Rational selection of adjuvant chemotherapy after cytoreduction surgery for murine neuroblastoma

Improving the prognosis of advanced neuroblastoma remains an important yet unachieved goal of pediatric oncology, a fact which may be related to an insufficient analysis of the role played by cytoreductive surgery. Utilizing strain A mice bearing C-1300 syngeneic neuroblastoma, tumor biology and host immunocompetence were studied after cytoreduction surgery and adjuvant chemotherapy. Cell kinetic analysis in the residual tumor demonstrated an increase of the proliferative fraction 18 to 42 h after operation, but the same peak proliferation was delayed in bone marrow cells to 24 to 96 h. The potential for drug distribution to the tumor after cytoreduction surgery was assessed by injecting Na251CrO4 and measuring tumor uptake. There were two significant (P less than 0.05) peaks of activity at 6 h and 3 days, suggesting local edema and neovascularity, respectively. Injection of both cell cycle specific and nonspecific adjuvant chemotherapeutic agents in a dosage of one-fourth of their 50% lethal dose at 24 or 72 h following surgical cytoreduction did not induce any antitumor activity at either injection time. However, when cyclophosphamide was given in this dose, the C-1300 tumor growth was impaired, an effect which was largely abrogated by first subjecting the tumor bearer to thymectomy and irradiation. The transfer of spleen cells from adjuvant cyclophosphamide-treated mice to tumor-inoculated normal mice significantly delayed tumor appearance when comparison was made with animals treated by operation alone, and such recipients also exhibited a more prolonged survival. These data suggest that the antitumor activity of cyclophosphamide following cytoreduction surgery of C-1300 neuroblastoma is mediated by both pharmacological and immunological mechanisms.