Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group

Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group
Children with intermediate risk (IR) germ cell tumors (GCT; Stage II-IV testicular, II-III ovarian and I-II extra-gonadal, stage I with recurrence after surgery alone) have excellent outcomes when treated with 4 cycles of PEb (Cisplatin, Etoposide, Bleomycin every 3 weeks). However, the risk of significant late effects such as hearing loss, neuropathy, nephrotoxicity, second malignancies, and cardiovascular disease has prompted the COG to study the effectiveness of a dose reduction strategy for these patients based on non-inferiority data on a similar regimen in adults with GCT, albeit with weekly Bleomycin.
This was a phase 3, single arm trial (from 2003 to 2011) with a stopping threshold of an EFS of
210 patients were enrolled and treated with 3 cycles of PEb with compression from 5 days to 3 days per cycle. EFS was 89% with a 4 year OS of 97% but enrollment was stopped early due to EFS less than the 92% target. However, post hoc analysis revealed that Stage I and II patients treated with 3 cycles had similar outcomes to historical controls treated with 4. The EFS was significantly worse for Stage IV patients when compared to historical counterparts. More grade 3/4 neutropenia was seen on the 3 day regimen.
This study was limited by its single arm design, relatively small sample size and patient heterogeneity.
The data from this study do not support a reduction of therapy to 3 compressed cycles for all IR GCTs. However, it is not known whether the use of weekly Bleomcyin would compensate for the reduction of cycles as this was not tested. A subset of patients with lower stage tumors may still benefit from a reduction to 3 cycles and this needs further dedicated study.