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Two-drug combination treatment protocol successful for germ cell tumors at a small institution
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Results from the Brazilian Pediatric Oncology Society GCT-91 protocol indicate that treating children with germ cell tumors with the combination of cisplatin and etoposide had favorable survival outcomes.
“The information derived from our experience with this effort may be relevant to others planning clinical cooperative studies on germ cell tumors in countries with more limited medical resources,” the researchers wrote.
The researchers evaluated 106 patients with germ cell tumors. Thirty-five patients were assigned to surgery alone and 71 were assigned chemotherapy.
Patients with stage I or II disease, classified as intermediate risk, or stage III or IV disease, classified as high risk, were assigned to chemotherapy. Patients in the intermediate group (n=18) were assigned to 20 mg/m2 daily cisplatin for five days and 100 mg/m2 daily etoposide for five days in three week cycles for 14 weeks.
Patients in the high-risk group (n=53) were assigned to 30 mg/m2 daily cisplatin for five days and 100 mg/m2 daily etoposide for five days in three week cycles for 14 weeks.
Researchers re-evaluated both groups at week 10. Seventeen patients in the high-risk group who responded poorly to initial chemotherapy were assigned to a regimen of two cycles of 1.5 g/m2 ifosfamide, 3 mg/m2 vinblastine and 15 mg/m2 bleomycin.
Five-year OS was 88.9% for patients with stage I and II disease, 83.8% for patients with stage III disease and 56.3% for those with stage IV tumors. Five-year OS for the entire high-risk group was 83.3% compared with 58.8% for the high-risk patients assigned to additional treatment with ifosfamide, vinblastine and bleomycin.
J Clin Oncol. 2009;doi:10.1200/JCO.2008.16.4202.
There are three things that are interesting to me here. One is it looks as though you can avoid using bleomycin in intermediate-risk patients by giving cisplatin and etoposide (PE) instead of cisplatin, etoposide and bleomycin (PEB), which had been standard therapy, though their results in the intermediate-risk group are not as good as our results in the United States using PEB. That probably has to do more with their patient population and the challenges of delivering care in a still-developing country. It's hard to know without the details whether there were delays in therapy or other reasons why their numbers were slightly lower than ours.
Of note, the Brazilian regimen of five cycles of PE does not reduce the total exposure to cisplatin or etoposide when compared to three to four cycles of PEB, so I would hope in future protocol we may find a way to safely cut back on exposure to these drugs as well. In terms of their high-risk group, they showed that intensifying chemotherapy with ifosfamide, vinblastine and bleomycin was not sufficient, and more importantly, patients who are not in complete remission after three cycles of chemotherapy are by definition a high-risk group. We still need to think harder about how we treat patients we identify as high risk.
The most intriguing thing about the article is this finding that lactate dehydrogenase is prognostic. They found that among patients in their high-risk group, those who had increased at diagnosis had an OS of only 20%. In this study, that subset consisted of very small numbers, only five patients, but that is certainly worth following up on. LDH has been found to be prognostic in adults, but not so definitely shown in children.
Germ cell tumors are relatively rare in childhood and even in a large national study in a large country, it took nine years for Lopes et al to accrue 115 patients. We need to institute international trials for germ cell tumors in children where an international consortium of physicians jointly decide what constitutes risk, how to risk-stratify our patients and together design strategies for patients who are high risk.
What's really exciting is the Brazilians have obviously put together a network of oncology centers across the country and now can do these large scale cooperative trials. As the researchers rightly point out in the first paragraph of the discussion, that really is one of the most significant findings in this paper — they have managed to put together a cooperative clinical trial on a national basis, and that in and of itself has improved patients' prognosis.
– A. Lindsay Frazier MD
Associate Professor of Pediatrics, Dana-Farber Cancer Institute