131I-MIBG-treated patients and ten patients that received chemotherapy-only. The patients were selected based on the availability of cryopreserved PBSC, with a total collected harvest of 1-2 x 106/ CD34/kg, equally divided between the two groups. Reference ampoules of the transplants were thawed in a water bath at 37°C. Vitality of the nucleated cells was determined using trypan blue exclusion. Cell recovery of the nucleated cells was calculated as the number of cells determined after thawing divided by the number of cells before cryopreservation.
Post-thaw CD34(+) cell viability was determined based on the ISHAGE guidelines (15) combined with
130 Chapter 6 7-amino actinomycin D (7-AAD) staining (BD biosciences, San Jose CA, USA), and measured using a CANTO ll flow cytometer (BD). A minimum of two hundred thousand CD45(+) events were collected. Viable hematopoietic progenitor and stem cells (CD34+ HSPCs) were defined as 7-AAD negative.
Determination of surface marker expression of CD34-positive cells CD34(+) cells were characterized for surface expression of various receptors by flow cytometry. Cells were washed and resuspended in PBS containing 0.2% BSA and incubated for 20 minutes at RT with the following monoclonal antibodies: Antibodies purchased from BD biosciences, San Jose CA, USA: CD45-Percp (clone 2D1), CD34-APC (clone 8G12), CD62L-FITC (clone SK11), CD33-PE-Cy7 (clone p67.6), IgG2a-FITC, IgG1-PE, IgG1-PeCy7. Purchased from Dako, Cambridgeshire, UK: CD45-PB (clone T29/33). Purchased from Beckman Coulter, Marseille, France: CD41-PE (clone P2). Isotype controls were used to set boundaries for gating.
Statistical analysis Patients treated with upfront 131I-MIBG and chemotherapy-only were compared by using Chi Square test for categorical variables and the independent student t-test for continuous variables. A multivariate linear regression model was employed to study the association between patient characteristics, treatment and HSPC harvest. To account for repeated measures a generalized linear mixed model (GLMM) has been used to estimate marginal mean quality (CFU-GM per CD34+ cells) for each group during the first day of harvest session. GLMM is a well-known statistical methodology used in the analysis of data that are correlated within subjects such as data provided in this study. (11) The adjusted mean for each group with their corresponding standard error and confidence intervals were computed. The CD34+/41+ megakaryocyte precursors, CD34+/CD62L, CD34/ CD33 (myeloid marker) and vitality/ viability were tested in the PBSC and compared in the 2 groups using Mann-Whitney U test and t-test.
Survival analysis techniques were used to compare time to platelet and neutrophil reconstitution for patients treated with 131I-MIBG or chemotherapy-only. The log rank test has been used to assess the statistical significant difference between the two groups. Time to event was defined as time from ASCT until time of platelet or neutrophil reconstitution. Patients who did not engraft after first ASCT were censored at time of second infusion. A multivariate Cox proportional hazards regression model was employed to estimate the effect of risk factors on platelet and neutrophil reconstitution. Results are presented as hazard ratios (HR) with the corresponding 95% confidence interval (CI).
Results Patients’ characteristics Eighty-two children (56% male) were identified: 38/82 (46%) treated with upfront 131I-MIBG therapy and 44/82 (54%) received chemotherapy-only. The median age (range) at diagnosis was 3.2 (0.1-16.4) years
Autologous stem cell transplantation harvesting and hematological reconstitution 131 (Table I). Nearly all patients had BM metastases at diagnosis (n=72; 88%). MYCN-amplification was found in a greater proportion of patients treated with chemotherapy-only (19/39; 49%) compared to patients who received upfront 131I-MIBG therapy (9/36; 25%) (p=0.034).
131I-MIBG therapy During the first 131I-MIBG therapy a median dose (range) of 0.42 GBq/kg (0.13-0.56) or 11.2 mCi/kg (3.5-15.2) was administered; the second course consisted of median 0.37 GBq/kg (0.12-0.69) or 9.9 mCi/ kg (3.2-18.7). Total cumulative dose of patients treated with two courses was median (range) 0.81 GBq/
Overall 131I-MIBG Chemotherapy- treatment only
Total, n (%) 82 38 (46) 44 (54) Gender Male, n (%) 46 (56) 25 (66) 21 (48) Female, n (%) 36 (44) 13 (34) 23 (52) Age At diagnosis, years (range) 3.2 (0.1-16.4) 3.3 (0.1-16.4) 3.1 (0.5-15.9) At ASCT, years (range) 4.1 (1-17.2) 4 (1.4-17.2) 4.1 (1-11.9) Genetic MYCN amplification, n/n measured 28/75 (37) 9/36 (25) 19/39 (49) aberrations (%) LOH1p, n/n measured (%) 16/57 (28) 6/24 (25) 10/33 (30) Metastases at diag- Bone marrow, n (%) 73 (89) 34 (89) 39 (89) nosis Curie score, median (range) 16.5 (0-30) 16.5 (0-25) 17.0 (0-30) Cumulative dose 320 (160-640) 320 (160-480) 320 (160-640) of Cisplatin, mg/m² (range) ASCT, n (%) 59 (72) 28 (74) 31 (71) Patient characteristics Months since diagnosis, median 7.2 (4.3-12.1) 8.5 (6.2-12.1) 5.8 (4.3-11.4) before ASCT (range)
Curie score, median (range) 0 (0-17) 0 (0-17) 0 (0-5) ORR, % 60 61 59 Bone marrow, n (%) Negative 52 (88) 26 (93) 26 (84) Positive 1 (2) 1 (4) 0 NE 6 (10) 1 (4) 5 (16)
Data are expressed as median with range or number (%). Missing data were excluded from table.
131I-MIBG, 131Iodine- metaiodobenzylguanidine; ASCT, autologous stem cell transplantation; LOH1p, 1p loss of heterozygosity; m², square meters; mg, milligram; n, number; NA, not applicable; NE, not evaluable; ORR, objective response rate (defined as proportion of patients with complete response, very good partial response or partial response). Table I. Demographical and clinical characteristics of the study cohort
132 Chapter 6 Overall 131I-MIBG treatment Chemotherapy-only
PBSC apheresis, n (%) 71 (97) 34 (90) 37 (84)
Prior chemotherapy course (N5/N6) 4 (1-8) 4 (1-8) 4 (2-7) PBSC harvest sessions, 1 (1-4) 1 (1-4) 1 (1-2) Days of PBSC apheresis, 1 (1-8) 1 (1-8) 1 (1-8) Harvest yield, CD34+ cells x106/kg 5.4 (0.5-44.5) 5.4 (0.9-32.3) 5.6 (0.5-44.5)
Data are expressed as median (range) or number (%). Missing data were excluded from table.
131I-MIBG, 131Iodine- metaiodobenzylguanidine; kg, kilogram; n, number; PBSC, peripheral blood stem cell. Table II. Peripheral blood stem cell apheresis (PBSC)
kg (0.26-1.10) or 22.1 mCi/kg (7-29.8). In 8 patients receiving only the first cycle of 131I-MIBG therapy the median (range) cumulative dose was 0.41 GBq/kg (0.17-0.56) or 11.2 mCi/kg (range 4.7-15.2).
Stem cell harvesting In seventy-four patients (90%) stem cells were collected: 36 (95%) 131I-MIBG treated and 38 (86%) chemotherapy-only patients. Median timing was after the 4th chemotherapy course (cumulative dose of chemotherapy). In the majority of patients (n=71, 97%), apheresis was used to harvest stem cells with a median total harvested PBSC dose of 5.4 x106 CD34+ cells/kg (range 0.9-32.3) in 131I-MIBG treated patients compared to 5.6 x 106 CD34+ cells/kg (range 0.5-44.5) in chemotherapy-only patients (Table II). No significant differences were found in the total PBSC harvest yield, the total number of apheresis days and sessions between both groups. One apheresis day was sufficient to collect ≥2x106/kg CD34+ cells in 59% of 131I-MIBG-therapy and 65% of chemotherapy-only patients, two days in respectively 74% and 76% (Table III). A multivariate regression analysis of PBSC harvest yield was performed, showing significant association of stem cell harvest yield with bone marrow infiltration at diagnosis, when adjusted for age, gender, MYCN-amplification, LOH1p and cumulative dose of both131 I-MIBG and Cisplatin prior to apheresis (p=0.004) (Supplemental Table 1). In three out of 71 patients (4%), there was failure to harvest PBSC: one 131I-MIBG treated (1.2 x106/kg CD34+ in 8 apheresis days performed in 4 sessions) and two chemothera- py-only patients (0.5 x106/kg and 0.8 x106/kg CD34+ in one session of respectively 3 and 2 days). Additional BM harvesting was performed, with a harvest yield of 0.3 x106/kg in the 131I-MIBG treated patient and respectively 5.9 x106/kg and 8.4x106/kg SC in the chemotherapy-only patients.
Autologous stem cell transplantation Fifty-nine of 82 patients (72%) underwent MAT+ASCT: 28 (74%) 131I-MIBG -therapy patients and 31 (71%) treated with chemotherapy-only. The majority of patients who did not receive MAT with ASCT had PD (n=19, 23%), or died of disease (n=4, 5%). Median dose (range) of CD34+ cells infused was 3.4x106/kg (1.2-10.5) in 131I-MIBG patients and 3.5x106/kg (1.2-11.6) in chemotherapy-only patients (Table IV).
Autologous stem cell transplantation harvesting and hematological reconstitution 133 Overall 131I-MIBG treatment Chemotherapy-only N Cum % N Cum % N Cum % PBSC apheresis 71 97 34 90 37 84 1 day 44 62 20 59 24 65 2 days 9 75 5 74 4 76 3 days 4 80 3 82 1 78 4 days 7 90 3 91 4 89 5 days 2 93 1 94 1 92 6 days NA NA NA NA NA NA 7 days NA NA NA NA NA NA 8 days 2 96 1 97 1 95 Failure 3 4 1 3 2 5 Session number Session 1 63 89 32 94 31 84 Session 2 4 95 NA NA 4 95 Session 3 1 96 1 97 NA NA
Table displaying the number of patients in whom successful PBSC apheresis (≥2x106 CD34-positive cells/kg) was obtained. Days are given as the number of cumulative apheresis days. Cum % shows the cumulative percentage of patients with successful apheresis at that (time) point.
131I-MIBG, 131Iodine- metaiodobenzylguanidine; N, number; NA, not applicable; PBSC, peripheral blood stem cells.
Table III. Cumulative apheresis days for successful apheresis
Haematological recovery after MAT + ASCT
Median time (95% CI) to platelet reconstitution was 29 (11-47) and 15 days (12-18) respectively for 131I-MIBG and chemotherapy-only group (log rank overall 0.037) (Table IV; Figure 1), neutrophil reconstitution after respectively 11 (10-12) and 10 (9-11) days (log rank overall 0.734) (Supplemental Figure 2). A multivariate Cox’s regression model was performed to estimate the effect of BM infiltration at diagnosis, cumulative dose of 131I-MIBG therapy and infusion dose of CD34+ cells on both platelet and neutrophil reconstitution. A significant statistical association for platelet reconstitution was found between both cumulative dose of 131I-MIBG (HR 0.395 [95% CI 0.19-0.85], p=0.017) and number of infused stem cells (HR 1.242 [95% CI 1.1-1.4], p=0.001) (Table V). Concerning neutrophil reconstitution, there was a significant association with both bone marrow infiltration at diagnosis (HR 0.377 [95% CI 0.16-0.89], p = 0.026) and number of infused stem cells (HR 1.282 [95% CI 1.13-1.46], p=0.000) (Table V).
In two patients treated with 131I-MIBG therapy, there was need for a second stem cell infusion due to delayed hematopoietic reconstitution, after which haematological recovery was achieved in both. A third patient (chemotherapy-only group) did receive two autologous stem cells infusions, but there was engraftment
134 Chapter 6 Overall 131I-MIBG treatment Chemotherapy-only Number of patients with ASCT, (%) 59 (72) 28 (74) 31 (71) Dose of infused stem cells Median CD34+ x106/kg (range) 3.4 (1.2-11.6) 3.4 (1.2-10.5) 3.5 (1.2-11.6) Platelet reconstitution, days* (95% CI) 19 (10-28) 29 (11-47) 15 (12-18) Neutrophil reconstitution, days* (95% CI) 11 (10-12) 11 (10-12) 10 (9-11)
131I-MIBG, 131Iodine- metaiodobenzylguanidine; ASCT, autologous stem cell transplantation; kg, kilogram; Risk factors for time to platelet and neutrophil reconstitution. Hazard ratios (HR) and 95% confidence intervals (CI) * p value < 0.05 is considered statistically significant. 131I-MIBG, 131Iodine- metaiodobenzylguanidine Table IV. Autologous stem cell transplantation
HR 95% CI p-value Platelet reconstitution Bone marrow infiltration at diagnosis 1.374 0.58 -3.28 0.474 Cumulative dose of 131I-MIBG 0.395 0.19 - 0.85 0.017* ASCT infusion dose of CD34-positive cells 1.242 1.1 - 1.4 0.001* HR 95% CI p-value Neutrophil reconstitution Bone marrow infiltration at diagnosis 0.377 0.16 -0.89 0.026* Cumulative dose of 131I-MIBG 1.437 0.68 - 3.03 0.341 infused number of CD34-positive cells 1.282 1.13 - 1.46 0.000*
Risk factors for time to platelet and neutrophil reconstitution. Hazard ratios (HR) and 95% confidence intervals (CI)
* p value < 0.05 is considered statistically significant. 131I-MIBG, 131Iodine- metaiodobenzylguanidine; Table V. Platelet and neutrophil reconstitution
failure of both. Allogeneic stem cell transplantation was performed using cord blood after which neutrophils reconstituted in 12 days. However, the patient died before platelet recovery was achieved (one month after allogenic stem cells infusion) due to septic disease and multi-organ failure.
Quality of stem cells harvested Quality assessment of fresh material, by flow cytometric CD34(+) cell enumeration and assessment of clonogenic output (CFU-GM/CD34+ cells), did not reveal a significant difference between the two patient groups, tested in 81 samples, 45 (55%) patients (Supplemental Figure 2, supplemental Table 2).
Analysis of delayed platelet reconstitution in subgroup of patients
Autologous stem cell transplantation harvesting and hematological reconstitution 135 Numbers at risk 131I-MIBG 25 15 7 4 2 1 1 Chemotherapy-only 30 12 4 2 0 0 0
Cumulative percentage of patients achieving platelet reconstitution after autologous stem cell transplantation (infusion) treated with 131I-MIBG therapy versus chemotherapy-only. Figure 1. Percentage of patients with platelet reconstitution
In search of a possible explanation for the delayed platelet recovery after ASCT in MIBG-treated patients, we analyzed cryopreserved reference ampoules of PBSC transplants of a selected ‘subgroup’ of nineteen patients: nine 131I-MIBG-treated and ten chemotherapy-only patients. The patients were selected based on the availability of post-thawing CFU-GM results, cryopreserved PBSC with a total collected harvest of 1-2 x 106/ CD34/kg, equally divided between the two groups. Reference ampoules of the transplants were thawed and PBSC quality was determined. 131I-MIBG- therapy did not affect nucleated blood cell (NBC) vitality (Figure 2A) and recovery after cryopreservation (Figure 2B). However, the percentage of viable CD34+ cells was significantly lower in 131I-MIBG compared to chemotherapy-only -treated patients, 63 and 83% respectively, as determined using the permeability marker (7-AAD) (Figure 2C). To further test the progenitor capacity of CD34+ cells we performed Colony Forming Unit- Granulocyte/ Macrophage (CFU-GM) assays. Median CFU-GM potential (range) before cryopreservation was 30,2 x104/kg (9,0 – 173,8) in 131I-MIBG- treated patients versus 71,1x104/kg (33,0 - 378,1) in chemotherapy-only patients, showing that
136 Chapter 6 (A) Post-thaw nucleated blood cell (NBC) vitality, determined using trypan blue. (B) Nucleated blood cell recovery: expressed as the percentage of cells recovered after thawing in comparison to the value before cryopreservation. (C) Percentage of viable CD34+ cells after thawing, determined using 7-AAD. (D) Clonogenic output: Colony-forming units granulocyte-macrophage (CFU-GM) assay. Percentage of CFU-GM recovered after thawing in comparison to the value before cryopreservation. (E) Percentage of viable CD34+ cells expressing CD33 after thawing. (F) Percentage of viable CD34+ cells expressing CD41 after thawing. (G) Percentage of viable CD34+ cells expressing CD62L after thawing. (H) Correlation between platelet reconstitution after ASCT and percentage of CD34+ cells expressing CD62L in reference ampoules of PBSC transplants of chemotherapy-only and MIBG-therapy patient groups. Platelet reconstitution was defined as a platelet count >20 x 109/L. Data are mean (SD). *p<0.05, **p<0.01. Figure 2. Post-thaw viability, clonogenic capacity and adhesion molecule expression of cryopreserved PBSCs.
Autologous stem cell transplantation harvesting and hematological reconstitution 137 there is no significant effect (p=0,203) of131 I-MIBG- therapy on the capacity of CD34(+) cells to differentiate into granulocyte/ macrophage progenitors. There was also no effect on CFU-GM recovery after cryopre- servation (Figure 2D), which was calculated as the number of colonies formed after thawing divided by the number of colonies before cryopreservation. Of the patient with graft failure vitality of CD34+ cells pre- and post-freezing was 80% and 84%, respectively with pre-freezing count of 4.8 x 106 and post-thawing 4.5 x 106. No post thawing CFU-GM was tested.
The viable CD34+ cells were further characterized for cell-surface marker expression by flow cytometry. No difference in expression of the myeloid marker CD33 (Siglec-3) was observed between the two patient groups (Figure 2E), which is in line with the observation that neutrophil recovery after ASCT was comparable (Table 4). To test the hypothesis that 131I-MIBG- therapy may reduce the number of megakaryocyte progenitors, we analyzed expression of the marker CD41 (integrin alpha chain 2b). There was only a mild and non-sig- nificant trend for a reduced percentage CD41-positive viable CD34+ cells in the 131I-MIBG-treated patient group (Figure 2F). Another adhesion molecule described to be predictive for rapid platelet recovery after PBSC transplantation is CD62L, also known as L-selectin (12-14). Interestingly, the percentage of CD62L-po- sitive CD34(+) cells was significantly lower in the viable CD34+ cells of the 131I-MIBG-therapy compared to the chemotherapy group: 37 and 54%, respectively (Figure 2G). Analysis showed that the percentage of reinfused CD62L+ stem cells correlated with the time to platelet recovery in these patient groups (Figure 2H). Taken together, viability of mobilized peripheral blood-derived CD34+ cells after cryopreservation was lower in 131I-MIBG- compared to chemotherapy- treated patients. Although there was no impact of 131I-MIBG therapy on clonogenic capacity, recovery and CD33 expression of cryopreserved CD34+ cells, expression of CD62L, a predictive marker for rapid platelet recovery, was reduced.
Discussion Our study shows stem cell apheresis to be feasible after upfront 131I-MIBG-therapy in newly diagnosed HR NBL patients. We found no difference in the total PBSC harvest yield in patients treated with MIBG therapy compared to those who were treated with chemotherapy-only. In both groups, PBSC harvesting was feasible and could be performed in equal apheresis days and sessions. Failure to harvest stem cells occurred in only three patients of which one was 131I-MIBG treated. These results are in accordance with other studies using upfront 131I-MIBG-therapy in newly diagnosed HR NBL patients. (8, 15)
Our data suggest bone marrow infiltration at diagnosis to be associated with lower PBSC harvest yield, even though apheresis was only started after clearing of initial BM disease. Difficulty to mobilize CD34+ cells, in patients with prior BM involvement, has been previously described in patients with non-Hodgkin’s lymphoma. (16)
138 Chapter 6 In our study, post-transplant neutrophil reconstitution was also associated with BM infiltration at diagnosis and number of CD34+ cells reinfused, and no correlation with MIBG could be established. In contrast, a significant difference in time to platelet reconstitution after ASCT in patients treated with131 I-MIBG-therapy compared to patients treated with chemotherapy only was noted. Several studies reported 131I-MIBG therapy to be correlated with more hematotoxicity.(17-18) However, others report comparable time to haematological recovery when comparing 131I-MIBG to chemotherapy-only treated patients.( 19) Both BM infiltration at diagnosis (positive BM biopsy or immunocytology) and higher cumulative 131I-MIBG dose has been suggested to be risk factors for prolonged myelosuppression in a previous report by DuBois et al.(18) Reason might be that NBL cells in the BM might take up 131I-MIBG, which might damage adjacent hematopoietic and stromal cells. The difference in ability to engraft between platelets and neutrophils might also be explained by selective uptake of 131I-MIBG by megakaryocytes, consequently resulting in delayed platelet recovery following ASCT.(20)
The cumulative administered 131I-MIBG dose in our study was high compared to the maximum tolerated dose of 12 mCi/kg without stem cell support as previously described in relapsed or refractory NBL patients. This is due to the fact we included only newly diagnosed HR NBL patients who were not chemotherapy pre-treated.
Both the quality assessment of fresh material, CD34+ cell enumeration, and assessment of clonogenic output (CFU-GM/CD34+ cells) tested in 81 samples of 45 (55%) patients, did not reveal a significant difference between the two patient groups, although we did not have data on the clonogenic efficacy of all patients.
In contrast, cryopreserved reference ampoules of PBSC transplants of 131I-MIBG-treated patients contained lower post-thaw viable CD34(+) counts compared to chemotherapy-only patients. However, no difference in CD34(+) cell viability was observed in fresh material of these patient groups, suggesting that CD34(+) cells of MIBG-treated patients are more sensitive for the cryopreservation process. Our study found a dose-response relationship between reinfused PBSC and haematological recovery, as previously described. (21) We were unable to define a minimum number of CD34+ cells per kilogram to be infused, because there were no patients receiving less than 1.0 × 106 CD34+ cells /kg and only 6 patients with less than 2.0 × 106/ kg, who all but one reached haematological reconstitution. It is certainly plausible that the viable CD34+ cell number reinfused into MIBG-treated patients is lower than estimated based on the CD34+ count before cryopreservation. Next to a lower viability of post-thaw CD34+ cells in the 131I-MIBG-treated group, the percentage of CD62L-expressing viable CD34+ cells was reduced. Previously, a highly significant correlation between the number of re-infused CD62L-CD34+ cells and platelet recovery was described, suggesting a role for L-selectin in engraftment and probably megakaryopoiesis (12;14;22).
Autologous stem cell transplantation harvesting and hematological reconstitution 139 CD62L-mediated rolling of PBSC on the endothelium is suggested to be a critical step in the homing process to the bone marrow. Of interest, in vitro studies by blocking the CD62L-ligand interaction in CFU-MK assays showed no key role for CD62L during clonogenic outgrowth of CD34(+) cells into megakaryocyte progenitors, (23). So further study is required to assess the functional relevance of decreased CD62L-ex- pressing PBSCs in 131I-MIBG-treated patients and the relation with delayed platelet reconstitution. Recently, Morgenstern and colleagues used granulocyte-monocyte colony-forming unit assays to describe the failure of post-thaw viable CD34+ cells to form CFU-GM colonies. (24) One patient had engraftment failure of both autologous harvests with successful neutrophil reconstitution in 12 days of an allogeneic stem cell transplantation using cord blood. The CD34+ viability was good after thawing, but no post-thawing CFU-GM colony testing was performed. Possibly in this case, graft failure was caused by malfunctioning of CD34+ cells, since allogenic stem cells did result in neutrophil recovery. As this is a population that will receive large amounts of chemotherapy, with the need to harvest at least 4 x 106/kg CD34+ cells, we suggest that both the number of viable CD34+ cells in post-thaw PBSC samples should be incorporated into the routine CD34+ cell quality assessment of clinical laboratories, as well as the post-thawing CFU-GM colony testing and correct for that. Furthermore, since MIBG is shown to reduce CD34+ post-thaw viability, it should be considered to be given at a later moment during the treatment.
The strength of our study is the complete, coherent data selection, including all Dutch HR NBL patients treated following a standardized treatment protocol. To our knowledge, there are no comparable studies published yet addressing both stem cell apheresis and haematological reconstitution in upfront MIBG-treated patients. Interpretation of our results might be limited due to selection bias, as more than half (54%) of patients were excluded to receive 131I-MIBG therapy because of poor clinical condition or non-MIBG avid disease.
Conclusion In conclusion, we provide further evidence that stem cell harvesting is feasible after upfront 131I-MIBG therapy in newly diagnosed HR NBL patients. MIBG might affect post-thawing CD34+ viability. After infusion of an equivalent number of pre-freezing, but possibly not post-thawing, CD34+ stem cells, comparable neutrophil, but delayed platelet reconstitution occurred in 131I-MIBG treated patients when compared to chemotherapy-only patients, so further studies of the optimal place of MIBG in HR NBL protocols, need to be performed.
140 Chapter 6 (β) 95% CI p-value Age -0.047 -0.94 - 0.84 0.916 Gender -1.176. -5.50 --3.15 0.586 MYCN amplification -2.227 -7.59 - 3.14 0.406 LOH1p 3.812 -1.07 - 8.7 0.123 Bone marrow infiltration at diagnosis -11.313 -18.90 - -3.74 0.004* Cumulative dose of 131I-MIBG -2.005 -7.55 - 3.54 0.469 Cumulative dose of Cisplatin 0.003 -0.02 - 0.02 0.786
131I-MIBG, 131Iodine- metaiodobenzylguanidine; LOH1p, 1p loss of heterozygosity Supplemental Table I. Peripheral blood stem cell harvest yield Regression coefficient s(β) and their associated 95% confidence interval (CI)
Time (days) 131I-MIBG therapy Mean 95% CI CFU-GM / CD34+ Lower Bound Upper Bound 1 no 131I-MIBG therapy 0,226 0,069 0,383 131I-MIBG therapy 0,351 0,18 0,522 2 no 131I-MIBG therapy 0,139 -0,037 0,316 131I-MIBG therapy 0,376 0,2 0,552 3 no 131I-MIBG therapy 0,323 0,118 0,529 131I-MIBG therapy 0,365 0,166 0,563 4 no 131I-MIBG therapy 0,343 0,121 0,565 131I-MIBG therapy 0,116 -0,096 0,329
Marginal mean quality (CFU-GM per CD34+ cells/kg) with their corresponding 95% confidence intervals
CFU-GM, Colony-forming units granulocytes macrophages; kg, kilograms; CI, confidence interval;131 I-MIBG, metaiodobenzylguanidine Supplemental Table II. Quality of stem cells harvested
Autologous stem cell transplantation harvesting and hematological reconstitution 141 Supplemental figure 1. Quality of PBSC harvest yield
142 Chapter 6 Numbers at risk MIBG 27 3 2 1 1 0 Chemotherapy-only 30 3 1 0 0 0
Cumulative percentage of patients achieving neutrophil reconstitution after autologous stem cell transplantation (infusion) in those treated with 131I-MIBG therapy versus chemotherapy only. Event is defined as neutrophil engraftment (>0.5x109/L), censor is defined as need for second reinfusion or death. Missing values are excluded from analysis. P-value is based on log-rank test.
MIBG, 131Iodine- metaiodobenzylguanidine Supplemental Figure 2. Percentage of patients with neutrophil reconstitution
Autologous stem cell transplantation harvesting and hematological reconstitution 143 Reference List chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic 1. Bleeker G, Tytgat GA, Adam JA, et al. acid. N Engl J Med 1999; 341: 1165–1173. 123I-MIBG scintigraphy and 18F-FDG-PET imaging for diagnosing neuroblastoma. 7. Hoefnagel CA, De KJ, Valdes Olmos RA, Voute Cochrane Database Syst Rev 2015,9, PA. 131I-MIBG as a first-line treatment in CD009263. high-risk neuroblastoma patients. Nucl Med Commun 1994 Sep,15(9), 712-717. 2. Yalcin B, Kremer LC, van Dalen EC. High-dose chemotherapy and autologous 8. de KJ, Hoefnagel KA, Verschuur AC, van haematopoietic stem cell rescue for children EB, van Santen HM, Caron HN. Iodine-131- with high-risk neuroblastoma. Cochrane metaiodobenzylguanidine as initial induction Database Syst Rev 2015,10, CD006301. therapy in stage 4 neuroblastoma patients over 1 year of age. Eur J Cancer 2008 3. Yanik GA, Villablanca JG, Maris JM, et al. Mar,44(4), 551-556. 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell 9. Matthay KK, DeSantes K, Hasegawa transplantation for high-risk neuroblastoma. B, et al. Phase I dose escalation of A new approaches to neuroblastoma therapy 131I-metaiodobenzylguanidine with (NANT) phase II study. Biol Blood Marrow autologous bone marrow support in Transplant 2015 Apr,21(4), 673-681. refractory neuroblastoma. J Clin Oncol 1998 Jan,16(1), 229-236. 4. Berthold F, Boos J, Burdach S, et al. Myeloablative megatherapy with autologous 10. Gooskens SL, Braakman E, van den Boom stem-cell rescue versus oral maintenance AL, et al. Peripheral stem cell harvest using chemotherapy as consolidation treatment regular chemotherapy schedules in childhood in patients with high-risk neuroblastoma: a cancer. Pediatr Transplant 2012 Nov,16(7), randomised controlled trial. Lancet Oncol 758-765. 2005 Sep,6(9), 649-658. 11. Breslow N E, Clayton DG. Approximate 5. JD Fish and SA Grupp. Stem cell Inference in Generalized Linear Mixed transplantation for neuroblastoma. Bone Models. Journal of the American Statistical Marrow Transplantation 2008 41, 159–165 Association 1993, 88 (421): 9–25.
6. Matthay KK, Villablanca JG, Seeger RC, Stram 12. Dercksen MW, Gerritsen WR, Rodenhuis S, DO, Harris RE, Ramsay NK et al. Treatment et al. Expression of adhesion molecules on of high-risk neuroblastoma with intensive CD34+ cells: CD34+ L-selectin+ cells predict a
144 Chapter 6 rapid platelet recovery after peripheral blood treatment of refractory neuroblastoma. Med stem cell transplantation. Blood 1995 Jun Pediatr Oncol 1998 Jun,30(6), 339-346. 1,85(11), 3313-3319. 18. DuBois SG, Messina J, Maris JM, et al. 13. Feng R, Shimazaki C, Inaba T, Takahashi R, Hematologic toxicity of high-dose iodine- Hirai H, Kikuta T, Sumikuma T, Yamagata N, 131-metaiodobenzylguanidine therapy for Ashihara E, Fujita N, Nkagawa M. Cd34+/ advanced neuroblastoma. J Clin Oncol 2004 CD41a+ cells best predict platelet recovery Jun 15,22(12), 2452-2460. after autologous peripheral blood stem cell transplantation. Bone Marrow Transplantation 19. French S, DuBois SG, Horn B, et al. 131I-MIBG 1998 Jun, 21(12):1217-22. followed by consolidation with busulfan, melphalan and autologous stem cell 14. Watanabe T, Dave B, Heimann DG et al. Cell transplantation for refractory neuroblastoma. adhesion molecule expression on CD34+ Pediatr Blood Cancer 2013 May,60(5), cells in grafts and time to myeloid and 879-884. platelet recovery after autologous stem cell transplantation. Exp Hematol 1998, 26:10-18. 20. Tytgat GA, van den Brug MD, Voute PA, Smets LA, Rutgers M. Human megakaryocytes 15. Bleeker G, Schoot RA, Caron HN, et al. Toxicity cultured in vitro accumulate serotonin but of upfront (1)(3)(1)I-metaiodobenzylguanidine not meta-iodobenzylguanidine whereas ((1)(3)(1)I-MIBG) therapy in newly diagnosed platelets concentrate both. Exp Hematol 2002 neuroblastoma patients: a retrospective Jun,30(6), 555-563. analysis. Eur J Nucl Med Mol Imaging 2013 Oct,40(11), 1711-1717. 21. Shpall EJ, Champlin R, Glaspy JA. Effect of CD34+ peripheral blood progenitor cell dose 16. Xia W, Ma CK, Reid C, et al. Factors on hematopoietic recovery. Biol Blood Marrow determining pbsc mobilization efficiency Transplant 1998,4(2), 84-92. and nonmobilization following ICE with or without rituximab (R-ICE) salvage therapy 22. Pratt G, Rawstron AC, English AE, et al. (2001) for refractory or relapsed lymphoma prior to Analysis of CD34 cell subsets in stem cell autologous transplantation. J Clin Apher 2014 harvests can more reliably predict rapidity and Dec,29(6), 322-330. durability of engraftment than total CD34 cell dose, but steady state levels do not correlate 17. Goldberg SS, DeSantes K, Huberty JP, et al. with bone marrow reserve. Br J Haematol Engraftment after myeloablative doses of 114:937. 131I-metaiodobenzylguanidine followed by autologous bone marrow transplantation for
Autologous stem cell transplantation harvesting and hematological reconstitution 145 23. de Boer F, Kessler FL, Netelenbos T, Zweegman S, Huijgens PC, van der Wall E, van der Linden JA, Pinedo HM, Schuurhuis GJ, Drager AM. Homing and clonogenic outgrowth of CD34+ peripheral blood stem cells: a role for L-selectin?. Exp Hematol 2002 Jun,30(6):590-7 . 24. Morgenstern DA, Gulrukh A, Brocklesby M, Ings S, Balsa C, et al. Post-thaw viability of cryopreserved peripheral blood stem cells (PBSC) does not guarantee functional activity: important implications for quality assurance of stem cell transplant programmes. Br J of Haematol 2016, 174:942-951.
146 Chapter 6 Autologous stem cell transplantation harvesting and hematological reconstitution 147
Part B
Neuroblastoma patients with intraspinal extension
Tho’ much is taken, much abides; and though we are not now that strength which in old days moved earth and heaven; that which we are, we are. One equal temper of heroic hearts, made weak by time and fate, but strong in will. To strive, to seek, to find, and not to yield.
Dame M (Judi Dench) quotes a stirring passage from “Ulysses,” by Alfred, Lord Tennyson in the James Bond movie, “Skyfall.” November 2012. 1. Department of pediatric oncology, Emma Children’s Hospital / Academic Medical Centre (EKZ/AMC), Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. 2. Department of pediatric endocrinology, Wilhelmina Children’s Hospital (WKZ), Utrecht, the Netherlands. 3. Princess Máxima Center for pediatric oncology, Utrecht, the Netherlands. 4. Department of radiology, Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. 5. Department of orthopedic surgery, Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. 6. Department of medical oncology, Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands Chapter 7 Neuroblastoma with intraspinal extension: health problems in long-term survivors
KCJM Kraal1,3, AJ Blom1, GAM Tytgat1,3, HM van Santen2, MM van Noesel3, AMJB Smets4, JAM Bramer5, HN Caron1, LCM Kremer¹ and HJH van der Pal1,6.
Pediatr Blood Cancer. 2016 Jun;63(6):990-6. Abstract Aim To evaluate the prevalence of health problems in 5-year survivors treated for neuroblastoma (NBL) with intraspinal extension.
Patients and methods Retrospective, single centre cohort study (using data from Childhood Cancer Registry and medical records) of patients treated for NBL with intraspinal extension (between 1980-2007) who survived ≥ 5 years after diagnosis. Health problems were graded according to the Common Terminology Criteria for Adverse Events (CTCAEv.3.0).
Results All eligible patients (n=19) were included (n=7 no neurological symptoms at diagnosis), median age at diagnosis was 1.2 years (0.6 – 10.8 years), median follow-up time was 15.6 years (6.3 – 29.5 years). Ninety-five percent of survivors had ≥ 1 health problem and 48% of survivors ≥ 4 with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (Grade 3) or life-threatening/disabling (Grade 4) health problem. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor-(32% of patients) and -sensory neuropathy (26% of patients). Of the 13 patients that underwent a laminectomy, 54% (7/13) developed a grade 3- and 23% (3/13) a grade 4 health problem. Six patients, without laminectomy, developed in 17% (1/6) a grade 3- and in 17% (1/6) a grade 4 health problem.
Conclusion Ninety-five percent of 5-year survivors treated for a childhood intraspinal NBL have health problems. The high prevalence of grade 3 and 4 health problems (especially in the laminectomy group) emphasizes the importance of specialized long-term multidisciplinary follow-up and to identify optimal treatment with limited morbidity and maximal efficacy.
