This chapter addresses the challenges of treating patients with high-risk neuroblastoma who have failed front-line therapy. Partially resected, incompletely responding, or locally recurrent low-risk neu-roblastomas can usually be successful treated with little or no cytotoxic therapy (see Chap. 11.1). By contrast, despite aggressive multi-modality treatment, including dose-intensive and myeloablative chemotherapy, high-risk neuroblastoma eventually progresses and eventually proves lethal in more than 70% of cases (see Chap. 11.3). The prognosis of recurrent intermediate-risk disease is also guarded. This chapter focuses on resistant disease that portends a lethal outcome.

Relapse and recurrence are synonymous and refer to disease that re-emerges after complete or very good partial remission (CR/VGPR) has been achieved. Refractory disease indicates neuroblas-toma that is stable or possibly reduced but still evident in macroscopic amounts after several months of adequate therapy, i.e., disease that responds incompletely to treatment. Resistant neuroblastoma encompasses both relapsed and refractory disease. In the International Neuroblastoma Response Criteria (INRC), refractory disease can be partial response, minor response, or no response, while relapsed/recurrent disease is progressive disease (PD). Persistence of metastases is particularly ominous after multiple cycles of intensive chemotherapy, whereas a partial response of the primary tumor may often be rendered CR or VGPR with surgery and radiotherapy. Progressive disease is also present when refractory disease spreads to a new site or when the volume of a refractory or residual lesion increases more than 25% (Brodeur et al. 1993).

If refractory disease could be detected at diagnosis or very early in induction, then such patients might be treated with novel approaches. Early detection of primary refractory disease is now possible via use of metaiodobenzylguanidine (MIBG) scintigraphy during the induction period as a semi-quantitative response measure (Matthay et al. 2003a; Ladenstein et al. 1998). Measurement of tumor cells in both blood and bone marrow by immunocytology and by the possibly more sensitive technique of reverse tran-scriptase-polymerase chain reaction may also be a means of early detection of refractory disease (Cheung et al. 2003; Burchill et al. 2001; Seeger et al. 2000) (see Chap. 11.7). In addition, genome-wide screening may lead to the identification of favorable vs unfavorable genetic patterns, which may, in the future, be used to distinguish resistant cases and stratify treatment at diagnosis (Keshelava et al. 2001; Takita et al. 2004; Hiyama et al. 2004).

Depending on the biology of the tumor, resistance to standard therapy is evident in 10-15 % of children, resulting in disease that responds incompletely (primary refractory disease) to induction or initially responds but then recurs and progresses rapidly. More frequently, the typical patient with high-risk neuroblastoma will achieve remission, but suffer a relapse later, commonly within 2 years after myeloab-lative therapy with hematopoietic stem-cell support (Matthay et al. 1999). The approach to therapy of relapse in such patients should assume systemic dissemination. It is rare that even an isolated recurrence will be successfully treated with only local control measures. Bone and bone marrow are by far the most frequent sites of relapse (DuBois et al. 1999; Matthay et al. 1993b). Metastases in sites that are rarely involved at diagnosis, such as the central nervous system (CNS) and lungs, have been reported in up to 8% of relapsed patients (DuBois et al. 1999; Matthay et al. 2003b; Kramer et al. 2001). Regrowth of disease in the primary site has occurred in 10-20% of cases without and up to 50% of cases with distant disease. The incidence of local recur rence may decrease with dose-intensive chemotherapy, total resection, and adequate radiotherapy to the primary tumor bed plus regional nodal groups (Wolden et al. 2000; Haas-Kogan et al. 2002; Ikeda et al. 1992).

Mechanisms of tumor resistance are manifold, ranging from anatomic factors, such as sanctuary sites (CNS and testes), hypoxic conditions (bone or poorly perfused primary tumor), host factors (drug pharmacokinetics), and molecular features of the tumor cells. Examples of molecular changes include emergence of MRP1 and p-glycoprotein-mediated multi-drug resistance (Norris et al. 1996; Blanc et al. 2003; Manohar et al. 2004), altered DNA repair, decreased ability to undergo apoptosis because of p53 mutation (Keshelava et al. 2001; Tweddle et al. 2001, 2003), over-expression of Bcl-2 or Bcl-XL Dole et al. 1994; Dole et al. 1995), and detoxification of alkyla-tors via various enzymes that conjugate xenobiotics to glutathione (Tew 1994).

Relapse may also result from occult tumor cells admixed with autologous hematopoietic stem cells infused after myeloablative therapy. Support for this possibility comes from (a) the report that after infusion of unpurged autologous bone marrow marked with transduced neomycin-resistance gene, tumor cells in the recurrent neuroblastoma in all three cases showed the genetic marker (Rill et al. 1994), and (b) the occasional reports after autologous bone marrow transplantation of miliary metastases to the lung, a site at risk from infusion of tumor cells through a central venous catheter (Watts and Mroczek-Musul-man 1996)and reports that circulating neuroblastoma cells in blood are clonogenic (Moss et al. 1994). The current Children's Oncology Group (COG) protocol for high-risk neuroblastoma is investigating the importance of tumor-free stem cells via a randomized study of ex vivo purging.

Herein we discuss the ever-expanding repertoire of cytotoxic agents (chemotherapy), tumor-targeted agents, and differentiating agents available for resistant neuroblastoma, and suggest how these therapies might best be integrated in an overall treatment plan for different subsets of resistant disease.

Table 12.1. Treatment approaches for different types of relapse (MIBG 131I-metaiodobenzylguanidine,MRD multiply relapsed disease)

Disease status

Treatment approach

Primary refractory Novel chemotherapy, MIBG+myeloablative therapy, MRD therapy

Early relapse Novel chemotherapy, then targeted therapy, myeloablative therapy, MRD therapy

Late relapse Standard combination chemotherapy, surgery, radiotherapy or MIBG, and novel MRD therapy

Multiple relapse Low-toxicity oral chemotherapy or outpatient-targeted therapy

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