February 9, 2012 — Testicular cancer is highly curable with chemotherapy, but about 20% to 30% of patients will relapse and require some form of salvage therapy.
Unfortunately, the optimal salvage chemotherapy for patients with first-relapse testicular cancer is "still unknown," according to an American expert commenting on a German phase 3 trial of this study population.
The trial compared 2 approaches to high-dose chemotherapy in men with relapsed and/or refractory germ cell tumors, and was conducted by the German Testicular Cancer Study Group.
"They are to be congratulated for initiating one of the few phase 3 studies in this patient population and for reporting the results with a median follow-up of 7.5 years," writes Lawrence Einhorn, MD, from the Simon Cancer Center at Indiana University in Indianapolis, in an editorial that accompanies the new study, both of which were published online January 30 in the Journal of Clinical Oncology.
However, the 211-patient study found no difference in 5-year progression-free survival between patients randomized to "single" high-dose chemotherapy and those treated with a "sequential" high-dose regimen (45% vs47%; P = .454). All patients also received autologous hemopoietic stem cell rescue after their chemotherapy.
The single high-dose chemotherapy regimen consisted of 3 cycles of etoposide, ifosfamide, and cisplatin (VIP), followed by 1 cycle of high-dose carboplatin, etoposide, and cyclophosphamide.
The sequential regimen consisted of 1 cycle of VIP plus 3 cycles of high-dose carboplatin and etoposide.
Recruitment in the trial was stopped prematurely because of increased treatment-related mortality with the high-dose single cycle that included cyclophosphamide (14% vs 4%; P = .01).
The results are "disappointing," says Dr. Einhorn.
The investigators say that they studied high-dose chemotherapy as a salvage therapy in this setting because it "has become standard treatment for patients with relapsed or refractory germ cell tumors at many centers worldwide."
But Dr. Einhorn says that it is not known whether high-dose salvage treatment regimens are better than standard-dose regimens.
"There are 2 approaches to salvage chemotherapy," writes Dr. Einhorn. One approach is a standard-dose cisplatin-based regimen with drugs not previously used, which may include cisplatin, ifosfamide, and either vinblastine or paclitaxel. The other approach is high-dose chemotherapy with autologous hematopoietic stem cell rescue.
Dr. Einhorn adds that there have been no studies to determine if "one strategy of high-dose chemotherapy is preferred over a different [high-dose] regimen." Thus, the new study addressed just one of the many questions in this setting.
There are silver linings to be found in the cloud of the new results and in salvage chemotherapy in general, Dr. Einhorn explains.
"It is remarkable that salvage chemotherapy can reproducibly cure patients when used as second- or third-line chemotherapy," he writes.
Indeed, with a median follow-up time of more than 7 years, 45% of these salvage patients — the great majority of whom experienced failure on a first-line chemotherapy (86%) — were still alive. "Hopefully, cures remain durable in a substantial proportion of patients," write the German investigators, led by Anja Lorch, MD, from the University of Giessen and Marburg.
Overall Survival Needs Interpretation
In the study, from November 1999 to November 2004, 211 patients with relapsed or refractory testicular cancer were randomly assigned to 1 of 2 treatment regimens, both followed by autologous stem cell reinfusion: the sequential regimen consisted of 1 cycle of cisplatin 100 mg/m², etoposide 375 mg/m², and ifosfamide 6 g/m² (VIP) plus 3 cycles of high-dose carboplatin 1500 mg/m² and etoposide 1500 mg/m²; the single regimen consisted of 3 cycles of VIP plus 1 cycle of high-dose carboplatin 2200 mg/m², etoposide 1800 mg/m², and cyclophosphamide 6400 mg/m².
Overall survival was better with the sequential regimen than with the single regimen (49% vs 39%; P = .057), the investigators report. However, this was not a result of improved therapeutic efficacy. Instead, the difference was due to the abovementioned treatment-related mortality associated with the single regimen.
Two subgroups in the study "deserve to be mentioned in particular," say the investigators. One is a small group of 6 patients who were part of a larger group of patients who relapsed or progressed after high-dose chemotherapy (the majority of whom died from their disease). These 6 patients not only survived, they became "permanently free of tumor with third-line chemotherapy and/or desperation surgery." These men "serve as a reminder that expert treatment might successfully salvage individual patients."
The other group was patients with relapses more than 2 years after their cisplatin-based first-line chemotherapy. Such men are considered "poor candidates" for subsequent chemotherapy, the investigators explain. However, 4 such patients achieved complete remission with high-dose chemotherapy in the trial. "Patients with unresectable late relapses of germ cell tumors should therefore not routinely be excluded from high-dose chemotherapy," they write.
However, Dr. Einhorn is not convinced, and he maintains that it is unclear whether high-dose chemotherapy — as opposed to less toxic standard chemotherapy — should be offered to such men.
The study authors have disclosed no relevant financial relationships. Dr. Einhorn reports owning stock in Amgen.
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