Intermediate Risk Disease

Intermediate-risk patients are defined as infants with stage-4 disease without MYCN amplification, favorable biology stage 3, or INSS 4s with unfavorable histology or DNA index. Three-year survival rates for this group of patients are 75-98% and recent studies have focused on minimizing treatment-related side effects while maintaining high event-free and overall survival rates. The current approach to intermediate-risk patients consists of four to eight cycles of standard doses of chemotherapy and primary tumor resection.

Studies that have addressed the use of radiation for intermediate-risk disease combine INSS 2B and 3 patients and use various outdated staging systems precluding conclusive recommendation regarding when and how to incorporate radiation into the treatment of intermediate-risk patients (Evans et al. 1980; Rosen et al. 1984; McGuire et al. 1985; de Bernardi et al. 1987; West et al. 1993). For patients residing in the more favorable portion of the intermediate-risk group, radiation therapy is not indicated in their initial management. Matthay et al. reviewed the Children's Cancer Study Group (CCSG) experience of stage-2 disease from 1978 to 1985 and found excellent 5-year progression-free survival (PFS) and OS rates of 90 and 96%, respectively. Germane to the current discussion is the finding that radiation therapy did not influence clinical outcome. Six-year survival was 98 % for those treated initially with surgery alone compared with 95 % for those receiving radiation and/or chemotherapy (Matthay et al. 1989); thus, intermediate-risk patients with stage-2B disease do not require routine radiation as part of their initial treatment.

The role of radiation therapy is better established for a subgroup of patients with stage-3 disease. Older studies,before the era of biologic staging,reported an advantage to radiotherapy in patients with Evans stage 3 and/or with positive lymph nodes (POG stage C) neuroblastoma. In a small series, Koop and Johnson found that postoperative irradiation improved survival, since 6 of 7 who were irradiated were alive compared with only 1 of 9 patients who did not receive postoperative radiation (Koop and Johnson 1971). A randomized trial addressed the role of radiation in patients with unresectable non-metastatic disease. Stage-C patients older than 1 year were randomized to receive postoperative chemotherapy or chemotherapy plus regional RT (24-30 Gy, 1.6-2.0 fractions). Of those receiving chemotherapy alone, 45% achieved complete remissions and 31 % were disease free at a median of 35 months. For patients receiving radiation in addition to chemotherapy, 67% achieved complete remission and 58% remained disease free at a median of 23 months (Castleberry et al. 1991). Conclusions drawn from this study should be applied to current management with great caution since neuroblastoma treatment now utilizes a different staging system, biologic tumor characteristics, and more intensive chemotherapy regimens. Incorporation of biologic factors (hyperdiploidy, favorable histology, absence of MYCN amplification) in the management of stage-3 patients suggests that radiation is not essential (Matthay et al. 1998). Survival and local control for patients with amplified MYCN are lacking and the role of more aggressive irradiation in such patients is a testable question.

In the most recent COG study for intermediate-risk patients (COG Protocol A3961), including those with INSS 3 with favorable biology and infant with INSS 4, surgery provides diagnostic material at diagnosis and maximal safe resection of the primary tumor after chemotherapy. The duration of chemotherapy, consisting of cyclophosphamide, doxorubicin, carboplatin, and etoposide, is based on the biologic risk factors. Radiation therapy is indicated for patients with clinical deterioration despite chemotherapy and surgery or those with persistent tumor after chemotherapy and second-look surgery.

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