152 Chapter 7 Background Patients with intraspinal extension of neuroblastoma (NBL) can suffer from acute and long term toxicity, caused both by spinal cord compression and/or by the treatment.[1]
Presenting symptoms include neurological deficits, but patients can also be asymptomatic at diagnosis. Patients with a NBL with intraspinal extension seem to have a better outcome than NBL patients without intraspinal extension, but is associated with more health problems, due to spinal cord compression.[2;3] Chemotherapy, causing rapid regression of intraspinal extending tumors, could be a good alternative to laminectomy and radiotherapy (RT) for neurological recovery.[4;5] Plantaz et al. studied prospectively patients with intraspinal extension, and concluded that first-line chemotherapy (avoiding laminectomy) could improve partial neurologic deficits in 92%, and neurosurgical decompression could be avoided in 60%. Neurologic deficits improved in 83% of patients requiring immediate neurosurgical intervention.[6] De Bernardi et al. showed that in patients with intraspinal extension, sequelae were reported in 44% of surviving patients and suggested that chemotherapy is the preferred therapeutic modality in these patients .[3] Katzenstein et al. reported that the frequency of complete neurologic recovery in children with intraspinal NBL inversely correlated with the severity of the presenting neurologic deficits. The rate of neurologic recovery was similar for patients treated with chemotherapy compared to laminectomy. Fewer orthopedic sequelae were observed in the chemotherapy group than in children treated with laminectomy.[7] Angelini et al. described that severity of motor dysfunction at diagnosis was the most important risk factor for any health problem.[8] However, Simon et al. suggested that the interval between onset of symptoms and start of treatment had no impact on the likelihood and frequency of late health problems. They concluded furthermore that there was no clear advantage of either first-line neurosurgery or chemotherapy. [2] Hoover et al commented that a higher incidence of spinal deformities was seen in the patients treated with initial laminectomy.[9]
Using a standardized approach, our aim was to evaluate the prevalence and severity of health problems in a complete cohort of long-term NBL survivors with intraspinal extension, treated at the Emma Children’s Hospital / Academic Medical Centre (EKZ/AMC) in Amsterdam.
Procedure Study cohort Patients were identified using the Childhood Cancer Registry of the EKZ/AMC. This registry, established in 1966, contains data on all patients treated for childhood cancer in the EKZ/AMC regarding diagnosis, treatment, and follow-up.[10;11] To be eligible for inclusion in this study, patients had to meet the following criteria: 1) diagnosis of a primary malignancy between 1980 and 2007, 2) age <18 years at diagnosis, 3) ≥5 year survival after diagnosis, 4) treated primarily in EKZ/AMC, 5) diagnosed with ganglioneuroma (GN), ganglioneuroblastoma (GNBL) or NBL with intraspinal extension.
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 153
Data collection for diagnosis and treatment Clinical characteristics, included time of cancer diagnosis, time interval (weeks, median and range) from neurological symptoms to diagnosis, therapy including treatment for recurrence(s), date of last medical follow-up and presence of health problems. Intraspinal extension was defined as tumor growing through and beyond the intervertebral foramina into the spinal canal. An independent pediatric radiologist [AS] reviewed imaging at diagnosis (CT/ MRI scans) for eligibility.
Tumor was staged according to the International Neuroblastoma Staging System (INSS) or the Evans staging system (the latter were re-classified retrospectively according to the INSS).[12] Overall response was defined using the revised criteria for International Neuroblastoma Response Criteria (INRC).[13] Data were collected from the Childhood Cancer Registry and complemented with retrospectively collected data from medical records, medical imaging, surgical reports and histological examinations.
Health problems In 1996, the Outpatient Clinic for Late Effects of Childhood Cancer (PLEK/LATER) was established in the EKZ/AMC, after approval by the hospital’s Institutional Review Board. All eligible childhood cancer survivors (CCS) were traced using the Childhood Cancer Registry and were invited to participate in prospective follow-up protocols tailored to initial diagnosis and treatment. After informed consent was given, they were included in the study. The main purpose of the outpatient clinic is to actively screen for health problems in the population of childhood cancer survivors using standardized evidence-based follow-up guidelines. [10;11;14-16] Health problems are defined as total burden of adverse health outcomes (clinical and subclinical disorders), including possible events that sometimes may not be related to the childhood cancer or its treatment.
Data on all health problems were also collected from the registry and medical records, independent of causality or time of occurrence. Length of follow-up was calculated as the time of diagnosis to the last examination at the LATER outpatient clinic. Data were collected till June 2013.
Health problems were graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0). For each health problem, the severity of each event and clinical description was scored grade 1-5, withgrades 1 and 2 being mild and moderate respectively, grade 3 severe, grade 4 life-threa- tening or disabling health problems, and grade 5 is death related to the health problem. All events were independently scored by two researchers [KK and AB]. In the rare event that a suitable CTCAE term could not be found, an appropriate term was added via the ‘other, specify’ mechanism. For two neurologic health problems associated with NBL we were not able to find a suitable CTCAE term. We graded the presence of Horner’s syndrome as a grade 2 event, in case of surgical correction a grade 3 event. We graded the
154 Chapter 7 presence of opsoclonus-myoclonus syndrome (OMS) as a grade 3 event. Neurologic motor dysfunction was graded ranging from asymptomatic to paraparesis, i.e. weakness or partial loss of voluntary movement in both legs, and paraplegia, indicating complete absence of motor function. Bladder and bowel dysfunction were scored as dichotomous variables. For all survivors the neurologic outcome at the end of follow-up was compared with the neurologic status at diagnosis. An overview of the frequencies of the health problems was composed.
A classification, based on total number and grade of each health problem, was used to determine the total burden of late effects for each survivor. Survivors with ≥1 grade 1 health problem were classified as having a low burden; those with ≥1 grade 2 and or 1 grade 3, a medium burden; those with ≥2 grade 3 health problem, or 1 grade 4 health problem and at most 1 grade 3 health problem, a high burden; and those with more grade 3/4 health problems or a grade 5 , a severe burden.[8]
Statistical analysis Patients were grouped according to different variables: site of disease, gender, treatment/ no treatment, laminectomy/ no laminectomy and neurological status and outcome. Data was expressed as descriptive statistics, (median and ranges) SPSS version 20 was used. Differences between proportions with respect to neurological symptoms at diagnosis and laminectomy/ no laminectomy and grade 3/ grade 4 health problems were tested using Fisher’s exact test and Chi-squared testing.
Results Between 1980 and 2007 seventeen hundred and ten patients were registered in the EKZ/AMC registry as having survived childhood cancer for at least 5 years. In 137 patients GN, GNBL or NBL was the primary tumor. Intraspinal extension was seen in 19 of these 137 patients (14%), all were included in our study cohort.
Table I shows the patient characteristics of the 19 survivors, 74% were female,median age at diagnosis was 1.2 years (range 0.6 – 10.8 years) and the median follow-up time was 15.6 years (range 6.3 – 29.5). In the cohort there were 4/19 GN, 3/19 GNBL and 12/19 NBL. Of the 12 NBL patients, 8 (67%) were diagnosed at the age of 1 year or younger. There were no patients with HR disease. All primary tumors originated from the paravertebral sympathetic trunk and were located at cervico-thoracic level (n=1; 5%), thoracic- (n=6; 32%), thoracic-lumbar- (n=4; 21%), lumbar- (n=5; 26%), or presacral level (n=3; 16%). Supplemental Table I shows the complete data on all 19 survivors and Table III shows a summary of these data.
Median (range) time interval from neurological symptoms to diagnosis was 6 weeks (1.5- 12), measured in 11/ 12 symptomatic patients. Seven of the 19 patients (37%) had no neurological symptoms at diagnosis, 2/19 (11%) patients presented with paresthesia, 8/19 (42%) patients presented with paraparesis and 2/19
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 155 Characteristic n=19 Characteristic n=19 No. (%) No. (%) Sex Primary tumor localisation Male 5 26 Paravertebral cerv-tho 1 5 Female 14 74 Paravertebral thoracic 6 32 Vital status at end of FU Paravertebral tho-lum 4 21 Alive 19 100 Paravertebral lumbar 5 26 Age at diagnosis (years) Presacral 3 16 Median 1.2 Neurological symptoms at diagnosis (range) (0.6 – 10.8) Paraplegia 2 11 Interval neuro symptoms – diagnosis (weeks) + additional sphincter 01-Feb Median 6 dysfunction (range) (1.5 – 12) Paraparesis 8 42 Duration of follow-up (years) + additional sphincter 03-Aug Median 15.6 dysfunction (range) (6.3 – 29.5) Minor neuro symptoms 2 11 Genetics – MYCN status (paresthesia) Amplified 0 0 Asymptomatic 7 37 Single copy 14 74 Treatment N/A 5 26 Laminectomy + surgery 8 42 Tumor type at diagnosis Laminectomy + MIBG 2 11 Ganglioneuroma 4 21 Laminectomy + surgery 1 5 Ganglioneuroblastoma 3 16 + MIBG Neuroblastoma 12 63 Laminectomy + surgery 1 5 + CT INSS stage (NBL + GNBL n=15) Laminectomy + surgery 1 5 I 3 16 + CT + RT + MIBG II A + B 5 26 Surgery 3 16 III 4 21 Surgery + MIBG 1 5 IV 2 11 Surgery + CT 1 5 N/A 1 5 Surgery + MIBG + CT 1 5
Abbreviations: FU = follow-up, N/A = not available, INSS = International Neuroblastoma Staging System, No. = number, %= percentage, MYCN= MycN amplified, NBL= neuroblastoma, GNBL= ganglioneuroblastoma, surgery = extraspinal surgery, CT = chemotherapy, RT = radiotherapy, MIBG = 131I-MIBG therapy. Table I: Patient characteristics
156 Chapter 7 Geenen (2007) No. (%) No. (%) Health problems at end of FU Yes 18 95 1,015 75 No 1 5 269 20 Unknown 0 0 78 6 Number of HP found Grade 1 23 32 1,292 34 Grade 2 31 43 1,65 44 Grade 3 13 18 768* 20* Grade 4 5 7 Grade 5 0 0 + 41 1 Total number of HP found 72 3,751
Number of HP per survivor 0 1 5 269 21 1-3 9 47 585 46 4-6 6 32 ^^ ^^ 7-9 3 16 ^^^ ^^^ Maximum grade of HP per survivor 1 2 11 141 11 2 6 32 360 28 3 6 32 311 24 4 4 21 162 13 5 0 0 41 3 No AE 1 5 269 20 Burden score of HP Low 2 11 141 11 Medium 9 47 573 45 High 5 26 220 17 Severe 2 11 81 6 No AE 1 5 269 21
* Grade 3 / 4 combined, ^^= 208 (4-5 number of HP per survivor),= 16% ^^^= 222 (≥ 6 number HP per survivor), = 17% Abbreviations: FU = follow-up, HP = health problems, No.= number, Clinical descriptions of the severity of HP: Grade 1 mild; Grade 2 moderate; Grade 3 severe; Grade 4 life-threatening or disabling; Grade 5 is death related to the HP. Burden score: Survivors with ≥1 grade 1 HP were classified as having a low burden; those with ≥1 grade 2 and/or 1 grade 3 HP, a medium burden; those with ≥2 grade 3 HP, or 1 grade 4 HP and at most 1 grade 3 HP, a high burden; and those with more grade 3/4 HP or a grade 5 HP, a severe burden. Table II: Summary of the health problems and burden score.
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 157 Neurologic symptoms CTCAE grade # Age at dx Sex Intraspinal At dx End FU Other sympt at dx Interval neuro sympt - dx Treatment Response 1/2 3 4 Total Details on Grade 3 and Follow-up extension HP 4 HPs (years) PA Stage
1 1.3 F Th2 – Th6 2 → 2 BL 12 wks L, S CR 3 2 - 5 3: Paraparesis 28.3 GNBL I 3: Neurogenic bladder
2 1.9 F Th12 – L3 2 → 1 BL/BW, mass 1.5 wks CT [3], L, S CR 4 1 1 6 3: Neurogenic bladder 29.5 NBL II-a 4: Obesity, BMI 40,6
5 0.6 F Th12 – L1 2 → 0 P 3 wks L, S CR 1 - - 1 15.6 NBL -
6 1.0 F Th9 – Th12 0 → 0 P, const N/A L, S CR 3 - - 3 22.3 NBL II-b
7 1.0 F Th11 – L1 2 → 0 P, mass 8 wks L, S CR 3 - - 3 20.2 NBL IV
8 1.2 F Th10 – L2 * → 2 dist, const N/A CT [4], S, CT [4], residual GN 7 2 - 9 3: Scoliosis Cobb angle 22.1 Ret.acid, MIBG [5, 55° 21,3GBq/575mCi] + HBO, S, RT, L NBL III 3: Thrombosis
9 2.8 M Th6 – Th9 * → 0 mass N/A MIBG [7, 18,9 residual GN 2 1 - 3 3: Scoliosis Cobb angle 20.7 GBq/511mCi], L 60° NBL III
10 0.8 M Th10 – L2 2 → 2 BL, P, const 3 wks L, S VGPR 3 3 1 7 3: Neurogenic bladder 18.4 NBL I 3: Osteomyelitis feet 3: Constipation, ileostomy 4: Paraparesis, wheelchair bound
11 1.5 F S3 – Cog1 0 → 0 mass N/A S, MIBG [5, residual GN 2 - - 2 18.0 13,5GBq/365mCi] GNBL III
13 1.3 M S1 – S2 2 → 2 OMS 10 wks S VGPR 1 2 - 3 3: OMS with head ataxia 7.4 NBL I 3: Mental retardation
14 0.8 F C7 – Th7 3 → 1 - Unknown MIBG [3, VGPR 3 - 1 4 4: 2nd malignancy: DNET 14.6 13,5GBq/365mCi], CT [1], tumor, after resection S, CT [3] seizure free NBL IV
15 1.1 M Th7 – Th10 0 → 0 - N/A L, S VGPR 1 - - 1 13.5 GNBL II-b
16 0.7 M Th12 – L4 2 → 1 mass, const 1 mnth L, MIBG [2, VGPR 2 - 2 4 4: 2nd malignancy: ALL 9.3 6,8GBq/184mCi] high risk NBL II-b 4: 2nd malignancy melanoma
158 Chapter 7 Neurologic symptoms CTCAE grade # Age at dx Sex Intraspinal At dx End FU Other sympt at dx Interval neuro sympt - dx Treatment Response 1/2 3 4 Total Details on Grade 3 and Follow-up extension HP 4 HPs (years) PA Stage
1 1.3 F Th2 – Th6 2 → 2 BL 12 wks L, S CR 3 2 - 5 3: Paraparesis 28.3 GNBL I 3: Neurogenic bladder
2 1.9 F Th12 – L3 2 → 1 BL/BW, mass 1.5 wks CT [3], L, S CR 4 1 1 6 3: Neurogenic bladder 29.5 NBL II-a 4: Obesity, BMI 40,6
5 0.6 F Th12 – L1 2 → 0 P 3 wks L, S CR 1 - - 1 15.6 NBL -
6 1.0 F Th9 – Th12 0 → 0 P, const N/A L, S CR 3 - - 3 22.3 NBL II-b
7 1.0 F Th11 – L1 2 → 0 P, mass 8 wks L, S CR 3 - - 3 20.2 NBL IV
8 1.2 F Th10 – L2 * → 2 dist, const N/A CT [4], S, CT [4], residual GN 7 2 - 9 3: Scoliosis Cobb angle 22.1 Ret.acid, MIBG [5, 55° 21,3GBq/575mCi] + HBO, S, RT, L NBL III 3: Thrombosis
9 2.8 M Th6 – Th9 * → 0 mass N/A MIBG [7, 18,9 residual GN 2 1 - 3 3: Scoliosis Cobb angle 20.7 GBq/511mCi], L 60° NBL III
10 0.8 M Th10 – L2 2 → 2 BL, P, const 3 wks L, S VGPR 3 3 1 7 3: Neurogenic bladder 18.4 NBL I 3: Osteomyelitis feet 3: Constipation, ileostomy 4: Paraparesis, wheelchair bound
11 1.5 F S3 – Cog1 0 → 0 mass N/A S, MIBG [5, residual GN 2 - - 2 18.0 13,5GBq/365mCi] GNBL III
13 1.3 M S1 – S2 2 → 2 OMS 10 wks S VGPR 1 2 - 3 3: OMS with head ataxia 7.4 NBL I 3: Mental retardation
14 0.8 F C7 – Th7 3 → 1 - Unknown MIBG [3, VGPR 3 - 1 4 4: 2nd malignancy: DNET 14.6 13,5GBq/365mCi], CT [1], tumor, after resection S, CT [3] seizure free NBL IV
15 1.1 M Th7 – Th10 0 → 0 - N/A L, S VGPR 1 - - 1 13.5 GNBL II-b
16 0.7 M Th12 – L4 2 → 1 mass, const 1 mnth L, MIBG [2, VGPR 2 - 2 4 4: 2nd malignancy: ALL 9.3 6,8GBq/184mCi] high risk NBL II-b 4: 2nd malignancy melanoma
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 159 17 0.7 F Th10 – L2 3 → 2 BL/BW 3 wks L, MIBG [2, CR 6 1 - 7 3: Neurogenic bladder 11.0 6,8GBq/184mCi], S NBL III
19 1.0 F Th10 – Th12 2 → 1 const 8 wks S, CT [6] VGPR 4 - - 4 6.3 NBL II-b
3 3.1 F Th12 – L3 * → 2 FtT, gait N/A S, L residual GN 2 - - 2 14.7 GN
4 10.4 F L3 – S2 1 → 1 - 4 wks S residual GN 3 - - 3 28.1 GN
12 7.3 F S1 – S2 0 → 0 dist N/A S residual GN - - - 0 10.2 GN
18 10.8 F C6 – Th4 1 → 1 dysp, asym 8 wks S, L residual GN 4 1 - 5 3: Horner’s syndrome: 11.1 correction ptosis GN
#= patient number, dx= diagnosis, PA= pathology, stage = INSS-stage (International Neuroblastoma Staging System), FU = follow-up, sympt = symptoms, neuro = neurologic, CTCAE = Common Terminology Criteria for Adverse Events, HP = health problems, NBL= neuroblastoma, GNBL= ganglioneuroblastoma, GN= ganglioneuroma. F = female, M = male, C = cervical, Th = thoracic, L = lumbar, S = sacral, Cog = coccygeal. Neurologic symptoms: * = no neurological symptoms at diagnosis, development neurological symptoms during course of disease, 0 = none, 1 = minor neurologic symptoms (paresthesia), 2 = paraparesis, 3 = paraplegia, BL = bladder dysfunction, BW = bowel dysfunction, P = pain, mass = paravertebral mass/swelling, dist = abdominal distension, const = constipation, OMS = opsoclonus-myoclonus syndrome, FtT = failure to thrive, gait = gait abnormality, dysp = dypnea, asym = asymmetrical thorax, N/A = not applicable, wks = weeks, mnths = months, L = laminectomy, S = surgical resection extraspinal tumor, CT = chemotherapy (with number of courses between brackets), MIBG = 131I-MIBG therapy (with number of courses and cumulative dose between brackets), HBO = hy- perbaric oxygen, Ret.acid = retinoic acid differentiation therapy, GBq = gigabecquerel, mCi = millicurie, CR = complete remission, VGPR = very good partial response, BMI = body mass index, OMS = opsoclonus-myoclonus syndrome, DNET = Dysembryoplastic neuroepithelial tumor, ALL = Acute lymphoblastic leukemia. Table III: Details of 19 long-term survivors of neuroblastoma with intraspinal extension
(11%) with paraplegia. Four patients out of 19 (21%) had a combined neurologic deficit and bowel and/ or bladder dysfunction. Frequent general symptoms were constipation 5/19 (26%), pain 4/19 (21%), and visible paravertebral mass 4/19 (21%). Treatment consisted of combinations of laminectomy, (extra spinal) surgery, chemotherapy, 131I-MIBG therapy, and/or RT (Table I). Thirteen out of 19 survivors (68%) underwent laminectomy, five out of 19 (26%) received131 I-MIBG therapy and RT was given in 1/19 (5%). Ninety-five percent (18/19) of the survivors had ≥ 1 health problem, and 9 patients (48%) ≥ 4 (Table II). Grade 3 or 4 health problems were recorded in 10 out of 19 (53%) survivors; no grade 5 events were reported. The mean number of health problems per survivor was 3.8 and the median 3.0. Seventy five percent of health problems were grade 1 or 2 events. Two out of 19 (11%) survivors had a severe burden of health problems, 5 out of 19 (26%) had a high burden, 9 out of 19 (47%) a medium burden, and 2 out of 19 (11%) survivors had a low burden health problems.
Figure 1 shows an overview of the frequencies of health problems observed in our cohort. Overall, most health problems belong in the category neurology, being: 18/72 (25%); musculoskeletal: 14/72 (19%);
160 Chapter 7 17 0.7 F Th10 – L2 3 → 2 BL/BW 3 wks L, MIBG [2, CR 6 1 - 7 3: Neurogenic bladder 11.0 6,8GBq/184mCi], S NBL III
19 1.0 F Th10 – Th12 2 → 1 const 8 wks S, CT [6] VGPR 4 - - 4 6.3 NBL II-b
3 3.1 F Th12 – L3 * → 2 FtT, gait N/A S, L residual GN 2 - - 2 14.7 GN
4 10.4 F L3 – S2 1 → 1 - 4 wks S residual GN 3 - - 3 28.1 GN
12 7.3 F S1 – S2 0 → 0 dist N/A S residual GN - - - 0 10.2 GN
18 10.8 F C6 – Th4 1 → 1 dysp, asym 8 wks S, L residual GN 4 1 - 5 3: Horner’s syndrome: 11.1 correction ptosis GN
#= patient number, dx= diagnosis, PA= pathology, stage = INSS-stage (International Neuroblastoma Staging System), FU = follow-up, sympt = symptoms, neuro = neurologic, CTCAE = Common Terminology Criteria for Adverse Events, HP = health problems, NBL= neuroblastoma, GNBL= ganglioneuroblastoma, GN= ganglioneuroma. F = female, M = male, C = cervical, Th = thoracic, L = lumbar, S = sacral, Cog = coccygeal. Neurologic symptoms: * = no neurological symptoms at diagnosis, development neurological symptoms during course of disease, 0 = none, 1 = minor neurologic symptoms (paresthesia), 2 = paraparesis, 3 = paraplegia, BL = bladder dysfunction, BW = bowel dysfunction, P = pain, mass = paravertebral mass/swelling, dist = abdominal distension, const = constipation, OMS = opsoclonus-myoclonus syndrome, FtT = failure to thrive, gait = gait abnormality, dysp = dypnea, asym = asymmetrical thorax, N/A = not applicable, wks = weeks, mnths = months, L = laminectomy, S = surgical resection extraspinal tumor, CT = chemotherapy (with number of courses between brackets), MIBG = 131I-MIBG therapy (with number of courses and cumulative dose between brackets), HBO = hy- perbaric oxygen, Ret.acid = retinoic acid differentiation therapy, GBq = gigabecquerel, mCi = millicurie, CR = complete remission, VGPR = very good partial response, BMI = body mass index, OMS = opsoclonus-myoclonus syndrome, DNET = Dysembryoplastic neuroepithelial tumor, ALL = Acute lymphoblastic leukemia. Table III: Details of 19 long-term survivors of neuroblastoma with intraspinal extension
growth and development 5/72 (7%) and pain and renal/genitourinary 5/72 (7%).
The most frequent encountered health problems were scoliosis and/or kyphosis 16/72 (22%) in 13/19 (68%) patients, neuropathy-motor 6/72 (8%) in 6/19 (32%) of patients, and neuropathy-sensory (5/72 (7%) in 5/19 (26%) of patients. Urinary tract infection, urinary retention due to neurogenic bladder, and hypergo- nadotropic hypogonadism were each individually found in 4/72 (6%).
We observed 3 secondary malignancies in 2 survivors. One survivor suffered from epileptic seizures caused by a dysembryoplastic neuroepithelial tumor. The other patient was diagnosed with leukemia (ALL high-risk) 6 years after diagnosis of NBL and 2 years later, with a malignant melanoma.
Table III and supplemental Table I show the neurological outcome at the end of follow-up compared with the neurologic status at diagnosis. Twelve patients presented with neurological symptoms, seven were asymptomatic at diagnosis. Thirteen of the 19 patients underwent a laminectomy at diagnosis. Of the
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 161 Abbreviations: OMS = opsoclonus-myoclonus syndrome, Horner’s syndr. = Horner’s syndrome, Involuntary mov. = Involuntary move- ment, Uri. electrolyte wasting = Urinary electrolyte wasting, NOS = not otherwise specified, Constit. Sympt = constitutional symptoms. Figure 1: Overview of the frequencies of Health problems.
162 Chapter 7 12 patients with neurological symptoms at diagnosis, 5 showed no improvement during follow-up (3/5 with laminectomy), 5 patients improved during follow-up (3/5 with laminectomy) and 2 patients recovered completely (2/2 with laminectomy). Seven out of 19 (37%) patients had no neurological symptoms at diagnosis, 6/7 (86%) were free of neurologic health problems at the end of follow-up. Five patients (# 8, 6, 9, 3, 15) who underwent a laminectomy had no symptoms of spinal cord compression at diagnosis. Three (# 8, 9, 3) of these patients developed neurologic symptoms years after diagnosis due to tumor progression with spinal cord compression.
Table III and supplemental Table I show the number of health problems and grade 3/4 events per survivor. Of the 13 patients who underwent a laminectomy, 7/13 (54%) developed a grade 3 health problem and 3/13 (23%) grade 4 health problem. There were 6 patients who had no laminectomy, 1/6 (17%) developed a grade 3 health problem and 1/6 (17%) a grade 4. There were no statistical differences in patients having a laminectomy vs. no laminectomy with respect to grade 3 (p=0,18)/ and grade 4 health problems (p=1,00). The median number of health problems in the laminectomy group was 4 (1-9) and in the no laminectomy group was 3 (0-4). Differences between neurological symptoms at diagnosis and grade 3 (p=0,17) and 4 health problems (p=0,22) were not statistically significant.
Discussion We found a high percentage (95%) of health problems in survivors treated for a childhood intraspinal NBL. Although the majority of health problems were either mild or moderate (Grade 1 and 2, respectively), 53% of survivors experienced either a severe (Grade 3) or life-threatening / disabling event (Grade 4), with a mean number of health problems per survivors of 3.8. Considering the young age and excellent survival of the study cohort (median age at the end of follow-up was 19.2 years; range 7.3 – 38.5 years), attention to health problems attributable to the combined effects of tumor and treatment is essential.
Some studies have already reported on late sequelae in survivors of NBL with intraspinal extension. However, these studies almost exclusively focused on neurological deficits, sphincter dysfunction, and spinal deformities. By using the CTCAE classification system, we identified less well known complications of treatment and disease (Figure 1). It is noteworthy that in other reported studies 131I-MIBG therapy is almost never reported and this could play an important role in having identified some new late health problems in our study. For example, we found that 26% (5/19) of survivors suffered from endocrine disorders, more specifically hypothyroidism (n=3) and hypergonadotropic hypogonadism (n=2). All 5 patients had been treated with 131I-MIBG-therapy and suggest these late effects maybe 131I-MIBG related.[17] The development of hypergonadotropic hypogonadism after 131I-MIBG-therapy requires more study, but might be influenced by urine stasis containing MIBG.[18] However, some of the new found health problems, i.e. fatigue, pulmonary, cardiac, vascular and short stature cannot purely be amenable to 131I-MIBG-therapy. As
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 163 such, they are not mentioned in the publications by other authors.[2;7-8]
This study has demonstrated that treatment of NBL with intraspinal extension is diverse; the optimal treatment strategy for these patients is still unclear.
Surgical and medical treatment modalities are often compared in retrospective cohort studies with regard to their short and long-term outcome. In our study, of the 13 patients that underwent a laminectomy we found a higher health problem burden as compared to the small group of patients treated with chemotherapy and no laminectomy. However, it cannot be ruled out that the higher morbidity and lower recovery rate often found with neurosurgery could, at least partly, be explained by the fact that the most severely affected, paraplegic patients are more likely to undergo neurosurgery and the study cohort is small. Sample selection bias, rather than true superiority of one treatment modality over the other would then explain the differences found in the burden of health problems. Part of the health problems can be attributed to therapy/ disease, but some health problems could also be due to an inherent condition.
Limitations of our current study are the relatively small study cohort, so we could not perform multivariate analyses. Strengths of our study are the completeness of (medical) follow-up and the complete evaluation of health problems, performed not only by questionnaires, but by physical examination in an outpatient setting, by using the CTCAE scoring system.
In conclusion, our study has demonstrated that the prevalence of health problems in long-term survivors of NBL with intraspinal extension is high, emphasizing the importance of specialized follow-up programs for survivors of NBL with intraspinal extension. Also, there is a need to identify optimal treatment for these patients with limited morbidity and maximal efficacy.
Funding This work was supported by Stichting Kinderen Kankervrij (KiKa). The funding source did not have any involvement in the study design, collection, analysis and interpretation of data, writing of the report or in the decision to submit the article for publication.
Conflict of interest statement None declared.
164 Chapter 7 Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 165 Neurologic symptoms Treatment Health Problems graded according to CTCAE # Age at dx Primary tumor At dx End Other sympt Interval neuro Time after dx (years) Treatment Response Category Health problem Remark Gr. at dx sympt - dx
PA FU ↘ Clinical course Follow-up (years) Sex Intraspinal Stage extension
1 1.3 paravert. Th 2 → 2 BL 12 wks 0 – at dx Laminectomy Th2-Th6 + CR Neurology Neuropathy- Paraparesis. SCC Th4. 3 symp. chain Thoracotomy (1 month interval) motor Surgical correction pes planovalgus
GNBL ↘ Complete resection intra- and Lu extraspinal tumor. F Th2 – Th6 28.3 Growth & dev Lordosis Th R convex - Cobb angle 1 unknown I Musculoskel. Scoliosis Neurogenic bladder 1 Renal/genitouri Urinary retention Recurrent; AB prophylaxis; 1 urosepsis (2003) Infection Urinary tract 3
2 1.9 paravert. L symp. 2 → 1 BL/BW, mass 1.5 wks 0 – at dx CT - 3 courses OPEC CR Growth & dev Kyphosis/ Kyphosis Th and lordosis Lu 1 chain Constit. sympt lordosis
NBL ↘ Progression neurologic deficit. Cardiac Obesity BMI = 40.6 (2013) 4 F Th12 – L3 0.2 Laminectomy Th9-L2 + laparotomy 29.5 GI Hypertension Beta blocker -> non- 2 (combined approach) compliant
II-a ↘ Macroscopic complete resection. Infection Constipation Recurrent 1 Later no evidence of disease. Renal/genitouri Urinary tract Neurogenic bladder. 2 Catheterization. Afunctional L kidney, hydronephrotic R kidney. Bladder augmentation. Urinary retention 3
5 0.6 paravert. Th-L 2 → 0 P 3 wks 0 – at dx Laminectomy Th12-L2 + CR Pulmonary Bronchospasm Med: bronchodilators and 2 symp. chain Laparotomy (10 day interval) steroids
NBL ↘ Complete resection intra- and extraspinal tumor. F Th12 – L1 15.6 -
6 1.0 paravert. Th 0 → 0 P, const N/A 0 – at dx Laminectomy Th10-Th12 + CR Growth & dev. Short stature < - 2SD 1 symp. chain Thoracotomy (18 day interval)
NBL ↘ Complete resection intra- and Musculoskel. Scoliosis S-type Th-Lu L - Cobb angle 2 extraspinal tumor. 42° (2012) F Th9 – Th12 22.3 Pain Back pain 2 II-b
166 Chapter 7 Neurologic symptoms Treatment Health Problems graded according to CTCAE # Age at dx Primary tumor At dx End Other sympt Interval neuro Time after dx (years) Treatment Response Category Health problem Remark Gr. at dx sympt - dx
PA FU ↘ Clinical course Follow-up (years) Sex Intraspinal Stage extension
1 1.3 paravert. Th 2 → 2 BL 12 wks 0 – at dx Laminectomy Th2-Th6 + CR Neurology Neuropathy- Paraparesis. SCC Th4. 3 symp. chain Thoracotomy (1 month interval) motor Surgical correction pes planovalgus
GNBL ↘ Complete resection intra- and Lu extraspinal tumor. F Th2 – Th6 28.3 Growth & dev Lordosis Th R convex - Cobb angle 1 unknown I Musculoskel. Scoliosis Neurogenic bladder 1 Renal/genitouri Urinary retention Recurrent; AB prophylaxis; 1 urosepsis (2003) Infection Urinary tract 3
2 1.9 paravert. L symp. 2 → 1 BL/BW, mass 1.5 wks 0 – at dx CT - 3 courses OPEC CR Growth & dev Kyphosis/ Kyphosis Th and lordosis Lu 1 chain Constit. sympt lordosis
NBL ↘ Progression neurologic deficit. Cardiac Obesity BMI = 40.6 (2013) 4 F Th12 – L3 0.2 Laminectomy Th9-L2 + laparotomy 29.5 GI Hypertension Beta blocker -> non- 2 (combined approach) compliant
II-a ↘ Macroscopic complete resection. Infection Constipation Recurrent 1 Later no evidence of disease. Renal/genitouri Urinary tract Neurogenic bladder. 2 Catheterization. Afunctional L kidney, hydronephrotic R kidney. Bladder augmentation. Urinary retention 3
5 0.6 paravert. Th-L 2 → 0 P 3 wks 0 – at dx Laminectomy Th12-L2 + CR Pulmonary Bronchospasm Med: bronchodilators and 2 symp. chain Laparotomy (10 day interval) steroids
NBL ↘ Complete resection intra- and extraspinal tumor. F Th12 – L1 15.6 -
6 1.0 paravert. Th 0 → 0 P, const N/A 0 – at dx Laminectomy Th10-Th12 + CR Growth & dev. Short stature < - 2SD 1 symp. chain Thoracotomy (18 day interval)
NBL ↘ Complete resection intra- and Musculoskel. Scoliosis S-type Th-Lu L - Cobb angle 2 extraspinal tumor. 42° (2012) F Th9 – Th12 22.3 Pain Back pain 2 II-b
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 167 7 1.0 paravert. Th 2 → 0 P, mass 8 wks 0 – at dx Laminectomy Th11-L1 + combined CR Neurology Mood alteration Depression 2 symp. chain laparotomy / thoracotomy (11 day interval)
NBL ↘ Complete resection intra- and Musculoskel. Scoliosis C-type Th R - Cobb angle 22° 2 extraspinal tumor. (2007) F Th11 – L1 20.2 Pain Headache 2 IV
8 1.2 paravert. Th-L * → 2 dist, const N/A 0 – at dx CT - 4 courses VECI. Laparotomy. residual GN Neurology Neuropathy- Sensory loss legs 2 symp. chain CT - 4 courses VECI. Retinoic acid sensory differentiation therapy
NBL ↘ Progressive disease: increase Neurology Neuropathy- Loss motor strength legs 2 tumor volume + excretion motor during exertion (-> spinal catecholamines. canal stenosis) F Th10 – L2 MIBG (5 courses: cumulative dose 22.1 T-score= -2,1 21,3GBq/575mCi) combined with HBO therapy
III ↘ Thrombopenia in combination Musculoskel. Osteoporosis C-type Lu L, compensatory 1 with difficulty of tolerance MIBG => curve R - Cobb angle 55° consultation surgery. (2011) 1.1 Laparotomy Musculoskel. Scoliosis Tubulopathy (after 3 ifosfamide)
↘ Residual intraspinal tumor. Premature ovarian failure Initially observation only. In course -> HRT of 9 years, increase in tumor volume and development neuro deficit. Radiotherapy - Th12-L4 Renal/genitouri Urinary Anti-coagulant 1 electrolyte wasting
↘ Insufficient response. Sexual/repro Sterility/infertility Aplasia permanent molars 2 2.0 Laminectomy L1-L3 Vascular Thrombosis 3
↘ PA: GN. Partial recovery neuro GI Teeth 1 deficit. Residual paravertebral development tumor. Pain Back pain 1 11.3 11.6
9 2.8 paravert. Th * → 0 mass N/A 0 – at dx MIBG (7 courses: cumulative dose residual GN Musculoskel. Scoliosis C-type Th R - Cobb angle 60°. 3 symp. chain 18,9 GBq/511mCi). Hypothyroidism Spondylodesis.
NBL ↘ Development neurologic deficit. Endocrine Vital capacity Thyroid hormone 2 replacement M Th6 – Th9 2.0 Laminectomy Th6-Th9 20.7 Pulmonary Forced Vital Capacity = 72% 2
III ↘ Improvement neuro deficit. Residual tumor. Histology: maturation into GN.
168 Chapter 7 7 1.0 paravert. Th 2 → 0 P, mass 8 wks 0 – at dx Laminectomy Th11-L1 + combined CR Neurology Mood alteration Depression 2 symp. chain laparotomy / thoracotomy (11 day interval)
NBL ↘ Complete resection intra- and Musculoskel. Scoliosis C-type Th R - Cobb angle 22° 2 extraspinal tumor. (2007) F Th11 – L1 20.2 Pain Headache 2 IV
8 1.2 paravert. Th-L * → 2 dist, const N/A 0 – at dx CT - 4 courses VECI. Laparotomy. residual GN Neurology Neuropathy- Sensory loss legs 2 symp. chain CT - 4 courses VECI. Retinoic acid sensory differentiation therapy
NBL ↘ Progressive disease: increase Neurology Neuropathy- Loss motor strength legs 2 tumor volume + excretion motor during exertion (-> spinal catecholamines. canal stenosis) F Th10 – L2 MIBG (5 courses: cumulative dose 22.1 T-score= -2,1 21,3GBq/575mCi) combined with HBO therapy
III ↘ Thrombopenia in combination Musculoskel. Osteoporosis C-type Lu L, compensatory 1 with difficulty of tolerance MIBG => curve R - Cobb angle 55° consultation surgery. (2011) 1.1 Laparotomy Musculoskel. Scoliosis Tubulopathy (after 3 ifosfamide)
↘ Residual intraspinal tumor. Premature ovarian failure Initially observation only. In course -> HRT of 9 years, increase in tumor volume and development neuro deficit. Radiotherapy - Th12-L4 Renal/genitouri Urinary Anti-coagulant 1 electrolyte wasting
↘ Insufficient response. Sexual/repro Sterility/infertility Aplasia permanent molars 2 2.0 Laminectomy L1-L3 Vascular Thrombosis 3
↘ PA: GN. Partial recovery neuro GI Teeth 1 deficit. Residual paravertebral development tumor. Pain Back pain 1 11.3 11.6
9 2.8 paravert. Th * → 0 mass N/A 0 – at dx MIBG (7 courses: cumulative dose residual GN Musculoskel. Scoliosis C-type Th R - Cobb angle 60°. 3 symp. chain 18,9 GBq/511mCi). Hypothyroidism Spondylodesis.
