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Nephroblastoma High-Dose Chemotherapy with Autologous Stem Cell Rescue in Children with Nephroblastoma

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Nephroblastoma High-Dose Chemotherapy with Autologous Stem Cell Rescue in Children with Nephroblastoma Bone Marrow Transplantation (2002) 30, 893–898 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Nephroblastoma High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma B Kremens1, B Gruhn2, T Klingebiel13, C Hasan3, H-J Laws4, E Koscielniak12, B Hero5, B Selle6, C Niemeyer7, FG Finckenstein8, A Schulz9, A Wawer10, F Zintl2 and N Graf11 1Department of Pediatric Hematology/Oncology, University of Essen, Germany; 2Department of Pediatric Hematology/Oncology, University of Jena, Germany; 3Department of Pediatric Hematology/Oncology, University of Bonn, Germany; 4Department of Pediatric Hematology/Oncology, University of Du¨sseldorf, Germany; 5Department of Pediatric Hematology/Oncology, University of Cologne, Germany; 6Department of Pediatric Hematology/Oncology, University of Heidelberg, Germany, 7Department of Pediatric Hematology/Oncology, University of Freiburg, Germany; 8Department of Pediatric Hematology/Oncology, University of Hamburg, Germany; 9Department of Pediatric Hematology/Oncology, University of Ulm, Germany; 10Department of Pediatric Hematology/Oncology, University of Halle, Germany; 11Department of Pediatric Hematology/Oncology, University of Homburg/Saar, Germany; 12Department of Pediatric Hematology, Oncology and Immunology, Olga-Hospital, Stuttgart, Germany; and 13Department of Pediatric Hematology/Oncology, University of Frankfurt, Germany Summary: Keywords: Wilms tumor; high-dose chemotherapy; auto- logous bone marrow transplantation Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and auto- logous peripheral blood stem cell rescue in order to A child with newly diagnosed Wilms tumor (WT) has a improve their probability of survival. From April 1992 probability of about 85% of being cured with multimodal to December 1998, 23 evaluable patients received HDC treatment nowadays. Current treatment strategies stratify within the German Cooperative Wilms Tumor Studies. intensity and scheduling of the different treatment Nineteen were given melphalan, etoposide and car- modalities – surgery, radiation and chemotherapy – accord- boplatin (MEC); the others received different regimens. ing to biologic and prognostic features of the initial disease, The dose of carboplatin was adjusted according to renal most importantly, stage and histology. Three large multi- function. Indications for HDC were high-risk relapse in institutional study groups have contributed to this develop- 20 patients, bone metastases in two patients and no ment: the National Wilms Tumor Study (NWTS), USA,1–3 response in one patient. Fourteen of 23 patients are alive the United Kingdom Children’s Cancer Study Group4,5 and after a median observation time of 41 months, 11 of the International Society of Pediatric Oncology (SIOP).6–9 14 in continuous complete remission, three in CR after For the 15% of patients with relapse or refractory disease, relapse post HDC. The estimated survival and event- attempts have been made to use a similar risk-adapted strat- free survival for these patients are 60.9% and 48.2%. egy. These efforts were based upon the analysis of Grundy Twelve children relapsed after HDC; nine of them died et al10 demonstrating a 3-year survival of 30% in 367 within 12 months and three are surviving from 20 to 33 patients who relapsed following treatment within studies months after relapse. The main toxicities were hematol- NWTS-2 and -3. The authors identified prognostic factors ogic, mucositis and renal (tubular dysfunction; intermit- with respect to time and site of relapse, histology and pre- tent hemodialysis in one patient). There were no toxic vious therapy, and used them to identify a good-risk group deaths. About half of the children suffering from Wilms of relapsed patients who had a survival of >40% with con- tumor with very unfavorable prognostic factors survive ventional therapy.10 For the complementary group of very disease-free after HDC for over 3 years. Besides hema- high-risk patients, treatment alternatives were investigated. tological toxicity, mucositis and infections, renal func- In phase II studies, single drugs or combinations gave the tion is at risk during HDC. With dose adjustment on following results: single drug etoposide: 42% of response;11 glomerular filtration rate, however, no permanent renal ifosfamide plus etoposide: overall response rate 39.5%;12 failure was observed. etoposide and ifosfamide: 15% complete and 54% partial Bone Marrow Transplantation (2002) 30, 893–898. remission;13 etoposide plus carboplatin: 70% response.14 doi:10.1038/sj.bmt.1703771 None of these approaches, however, could improve the long-term survival of these patients above 30%.14 Conse- quently, dose–response strategies were investigated. Wark- 15 Correspondence: Dr B Kremens, Universita¨ts-Kinderklinik, Hufel- entin et al who administered etoposide and thiotepa, andstr.55, D-45122 Essen, Germany. reported eight out of 12 relapse-free