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© 2002 American Society for Clinical Oncology Pilot Study of Iodine-131–Metaiodobenzylguanidine in Combination With Myeloablative Chemotherapy and Autologous Stem-Cell Support for the Treatment of NeuroblastomaByFrom the Blood and Marrow Stem Cell Transplantation Program, Division of Pediatric Hematology-Oncology, and Division of Nuclear Medicine, University of Michigan Medical Center, Ann Arbor, MI; and Department of Pediatrics, University of California San Francisco, San Francisco, CA. Address reprints requests to Gregory Yanik, MD, B1-208 Cancer Center, Blood and Marrow Stem Cell Transplantation Program, University of Michigan Medical Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109; email: gyanik{at}umich.edu
PURPOSE: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131–metaiodobenzylguanidine (131I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining 131I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received 131I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m2), etoposide (800 mg/m2), and melphalan (210 mg/m2) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated.
RESULTS: The 131I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil ( CONCLUSION: Treatment with 131I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.
NEUROBLASTOMA IS the most common extracranial solid tumor of childhood, accounting for 8% to 10% of all childhood malignancies.1 Despite intensive chemotherapy with autologous bone marrow transplantation followed by 13-cis-retinoic acid, the 3-year progression-free survival in patients over 1 year of age who present with metastatic disease remains less than 35%.2,3 Patients who did not achieve a complete response (CR) to induction therapy and patients who relapse after a prior transplantation have a less than 20% event-free survival rate.4-6 Newer approaches for treating such high-risk patients are needed. Studies at the University of Michigan in the 1970s identified a number of guanethidine derivatives, including metaiodobenzylguanidine (MIBG), that exhibited binding with adrenal medullary tissue.7 Structurally similar to norepinephrine, MIBG was found to concentrate within the neurosecretory granules of catecholamine-producing cells.7,8 Subsequent scintigraphic studies in the 1970s and 1980s demonstrated the effectiveness of MIBG for the localization of pheochromocytomas, neuroblastomas, and other neuroendocrine tumors.9-16 Approximately 90% of neuroblastomas concentrate MIBG, with uptake well described in both primary tumor sites and metastases.17 MIBG concentrates in tumors with favorable or unfavorable histologic patterns, amplified or nonamplified MYCN oncogene expression, and low-stage as well as advanced-stage disease.17,18 The use of iodine-131–metaiodobenzylguanidine (131I-MIBG) as a therapeutic agent for patients with advanced neuroblastoma has been reported in Europe, the University of California San Francisco, and the University of Michigan.19-27 The majority of these trials were single-agent studies, with response rates ranging from 10% to 50%. The durations of response were often brief, ranging from 100 to over 500 days. Reported toxicity was mild, including nausea and vomiting, myelosuppression, and occasional hypothyroidism. To date, dose escalation of 131I-MIBG therapy for neuroblastoma has failed to achieve nonhematologic dose-limiting toxicity.23 Given the poor progression-free survival for patients with refractory or relapsed disease, attempts to improve prognosis with a combination of 131I-MIBG, myeloablative chemotherapy, and autologous bone marrow transplantation have been reported.24,25,27 The current pilot trial combined a fixed dose of 131I-MIBG with a high-dose chemotherapy regimen of carboplatin, etoposide, and melphalan followed by autologous marrow or stem-cell rescue. Toxicity, engraftment parameters, and response rates were determined for this patient group.
Patient Population Eligible patients were 1 to 18 years of age, had histologically proven neuroblastoma that had relapsed or progressed with induction therapy, and had not achieved complete remission with induction therapy. Patients were required to have evidence of MIBG avidity, as determined by a 123I-MIBG or 131I-MIBG imaging scan, before study entry. Patients who had undergone a previous autologous transplantation were eligible, provided that more than 6 months had elapsed from their initial transplantation. A glomerular filtration rate or 24-hour creatinine clearance  60 mL/min/1.73 m2 was required at study entry. The study was approved by the institutional review board at the University of Michigan, and informed consent was obtained from all parents/guardians.
