Abstract
We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, × 4 days; thiotepa 300 mg/m2/day, × 3 days; and carboplatin ∼500 mg/m2/day, × 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, ±oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.±8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.
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References
Kramer K, Kushner B, Heller G, Cheung NKV . Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 2001; 91: 1510–1519.
Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 1999; 341: 1165–1173.
Houghton PJ, Cheshire PJ, Myers L, Stewart CF, Synold TW, Houghton JA . Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 1992; 31: 229–239.
Hendricks CB, Rowinsky EK, Grochow LB, Donehower RC, Kaufmann SH . Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. Cancer Res 1992; 52: 2268–2278.
Kaufmann SH, Peereboom D, Buckwalter CA, Svingen PA, Grochow LB, Donehower RC et al. Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 1996; 88: 734–741.
Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF . Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996; 37: 195–202.
Pratt CB, Stewart C, Santana VM, Bowman L, Furman W, Ochs J et al. Phase 1 study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 1994; 12: 539–543.
Tubergen DG, Stewart CF, Pratt CB, Zamboni WC, Winick N, Santana V et al. Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a Pediatric Oncology Group study. J Pediatr Hematol/Oncol 1996; 18: 352–361.
Nitschke R, Parkhurst J, Sullivan J, Harris MB, Bernstein M, Pratt C . Topotecan in pediatric patients with recurrent and progressive solid tumors: a Pediatric Oncology Group phase II study. J Pediatr Hematol/Oncol 1998; 20: 315–318.
Kretschmar C, Kletzel M, Murray K, Thorner P, Joshi V, Marcus R et al. Response to paclitaxel, topotecan, and topotecan-cyclophsphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a Pediatric Oncology Group study. J Clin Oncol 2004; 22: 4119–4126.
O’Reilly S, Rowinsky E, Slichenmyer W, Donehower RC, Forastiere A, Ettinger D et al. Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function. J Natl Cancer Inst 1996; 88: 817–824.
O’Reilly S, Rowinsky E, Slichenmyer W, Donehower RC, Forastiere A, Ettinger DS et al. Phase I and pharmacologic studies of topotecan in patients with impaired renal function. J Clin Oncol 1996; 14: 3062–3073.
Kushner BH, Cheung N-KV, Kramer K, Dunkel IJ, Calleja E, Boulad F . Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. Bone Marrow Transplant 2001; 28: 551–556.
Park JR, Slattery J, Gooley T, Hawkins D, Lindsley K, Villablanca JG et al. Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors. Med Pediatr Oncol 2000; 35: 719–723.
Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE et al. Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756.
Kushner BH, Wolden S, LaQuaglia MP, Kramer K, Verbel D, Heller G et al. Hyperfractionated low-dose (21 Gy) radiotherapy for high-risk neuroblastoma following intensive chemotherapy and surgery. J Clin Oncol 2001; 19: 2821–2828.
Cheung N-KV, Kushner BH, Cheung IY, Canete A, Gerald W, Liu C et al. Anti-GD2 antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 1998; 16: 3053–3060.
Kushner BH, Kramer K, Cheung N-KV . Phase II trial of the anti-GD2 monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol 2001; 19: 4189–4194.
Kushner BH, Kramer K, Cheung N-KV . Oral etoposide for refractory and relapsed neuroblastoma. J Clin Oncol 1999; 17: 3221–3225.
Brodeur GM, Pritchard J, Berthold F, Carlsen NLT, Castel V, Castleberry RP et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11: 1466–1477.
Kushner BH, Kramer K, LaQuaglia MP, Modak S, Yataghene K, Cheung N-KV . Reduction from seven to five cycles of intensive induction chemotherapy in children with high-risk neuroblastoma. J Clin Oncol 2004; 22: 4888–4892.
Modak S, Kramer K, Gultekin SH, Guo HF, Cheung N-KV . Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. Cancer Res 2001; 61: 4048–4054.
Kramer K, Cheung NKV, Humm JL, Dantis E, Finn R, Yeh SJ et al. Targeted radioimmunotherapy for leptomeningeal cancer using 131-I-3F8: patient imaging and dosimetry. Med Pediatr Oncol 2000; 35: 716–718.