NBL ↘ Development neurologic deficit. Endocrine Vital capacity Thyroid hormone 2 replacement M Th6 – Th9 2.0 Laminectomy Th6-Th9 20.7 Pulmonary Forced Vital Capacity = 72% 2
III ↘ Improvement neuro deficit. Residual tumor. Histology: maturation into GN.
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 169 10 0.8 paravert. Th-L 2 → 2 BL, P, const 3 wks 0 – at dx Laminectomy Th12-L3 + VGPR Neurology Neuropathy- Loss sensibility legs 2 symp. chain laparotomy (29 day interval) sensory
NBL ↘ Macroscopic complete Neurology Neuropathy- Paraparesis -> SCC tumor. 4 resection. motor Surgical correction pes equinus. Wheelchair bound M Th10 – L2 18.4 Th - Cobb angle unknown. Asymptomatic I Musculoskel. Scoliosis Neurogenic bladder. 1 Urostomy Renal/genitouri Urinary retention Recurrent; AB prophylaxis 3 Infection Urinary tract 2 NOS Infection Osteomyelitis -> ileostomy 3 - Feet GI Constipation 3
11 1.5 presacral symp. 0 → 0 mass N/A 0 – at dx Surgery - excision presacral, residual GN Sexual/repro Sterility/infertility Premature ovarian failure 2 chain intraspinal tumor with extirpation -> HRT os coccygis.
GNBL ↘ Incomplete resection. Endocrine Hypothyroidism Transient TSH elevation; no 1 substitution. Multinod. goiter F S3 – Cog1 MIBG (5 courses: cumulative dose 18.0 13,5GBq/365mCi)
III 0.1 ↘ Decrease in tumor volume. Residual tumor. Histology: transanal biopsy: maturation into GN.
13 1.3 presacral symp. 2 → 2 OMS 10 wks 0 – at dx Laparotomy VGPR Neurology Neuropathy- Paraparesis 2 chain motor
NBL ↘ Incomplete resection. Neurology OMS with Ataxia head 3 M S1 – S2 7.4 Neurology Cognitive Mental retardation 3 disturbance I
14 0.8 paravert. Th 3 → 1 - UKW 0 – at dx MIBG (3 courses: cumulative dose VGPR Neurology Horner's syndr. 2 symp. chain 13,5GBq/365mCi)
NBL ↘ Improvement neuro deficit. Endocrine Hypothyroidism Thyroid hormone 2 Consultation surgery => start with replacement chemotherapy to reduce tumor volume before surgery. F C7 – Th7 CT - 1 course of VECI. 14.6 Sexual/repro Sterility/infertility Premature ovarian failure 2 Thoracotomy. CT - 3 courses of -> HRT VECI.
IV ↘ Microscopic complete resection. 2nd malignancy Dysembryoplastic 4 Recovery neuro deficit. neuroepithelial tumor: after resection seizure free 0.3
170 Chapter 7 10 0.8 paravert. Th-L 2 → 2 BL, P, const 3 wks 0 – at dx Laminectomy Th12-L3 + VGPR Neurology Neuropathy- Loss sensibility legs 2 symp. chain laparotomy (29 day interval) sensory
NBL ↘ Macroscopic complete Neurology Neuropathy- Paraparesis -> SCC tumor. 4 resection. motor Surgical correction pes equinus. Wheelchair bound M Th10 – L2 18.4 Th - Cobb angle unknown. Asymptomatic I Musculoskel. Scoliosis Neurogenic bladder. 1 Urostomy Renal/genitouri Urinary retention Recurrent; AB prophylaxis 3 Infection Urinary tract 2 NOS Infection Osteomyelitis -> ileostomy 3 - Feet GI Constipation 3
11 1.5 presacral symp. 0 → 0 mass N/A 0 – at dx Surgery - excision presacral, residual GN Sexual/repro Sterility/infertility Premature ovarian failure 2 chain intraspinal tumor with extirpation -> HRT os coccygis.
GNBL ↘ Incomplete resection. Endocrine Hypothyroidism Transient TSH elevation; no 1 substitution. Multinod. goiter F S3 – Cog1 MIBG (5 courses: cumulative dose 18.0 13,5GBq/365mCi)
III 0.1 ↘ Decrease in tumor volume. Residual tumor. Histology: transanal biopsy: maturation into GN.
13 1.3 presacral symp. 2 → 2 OMS 10 wks 0 – at dx Laparotomy VGPR Neurology Neuropathy- Paraparesis 2 chain motor
NBL ↘ Incomplete resection. Neurology OMS with Ataxia head 3 M S1 – S2 7.4 Neurology Cognitive Mental retardation 3 disturbance I
14 0.8 paravert. Th 3 → 1 - UKW 0 – at dx MIBG (3 courses: cumulative dose VGPR Neurology Horner's syndr. 2 symp. chain 13,5GBq/365mCi)
NBL ↘ Improvement neuro deficit. Endocrine Hypothyroidism Thyroid hormone 2 Consultation surgery => start with replacement chemotherapy to reduce tumor volume before surgery. F C7 – Th7 CT - 1 course of VECI. 14.6 Sexual/repro Sterility/infertility Premature ovarian failure 2 Thoracotomy. CT - 3 courses of -> HRT VECI.
IV ↘ Microscopic complete resection. 2nd malignancy Dysembryoplastic 4 Recovery neuro deficit. neuroepithelial tumor: after resection seizure free 0.3
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 171 15 1.1 paravert. Th 0 → 0 incid N/A 0 – at dx Observation only VGPR Musculoskel. Scoliosis Th-L convex R - Cobb angle 1 symp. chain 9°. Compensatory pelvic obliquity.
GNBL ↘ In course of 2 years, increase tumor volume and development intraspinal extension. M Th7 – Th10 Laminectomy + thoracotomy (65 13.5 day interval)
II-b 2.1 ↘ Macroscopic residual tumor. 16 0.7 paravert. Th-L 2 → 1 mass, const 1 mnth 0 – at dx Laminectomy L1-L4 VGPR Neurology Neuropathy- Paresis peroneal nerve. 2 symp. chain motor Surgical correction Achilles tendon
NBL ↘ Improvement neuro deficit. Minimal; asymptomatic. Period of observation. Increase tumor volume + excretion catecholamines. M Th12 – L4 MIBG (2 courses - cumulative dose 9.3 Musculoskel. Scoliosis ALL high-risk (2004) 1 6,8GBq/184mCi)
II-b 0.3 ↘ Tumor regression. Stable 2nd malignancy Melanoma (2006) 4 extraspinal residual tumor. 2nd malignancy 4
17 0.7 paravert. L symp. 3 → 2 BL/BW 3 wks 0 – at dx Laminectomy Th10-L4 + MIBG CR Neurology Neuropathy- Loss sensibility legs 2 chain (2 courses; cumulative dose sensory 6,8GBq/184mCi)
NBL ↘ Residual retroperitoneal tumor. Neurology Neuropathy- Paraparesis. Surgical 2 Decrease in tumor volume after motor correction pes equinovarus MIBG. F Th10 – L2 Laparotomy - excision extraspinal 11.0 Minimal; asymptomatic. tumor.
III ↘ Complete resection extraspinal Musculoskel. Scoliosis Recurrent 1 tumor. 0.4 Infection Urinary tract Premature ovarian failure 2 NOS -> HRT Sexual/repro Sterility/infertility Monthly bowel lavage 2 GI Constipation Neurogenic bladder. Self 2 catheterization. Renal/genitouri Urinary retention 3
19 1.0 paravert. L symp. 2 → 1 const 8 wks 0 – at dx Laparotomy VGPR Neurology Involuntary mov. Myoclonus leg 1 chain
NBL ↘ Excision paravertebral tumor. No Neurology Neuropathy- Loss sensibility L5/S1 1 improvement neurologic deficit. sensory F Th10 – Th12 CT - 6 courses etoposide + 6.3 Growth & dev. Kyphosis Gibbus deformity L 1 cm. 1 carboplatin
II-b 0 ↘ Improvement neuro deficit. Musculoskel. Scoliosis Th L convex - Cobb angle 1 Decrease tumor volume. 10° (2013) Observation.
172 Chapter 7 15 1.1 paravert. Th 0 → 0 incid N/A 0 – at dx Observation only VGPR Musculoskel. Scoliosis Th-L convex R - Cobb angle 1 symp. chain 9°. Compensatory pelvic obliquity.
GNBL ↘ In course of 2 years, increase tumor volume and development intraspinal extension. M Th7 – Th10 Laminectomy + thoracotomy (65 13.5 day interval)
II-b 2.1 ↘ Macroscopic residual tumor. 16 0.7 paravert. Th-L 2 → 1 mass, const 1 mnth 0 – at dx Laminectomy L1-L4 VGPR Neurology Neuropathy- Paresis peroneal nerve. 2 symp. chain motor Surgical correction Achilles tendon
NBL ↘ Improvement neuro deficit. Minimal; asymptomatic. Period of observation. Increase tumor volume + excretion catecholamines. M Th12 – L4 MIBG (2 courses - cumulative dose 9.3 Musculoskel. Scoliosis ALL high-risk (2004) 1 6,8GBq/184mCi)
II-b 0.3 ↘ Tumor regression. Stable 2nd malignancy Melanoma (2006) 4 extraspinal residual tumor. 2nd malignancy 4
17 0.7 paravert. L symp. 3 → 2 BL/BW 3 wks 0 – at dx Laminectomy Th10-L4 + MIBG CR Neurology Neuropathy- Loss sensibility legs 2 chain (2 courses; cumulative dose sensory 6,8GBq/184mCi)
NBL ↘ Residual retroperitoneal tumor. Neurology Neuropathy- Paraparesis. Surgical 2 Decrease in tumor volume after motor correction pes equinovarus MIBG. F Th10 – L2 Laparotomy - excision extraspinal 11.0 Minimal; asymptomatic. tumor.
III ↘ Complete resection extraspinal Musculoskel. Scoliosis Recurrent 1 tumor. 0.4 Infection Urinary tract Premature ovarian failure 2 NOS -> HRT Sexual/repro Sterility/infertility Monthly bowel lavage 2 GI Constipation Neurogenic bladder. Self 2 catheterization. Renal/genitouri Urinary retention 3
19 1.0 paravert. L symp. 2 → 1 const 8 wks 0 – at dx Laparotomy VGPR Neurology Involuntary mov. Myoclonus leg 1 chain
NBL ↘ Excision paravertebral tumor. No Neurology Neuropathy- Loss sensibility L5/S1 1 improvement neurologic deficit. sensory F Th10 – Th12 CT - 6 courses etoposide + 6.3 Growth & dev. Kyphosis Gibbus deformity L 1 cm. 1 carboplatin
II-b 0 ↘ Improvement neuro deficit. Musculoskel. Scoliosis Th L convex - Cobb angle 1 Decrease tumor volume. 10° (2013) Observation.
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 173 3 3.1 paravert. L symp. * → 2 FtT, gait N/A 0 – at dx Laparotomy residual GN Growth & dev. Lordosis Lordosis Lu 2 chain
GN ↘ Residual intraspinal tumor. Musculoskel. Scoliosis S-type Th R convex, Lu L 2 Combination GN and no neuro convex -Cobb angle 25° deficit => observation only. (1998) Symptoms tethered cord in course of years. F Th12 – L3 Laminectomy Th11-L5 14.7
↘ Recovery neuro deficit. Residual intraspinal and retroperitoneal tumor. 3.4
4 10.4 paravert. L symp. 1 → 1 - 4 wks 0 – at dx Laparotomy residual GN Neurology Neuropathy- Paresthesia legs 1 chain sensory
GN ↘ Residual intraspinal tumor. Musculoskel. Arthritis Reumatoid arthritis - MTX tx 2 F L3 – S2 28.1 Pain Back pain 2 with radicular symptoms
12 7.3 presacral symp. 0 → 0 dist N/A 0.2 Laparotomy residual GN chain
GN ↘ Incomplete resection. Residual tumor. F S1 – S2 10.2
18 10.8 paravert. C-Th 1 → 1 dysp, asym 8 wks 0 – at dx Excision cervical GN residual GN Neurology Horner's syndr. Surgical correction ptosis 3 symp. chain 2009
GN ↘ No FU. 4.5 yrs after diagnosis Neurology Mood alteration Depression 1 recurrent disease. F C6 – Th4 5.5 Laminectomy C7-Th2 + 11.1 Musculoskel. Scoliosis S-type Th L convex, Th-Lu R 1 thoracotomy (combined approach) convex -Cobb angle 20°
↘ Excision 98% tumor. Observation residual tumor. Pain Neck and 2 shoulder Constit. sympt Fatigue 1
#= patient number, dx= diagnosis, PA= pathology, stage = INSS-stage (International Neuroblastoma Staging System), FU = follow-up, sympt incid= incidental finding medical imaging, OMS = opsoclonus-myoclonus syndrome, FtT = failure to thrive, gait = gait abnormality, dysp = symptoms, neuro = neurologic, CTCAE = Common Terminology Criteria for Adverse Events, HP = health problems. NBL= neuroblastoma, = dypnea, asym = asymmetrical thorax. N/A = not applicable, wks = weeks, mnths = months. L = laminectomy, S = surgical resection GNBL= ganglioneuroblastoma, GN= ganglioneuroma. F = female, M = male. Paravert. = paravertebral, symp. = sympathetic. C = cervical, Th = extraspinal tumor, CT = chemotherapy (with number of courses between brackets), OPEC = vincristine (O), cisplatin (P), Etoposide thoracic, L = lumbar, S = sacral, Cog = coccygeal. Neurologic symptoms: * = no neurological symptoms at diagnosis, development neurological (E),Cyclophosphamide (C). VECI= Vincristin (V), Etoposide (E), carboplatin (C) and Ifosfamide (I). MIBG = 131I-MIBG therapy (with number symptoms during course of disease, 0 = none, 1 = minor neurologic symptoms (paresthesia), 2 = paraparesis, 3 = paraplegia. BL = bladder of courses and cumulative dose between brackets), HBO = hyperbaric oxygen, Ret.acid = retinoic acid differentiation therapy, GBq = dysfunction, BW = bowel dysfunction, P = pain, mass = paravertebral mass/swelling, dist = abdominal distension, const = constipation, gigabecquerel, mCi = millicurie. CR = complete remission, VGPR = very good partial response. BMI = body mass index, OMS = opsoclo- nus-myoclonus syndrome, DNET = Dysembryoplastic neuroepithelial tumor, ALL = Acute lymphoblastic leukemia. Supplemental Table I: Complete data on 19 long-term survivors of neuroblastoma with intraspinal extension
174 Chapter 7 3 3.1 paravert. L symp. * → 2 FtT, gait N/A 0 – at dx Laparotomy residual GN Growth & dev. Lordosis Lordosis Lu 2 chain
GN ↘ Residual intraspinal tumor. Musculoskel. Scoliosis S-type Th R convex, Lu L 2 Combination GN and no neuro convex -Cobb angle 25° deficit => observation only. (1998) Symptoms tethered cord in course of years. F Th12 – L3 Laminectomy Th11-L5 14.7
↘ Recovery neuro deficit. Residual intraspinal and retroperitoneal tumor. 3.4
4 10.4 paravert. L symp. 1 → 1 - 4 wks 0 – at dx Laparotomy residual GN Neurology Neuropathy- Paresthesia legs 1 chain sensory
GN ↘ Residual intraspinal tumor. Musculoskel. Arthritis Reumatoid arthritis - MTX tx 2 F L3 – S2 28.1 Pain Back pain 2 with radicular symptoms
12 7.3 presacral symp. 0 → 0 dist N/A 0.2 Laparotomy residual GN chain
GN ↘ Incomplete resection. Residual tumor. F S1 – S2 10.2
18 10.8 paravert. C-Th 1 → 1 dysp, asym 8 wks 0 – at dx Excision cervical GN residual GN Neurology Horner's syndr. Surgical correction ptosis 3 symp. chain 2009
GN ↘ No FU. 4.5 yrs after diagnosis Neurology Mood alteration Depression 1 recurrent disease. F C6 – Th4 5.5 Laminectomy C7-Th2 + 11.1 Musculoskel. Scoliosis S-type Th L convex, Th-Lu R 1 thoracotomy (combined approach) convex -Cobb angle 20°
↘ Excision 98% tumor. Observation residual tumor. Pain Neck and 2 shoulder Constit. sympt Fatigue 1
#= patient number, dx= diagnosis, PA= pathology, stage = INSS-stage (International Neuroblastoma Staging System), FU = follow-up, sympt incid= incidental finding medical imaging, OMS = opsoclonus-myoclonus syndrome, FtT = failure to thrive, gait = gait abnormality, dysp = symptoms, neuro = neurologic, CTCAE = Common Terminology Criteria for Adverse Events, HP = health problems. NBL= neuroblastoma, = dypnea, asym = asymmetrical thorax. N/A = not applicable, wks = weeks, mnths = months. L = laminectomy, S = surgical resection GNBL= ganglioneuroblastoma, GN= ganglioneuroma. F = female, M = male. Paravert. = paravertebral, symp. = sympathetic. C = cervical, Th = extraspinal tumor, CT = chemotherapy (with number of courses between brackets), OPEC = vincristine (O), cisplatin (P), Etoposide thoracic, L = lumbar, S = sacral, Cog = coccygeal. Neurologic symptoms: * = no neurological symptoms at diagnosis, development neurological (E),Cyclophosphamide (C). VECI= Vincristin (V), Etoposide (E), carboplatin (C) and Ifosfamide (I). MIBG = 131I-MIBG therapy (with number symptoms during course of disease, 0 = none, 1 = minor neurologic symptoms (paresthesia), 2 = paraparesis, 3 = paraplegia. BL = bladder of courses and cumulative dose between brackets), HBO = hyperbaric oxygen, Ret.acid = retinoic acid differentiation therapy, GBq = dysfunction, BW = bowel dysfunction, P = pain, mass = paravertebral mass/swelling, dist = abdominal distension, const = constipation, gigabecquerel, mCi = millicurie. CR = complete remission, VGPR = very good partial response. BMI = body mass index, OMS = opsoclo- nus-myoclonus syndrome, DNET = Dysembryoplastic neuroepithelial tumor, ALL = Acute lymphoblastic leukemia. Supplemental Table I: Complete data on 19 long-term survivors of neuroblastoma with intraspinal extension
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 175 Reference list Coze C, Chastagner P, Frappaz D, Gigaud M, Passagia JG, Hartmann O. The treatment of 1. Joaquim AF, Cheng I, Patel AA. Postoperative neuroblastoma with intraspinal extension with spinal deformity after treatment of chemotherapy followed by surgical removal intracanal spine lesions. Spine J 2012 of residual disease. A prospective study of 42 November;12(11):1067-74. patients--results of the NBL 90 Study of the French Society of Pediatric Oncology. Cancer 2. Simon T, Niemann CA, Hero B, Henze G, 1996 July 15;78(2):311-9. Suttorp M, Schilling FH, Berthold F. Short- and long-term outcome of patients with 7. Katzenstein HM, Kent PM, London WB, Cohn symptoms of spinal cord compression by SL. Treatment and outcome of 83 children neuroblastoma. Dev Med Child Neurol 2012 with intraspinal neuroblastoma: the Pediatric February 13. Oncology Group experience. J Clin Oncol 2001 February 15;19(4):1047-55. 3. De Bernardi BB, Pianca C, Pistamiglio P, Veneselli E, Viscardi E, Pession A, Alvisi P, 8. Angelini P, Plantaz D, De BB, Passagia Carli M, Donfrancesco A, Casale F, Giuliano JG, Rubie H, Pastore G. Late sequelae of MG, di Montezemolo LC, Di Cataldo A, symptomatic epidural compression in Lo Curto M, Bagnulo S, Schumacher RF, children with localized neuroblastoma. Pediatr Tamburini A, Garaventa A, Clemente L, Bruzzi Blood Cancer 2011 September;57(3):473-80. P. Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment 9. Hoover M, Bowman LC, Crawford SE, Stack and results with 76 cases. J Clin Oncol 2001 C, Donaldson JS, Grayhack JJ, Tomita T, January 1;19(1):183-90. Cohn SL. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 4. King D, Goodman J, Hawk T, Boles ET, Jr., 1999 May;32(5):353-9. Sayers MP. Dumbbell neuroblastomas in children. Arch Surg 1975 10. Geenen MM, Cardous-Ubbink MC, Kremer August;110(8):888-91. LC, van den BC, van der Pal HJ, Heinen RC, Jaspers MW, Koning CC, Oldenburger F, 5. Hayes FA, Thompson EI, Hvizdala E, Langeveld NE, Hart AA, Bakker PJ, Caron O’Connor D, Green AA. Chemotherapy as an HN, van Leeuwen FE. Medical assessment alternative to laminectomy and radiation in of adverse health outcomes in long-term the management of epidural tumor. J Pediatr survivors of childhood cancer. JAMA 2007 1984 February;104(2):221-4. June 27;297(24):2705-15.
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176 Chapter 7 Dalen EC, Knijnenburg SL, van der Pal HJ, AT, Friedman DL, Marina N, Hobbie W, Mud MS, Heinen RC, Caron HN, Kremer LC. Kadan-Lottick NS, Schwartz CL, Leisenring W, The EKZ/AMC childhood cancer survivor Robison LL. Chronic health conditions in adult cohort: methodology, clinical characteristics, survivors of childhood cancer. N Engl J Med and data availability. J Cancer Surviv 2013 2006 October 12;355(15):1572-82. September;7(3):439-54. 17. Clement SC, van Eck-Smit BL, van 12. Brodeur GM, Seeger RC, Barrett A, Berthold Trotsenburg AS, Kremer LC, Tytgat GA, F, Castleberry RP, D’Angio G, De Bernardi B, van Santen HM. Long-term follow-up of Evans AE, Favrot M, Freeman AI. International the thyroid gland after treatment with criteria for diagnosis, staging, and response 131I-Metaiodobenzylguanidine in children with to treatment in patients with neuroblastoma. neuroblastoma: importance of continuous J Clin Oncol 1988 December;6(12):1874-81. surveillance. Pediatr Blood Cancer 2013 November;60(11):1833-8. 13. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De 18. Clement SC, Kraal KC, van Eck-Smit Bernardi B, Evans AE, Favrot M, Hedborg BL, van den Bos C, Kremer LC, Tytgat F, Kaneko M, Kemshead J, Lampert F, Lee GA, van Santen HM. Primary ovarian REJ, Look T, Pearson ADJ, Philip T, Roald insufficiency in children after treatment B, Sawada T, Seeger RC, Tsuchida Y, Voute with 131I-metaiodobenzylguanidine for PA. Revisions of the international criteria neuroblastoma: report of the first two for neuroblastoma diagnosis, staging, and cases. J Clin Endocrinol Metab 2014 response to treatment. J Clin Oncol 1993 January;99(1):E112-E116. August;11(8):1466-77.
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Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors 177 The first 2 authors have contributed equally to this systematic review. The last 2 authors have contributed equally to this systematic review.
1. Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. 2. Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands 3. Department of Medical Oncology, Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands Chapter 8 Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review
KCJM Kraal1,2, AJ Blom¹, MM van Noesel¹, LCM Kremer², HN Caron², GAM Tytgat1,2, and HJH van der Pal³.
Submitted for publication Abbreviations NBL Neuroblastoma EROS Early Review Organizing Software OS overall survival EFS event free survival RT radiotherapy SEC symptoms of epidural compression SIOP International Society of Paediatric Oncology Europe Neuroblastoma
Abstract We performed a systematic review to define the long-term health problems and optimal treatment strategy for patients with neuroblastoma with intraspinal extension. Out of 685 identified studies, 28 were included in this review. The burden of long-term health problems is high; a median of 50% of patients suffered from neurological motor deficit, 33.5% from sphincter dysfunction, and 30% from spinal deformity. Unfortunately, the currently available literature remains suboptimal as a guide for treatment of NBL with intraspinal extension. However, neurosurgery is often suggested as main contributor to the burden experienced. More well-designed, prospective studies are needed to determine the optimal treatment strategy.
180 Chapter 8 Introduction Neuroblastoma (NBL), a malignancy of the sympathetic nervous system, may extend into the interver- tebral foramina, especially when arising from the sympathetic side chain, and consequently induce spinal cord and nerve root compression with symptoms of neurological motor and sensory deficits, sphincter dysfunction, and pain. These symptoms are a medical emergency and require prompt initiation of treatment to prevent these symptoms to become permanent, irreversible neurological changes. An accurate and timely diagnosis, however, is challenging because of difficulties in expressing and/ or assessing these symptoms in young children. Relief of symptoms can be obtained by neurosurgical decompression, radiotherapy, and chemotherapy, but all these therapeutic modalities are associated with short- and long-term morbidities. Neurosurgical decompression leads to immediate spinal decompression and is considered the most appropriate treatment modality for patients with differentiated tumors which are unresponsive to chemotherapy and for patients who have progressive neurological deterioration, while receiving chemotherapy. Orthopedic problems, especially spinal deformity increasing with time, typically ensue (1), although it is reported that modern, less invasive neurosurgical techniques may lead to less treatment associated long-term health problems (2,3). Moreover, surgical complications leading to spinal cord ischemia and complete paraplegia are described (4). Radiotherapy is mainly associated with problems of growth and development, furthermore, post-irradiation thyroid problems are reported when the upper spine is involved (5,6). Both radiotherapy and laminectomy were found to be the major risk factors for the development of scoliosis in children treated for neuroblastoma (7) Since Hayes et al. demonstrated in 1984 that chemotherapy is an excellent alternative in control of NBL with intraspinal extension, the mainstay of treatment shifted from neurosurgery in combination with radiotherapy to initial chemotherapy with avoidance of neurosurgery and radiotherapy (8). Chemotherapy does not lead to immediate relief of spinal cord compression, however the therapeutic time window seems to extend beyond the first hours of paralysis (9). Second malignant neoplasms, especially after high-dose regimens (10-12), ototoxicity as a consequence of platinum-based antineoplastic drug administration (13-15), and anthracycline-induced cardiotoxicity (16-18) are some of the well-documented long-term health problems encountered after chemotherapy.
The optimal treatment strategy for patients affected by NBL with intraspinal extension is still unclear, more specifically, the questions which children can be treated by chemotherapy alone and when neurosurgery should be employed to prevent life-long paraplegia remains unanswered. Meanwhile, survivors of this type of childhood cancer continue to suffer from long-term health problems, unclear whether these are caused by disease and/or treatment. To reduce these complications and to establish adequate treatment and follow-up protocols, more insight into the treatment, outcome and especially the prevalence of long-term health problems is essential. In this systematic review we evaluated and summarized all available evidence with regard to treatment and long-term outcome of patients suffering from NBL with intraspinal extension.
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 181 Methods Search strategy for identification of studies The objective of the literature search was to identify all studies reporting on treatment and outcome of patients with NBL with intraspinal extension, with particular attention for long-term health problems. At the start of the selection process, MEDLINE/PubMed (from 1945 to 2016) and EMBASE/Ovid (from 1947 to 2016) were searched for potentially relevant articles. The search strategy used can be found in Supplementary Table S1.
After performing the search strategy, two reviewers (KK and AJB) independently selected studies that met predefined inclusion criteria: (1) original reports; (2) all study designs other than case report/case series; (3) study population of at least 10 childhood patients with NBL with intraspinal extension; (4) survival, neurological outcome and/or prevalence of long-term health problems as outcome. Studies reporting on NBL patients with spinal involvement as a consequence of osteo-medullary metastases or relapsed disease were not considered for this review. To be included in this systematic review, each article had to meet all four criteria. Inter-observer agreement was calculated. Discrepancies between reviewers were resolved by consensus or consultation of a third reviewer (HvdP). The reference lists of all relevant articles were screened for additional references not registered in MEDLINE or EMBASE. The study selection process was aided by EROS (Early Review Organizing Software, developer IECS, Argentina).
Data collection Two reviewers (KK and AJB) independently performed data extraction using a standardized data abstraction form including information about study characteristics, study population, symptoms at diagnosis, charac- teristics of interventions and response to treatment, duration and completion of follow-up, long-term health problems, and risk/prognostic factors for morbidity.
Quality assessment of the included studies The assessment of risk of bias was based on earlier described criteria for observational studies according to Evidence-Based Medicine Criteria (19,20). Each study was graded on the basis of these dichotomous criteria, concerning the study group, the follow-up, the outcome assessment, methods used for risk estimation, and adjustment for confounding factors. The risk of bias assessment criteria are described in detail in Supplementary Table S2.
Results Selection of articles A total of 685 potentially relevant references were identified, of which 590 remained after removing duplicates. Screening of the titles and/or abstracts excluded 515 articles, and the inter-observer agreement
182 Chapter 8 was >90%. Of the 75 articles selected for full-text reading, twenty-five met the inclusion criteria, with an inter-observer agreement of 94.6%. Consensus was achieved on the disputed studies; consultation of a third reviewer was not required. No further articles were found/included after reviewing the bibliographies of the included articles. The study of De Bernardi (2005) (21) described the clinical experience of Pediatric Oncology Groups of seven different nations, including three unique national cohorts, (Poland (Balwierz); United Kingdom (Bejent), and Japan (Iehara)), so we included these as separate cohorts, resulting in a total of 28 studies (21-45). There might be partial overlap between the studies of Plantaz (1996)(33), De Bernardi (2001)(37), De Bernardi (2005)(21), Angelini (2011)(41), and De Bernardi (2014)(43). A flow chart of the search and selection process can be found as supplement (Supplementary Figure S3).
Characteristics of NBL with intraspinal extension In Table 1, characteristics of patients with intraspinal extension and the corresponding whole cohort are shown. Three studies reported lower age at diagnosis in patients with intraspinal extension compared to other NBL patients (33,37,42), the difference being significant in only one study (42). More thoracic tumors were observed in three studies (33,37,42). Two studies found a lower rate of disseminated disease compared to NBL patients without spinal cord compression (37,42). Six studies found an overall survival (OS) benefit for NBL patients with intraspinal extension compared to patients without spinal involvement (26,33,37,40,42,43), the difference being significant in only two studies (37,42). An improved event free survival (EFS) was reported by 4 studies (33,34,42,43), the difference being significant in only one study (34) Perez (2000) found a significant adverse effect on EFS, but not on OS for stage II NBL patients with intraspinal extension (36). Sixteen studies reported both the number of symptomatic and asymptomatic patients with intraspinal extension in the total NBL cohort (see Supplementary table S4 for complete data of all included studies). They found a median prevalence of intraspinal extension of 14.6% (range 4.9% - 37.5%) (21,22,26- 29,31-34,36,40,44,45). Of all NBL patients with intraspinal extension 63.2% (range 30.3% - 94.7%) was symptomatic at time of diagnosis. Seven studies reported on symptomatic spinal cord compression only (21,23,37,39,41-43). The median prevalence of symptomatic spinal cord compression within the whole NBL cohort was 5.2% (range 4.6% - 21.3%).
Neurological motor deficit Figure 1 en 2A illustrate the prevalence of neurological motor deficit at diagnosis and at the end of follow-up. Twenty-three studies reported on the prevalence of the neurological motor deficit at diagnosis, which ranged from 18% to 100% (median 85%) (21-26,29-31,33,35,37-45). The lower limit of this range was determined in the study of Iehara (2005) in which most patients were diagnosed in a mass screening program (21) Nine of the 23 studies included symptomatic patients only, with prevalences ranging from 95% to 100% (21,23,24,30,37,39,41-43). The severity of the motor deficit at diagnosis was reported in fifteen studies (21,23,26,30,31,33,35,37-43,45) The symptom to diagnosis-interval, reported as amean
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 183 Neuroblastoma with Neuroblastoma p value IE / SCC without IE / SCC Age at diagnosis Plantaz 1996 loc. 8m 12m Unknown De Bernardi 2001 16m 22m 0.36 Simon 2012 0.74y 1.28y <0.01 Stage De Bernardi 2001 Stage 2-3 71% 46% <0.001 Stage 4 25% 44% Stage 4s 4% 10% Simon 2012 Stage 1-3 71% 52% <0.01 Stage 4 20% 37% Stage 4s 8% 11% MYCN Amplification Plantaz 1996 loc. 3% 11% NS Simon 2012 5% 16% <0.01 Shimada favorable histology Simon 2012 74% 60% 0.02 Primary tumor location Plantaz 19961 Cervical 5% 10% NS Thorax 40% 28% 0.08 Abdomen 45% 63% 0.03 Pelvis 10% 7% NS De Bernardi 2001 Thorax 37% 15% <0.001 Abdomen 55% 79% Pelvis 7% 4% Simon 2012 Neck 3% 0% <0.01 Chest 39% 12% Abdomen 52% 77% Pelvis 7% 2% Event free survival Matthay 1989 5y, stage II No effect 0.78 Plantaz 1996 5y, loc. 90% 83% Unknown Matthay 1998 4y, stage III 92% 73% 0.016 Perez 2000 4y, stage II Worse EFS 81% <0.05 Simon 2012 5y 69.9% [±4.2%] 61.9% [±1.0%] 0.14 De Bernardi 2014 5y 85.3% (CI 68.2-93.6) 82.5% (CI 78.8-85.7) 0.629 Overall survival Massad 1985 5y 50% 21.5% Unknown Plantaz 1996 5y, loc 97% 92% Unknown Perez 2000 4y, stage II 97% 98% NS De Bernardi 2001 5y 70% [±5.3%] 54% [±1.4%] 0.005
184 Chapter 8 Aydin 2010 5y 44% 24.1% 0.1 Simon 2012 5y 86.2% [±3.2%] 72.7% [±0.9%] <0.01 De Bernardi 2014 5y 100% 90.3% (CI 88.2-92.8) 0.055
IE: intraspinal extension; SCC: spinal cord compression; loc: localized; NS: not significant; CI: 95% confidence interval; m: months; y: years. 1: localized NBL with IE vs localized NBL without IE. TABLE 1 Key characteristics of patients with intraspinal extension
or median showed considerable variation, ranging from three days to two months (median 25.5 days) (21-24,26,33,35,37-43,45). Nineteen studies reported on the prevalence of neurological motor deficit at the end of follow-up, which ranged from 17% to 69% (median 50%) (21-26,29,30,33,35,37-39,41-45) Fourteen studies described the severity of the motor deficit at the end of follow-up (21-24,30,33,35,37-39,41-43,45). Because of lack of uniformity in classification criteria, a comparison between the studies was not possible. Of the nineteen studies that reported both the prevalence at diagnosis and at follow-up, seventeen studies showed a decreased prevalence, and only two studies showed an increased prevalence of the motor deficit at the end of follow-up compared to diagnosis (Figure 2A) (26,29).
Variables affecting neurological motor deficit reported in the various studies are listed in Table 2. Seven studies found a directly proportional association between neurological deficit at diagnosis and neurological outcome (35,37-42) Four studies found no statistically significant association between treatment modality and neurological outcome (38,42-44). However, multivariate analysis indicated a significant association between motor sequela and neurosurgery (41). The evidence on the role of the symptom-diagnosis interval in the occurrence of late motor deficit is ambiguous; three studies report a significant better outcome with shorter symptom-diagnosis interval (40,43,44), while two studies found no association between the two parameters (41,42).
Sphincter dysfunction Figure 1 and 2B show the prevalence of sphincter dysfunction at diagnosis and at the end of follow-up. Bladder dysfunction was present at diagnosis in 37% (6% – 53%), and at end of follow-up in 25% (9% – 50%) of patients, in respectively 11 (22,23,26,35,38,40-45) and nine studies (24,26,35,38,40-43,45). Bowel dysfunction was present at diagnosis in 30% (4 – 53%), and at end of follow-up in 16% (4 – 29%) of patients, in respectively ten (24,35,38,41-43,45) and seven studies (24,35,38,41-43,45). Sphincter dysfunction not otherwise specified was present at diagnosis in 35% (6% – 45%), and at end of follow-up in 33.5% (10% – 57%) of patients, in respectively nine studies (21,24,25,31,33,37) and two studies (21,37). All percentages are medians (range). Half of the studies that reported both the prevalence of bladder (26,35,38,40-43,45) and bowel (35,38,41-43,45) dysfunction at diagnosis and at the end of follow-up do not show an improvement
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 185 in symptoms at the end of follow-up (Figure 2B).
Variables affecting sphincter dysfunction reported in the various studies are listed in Table 3. Angelini (2011) reported significant less sphincter dysfunction in the group treated with chemotherapy (41). De Bernardi (2014) also found an advantageous outcome for the group treated with chemotherapy in comparison with neurosurgery, however, this difference did not reach statistical significance (43). The symptomatology at diagnosis (motor deficit and/or sphincter dysfunction) has strong predictive value for sphincter problems experienced at the end of follow-up (41).