Autologous Marrow or Stem-Cell Harvest
131I-MIBG Preparation
Treatment With 131I-MIBG
Myeloablative Chemotherapy Administration
Supportive Care
Posttransplant Therapy
Toxicity, Engraftment, and Response Evaluation Toxicities were graded according to the National Cancer Institute common toxicity criteria. Endocrine function was assessed by thyroid-stimulating hormone, thyroxine, adrenocorticotropic hormone, and cortisol measurements obtained before and after therapy. Cardiac function (echocardiogram, ECG) and pulmonary assessment (chest x-ray, pulmonary function testing in patients older than 6 years of age) were made before therapy, at day 100, and then yearly after transplantation.
Neutrophil recovery was defined as the first of 3 consecutive days of an ANC
Patient Characteristics Twelve patients were treated on study between May 1998 and September 2000 (Table 1).32 All patients had received extensive prior therapy, including eight patients who had received more than one chemotherapy regimen before study entry. Three patients (patients no. 10, 11, and 12) had undergone a previous autologous stem-cell transplantation 6 months to 3 years before enrollment on study. Four patients (patients no. 8, 9, 11, and 12) had MYCN-amplified tumors.
At the time of study entry, eight patients had metastatic and four had localized disease. Bone metastases were present in eight patients, including two patients who exhibited more than 10 sites of abnormal MIBG uptake and two patients with pathologic fractures at the time of 131I-MIBG therapy. Bone marrow disease was present in six patients. In five of the six, the marrow had isolated tumor rosettes, occupying less than 5% of the marrow biopsy. In one case, the marrow involvement was greater than 50% of the biopsy specimen at the time of 131I-MIBG therapy. Five patients had pulmonary or mediastinal involvement, and two patients had intra-abdominal lesions, the largest lesion measuring 10 x 8 x 6 cm at the time of MIBG therapy. Ten of 11 patients had a creatinine clearance greater than 100 mL/min/1.73 m2 at study entry.
Treatment Course
Nonhematologic Toxicity
Hematologic Toxicity Hematologic features are listed in Table 3. In all 12 patients, neutrophil counts remained stable (> 1.5 x 103/µL) for 2 weeks after the 131I-MIBG administration. The median time to count nadir (ANC < 0.5 x 103/µL) was day 0 of therapy (range, day -2 to day 1). The median time to neutrophil recovery was day 10 (range, day 6 to day 31). Eleven of 12 patients achieved an ANC 0.5 x 103 by day 15 after transplantation.
The median time to platelet nadir (< 20 x 103/µL) was day 1, with a median time to platelet recovery on day 28 (range, day 7 to day 99). Two patients required platelet transfusions after day 50 because of hematuria.
Response Rates
Relapse or disease progression has occurred in eight patients, 2 to 13 months (median, 8.5 months) after transplantation. Relapses have occurred in previously uninvolved bony sites (patients no. 1, 2, and 12), in previously involved bony sites (patients no. 8 and 11), in marrow (patients no. 4, 9, and 10), and in a primary abdominal mass (patient no. 11).
