Treatment Approach for High Risk Disease

The high-risk group in neuroblastoma is comprised primarily of children (>1 year of age at diagnosis) with stage-4 disease and stage 3 with tumor MYCN amplification or unfavorable histopathology. Although there is no worldwide consensus, stage 2 plus MYCN amplification, or stage-3, stage-4, and stage-4s infants plus MYCN gene amplification are currently treated in the COG with high-risk treatment protocols. Recent data suggest that this must be further qualified, as analysis of the most recent high-risk study in the Children's Cancer Group showed that toddlers between 12 and 18 months of age with stage-4 MYCN-non-amplified disease have an improved outcome compared with those >18 months (Schmidt et al. 2003). Similarly, studies from the Pediatric Oncology Group demonstrate that hyperdiploidy and non-amplified MYCN confers a favorable prognosis in children 12-18 months of age with disseminated neuroblastoma (George et al. 2003). The 4-year survival for stage-4 patients >1 year at diagnosis in the CCG studies from 1978 to 1985 (n=507) near tripled by 1991-1995 (n=675; p<0.001; Matthay 1997), although the projected cure rate remained <25%. The most recent phase-III studies indicate that the eventfree survival and overall survival of this group has now increased a little further, with myeloablative therapy becoming standard and with more widespread use of treatment of minimal residual disease (Matthay et al. 1999; Reynolds et al. 2002; Ladenstein et al. 1998; Grupp et al. 2000; Cheung et al. 2001a; Villablanca et al. 1998).

Therapy for high-risk neuroblastoma is currently divided into four phases: intensive induction treatment; primary site local control; high-dose marrow ablative therapy; and management of minimal residual disease. The goal of induction therapy is to achieve maximum reduction of tumor burden, including reduction of bone marrow tumor (in vivo purging), within a time frame which will minimize the risk of developing resistant tumor clones and clinical progression. Surgical resection of primary tumor, with addition of local radiotherapy either at the time of resection or later, is essential in preventing primary site relapse. Subsequently, very highdose marrow ablative therapy may be used to try to overcome residual and potentially resistant tumor, followed by hematopoietic cell transplant (HCT). The high relapse rate even after such treatment (Ladenstein et al. 1998;Matthay et al. 1993); has led to the approach of using tumor-targeted therapies following myeloablative treatment, to try to eliminate microscopic resistant clones [minimal residual disease (MRD)] (Matthay 1999; Cheung et al. 1998a; Ozkay-nak et al. 1998).

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