Ifosfamide, carboplatin, and etoposide for neuroblastoma

Abstract

BACKGROUND:The authors report a retrospective analysis of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB. METHODS: Treatment comprised ifosfamide (2000 mg/m 2 daily for 5 days), carboplatin (500 mg/m 2 daily for 2 days), and etoposide (100 mg/m 2 daily for 5 days). Patients who had poor hematologic reserve (platelet count <100,000/lL) from previous therapy received peripheral blood stem cells (PBSCs) after HD-ICE. Disease status before and after HD-ICE was defined according to International Neuroblastoma Response Criteria (expanded to include 123 I-metaiodobenzylguanidine findings). Publications that were informative about ICE for NB were reviewed. RESULTS: Seventy-four patients received 92 cycles of ICE, including 37 patients who received PBSC rescue. Grade 3 toxicities were rare: 1-3 patients had encephalopathy, mucositis, or gastroenteritis. Bacteremia was documented in 24 of 92 cycles (26%). The absolute neutrophil count reached 500/lL on day 17-30 (median, day 22) in patients who had satisfactory hematologic reserve. Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory NB, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P ¼ .005). In the literature, patients received ICE at lower dosages and achieved major response rates >36% in phase 1 and 2 studies (in which less comprehensive staging evaluations were used) that involved resistant NB and >70% in induction for newly diagnosed NB. CONCLUSIONS: HD-ICE is appealing as salvage treatment or consolidative therapy because of its anti-NB activity and the low risk of major nonhematologic toxicity. PBSC support is unnecessary for patients who had intact hematologic reserve.

Phase I Trial of a Bivalent Gangliosides Vaccine in Combination with β-Glucan for High-Risk Neuroblastoma in Second or Later Remission

“…The time from diagnosis to first relapse was <12 months (n=2), 12–18 months (n=5), 19– 24 months (n=4), and >24 months (n=4). Retrieval therapy before study enrollment included local control with radiotherapy alone (n=7), radiotherapy plus surgery (n=7), strongly myelosuppressive chemotherapy (n=8), 5–8 and non-immunosuppressive treatments such as irinotecan-temozolomide (n=9) 3,4 and anti-GD2 MoAb 13 (n=5); no patient underwent stem-cell transplantation as part of retrieval. These retrieval treatments were for relapses that were localized in 10 patients, including soft tissue (n=7) or osteomedullary by MIBG and MRI (n=3), and widespread in five patients, including BM by histology and MIBG scan (n=2), multifocal MIBG osteomedullary with (n=1) or without (n=1) soft tissue, and retroperitoneal nodes plus brain (n=1).…”

“…2 Second, relapse is treated with a multimodality program that comprises surgery and/or radiotherapy for local control, plus salvage chemotherapy combining agents with well-established anti-NB activity and tailored to the patient’s particular clinical context or past treatment history. 3–8 Third, after achieving a maximal response with the standard modalities (chemotherapy, radiotherapy, surgery), remission is consolidated via immunotherapy using monoclonal antibody (MoAb) or vaccine, the latter being the subject of this report.…”

Striking dichotomy in outcome of MYCN‐amplified neuroblastoma in the contemporary era

“…Consolidation of CR/VGPR included anti-G D2 MoAb ± autologous stem-cell transplantation (ASCT). 24 Initial 2 nd -line treatments for refractory or progressive disease with induction included high-dose conventional chemotherapy 31–34 or moderate-dose regimens 28,35 using agents with known anti-NB activity. Relapse was also treated uniformly, including intra-thecal radioimmunotherapy for central nervous system relapse, 36 high-dose conventional chemotherapy 31–34 for disseminated or soft-tissue relapse, and moderate-dose chemotherapy 28,35 plus radiotherapy for focal skeletal relapse.…”

Irinotecan–temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial

“…(37),(38, 39),(40),(41) A widely used induction regimen now includes topotecan;(42, 43) response rates to topotecan-based therapy are expected to be lower in previously-exposed patients. Similarly, while 9/17 patients in first relapse responded to high-dose ifosfamide/carboplatin/etoposide in one study,(44) a lower response rate could be expected in patients treated with the high-dose carboplatin and etoposide used in current-era North American consolidation regimens. (43, 45, 46) In a study of a GD2-directed antibody with GM-CSF without chemotherapy, a 38% response rate was observed in patients with non-progressing, primary refractory, evaluable (non-irradiated) osteomedullary disease.…”