survivors after 1 year. Received 14 March 2002; accepted 30 July 2002 The Solid Tumor Registry of the EBMT reviewed 24 HDC with autologous PBSC rescue in children with nephroblastoma B Kremens et al 894 patients who had received different regimens, mostly con- dren received vincristine (VCR) and actinomycin D (ACT- taining melphalan, 34% of whom survived after a median D) (plus doxorubicin (DOX) if they had stage IV) preoper- of 14 months.16 The French Society of Pediatric Oncology atively. Histology was intermediate-risk in 14, high-risk in (SFOP) initiated a prospective study of HDC18 in children five and completely necrotic in four tumors (Table 2). After with a high risk of failure as defined by the NWTS. Chemo- surgery, patients with stage I disease were treated with therapy consisted of a combination of melphalan, etoposide VCR and ACT-D, stage II, III and responsive stage IV with and carboplatin (MEC), a regimen extensively applied in additional DOX. Patients with unresponsive stage IV dis- other solid tumors. Since the majority of patients underwent ease and unfavorable histology – except for stage I ana- HDC after unilateral nephrectomy, the dose of carboplatin plasia – were given etoposide (E), carboplatin (C), ifosfam- administered was adjusted to individual glomerular func- ide (IFO) and DOX. Local radiotherapy was delivered tion using the formula defined by Calvert et al.17 The esti- according to the study protocol; in eight patients an mated overall and disease-free survival in this study were abdominal site, in eight other patients a thoracic site and 60% of 50%, respectively.18 Here, we report the outcome in one child both sites were irradiated (Table 3). of 23 children with Wilms tumor and very high risk fea- Four patients received HDC in first remission according tures treated during a similar time period within the Wilms to the high-risk criteria listed in Table 1 (incomplete Tumor Study of the German ‘Gesellschaft fu¨rpa¨diatrische response to chemotherapy, with initial stage IV in two and Onkologie und Ha¨matologie’ (GPOH, ie Society of Pedi- bone metastases in two children). After the first relapse, atric Oncology and Hematology). The outcome of eight of which occurred 9.5 months after diagnosis (median; range these patients was reported earlier.19 2–24), 19 patients were treated with different drug combi- nations, all including C and E. The site of first relapse was the lung in 10, lymph node, primary site and liver in two Patients and methods each, skeletal in one and renal with an extrarenal primary tumor in one child. One patient had a combined local and Between April 1992 and December 1998, 23 patients with pulmonary relapse. Second-line treatment consisted of vari- Wilms tumor underwent high-dose chemotherapy (HDC) ous drug regimens and thoracotomy for resectable tumor with autologous stem cell rescue in 12 pediatric oncology lesions as well as local irradiation. Patients with chemosen- centers within the German Society of Pediatric Oncology sitive tumors, ie in CR or PR after treatment of relapse, and Hematology (GPOH). Two children with rhabdoid were considered for HDC according to the high-risk criteria tumor of the kidney treated with HDC during the same given in Table 1. At the time of HDC, 13 patients were in period were excluded from this analysis. complete remission (CR) and 10 in partial remission (PR, Diagnosis and first-line treatment followed the SIOP 9 cf. Table 2). Autologous peripheral blood stem cells were study and the SIOP 93-01/GPOH study. HDC was rec- harvested and cryopreserved according to the current prac- ommended for patients with high-risk criteria (cf. Table 1), tice of the participating institutions. but it was not a compulsory part of the protocol. Therefore, The conditioning regimen consisted of C, E and M in 20 not all patients with such criteria received HDC, and it can- patients. On days Ϫ7toϪ3, 200 mg/m2/day of E were not be determined exactly how many may have died before given i.v. over 4 h. For C, the total dose of a targeted area they could have received it. The studies included 830 under the curve of 20 mg ϫ min/ml using the formula patients during the period mentioned above; 120 of them defined by Calvert et al17 was administered in five doses relapsed and 65/120 with one or more high-risk features. on days Ϫ7toϪ3 as a 1 h i.v infusion. Glomerular fil- Of these 65, children, 43 have died (66%). tration rate was estimated by the creatinine clearance in The 11 girls and 12 boys studied in this report had a most children, since routine EDTA clearance was only median age of 74 months at diagnosis (range 11–210 available for a few. M was given as an i.v. bolus of months). Thirteen had stage IV disease, three stage III, four 180 mg/m2 on day Ϫ2, followed by reinfusion of the stage II and four stage I at the time of diagnosis. The chil- thawed peripheral hematopoietic stem cells on day 0. Five children were treated with alternative high-dose regimens: Table 1 High-risk criteria to select patients for high-dose chemo- melphalan and ifosfamide (2), double melphalan (1), M and therapy TBI 12 Gy (1) and E, thiotepa and cyclophosphamide (1).
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