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Study of cisplatin, etoposide, bleomycin, and escalating dose cyclophosphamide therapy for children with high-risk germ cell tumors: A Children's Oncology Group report.

10035 Background: In the intergroup high-risk germ cell tumors (HR-GCT) study (CCG-8882/POG-9049) patients with extragonadal GCT treated with high-dose cisplatin, etoposide, and bleomycin (HD-PEB) had a 2 year-EFS of 84% versus 74% for those treated with standard PEB (PEB), suggesting that treatment intensification might be beneficial. The goal of this study was to establish the maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide combined with PEB in untreated patients with HR-GCT.


METHODS
From July 2004 to August 2007, 19 eligible children and adolescents with stage III/IV extragonadal GCT received cisplatin 20 mg/m2/day × 5, etoposide 100 mg/m2/d × 5, bleomycin 15 mg/m2 on d1, and escalating doses of cyclophosphamide (1.2, 1.8 or 2.4 g/m2) on d1. DLT was defined as any grade 4 non-hematologic toxicity other than nausea and vomiting, fever and infection, and any non-hematologic grade 3 toxicity which had not reversed (< grade 2) within 28 days of treatment; or hematologic toxicity grade 3 or 4, which despite hematopoietic growth factor support, was not reversible within 28 days of treatment.


RESULTS
The toxicities reported were expected for this treatment regimen, protocol therapy was well tolerated and all 3 cyclophosphamide levels were feasible. Only 1 patient who had hyperglycemia was considered to have DLT by the institutional investigator. Fifteen of the 19 patients were removed from protocol therapy after 4 cycles of therapy; 11 were disease-free, 2 electively terminated protocol therapy, 1 patient was lost to follow-up, and 1 had progressive disease (PD). Four patients received 2 more cycles of C-PEB, of these 3 were disease-free and 1 had PD. The 2 year-EFS and OS were 71% (95% CI: 43-87%) and 88% (95% CI: 59-97%), respectively.


CONCLUSIONS
The addition of cyclophosphamide to the standard PEB regimen is feasible and well tolerated at all dose levels used on this study. Due to the small sample size we cannot establish that the addition of cyclophosphamide to the standard PEB regimen is beneficial in increasing the EFS when compared to the standard PEB regimen. Further evaluation of this regimen is warranted. No significant financial relationships to disclose.