Chemotherapy for the treatment of children and adolescents with malignant germ cell tumors.

The prognosis for children with advanced malignant germ cell tumors (MGCTs) before the introduction of cisdiamminedichloroplatinum (cisplatin) – based chemotherapy regimens was poor. The survival rate was less than 20% for those with localized presacral yolk sac tumors and 0% for those who presented with metastases. In 1974, Einhorn and Donohue initiated studies of the combination of cisplatin (20 mg/m/d for 5 days), vinblastine, and bleomycin (PVblB) for the treatment of adults with advanced testicular germ cell tumors. They reported an overall complete response rate of 74% (35 of 47 patients) including two of two patients with yolk sac tumors. Experimental data suggested that the administration of non– cross-resistant drug combinations would eradicate specifically resistant cells. Clinical application of this principle resulted in improved survival of patients with Hodgkin’s disease and acute myelogenous leukemia. The combination of vincristine, dactinomycin, and cyclophosphamide (VAC) was active against MGCTs. Administration of an induction phase of cisplatin (1 mg/kg/wk for 6 weeks), vincristine, and bleomycin, followed by a maintenance phase of VAC (dactinomycin 1 mg/m, cyclophosphamide 600 mg/m) to children with MGCTs was an extension of the previously validated strategy of administering non–cross-resistant drug combinations using dose-intensive scheduling. The four patients described in the original report of this alternating regimen remain continuously free of disease 25 years after the publication of the preliminary results. Subsequently, several groups investigated the efficacy of cisplatincontaining chemotherapy regimens, as well as the use of alternating cycles of VAC and cisplatin-containing regimens for the treatment of pediatric patients with MGCTs. Flamant et al reported that the overall survival (OS) rate at 28 months was 75% for patients with stage III disease and 65% for patients with stage IV disease treated with alternating courses of VAC (dactinomycin 300 g/m/d for 5 days, cyclophosphamide 300 mg/m/d for 5 days) and cisplatin (100 mg/m), bleomycin, and doxorubicin (60 mg/m/d). The French Society for Pediatric Oncology evaluated alternating courses of dactinomycin (10 g/kg/d for 5 days) plus cyclophosphamide (300 mg/m/d for 5 days) and PVblB (cisplatin 100 mg/m) in 41 patients with MGCTs. The complete response rate was 68% (28 of 41 patients). Eight patients who achieved a complete response experienced relapse; the 2-year relapse-free survival rate was 72%. Ablin et al of the Children’s Cancer Study Group evaluated a regimen that alternated PVblB (cisplatin 60 mg/m), cyclophosphamide (600 mg/m), and dactinomycin and single-agent doxorubicin (40 mg/m) on an alternating every 3-week schedule. The 4-year event-free survival (EFS) rate was 49%, and the 4-year OS rate was 54%, perhaps reflecting the modest dose-intensity of the regimen. VAC alone, using an oral, daily for 7 days cyclophosphamide schedule, was less effective than PVlbB for the treatment of extragonadal MGCTs. Durable responses were seen in only one (11%) of nine patients treated with VAC compared with six (86%) of seven patients treated with VAC alternating with PVlbB. Mann et al reported that only one (8%) of 12 patients treated with low-dose VAC (cyclophosphamide 300 mg/m/wk for 6 weeks, followed by 300 mg/m every 3 weeks) survived compared with eight (80%) of 10 patients treated with high-dose VAC (cyclophosphamide 1,000 mg/m every 3 weeks). The survival rate of patients treated with high-dose VAC was similar to that of patients treated with PVblB (six of nine patients). The high frequency of fatal pneumonitis attributed to bleomycin administered weekly led these investigators to evaluate the combination of cisplatin, etoposide, and bleomycin (BEP; administered once every 3 weeks) in children with MGCTs. Twenty-four of 27 children treated with BEP survived, and none developed pneumonitis related to bleomycin administration. Recent research evaluated the use of higher doses of cisplatin to explore the dose-response relationship of PVlbB in childhood MGCTs and the use of platinum analogs, with the goal of avoiding the renal and auditory toxicity associated with the use of cisplatin. The United Kingdom Children’s Cancer Study Group evaluated the combination of cis-diammine(1,1-cyclobutanedicarboxylato)platinum II (Johnson Matthey Research Centre 8, London, United Kingdom), etoposide, and bleomycin (JEB). The overall 5-year EFS rate was 87.8% (95% CI, 81.1% to 92.4%). The 5-year EFS rate was 84.8% (95% CI, 69.1% to 93.4%) for patients with stage III MGCTs and 78.0% (95% CI, 63.2% to 88.0%) for patients with stage IV MGCTs. One patient developed acute myeloid leukemia; grade 3 and 4 hematologic toxicity was frequent, but no patient developed permanent renal toxicity or ototoxicity. The Pediatric Oncology Group and Children’s Cancer Group undertook a randomized intergroup study that compared standarddose cisplatin (PEB) with high-dose cisplatin (HDPEB), both in combination with etoposide and bleomycin for the treatment of extragonadal and advanced gonadal MGCTs. The 6-year EFS rate was 89.6% 3.6% for patients treated with HDPEB compared with 80.5% 4.8% for patients treated with PEB (P .0284). The 6-year OS rate was 91.7% 3.3% for patients treated with HDPEB JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 26 NUMBER 20 JULY 1