Treatment A wide variation in treatment of NBL with intraspinal extension was found. Twenty-two studies provided data on the number of children treated with neurosurgery, radiotherapy, and/or chemotherapy (21-26,30,31,33,35,37-45). The percentage of children treated with neurosurgery ranged from 0% to 95% (median 48.5%). In the nine studies published before 2000, the median was 80% (22-26,30,31,33,35). In the 13 studies published since 2000, the median was 33% (21,37-45). (see also Supplementary table S5) The percentage of children treated with radiotherapy (RT) ranged from 0% to 100% (median 14.5%(overall); 81%(pre 2000); 8%(post 2000)), and with chemotherapy from 19% to 100% (median 88%(overall); 65%(pre 2000); 91%(post 2000)).
The effect of the administration of glucocorticoids on the short- and long-term neurological outcome was analyzed in only one study (42). In the study of Simon (2012), it was associated with improved early symptom relief, while glucocorticoids did not prevent late residual impairment (see also Table 2).
Follow-up and survival For the twenty-three studies that reported follow-up, the duration varied widely from 1 week to 31 years with a mean/median ranging from 14.8 months (44) to 15.6 years (45) (21,23,24,26,27,29-31,33,35-45). In thirteen studies follow-up was less than one year for some of the patients in the cohort (21,24,27,29,30,36- 40,42,44). Overall survival was reported in twenty-four studies and ranged from 25% 32 to 100% (43,45) (median 81%) (21-27,29-33,35-40,42,43,45). The studies published after the year 2000 show a better OS (median 86%; range 44% -100%), than the studies published before 2000 (median 70%; range 25% - 97%) (see Supplementary table S5).
Spinal deformity and other long term health-problems Ten studies mentioned the prevalence of long-term health problems in survivors of NBL with intraspinal extension, which varied between 41% and 95% (median 59%) (21,24-26,33,35,37,41,43,45). Nineteen studies reported on the prevalence of spinal deformity at the end of follow-up, which ranged from 0% to 80% (median 30%). 21-26,30,31,33,35,37-43,45 Less spinal deformity is reported in the studies published
186 Chapter 8 after the year 2000 (see Supplementary table S5).
Variables affecting spinal deformity and other long-term health problems reported in the various studies are listed in Table 3. Neurosurgery and radiotherapy as risk factor for the development of spinal deformity are identified in multivariate analysis in the study of Angelini (2011) (41). The association between neurosurgery and/or radiotherapy and the development of spinal deformity was found in more studies (31,35,37,38,40). However, in the study of De Bernardi (2014) the difference in prevalence of spinal deformities between the group treated with neurosurgery and chemotherapy was not statistically significant (43). The association between the primary tumor location and the prevalence of spinal deformity is disputed. Two studies found more spinal deformity with thoracic located tumors (22,38), while two other studies did not found such an association (30,41).
Asymptomatic patients with intraspinal extension In nineteen studies, a total of 275 patients with intraspinal extension but without neurological symptoms at diagnosis are described (21,22,25-29,31-36,38,40,44,45). In these patients the intraspinal tumor extension is a radiological, or seldom a perioperative finding. For the majority (n=152) of these patients, it is unclear what treatment was applied, either because no details on treatment are provided or because reports are on symptomatic patients only (21,22,28,29,32,34,36,40,44). In eight studies, a subset (22/98 = 22%) of asymptomatic patients received neurosurgery despite the absence of neurological symptoms (21,25- 27,31,33,38,45) In two studies, none of the 25 asymptomatic patients received neurosurgery (21,35). To determine the outcome of this asymptomatic patient group is not straightforward, since it is often not assessed and/or reported (21,22,28,32,34,36,40,44) In three studies, it is explicitly mentioned that the asymptomatic patients do not have any long-term health problems (25,27,29) Long-term health problems encountered in this patient group are neurological motor deficits (31,33,38,45) and spinal deformity (35,38,45).
Quality assessment of the included studies Data on the internal and external validity of the 28 cohort studies are shown in Table 4. All studies were found to have methodological limitations. Eight of the 28 studies (28.6%) showed serious limitations defined as a validity score ≤4 (24-26,28-30,32,35). In four of the 28 studies, the study group was not well-defined, since it was unclear whether the study population consisted of NBL with intraspinal extension, metastatic spinal cord compression, or a combination of both (26,28,30,32) In five studies there is an increased risk of a unrepresentative study group. Four have a risk for selection bias because the number of patients in the whole original cohort were not mentioned (24,25,35,38). In one study, exclusion of patients due to missing data posed a risk of an unrepresentative study group (43). Twenty-seven (96.4%) studies reported the length of follow-up and therefore had a well-defined follow-up (21-27,29-45). All studies had an adequate follow-up (100%), meaning that the outcome was assessed for more than 90% of the study group of interest. In
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 187 three of the 28 studies, the outcome definitions were considered not objective and/or imprecise. These studies lacked a well-defined classification scheme for the evaluation of impaired motor function (25,29,32) None of the studies reported that the outcome was assessed by an investigator who was blinded for the treatment status of the patients. Eight studies (28.6%) assessed the influence of prognostic/risk factors on
Independent variable Effect on NEUROLOGICAL MOTOR DEFICIT p value Neurologic deficit at diagnosis Favors worse outcome Hoover 1999 Severe deficit: 27% recovery vs Mild/ - moderate deficit: 75% recovery De Bernardi 2001 Grade 1: 74% recovery/improvement; - Grade 2: 64%; Grade3: 0% Katzenstein 2001 Direct relation severity symptoms at dx 0.044 and neuro outcome More complete neuro recovery with mild 0.017 symptoms at dx Yiin 2003 Mild symptoms: 100% recovery/ - improvement; Moderate 71%; Severe 33% Aydin 2010 Lower recovery rate with severe deficit 0.002 at dx Angelini 2011 Severe deficit at dx: more motor sequela <0.001 (OR 12.8, CI 3.5-46.6) MV Simon 2012 More residual motor impairment with 0.03 severe deficit at dx Symptom-diagnosis interval Favors worse outcome Traggis 1977 S-D interval 2w (full neuro recovery), 4w - (partial recovery), 14w (no recovery) Holgersen 1983 S-D interval ≤4w best prognostic factor for - reversal neuro deficit Katzenstein 2001 Severe symptoms at dx: inverse relation - S-D interval and neuro recovery Mild/moderate symptoms at dx: unclear relation S-D interval and neuro recovery Begent Non-ambulant children either congenital - NBL or S-D interval ≥2w Aydin 2010 S-D interval <4w higher recovery rate 0.02 neuro deficit De Bernardi 2014 S-D interval 41d (grade 3 at dx) vs 11d 0.011 (grade 1-2 at dx) Fawzy 2015 Complete recovery 78.6% (SDI ≤4w 0.008 symptoms) vs 25% (SDI >4w) No effect De Bernardi 2001 No correlation S-D interval and neurologic - response to treatment
188 Chapter 8 Angelini 2011 No association S-D interval and motor 0.89 sequela Simon 2012 No association S-D interval and late effects 0.94 Neurosurgery Favors worse outcome Angelini 2011 Neurosurgery: more motor sequela (OR 0.006 2.5, CI 1.1-5.7) MV No effect Katzenstein 2001 No association treatment modality and MV neurologic outcome Simon 2012 Early response symptoms 64% (CT) vs 0.77 69% (neurosurgery) Late response symptoms 72% (CT) vs 0.60 81% (neurosurgery) Residual McCormick grade II-IV 45% (CT) 0.07 vs 42% (neurosurgery) De Bernardi 2014 Recovery / Improvement 30.0%/30.0% 0.910 (CT) vs 35.7%/21.4% (neurosurgery) Motor sequelae 52.9% (CT) vs 58.9% 0.730 (neurosurgery) Fawzy 2015 No association neurologic outcome and 0.37 therapy (CT ± steroids vs neurosurgery) Glucocorticoids Favors improved outcome Simon 2012 Early symptom relief / Deterioration 0.03 70%/0% (steroids) vs 62%/8% (no- steroids) No effect Simon 2012 Late residual impairment 67.5% (steroids) 0.50 vs 74.6% (no-steroids) Age at diagnosis Favors worse outcome Punt 1980 Symptomatic SCC from birth associated - with worse neurological outcome Angelini 2011 < 2y age at dx: more motor sequela (OR 0.033 0.37, CI 0.13-1.06) MV No effect Katzenstein 2001 No association age at diagnosis and - neurological outcome Aydin 2010 No association age at diagnosis and 0.3 neurological improvement Fawzy 2015 No association age at diagnosis and 0.12 neurological improvement Primary tumor site No effect Katzenstein 2001 No association primary tumor site and - neurological outcome
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 189 Angelini 2011 No association primary tumor site and 0.55 neurological sequelae Fawzy 2015 No association primary tumor site and - neurological outcome Stage / NMA No effect Katzenstein 2001 No association stage/NMA and - neurological outcome Fawzy 2015 No association stage and neurological 0.14 outcome Percentage spinal canal invasion No effect De Bernardi 2014 No association percentage spinal canal 0.576 invasion and motor deficit at dx
SCC: spinal cord compression; dx: diagnosis; neuro: neurological; freq: frequent; w: weeks, y: years; CT: chemotherapy; S-D interval/ SDI: symptom – diagnosis interval; NMA: NMYC amplification; OR: odds ratio; CI: 95% confidence interval; MV: multivariate analysis. TABLE 2 Variables affecting Neurological motor deficit
Independent variable Effect on SPHINCTER DYSFUNCTION p value Treatment Favors improved outcome Angelini 2011 Chemotherapy: less sphincter dysfunction 0.005 (OR 0.14, CI 0.03-0.72) MV No effect Angelini 2011 No association RT and sphincter 0.56 dysfunction No association neurosurgery and 0.19 sphincter dysfunction De Bernardi 2014 Neurosurgery: Bladder dysfunction 58.8% 0.303 vs Chemotherapy: 41.2% Neurosurgery: Bowel dysfunction 41.2% vs 0.132 Chemotherapy: 17.7% Motor deficit at diagnosis Favors worse outcome Angelini 2011 More motor deficit at dx: more sphincter 0.037 dysfunction (OR 16.1, CI 5.0-51.2) MV Sphincter dysfunction at diagnosis Favors worse outcome Angelini 2011 Sphincter dysfunction at diagnosis: more <0.001 sphincter dysfunction (OR 15.98, CI 4.18- MV 56.95) Age at diagnosis No effect Angelini 2011 No association age at dx and sphincter 0.46 dysfunction Primary tumor site No effect
190 Chapter 8 Angelini 2011 No association primary tumor site and 0.27 sphincter dysfunction Symptom-diagnosis interval No effect Angelini 2011 No association S-D interval and sphincter 0.7 dysfunction
Independent variable Effect on SPINAL DEFORMITY p value Neurosurgery Favors worse outcome Plantaz 1993 Laminectomy: serious orthopedic sequela - 36% vs no-laminectomy: 0% Katzenstein 2001 Neurosurgery: scoliosis 29% vs no- 0.001 neurosurgery: 2% Angelini 2011 Neurosurgery: more spinal deformity (OR 0.048 2.9, CI 1.1-7.5) MV No effect De Bernardi 2014 Neurosurgery: Spine abnormalities 52.9% 0.078 vs Chemotherapy: 23.5% Radiotherapy Favors worse outcome De Bernardi 2001 RT: Scoliosis 60%, Neurosurgery: 33%, - Chemotherapy: 7% Angelini 2011 Radiotherapy: more spinal deformity (OR 0.008 4.1, CI 1.3-12.5) MV Thoracic primary tumor Favors worse outcome King 1975 Thoracic tumors: Spinal deformity 100% - vs Abdominal tumors: 50% Katzenstein 2001 Thoracic tumors: Scoliosis 13% vs Non- - thoracic: 4% No effect Conrad 1992 No association extent or level of - laminectomy and spinal deformity Angelini 2011 No association primary tumor site and 0.82 spinal deformity Age at diagnosis Favors worse outcome Conrad 1992 Association younger age at treatment and MV spinal deformity No effect Angelini 2011 No association age at diagnosis and spinal 0.68 deformity Motor deficit at diagnosis Favors worse outcome Angelini 2011 More motor deficit at dx: more spinal 0.022 deformity (OR 4.2, CI 1.5-11.9) MV Symptom-diagnosis interval No effect
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 191 Angelini 2011 No association S-D interval and spinal 0.93 deformity Length of follow-up Favors worse outcome Angelini 2011 Spinal deformity 11% (≤6y at most recent - FU) vs 30% (>6y recent FU)
Independent variable Effect on other LONG-TERM HEALTH PROBLEMS p value Treatment No effect Simon 2012 Initial Chemotherapy: Late residual 0.12 impairment 64% vs Neurosurgery: 79% De Bernardi 2014 Neurosurgery: Long-term sequela 76,5%vs 0.271 Chemotherapy 58,8% Kraal 2016 Grade 3 health problems laminectomy vs 0.18 no-laminectomy Grade 4 health problems laminectomy vs 1.0 no-laminectomy Motor deficit at diagnosis No effect De Bernardi 2014 Grade 3: Severe sequela score 60% vs 0.084 Grade 1-2: 35% Kraal 2016 No association neurological symptoms at 0.17 dx and Grade 3 or Grade 4 health problems Gr.3 0.22 Gr.4 Percentage spinal canal invasion Favors worse outcome De Bernardi 2014 Spinal canal invasion >66% associated 0.039 with severe burden score Age at diagnosis No effect Simon 2012 No association age at dx and late effects 0.48 <12m 0.80 <18m Stage / NMA No effect Simon 2012 No association stage/NMA and late 0.56 effects stage 1.0 NMYC
Freq: frequent. CT: chemotherapy; RT: radiation therapy. S-D interval/SDI: symptom – diagnosis interval; NMA: NMYC amplification. OR: odds ratio; CI: 95% confidence interval; MV: multivariate analysis; stat sign: statistically significant. TABLE 3 Variables affecting long-term health problems
192 Chapter 8 survival, neurological outcome and/or long-term health problems (27,34,38,41-45). Only two studies (7.1%) adjusted for possible confounders in a multivariate analysis (38,41).
Discussion In this review all available evidence with regard to treatment and outcome of patients suffering from NBL with intraspinal extension was critically evaluated among 28 studies that met the inclusion criteria. All studies had methodological limitations. We found that a median of 14.6% of NBL is complicated by an intraspinal extension, of which 63.2% gives rise to neurological symptoms. These patients seem to differ from NBL patients without intraspinal extension with younger age at diagnosis, less abdominally located primary tumors, more low stage disease, less MYCN amplification, and more favorable histology. Differences in these patient characteristics can explain the superior overall survival for patients with intraspinal extension found in six studies (while significant in only two studies). A recent report by Vo (2014) also indicated that thoracic located primary tumors showed less MYCN amplification, less disseminated disease, and a superior overall and event-free survival (46). The biological origin of these differences remain unknown and are, hopefully, elucidated in future research to allow for a risk-based treatment approach.
Treatment strategies differed widely among study groups in the absence of optimal evidence-based treatment guidelines. The primary role of neurosurgery in combination with radiotherapy has been substituted for chemotherapy since Hayes et al. pioneered the use of primary chemotherapy in management of tumors with intraspinal extension in 1984 (8). The question when neurosurgery should be performed, remains unanswered. Fifty-nine percent of all survivors suffer from long-term health problems. At the end of follow-up, we found a median prevalence of neurological motor deficit of 50%, bladder dysfunction of 25%, bowel dysfunction of 16%, and spinal deformity of 30%. The reported prevalences varied widely among the different studies. This may be a reflection of the incremental advancements made in cure and care of childhood cancer, the heterogeneity of study populations, the absence of treatment guidelines, the lack of uniformity in terminology and reporting criteria, and differences in length of follow-up. Almost all studies reported the length of follow-up, and the minimum and maximum duration varied widely. With short follow-up, it is possible that health problems encountered may be transient and reversible. With longer follow-up, more patients will be at risk for late treatment- or disease-related health problems. It is well known that spinal deformity tends to aggravate during puberty and is therefore a classic example of a health problem that can significantly worsen with longer follow-up (47-50). Cautious interpretation of the results is thus warranted, because it is not always clear whether risks of long-term health problems will continue to increase with more prolonged follow-up.
The severity of the symptoms at diagnosis and treatment modalities applied were most often associated with the different long-term health problems. It seems uncontroverted that the severity of the neurological
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 193 motor deficit at diagnosis has the most predictive power for the neurological outcome. The motor deficit at diagnosis is also significantly associated with spinal deformity and sphincter dysfunction at the end of follow-up, while sphincter dysfunction at diagnosis was correlated with long –term sphincter problems (41). Initiation of treatment before symptoms have deteriorated to complete loss of neurological function seems, therefore, of the utmost importance. The correlation between presence and severity of health problems and treatment modality remains very difficult, as more severely affected patients tends to receive the most aggressive treatment. Furthermore, the distinction between tumor-induced destruction of spinal anatomy and treatment-related spinal deformity is not possible. Three of the more recent studies found no significant difference between chemotherapy and neurosurgery in the ability to relieve neurological motor deficit (42-44). Differences found, are often not significant as a consequence of limited statistical power due to small sample sizes. Angelini (2011) found more motor sequela after neurosurgery (41). The last mentioned study also found significantly less sphincter dysfunction after chemotherapy. The presence of spinal deformity is strongly associated with neurosurgical treatment and radiotherapy (31,37,38,41), it should be mentioned that the historical nature of this review leaves the advancements made in pediatric neurosurgery underexposed. Only two studies conducted a multivariate analysis. Results from univariate analyses that do not take possible confounding factors into account may lead to an overestimation of the true prognostic influence of a single variable. This systematic review has shown that the burden of long-term health problems in survivors of NBL with intraspinal extension is high. Unfortunately, the currently available literature remains suboptimal as a guide for the treatment of NBL with intraspinal extension. More well-designed studies are needed to reliably establish the optimal treatment strategy for NBL with intraspinal extension. Therefore, the SIOPEN Neuroblastoma Spinal Canal Invasion Study Group initiated a prospective study registry aimed at resolving the question regarding the optimal treatment of NBL with intraspinal extension. Patient enrolment started in 2014, and as of June 2016, data have been collected on 32 patients from six countries (51). As results from this and other studies will become available, clinicians will be able to make better-informed decisions on treatment for future patients. Until that time, we can only advise to follow international protocol recommendations to limit neurosurgery to patients with rapid neurological deterioration only; to maintain a high index of suspicion for neurological symptoms as presenting symptoms of NBL with intraspinal extension; and to be aware of the frequency and severity of long-term health problems in survivors and to develop targeted follow-up programs for this group.
Conflicts of Interest Statement None
Funding This work was supported by Stichting Kinderen Kankervrij (KiKa) (Children Cancer Free Foundation) and
194 Chapter 8 Zeldzame Ziekte Fonds (Rare Disease Fund). Role of the funding source: The funding source had no role in study design; collection, analysis, and interpre- tation of data; writing of the paper; or the decision to submit it for publication.
Acknowledgements The authors thank Edith Leclercq, PhD., for her help with developing the search strategies for this review. We thank Sebastiaan van de Water, MA, for critical reading of the manuscript.
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 195 Validity score score Validity (0-8) 5 5 4 3 4 6 4 3 4 5 3 5 6 4 5 6 5 5 5 5 5 5 5 Adjustment confounders 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 Risk estimation Well- defined 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 Blind UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC UC Outcome Well- Well- defined 1 1 1 0 1 1 0 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 Complete FU 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Follow-up Well- defined 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Selection bias 1 1 0 0 1 1 1 1 1 1 1 1 1 0 1 0 1 1 1 1 1 1 1 Study group Well- defined 1 1 1 1 0 1 1 0 0 1 0 1 1 1 1 1 1 1 1 1 1 1 1 Author-Year King-1975 Traggis-1977 Punt-1980 Holgersen-1983 Massad-1985 Matthay-1989 Rubie-1991 Klein-1991 Conrad-1992 Plantaz-1993 Ribet-1994 Plantaz-1996 Matthay-1998 Hoover-1999 Perez-2000 Katzenstein-2001 De Bernardi-2001 Yiin-2003 De Bernardi-2005 (Balwierz)-2005 (Begent)-2005 (Iehara)-2005 Aydin-2010
196 Chapter 8 7 6 5 6 6 1 0 0 0 0 2 1 1 1 1 1 8 UC UC UC UC 0 0 1 1 1 1 1 25 1 1 1 1 1 28 1 1 1 1 1 27 1 1 0 1 1 23 1 1 1 1 1 24 Angelini-2011 1: good; 0: poor; UC: unclear 4 Quality assessment of included studies TABLE Simon-2012 Bernardi -2014 Bernardi Fawzy-2015 Kraal-2016 No of studies with good quality
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 197 The three horizontal lines represent, from left to right, the first quartile, median, and third quartile. The numerical value represents the median. Horizontal lines depict the minimum and maximum value. In the right column, the references on which the box plot is based can be found. Figure 1: Box plots of most important outcome measures
198 Chapter 8 Dx: motor deficit at diagnosis. FU: motor deficit at end of follow-up. Parapl: paraplegia. Gait abn: gait abnormality. Cauda eq: cauda equina syndrome / radicular deficit. McC: McCormick. NM: not mentioned. 1: paraparesis. 2: paraplegia. 3: Monoparesis or –plegia. 4: Plantaz 1996 follow-up: 2% paraparesis. 5: Simon 2012 diagnosis: 2% McCormick grade III. Color legend: white represents ASIA grade 1, McCormick II, CTCAE grade 2, gait abnormality, or cauda equina syndrome / radicular de- ficit. Light grey represents ASIA grade 2, McCormick III, CTCAE grade 3, or paraparesis. Dark grey represents ASIA grade 3, McCormick IV, CTCAE grade 4, or paraplegia. White with black dots represents motor deficit not otherwise specified/graded. For details on the ASIA, McCormick, and CTCAE grading schemes see Supplementary table S6: Details on the different grading schemes for motor deficit. Figure 2A - Motor deficit at diagnosis and end of follow-up. Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 199 Dx: diagnosis; FU: Follow-up. Dysf: dysfunction. NOS: not otherwise specified. NM: not mentioned. 1: Bowel dysfunction. 2: Sphincter dysfunction NOS. 3: Bladder dysfunction. Color legend: white represents “sphincter dysfunction NOS”, light grey “bladder dysfunction”, and dark grey “bowel dysfunction”. Figure 2B Sphincter dysfunction at diagnosis and end of follow-up.
200 Chapter 8 Search results for MEDLINE/ PubMed: 04-03-2016 15:42 Search Query Items found #5 Search (((#1 AND #2 AND #3) NOT #4)) 418 #4 Search (((case report OR case reports))) 1839560 #3 Search (((late adverse effects OR late adverse effect OR late adverse effect* OR follow-up OR 4425265 sequelae OR outcome* OR complication* OR survivor* OR surviving))) #2 Search (((spinal cord compression OR compression[tiab] OR intraspinal OR epidural 502635 OR extradural OR extra-dural OR spinal column OR cauda equina OR dumbbell OR polyradiculopathy OR myelopathy))) #1 Search (((neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR 41023 ganglioneuroblastomas))) Search results for Ovid/Embase: 04-03-2016 15:55 1 exp neuroblastoma/ 29496 2 (neuroblastoma or neuroblastomas or neuroblast$).mp. 55351 3 (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp. 1026 4 or/1-3 55450 5 exp spinal cord compression/ 13746 6 spinal cord compression.mp. 15197 7 compression.ti,ab. 115145 8 (intraspinal or epidural or extradural or extra-dural).mp. 75340 9 spinal column.mp. or exp spine/ 168721 10 cauda equina.mp. or exp cauda equina/ 7190 11 dumbbell.mp. 2142 12 polyradiculopathy.mp. or exp radiculopathy/ 29903 13 myelopathy.mp. or exp spinal cord disease/ 241905 14 or/5-13 566856 15 (late adverse effects or late adverse effect or late adverse effect$).mp. 375 16 follow-up.mp. or exp follow up/ 1377756 17 sequelae.mp. 72750 18 (outcome$ or complication$).mp. 3216020 19 (survivor$ or surviving).mp. 162849 20 or/15-19 4120719 21 (case report or case reports).mp. 2168954 22 4 and 14 and 20 351 23 (22 not (case report or case reports)).af. 267
Search strategy for MEDLINE/ PubMed 1.. (neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas) 2.. (spinal cord compression OR compression[tiab] OR intraspinal OR epidural OR extradural OR extra-dural OR spinal column OR cauda equina OR dumbbell OR polyradiculopathy OR myelopathy) 3.. (late adverse effects OR late adverse effect OR late adverse effect* OR follow-up OR sequelae OR outcome* OR complication* OR survivor* OR surviving) 4.. (case report OR case reports) 5.. (1 AND 2 AND 3) NOT 4
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 201 Search strategy for Ovid/Embase Late effects Neuroblastoma 15. (late adverse effects or late adverse effect or late adverse 1. exp neuroblastoma/ effect$).mp. 2. (neuroblastoma or neuroblastomas or neuroblast$).mp. 16. follow-up.mp. or exp follow up/ 3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglio- 17. sequelae.mp. neuroblast$).mp. 18. (outcome$ or complication$).mp. 4. or/1-3 19. (survivor$ or surviving).mp. 20. or/1-5 Spinal cord compression 5. exp spinal cord compression/ Case reports 6. spinal cord compression.mp. 21. (case report or case reports).mp. 7. compression.ti,ab. 8. (intraspinal or epidural or extradural or extra-dural).mp. Final search 9. spinal column.mp. or exp spine/ 22. 4 and 14 and 20 10. cauda equina.mp. or exp cauda equina/ 23. (22 not((case report or case reports)).af. 11. dumbbell.mp. 12. polyradiculopathy.mp. or exp radiculopathy/ [mp = title, abstract, subject headings, heading word, drug trade 13. myelopathy.mp. or exp spinal cord disease/ name, original title, device manufacturer, drug manufacturer 14. or/1-9 name; / = Emtree term; $=zero or more characters]
Supplementary table S1 - Search strategy and results March 2016
External validity Internal validity Study group Reporting bias (Well-defined: yes/no) Selection bias (Representative: yes/no) · Neuroblastoma, ganglioneuroblastoma and · If the described study group consisted of ganglioneuroma with (a)symptomatic intraspinal more than 90% of the patients with intraspinal extension extension included in the original cohort. Or if it was a random sample of these patients. Follow-up Reporting bias (Well-defined: yes/no) Attrition bias (Complete: yes/no) · If the length of follow-up was mentioned. · If the outcome was assessed for more than 90% of the study group of interest. Outcome Reporting bias (Well-defined: yes/no) Detection bias (Blind: yes/no) · If the tumor specific outcome definitions · If the outcome assessors were blinded to the provided were objective and precise. investigated determinant. Risk estimation Analyses (Well-defined: yes/no) Confounding (Adjustment other factors: yes/no) · If a relative risk, odds ratio, mean difference, · If important prognostic factors (age, gender, Chi-square were used for statistical testing. co-treatment) or follow-up were taken adequately into account.
