5-day/5-drug myeloablative outpatient regimen for resistant neuroblastoma

Abstract

5-day/5-drug (5D/5D) is a novel high-dose regimen administered with autologous hematopoietic SCT (HSCT). It was designed to maximize cytoreduction via high dosing of synergistically interacting agents, while minimizing morbidity in patients with resistant neuroblastoma (NB) and ineligible for clinical trials due to myelosuppression from previous therapy. 5D/5D comprises carboplatin 500 mg/m 2 /day on days 1-2, irinotecan 50 mg/m 2 /day on days 1-3, temozolomide 250 mg/m 2 /day on days 1-3, etoposide 200 mg/m 2 /day on days 3-5 and cyclophosphamide 70 mg/kg/day on days 4-5. HSCT is on day 8. Sixteen patients received 21 courses. Treatment was in the outpatient clinic. Responses were noted against progressive disease (PD) that had developed while patients were off, or receiving only low-dose, chemotherapy but not against PD that emerged despite high-dose chemotherapy. Responses were also seen in patients with PD or stable disease after 131 I-metaiodobenzylguanidine therapy. Grade 3 toxicities were limited to transient elevations in liver enzymes (three courses) and hyponatremia (one course). Bacteremia occurred in 2/21 (10%) courses. Hematological recovery allowed patients to be enrolled on clinical trials. In conclusion, 5D/5D (including HSCT) spares vital organs, entails modest morbidity, shows activity against resistant NB and helps patients meet eligibility requirements for formal clinical trials. Keywords: novel therapeutics; neuroblastoma; salvage therapy INTRODUCTION Standard chemotherapy for high-risk neuroblastoma (NB) includes dose-dense or dose-intensive and myeloablative regimens using alkylating agents, platinum compounds, topoisomerase-II inhibitors, and, most recently, the topoisomerase-I inhibitor topotecan. 1 Common salvage chemotherapy regimens for resistant NB combine topoisomerase-I inhibitors (topotecan, irinotecan) with alkylators (cyclophosphamide, temozolomide), 2-4 topoisomerase-II inhibitors (doxorubicin, etoposide) 5,6 or both classes of drugs. 7 For patients with NB resistant to a wide range of agents, and ineligible for clinical trials, we have used a 5-day/5-drug (5D/5D) regimen consisting of carboplatin-irinotecan-temozolomideetoposide-cyclophosphamide, followed by autologous hematopoietic SCT (HSCT). The development of 5D/5D was based on previous Memorial Sloan-Kettering Cancer Center (MSKCC) studies that used its five components. [8][9][10] These agents have broad anti-NB activity, display synergistic antineoplastic effects, penetrate into the central nervous system and lack overlapping extramedullary toxicities. The 5D/5D regimen's manageable and tolerable acute toxicity allows outpatient administration, an important consideration given the issue of quality of life for heavily previous-treated patients.HSCT is also performed in the outpatient setting. HSCT is necessary because high dosing makes this regimen strongly myelosuppressive, possibly even myeloablative, especially in patients with pre-existing poor hematological reserve due to previous therapy. HSCT results in normal bloo...

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

“…However, major responses (CR + PR by INRC, as used in this current study) were uncommon (<10%). We and others have attempted to enhance the anti‐NB activity of irinotecan or IT by combining standard or newer chemotherapeutic agents such as temsirolimus, gefitinib, or alisertib, or targeted radiotherapy with 131 I‐MIBG . However, response rates were not significantly improved ranging from 0 to 25%.…”

The efficacy and safety of Iodine-131-metaiodobenzylguanidine therapy in patients with neuroblastoma: a meta-analysis

“… INRC 41 b 27 5 4 4 2009 Matthay [ 20 ] USA Single-arm Phase I Day 0 and day 14, 12-21mCi/kg RECIS T[ 33 ] 20 10 3 7 8 2011 Johnson [ 21 ] USA Single-arm Phase II 18mCi/kg If necessary, additional 18mCi/kg were received within 100 days. INRC 117 35 52 30 - 2011 Mastrangelo [ 34 ] Italy Pilot study 131 I-MIBG combined with other therapies INRC 13 6 - - 1 2011 Polishchuk [ 22 ] USA Single-arm Phase II 17.8 millicuries (mCi)/kg INRC 39 18 17 2 2 2012 DuBois [ 35 ] USA Single-arm Phase I 131 I-MIBG combined with other therapies NANT Response Criteri a[ 35 ] 24 6 - - - 2013 Kushner [ 36 ] USA NS 131 I-MIBG combined with other therapies INRC 3 1 2 0 0 2015 DuBois [ 37 ] USA Single-arm Phase I, II …”

Optimization of a Neural Stem-Cell-Mediated Carboxylesterase/Irinotecan Gene Therapy for Metastatic Neuroblastoma

“…Tumor growth was monitored by bioluminescent imaging, and mean signal intensities were obtained from these scans at multiple times points for each mouse. Two days after intravenous administration of hCE1m6-NSCs, mice were treated with three rounds of irinotecan using an established clinical dosing regimen 38 . Treatment groups included: group A, tumor only; group B, irinotecan only (7.5 mg/kg, three times a week); group C, hCE1m6-NSCs + irinotecan (7.5 mg/kg, three times a week); group D, irinotecan only (15 mg/kg, three times a week); and group E, hCE1m6-NSCs + irinotecan at (15 mg/kg, three times a week).…”