Bone Marrow Transplantation (2002) 30, 565–569 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Medulloblastoma Possible benefits of high-dose chemotherapy and autologous stem cell transplantation for adults with recurrent medulloblastoma MI Zia1,2, P Forsyth1,3, A Chaudhry1,4, J Russell1,2,4 and DA Stewart1,2,4 1Department of Oncology, University of Calgary, Calgary, Alberta, Canada; 2Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 3Department of Neurosciences, University of Calgary, Calgary, Alberta, Canada; and 4Alberta Blood and Marrow Transplant Program, Tom Baker Cancer Centre, Calgary, Alberta, Canada Summary: The prognosis of adults with recurrent medulloblastoma remains poor, with median survival rates reported to be as In an attempt to improve the dismal prognosis of adults low as 5 months.1 Currently, there is no generally accept- with recurrent medulloblastoma, six patients were able therapy for tumor recurrences. The most active chemo- treated with aggressive salvage therapy including high- therapeutic agents include cisplatin or carboplatin,2–4 low- dose chemotherapy (HDCT) and autologous stem cell dose oral etoposide,5 PCV (procarbazine, CCNU, transplantation (ASCT). At relapse, all patients vincristine),6 MOPP (nitrogen mustard, vincristine, procar- underwent surgical debulking followed by HDCT/ASCT bazine, prednisone),7 and intraventricular and intrathecal and then radiotherapy when possible. The treatment therapy with Ara-C, methotrexate and thiotepa.8 Despite plan included two cycles of HDCT/ASCT; first with reasonably high response rates of 40–75% with these cyclophosphamide, etoposide and carboplatin (CECb) agents, no long-term disease-free survival has been and then 2 months later with cyclophosphamide and thi- reported.1–9 Given that these agents are amenable to sub- otepa (CT). Three of the six patients received the stantial dose-escalation, evaluation of high-dose chemo- planned therapy. One patient experienced severe tox- therapy (HDCT) and autologous stem cell transplantation icity requiring life-sustaining therapy. This patient (ASCT) has been suggested.9 Promising results with developed multi-organ dysfunction including multiple HDCT/ASCT prompted us to use this form of therapy for enhancing lesions in both cerebral hemispheres that young adults with recurrent medulloblastoma, who were slowly resolved over several months. Two other patients otherwise healthy and had no possibility of cure with did not mobilize sufficient stem cells for two ASCT pro- conventional dose therapy.10–15 cedures. They received one ASCT conditioned with Here, we report the outcomes of six adults who cyclophosphamide, thiotepa and carboplatin (CTCb). underwent HDCT (cyclophosphamide, carboplatin, thi- Three of six patients had a complete response (CR); the otepa, etoposide) with ASCT for medulloblastoma relapse. other three had a partial response (PR). Following the first ASCT, median duration of response was 13.5 months (range 9–29 months) and median survival was Patients and methods 21.5 months (range 12–42 months). There was no treat- ment-related mortality. We conclude that HDCT/ASCT Patients with CECb-CT or CTCb is active against recurrent medulloblastoma in adults and may be associated with Table 1 lists the clinical profile of patients 1–6. Between prolonged remissions. Multiple enhancing cerebral March 1995 and November 1999, these patients were lesions on brain MRI early post-HDCT/ASCT may be treated with this regimen at the Tom Baker Cancer Centre a consequence of the treatment rather than metastatic in Calgary, Alberta. This report includes follow-up of these disease. patients as of May 2001. The patient sample included five Bone Marrow Transplantation (2002) 30, 565–569. males and one female with a median age of 25 years (range: doi:10.1038/sj.bmt.1703725 8–33 years) at the time of initial diagnosis. All patients Keywords: medulloblastoma; autologous stem cell trans- were initially treated with surgery and radiation Ϯ pre-radi- plantation; neurotoxicity ation chemotherapy (three courses of vincristine and carboplatin). All patients had histologically documented recurrent medulloblastoma. The median age at relapse was 29.5 years (range: 21–35 years). The median time to relapse from initial diagnosis was 40 months (range: 19–204 months). Tumor staging at the time of relapse was done Correspondence: Dr D Stewart, Tom Baker Cancer Centre, 1331-29th using the Chang system. M0 indicates no evidence of meta- Street, NW, Calgary, Alberta, Canada, T2N 4N2 static disease, M1 is classified as positive CSF cytology, Received 30 January 2002; accepted 21 May 2002 M2 as gross nodular seeding of cerebral or cerebellar subar- HDCT and ASCT for recurrent medulloblastoma MI Zia et al 566 Table 1 Patient clinical profiles Patient Gender/Age Surgery RT (Gy) Age at Time to M Time from Histology No. at Initial