The feasibility of combining 131I-MIBG with myeloablative chemotherapy and hematopoietic stem-cell rescue for patients with neuroblastoma was examined in this pilot trial. The median age at the time of initial diagnosis (3.3 years), the percentage of patients with MYCN amplification (33%), and the median time from diagnosis to transplantation (12 months) were similar to that reported in other neuroblastoma trials.3,5,33 Despite extensive prior therapy, toxicity was acceptable and objective responses were observed in this group of patients. The nonhematologic toxicity of the regimen was limited, with fever/neutropenia and oral mucositis predominantly seen in all patients. Both toxicities occurred during the period of count nadir (after myeloablative chemotherapy), and presumably may have been related more to the intensive chemotherapy than to the 131I-MIBG. When given as single-agent therapy, 131I-MIBG has not been previously associated with the development of mucositis. Historically, the incidence of mucositis has been high in patients receiving myeloablative chemotherapy for the treatment of neurboblastoma.3,34,35 The potential for bladder injury was of concern in this trial. Urinary excretion of 131I-MIBG has been previously well described, with visualization of the bladder readily seen on routine 123I- and 131I-MIBG diagnostic scans. The majority of 131I-MIBG is excreted unchanged in the urine, with 40% to 55% of an administered dose excreted in the first day, and 70% to 90% by the fifth day after administration.36,37 In order to minimize 131I-MIBG contact with bladder epithelium, all patients in this trial had indwelling urinary catheters placed and intravenous hydration administered during the 131I-MIBG administration. Despite this precaution, hematuria developed after transplantation in two patients, with hemorrhagic cystitis documented by cystoscopy in one of the cases. The potential for bladder epithelial injury will need to be monitored in future 131I-MIBG trials. The cause of the skin rash that developed 4 days after 131I-MIBG infusion in one patient remains unclear, as no evidence for cutaneous neuroblastoma was noted on biopsy specimens. No other dermatologic toxicities were observed in this study or in previously reported 131I-MIBG trials.19,21-27 Although the follow-up has been short (median, 12 months), few late complications have been observed. The use of SSKI administration for 28 days after 131I-MIBG administration appears to have inhibited thyroid uptake of radiolabeled iodine in the majority of treated patients. The use of more vigorous measures to block thyroid uptake, such as the addition of perchlorate anion, or a greater duration of SSKI therapy may lower the incidence of hypothyroidism even further. Likewise, although 131I-MIBG will normally concentrate within the adrenal medulla, adrenal insufficiency has not been noted to date. Secondary leukemia was previously reported in a patient who received two courses of single-agent 131I-MIBG therapy.23 No cases of secondary leukemia have been noted in our study population to date. Because 131I-MIBG readily concentrates within the marrow, and as the majority of treated patients will have previously received high-dose alkylator and etoposide therapy, the potential for development of secondary leukemia is present in our study population. The hematopoietic toxicity of the therapy was acceptable, with 11 of 12 patients engrafting (ANC > 0.5 x 103/µL) within 15 days after transplantation. The dosage of 131I-MIBG used in this trial (12 mCi/kg) has previously been shown to be myelosuppressive, but not myeloablative, if given as single-agent therapy.23 Delayed neutrophil recovery was only observed in one case (patient no. 8), who also had the greatest degree of marrow involvement at the time of treatment (> 50% neuroblasts). 131I-MIBG may have particularly concentrated within this patient’s marrow because of the extensive tumor involvement. 131I-MIBG concentration within the marrow, particularly within megakaryocytes, has already been well described.22 Whether marrow precursor cells or stromal cells selectively bind 131I-MIBG at levels that may lead to prolonged cellular injury is still under investigation. An important finding in our study was the time to onset of neutropenia (median onset, day 0). Given that marrow suppression will typically occur 21 to 40 days after infusions of 131I-MIBG,23 day -21 was chosen as the 131I-MIBG infusion date for this trial. As the effective half-life of 131I-MIBG in tumors is estimated to be 42 to 72 hours,38 therapeutic dosages of 131I-MIBG may be administered even closer to the time of transplantation. However, as radioisotope emissions are often detectable for 3 to 7 days after 131I-MIBG infusion, administering 131I-MIBG within 7 days of stem-cell/marrow infusion may pose a risk to the graft.