Supplementary table S2 Risk of bias assessment criteria
202 Chapter 8 Supplementary Figure S3 Flow chart inclusion of studies
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 203 Author – year King - 1975 Traggis - 1977 Punt - 1980 Holgersen - 1983 Massad - 1985 Matthay - 1989 Rubie – 1991 Country – single / multi center USA – SC USA – SC UK – SC USA – SC Lebanon – SC USA, Canada – MC France – SC Start – end date 1948 – 1974 1947 – 1975 1960 – 1977 NM 1963 – 1983 1978 – 1985 1982 – 1987 Study population NBL with IE NBL with sympt SCC NBL with SCC NBL with IE NBL with SCC Stage II NBL Localized thoracic NBL NBL with IE / total NBL (%) 19 /134 (14%) 23 / 345 (7%) 21 / ? (?) 23 / ? (?) 12 / 80 (15%) 32 / 156 (21%) 15 / 40 (38%) F/M 11-Aug 12-Jul 14-Jul 12-Nov 04-Aug NM NM Age1 Mean 3y (0-15y) Mean 2.9y (0.1-13y) Med 1y (0-11y) (0-29y) Mean 3y (1d-11y) NM NM GN/GNBL/NBL - / 42% / 58% - / - / 100% - / 22% / 78% 13% / 26% / 61% - / 17% / 83% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) NM NM NM NM NM NM NM Stage NM Evans III 74%; IV 25% NM Evans II 55%; III 20%; IV 25% Evans II 17%; III 33%; IV 42%; Evans II 100 % NM IVs 8% Location primary tumor NM Cervical 5% 11% 5% 4% - - Thoracic 47% 21% 24% 39% 33% 100% Abdominal 47% Lumbar 53%; Retroperitoneal 33%; 57% Abdominal 17%; - Adrenal 11% Transdiaphragmatic 10% Adrenal 25% Pelvic 0% Sacral 5% - - 25% - Other - - No paraspinal mass 29% - - - Symptoms at diagnosis N=18/19 (95%) N=19/19 (100%) N=21/21 (100%) N=19/23 (83%) N=10/12 (83%) N=19/32 (59%) N=6/15 (40%) Motor deficit 17 (89%) 18 (95%) 21 (100%) 13 (57%) 5 (42%) NM 6 (40%) Sensory dysfunction 8 (42%) 18 (95%) NM NM 6 (50%) NM NM Bladder / bowel dysfunction 7 (37%) / NM 10 (53%) / 10 (53%) 9 (43%) NOS 8 (35%)NOS 6 (50%) / 6 (50%) NM NM Palpable mass 6 (32%) 1 (5%) 5 (24%) 3 (13%) 7 (58%) NM NM Pain / irritability 9 (47%) 19 (100%) 6 (29%) 8 (35%) 5 (42%) NM NM Other Scoliosis 7 (37%) NM Fever/night sweats 2 (10%) Horner’s syndr 2 (9%) NM NM NM Symptom-diagnosis interval2 Mean <6w Mean 7,3w (<1-24w) Med 4w (1d-3y) (6w-3y) Mean 6w (1d-12m) NM NM Treatment N=17 N=19 N=20 N=22 N=10 N=32 NM Neurosurgery 16 (94%) 17 (89%) 20 (95%) 19 (86%) 5 (50%) 18 (56%) Surgery 12 (75%) 12 (63%) 7 (33%) 11 50%) 7 (70%) NM RT 16 (94%) 19 (100%) 17 (81%) 19 (86%) 7 (70%) NM CT 3 (19%) 18 (95%) 12 (57%) 9 (41%) 9 (90%) NM Other Palliation 1 (6%) NM NM NM NM NM Follow-up3 Mean 9.5y. 89% FU >2y Med 9y (1.5-24y) Med 78m (9-192m) (13m- ≥2y) (6-17y) Med 45m (1m-13y) Med 40m (4-80m). Survival OS 65%, 6/17 DOD OS 47%, 10/19 DOD OS 61%, 7/21 DOD, 1/21 OS 70%, 6/23 DOD, 1/23 OS 42%; 7 DOD OS 91%, 29/32 NED OS 87%. 1 DOD, 1 operative fatality operative fatality complication Long-term health problems ?/11 survivors ?/9 survivors 8/13 survivors (62%) 9/16 survivors (56%) 3/5 survivors (60%) NM ?/13 survivors Motor deficit 4/11 (36%) 12/19 (63%) 7/13 (54%) 8/16 (50%) 3/5 (60%) NM 6/13 (46%) Bladder / bowel dysfunction NM NM 4/13 (31%) / 1/13 (8%) NM 1/5 (20%) / NM NM NM Other neurologic health NM NM NM NM Sensory dysf. 1/5 (20%) Neuro sequela: 6/19 SEC NM problems (32%); 0/13 (0%) non-SEC Spinal deformity 8/11 (73%) 6/9 (67%) 2/13 (15%) 4/16 (25%), 3 severe 0 (0%) NM NM Other NM Secondary tumor 2/9 (22%) 1/13 survivors lost to FU NM NM NM NM
204 Chapter 8 Author – year King - 1975 Traggis - 1977 Punt - 1980 Holgersen - 1983 Massad - 1985 Matthay - 1989 Rubie – 1991 Country – single / multi center USA – SC USA – SC UK – SC USA – SC Lebanon – SC USA, Canada – MC France – SC Start – end date 1948 – 1974 1947 – 1975 1960 – 1977 NM 1963 – 1983 1978 – 1985 1982 – 1987 Study population NBL with IE NBL with sympt SCC NBL with SCC NBL with IE NBL with SCC Stage II NBL Localized thoracic NBL NBL with IE / total NBL (%) 19 /134 (14%) 23 / 345 (7%) 21 / ? (?) 23 / ? (?) 12 / 80 (15%) 32 / 156 (21%) 15 / 40 (38%) F/M 11-Aug 12-Jul 14-Jul 12-Nov 04-Aug NM NM Age1 Mean 3y (0-15y) Mean 2.9y (0.1-13y) Med 1y (0-11y) (0-29y) Mean 3y (1d-11y) NM NM GN/GNBL/NBL - / 42% / 58% - / - / 100% - / 22% / 78% 13% / 26% / 61% - / 17% / 83% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) NM NM NM NM NM NM NM Stage NM Evans III 74%; IV 25% NM Evans II 55%; III 20%; IV 25% Evans II 17%; III 33%; IV 42%; Evans II 100 % NM IVs 8% Location primary tumor NM Cervical 5% 11% 5% 4% - - Thoracic 47% 21% 24% 39% 33% 100% Abdominal 47% Lumbar 53%; Retroperitoneal 33%; 57% Abdominal 17%; - Adrenal 11% Transdiaphragmatic 10% Adrenal 25% Pelvic 0% Sacral 5% - - 25% - Other - - No paraspinal mass 29% - - - Symptoms at diagnosis N=18/19 (95%) N=19/19 (100%) N=21/21 (100%) N=19/23 (83%) N=10/12 (83%) N=19/32 (59%) N=6/15 (40%) Motor deficit 17 (89%) 18 (95%) 21 (100%) 13 (57%) 5 (42%) NM 6 (40%) Sensory dysfunction 8 (42%) 18 (95%) NM NM 6 (50%) NM NM Bladder / bowel dysfunction 7 (37%) / NM 10 (53%) / 10 (53%) 9 (43%) NOS 8 (35%)NOS 6 (50%) / 6 (50%) NM NM Palpable mass 6 (32%) 1 (5%) 5 (24%) 3 (13%) 7 (58%) NM NM Pain / irritability 9 (47%) 19 (100%) 6 (29%) 8 (35%) 5 (42%) NM NM Other Scoliosis 7 (37%) NM Fever/night sweats 2 (10%) Horner’s syndr 2 (9%) NM NM NM Symptom-diagnosis interval2 Mean <6w Mean 7,3w (<1-24w) Med 4w (1d-3y) (6w-3y) Mean 6w (1d-12m) NM NM Treatment N=17 N=19 N=20 N=22 N=10 N=32 NM Neurosurgery 16 (94%) 17 (89%) 20 (95%) 19 (86%) 5 (50%) 18 (56%) Surgery 12 (75%) 12 (63%) 7 (33%) 11 50%) 7 (70%) NM RT 16 (94%) 19 (100%) 17 (81%) 19 (86%) 7 (70%) NM CT 3 (19%) 18 (95%) 12 (57%) 9 (41%) 9 (90%) NM Other Palliation 1 (6%) NM NM NM NM NM Follow-up3 Mean 9.5y. 89% FU >2y Med 9y (1.5-24y) Med 78m (9-192m) (13m- ≥2y) (6-17y) Med 45m (1m-13y) Med 40m (4-80m). Survival OS 65%, 6/17 DOD OS 47%, 10/19 DOD OS 61%, 7/21 DOD, 1/21 OS 70%, 6/23 DOD, 1/23 OS 42%; 7 DOD OS 91%, 29/32 NED OS 87%. 1 DOD, 1 operative fatality operative fatality complication Long-term health problems ?/11 survivors ?/9 survivors 8/13 survivors (62%) 9/16 survivors (56%) 3/5 survivors (60%) NM ?/13 survivors Motor deficit 4/11 (36%) 12/19 (63%) 7/13 (54%) 8/16 (50%) 3/5 (60%) NM 6/13 (46%) Bladder / bowel dysfunction NM NM 4/13 (31%) / 1/13 (8%) NM 1/5 (20%) / NM NM NM Other neurologic health NM NM NM NM Sensory dysf. 1/5 (20%) Neuro sequela: 6/19 SEC NM problems (32%); 0/13 (0%) non-SEC Spinal deformity 8/11 (73%) 6/9 (67%) 2/13 (15%) 4/16 (25%), 3 severe 0 (0%) NM NM Other NM Secondary tumor 2/9 (22%) 1/13 survivors lost to FU NM NM NM NM
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 205 Author – year Klein -1991 Conrad – 1992 Plantaz - 1993 Ribet – 1994 Plantaz - 1996 Matthay - 1998 Hoover - 1999 Country – single / multi center USA - SC USA - SC France – SC France – SC France – MC USA – MC USA – MC Start – end date 1962 – 1979 1980 – 1985 1982 – 1987 1967 – 1992 1990 – 1994 1989 – 1996 1967 – 1994 Study population Ped tumors with SCC Ped tumors with SCC Localized NBL with IE Thoracic neurogenic tumor NBL with IE Stage III NBL NBL with IE NBL with IE / total NBL (%) 32 / 402 (8%) 10 / ? (?) 25 / 108 (23%) 13 / 72 (18%) 42 / 315 (13%) 74 / 228 (32%) 26 / ? (?) F/M NM 07-Mar Ratio 1 / 0.9 Ratio 1 / 0.6 21/21 NM 17-Sep Age1 Med 4.4y Mean 1.5y Med 7m (1d-9y) NM Med 8m (1d-14y) NM Med 11m (4d-6.6y) GN/GNBL/NBL NM - / - / 100% - / 28% / 72% 15% / 31% / 54% - / 38% / 62% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) NM NM NM NM (69% / 2% / 29%) NM (35% / 4% / 62%) Stage NM NM NM NM NM Evans III 100% INSS I 15%; II+III 62%; IV 23% Location primary tumor NM NM Cervical - 4% - 5% - Thoracic 90% 48% 100% 40% 46% Abdominal Lumbar 10% 24% - 45% 42% Pelvic - 24% - 10% 4% Other - - - - Unknown 8% Symptoms at diagnosis N=11/32 (34%) N=10/10 (100%) N=15/25 (60%) N=8/13 (62%) N=27/42 (64%) N=33/74 (45%) N=23/26 (88%) Motor deficit NM 10 (100%) 15 (60%) NM 23 (55%) 22 (85%) Sensory dysfunction NM NM 4 (16%) NM NM NM Bladder / bowel dysfunction NM NM 8 (32%) NOS NM 12 (29%) NOS 4 (15%) / 7 (27%) Palpable mass NM NM NM NM NM NM Pain / irritability NM NM NM NM NM NM Other NM NM NM NM Cauda syndr 5 (12%), OMS 3 (12%) Pyramidal sympt 2 (5%) Symptom-diagnosis interval2 NM NM (1d-6m) NM Med 21d (1-277d) NM Med 7d (antenatal-16m) Treatment N=29 N=10 N=25 NM N=42 NM N=26 Neurosurgery 13 (45%) 8 (80%) 17 (68%) 17 (40%) 15 (58%) Surgery NM NM 23 (92%) 40 (95%) 23 (88%) RT NM 10 (100%) 8 (32%) 2 (5%) 4 (15%) CT NM 6 (60%) 20 (80%) 39 (93%) 17 (65%) Other Nonsurgical tx 16 (55%) Corticosteroids NM NM NM Corticosteroids prior neurosurgery 15 (58%). ACTH for OMS 3 (12%) Follow-up3 NM Mean 7.3m (6m-16y) Med 4.8y (1.7-7y) Mean 11y (4m-25y) Med 45m (12-72m) Med 45m (whole cohort) Med 10.2y (2-29 y) Survival NM OS 70%. 3 DOD EFS 88%. 1 DOD, 1 toxic OS 25%. 2/8 sympt SCC alive OS 97%. EFS 90%. 1 toxic EFS 4y 92% OS 92%. EFS 85%. 1 DOD, death CT, 1 fatal pneumonia (25%) death CT. 4 relapses: 4/4 1 accidental death. 2 disease free/2nd remission recurrences, rescued Long-term health problems NM ?/7 survivors ?/22 survivors NM 17/41 survivors (41%) NM 18/24 survivors (75%) Motor deficit NM 6/10 (60%) NM NM 10/41 (24%) NM 10/24 (38%) Bladder / bowel dysfunction NM NM NM NM NM NM 6 /24(25%) / 1/24 (4%) Other neurologic health NM NM Neuro sequelae: serious 8/22 NM NM NM OMS 1/24 (4%) problems (36%); moderate 5/22 (22%) Spinal deformity NM 8/10 (80%) 5/22 (23%), 5 severe NM 6/41 (15%), 1 severe NM 14 /24 (58%); 5 severe Other NM NM Cardiomyopathy 1/22 (5%) NM NM NM Lower extr. dysf 6/24 (25%)
206 Chapter 8 Author – year Klein -1991 Conrad – 1992 Plantaz - 1993 Ribet – 1994 Plantaz - 1996 Matthay - 1998 Hoover - 1999 Country – single / multi center USA - SC USA - SC France – SC France – SC France – MC USA – MC USA – MC Start – end date 1962 – 1979 1980 – 1985 1982 – 1987 1967 – 1992 1990 – 1994 1989 – 1996 1967 – 1994 Study population Ped tumors with SCC Ped tumors with SCC Localized NBL with IE Thoracic neurogenic tumor NBL with IE Stage III NBL NBL with IE NBL with IE / total NBL (%) 32 / 402 (8%) 10 / ? (?) 25 / 108 (23%) 13 / 72 (18%) 42 / 315 (13%) 74 / 228 (32%) 26 / ? (?) F/M NM 07-Mar Ratio 1 / 0.9 Ratio 1 / 0.6 21/21 NM 17-Sep Age1 Med 4.4y Mean 1.5y Med 7m (1d-9y) NM Med 8m (1d-14y) NM Med 11m (4d-6.6y) GN/GNBL/NBL NM - / - / 100% - / 28% / 72% 15% / 31% / 54% - / 38% / 62% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) NM NM NM NM (69% / 2% / 29%) NM (35% / 4% / 62%) Stage NM NM NM NM NM Evans III 100% INSS I 15%; II+III 62%; IV 23% Location primary tumor NM NM Cervical - 4% - 5% - Thoracic 90% 48% 100% 40% 46% Abdominal Lumbar 10% 24% - 45% 42% Pelvic - 24% - 10% 4% Other - - - - Unknown 8% Symptoms at diagnosis N=11/32 (34%) N=10/10 (100%) N=15/25 (60%) N=8/13 (62%) N=27/42 (64%) N=33/74 (45%) N=23/26 (88%) Motor deficit NM 10 (100%) 15 (60%) NM 23 (55%) 22 (85%) Sensory dysfunction NM NM 4 (16%) NM NM NM Bladder / bowel dysfunction NM NM 8 (32%) NOS NM 12 (29%) NOS 4 (15%) / 7 (27%) Palpable mass NM NM NM NM NM NM Pain / irritability NM NM NM NM NM NM Other NM NM NM NM Cauda syndr 5 (12%), OMS 3 (12%) Pyramidal sympt 2 (5%) Symptom-diagnosis interval2 NM NM (1d-6m) NM Med 21d (1-277d) NM Med 7d (antenatal-16m) Treatment N=29 N=10 N=25 NM N=42 NM N=26 Neurosurgery 13 (45%) 8 (80%) 17 (68%) 17 (40%) 15 (58%) Surgery NM NM 23 (92%) 40 (95%) 23 (88%) RT NM 10 (100%) 8 (32%) 2 (5%) 4 (15%) CT NM 6 (60%) 20 (80%) 39 (93%) 17 (65%) Other Nonsurgical tx 16 (55%) Corticosteroids NM NM NM Corticosteroids prior neurosurgery 15 (58%). ACTH for OMS 3 (12%) Follow-up3 NM Mean 7.3m (6m-16y) Med 4.8y (1.7-7y) Mean 11y (4m-25y) Med 45m (12-72m) Med 45m (whole cohort) Med 10.2y (2-29 y) Survival NM OS 70%. 3 DOD EFS 88%. 1 DOD, 1 toxic OS 25%. 2/8 sympt SCC alive OS 97%. EFS 90%. 1 toxic EFS 4y 92% OS 92%. EFS 85%. 1 DOD, death CT, 1 fatal pneumonia (25%) death CT. 4 relapses: 4/4 1 accidental death. 2 disease free/2nd remission recurrences, rescued Long-term health problems NM ?/7 survivors ?/22 survivors NM 17/41 survivors (41%) NM 18/24 survivors (75%) Motor deficit NM 6/10 (60%) NM NM 10/41 (24%) NM 10/24 (38%) Bladder / bowel dysfunction NM NM NM NM NM NM 6 /24(25%) / 1/24 (4%) Other neurologic health NM NM Neuro sequelae: serious 8/22 NM NM NM OMS 1/24 (4%) problems (36%); moderate 5/22 (22%) Spinal deformity NM 8/10 (80%) 5/22 (23%), 5 severe NM 6/41 (15%), 1 severe NM 14 /24 (58%); 5 severe Other NM NM Cardiomyopathy 1/22 (5%) NM NM NM Lower extr. dysf 6/24 (25%)
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 207 Author – year Perez - 2000 Katzenstein - 2001 De Bernardi - 2001 Yiin – 2003 De Bernardi – 2005 De Bernardi/Balwierz De Bernardi/Begent Country – single / multi center International – MC USA – MC Italy – MC Taiwan – SC Italy – SC Poland – MC UK – SC Start – end date 1989 – 1995 1990 – 1998 1979 – 1998 1985 – 2000 1999 – 2003 1997 – 2003 NM Study population Stage I+II NBL no NMA NBL with IE NBL with sympt SCC NBL with IE NBL with sympt SCC NBL with IE NBL with IE NBL with IE / total NBL (%) 66 / 374 (18%) 83 / ? (?) 76 / 1462 (5%) 13 / 61 (21%) 26 / 530 (4.9%) 22 / 185 (12%) 22 / 115 (19%) F/M NM NM 38/38 05-Aug 15-Nov NM 13-Sep Age1 NM Med 10m (0-13.2y) Med 16m (0-167m) Med 22m (6m-17y) Med 14m (0-18y) NM Med 0.81y (0-1.8y) GN/GNBL/NBL - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) (100% / 0% / 0%) (90% / 8% / 1%) NM NM NM (86% / 14% / 0%) (100% / 0 % / 0%) Stage Evans I 2%; II 98% INSS I 10%; II+III 64%; IV 25%; INSS II 29%; III 42%; IV 25%; INSS III 62%; IV 38% INSS II-III 77%; IV(s) 23% NM INSS II 36%; III 64% IVs 1% IVs 4% Location primary tumor NM Intraspinal extension NM Cervical - - - - - Thoracic 66% 37% Mediastinum 46% 46% 41% Abdominal Lumbar 20% 55% - 46% Lumbar 27% Pelvic Sacral 7% 7% - 4% 32% Other Mixed 6% Other 1% Retroperitoneum 54% Other 4% - Symptoms at diagnosis N=20/66 (30%) N=43/83 (52%) N=76/76 (100%) N=13/13 (100%) N=26/26 (100%) N=15/22 (68%) N=15/22 (68%) Motor deficit NM 43 (52%) 75 (99%) 13 (100%) 26 (100%) 15 (68%) 11 (50%) Sensory dysfunction NM NM 11 (14%) NM 5 (19%) 2 (9%) 0 (0%) Bladder / bowel dysfunction NM 7 (8%) / 6 (7%) 30 (39%) NOS NM 10 (38%) NOS 10 (45%) NOS 4 (18%) NOS Palpable mass NM NM NM NM NM NM NM Pain / irritability NM NM 47 (62%) NM 10 (38%) 4 (18%) 0 (0%) Other NM NM NM NM NM NM NM Symptom-diagnosis interval2 NM Med 10d (1-180d) Med 2m (0-20m) Med 3d (2-7d) 19% <1w; 38% 1-4w; 12% Med 1.2m (0.1-4.2m) Med 15d (1dy-3m) 1-2m; 23% >2m; 8% UK Treatment N=66. N=83 N=76 N=13 N=26 N=22 N=22 Neurosurgery NM 27 (33%) 34 (45%) 2 (15%) 11 (42%) 6 (27%) 7 (32%) Surgery 56 (85%) 31 (37%) NM 4 (31%) NM 11 (50%) 15 (68%) RT 2 (3%) 8 (10%) 15 (20%) 5 (38%) 0 (0%) 3 (14%) 2 (9%) CT 15 (23%) 66 (80%) 69 (91%) 13 (100%) 23 (88%) 22 (100%) 21 (95%) Other NM NM Corticosteroids 76 (100%) Corticosteroids after NM NM Corticosteroids 5 (23%) neurosurgery 2 (15%) Follow-up3 (0-92m) Med 2.4y (<1m-9.8y) N=43 Med 139m (4-209m) Mean 23m (7m-9y) Med 22m (12-55m) Med 45m (5-129m) Mean 9.3y (1-20y) SEC Survival OS 4y 97% (SE ±3,3). 20/66 OS 5y 71% (SE ±9). 12 DOD, 7 OS 5y 70% (SE ± 5.3) OS 77%. EFS 62%, 3 died OS 85% 4 DOD OS 73%; 5 DOD, 1 died OS 95%, 1/22 died of other recurrences died other cause complications, 2 recurrences leukemia, 2 residual disease cause Long-term health problems NM ?/64 survivors 30/54 survivors (56%) ?/10 survivors ?/22 survivors ?/16 survivors 10/21 (48%) survivors Motor deficit NM 14/83 (17%) 21/53 (40%) 6/10 (60%) 18/26 (69%) 10/15 sympt at dx (67%) 7/21 (33%) Bladder / bowel dysfunction NM 7 (9%) / 6 (7%) 10 (19%) NOS NM NM NM 12/21 (57%) NOS Other neurologic health NM Horner’s syndr. 4 (5%) NM NM NM Horner’s syndr 1/16 (6%) Sensory dysf 3/21 (14%) problems Spinal deformity NM 8 (10%), 1 severe 12/53 (22%) 0/10 (0%) NM 1/16 (6%) 10/21 (48%), 2 severe Other NM NM NM NM Late effects described in Secondary tumor 1/22 (5%) Foot size diff 2/21 (10%); Angelini 2011 Erectile dysf 2/21 (10%)
208 Chapter 8 Author – year Perez - 2000 Katzenstein - 2001 De Bernardi - 2001 Yiin – 2003 De Bernardi – 2005 De Bernardi/Balwierz De Bernardi/Begent Country – single / multi center International – MC USA – MC Italy – MC Taiwan – SC Italy – SC Poland – MC UK – SC Start – end date 1989 – 1995 1990 – 1998 1979 – 1998 1985 – 2000 1999 – 2003 1997 – 2003 NM Study population Stage I+II NBL no NMA NBL with IE NBL with sympt SCC NBL with IE NBL with sympt SCC NBL with IE NBL with IE NBL with IE / total NBL (%) 66 / 374 (18%) 83 / ? (?) 76 / 1462 (5%) 13 / 61 (21%) 26 / 530 (4.9%) 22 / 185 (12%) 22 / 115 (19%) F/M NM NM 38/38 05-Aug 15-Nov NM 13-Sep Age1 NM Med 10m (0-13.2y) Med 16m (0-167m) Med 22m (6m-17y) Med 14m (0-18y) NM Med 0.81y (0-1.8y) GN/GNBL/NBL - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% - / - / 100% MYCN (s.c. /amplified / unkn.) (100% / 0% / 0%) (90% / 8% / 1%) NM NM NM (86% / 14% / 0%) (100% / 0 % / 0%) Stage Evans I 2%; II 98% INSS I 10%; II+III 64%; IV 25%; INSS II 29%; III 42%; IV 25%; INSS III 62%; IV 38% INSS II-III 77%; IV(s) 23% NM INSS II 36%; III 64% IVs 1% IVs 4% Location primary tumor NM Intraspinal extension NM Cervical - - - - - Thoracic 66% 37% Mediastinum 46% 46% 41% Abdominal Lumbar 20% 55% - 46% Lumbar 27% Pelvic Sacral 7% 7% - 4% 32% Other Mixed 6% Other 1% Retroperitoneum 54% Other 4% - Symptoms at diagnosis N=20/66 (30%) N=43/83 (52%) N=76/76 (100%) N=13/13 (100%) N=26/26 (100%) N=15/22 (68%) N=15/22 (68%) Motor deficit NM 43 (52%) 75 (99%) 13 (100%) 26 (100%) 15 (68%) 11 (50%) Sensory dysfunction NM NM 11 (14%) NM 5 (19%) 2 (9%) 0 (0%) Bladder / bowel dysfunction NM 7 (8%) / 6 (7%) 30 (39%) NOS NM 10 (38%) NOS 10 (45%) NOS 4 (18%) NOS Palpable mass NM NM NM NM NM NM NM Pain / irritability NM NM 47 (62%) NM 10 (38%) 4 (18%) 0 (0%) Other NM NM NM NM NM NM NM Symptom-diagnosis interval2 NM Med 10d (1-180d) Med 2m (0-20m) Med 3d (2-7d) 19% <1w; 38% 1-4w; 12% Med 1.2m (0.1-4.2m) Med 15d (1dy-3m) 1-2m; 23% >2m; 8% UK Treatment N=66. N=83 N=76 N=13 N=26 N=22 N=22 Neurosurgery NM 27 (33%) 34 (45%) 2 (15%) 11 (42%) 6 (27%) 7 (32%) Surgery 56 (85%) 31 (37%) NM 4 (31%) NM 11 (50%) 15 (68%) RT 2 (3%) 8 (10%) 15 (20%) 5 (38%) 0 (0%) 3 (14%) 2 (9%) CT 15 (23%) 66 (80%) 69 (91%) 13 (100%) 23 (88%) 22 (100%) 21 (95%) Other NM NM Corticosteroids 76 (100%) Corticosteroids after NM NM Corticosteroids 5 (23%) neurosurgery 2 (15%) Follow-up3 (0-92m) Med 2.4y (<1m-9.8y) N=43 Med 139m (4-209m) Mean 23m (7m-9y) Med 22m (12-55m) Med 45m (5-129m) Mean 9.3y (1-20y) SEC Survival OS 4y 97% (SE ±3,3). 20/66 OS 5y 71% (SE ±9). 12 DOD, 7 OS 5y 70% (SE ± 5.3) OS 77%. EFS 62%, 3 died OS 85% 4 DOD OS 73%; 5 DOD, 1 died OS 95%, 1/22 died of other recurrences died other cause complications, 2 recurrences leukemia, 2 residual disease cause Long-term health problems NM ?/64 survivors 30/54 survivors (56%) ?/10 survivors ?/22 survivors ?/16 survivors 10/21 (48%) survivors Motor deficit NM 14/83 (17%) 21/53 (40%) 6/10 (60%) 18/26 (69%) 10/15 sympt at dx (67%) 7/21 (33%) Bladder / bowel dysfunction NM 7 (9%) / 6 (7%) 10 (19%) NOS NM NM NM 12/21 (57%) NOS Other neurologic health NM Horner’s syndr. 4 (5%) NM NM NM Horner’s syndr 1/16 (6%) Sensory dysf 3/21 (14%) problems Spinal deformity NM 8 (10%), 1 severe 12/53 (22%) 0/10 (0%) NM 1/16 (6%) 10/21 (48%), 2 severe Other NM NM NM NM Late effects described in Secondary tumor 1/22 (5%) Foot size diff 2/21 (10%); Angelini 2011 Erectile dysf 2/21 (10%)
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 209 Author – year De Bernardi/Iehara Aydin - 2010 Angelini - 2011 Simon - 2012 De Bernardi - 2014 Fawzy – 2015 Kraal – 2016 Country – single / multi Japan – MC Turkey – SC Italy, France – MC Germany - MC Italy – MC Egypt – SC Netherlands – SC center Start – end date 1994-2004 1972 – 2004 1979 – 2002 1989 – 2008 2000 – 2011 2007 – 2012 1980-2007 Study population NBL with IE ≤1y age NBL with sympt SCC Localized NBL with SEC NBL with sympt SCC NBL with SEC ≤1y age NBL with SCC NBL with IE NBL with IE / total NBL (%) 33 / 675 (4,5%) 49 / 523 (9%) 101 / 2185 (5%) 122 / 2603 (5%) 43 / 571 (8%) 51 / 576 (9%) 19 / 137 (14%) F/M 14/19 19/30 52/46 61/61 14/20 25/26 14-May Age1 Med 7m (incl screening) Med 3.3y Med 8m (0-150m) Med 0,74y (0-20,4y) Med 162d (10-363d) Med 2.7y (2.2m-13.3y) Med 1.2y (0.6-10.8y) GN/GNBL/NBL - / - / 100% 4% / 12% / 84% - / - / 100% - / - / 100% - / - / 100% 4% / 12% / 84% 21% / 16% / 63% MYCN (s.c. /amplified / (100% / 0% / 0%) NM NM (80% / 5% / 16%) (97% / 3% / 0%) (65% / 16% / 20%) (74% / 0% / 26%) unkn.) Stage INSS I 9%; II 36%; III 36%; INSS I 2%; II 2%; III 61%; INSS II 46%; III 54% INSS I-III 71%; IV 20%; IVs 8% INSS II 12%; III 74%; IV 9%; INSS I 2%; II 6%; III 41%; IV INSS I 16%; II 26%; III 21%; IV IV 18% IV 35% IVs 6% 49%; IVs 2 % 11%; N/A 5% Location primary tumor Cervical - 4% 3% - 6% - Cervicothoracic 5% Thoracic 52% 55% 36% 39% 32% Mediastinum 31% 32% Abdominal 42% 35% 50% 52% Thoracoabdominal 18%; Retroperitoneal 41%; Thoracolumbar 21%; Suprarenal 18% Abdominal38% Lumbar 26% Pelvic 6% 6% 11% 7% 6% Pelvic-abdominal 10% Presacral 16% Other - - - Extending one cavity 3% - - - Symptoms at diagnosis N=11/33 (33%) N=44/49 (90%) N=98/98 (100%) N=99/99 (100%) N=34/34 (100%) N=34/51 (67%) N=12/19 (63%) Motor deficit 6 (18%) 44 (90%) 94 (96%) 94 (95%) 34 (100%) 32 (63%) 10 (53%) Sensory dysfunction NM 19 (39%) NM 57 (58%) NM NM NM Bladder / bowel dysfunction 2 (6%) NOS 23 (47%) / 16 (33%) 30 (42%) / 13 (23%) 44 (44%) / 37 (34%) 11 (32%) / 7 (21%) 3 (6%) / 2 (4%) 4 (21%) / 7 (37%) Palpable mass NM NM NM NM 1 (3%) NM 4 (21%) Pain / irritability NM 7 (14%) NM 55 (56%) 14 (41%) NM 4 (21%) Other Horner’s syndr 4 (12%) NM NM NM Respiratory distr 3 (9%); NM NM Horner’s syndr 1 (3%) Symptom-diagnosis interval2 NM Med 60d Med 23d Med 12d (0-1838d) Med 12d (0-161d) 14/34 ≤ 4w; 20/34 > 4w Med 6w (1.5-12w) Treatment N=33 N=49 N=98 N=99 N=34 N=34 N=19 Neurosurgery 0 (0%) 13 (27%) 46 (47%) 52 (53%) 17 (50%) 4 (12%) 13 (68%) Surgery 31 (94%) NM NM NM NM NM 17 (89%) RT 1 (3%) 14 (29%) 8 (8%) 0 (0%) 0 (0%) 0 (0%) 1 (5%) CT 26 (79%) 47 (96%) 89 (91%) 82 (83%) 33 (97%) 30 (88%) 4 (21%) Other 0 (0%) NM NM Glucocorticoids 59 (60%) NM Glucocorticoids prior to CT 131I-MIBG 6 (32%) 14 (41%) Follow-up3 N=12 residual disease: med Med 6.6y (1w – 31y) whole Med 7.3y (2-23 y) Med 8y1m (1m – 19y6m) Med 82m (15-146m) Med 14.8m (6.2-51.7m) Med 15.6y (6.3-29.5y) 37m (1-101m); N=20 NED: NBL cohort med 65m (10-108m) Survival OS 97%. 1 DOD; 5 relapses, OS 5y 44% (excl GN) NM OS 5y 86,2% (SE 3.2%). EFS OS 5y 100%. EFS 5y 85%. 6 NM OS 100% (survivor cohort) rescued 5y 69,9% (SE 4.2%) tumor progression, 1 tumor dissemination
210 Chapter 8 Author – year De Bernardi/Iehara Aydin - 2010 Angelini - 2011 Simon - 2012 De Bernardi - 2014 Fawzy – 2015 Kraal – 2016 Country – single / multi Japan – MC Turkey – SC Italy, France – MC Germany - MC Italy – MC Egypt – SC Netherlands – SC center Start – end date 1994-2004 1972 – 2004 1979 – 2002 1989 – 2008 2000 – 2011 2007 – 2012 1980-2007 Study population NBL with IE ≤1y age NBL with sympt SCC Localized NBL with SEC NBL with sympt SCC NBL with SEC ≤1y age NBL with SCC NBL with IE NBL with IE / total NBL (%) 33 / 675 (4,5%) 49 / 523 (9%) 101 / 2185 (5%) 122 / 2603 (5%) 43 / 571 (8%) 51 / 576 (9%) 19 / 137 (14%) F/M 14/19 19/30 52/46 61/61 14/20 25/26 14-May Age1 Med 7m (incl screening) Med 3.3y Med 8m (0-150m) Med 0,74y (0-20,4y) Med 162d (10-363d) Med 2.7y (2.2m-13.3y) Med 1.2y (0.6-10.8y) GN/GNBL/NBL - / - / 100% 4% / 12% / 84% - / - / 100% - / - / 100% - / - / 100% 4% / 12% / 84% 21% / 16% / 63% MYCN (s.c. /amplified / (100% / 0% / 0%) NM NM (80% / 5% / 16%) (97% / 3% / 0%) (65% / 16% / 20%) (74% / 0% / 26%) unkn.) Stage INSS I 9%; II 36%; III 36%; INSS I 2%; II 2%; III 61%; INSS II 46%; III 54% INSS I-III 71%; IV 20%; IVs 8% INSS II 12%; III 74%; IV 9%; INSS I 2%; II 6%; III 41%; IV INSS I 16%; II 26%; III 21%; IV IV 18% IV 35% IVs 6% 49%; IVs 2 % 11%; N/A 5% Location primary tumor Cervical - 4% 3% - 6% - Cervicothoracic 5% Thoracic 52% 55% 36% 39% 32% Mediastinum 31% 32% Abdominal 42% 35% 50% 52% Thoracoabdominal 18%; Retroperitoneal 41%; Thoracolumbar 21%; Suprarenal 18% Abdominal38% Lumbar 26% Pelvic 6% 6% 11% 7% 6% Pelvic-abdominal 10% Presacral 16% Other - - - Extending one cavity 3% - - - Symptoms at diagnosis N=11/33 (33%) N=44/49 (90%) N=98/98 (100%) N=99/99 (100%) N=34/34 (100%) N=34/51 (67%) N=12/19 (63%) Motor deficit 6 (18%) 44 (90%) 94 (96%) 94 (95%) 34 (100%) 32 (63%) 10 (53%) Sensory dysfunction NM 19 (39%) NM 57 (58%) NM NM NM Bladder / bowel dysfunction 2 (6%) NOS 23 (47%) / 16 (33%) 30 (42%) / 13 (23%) 44 (44%) / 37 (34%) 11 (32%) / 7 (21%) 3 (6%) / 2 (4%) 4 (21%) / 7 (37%) Palpable mass NM NM NM NM 1 (3%) NM 4 (21%) Pain / irritability NM 7 (14%) NM 55 (56%) 14 (41%) NM 4 (21%) Other Horner’s syndr 4 (12%) NM NM NM Respiratory distr 3 (9%); NM NM Horner’s syndr 1 (3%) Symptom-diagnosis interval2 NM Med 60d Med 23d Med 12d (0-1838d) Med 12d (0-161d) 14/34 ≤ 4w; 20/34 > 4w Med 6w (1.5-12w) Treatment N=33 N=49 N=98 N=99 N=34 N=34 N=19 Neurosurgery 0 (0%) 13 (27%) 46 (47%) 52 (53%) 17 (50%) 4 (12%) 13 (68%) Surgery 31 (94%) NM NM NM NM NM 17 (89%) RT 1 (3%) 14 (29%) 8 (8%) 0 (0%) 0 (0%) 0 (0%) 1 (5%) CT 26 (79%) 47 (96%) 89 (91%) 82 (83%) 33 (97%) 30 (88%) 4 (21%) Other 0 (0%) NM NM Glucocorticoids 59 (60%) NM Glucocorticoids prior to CT 131I-MIBG 6 (32%) 14 (41%) Follow-up3 N=12 residual disease: med Med 6.6y (1w – 31y) whole Med 7.3y (2-23 y) Med 8y1m (1m – 19y6m) Med 82m (15-146m) Med 14.8m (6.2-51.7m) Med 15.6y (6.3-29.5y) 37m (1-101m); N=20 NED: NBL cohort med 65m (10-108m) Survival OS 97%. 1 DOD; 5 relapses, OS 5y 44% (excl GN) NM OS 5y 86,2% (SE 3.2%). EFS OS 5y 100%. EFS 5y 85%. 6 NM OS 100% (survivor cohort) rescued 5y 69,9% (SE 4.2%) tumor progression, 1 tumor dissemination
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 211 Long-term health problems ?/32 survivors NM 57/98 2y survivors (58%) 71/99 (71%) 23/34 survivors (68%) NM 18/19 survivors (95%) Motor deficit NM NM 50/98 (51%) 43/99 (43%) 19/34 (56%) 18/34 (53%) 6/19 (32%) Bladder / bowel dysfunction NM 8/49 (16%) / NM 31/94 (33%) / 13/48 (27%) 26/99 (26%) / 19/99 (19%) 17/34 (50%) / 10/34 (29%) NM 4/19 (21%) / 3/19 (16%) Other neurologic health 9 neurologic sympt at dx: 23/49 (47%) improvement NM Sensory dysf 17/99 (17%) NM NM Sensory dysf. 5/19 (26%); problems recovery 2/9; partial 4/9; sympt Horner’s syndr 2/19 (11%) stable 3/9 Spinal deformity NM 6/49 (12%) 27/91 (30%) 31/99 (31%) 13/34 (38%) NM 13/19 (68%); 2 severe Other NM NM NM Impaired growth 14/99 Def tracheostomy 2/34 (6%) NM Secondary tumor 2/19 (11%) (14%); Pain 5/99 (5%)
NBL: neuroblastoma; GNBL: ganglioneuroblastoma; GN: ganglioneuroma; IE: intraspinal extension; SCC: spinal cord compression; SEC: symptomatic epidural compression. Ped: pediatric. F: female; M: male. SC: single center. MC: multi center. INSS: International Neuroblastoma Staging System. NMA: NMYC amplification. RT: radiation therapy; CT: chemotherapy; ACTH: adrenocorticotropic hormone therapy. dx: diagnosis; tx: treatment; sympt: symptom(atic); NOS: sphincter dysfunction not otherwise specified; diff: difference; extr: extremity; dysf: dysfunction; syndr: syndrome; distr: distress; def: definitive. OMS: opsoclonus-myoclonus syndrome. FU: follow-up; OS: overall survival; EFS: event-free survival, SE: standard error. DOD: died of disease; NED: no evidence of disease; NM: not mentioned; UK: unknown. Med: median; d days; w weeks; m months; y years. 1: Age at diagnosis with (range). 2: Time from initial symptoms to diagnosis with (range). 3: Follow-up with (range).
Supplementary table S4 - Study characteristics and results of included studies
212 Chapter 8 Long-term health problems ?/32 survivors NM 57/98 2y survivors (58%) 71/99 (71%) 23/34 survivors (68%) NM 18/19 survivors (95%) Motor deficit NM NM 50/98 (51%) 43/99 (43%) 19/34 (56%) 18/34 (53%) 6/19 (32%) Bladder / bowel dysfunction NM 8/49 (16%) / NM 31/94 (33%) / 13/48 (27%) 26/99 (26%) / 19/99 (19%) 17/34 (50%) / 10/34 (29%) NM 4/19 (21%) / 3/19 (16%) Other neurologic health 9 neurologic sympt at dx: 23/49 (47%) improvement NM Sensory dysf 17/99 (17%) NM NM Sensory dysf. 5/19 (26%); problems recovery 2/9; partial 4/9; sympt Horner’s syndr 2/19 (11%) stable 3/9 Spinal deformity NM 6/49 (12%) 27/91 (30%) 31/99 (31%) 13/34 (38%) NM 13/19 (68%); 2 severe Other NM NM NM Impaired growth 14/99 Def tracheostomy 2/34 (6%) NM Secondary tumor 2/19 (11%) (14%); Pain 5/99 (5%)
NBL: neuroblastoma; GNBL: ganglioneuroblastoma; GN: ganglioneuroma; IE: intraspinal extension; SCC: spinal cord compression; SEC: symptomatic epidural compression. Ped: pediatric. F: female; M: male. SC: single center. MC: multi center. INSS: International Neuroblastoma Staging System. NMA: NMYC amplification. RT: radiation therapy; CT: chemotherapy; ACTH: adrenocorticotropic hormone therapy. dx: diagnosis; tx: treatment; sympt: symptom(atic); NOS: sphincter dysfunction not otherwise specified; diff: difference; extr: extremity; dysf: dysfunction; syndr: syndrome; distr: distress; def: definitive. OMS: opsoclonus-myoclonus syndrome. FU: follow-up; OS: overall survival; EFS: event-free survival, SE: standard error. DOD: died of disease; NED: no evidence of disease; NM: not mentioned; UK: unknown. Med: median; d days; w weeks; m months; y years. 1: Age at diagnosis with (range). 2: Time from initial symptoms to diagnosis with (range). 3: Follow-up with (range).
Supplementary table S4 - Study characteristics and results of included studies
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 213 All studies Study published before year 2000 Study published after year 2000 Studies with symptomatic patients Studies with symptomatic and asymp- only tomatic patients MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX Symptoms at diagnosis Motor deficit 18% 54% 85% 98% 100% 40% 56% 73% 94% 100% 18% 52% 90% 99% 100% 95% 96% 100% 100% 100% 18% 51% 56% 67% 90% Pain / irritability 0% 21% 38% 47% 100% 29% 35% 42% 47% 100% 0% 17% 30% 45% 62% 29% 39% 49% 61% 100% 0% 16% 21% 39% 47% Bladder dysfunction 6% 18% 37% 46% 53% 15% 32% 44% 51% 53% 6% 15% 32% 43% 47% 32% 40% 43% 46% 53% 6% 12% 21% 42% 50% Bowel dysfunction 4% 22% 30% 36% 53% 27% 50% 53% 4% 14% 23% 34% 37% 21% 23% 29% 39% 53% 4% 12% 30% 36% 50%
Sphincter dysf. NOS 6% 29% 35% 39% 45% 29% 31% 34% 37% 43% 6% 18% 38% 39% 45% 38% 39% 43% 6% 21% 31% 34% 45% S-D interval (days) 3 12 26 42 61 7 23 35 42 51 3 12 19 41 61 3 12 23 40 61 7 15 37 42 60 Treatment Neurosurgery 0% 32% 49% 68% 95% 40% 58% 80% 89% 95% 0% 27% 33% 47% 68% 15% 45% 50% 80% 95% 0% 27% 40% 68% 94% Radiotherapy 0% 5% 15% 62% 100% 5% 32% 81% 94% 100% 0% 0% 8% 14% 38% 0% 0% 20% 81% 100% 0% 5% 14% 32% 94% Chemotherapy 19% 69% 88% 95% 100% 19% 57% 65% 90% 95% 21% 83% 91% 96% 100% 57% 83% 91% 95% 100% 19% 65% 80% 93% 100% Follow-up Length (months) 14,8 43,8 78,6 108,9 187,2 40 45 67,8 109,5 122,4 14,8 27,4 80,6 100,7 187,2 22 64,3 84,8 99,8 139 14,8 43,8 51,3 112,2 187,2 Overall survival 25% 69% 81% 93% 100% 25% 58% 70% 89% 97% 44% 73% 86% 97% 100% 47% 68% 74% 85% 100% 25% 69% 88% 96% 100% Event free survival 62% 77% 85% 89% 92% 85% 87% 89% 91% 92% 62% 70% 85% 62% 70% 85% 85% 87% 89% 91% 92% Long-term health problems Overall prevalence 41% 56% 59% 67% 95% 41% 56% 60% 62% 75% 48% 56% 58% 68% 95% 56% 58% 60% 64% 68% 41% 50% 58% 71% 95% Motor deficit 17% 38% 50% 58% 69% 24% 42% 50% 60% 63% 17% 35% 47% 55% 69% 40% 51% 56% 60% 69% 17% 32% 39% 49% 60% Bladder dysfunction 9% 20% 25% 31% 50% 20% 25% 31% 9% 17% 24% 31% 50% 26% 30% 32% 37% 50% 9% 16% 20% 21% 25% Bowel dysfunction 4% 8% 16% 23% 29% 4% 6% 8% 7% 16% 19% 27% 29% 8% 16% 23% 28% 29% 4% 7% 16% Sphincter dysf. NOS 19% 38% 57% 19% 38% 57% 19% 57% Spinal deformity 0% 14% 30% 53% 80% 0% 23% 41% 67% 80% 0% 11% 26% 36% 68% 0% 20% 31% 45% 80% 0% 11% 25% 53% 73%
The minimum (MIN), first quartile (Q1), median (MED), third quartile (Q3) and maximum (MAX) are shown for all studies, for studies pu- blished before and after the year 2000, for studies which only included symptomatic patients at diagnosis, and for studies which included symptomatic as well as asymptomatic patients at diagnosis. Dark grey represent a disadvantageous value, light grey an equal value, and white an advantageous value compared to the overall outcome. Supplementary table S5: Five-number summary for most important outcome measures.
