Chemotherapy

In the United States, the standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]).[9-12] U.S. pediatric trials included patients aged 15 years and younger with testicular GCTs and patients aged 21 years and younger with ovarian and extragonadal GCTs. Patients received bleomycin only on day 1 of each cycle (cisplatin, etoposide, and bleomycin [PEb]).[3,13] The combination of carboplatin, etoposide, and bleomycin (JEb) underwent clinical investigation in the United Kingdom in children younger than 16 years. Treatment with this regimen produced event-free survival (EFS) rates by site and stage similar to those produced using treatment with PEb.[14,15]; [16][Level of evidence C1] For information about adult BEP and pediatric PEb and JEb chemotherapy dosing schedules, see Table 8.[3,9-11,13] In both adult and pediatric trials, the number of adolescent subjects was small. The optimal therapy for adolescents (aged ≥11 years) is not clear.[17]

The use of JEb appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEb.[14] In a retrospective meta-analysis of data from the Children’s Oncology Group (COG) and the Children’s Cancer and Leukaemia Group germ cell studies conducted contemporaneously, the multivariate cure model showed no difference in 4-year EFS rates. The 4-year EFS rate was 86% (95% confidence interval [CI], 83%–89%) for patients who received the cisplatin regimen (n = 620) and 86% (95% CI, 79%–90%) for patients who received the carboplatin regimen (n = 163) (P = .87).[18][Level of evidence C1] However, PEb and JEb have not been compared in a randomized pediatric GCT trial.

Several trials were conducted by the COG (previously the Children's Cancer Group and the Pediatric Oncology Group).[3,7,13] These trials explored the use of PEb for the treatment of localized gonadal GCT [3] and intensified regimens for patients with poor-risk features. The strategies included high-dose cisplatin (200 mg/m2) and cyclophosphamide or the protective agent amifostine.[13,20] None of these strategies had a significant effect on survival or decreased toxicity.

The COG conducted a trial of compressed and reduced PEb chemotherapy (three cycles in 3 days) for patients with low-risk or intermediate-risk malignant GCTs. This study was designed as a noninferior trial with a P value of .1. The 4-year EFS rate of 89% was significantly lower than the rate for the historical control model (92%; P = .08).[21] However, the number of patients in each stratum was small, and further investigation in patients with lower-stage disease may be warranted.