Introduction

Despite recent advances in the treatment of high-risk neuroblastoma (HR-NBL), such as the addition of immunotherapy to upfront intensive multimodal therapy , and consequent incremental improvements in outcome, only approximately half of patients will achieve a long-term cure ( Fig. 15.1 ). Approximately 10%–20% of HR-NBL patients, particularly adolescents whose tumors more commonly have loss-of-function mutations in the alpha thalassemia/mental retardation syndrome X-linked ( ATRX ) gene , have primary refractory disease and will not achieve remission. Of the remainder, 50%–60% will complete initial therapy only subsequently to relapse. Historically, outcomes for patients with relapsed HR-NBL have been very poor, with the European Neuroblastoma Study Group reporting 5-yr post-relapse overall survival (PROS) of only 5.6% for patients diagnosed 1982–1992 . Data from the International Neuroblastoma Risk Group (INRG) database similarly revealed 5-yr PROS of 8% for patients with metastatic disease at original diagnosis and only 4% for those with MYCN-amplified stage 4 disease . More recent data for patients with recurrent HR-NBL treated on a range of early phase trials suggests a potential for improved outcomes, with 20% 4-yr PROS and 6% 4-yr post-relapse progression-free survival . More encouraging outcomes have been reported for the selected subset of patients with recurrent HR-NBL in whom it is possible to achieve a second complete response (CR) or very good partial response (VGPR) and then consolidate with anti-GD2-based immunotherapy. With this approach, 33% 5-yr progression free survival (PFS) and 48% 5-yr overall survival (OS) have been reported .

Overall survival (OS) for Children’s Oncology Group (COG) high-risk neuroblastoma patients. 5-year OS rates for patients on COG studies diagnosed between 1990 and 2010. OS for patients diagnosed between the indicated years are shown.

Reprinted with permission © 2015 American Society of Clinical Oncology. All rights reserved. Pinto NR, et al. J Clin Oncol 2015;33(27):3008–3018.

By far the majority of patients with relapsed neuroblastoma will have had high-risk disease at initial diagnosis and the remainder of this chapter is focused on the treatment strategies for these patients. For the remainder who initially had low or intermediate-risk treatment, therapeutic approaches at relapse are in general more straightforward, and standard chemotherapy approaches can be used depending on individual circumstances. For example, patients who initially had localized disease treated with primary resection alone may be cured with minimal chemotherapy and reresection in the event of localized recurrence . Patients who were initially treated for intermediate risk disease will usually be treated with reinduction chemotherapy with the aim of consolidating the response with high-dose chemotherapy and stem cell rescue, followed by immunotherapy; essentially a similar approach to upfront high-risk therapy.

Management decisions for patients with relapsed HR-NBL are potentially complex as a result of several important considerations. First, at the patient level, quality of life, burden of therapy, disease-related symptoms, and toxicities from prior therapy, all need to be taken into account; particularly since there are as yet no proven curative therapies for relapsed HR-NBL. Second, although a wide range of therapeutic approaches has been developed for relapsed HR-NBL, only rarely have these been tested in a randomized fashion, and therefore, the benefits of one approach over another, or the relevance of a particular strategy based on clinical or biological features, is typically unknown. Third, in addition to cytotoxic chemotherapy, there is a growing interest in precision medicine approaches raising important questions about rebiopsy of disease at relapse (even when the diagnosis itself is not in doubt) to obtain tissue for genetic analyses, and about how targeted agents are incorporated into the overall therapeutic approach.

Standard Chemotherapy Approaches

For the majority of patients with relapsed HR-NBL, initial treatment will comprise reinduction chemotherapy typically based around combinations of topotecan or irinotecan, with temozolomide or cyclophosphamide. The relative efficacy of these combinations (summarized in Table 15.1 ) is difficult to ascertain since the majority of published studies have been single-arm Phase II trials, with no comparison of treatment strategies, endpoints of response rates (rather than survival) and heterogeneous populations in terms of the extent of disease at relapse (such as measurable soft-tissue lesions vs. evaluable metaiodobenzylguanidine (MIBG)-avid skeletal disease or bone marrow only disease). The combination of topotecan and cyclophosphamide (TopoCy) is generally well-tolerated and effective in up to ∼1/3 of patients; at least in terms of disease response. Although now incorporated into the upfront schedule of the standard HR-NBL approach in North America (Children’s Oncology Group), evidence suggests that retreatment (at a lower dose than used in initial induction) can lead to durable responses in the relapse setting . Higher doses of TopoCy combined with vincristine have also shown significant responses in the setting of relapsed HR-NBL (overall response rate, ORR, 52%), as well as for patients with primary refractory HR-NBL (ORR 19%) .

Other frequently used chemotherapy approaches incorporate temozolomide, either as monotherapy or in combination with irinotecan or topotecan . Response rates of 8%–24% have been reported, but the absence of randomized trial data makes it difficult to justify the choice of one or other regimen solely on the grounds of predicted disease response. The current European BEACON-Neuroblastoma study ( NCT02308527 ) is testing these three regimens in a randomized Phase II trial that will also test the potential benefit of adding bevacizumab to backbone chemotherapy.

More intensive and potentially toxic chemotherapy regimens have also been utilized in the relapse setting, with Memorial Sloan Kettering Cancer Center (MSKCC) pioneering the use of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE). Objective responses were reported in nine of 17 (53%) of patients with newly relapsed disease, although response rates for patients with primary refractory or progressive disease were lower . HD-ICE is associated with significant myelotoxicity, requiring preemptive stem cell rescue in patients predicted to have a poor hematological reserve. Importantly, HR-NBL patients treated at MSKCC typically do not receive high-dose chemotherapy (HDC) and stem cell rescue as part of their upfront therapy ; therefore the utility and risk/benefit balance of the HD-ICE approach for patients who have previously received HDC remains uncertain.

An alternative chemotherapy approach is to move from intensification towards low-dose metronomic chemotherapy approaches designed to elicit antitumor effects through antiangiogenesis. The combination of celecoxib, cyclophosphamide, vinblastine, and etoposide has been reported to have equivalent outcomes to standard chemotherapy for patients with relapsed HR-NBL , although this was a nonrandomized, retrospective study.

Novel Chemotherapy Combinations

In addition to the chemotherapy trials described above many trials are now incorporating chemotherapy backbones together with targeted therapies (see below, Precision Medicine Approaches section), immunotherapies or other noncytotoxic agents (e.g., angiogenesis inhibitors). These approaches vary from single-arm studies incorporating multiple agents to randomized trials including pick-the-winner and drop-the-loser designs to compare two or more novel agents on a backbone chemotherapy regimen. The RIST trial ( NCT01467986 ) is based on a regimen used for glioblastoma and includes 5 days of metronomic rapamycin (R) and dasatinib (Sprycel) followed by 5 days of irinotecan and temozolomide (I/T) . The early results demonstrated that of the first 21 patients 90% had an initial response based on imaging criteria with CR (57%), PR (14%) and SD (19%). The median progression-free survival (PFS) was 90 weeks. The ITCC has an ongoing randomized trial (BEACON Neuroblastoma ) (EudraCT 2012-000072-42) which will enroll 160 patients with relapsed and refractory neuroblastoma. The current version of the protocol includes six arms testing three backbone chemotherapy combinations (temozolomide alone, temozolomide plus irinotecan, and temozolomide plus topotecan) each with or without the addition of bevacizumab (Avastin).