214 Chapter 8 All studies Study published before year 2000 Study published after year 2000 Studies with symptomatic patients Studies with symptomatic and asymp- only tomatic patients MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX MIN Q1 MED Q3 MAX Symptoms at diagnosis Motor deficit 18% 54% 85% 98% 100% 40% 56% 73% 94% 100% 18% 52% 90% 99% 100% 95% 96% 100% 100% 100% 18% 51% 56% 67% 90% Pain / irritability 0% 21% 38% 47% 100% 29% 35% 42% 47% 100% 0% 17% 30% 45% 62% 29% 39% 49% 61% 100% 0% 16% 21% 39% 47% Bladder dysfunction 6% 18% 37% 46% 53% 15% 32% 44% 51% 53% 6% 15% 32% 43% 47% 32% 40% 43% 46% 53% 6% 12% 21% 42% 50% Bowel dysfunction 4% 22% 30% 36% 53% 27% 50% 53% 4% 14% 23% 34% 37% 21% 23% 29% 39% 53% 4% 12% 30% 36% 50%
Sphincter dysf. NOS 6% 29% 35% 39% 45% 29% 31% 34% 37% 43% 6% 18% 38% 39% 45% 38% 39% 43% 6% 21% 31% 34% 45% S-D interval (days) 3 12 26 42 61 7 23 35 42 51 3 12 19 41 61 3 12 23 40 61 7 15 37 42 60 Treatment Neurosurgery 0% 32% 49% 68% 95% 40% 58% 80% 89% 95% 0% 27% 33% 47% 68% 15% 45% 50% 80% 95% 0% 27% 40% 68% 94% Radiotherapy 0% 5% 15% 62% 100% 5% 32% 81% 94% 100% 0% 0% 8% 14% 38% 0% 0% 20% 81% 100% 0% 5% 14% 32% 94% Chemotherapy 19% 69% 88% 95% 100% 19% 57% 65% 90% 95% 21% 83% 91% 96% 100% 57% 83% 91% 95% 100% 19% 65% 80% 93% 100% Follow-up Length (months) 14,8 43,8 78,6 108,9 187,2 40 45 67,8 109,5 122,4 14,8 27,4 80,6 100,7 187,2 22 64,3 84,8 99,8 139 14,8 43,8 51,3 112,2 187,2 Overall survival 25% 69% 81% 93% 100% 25% 58% 70% 89% 97% 44% 73% 86% 97% 100% 47% 68% 74% 85% 100% 25% 69% 88% 96% 100% Event free survival 62% 77% 85% 89% 92% 85% 87% 89% 91% 92% 62% 70% 85% 62% 70% 85% 85% 87% 89% 91% 92% Long-term health problems Overall prevalence 41% 56% 59% 67% 95% 41% 56% 60% 62% 75% 48% 56% 58% 68% 95% 56% 58% 60% 64% 68% 41% 50% 58% 71% 95% Motor deficit 17% 38% 50% 58% 69% 24% 42% 50% 60% 63% 17% 35% 47% 55% 69% 40% 51% 56% 60% 69% 17% 32% 39% 49% 60% Bladder dysfunction 9% 20% 25% 31% 50% 20% 25% 31% 9% 17% 24% 31% 50% 26% 30% 32% 37% 50% 9% 16% 20% 21% 25% Bowel dysfunction 4% 8% 16% 23% 29% 4% 6% 8% 7% 16% 19% 27% 29% 8% 16% 23% 28% 29% 4% 7% 16% Sphincter dysf. NOS 19% 38% 57% 19% 38% 57% 19% 57% Spinal deformity 0% 14% 30% 53% 80% 0% 23% 41% 67% 80% 0% 11% 26% 36% 68% 0% 20% 31% 45% 80% 0% 11% 25% 53% 73%
The minimum (MIN), first quartile (Q1), median (MED), third quartile (Q3) and maximum (MAX) are shown for all studies, for studies pu- blished before and after the year 2000, for studies which only included symptomatic patients at diagnosis, and for studies which included symptomatic as well as asymptomatic patients at diagnosis. Dark grey represent a disadvantageous value, light grey an equal value, and white an advantageous value compared to the overall outcome. Supplementary table S5: Five-number summary for most important outcome measures.
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 215 American Spinal Injury Association (ASIA) Impairment Scale for motor deficit Grade 1 Mild hyposthenia with walking disability, or difficulty in raising one's hands above one's head Grade 2 Moderate hyposthenia with inability to walk or to move against gravity, or to raise one's hands above one's head Grade 3 Severe hyposthenia with paraplegia, no elicitable tendon reflexes, or no muscular movements
Reference: Rosman Np, Gilmore HE. Spinal cord injury. In: Swaiman KF, Ashwal S, editors. Pediatric neurology: Principles and practice, 3rd edition. St Louis, MO: Mosby; 1999. pp 954–966.
Common Terminology Criteria for Adverse Events (CTCAE); Neuropathy: Motor Grade 1 Asymptomatic, weakness on exam/testing only Grade 2 Symptomatic weakness interfering with function, but not interfering with ADL Grade 3 Weakness interfering with ADL; bracing or assistance to walk indicated; Grade 4 Life-threatening; disabling (e.g., paralysis). Grade 5 Death
Reference: Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. http.//ctep.cancer.gov. Published: August 9, 2006
McCormick clinical/functional classification scheme Grade I neurologically normal; mild focal deficit not significantly affecting function of involved limb; mild spasticity or reflex abnormality; normal gait Grade II presence of sensorimotor deficit affecting function of involved limb; mild to moderate gait difficulty; severe pain or dysesthetic syndrome impairing patient's quality of life; still functions and ambulates independently Grade III more severe neurological deficit; requires cane/brace for ambulation or significant bilateral upper extremity impairment; may or may not function independently Grade IV severe deficit; requires wheelchair or cane/brace with bilateral upper extremity impairment; usually not independent
Reference: McCormick PC, Torres R, Post KD, Stein BM. Intramedullary ependymoma of the spinal cord. J Neurosurg 1990; 72: 523–32.
Supplementary table S6: Details on the different grading schemes for motor deficit.
216 Chapter 8 Uncategorized References 7. Paulino AC, Fowler BZ. Risk factors for scoliosis in children with neuroblastoma. Int J 1. Mayfield JK, Riseborough EJ, Jaffe N, Nehme Radiat Oncol Biol Phys. 2005;61(3):865-869. ME. Spinal deformity in children treated for neuroblastoma. J Bone Joint Surg Am. 8. Hayes FA, Thompson EI, Hvizdala E, 1981;63(2):183-193. O’Connor D, Green AA. Chemotherapy as an alternative to laminectomy and radiation in 2. Liu J, Ebraheim NA, Sanford CG, Jr., et the management of epidural tumor. J Pediatr. al. Preservation of the spinous process- 1984;104(2):221-224. ligament-muscle complex to prevent kyphotic deformity following laminoplasty. Spine J. 9. Sanderson IR, Pritchard J, Marsh HT. 2007;7(2):159-164. Chemotherapy as the initial treatment of spinal cord compression due to 3. McGirt MJ, Chaichana KL, Atiba A, et al. disseminated neuroblastoma. J Neurosurg. Incidence of spinal deformity after resection 1989;70(5):688-690. of intramedullary spinal cord tumors in children who underwent laminectomy 10. Laverdiere C, Liu Q, Yasui Y, et al. Long-term compared with laminoplasty. J Neurosurg outcomes in survivors of neuroblastoma: a Pediatr. 2008;1(1):57-62. report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009;101(16):1131- 4. Boglino C, Martins AG, Ciprandi G, Sousinha 1140. M, Inserra A. cord vascular injuries following surgery of advanced thoracic neuroblastoma: 11. Perwein T, Lackner H, Sovinz P, et al. Survival an unusual catastrophic complication. Med and late effects in children with stage 4 Pediatr Oncol. 1999;32(5):349-352. neuroblastoma. Pediatr Blood Cancer. 2011;57(4):629-635. 5. Acharya S, Sarafoglou K, LaQuaglia M, et al. Thyroid neoplasms after therapeutic 12. Martin A, Schneiderman J, Helenowski IB, radiation for malignancies during childhood or et al. Secondary malignant neoplasms after adolescence. Cancer. 2003;97(10):2397-2403. high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma. 6. Armstrong GT, Stovall M, Robison LL. Pediatr Blood Cancer. 2014;61(8):1350-1356. Long-term effects of radiation exposure among adult survivors of childhood cancer: 13. Parsons SK, Neault MW, Lehmann LE, et results from the childhood cancer survivor al. Severe ototoxicity following carboplatin- study. Radiat Res. 2010;174(6):840-850. containing conditioning regimen for autologous marrow transplantation for
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 217 neuroblastoma. Bone Marrow Transplant. 20. Laupacis A, Wells G, Richardson WS, Tugwell 1998;22(7):669-674. P. Users’ guides to the medical literature. V. How to use an article about prognosis. 14. Kushner BH, Budnick A, Kramer K, Modak Evidence-Based Medicine Working Group. S, Cheung NK. Ototoxicity from high-dose JAMA. 1994;272(3):234-237. use of platinum compounds in patients with neuroblastoma. Cancer. 2006;107(2):417-422. 21. De Bernardi B, Balwierz W, Bejent J, et al. Epidural compression in neuroblastoma: 15. Gurney JG, Tersak JM, Ness KK, et al. Hearing Diagnostic and therapeutic aspects. Cancer loss, quality of life, and academic problems Lett. 2005;228(1-2):283-299. in long-term neuroblastoma survivors: a report from the Children’s Oncology Group. 22. King D, Goodman J, Hawk T, Boles ET, Jr., Pediatrics. 2007;120(5):e1229-1236. Sayers MP. Dumbbell neuroblastomas in children. Arch Surg. 1975;110(8):888-891. 16. Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical 23. Traggis DG, Filler RM, Druckman H, Jaffe cardiotoxicity following anthracycline N, Cassady JR. Prognosis for children with treatment for childhood cancer: the Pediatric neuroblastoma presenting with paralysis. J Oncology Group experience. J Clin Oncol. Pediatr Surg. 1977;12(3):419-425. 1997;15(4):1544-1552. 24. Punt J, Pritchard J, Pincott JR, Till K. 17. van Dalen EC, van der Pal HJ, Kok WE, Caron Neuroblastoma: a review of 21 cases HN, Kremer LC. Clinical heart failure in a presenting with spinal cord compression. cohort of children treated with anthracyclines: Cancer. 1980;45(12):3095-3101. a long-term follow-up study. Eur J Cancer. 2006;42(18):3191-3198. 25. Holgersen LO, Santulli TV, Schullinger JN, Berdon WE. Neuroblastoma with intraspinal 18. van der Pal HJ, van Dalen EC, Hauptmann (dumbbell) extension. J Pediatr Surg. M, et al. Cardiac function in 5-year survivors 1983;18(4):406-411. of childhood cancer: a long-term follow-up study. Arch Intern Med. 2010;170(14):1247- 26. Massad M, Haddad F, Slim M, et al. Spinal 1255. cord compression in neuroblastoma. Surg Neurol. 1985;23(6):567-572. 19. Grimes DA, Schulz KF. Cohort studies: marching towards outcomes. Lancet. 27. Matthay KK, Sather HN, Seeger RC, Haase 2002;359(9303):341-345. GM, Hammond GD. Excellent outcome of stage II neuroblastoma is independent of
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31. Plantaz D, Hartmann O, Kalifa C, Sainte-Rose 37. De Bernardi B, Pianca C, Pistamiglio P, et al. C, Lemoine G, Lemerle J. Localized dumbbell Neuroblastoma with symptomatic spinal neuroblastoma: a study of 25 cases cord compression at diagnosis: treatment treated between 1982 and 1987 using and results with 76 cases. J Clin Oncol. the same protocol. Med Pediatr Oncol. 2001;19(1):183-190. 1993;21(4):249-253. 38. Katzenstein HM, Kent PM, London WB, Cohn 32. Ribet ME, Cardot GR. Neurogenic tumors of SL. Treatment and outcome of 83 children the thorax. Ann Thorac Surg. 1994;58(4):1091- with intraspinal neuroblastoma: the Pediatric 1095. Oncology Group experience. J Clin Oncol. 2001;19(4):1047-1055. 33. Plantaz D, Rubie H, Michon J, et al. The treatment of neuroblastoma with intraspinal 39. Yiin JJ, Chang CS, Jan YJ, Wang YC. extension with chemotherapy followed Treatment of neuroblastoma with by surgical removal of residual disease. intraspinal extensions. J Clin Neurosci. A prospective study of 42 patients-- 2003;10(5):579-583. results of the NBL 90 Study of the French Society of Pediatric Oncology. Cancer. 40. Aydin GB, Kutluk MT, Buyukpamukcu M, 1996;78(2):311-319. Akyuz C, Yalcin B, Varan A. Neurological complications of neuroblastic tumors:
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 219 experience of a single center. Childs Nerv Syst. 2010;26(3):359-365. 47. Little DG, Song KM, Katz D, Herring JA. Relationship of peak height velocity to 41. Angelini P, Plantaz D, De Bernardi B, Passagia other maturity indicators in idiopathic JG, Rubie H, Pastore G. Late sequelae of scoliosis in girls. J Bone Joint Surg Am. symptomatic epidural compression in 2000;82(5):685-693. children with localized neuroblastoma. Pediatr Blood Cancer. 2011;57(3):473-480. 48. Escalada F, Marco E, Duarte E, et al. Growth and curve stabilization in girls with adolescent 42. Simon T, Niemann CA, Hero B, et al. Short- idiopathic scoliosis. Spine (Phila Pa 1976). and long-term outcome of patients with 2005;30(4):411-417. symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol. 49. Charles YP, Daures JP, de Rosa V, Dimeglio 2012;54(4):347-352. A. Progression risk of idiopathic juvenile scoliosis during pubertal growth. Spine (Phila 43. De Bernardi B, Quaglietta L, Haupt R, et Pa 1976). 2006;31(17):1933-1942. al. Neuroblastoma with symptomatic epidural compression in the infant: the 50. Tan KJ, Moe MM, Vaithinathan R, Wong HK. AIEOP experience. Pediatr Blood Cancer. Curve progression in idiopathic scoliosis: 2014;61(8):1369-1375. follow-up study to skeletal maturity. Spine (Phila Pa 1976). 2009;34(7):697-700. 44. Fawzy M, El-Beltagy M, Shafei ME, et al. Intraspinal neuroblastoma: Treatment options 51. Sorrentino S. SIOPEN Prospective Study and neurological outcome of spinal cord Registry of PNTs presenting with Spinal compression. Oncol Lett. 2015;9(2):907-911. Canal Involvement (SCI). Advances in Neuroblastoma Research (ANR); 2016; 45. Kraal K, Blom T, Tytgat L, et al. Neuroblastoma Cairns, Australia. With Intraspinal Extension: Health Problems in Long-Term Survivors. Pediatr Blood Cancer. 2016.
46. Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol. 2014;32(28):3169-3176.
220 Chapter 8 Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review 221
Chapter 9 General discussion and implications for clinical practice and future research General discussion In this thesis (part A) we have focused on optimising therapy with 131I-MIBG for relapsed/ refractory- and newly diagnosed neuroblastoma (NBL) patients and have performed a systematic review of the literature about the efficacy of MIBG therapy. We have described the yield of autologous stem cell harvests (quantity and quality) and hematological reconstitution after myeloablative therapy (MAT) with autologous stem cell transplantation (ASCT), in HR NBL patients with and without upfront 131I-MIBG.
In part B, we have described retrospectively a cohort of long term survivor NBL patients with intraspinal extension (IE) with regard to epidemiology, biology, clinical presentation, treatment, acute- and long term health problems. Furthermore, we have performed a systematic review of the literature on NBL patients with IE, focusing on acute and long term complications related with disease and therapy. In this chapter I will discuss the main findings and implications of our studies. Additionally, I will suggest recommendations for clinical practice. Based on the currently available data, I will suggest directions for future research regarding both topics.
Part A - Optimising therapy with 131I-MIBG for NBL patients In general, the radiopharmacon 131I-MIBG has shown in different studies around the world to have a significant antitumor efficacy against NBL. More than 95% of NBL tumors have an active uptake of 131I-MIBG. Given the unsatisfactory results of high-intensity induction chemotherapy it is rational to add a different treatment modality to the treatment of HR NBL, this could be 131I-MIBG, as “targeted radiotherapy”.
Is there a place for 131I-MIBG therapy in the treatment of NBL patients ? The prognosis for patients with HR NBL is still poor, new innovative treatment strategies are needed. Many studies have been performed with 131I-MIBG therapy in NBL patients. Initially, 131I-MIBG therapy was given for pain relief as part of palliative treatment, later on for patients with relapsed or refractory (prior to MAT ASCT in patients with residual MIBG positive metastatic disease) and finally up-front (before the start of induction chemotherapy) in patients with newly diagnosed HR NBL. If the diagnostic 123I-MIBG scans show that the primary tumor and distant metastasis take up MIBG, then 131I-MIBG therapy might be effective. MIBG is taken up by the NBL tumor cell and can then irradiate it’s neighboring cells.
In a review on 131I-MIBG therapy, Wilson et al. have reported that the objective tumour response rate reported in 25 studies ranged from 0% to 75%, mean 32%. They concluded that: “131I-MIBG therapy is an active treatment for NBL, but its place in the management of NBL remains unclear. Prospective randomised trials are essential to strengthen the evidence for the efficacy and tolerability of 131I-MIBG therapy”(1). Our Cochrane review studied the effect of 131I-MIBG therapy in patients with newly diagnosed neuroblastoma. (chapter 5) In this review we conclude that: “based on the currently available evidence, we cannot make
224 Chapter 9 recommendations for the use of 131I-MIBG therapy in newly diagnosed HR NBL patients in clinical practice. More high quality research is needed”.
Given the studies that have been performed worldwide and the concluding statements of the reviews that have been published on 131I-MIBG therapy so far, I think that there is a role for 131I-MIBG therapy, but the optimal timing and type of patient that should receive it should still be established.
What type of NBL patients can be considered for 131I-MIBG treatment? In the palliative phase, 131I-MIBG therapy causes fast pain relief, so patients can benefit from this therapy. In many studies, 131I-MIBG has been used in relapsed/ refractory NBL patients, which as a combined group is a very “heterogeneous” group of NBL patients, making it hard to draw conclusions about toxicity and efficacy. It would be worthwhile to separate refractory patients from relapsed NBL patients in studies. The group of NBL patients with relapsed disease are different to patients with refractory disease, in that they have generally, received more and different kinds of treatment modalities. This makes relapsed patients different from refractory patients, they have less bone marrow reserve, which in turn could lead to more hematotoxicity. The tumor might also have become chemo- resistant and/ or radio-resistant, due to outgrowth of certain sub clones. The genetic make-up and biological properties of relapsed NBL tumor can differ from the original tumor at diagnosis. For instance, Eleveld et. al. describe that relapsed NBL show frequent RAS-MAPK pathway mutations. (2)
Of course, even within the subgroup of relapsed NBL patients there are large differences, i.e. time between end of treatment to relapse, the kind of relapse (local-, mixed or metastatic). Multivariate analysis by Simon et al. including different first remission time cut-offs, MYCN status, and site of metastasis at relapse, the survival time after recurrence depended on MYCN amplification (hazard ratio (HR) = 1.701, P = 0.001), first remission time longer than 18 months (HR = 0.531, P = 0.001), first remission time longer than 24 months (HR = 0.502, P = 0.001), bone marrow involvement at recurrence (HR = 1.354, P = 0.044), and lung/pleura involvement at relapse (HR = 2.377, P = 0.060). All other factors were not significant.(3)
Also, different outcomes for relapsed versus refractory NBL patients after 131I-MIBG therapy have been reported by Zhou et al. The overall response rate (PR and CR) to 131I-MIBG based therapies for all patients was 27% (no difference for relapsed and refractory patients). However, after 131I-MIBG, 24% of relapsed patients had progressive disease (PD) compared to only 9% for refractory patients, and 39% of relapsed patients had stable disease (SD) compared to 59% of refractory patients (p= 0.02). The 2-year overall survival for refractory patients was significantly higher at 65.3%, compared to 38.7% for relapsed patients (p< 0.001). (4)
In the Netherlands, 131I-MIBG was initially given to relapsed/ refractory NBL patients (5;6). A different way
General discussion and implications for clinical practice and future research 225 of giving 131I-MIBG is at the end of induction, combined with MAT ASCT (in case of non-progressing residual MIBG positive metastatic disease, so called refractory patients) or as part of relapse therapy (7). The COG give tandem (double) infusions of 131I-MIBG (with a 2- week interval) followed by MAT ASCT to relapsed/ refractory NBL patients (8).
In chapter 2 we report on the results of a phase I/II study combining 131I-MIBG, hyperbaric Oxygen (HBO) and vitamin C in relapsed/ refractory HR NBL patients. This phase II study was preceded by a study that combined 131I-MIBG with HBO for patients with recurrent HR-NBL and compared with a group receiving 131I-MIBG only. It was concluded that the latter treatment was feasible and had an increased cumulative probability of survival of 32% versus 12%. It was thought that the addition of vitamin C to this regimen could diminish the hematological toxicity. The fact that tissue-damage by radiation and the cytotoxic effect of vitamin C both rely on double strand (ds)-DNA breaks, led to the hypothesis that the simultaneous use of 131I-MIBG, HBO and vitamin C could have an additive anti-tumor effect and enhance the efficacy even further. This combination therapy was clinically feasible, however the hematological toxicity was not decreased and the objective response rate (ORR 32%) was not superior to 131I-MIBG-HBO alone. There were clear signs of biological efficacy of this combination treatment, reflected in increased levels of 8-hydroxy- deoxy-guanosine (8OHDG), which is a specific hydroxyl radical-mediated end product of vitamin C induced ds-DNA breaks. Although the logistics of giving HBO therapy in combination with 131I-MIBG are difficult, this study showed that the addition of radio-sensitizers to MIBG treatment was feasible and should be studied more intensely in a group of patients with a poor outcome.
Historically, 131I-MIBG therapy alone, as upfront treatment in newly diagnosed HR NBL patients resulted in an ORR of 66% (9). Following on from this study, a combination of Topotecan (TPT) and 131I-MIBG was given upfront (prior to VECI chemotherapy) to newly diagnosed HR NBL patients in a prospective, windows phase II study (chapter 3). These data show that the combination of two courses of 131I-MIBG with Topotecan in newly-diagnosed HR NBL patients leads to an overall ORR of 57%, and a response of 94% in the primary tumor, thus being an effective treatment option for these patients. The ORR of this 131I-MIBG /TPT combination study were comparable but not superior to 131I-MIBG therapy alone. However, the VECI chemotherapy was not dose intensive. After 2 courses of 131I-MIBG/TPT the bone marrow (BM) was cleared in 43%, at the same time the median Curie score (123I-MIBG scan) reduced with 70%. The high response rates of BM and metastatic disease on 123I- MIBG scan in our study are in contrast to the study reported by Dubois and colleagues in relapsed/ refractory NBL patients combining 131I-MIBG therapy with Vincristin and Irinotecan (10).
Consequently, a pilot study followed, “feasibility, toxicity and response of upfront 131I-MIBG therapy followed by GPOH NB 2004 protocol in newly diagnosed stage 4 NBL patients” (chapter 4). There were 32 patients included in the study, 21 of those patients received up-front 131I-MIBG therapy. The eleven patients that
226 Chapter 9 received chemotherapy alone did not receive 131I-MIBG therapy because of: MIBG non-avid (N=5) and poor clinical condition (N=6).
In 95% of patients 131I-MIBG treatment was feasible within 2 weeks from diagnosis. Interval between chemotherapy courses was 25 days (131I-MIBG group) vs. 22 days (chemotherapy group). No stem cell support was needed after 131I-MIBG therapy. Stem cell harvest in both groups was feasible, neutrophil recovery was comparable, but platelet recovery post MAT ASCT was slower for 131I-MIBG treated patients. RR post 131I-MIBG was 38%, post MAT + ASCT: 71% (131I-MIBG group), 36% (chemotherapy group) and overall 59%. Induction therapy with 131I-MIBG prior to the HR GPOH NB 2004 protocol was found to be feasible, tolerable and effective in newly diagnosed stage 4 NBL patients. 131I-MIBG upfront therapy induces early responses.
The current practice in The Netherlands is, that the treatment protocol has recently been amended, the upfront 131I-MIBG therapy has been left out, as in too many patients it was not feasible to give it due to poor clinical condition at diagnosis.
Coming back to the question: “What type of NBL patients can be considered for 131I-MIBG treatment”? There is no standard answer, but as the previous text illustrates, it depends on whether the patient has NBL which is newly diagnosed, refractory disease or relapsed disease and also on the country/ center where the treatment is taking place. All these NBL patient categories can benefit from 131I-MIBG therapy, as the prior text has outlined. One has to take into account the prior toxicity, that the efficacy will vary between patients and that the feasibility will also be different from patient to patient. (see schematic overview).
What is the optimal timing for 131I-MIBG therapy? The effectiveness of 131I-MIBG therapy remains uncertain, and it’s optimal use undefined (11). There are no randomized controlled trials. It would help if studies report and separate newly diagnosed, relapsed from refractory patients as toxicity and efficacy can then be better reported and interpreted. It would also help to identify separate subgroups within these patients and potential risk groups.
In my opinion, the giving of upfront 131I-MIBG therapy in newly diagnosed HR NBL patients is no longer feasible. Too many of those patients are too ill at diagnosis, 131I-MIBG therapy further on in the treatment would be a better option. For instance, for the Dutch patients, after the 2nd course of N5/N6 chemotherapy or before surgery after the third course of N5/N6. (see schematic overview). The reason to give 131I-MIBG therapy as part of the induction therapy, would be for efficacy, as an additional treatment modality. Initially, the 131I-MIBG therapy was given upfront as there was a large tumor mass, the MIBG molecules are taken up the NBL tumor and can irradiate it’s neighboring cells. It was thought that that this was the optimal moment, with maximal effect of this therapy. However, later on in the induction, there can still be an effect
General discussion and implications for clinical practice and future research 227 of the 131I-MIBG therapy. Also, as previous studies have shown, after 131I-MIBG therapy, the dose intensity of the chemotherapy can still be given and stem cells successfully harvested.
For refractory patients, the 131I-MIBG therapy could be given at the end of induction, for those patients with non-progressing residual MIBG positive metastatic disease after induction chemotherapy, prior to MAT ASCT. As the paper by Decarolis et al. has shown, higher MIBG scores at diagnosis and occurrence of any residual MIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 NBL. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive (12). Thus, 131I-MIBG therapy at the end of induction can also be of additional value, to clear the remaining metastatic lesions. Whether it should be combined with MAT ASCT (single or double 131I-MIBG therapy), has not yet been elucidated. (see schematic overview).
For relapsed patients, it would at least depend on when the relapse occurs. We know in relapse NBL patients that the end of treatment interval is associated with prognosis and outcome (3). This interval has influence on the further treatment options that could be considered for these patients, one of them would be a role for 131I-MIBG therapy. If the relapse occurs within one year after end of treatment, 131I-MIBG therapy can be given for pain relief with/ without Gemcitabine as there are no curative options (see schematic overview). If the relapse occurs more than one year after treatment, 131I-MIBG therapy could follow after reinduction chemo (having achieved CR, VGPR or PR), prior to or combined with MAT ASCT. More well designed (international) studies, including uniform categorization of patients are needed, in order to decipher the optimal timing for 131I-MIBG therapy. (see schematic overview).
The optimal dose of 131I-MIBG therapy for response? Wilson et al. have reviewed the 131I-MIBG therapy literature by reporting on administered activity (AA), this refers to the amount of radioactive substance injected (measured in becquerel (Bq)) and “dose” relates to the amount of radiation absorbed by the body or tumour (measured in Gy.)
In their multivariate analysis of cumulative AA (measured in GBq) there was a positive association between RR and cumulative AA (p= 0.001); there was no clear relationship between response and AA/kilogram (kg) (p= 0.16). The Becquerel is the international system (SI) derived unit of radioactivity, mainly used in Europe. The curie (ci) is the non-SI unit of radioactivity, mainly used in America. Mastrangelo et al. showed in a pilot study with advanced NBL patients, that 131I-MIBG, in combination with chemotherapy, appears to play an important role in a new and effective induction regimen for advanced NBL. Doses of 131I-MIBG as high as 16.6 mCi/kg showed overall (number 13): two (15%) patients (with a complete response (CR), six (46%) very good partial responses (VGPR), four (31%) partial responses (PR), and one (8%) mixed response (MR) (1;13).
228 Chapter 9 In chapter 2, describing MIBG, HBO and vitamin C combination therapy in relapsed/ refractory HR NBL patients, the cumulative AA (median and range) was 10.2 GBq/ 275 mCi (3.7- 14.8GBq/100- 400 mCi/) and cumulative MIBG mCi/ kg 15.9 (6.3- 25.0). This is quite a high dose of 131I-MIBG therapy , especially considering that this is a heavily pre-treated group of NBL patients.
In chapter 3, the 131I-MIBG and Topotecan (TPT) combination therapy reported a mean cumulative AA of 12.4 GBq (335 mCi) , the mean AA/kg was 0.9 GBq/kg (24.3 mCi/kg), with a percentage responders 9/16 (57%) post MAT and ASCT. We calculated the cumulative AA and mean AA/kg of the 131I-MIBG cycles, but found no association with response. The mean cumulative AA and the mean AA/kg of the 2 infusions of 131I-MIBG in our study was high compared to the data reported by the Wilson review. Our ORR of 57% after MAT and ASCT is acceptable compared to the other reported responses. Unfortunately, in our study the radiation dosimetry data (whole body or tumor) were not collected, as this would have been of additional value.
In chapter 4, describing the results of the upfront 131I-MIBG therapy study in newly diagnosed NBL patients, fixed doses of 131I-MIBG were given; AA was 7.4 GBq/ 200 mCi (first course) and 5.5 GBq/ 150 mCi (second course), cumulative AA of 12.9 GBq (350 mCi). For the patients receiving 2 courses of 131I-MIBG, the cumulative AA 131I-MIBG was 0.85 (0.63-1.04) GBq/kg and 23.0 (17.1-28.2) mCi/kg), for the patients receiving only 1 course of 131I-MIBG the median AA was 0.41 (0.17-0.56) GBq/kg and 11.1 (4.7- 15.2) mCi/ kg. Our study shows a post induction RR of 63% and post MAT and ASCT of 59%. This RR as a whole is comparable, but not superior to RR reported in other 131I-MIBG therapy studies in newly diagnosed patients.
Our studies did not show a relationship between the cumulative AA and response or between response and AA/kg.
What is the haematological toxicity of 131I-MIBG therapy? The dose limiting toxicity of 131I-MIBG therapy is myelosuppression. Several studies have reported that approximately one third of patients treated with AA more than 12 mCi/kg 131I-MIBG, require support with ASCT to prevent for prolonged myelosupression, especially thrombocytopenia. Two phase I/II study of Vincristine, Irinotecan (IRN) and 131I-MIBG by Dubois et al, consisted of 131I- MIBG (15 mCi/kg or 18mCi/ kg) and reinfusion of PBSC. Grade 4 thrombocytopenia was seen in 17% of patients (15 mCi/kg) and 58% of patients (18 mCi/kg). (14-16).
A study by Bleeker et. al in patients with newly diagnosed HR NBL receiving upfront 131I-MIBG, the main reported toxicity was grade IV haematological, occurring only in stage 4 patients (BM involvement), after the first and second 131I-MIBG therapies: thrombocytopenia was seen in 2% and 4%, needing no stem cell rescue.There was no significant difference in the administered first 131I-MIBG dose between patients with
General discussion and implications for clinical practice and future research 229 and without haematological toxicity (P = 0.269) (17).
In chapter 2, we describe that the median (range) cumulative AA/kg was 15.9 (6.3- 25.0) mCi/kg, in a heavily pre-treated group of relapsed/ refractory HR NBL patients, however, no stem cell rescue was needed. The addition of vitamin C to the HBO-MIBG combination therapy, did not influence the nadir or the duration of thrombocytopenia, the mean duration of the grade 3 thrombocytopenia was substantial.
In chapter 3, we describe that the mean cumulative AA/kg was 24.3 mCi/kg. Hematologic grade 4 toxicity: after first and second 131I-MIBG (platelets 33%, neutrophils 33% and hemoglobin 7%).
In chapter 4, as reported in our study, despite the high doses of administered 131I-MIBG (median cumulative AA 23 mCi/kg), no stem cell support was needed. The platelet toxicity (median nadir) after each 131I-MIBG course was very mild, in the 131I-MIBG group, the nadir of the platelet counts were lower compared to the chemotherapy group in between chemotherapy courses, but without delay in recovery. In our study it was feasible to harvest stem cells in 78% of the patients, and there was no difference between the 2 groups. The yield of the stem cells was comparable to data reported in the literature (18). The platelet recovery post MAT + ASCT took longer in the 131I-MIBG group than in the chemotherapy group, but was similar to the recovery times reported in the literature (18;19).
The median/ mean cumulative AA/kg was high in the three performed studies (two out of three in newly diagnosed NBL patients received more than 12 mCi/kg), yet no stem cell support was necessary.
It has been hypothesized that the 131I-MIBG therapy (taken up by NBL cells in the bone marrow) might influence the microenvironment of the hematopoietic and stromal cells, impairing the ability to harvest stem cells. The bone marrow infiltration at diagnosis and higher cumulative131 I-MIBG dose has been suggested to be risk factors for prolonged myelosuppression in a previous report by Dubois et al (16). The difference in ability to engraft between platelets and neutrophils might be explained by the selective uptake of 131I-MIBG by megakaryocytes, consequently resulting in delayed platelet recovery, as suggested by Tytgat et al. (20).
Chapter 6, describes the yield of autologous stem cell harvests (quantity and quality) in a study performed in newly diagnosed HR NBL patients with upfront 131I-MIBG or chemotherapy. The median cumulative AA/ kg was 22.1 mCi (0.81 GBq). The median stem cell harvest yield (CD34 positive cells) was the same in both groups. A multivariate regression model for stem cell harvest yield showed, adjusted for age/gender/ MYCN-amplification/LOH1p/Cisplatin dose, a significant association with bone marrow infiltration at diagnosis (p=0.004), but not for 131I-MIBG therapy dose. The difficulty to harvest stem cells in patients with prior bone marrow involvement has been described in patients with Hodgkin’s lymphoma (21). In the same study (chapter 6), the hematological reconstitution after myeloablative therapy (MAT) with
230 Chapter 9 autologous stem cell transplantation (ASCT) was analyzed. Following MAT ASCT (comparable stem cell infusion dose in the two groups), in the 131I-MIBG therapy group, it resulted in delayed platelet recovery while comparable neutrophil recovery was observed, when compared to chemotherapy-only patients. A statistically significant association was found between cumulative dose of 131I-MIBG and dose of stem cells infused with platelet reconstitution. Contrary to the paper by DuBois et al., we did not find an association with bone marrow infiltration and prolonged myelosuppression, but it was associated with 131I-MIBG dose. There was a reduced expression of CD62L and viability in the 131I-MIBG group (predictive markers for rapid platelet recovery) of the CD34+ stem cells. This could explain the comparable neutrophil, but delayed platelet reconstitution occurring in 131I-MIBG treated patients when compared to chemothera- py-only patients. We concluded that harvesting of CD34+ cells or HSPC is feasible after upfront 131I-MIBG in HR NBL patients, however, it resulted after ASCT, in delayed platelet recovery while comparable neutrophil recovery was observed, when compared to chemotherapy-only patients.
Implications for clinical practice • To study and report the effect of 131I-MIBG therapy in NBL patients separately, being either newly diagnosed, refractory or relapsed. • A suggestion for future clinical use of 131I-MIBG therapy in NBL patients (see enclosed schematic overview): • In newly diagnosed patients: two cycles of 131I-MIBG therapy after the 4th course of chemotherapy and before myeloablative therapy with autologous stem cell transplantation (MAT ASCT). • In patients with refractory disease with non- progressing residual MIBG positive metastatic disease: two cycles of 131I-MIBG therapy before MAT ASCT. • In patients with relapsed disease more than one year after end of treatment: reinduction chemotherapy followed by 131I-MIBG therapy followed by MAT ASCT. • In patients with relapsed disease within one year after end of treatment: 131I-MIBG therapy with or without Gemcitabine. • More international collaboration is needed in order to establish the optimal role, timing and dose of 131I-MIBG therapy in the small numbers of NBL patients. The joining of international groups to participate in the same treatment protocols, will enable important questions to be answered quicker and should eventually lead to a better prognosis for these patients.
Implications for future research • Randomized controlled trials comparing 131I-MIBG therapy vs. chemotherapy/ immunotherapy in newly diagnosed and refractory NBL patients investigating feasibility/ tolerability and efficacy. One could consider a second randomization, within the 131I-MIBG therapy group, for one or two cycles of 131I-MIBG therapy.
General discussion and implications for clinical practice and future research 231 • Tandem 131I-MIBG therapy, followed bij MAT with ASCT (conditioning regimen Carboplatin/ Etoposide/ Melphalan (CEM) vs. Busulphan/ Melphalan (BuMel)). • Dose finding studies of 131I-MIBG therapy with or without the addition of radio-sensitizers. • Further study is required to assess the functional relevance of decreased CD62L expression and viability on/ of PBSC of 131I-MIBG-treated patients.
