Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study

Abstract

Purpose: Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([¹²³I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate.

Materials and methods: Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m²/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m², and doxorubicin, 45 mg/m².

Results: Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%).

Conclusion: TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Keywords: Child; Neoplasm; Neuroblastoma; Phase 2 clinical trial; Recurrence; Second line drugs.

Fig. 1.

The topotecan-vincristine-doxorubicin (TVD) salvage therapy for children included in the HR-NBL-1 protocol. Patients with persistent metastatic disease after the COJEC induction therapy of the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol were eligible for TVD therapy with the aim of eradicating the metastatic disease. Children achieving complete remission (CR) or good partial response (GPR) become eligible for consolidation with high dose therapy (HDT) as planned by the original HR-NBL-1 protocol, all the other were considered failures. PPR, poor partial response; MR, mixed response; SD, stable disease; PD, progressive disease.