The response rates seen in our trial compare favorably with prior single-agent 131I-MIBG trials17,19-23 and trials combining 131I-MIBG with intensive chemotherapy.24-27 Previous single-agent 131I-MIBG trials have found a threshold for tumor response, with dosages more than 9 mCi/kg achieving the greatest tumor response. Matthay et al23 noted responses in 37% of patients treated with single-agent therapy, with 131I-MIBG dosages ranging from 9 to 18 mCi/kg. Ten (48%) of 21 patients treated with dosages Whether patients in our trial relapsed because of failure of control of in situ disease, or because of reinfusion of undetected tumor cells within the stem-cell or marrow product, is difficult to determine in a trial of this size. Three of the relapses occurred in sites of new disease in patients who had received unpurged stem-cell products. It is likewise difficult to determine whether the responses seen in this trial were principally secondary to the MIBG therapy, to the high-dose chemotherapy, or to the combination of the two. No diagnostic studies were routinely performed on day -7, immediately before the chemotherapy. Prior single-agent studies have found that MIBG does not usually achieve its maximal effect for at least 4 to 6 weeks after infusion.18,20,22 The determination of optimal candidates for MIBG therapy is still under investigation. Historically, patients with relapsed neuroblastoma have an extremely poor rate of survival, especially if nonlocalized disease is present at the time of relapse.1-6 The presence of a chemoresistant relapse or relapse after transplantation are two adverse factors previously reported by Ladenstein et al4 in a large European trial. In agreement with the report by Ladenstein et al, we noted that patients who had received a prior transplant appeared less responsive to our study therapy. Patients who have a persistent MIBG-avid tumor at the completion of induction therapy,5 or the presence of more than 100 tumor cells per 100,000 by marrow immunocytology on completion of induction therapy,39 are known to be at high risk for treatment failure. The addition of 131I-MIBG to consolidation therapy in these high-risk groups may be considered in the future. As the patient population is small, larger studies will be required to more adequately assess efficacy and impact on overall survival. This pilot study examined the role of 131I-MIBG with myeloablative chemotherapy at only one dose level. A multicenter trial is currently in progress, in which dose escalation of both the 131I-MIBG and the chemotherapy regimen are being examined. In conclusion, the combination of 131I-MIBG with a fixed dose of myeloablative chemotherapy and autologous stem-cell rescue appears feasible for patients with relapsed or persistent MIBG-avid disease. Overall, therapy was well tolerated in this small group of patients, with limited nonhematopoietic toxicity, and responses were seen even in patients with progressive disease. Future trials combining 131I-MIBG with high-dose chemotherapy are warranted.
APPENDIX The following physicians referred patients for therapy and provided follow-up data:Valerie Castle, MD, University of Michigan, Ann Arbor, MI; Roshni Kulkarni, MD, Renuka Gera, MD, and Jovi Scott-Emuakpor, MD, Michigan State University, Lansing, MI; Len Mattano, MD, Tina Elliot, MD, Jeffrey Lobell, MD, Michigan State University–Kalamazoo Center for Medical Studies, Kalamazoo, MI; Ken DeSantes, MD, University of Wisconsin, Madison, WI; Fred Goldman, MD, University of Iowa, Iowa City, IA; Jonathan Bernstein, MD, Sunrise Children’s Hospital, Las Vegas, NV; Bradley George, MD, Emory University and Scottish Rite Medical Center, Atlanta, GA; and Kanta Bhambani, MD, and Esteban Abella, MD, Children’s Hospital of Michigan and Wayne State University, Detroit, MI.
Supported in part by National Institutes of Health grant no. MO1 RR00042 from the University of Michigan Clinical Research Center and by National Cancer Institute grant no. CA81403 for the New Approaches to Neuroblastoma Therapy Consortium. We thank Cynthia Bower and the General Clinical Research Center nurses, Shelli Anuskiewicz, Deborah Fatchett, and Brenda Pontillo (Pediatric Bone Marrow Transplant Service), and Clark Hagen, Robert Blackburn, and Marcian Van Dort (Phoenix Laboratory).
1. Brodeur GM, Castleberry RP: Neuroblastoma, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatrics. Philadelphia, PA, Lippincott-Raven, 1997, pp 761-797 2. Matthay KK: Neuroblastoma, in Pochedly C (ed): Neoplastic Diseases in Childhood. Amsterdam, the Netherlands, Harwood Academic Publishers, 1994, pp 735-778
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Ladenstein R, Lasset C, Hartmann O, et al: Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: A report from the European Group for Bone Marrow Transplantation. J Clin Oncol 11: 2330-2341, 1993 5. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16: 953-965, 1998[Abstract] 6. Stram DO, Matthay KK, O’Leary M, et al: Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma. J Clin Oncol 14: 2417-2426, 1996[Abstract]
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Seeger RC, Reynolds CP, Gallego R, et al: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: A Children’s Cancer Group study. J Clin Oncol 18: 4067-4076, 2000 Submitted March 26, 2001; accepted January 15, 2002. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