Newly diagnosed
2x 131I-MIBG therapy
131I-MIBG Induction MAT therapy? chemo +ASCT
1 2 3
Refractory NBL patients
non- progressing 2x 131I-MIBG residual MIBG positive therapy metastatic disease
Induction MAT chemo +ASCT
Relapse > 1 year after end of treatment
Chemotherapy (re-induction or radio-sensitizers) re-induction 131I-MIBG chemo therapy MAT + ASCT
[If CR/ VGPR or PR]
Relapse < 1 year after end of treatment Pain-relieve (+ Gemcitabine)
Schematic overview 131I-MIBG therapy
232 Chapter 9 Part B - Neuroblastoma patients with intraspinal extension What are the long term health problems in NBL patients with intraspinal extension? De Bernardi et al. showed that in NBL patients with IE, sequelae were reported in 44% of surviving patients (22). Katzenstein et al. reported that fewer orthopedic sequelae were observed in the chemotherapy group than in children treated with laminectomy (23). Angelini et al. described that severity of motor dysfunction at diagnosis was the most important risk factor for any health problems (24). Short- and long-term outcome of patients with symptoms of spinal cord compression by NBL have been described by Simon et al. Patients first presented with lower extremity motor impairment (95%), impaired cutaneous sensibility (58%), neuropathic pain (56%), bladder dysfunction (44%), and/or constipation (34%). Symptoms improved after first-line neurosurgery in 36 out of 52 patients and after first line chemotherapy in 30 out of 47 patients (p=0.77). After a median observation time of 8 years 1 month (range 1month-19y 6months), 71 out of 99 patients still had residual impairments: motor impairment (43%), scoliosis (31%), impaired bladder function (26%), constipation (19%), impaired cutaneous sensibility (17%), growth delay (14%), and neuropathic pain (5%). Most patients still exhibit residual symptoms and require specialized care (25).
In chapter 7, we describe a retrospective cohort of NBL survivors with IE. Ninety-five percent of survivors had ≥ 1 health problem (HP) and 48% of survivors ≥ 4 with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (Grade 3) or life-threatening/ disabling (Grade 4) health problems. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor-(32% of patients) and -sensory neuropathy (26% of patients). Of the 13 patients that underwent a laminectomy, 54% (7/13) developed a grade 3- and 23% (3/13) a grade 4 health problems. Six patients, without laminectomy, developed in 17% (1/6) a grade 3- and in 17% (1/6) a grade 4 health problems. The high prevalence of grade 3 and 4 health problems emphasizes the importance of specialized long-term multidisciplinary follow-up and to identify optimal treatment with limited morbidity and maximal efficacy.
In chapter 8, we performed a systematic review to define the long-term health problems and optimal treatment strategy for patients with NBL with IE. Long-term health problems are common; a median of 50% of patients suffered from neurological motor deficit, 33.5% from sphincter dysfunction, and 30% from spinal deformity. No conclusions could be drawn to what extent disease and/or treatment contributed to long-term health problems. However, neurosurgery is often suggested as main contributor to the high health problems burden.
What is the best treatment for NBL patients with intraspinal extension? Since Hayes et al. demonstrated in 1984 that chemotherapy is an excellent alternative in control of NBL with intraspinal extension, the mainstay of treatment shifted from neurosurgery in combination with RT to initial chemotherapy with avoidance of neurosurgery and RT (26).
General discussion and implications for clinical practice and future research 233 Katzenstein et al. have reported that the rate of neurologic recovery was similar for patients treated with chemotherapy compared to laminectomy (23). De Bernardi et al. suggested that chemotherapy is the preferred therapeutic modality in NBL patients with intraspinal extension (22).
Simon et al reported in his retrospective analysis that there was no clear advantage of either first-line neurosurgery or chemotherapy (25).
In chapter 7, we have demonstrated that treatment of NBL with intraspinal extension is diverse; the optimal treatment strategy for these patients is still unclear. In chapter 8, we conclude that more well-designed, prospective studies are needed to determine the optimal treatment strategy.
Unfortunately, the currently available literature remains suboptimal as a guide for the treatment of NBL with intraspinal extension.
Are NBL patients with intraspinal extension different to other NBL patients? Patients with a NBL with intraspinal extension seem to have a better outcome than NBL patients without intraspinal extension, but are associated with more health problems, due to spinal cord compression(18;21). Presenting symptoms include neurological deficits, but patients can also be asymptomatic at diagnosis. The systematic review described in chapter 8, showed that NBL with intraspinal extension patients seem to differ from NBL patients without spinal involvement with respect to age at diagnosis, primary tumor location, percentage of disseminated disease, MYCN amplification, and favorable histology. Differences in these patient characteristics can explain the superior overall survival for NBL patients with intraspinal extension found in six studies (while significant in only two studies).
Implications for clinical practice • More uniform reporting of health problems in specialized long-term multidisciplinary follow-up and to develop targeted follow-up programs for NBL patients with intraspinal extension. • Prospective Study (International) registry on children with peripheral Neuroblastic Tumor with spinal canal involvement protocol (NB-SCI), SIOPEN, Co-/ National investigator KCJM Kraal (Principle investigators: Dr. Shifra Ash, Israel and dr. Ricardo Haupt, Genova, Italy). Started June 2014. This prospective study registry for patients with NBL and spinal cord involvement will enable us to collect information in these patients. This will aid us in the development of new diagnostic and treatment guidelines for NBL and spinal cord involvement patients. The setting up of this registry has now been agreed upon in a broad European (SIOPEN) consortium. This platform will also allow for, complex patients with intraspinal extension cases, to be discussed, using a web based forum.
Implications for future research
234 Chapter 9 • More well-designed, prospective studies are needed to reliably, establish the optimal treatment strategy for NBL patients with intraspinal extension. Currently, there are some suggestions in the literature, that chemotherapy would be the preferential treatment modality for these patients. However, the definitive conclusions have not yet been drawn. Certainly, the “standard” NBL patient with intraspinal extension does not exist and it could well be, that this disease requires specialized and tailored care/ therapy. The only way to decipher this, would be to perform a well-designed, prospective study ,with sufficient numbers of patients, to do statistical testing and analysis of the data. • Multidisciplinary out-patient clinic for patients with neuroblastoma patients/ -survivors with intraspinal extension. This outpatient clinic has already been piloted (by this author) in the Amsterdam Medical Centre. The multidisciplinary team consists of: pediatric-/ medical oncologist, orthopedic surgeon, neurosurgeon, psychologist, rehabilitation medicine physician and physiotherapist. The goals of this clinic would be to report health problems, ensure more integrated cure/ care and eventually, to define the optimal treatment strategy, for this very specific category of patients-/ survivors. • Genome wide sequencing of the tumors of NBL patients with intraspinal extension. Currently, in the prospective registry study we are collecting data on segmental- and numerical aberrations, as found using array- comparative genomic hybridization (CGH) in tumor material. It is important to obtain tissue for appropriate biologic studies to guide risk adapted therapy.
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General discussion and implications for clinical practice and future research 237 21. Xia W, Ma CK, Reid C, Bai L, Wong K, Kerridge the management of epidural tumor. J Pediatr I et al. Factors determining pbsc mobilization 1984 February;104(2):221-4. efficiency and nonmobilization following ICE with or without rituximab (R-ICE) salvage therapy for refractory or relapsed lymphoma prior to autologous transplantation. J Clin Apher 2014 December;29(6):322-30.
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23. Katzenstein HM, Kent PM, London WB, Cohn SL. Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 2001 February 15;19(4):1047-55.
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238 Chapter 9 General discussion and implications for clinical practice and future research 239
Appendix English summary
Nederlandse samenvatting (Summary in Dutch) List of co-authors and their contribution to the manuscript List of publications PhD portfolio Acknowledgements Curriculum Vitae Abbreviations English Summary Optimising therapy with 131I-MIBG for neuroblastoma patients and for neuroblastoma patients with intraspinal extension.
Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood. There are approximately 20-25 children diagnosed with NBL per year in the Netherlands. The peak incidence is 0-4 years, with a median age of 23 months. The prognosis of high risk (HR) NBL is still poor (30-40% survival). With the addition of immunotherapy (IT) to the HR maintenance treatment regimen, this has improved survival with 20%. However, this poor outcome still necessitates the search for new therapies. The majority of NBL tumors accumulate meta-iodobenzylguanidine (MIBG). When radiolabeled with 123I-, MIBG can be used for imaging and when labelled with 131I- it can be used as a form of targeted radiotherapy. 131I-MIBG treatment has shown high response rates both in a phase 2, palliative setting and upfront in newly diagnosed patients. Current HR NBL treatment consists of: intensive multi-agent chemotherapy induction, extensive surgical resection of the primary tumor, external beam irradiation of residual primary tumor, myelo-ablative chemotherapy (MAT) followed by autologous stem cell reinfusion (ASCT) and maintenance with differen- tiation and IT. The optimal place, timing and dose of 131I-MIBG treatment has not yet been established. Therefore, during this dissertation, various 131I-MIBG containing studies and a Cochrane review of the literature have been performed.
Patients with NBL and intraspinal extension (IE) are scarce (approximately 10-15% of NBL patients). Approximately 60% of NBL with IE patients present with neurological deficit (symptomatic patients). These patients commonly have favorable prognostic features, making survival of these patients superior to other NBL patient categories. Their long-term survival is quite often altered by severe neurologic and orthopedic health problems (HP). Optimal treatment strategies are important in the perspective of reducing the number of early-/ late HP. The literature concerning this important clinical issue does not provide agreed therapeutic guidelines. Few studies have reported HP (systematically) in this group of patients. More well-designed studies registering HP and functionality are needed. In this chapter, the results of the studies will be summarized.
Part A: Optimising therapy with 131I-MIBG for neuroblastoma patients
In chapter 2, we reported the results of a phase I/II study combining 131I-MIBG, hyperbaric oxygen (HBO) and vitamin C in relapsed/ refractory HR NBL patients. The vitamin C dose (100 mg/kg/day) was escalated per patient with 50 mg/kg/day with each course, as well as the starting dose (+ 50 mg/kg/ day) for the next cohort (n=3). The toxicity of the vitamin C combination was not different from 131I-MIBG –HBO therapy and was well tolerated. The dose limiting toxicity (DLT) of vitamin C was 250 mg/kg/day
242 English summary because of patient compliance with drug intake (too large volume for oral intake). 8-hydroxy-deoxy-gu- anosine (8OHDG), reflecting vitamin C induced DNA double-strand breaks, was increased in 15/22 patients after the first course. Furthermore, 131I-MIBG-HBO and vitamin C therapy was clinically feasible (ORR 32%) with clear signs of biological efficacy.
In chapter 3 we evaluated the efficacy of the upfront treatment of newly diagnosed HR NBL with 2 courses of 131I-MIBG therapy and Topotecan (TPT) in a prospective, window phase II study. 131I-MIBG has a significant anti-tumor effect against NBL. TPT can act as a radio-sensitizer and can up-regulate 131I-MIBG uptake in vitro in NBL. After these 2 courses, standard induction treatment (4 courses of VECI), surgery and MAT with ASCT was given. MIBG administered activity (AA) (median and range) of the first course was 0.5 (0.4-0.6) GBq/kg (giga Becquerel/ kilogram)and of the second course 0.4 (0.3-0.5) GBq/kg. The overall objective response rate (ORR) after 2 x MIBG/TPT was 57%, the primary tumor RR was 94%, and bone marrow RR was 43%. The ORR post MAT and ASCT was 57%. Platelet grade 4 toxicity: after first and second 131I-MIBG was 25/ 33%. Topoisomerase-1 activity levels were increased in 10/10 (100%) measured tumors. Combination therapy with MIBG-TPT is an effective window treatment in newly diagnosed HR NBL patients. This combination is now being tested in various phase II studies in patients with metastatic NBL.
In chapter 4 we studied the feasibility, toxicity and efficacy of upfront 131I-MIBG therapy followed by GPOH NB 2004 protocol in newly diagnosed stage 4 NBL patients, in a prospective, multi-centre pilot study. 131I-MIBG was administered in a fixed dose (aimed at a whole body exposure of 4 Gy. for the combined 2 cycles), to reduce bone marrow toxicity. Not all patients received 131I-MIBG therapy, because of: MIBG non-avid and poor clinical condition at diagnosis (hypertension). In 95% of eligible patients 131I-MIBG treatment was feasible within 2 weeks from diagnosis. Furthermore, no stem cell (SC) support was needed after 131I-MIBG therapy. SC harvest in both groups was feasible, neutrophil recovery was comparable, but platelet recovery post MAT ASCT was slower for 131I-MIBG treated patients. RR post 131I-MIBG was 38%, post MAT + ASCT: 71% (131I-MIBG group), 36% (chemotherapy group) and overall 59%. Upfront 131I-MIBG therapy prior to induction chemotherapy was feasible, tolerable and effective in newly diagnosed stage 4 NBL patients and upfront 131I-MIBG therapy can induce early responses. Despite the limited toxicity and the high response rate at end of induction, the upfront 131I-MIBG therapy has been abandoned in the current HR NBL Dutch protocol, as too many patients weren’t eligible at diagnosis (poor clinical condition). This made it impossible to assess for response (due to selection bias) at the end of the study. In future trials, including patients with newly diagnosed HR NBL, the 131I-MIBG therapy could be given later on in the induction therapy, making more patients eligible for this treatment.
Chapter 5 is a systematic Cochrane review on the literature in order to assess the efficacy and adverse effects of 131I-MIBG therapy in patients with newly diagnosed high-risk NBL. We identified 2 eligible cohort studies, including 60 newly diagnosed HR NBL patients. No randomised controled trials (RCTs) or clinically
243 controlled trials (CCTs) comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in newly diagnosed HR NBL patients were identified. Response rates were 56% and 73%. The median overall survival (OS) duration was 15 months, the median event-free survival (EFS) duration was 10 months. The 5-year OS was 14.6%, 10-year OS 12.2%. Hematological toxicity, especially trombocytopenia, did occur. One study assessed long-term adverse events in part of the patients: thyroid toxicity occurred, but no secondary malignancies were observed. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in newly diagnosed HR NBL patients. More high quality research is needed before definite conclusions can be made.
In chapter 6 we evaluated the feasibility of stem cell (SC) apheresis (quantity and quality) and haematological reconstitution after autologous stem cell transplantation (ASCT) in HR NBL patients treated with upfront 131I-MIBG therapy or chemotherapy. In two prospective, multi-centre cohort studies, 82 newly diagnosed high-risk NBL patients were included: thirty-eight (46%) treated with 131I-MIBG therapy, forty-four (54%) received chemotherapy-only, because of poor clinical condition (n=27), MIBG non-avid tumours (n=11) and logistic failure (n=6). Median PB (peripheral blood) SC-apheresis yield: 5.4 x106/kg (range 0.9-32.3) in 131I-MIBG (n=34) and 5.6 x106/kg (range 0.5-44.5) in chemotherapy-only (n=37) patients. Median cumulative apheresis days: 1 (range 1-8), comparable between groups. Failure to harvest PBSC: 131I-MIBG therapy one and chemotherapy group two patients. A multivariate regression model for PBSC harvest yield showed, adjusted for age/gender/MYCN-amplification/LOH1p/Cisplatin dose, a significant association with bone marrow infiltration at diagnosis (p=0.004). Median time to platelet recovery (95% CI) was 29 (11-47) and 15 days (12-18) respectively for 131I-MIBG and chemotherapy-only group (p=0.037). There was a reduced expression of CD62L and viability in the 131I-MIBG group (predictive markers for rapid platelet recovery) of the CD34+ stem cells. This could explain the comparable neutrophil, but delayed platelet reconstitution occurred in 131I-MIBG treated patients when compared to chemotherapy-only patients. We concluded that harvesting of CD34+ cells or PBSC is feasible after upfront 131I-MIBG in high-risk NBL patients, however, it resulted after ASCT, in delayed platelet recovery while comparable neutrophil recovery was observed, when compared to chemotherapy-only patients.
Part B: Neuroblastoma patients with intraspinal extension
In chapter 7, we have evaluated the prevalence of health problems in 5-year survivors treated for NBL with intraspinal extension. Retrospective, single centre cohort study (using data from Childhood Cancer Registry and medical records) of patients treated for NBL with intraspinal extension. Health problems were graded according to the Common Terminology Criteria for Adverse Events (CTCAEv.3.0). All eligible patients (n=19) were included, 7 patients were asymptomatic at diagnosis, median follow-up was 15.6 years (6.3 – 29.5 years). Ninety-five percent of survivors had ≥ 1 health problem and 48% of survivors ≥ 4 with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (Grade 3) or life-threatening/disabling
244 Appendix (Grade 4) health problem. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor-(32% of patients) and -sensory neuropathy (26% of patients). Of the 13 patients that underwent a laminectomy, 54% (7/13) developed a grade 3- and 23% (3/13) a grade 4 health problem. Six patients, without laminectomy, developed in 17% (1/6) a grade 3- and in 17% (1/6) a grade 4 health problem. The high prevalence of grade 3 and 4 health problems (especially in the laminectomy group) emphasizes the importance of specialized long-term multidisciplinary follow-up and to identify optimal treatment with limited morbidity and maximal efficacy.
In chapter 8, we have systematically searched and evaluated all literature concerning the treatment and outcome of NBL with intraspinal extension. Out of 685 identified studies, 75 were selected for full-text screening and 28 were included in this systematic review. We show that patients with intraspinal extension, differ significantly with the general NBL cohort on clinical relevant prognostic factors. Long-term health problems are a frequent consequence of disease and/or treatment in patients of NBL with intraspinal extension; a median of 50% of patients suffered from neurological motor deficit, 25% from bladder dysfunction, 16% from bowel dysfunction and 30% from spinal deformity. Although no evident conclusions could be drawn on the effect of treatment on the prevalence of long-term health problems, there are studies that show worse outcome after neurosurgery. All studies had methodological limitations. Well-designed, prospective studies are needed to determine the optimal treatment strategy for these patients. Our group (DCOG) has currently joined a SIOPEN international collaboration, neuroblastoma spinal cord involvement prospective study registry collecting data on NBL patients with intraspinal extension.
245 Nederlandse Samenvatting Het optimaliseren van 131I-MIBG therapie voor neuroblastoom patiënten en voor zandloper neuroblastoom patiënten.
Deels hergebruikt van artikel “Nieuwe behandelingen voor patiënten met een hoog risico neuroblastoom”. K.C.J.M. Kraal, B.L.F. van Eck-Smit, M.M. van Noesel, H.N. Caron en G.A.M. Tytgat. NTvO 2013;10(1): 11-19.
Neuroblastoom Het neuroblastoom (NBL) is een kwaadaardige tumor van de kinderleeftijd met een piekincidentie tussen de 0-4 jaar. In Nederland worden per jaar 20-25 kinderen gediagnosticeerd met een NBL. Het NBL ontstaat vanuit voorlopers van het sympathische (onbewuste) zenuwstelsel en kan overal in de grensstreng ontstaan (cervicaal, thoracaal, abdominaal en in het bekken), maar ontstaat vooral in de bijnieren. De behandeling en de daarmee samenhangende uitkomst zijn afhankelijk van de risico classificatie. Risicofactoren zijn factoren die van invloed zijn op de uiteindelijke kans op genezing. De risicofactoren voor NBL zijn onder andere; de leeftijd ten tijde van diagnose, de plek waar de tumor zich bevindt, de uitgebreidheid van de tumor en de aanwezigheid van vermeerdering van een gen, namelijk MycN. Er bestaat een indeling in drie risicogroepen: laag risico (LR), medium risico (MR) en hoog risico (HR). De prognose van het HR-NBL is zeer matig (30-40%) ondanks intensieve behandeling. Recentelijk wordt er aan het einde van de behandeling nog afgesloten met aanvullende immuuntherapie, hierbij zijn de overlevingskansen gestegen naar 40-60%.
Klinische presentatie Patiënten met gemetastaseerde (uitgezaaide) ziekte bij diagnose hebben veelal specifieke klachten. Uitzaaiingen in het beenmerg en de botten geven vaak aanleiding tot nachtelijke botpijnen en koorts/ nachtzweten. Daarnaast ontstaat er door invasie (ingroei) van het NBL in het beenmerg (BM) vaak bloedarmoede en lage bloedplaatjes. Uitzaaiingen naar de oogkassen kunnen een blauw- zwarte verkleuring rondom de ogen geven.
Diagnostiek De diagnose kan gesteld worden met urine onderzoek, beeldvorming en BM onderzoek. In de urine kunnen catecholamines en zure metabolieten worden gemeten (stoffen die vrijkomen uit het NBL). De primaire tumor kan afgebeeld worden met een echo en/of longfoto en voor meer gedetailleerde beelden met een CT/ MRI scan. Om de uitzaaiingen te kunnen beoordelen wordt er een zogenaamde 123I-metaiodoben- zylguanidine (123I-MIBG) scan gemaakt. Ongeveer 95% van de NBL tumoren kunnen de stof MIBG (een noradrenaline-achtige) opnemen. Het MIBG kan gekoppeld worden aan een radioactief isotoop 123I, hierna kan de tumor worden afgebeeld op een 123I-MIBG scan. BM en botbiopten kunnen bij de patiënt onder narcose worden afgenomen, met verscheidende technieken kan hierna beoordeeld worden of er NBL cellen in zitten.
246 Nederlandse samenvatting Behandeling en 131I-MIBG therapie De behandeling van kinderen met een NBL, is volgens de Nederlandse Stichting voor Kinderoncologie (SKION) NBL 2009 behandelprotocol, dit is gebaseerd op het Duitse (GPOH) protocol. De behandeling bestaat uit chemotherapie, chirurgie en eventueel (afhankelijk van risico-classificatie) gevolgd door hoge dosis chemotherapie (MAT) met een stamcel transplantatie (ASCT) en/of bestraling. Deze MAT ASCT wordt gedaan met stamcellen verkregen uit het bloed van het eigen lichaam (autoloog noemen we dit). Voor kinderen met een HR NBL begint de behandeling met de zogenaamde 131I- Meta-Iodobenzylguanidine (131I-MIBG) therapie. 131I-MIBG therapie is een doelgerichte vorm van bestraling (via een radioactief medicijn), met een significante werking tegen NBL. Dit medicijn kan via een bloedvat worden toegediend aan de patiënt Er zijn wel bijwerkingen, zoals bijvoorbeeld misselijkheid en/ of lage bloedplaatjes. Verder zijn er specifieke voorzorgsmaatregelen die bij deze behandeling horen om de patiënten en de ouders/ verzorgers te beschermen tegen de radioactieve bestraling.
Deel A van dit proefschrift gaat over diverse behandelingen met 131I-MIBG therapie.
In hoofdstuk 2, hebben wij in een fase I/ II studie onderzocht, bij NBL patiënten met een recidief/ refractaire ziekte, het toevoegen van hyperbare zuurstof (HBO), vitamine C aan 131I- MIBG therapie. De dosering van de vitamine C (100 mg/kg/dag) werd per patiënt opgehoogd met 50 mg/kg/dag na elke kuur, na elke 3e patiënt werd de start dosering eveneens opgehoogd met (+ 50 mg/kg/dag) voor de daaropvolgende patiënten. De toxiciteit van de HBO-vit C-131I- MIBG combinatie was niet verschillend van de 131I-MIBG-HBO therapie en werd over het algemeen goed verdragen. De dosis beperkende toxiciteit (DLT) van de vitamine C was 250 mg/kg/dag, boven deze dosering, konden de patiënten de vitamine C niet goed meer innemen (te grote hoeveelheid voor orale inname). 8-hydroxy-deoxy-guanosine (8OHDG), weerspiegeld de door vitamine C geïnduceerde dubbel strengs DNA breuken. Bij 15 van de 22 patiënten was de 8OHDG verhoogd na de eerste kuur. De 131I-MIBG-HBO and vitamine C behandeling bleek klinisch haalbaar te zijn, respons van de tumor werd gezien in 32% van de gevallen, met daarbij duidelijke aanwijzingen van biologische effectiviteit.
In hoofdstuk 3, beschrijven wij de uitkomsten van een studie bij patiënten met nieuw gediagnosticeerde hoog-risico (HR) NBL, met als doel om het behandeleffect vast te stellen van twee kuren 131I-MIBG therapie in combinatie met Topotecan (TPT) (MIBG/ TPT). TPT is een effectief middel voor het behandelen van NBL, het versterkt de bestralingseffecten en verhoogt in vitro (in de cel) de opname van 131I-MIBG in NBL cellen. TPT is een remmer van topo-isomerase-1, deze activiteit kan gemeten worden in de tumor. Deze MIBG-TPT combinatie therapie werd gevolgd door verdere behandelmodaliteiten, o.a. standaard inductie therapie
247 (4 kuren VECI), chirurgie en MAT en ASCT. Het effect van deze behandeling werd beoordeeld na 2 kuren MIBG/TPT. De toxiciteit op het vermogen van bloedcel aanmaak en het oogsten van stam cellen (HSPC) werd geanalyseerd. In totaal hebben 16 patiënten (10 jongens) meegedaan aan de studie, de respons op de behandeling na 2 x MIBG/TPT was 57% (9/16) patiënten. De toxiciteit op de bloedcelaanmaak was acceptabel (vooral bloedplaatjes), het oogsten van HSPC was nog steeds mogelijk en veroorzaakte geen vertraging in het verdere beloop van de behandeling. De waarden van de topoisomerase-1 activiteit waren verhoogd in 100% van de (10/10) gemeten primaire tumoren, suggererend, dat het medicijn TPT potentieel een werkbaar middel kan zijn tegen deze tumor. Wij concludeerde dat deze combinatie therapie van 2x MIBG/ TPT een effectieve behandeling voor patiënten met een nieuw gediagnosticeerde HR NBL kan zijn.
In hoofdstuk 4, onderzochten wij in een prospectieve, multi-center piloot studie, de uitvoer-baarheid, toxiciteit en respons van het vooraf geven (up-front) van 131I-MIBG therapie, gevolgd door het “Duitse” GPOH NBL 2004 inductie behandel protocol aan patiënten met een nieuw gediagnosticeerde stadium 4 NBL. 131I-MIBG werd toegediend volgens een vaste dosering, met een totale lichaams beschikbaarheid van 4 Gy, om de BM toxiciteit te kunnen beperken. Niet alle patiënten kregen de 131I-MIBG therapie: omdat de tumor niet/ onvoldoende MIBG aankleurde (avide) op de 123I-MIBG scan of als er een slechte klinische conditie was bij diagnose, b.v. een te hoge bloeddruk. In 95% van de daarvoor in aanmerking komende patiënten, was het mogelijk om de 131I-MIBG behandeling te geven, binnen 2 weken na diagnose. Het was mogelijk om HSPC te kunnen oogsten in beide patiëntengroepen (131I-MIBG therapie en chemotherapie). Het was niet nodig om HSPC terug te geven na afloop van de 131I-MIBG therapie. De opkomst van de neutrofiele witte bloedcellen na MAT ASCT was vergelijkbaar in beide groepen, maar het herstel van de bloedplaatjes duurde langer bij de patiënten die up-front 131I-MIBG therapie hadden gekregen. De respons getallen na 131I-MIBG waren 38%, na myeloablatieve therapie met stamceltransplantatie: 71% (131I-MIBG groep), 36% (chemotherapie groep) en voor de gehele groep 59%. Samenvattend, was het mogelijk om up-front 131I-MIBG therapie, gevolgd door inductie behandeling te geven en was de behandeling voor de patiënten goed te verdragen en bleek het voldoende effectief.
Ondanks, de lage toxiciteit en de hoge respons, wordt de up-front 131I-MIBG therapie niet meer gegeven in het huidige Nederlandse HR behandelprotocol. Teveel NBL patiënten kwamen er, zo kort na de diagnose, niet voor in aanmerking door een te slechte klinische toestand. Hierdoor werd het onmogelijk, om bij deze NBL patiënten, de response voldoende te kunnen beoordelen. In toekomstige studies, bij patiënten met een nieuw gediagnosticeerde HR NBL, zou de 131I-MIBG therapie verderop in de inductie behandeling gegeven kunnen worden, om de deelname te kunnen optimaliseren.
Om na te gaan wat de exacte effectiviteit en gezondheidsproblemen (HP) van 131I-MIBG therapie, bij patiënten met een nieuw gediagnosticeerde HR NBL zijn, werd in hoofdstuk 5 de medische literatuur doorzocht en het wetenschappelijk bewijs samengevat. Twee cohort studies voldeden aan de inclusie
248 Nederlandse samenvatting criteria, met daarin beschreven 60 nieuw gediagnosticeerde HR NBL patiënten. Er waren geen gerandomi- seerde- of klinisch gecontroleerde studies beschikbaar om de effectiviteit van 131I-MIBG therapie vs. geen 131I-MIBG therapie mee te kunnen vergelijken. De resultaten van deze studies laten zien dat de respons getallen tussen de 56% en 73% zijn. De duur van de mediane totale overleving (OS) was 15 maanden, mediane gebeurtenis vrije overleving (EFS) was 10 maanden. De 5-jaars OS was 14.6%, 10-jaars OS 12.2%. De voornaamste hematologische toxiciteit was trombocytopenie (een verlaagde bloedplaatjes getal). Eén studie, bekeek de lange termijn HP, bij een deel van de patiënten werd een vertraagde schildklierfunctie (hypothyreodie) gezien, geen secundaire kwaadaardige tumoren (ten gevolge van de behandeling) werden geconstateerd. Gebaseerd, op de huidige data, kunnen we nu nog geen aanbeveling geven voor het gebruik van 131I-MIBG therapie in patiënten met een nieuw gediagnosticeerde HR NBL. Meer hoog kwalitatief onderzoek is noodzakelijk om hier een definitieve conclusie uitspraak over te kunnen doen.
In hoofdstuk 6, werd de uitvoerbaarheid voor het verkrijgen (aferese) van autologe (lichaamseigen) stam cellen (kwantitatief en kwalitatief) en het herstel van de eigen bloedaanmaak (hematologische) na MAT en ASCT, in HR NBL, vergeleken in patiënten met up-front 131I-MIBG therapie of chemotherapie. In twee prospectieve uitgevoerde multi-center cohort studies, met 82 patiënten met een nieuw gediagnosticeerde HR NBL: 38 (46%) werden behandeld met up-front 131I-MIBG therapie, 44 (54%) kregen chemotherapie. De reden voor het niet geven van up-front 31I-MIBG therapie: slechte klinische conditie (n=27), MIBG niet-avide (n=11) en logistiek falen (n=6). De mediane opbrengst van de oogst van de perifeer bloed stam cellen (PBSC): 5.4 x106/kg (range 0.9-32.3) in 131I-MIBG (n=34) and 5.6 x106/kg (range 0.5-44.5) in chemotherapie (n=37) patiënten. De mediane cumulatieve aferese dagen: 1 (range 1-8) was vergelijkbaar in de twee groepen. Een multivariate regressie model voor de opbrengst van de HSPC toonde, rekening houdende met leeftijd/geslacht/ MYCN-amplificatie/verlies van chromosoom 1 p (LOH1p)/Cisplatinum dosering, een significant verschil met BM infiltratie bij diagnose (p=0.004). De mediane tijd tot bloedplaatjes herstel (95% betrouwbaarheids interval) was 29 (11-47) en 15 dagen (12-18) respectievelijk voor 131I-MIBG therapie en chemotherapie groep (p=0.037). De kwaliteit van de geoogste PBSC werd retrospectief geanalyseerd, er werd een verlaagde expressie gevonden van CD62ligand (CD62L) op de stamcellen en de levensvat- baarheid (viabiliteit) van deze cellen was eveneens verlaagd in de 131I-MIBG therapie patiënten groep. Dit kan mogelijk een verklaring zijn voor het tragere herstel van de bloedplaatjes na ASCT. Wij concluderen, dat het oogsten van HSPC mogelijk is na up-front 131I-MIBG in HR NBL patiënten, maar, dat na ASCT, er een trager herstel is van de bloedplaatjes in de 131I-MIBG groep in vergelijking met de chemotherapie groep.
Deel B: Zandloper NBL
Een speciale categorie van NBL patiënten heeft een zogenaamde “zandloper” NBL, ook wel bekend als NBL met intra spinale ingroei (IE). Gemiddeld krijgen 1 à 2 kinderen dit type kanker per jaar in Nederland. De typische vorm van een zandloper is trechtervormig, waarbij zand door een hele nauwe opening van de ene
249 naar de andere kant gaat. Bij dit type NBL zakt en groeit de tumor als het ware door de (nauwe) trechter- vormige opening van het wervelkanaal heen, gezien de gelijkenis met een zandloper (Engels = “dumbbell”) is deze naam ontstaan. De plek waar deze tumor in het wervelkanaal zit, is bepalend voor de klachten die je krijgt. Doordat de tumor op het zenuwstelsel drukt kunnen deze kinderen zich vaak presenteren met neurologische problemen zoals krachtsverlies, verlammingen, pijnklachten en/of incontinentiever- schijnselen. De behandeling bestaat uit chemotherapie en (neuro-)chirurgie. Bij sommige patiënten is de urgentie groot (voornamelijk bij ernstige neurologische uitval) en is een spoed operatie noodzakelijk. Tot nu toe is bekend dat de overlevingskansen hoog zijn maar gepaard gaan met een substantiële hoeveelheid aan (onomkeerbare) neurologische problemen en problemen van de spieren en het skelet.
In hoofdstuk 7, beschrijven wij de resultaten van een studie waarbij wij gekeken hebben naar het voorkomen van gezondheidsproblemen (HP) op de lange termijn, binnen een groep van overlevende, die langer dan 5 jaar na diagnose nog in leven zijn van neuroblastoom met intra spinale ingroei. Het betrof een retrospectieve, cohort studie (gebruikmakende van lange termijn effecten polikliniek (LATER) registratie en medische dossiers) voor patiënten die werden behandeld in het Amsterdam Medisch Centrum (AMC) tussen 1980- 2007. De gezondheidsproblemen werden methodologisch gescoord volgens een gevalideerd classificatie systeem. Er werden 19 patiënten geïncludeerd, 95 procent van de overlevende hadden ≥ 1 gezondheids- probleem en 48% ≥ 4 gezondheidsproblemen, met een gemiddelde 3.8 gezondheidsproblemen/ overlevende. Drie en vijftig procent van de overlevende had tenminste 1 ernstige (graad 3) of levensbedreigende/ invaliderende (graad 4) gezondheidsproblemen. De 3 meest voorkomende gezondheidsproblemen waren kyfose/ scoliose (68%), motor- (32%) en -sensore neuropathie (26%). Van de 13 overlevende die een ingreep aan de rug ondergingen (laminectomie) als onderdeel van de behandeling, ontwikkelde 54% (7/13) een graad 3 gezondheidsprobleem en 31% (4/13) een graad 4 gezondheidsprobleem. Van de 6 overlevende die geen laminectomie kregen, ontwikkelde 17% (1/6) een graad 3 gezondheidsprobleem en in 17% (1/6) een graad 4 gezondheidsprobleem. Concluderend, het vaak voorkomen van graad 3 en 4 gezondheidspro- blemen bij overlevende van NBL met intra spinale ingroei, benadrukt het belang van actieve follow-up in speciaal daarvoor opgezette multidisciplinaire spreekuren.
In hoofdstuk 8, werd de medische vakliteratuur systematisch doorzocht en het wetenschappelijk bewijs samengevat met betrekking tot behandeling en uitkomsten van gezondheidsproblemen (HP)) van NBL patiënten met intra spinale ingroei. In totaal werden 685 studies gevonden, 75 geselecteerd voor het screenen van de volledige tekst en 28 werden geïncludeerd in deze systematische review. We konden aantonen dat NBL patiënten met intra spinale ingroei significant verschillen, van de algehele NBL groep, met betrekking tot klinisch relevante prognostische factoren. Lange termijn gezondheidsproblemen ontstaan regelmatig binnen deze patiënten groep, door de ziekte zelf en/of door de behandeling; een mediaan van 50% van de patiënten heeft een neurologische motorische stoornis, 25% een blaas stoornis, 16% een darm stoornis en 30% heeft een afwijking van de rug. Er konden geen duidelijke conclusies worden getrokken
250 Nederlandse samenvatting over de prevalentie (het aantal gevallen), van de lange termijn gezondheidsproblemen, ontstaan door een specifieke behandeling. Wel zijn er in enkele studies aanwijzingen dat er door neurochirurgische ingrepen er een slechtere uitkomst is. In alle gevonden studies waren er methodologische beperkingen. Om de optimale behandelstrategie voor NBL patiënten met intra spinale ingroei te kunnen bepalen, is het noodzakelijk om goed ontworpen, prospectieve studies uit te voeren. De Nederlandse NBL behandelaren zijn samengebracht in de SKION. Deze groep, is recentelijk een samenwerkingsverband aangegaan, met een andere Europese artsen organisatie (SIOPEN), voor een prospectieve registratie studie voor het verzamelen van data van NBL patiënten met intra spinale ingroei. Tezamen met goed uitgevoerde onderzoeken, zou hiermee op termijn, o.a. het antwoord moeten volgen op de vraag wat de optimale behandelstrategie voor deze patiënten zou moeten zijn.