at Initial craniospinal/ relapse relapse stage at relapse to Dx Dx primary (months) relapse protocol at initial Dx (months) 1 M/33 Total resection 36/54 35 24 2 2 DM 2 M/8 Subtotal resection 20/55 21 168 0 2 DM 3 M/10 Total resection 40/35 27 204 2 16 M 4 F/30 Total resection 36/50 (+ Cx) 32 19 0 22 M 5 M/31 Total resection Ϫ/55 35 50 1 12 DM 6 M/20 Subtotal resection 36/56 (+ Cx) 22 30 3 2 M Dx ϭ diagnosis; M ϭ male; F ϭ, female; RT ϭ radiation therapy; Cx ϭ chemotherapy (vincristine and carboplatin); DM ϭ desmoplastic medulloblas- toma; M ϭ ‘classic’ medulloblastoma. achanoid space or in the third or lateral ventricles, M3 as Response assessment gross nodular seeding of the spinal subarachnoid space, and M4 as extraneuroaxial metastases. At the time of relapse, Patients were assessed by the use of brain and spine MRI the M stage was M0 in two patients, M1 in one patient, after the first and second cycles of HDCT/ASCT, along M2 in two patients, M3 in one patient and M4 in no patient. with CSF cytology if there were prior evidence of metasta- Histologically, three patients had the classic form of medul- sis. Standard radiographic criteria were used to determine loblastoma, whereas the other three had the desmoplastic response. Complete response (CR) was defined as complete variant. resolution of all lesions and no clinical progression. Partial After relapse, three of the six patients underwent surgical response (PR) was defined as a >50% reduction in the pro- resection, two had a combination of surgery and chemo- duct of the maximum perpendicular diameters of all lesions therapy, and one patient had chemotherapy alone. None of and no clinical progression. Stable disease (SD) was the six patients received radiation therapy. Despite these defined as <50% reduction and <25% increase in size with efforts, all patients had symptomatic disease at the time of no clinical progression, and progressive disease (PD) was protocol. The median time from radiographic relapse to the defined as >25% increase in size. The patients’ Karnofsky first cycle of HDCT/ASCT was 7 months (range: 2–22 scores at the time of relapse and shortly (<30 days) after months). All patients had a Karnofsky score of 60% or completing the course of chemotherapy were also recorded. greater before the administration of the protocol. Results Protocol Protocol delivery Three out of six patients (Nos 2, 3 and 5) received the The original protocol consisted of two cycles of high-dose planned two cycles of HDCT/ASCT with CECb followed chemotherapy as follows. Leukapheresis was performed in by CT. Two patients (Nos 4 and 6) did not mobilize suf- all patients after chemotherapy and G-CSF administration, ficient stem cells for two ASCT procedures (only 1.3 and leading to the collection and cryopreservation of stem cells. 3.2 ϫ 106 CD34 cells/kg collected). Both these patients had On days Ϫ6, Ϫ5, and Ϫ4 patients received carboplatin (600 received craniospinal radiotherapy in the past. Conse- mg/m2 over 1 h), etoposide (600 mg/m2 over 3 h) and quently, these two patients received only one cycle of cyclophosphamide (50 mg/kg over 1 h). Approximately HDCT using cyclophosphamide, carboplatin and thiotepa 96 h after completion of chemotherapy, the cryopreserved (same doses as above). One patient (No. 1) experienced stem cells were reinfused. On day +1, granulocyte colony- severe toxicity from CECb/ASCT and declined the second stimulating factor (G-CSF) was administered at a dose of + transplant. For all six patients, the CD34 cell dose ranged 300 ␮g (if less than 70 kg) or 480 ␮g (if over 70 kg) via from 1.3 to 7.5 ϫ 106 cells/kg for the first cycle of the subcutaneous route once daily, until the neutrophils + HDCT/ASCT. The CD34 cell dose for the three patients engrafted. who received the second ASCT ranged from 3.6 to 15 ϫ For the patients who had initially mobilized sufficient 106 CD34 cells/kg. stem cells and established hematopoietic recovery, the second cycle of chemotherapy was administered. On days Ϫ Ϫ Ϫ 2 7, 6, 5, thiotepa (250 mg/m over 24 h) and cyclopho- Toxicity sphamide (2 g/m2 over 24 h) were administered. About 120 h later, the remaining stem cells from the initial harvest Hematological recovery post-ASCT was prompt for all were reinfused. Once again, G-CSF was administered as patients. No patient experienced treatment-related mor- per the first cycle. tality. Only one patient experienced severe life-threatening, Bone Marrow Transplantation HDCT and ASCT for recurrent medulloblastoma MI Zia et al 567 regimen-related toxicity (RRT). This patient developed a systemic inflammatory syndrome with multisystem dys- function of renal, pulmonary, cardiovascular, gastrointes- tinal and central nervous systems. His carboplatin dose was based on the Calvert formula using a measured 24-h creati- nine clearance of 230 ml/min and an area-under-the-curve (AUC) of 21.