Frei III E, Teicher BA, Holden SA, Cathcart KNS, Wang Y . Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 1988; 48: 6417–6423.
Teicher BA, Cucchi CA, Lee JB, Flatow JL, Rosowsky A, Frei E . Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. Cancer Res 1986; 46: 4379–4388.
Kaufmann SH, Peereboom D, Buckwalter CA, Svingen PA, Grochow LB, Donehower RC et al. Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 1996; 88: 734–741.
Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Brown RA, Frei-Lahr D et al. High-dose N, N′, N′ – triethylenethio-phosphoramide (thiotepa) with autologous bone marrow transplantation: phase I studies. Semin Oncol 1990; 17: 2–6.
Ettinger LJ, Gaynon PS, Krailo MD, Ru N, Baum ES, Siegel SE et al. A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Children's Cancer Group. Cancer 1994; 73: 1297–1301.
Shea TC, Flaherty M, Elias A, Eder JP, Antman K, Begg C et al. A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 1989; 7: 651–661.
Miller AA, Hargis JB, Lilenbaum RC, Fields SZ, Rosner GL, Schilsky RL . Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a Cancer and Leukemia Group B study. J Clin Oncol 1994; 12: 2743–2750.
Rowinsky EK, Kaufman SH, Baker SD, Grochow LB, Chen TL, Peereboom D et al. Sequences of topotecan and cisplatin: Phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996; 14: 3074–3084.
Murren JR, Anderson S, Fedele J, Pizzorno G, Belliveau D, Zelterman D et al. Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer. J Clin Oncol 1997; 15: 148–157.
Saylors III RL, Stewart CF, Zamboni WC, Wall DA, Bell B, Stine KC et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group study. J Clin Oncol 1998; 16: 945–952.
Kushner BH, Kramer K, Modak S, Cheung N-KV . Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. Clin Cancer Res 2004; 10: 84–87.
Kushner BH, O’Reilly RJ, Mandell LR, Gulati SC, LaQuaglia M, Cheung N-KV . Myeloablative combination chemotherapy without total body irradiation for neuroblastoma. J Clin Oncol 1991; 9: 274–279.
McCowage GB, Vowels MR, Shaw PJ, Lockwood L, Mameghan H . Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation. J Clin Oncol 1995; 13: 2789–2795.
Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M et al. Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 2000; 18: 2567–2575.
Kletzel M, Katzenstein HM, Haut PR, Yu AL, Morgan E, Reynolds M et al. Treatment of high-risk neuroblastoma with triple-tendem high-dose therapy and stem-cell rescue: results of the Chicago pilot II study. J Clin Oncol 2002; 20: 2284–2292.
Hartmann O, Vaslteau-Couanet D, Vassal G, Lapierre V, Brugieres L, Delgado R et al. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 1999; 23: 789–795.
Choi HS, Koh SH, Park ES, Shin HY, Ahn HS . CNS recurrence following CD34+ peripheral blood stem cell transplantation in stage 4 neuroblastoma. Pediatr Blood Cancer 2005; 45: 68–71.
Blaney SM, Heideman R, Berg S, Adamson P, Gillespie A, Geyer RJ et al. Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 2003; 21: 143–147.
Blaney SM, Balis FM, Berg S, Arndt CA, Heideman R, Geyer JR et al. Intrathecal mafosfamide: a preclinical pharmacology and phase I trial. J Clin Oncol 2005; 23: 1555–1563.
Acknowledgements
Supported in part by Grants from the National Cancer Institute (CA61017, CA72868), Bethesda, MD; Hope Street Kids, Alexandria, VA; the Justin Zahn Fund, New York, NY; the Katie's Find A Cure Fund, New York, NY; and the Robert Steel Foundation, New York, NY.
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Kushner, B., Kramer, K., Modak, S. et al. Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system. Bone Marrow Transplant 37, 271–276 (2006). https://doi.org/10.1038/sj.bmt.1705253
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DOI: https://doi.org/10.1038/sj.bmt.1705253
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