251 List of co-authors and their contribution to the manuscript
A phase I/II study of 131I-Meta-Iodobenzylguanidine (MIBG), hyperbaric oxygen (HBO) and vitamin C in patients with recurrent neuroblastoma (NBL). Submitted for publication. K.C.J.M. Kraal: acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. N.G. Abeling: critically reviewing the manuscript, final approval of the manuscript. B.L.F. van Eck-Smit: critically reviewing the manuscript, final approval of the manuscript. M.M. van Noesel: critically reviewing the manuscript, final approval of the manuscript. H.N. Caron: study concept and design, critically reviewing the manuscript, final approval of the manuscript. G.A.M. Tytgat: study concept and design, acquisition of data, supervision of analysis and interpretation of data, drafting the manuscript, critically reviewing the manuscript, final approval of the manuscript.
Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. Pediatric Blood and Cancer 2015 Nov;62(11):1886-91. K.C.J.M. Kraal: acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. G.A.M. Tytgat: study concept and design, acquisition of data, supervision of analysis and interpretation of data, drafting the manuscript, critically reviewing the manuscript, final approval of the manuscript. J. de Kraker: study concept and design, acquisition of data. B.L.F. van Eck-Smit: critically reviewing the manuscript, final approval of the manuscript. H.N. Caron: study concept and design, critically reviewing the manuscript, final approval of the manuscript. M.M. van Noesel: study concept and design, supervision of analysis and interpretation of data, critically reviewing the manuscript, final approval of the manuscript.
Feasibility/ Toxicity and response of Upfront 131I-MIBG therapy followed by standard arm GPOH NB 2004 protocol in newly diagnosed stage 4 neuroblastoma patients. Submitted for publication. K.C.J.M. Kraal: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. G.M. Bleeker: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. B.L.F. van Eck-Smit: study concept and design, critically reviewing the manuscript, final approval of the manuscript. N.K.A. van Eijkelenburg: study concept and design, critically reviewing the manuscript, final approval of the
252 List of co-authors manuscript. F. Berthold: critically reviewing the manuscript, final approval of the manuscript. M.M. van Noesel: study concept and design, supervision of analysis and interpretation of data, critically reviewing the manuscript, final approval of the manuscript. H.N. Caron: study concept and design, critically reviewing the manuscript, final approval of the manuscript. G.A.M. Tytgat: study concept and design, acquisition of data, supervision of analysis and interpretation of data, drafting the manuscript, critically reviewing the manuscript, final approval of the manuscript.
Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high risk neuroblastoma, a Cochrane review. Submitted for publication. K.C.J.M. Kraal: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. E.C. van Dalen: study concept and design, acquisition of data, supervision of analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. G.A.M. Tytgat: study concept and design, acquisition of data, supervision of analysis and interpretation of data, final approval of the manuscript. B.L.F. van Eck-Smit: acquisition of data, analysis and interpretation of data, final approval of the manuscript.
Autologous stem cell transplantation harvesting and hematological reconstitution in high-risk neuroblastoma patients treated with 131Iodine-metaiodobenzylguanidine. Manuscript in preparation. K.C.J.M. Kraal: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. H.M. Kansen: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. C. Voermans: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript. C. vd Bos: acquisition of data, final approval of the manuscript. J. Zsiros: acquisition of data, final approval of the manuscript. H. van den Berg: acquisition of data, final approval of the manuscript. S. Somers: final approval of the manuscript. E. Braakman: acquisition of data, final approval of the manuscript. A.M.L. Peek: acquisition of data, final approval of the manuscript. MM van Noesel: final approval of the manuscript. C.E. van der Schoot: study concept and design, final approval of the manuscript. M. Fiocco: supervision of analysis and interpretation of data, drafting the manuscript, final approval of the
253 manuscript. H.N. Caron: study concept and design, final approval of the manuscript. G.A.M. Tytgat: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript.
Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors. Pediatric Blood and Cancer. 2016 Jun;63(6):990-6. K.C.J.M. Kraal: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. A.J. Blom: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. G.A.M. Tytgat: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript. H.M. van Santen: supervision of analysis and interpretation of data, final approval of the manuscript. MM van Noesel: study concept and design, final approval of the manuscript. AJM Smets: acquisition of data, final approval of the manuscript. J Bramer: acquisition of data, final approval of the manuscript. HN Caron: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript. LCM Kremer: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript. HJH van der Pal: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript.
Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review. Submitted. KCJM Kraal: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. AJ Blom: study concept and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the manuscript. MM van Noesel: study concept and design, final approval of the manuscript. LCM Kremer: study concept and design, final approval of the manuscript. HN Caron: study concept and design, final approval of the manuscript. GAM Tytgat: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript. HJH van der Pal: study concept and design, supervision of analysis and interpretation of data, final approval of the manuscript.
254 List of co-authors 255 List of publications
1. KCJM Kraal, NG Abeling, BLF van Eck-Smit, MM van Noesel, HN Caron and GAM Tytgat. A phase I/ II study of 131I-Meta-Iodobenzylguanidine (MIBG), hyperbaric oxygen (HBO) and vitamin C in patients with recurrent neuroblastoma (NBL). Submitted for publication.
2. KCJM Kraal, GAM Tytgat, J de Kraker, BLF van Eck-Smit, HN Caron and MM van Noesel. Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. Pediatric Blood and Cancer 2015 Nov;62(11):1886-91.
3. KCJM Kraal, GM Bleeker, BLF van Eck-Smit, NKA van Eijkelenburg, F Berthold, MM van Noesel, HN Caron and GAM Tytgat. Feasibility/ Toxicity and response of Upfront 131I-MIBG therapy followed by standard arm GPOH NB 2004 protocol in newly diagnosed HR NBL patients. Submitted for publication.
4. KCJM Kraal, EC van Dalen, GAM Tytgat, BLF van Eck-Smit, HN Caron. Cochrane protocol: “Iodine- 131-meta-iodobenzylguanidine therapy for patients with high risk neuroblastoma”. The Cochrane Library 2013, Issue 2. Full review KCJM Kraal, EC van Dalen, GAM Tytgat, BLF van Eck-Smit. Cochrane protocol: “Iodine-131-meta- iodobenzylguanidine therapy for patients with high risk neuroblastoma”. Submitted for publication.
5. KCJM Kraal, HM Kansen, I Timmerman, C vd Bos, J Zsiros, H van den Berg, S Somers, E Braakman, AML Peek, MM van Noesel, CE van der Schoot, M Fiocco, HN Caron, C. Voermans GAM Tytgat. Autologous stem cell transplantation harvesting and hematological reconstitution in high-risk Submitted for publication.
6. KCJM Kraal, AJ Blom, GAM Tytgat, HM van Santen, MM van Noesel, AJM Smets, J Bramer, HN Caron, LCM Kremer, HJH van der Pal. Neuroblastoma With Intraspinal Extension: Health Problems in Long-Term Survivors. Pediatric Blood and Cancer. 2016 Jun;63(6):990-6.
7. KCJM Kraal, AJ Blom, MM van Noesel, LCM Kremer, HN Caron, GAM Tytgat and HJH van der Pal. Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review. Submitted for publication.
8. GAM Tytgat, KCJM Kraal, M van Grotel, PM Hoogerbrugge, MM van Noesel. Immunotherapie bij kinderen met neuroblastoom. Kankerbreed 2016;1(8):10-13.
256 List of publications 9. T Trahair, S Sorrentino, L Selek, D Plantaz, T Simon, K Kraal, M beck-Popovic, R Haupt, S Ash, B de Bernardi. Spinal canal involvement in neuroblastoma; time for an international prospective registry. Submitted for publication.
10. GH Boerman, MM van Ostaijen-ten Dam, KCJM Kraal, SJ Santos, LM Ball, AC Lankester, MW Schilham, RM Egeler, MJD van Tol. Role of NKG2D, DNAM-1 and Natural Cytotoxicity receptors in cytotoxicity towards Rhabdomyosarcoma cell Lines mediated by resting and IL-15 activated Natural Killer cells. Cancer Immunol Immunother. 2015 May;64(5):573-8.
11. SC Clement, KCJM Kraal, BLF van Eck, C van den Bos, LCM Kremer, GAM Tytgat, H.M. van Santen. Primary Ovarian Insufficiency in Children after Treatment with 131I- Metaiodobenzylguanidine for Neuroblastoma: Report of the First Two Cases. J Clin Endocrinol Metab. 2014 Jan;99(1):E112-6.
12. Kraal KCJM, BLF van Eck-Smit, MM van Noesel, HN Caron en GAM Tytgat. Nieuwe behandelingen voor pediatrische (HR) NBL patiënten. Ned Tijdschr Oncol 2013;10:11-9.
13. LM Ball, KCJM Kraal, SM van Walraven, AC Lankester. Cells, cells and more cells. Oncologica, nummer 01.2009.
14. LFA Visser, KCJM Kraal, D Bresters, LM Ball, RM Egeler. Hemofagocytaire lymfohistiocytose: een zeldzame, maar ernstige complicatie bij kinderen met een hemato-oncologische maligniteit. NTVG, accepted for publication 2008.
15. AML Peek, KCJM Kraal, Overweg- Plandsoen, RM Egeler. Posterior Reversible Encephalopathy Syndrome bij kinderen met leukemie. Ned Tijdschr Hemat 2007;4:310-5.
16. KCJM Kraal, LM Ball et al. Optic nerve relapse in a child with with a common ALL, treated with systemic anti-CD20 treatment. Haematologica 2005 Nov;90 Suppl:ECR24.
17. KCJM Kraal, N Paassen, LM Ball, PM Jansen, R ten Cate. Drie kinderen met algehele malaise, koorts, gewichtsverlies en cervicale lymfadenopathie. Ned Tijdschr Geneeskd 2004 Mar 6;148(10):453-7.
18. KCJM Kraal, AC Lankester, B Granzen, M Oudshoorn, RM Egeler. Twee broers met familiaire hemofagocytaire lymfohistiocytose, behandeld met transplantatie van stamcellen van dezelfde onverwante donor. Ned Tijdschr Geneeskd 2002; 146 (48): 2309-12.
257 PhD Portfolio
Name: Kathelijne Kraal PhD period: March 2011– August 2016 Promotors: Prof. dr. H.N. Caron Co-promotor: dr. G.A.M. Tytgat1,2, dr. M.M. van Noesel2 Department: 1Pediatric Oncology, Emma Children’s Hospital, AMC, 2Pediatric Oncology, Princess maxima Centre (PMC) I. PhD training Year Workload (ECTS) Courses The AMC World of Science 2011 0.7 Basic Course Legislation and Organization for Clinical Researchers (BROK 2012 - 1.2 2016 Medical Literature: PubMed Basics 2012 0.1 Medical Literature: Reference Manager 2012 0.1 Medical Literature: Evidence-Based Searching 2012 0.1 JACIE auditor training 2012 0.6 teach the teacher training, part 1A 2016 Seminars, workshops and master classes Weekly research meetings, Pediatric Oncology, Emma Children’s Hospital, 2011 - Amsterdam 2014 weekly research meetings, Pediatric Oncology, Princess maxima Centre, Utrecht 2015 - 2016 Masterclass “Amsterdam Kindersymposium” 2016 0.4 Oral Presentations Upfront treatment of high risk neuroblastoma with 131I-MIBG therapy and 2013 Topotecan; SIOP Hong Kong Invited speaker SIOPEN meeting (Paris); spinal cord compression in 2014 neuroblastoma patients. Retrospective and prospective study: “The Dutch experience”. First 131I-MIBG therapy workshop (Chair: Dr. GAM Tytgat, presenter Drs. KCJM 2014 Kraal), Advances in Neuroblastoma research (ANR), Koln. Feasibility/ Toxicity and response of Upfront 131I-MIBG therapy followed by 2015 standard arm GPOH NB 2004 protocol in newly diagnosed HR NBL patients, SIOP, Cape Town, South Africa
258 PhD portfolio Poster Presentations Pilot feasibility and toxicity of 2 cycles of upfront 131I- meta-iodobenzylguanidine 2012 (MIBG) therapy followed by the standard arm of high-risk GPOH NB 2004 protocol. POC37. Advances in Neuroblastoma Research (ANR), Toronto. A phase I/II study of 131I-meta-Iodobenzylguanidine (MIBG), hyperbaric oxygen 2012 (HBO) and Vitamin C in patients with recurrent neuroblastoma (NBL). ANR, Toronto. Late adverse events in long-term dumbbell neuroblastoma survivors. Amsterdam 2013 Kindersymposium. Neuroblastoma with intraspinal extension: late adverse events in long term 2014 survivors. ANR, Koln. The sense and sensibility of Philadelphia score in stage 4S neuroblastoma 2014 patients. ANR, Koln. Tumor regression rate in neuroblastoma stage 4S: clinical, biochemical and 204 radiological parameters and recommendations. ANR, Koln. Treatment and outcome of neuroblastoma with intraspinal extension: A systematic 2016 review. SIOP, Dublin. (Inter)national conferences Tuebingen Symposium on pediatric solid tumors 2011 1.0 yearly conference, Dutch Childhood Oncology Group (DCOG), Utrecht. 2011 - 2016 Amsterdam Kindersymposium, Amsterdam, the Netherlands 2012 - 1.3 2014 44th Congress of the International Society of Pediatric Oncology, London, United 2012 1.0 Kingdom 46th Congress of the International Society of Pediatric Oncology, Toronto, Canada 2014 1.0 Advances in neuroblastoma research, Cologne 2014 1.0 Dutch Childhood Oncology Group Symposium, Utrecht, the Netherlands 2015 0.5 Research Retraite Princess Máxima Center for pediatric oncology, Bilthoven, the 2015 0.5 Netherland 48th Congress of the International Society of Pediatric Oncology,Dublin, Ireland 2016 1.0
II. Teaching Year Workload (ECTS) Lecturing Medical students years 3-4 (AMC and PMC) 2011- 2016
259 Nursing education (AMC and PMC) 2011- 2016 Supervising Michelle Tas, Bachelor and master student 2013- 2014 0.2 Michelle Nagtegaal, Bachelor and master student 2013- 2014 0.2 Thomas Blom, bachelor and masterstudent 2013- 2016 1
III. Parameters of esteem Year Workload (ECTS) Grants, awards, and prizes Zeldzame Ziekten Fonds (ZZF) 2011- 2013 KIKA 2012- 2016 Other member SIOP 2011- 2016 Dutch Childhood Oncology Group (DCOG) 2011- 2016 Dutch Childhood Oncology Group (DCOG), protocol committee Neuroblastoma 2011- 2016 member SIOPEL 2015- 2016
260 PhD portfolio Acknowledgements Dankwoord
Wie zou het ooit gedacht hebben, Kathelijne Kraal, gaat promoveren. Ik een aantal jaren geleden in ieder geval niet. Ik wilde respectievelijk, “olympisch” hockeyster worden, toen arts, vervolgens kinderoncoloog, en uiteindelijk neuroblastoom expert en onderzoekster. Wat was en is het een boeiende reis. Ik zou graag de vergelijking trekken met topsport, zoals mijn inmiddels “98-jarige” oma nog steeds zegt, “het leven is topsport, en topsport wordt steeds belangrijker naarmate je ouder wordt”. Om te kunnen promoveren, moet je kunnen doorzetten, tegen een stootje kunnen, discipline hebben, allen belangrijke kwaliteiten in het leven. En dan op een dag is “Het boek af”! Maar het onderzoek nog lang niet en ik hoop nog lang door te kunnen gaan met het bedrijven van de wetenschap door middel van “de bagage/ instrumenten” die ik van velen van jullie heb mogen leren.
Promotiecommissie Dr. GAM Tytgat, lieve Lieve, mijn co-promotor, mentor, collega, vriendin, wat hebben wij samen al een hoop (mooie) dingen meegemaakt. Je bent een Tytgat en “Tytgatters kunnen hard werken”, en wat draag je dit adagium in het breedste zin des woord uit. Wat jij allemaal niet hebt meegemaakt, recentelijk nog langdurig uit de running, maar mij dan wel (vanuit je bed) toch nog ondersteunen om mijn proefschrift tot een goed einde af te ronden. Geweldig, dank. De manier waarop je recht overeind blijft staan, tekent je kracht en slagvaardigheid. “Punten en komma’s ”, ik zal het (ben ik bang) nooit zo goed gaan zien en doen als jij. Ieder zijn ding, zullen we maar zeggen. Samen hebben we veel levendige discussies gehad, waren we het niet altijd eens, maar kwamen er toch altijd wel weer samen uit. Het onderzoek en “de onderzoekster” in mij zijn er zeker beter van geworden. Nog lang niet alle vraagstukken in de “wondere wereld van NBL” zijn opgelost, en waar onderzoek gedaan wordt komen er vaak alleen maar vragen bij, toch vind ik het een eer om o.a. samen met jou ( en overige NBL behandelaren) deze route verder te bewandelen. Een beetje optimist moet je wel zijn in deze wereld….
Dr. MM van Noesel, beste Max, mijn co-promotor, je bent er op belangrijke momenten en dat is belangrijker dan er altijd zijn! Mijn eerste contacten bestonden uit kortstondige onderhouden in Rotterdam (vele patiënten dossiers doorgespit). Later, en vooral toen we gingen samenwerken in “het Maxima” werd de verhouding anders. Ik kan altijd bij je terecht en ben blij met jou “nuchtere en vaak verhelderende” kijk op de zaak.
Prof. Dr. HN Caron, beste Huib, je bent een inspiratie bron voor velen, motiverend, kritisch en “niet bij te houden”. Ik heb het mijn hele leven zelf gehoord, “wat wil jij veel en wat ben jij snel”, maar vergeleken met jou tempo lig ik ruim achter! Ook dit, zal je vast niet voor de eerste keer horen. De kinderarts in jou kwam boven drijven, toen je de AMC kinderoncologen bij jou thuis uitnodigde als afsluiting van je AMC periode. Ik zag
261 een andere Huib verschijnen. Vol passie en met dezelfde overgave als hoe jij je beweegt als kinderoncoloog, leidde jij mijn twee dochters rond op jou terrein (stallen etc.), mijn kinderen waren zwaar onder de indruk. Het mooiste vond ik toen we weg gingen en mijn dochter zei: “dag Huibbie”, je ogen straalden! Ik denk dat de mensen van Roche, in jou een goede hebben, jij bent als geen ander in staat de vertaalslag van “kliniek naar de bench” te maken. Laten we hopen dat er nog veel mooie “targeted drugs” voor de kinderoncologie uit voort komen.
Prof dr. Booij, dank dat u plaats wilt nemen in mijn promotiecommissie.
Prof dr. P Hoogerbrugge, beste Peter, alweer ruim twee jaar één van de vaste kamergenoten in de “tuin”. Met een scherp oog voor kwaliteit, zorg jij voor een constante stroom van verbeter- processen. Vaak ook interessante, inhoudelijke discussies over neuroblastoom patiënten met jou gevoerd, dank daarvoor!
Prof dr. E. van der Schoot, dank dat u plaats wilt nemen in mijn promotiecommissie
Prof. dr. JB van Goudoever, dank dat u plaats wilt nemen in mijn promotiecommissie..
Dr. P Brock, dear Peppy (consultant Great Ormond Street Hospital (GOSH)), thank you very much for participating in my dissertation committee. Your enthusiasm is to be admired and I am in awe of your many achievements within the field of pediatric oncology. I will always remember the tumor board meetings during my time at GOSH “It’s just a question of dotting the I’s and crossing the t’s”. Your endless ward rounds, will remain legendary. You first introduced me to “audits” and the do’s/ don’ts of practicing medicine in an English hospital, I had a wonderful time!
Prof dr. T Simon, dear Thorsten, thank you very much for participating in my dissertation committee. The international collaboration with our GPOH partners and in the field of NB-SCI are also of utmost importance to me.
Prof. Dr. BLF van Eck-Smit, beste Berthe, dank voor jou introductie in de wondere wereld van de “131I-MIBG therapie”! Ik dank je ook, voor je kritische opmerkingen voor de beoordeling van enkele research projecten (ruim voor de deadline, erg prettig) en jou nauwgezetheid binnen de patiëntenzorg. Een van je opmerkingen tijdens de eerste MIBG consensus dagen, blijft mij bij, tijdens de beoordeling van een 123I-MIBG scan na 131I-MIBG therapie: “sterk spul hè MIBG”.
Paranimfen Dr. Fleur Rijcken, gespot tijdens de EL-CID week (1993, wat lang geleden) en hierna van vaste waarde gebleken. Jij rechtsreeks uit de Keniaanse schoolbanken en ik uit Londen. Wat hebben we ongelofelijk veel
262 Acknowledgements overeenkomsten (qua interesses, carrière, relaties), maar oh wat zijn we toch ook verschillend. Geweldige ingrediënten voor de beste vriendin van de wereld. Dank daarvoor. En nu ook een van mijn twee paranimfen, ontzettend leuk.
Dr. Martine van Grotel, het is een feest om met jou samen te werken! Goed om af en toe even te reflecteren (met een kop koffie) en oude herinneringen van “GOSH” op te halen, hilarisch! Nu blik op de toekomst, we gaan mooie tijden tegemoet, nu en straks in het nieuwe “Maxima” met een deur! Moge de samenwerking nog lang door gaan. Fijn dat jij mij bij wil staan als paranimf, tijdens deze belangrijke gebeurtenis. We maken er een “feest van”!
Lieve Ilse en Marrit, de dames van het Amsterdamse WKT secretariaat, dank jullie wel voor alle secretariële ondersteuning tijdens mijn jaren bij de kinderoncologie van F8 Noord en -Zuid!
Lieve Antoinet Gobee, dank Antoinet. Voor jou is het topsport om de agenda van Huib bij te kunnen houden en op tijd alle stukken weer paraat te toveren. Respect hoor!
Dr. Gitta Bleeker, beste Gitta, dank dat ik samen met jou de “pilot N5/ N6 data” heb mogen attaqueren. Sorry, voor mijn ongeduldheid bij tijd en wijlen. Succes met jou verdere carrière binnen de nucleaire geneeskunde/ radiologie en wellicht komen we elkaar nog tegen.
Zandloper carrousel poli AMC, Jos, Femke, Peter, Martha, Barbara, Heleen, het was fantastisch leuk om iets nieuwe op te zetten. Deze pioniers fase heeft mij geholpen met mijn overgang naar het Prinses Maxima Centrum. Spoedig start de Zandloper carrousel poli versie 2.0 in het PMC!
Datamanagers AMC, kinderoncologie, dank voor alle ondersteuning op het gebied van data verzameling, wat de patiëntenzorg - en onderzoek zeer ten goede komt.
Mede kinderoncologen AMC, Cor, Marianne, Netteke, Henk, Rutger, Lianne, Hans, dank voor het indertijd opnemen “van een nieuwe collega” afkomstig van buiten het AMC. Ik voelde mij al snel als een vis in het water.
Verpleegkundigen F8Noord en later F8Zuid, ook jullie hebben mij warm ontvangen en later met een warm afscheid! Dank voor de prettige samenwerking.
Carlijn Voermans, Ilse Timmerman, de dames van Sanquin, dank voor de prettige collegiale samenwerking!
Esther van Wezel, mede promovenda, jij nu al doktor en microbioloog “to be” in Groningen. Jij was mijn
263 maatje in de begin fase van mijn promotie tijdens internationale congressen, het was goed om soms samen tijdens de congressen even “uit te breken” en allerlei zaken door te spreken en een sportieve verhelderende wandeling te ondernemen.
Sasja, Martha, Laura, Esther, Jaap en Anouk, dank voor de hulp bij alle psychosociale problematiek bij de kinderen met kanker en (een aantal van jullie) als ondersteuners van het zandloper NBL spreekuur in het PMC. Dankzij jullie inspanningen bestaat er nu in KLIK een ware “zandloper NBL” KLIK knop, dit gaat zeer behulpzaam zijn bij de in-/ uitvoering en verdere totstandkoming van de zandloper NBL spreekuur.
Heleen van der Pal en Leontien Kremer, dank voor jullie “heldere kijk” op de zaak van systematic reviews, methodologie en de LATER wereld. Heb er veel aan gehad, dank! Heleen, fijn om ook met jou samen te gaan werken binnen LATER en PMC. Eén opmerking van jou vergeet ik niet “De parel van Kraal”, quote van HJH van der Pal n.a.v. eerste zandloper NBL poli d.d. 13 september 2012.
Elvira van Dalen, bedankt voor je hulp bij het schrijven van een Cochrane protocol en review. Er komt inderdaad een “hoop” bij kijken.
Edith Leclerq, Jos Noorman, dank voor de ondersteuning bij het schrijven en de “search” bij een Cochrane review.
Prof. Dr. Maarten Egeler, mijn hoofd afdeling van de IHOBA, voorzitter SIOP, “motivator pur sang”. Maarten, ik heb veel aan jou te danken, jou enthousiasme werkte als zeer inspirerend. Jij zag het al vroeg in mij, gaf vertrouwen waar nodig en was altijd positief en steunend. Kritische noot was altijd, “blijf meer lezen en je verdiepen en zoek een niche”! Jou niche was LCH, nou, ik heb hem gevonden, die van mij heet “zandloper neuroblastoom”. Geniet van je pensioen!
Dr. Lynne Ball, dear Lynne, what an incredible person/ doctor you are! You were the one that introduced me to the field of pediatric oncology, amazing skills (bone marrow aspirates, I have never been seen performed swifter than with you!). Lectures at the top of your head “pick any topic”, always nearby when things were getting “hairy” on the ward. And a very good laugh! Thank you so much.
Wouter Kollen, mijn IHOBA maatje, we wilde allebei kinderoncoloog worden, koste wat koste en het is ons gelukt!
Jakob Anninga, Dorine Bresters, Arjan Lankester, Robert Bredius, Frans Smiers, Rebecca ten Cate, Danielle Brinkman (oud collega’s IHOBA LUMC). Ik ben begonnen, op de stamcel-transplantatie afdeling als AGNIO en was gelijk enthousiast! Dit was wat ik wilde, het voelde als een warm bad, veel goede herinneringen heb
264 Acknowledgements ik eraan overgehouden. Dank voor de prettige samenwerking.
My dear colleagues, specialist registrars, during my time at GOSH, Helen Rees, Olga Slater and Mette Jorgensen. I look back on good times, busy times and drinks at the end (of a usually) long hard working day. It is good to see, that we occasionally, still meet up during Pediatric Oncology International meetings.
Thomas Blom, geneeskunde student (inmiddels basisarts), eerste student die ik heb mogen begeleiden, op het “zandloper neuroblastoom project”. Het onderzoek liep uitstekend door jou gedegen aanpak en flexibiliteit. We hebben veel plezier gehad, zeker met het doorzoeken van oude röntgen materiaal in het “Noodhospitaal” van het AMC, met dank aan Guus! Er gingen steeds weer deuren open….. Gaandeweg hebben we een zandloper groep “app” aangemaakt en volgt er spoedig een doorstart van het zandloper NBL spreekuur versie 2.0 in het PMC. Succes met jou promotie de komende jaren.
Michelle Nagtegaal, Michelle Tas en Hannah Kansen, respectievelijk tweede, derde en vierde geneeskunde studenten, die ik heb mogen begeleiden tijdens diverse NBL projecten. Ik denk met veel plezier terug aan al onze overleg momenten!
Marlies van Mierlo, drijvende kracht achter DCOG NBL 2009 protocol, database, CRF’s…., rust zacht Marlies.
Lenie Scheffer, datamanager van het SKION, dankjewel voor alle ondersteuning “achter de schermen”, zowel op administratief en onderzoek vlak. Je bent een zeer waardevolle kracht achter alle neuroblastoom protocollen en verdere ontwikkelingen binnen “kinderoncologisch” Nederland.
Martha Fiocco, statistica van de Leidse faculteit Wiskunde en SKION (neuroblastoom commissie), dank voor jou “haarfijne” analyses van de data gegenereerd op het gebied van neuroblastoom. De neuroblastoom patiënten zijn qua aantallen klein en daarbij divers, dit maakt het (statistisch) analyseren van de gegevens moeizaam, dank dat jij de vertaalslag en het translationele tussen de “geneeskunde” en “wiskunde” kan zien.
Nucleair geneeskundige, tijdens de MIBG consensus dagen in voorgaande jaren, Berthe, Boen, Adrienne en Boudewijn, het was gezellig, gemengd met de generatie van veel betrouwbare data.
Kinderoncologen en kinderchirurgen van het Prinses Máxima Centrum voor Kinderoncologie, het is prachtig om dagelijks met dit nieuwe team aan de gang te gaan en steeds meer een “geoliede oranje machine” te smeden op weg naar het “nieuwe Máxima”. Samen kunnen we het!
Verpleegkundigen PMC, verpleegkundig specialisten (in opleiding), ik kijk uit naar een goede, verdere samenwerking.
265 Dames van het secretariaat, polikliniek en planbureau van PMC, dank voor jullie immer aflatende hulp bij alle administratieve en logistieke zaken die op ons pad komen.
Datamanagers/ trial bureau PMC, dank voor jullie nauwgezetheid bij het invoeren en reproduceren van alle data.
Kinderradiologen, radiotherapeuten, pathologen en nucleair geneeskundige van het PMC, wat hebben we jullie input hard nodig voor de verbetering van de zorg en overlevingskansen voor het kind met kanker. Dit is multidisciplinair werken “pur sang”. Ik kijk uit naar het voeren van nog veel meer vruchtbare discussies tijdens de WKT in de komende jaren.
Jan Molenaar, beste Jan, ik heb al fijn met jou mogen samenwerken in het AMC en nu alweer even in het “Maxima”. ITHER gaat er komen en gaat nog veel moois opleveren voor neuroblastoom patiënten (en andere vormen van kinderkanker)de komende jaren, daar ben ik van overtuigd!
Dear SIOPEN partners, colleagues in the field of neuroblastoma spinal cord involvement (NB-SCI) prospective registry. Bruno, Shifra, Toby and many more. Bruno, thank you for “spotting” my poster during one of the SIOP meetings. Your enthusiasm to improve the knowledge and care for neuroblastoma patients with intraspinal extension is magical. Now that this thesis has finished, I promise to be more involved in future meetings.
Graag zou ik nog alle kinderen en ouders die deelgenomen hebben aan de studies willen bedanken.
Oma Aghina, wat ontzettend fijn dat je erbij bent op deze speciale dag voor mij. Je bent heel bijzonder, vergeet dat niet.
Nanette en Maurice, 3e weekend van November, vaste prik, het wordt al bijna een traditie!
Lieve Jaarclubgenoten “Cordite”, al sinds 1993 een jaarclub binnen LSVM om rekening mee te houden! Leuk dat jullie, op deze voor mij “memorabele”, dag aanwezig zijn. Volgens mij ben ik alweer de 3e van de 7 medico’s in de club die gaat promoveren, een mooi gemiddelde!
IJsselsteinse vrienden, wat een mooie stad is IJsselstein. Ik woon er nu twee jaar en heb al snel mijn draai gevonden, mede dankzij jullie! Hopelijk heb ik de komende jaren nog meer tijd om jullie en ook het sociale leven beter te gaan leren kennen.
266 Acknowledgements Dineke, je hoort al jaren over mijn proefschrift, dank dat je elke keer weer geïnteresseerd bent. Ik kijk uit naar jou vaste schriftelijke bijdragen in het blad “Over Oegstgeest” in het kader van de vereniging oud Oegstgeest!
Adri, dank voor de beste “oppas” in de wereld en de brownies!
Lief ”zusje” Roos, David, Ella en Luke, what a wonderful family I have, just across the channel! The recent new member of the family ”Max” Cockapoodle, what a bundle of joy. I had a lovely time during the past retreat at your home this Christmas, couldn’t hope for anything better.
Mijn ouders, Peet en Mar, “mijn rotsen” in de branding, zonder jullie….. was dit boek er zeker niet gekomen en nog veel meer niet. Goede tijden en heel soms slechte tijden (die achter mij liggen). Altijd staan jullie paraat, bereid om te helpen, al 5 jaar lang passen jullie wekelijks op mijn meest kwetsbaarste en dierbaarste bezitten! Wat gaat het goed met ze! Dank. Dank voor de heerlijke avonden om samen lekker te lachen. Ik ben de bijdrage van jullie quotes, gevraagd en ongevraagd, niet vergeten! Peet, de stellingen hebben ze helaas niet gehaald, maar ze zijn te mooi om hier niet te noemen. Daarom, bijna als laatste woorden van dit proefschrift! 1. Een wolk is eigenlijk een “zwevende gedachte”. 2. Kinderen zijn de tastbare gevoelens van onze jeugd…. Wanneer komt dat boek nou van jullie?
Merel en Lotte, lieve, lieve meiden, wat zijn jullie stoer, lief, cool en nog zo veel meer, woorden schieten mij tekort om al het mooie in jullie te beschrijven. Wat hebben we het “heerlijk” met z’n allen!
267 Curriculum Vitae Kathelijne Kraal was born in Zaandam on the 19th of February 1975. From 1986 to1993 she attended secondary school at Greenshaw High, Sutton, United Kingdom. She studied medicine at the University of Leiden (RUL), starting in 1993. In July 1999 she received her medical degree. Starting July 1999, she worked as a resident (ANIOS) at the department of pediatrics of the Groene Hart hospital, Gouda (dr. J. Hoekx). In October 2000, Kathelijne started as a resident in paediatrics at the Leiden University Medical Centre (LUMC) and Reinier de Graaf Gasthuis (RdGG), Delft. This is where she started as a paediatrician in training under supervision of prof. dr. J.M. Wit (LUMC) and dr. N van der Lely (RdGG). In her last year as a resident paediatrics, she started her fellowship in pediatric hemato-oncology (LUMC) under supervision of prof. dr. R.M. Egeler. Between October 2004 and September 2005 she worked, as part of her fellowship, as a specialist registrar (Clinical Trust fellow) pediatric hemato-Oncology at Great Ormond Street Hospital (GOSH), London, United Kingdom. In October 2005 she qualified as a paediatrician. She continued her fellowship pediatric hemato-oncology (LUMC) till January 2008, when she qualified as a pediatric hemato-oncologist. From January 2008 till march 2011 she worked as a consultant pediatric hemato-onco- logist in the department of immunology-hematology-oncology and bone marrow transplantation (IHOBA), LUMC (prof. dr. R.M. Egeler). From March 2011 till December 2014 she worked at the Department pediatric oncology, Emma children’s Hospital (EKZ)/ Amsterdam Medical Centre (AMC), Amsterdam (prof. dr. H.N. Caron). At the same time, prof. dr. H.N. Caron invited her to start as a PhD student, and she started the work described in this thesis focussing on optimising therapy with 131I-MIBG for neuroblastoma patients and for neuroblastoma patients with intraspinal extension (promotor prof. dr. H.N. Caron, co-promotores dr. G.A.M. Tytgat and dr. M.M. van Noesel). She received grants from Stichting Kinder Kanker (SKK) (later Tom Voute Fonds (TVF)), Kinderen voor Kanker (KIKA), and stichting Zeldzame Ziekten Fonds (ZZF). The work of this thesis was presented at the Nederlandse vereniging voor kindergeneeskunde (NvK), Advances Neuroblastoma research (ANR), Societé International Oncologie et Pediatrie (SIOP). As of January 2015, she works as a consultant pediatric oncologist/ staff member at the department of pediatric oncology at the Princess Maxima Centre (PMC), Utrecht (dr. M.M. van Noesel). She is a member of the neuroblastoma group Dutch Childhood Oncology Group (DCOG), ANR and SIOP. Kathelijne lives in IJsselstein and has two daughters Merel and Lotte.
268 Curriculum Vitae Abbreviations
AA Administered Activity ASCT Autologous stem cell transplantation BM Bone marrow CME Catecholamines COG Childhood Oncology Group CR Clinical Response CT Computed tomography DCOG Dutch Childhood Oncology Group ds double strand EFS Event free survival GCSF Granulocyte colony-stimulating factor GPOH Gesellschaft fur Padiatrische Onkologie und Hematologie HBO Hyperbaric oxygen HP Health problems HR High- Risk HVA Homo-vanillic acid IE Intraspinal extension IL Interleukine INPC International Neuroblastoma Pathology Classification INRC International Neuroblastoma Response Criteria INRG(SS) International Neuroblastoma Risk Group (Staging System) INSS International Neuroblastoma Staging System IRN Irinotecan IT Immunotherapy LN Lymph nodes LOH1p Loss of heterozygosity chromosome 1 p LR Low risk mBq mega-Becquerel mCi microCurie Mel Melphalan MIBG 131I-Meta-Iodobenzylguanidine MKI Mitosis-karyorrhexis index MNA Amplification of Myc-N oncogene MR Mixed response MR Medium risk
269 MRD Minimal Residual Disease 3-MT 3-Methoxytyramine NBL Neuroblastoma NR No response 8OHDG 8-hydroxydeoxy-guanosine OS Overall survival PBSC(T) Peripheral Blood Stem Cells (Transplantation) PD progressive disease PR Partial response RA Retinoic acid RR Response rate RT Radiotherapy SC Stem cells SIOPEN International Society of Pediatric Oncology European Neuroblastoma SPECT Single photon emission computed tomography TPT Topotecan TRM Transplant related morbidity Treo Treosulphan VGPR Very good partial response VMA Vanyl manilic acid
270 Abbreviations