Alternatives to Standard BEP x 3 in Good-Prognosis Germ Cell Tumors--You Bet Your Life
Authors: C. Nichols, C. Kollmannsberger
Journal: JNCI Journal of the National Cancer Institute (2010)

Curing systemic cancer is rare and precious. In treating adult patients with systemic malignancies, rarely do medical oncologists have the opportunity to operate at the favorable asymptote of the therapeutic curve, perhaps only in early-stage favorable Hodgkin lymphoma and good-prognosis testicular cancer. In both cases, expectations for a cure with standard therapy routinely exceed 95% in clinical trials and in large population-based experiences. This situation has not changed for either disease for many years. Particularly in such rare diseases, it is logistically and statistically impossible to demonstrate any strategy that will improve cure rates. Indeed, in good-prognosis testicular cancer, there have been a number of attempts to demonstrate only equivalence to the standard bleomycin, etoposide, and cisplatin (BEP) chemotherapy regimen (in hopes of defining a regimen that might have some toxicity advantages). In 20 years of attempts to decrease standard BEP doses, and as reported by Grimison et al. (1) in this issue of the Journal, virtually all efforts have fallen short of the standard BEP effectiveness bar (2–7). Not curing one patient with a good-prognosis disseminated germ cell tumor costs, on average, 40 years of productive highquality life. What clinical trial questions are of sufficient magnitude to jeopardize the meaty therapeutic gains of standard BEP? One could certainly argue that few of the attempts to date to improve the toxicity profile of three cycles of standard BEP (BEP × 3) while trying to maintain efficacy was worth the effort. Like the challenge of proving equivalent therapeutic punch, proving that any testicular cancer chemotherapeutic regimen is better tolerated than standard BEP × 3 is difficult precisely because in the modern era with the brief 9-week schedule, low cumulative doses, and modern supportive care, BEP × 3 is generally well tolerated with largely only short-term toxicity. The results of clinical trials on the toxicity side of the equation have shown mostly clinically insignificant and often evanescent improvements in toxicity, in particular, slightly fewer low-grade cutaneous and vascular side effects. Adding an additional cycle of cisplatin in an attempt to accommodate less than full doses of bleomycin or etoposide may, in aggregate, be adding long-term toxicity as seen in this 8-year follow-up study by Grimison et al. (1). A careful review of modern trials and large experiences with good-prognosis testicular cancer treatment reveals that the current delivery of standard BEP for three cycles only is nearly devoid of serious or fatal pulmonary toxicity, etoposideinduced leukemia, or death from neutropenic complications. BEP in the standard dose and schedule that was described more than 25 years ago has been a remarkably effective, remarkably safe, 9-week, largely outpatient regimen. When given by skilled and attentive chemotherapists with appropriate modern supportive care, patients are reliably cured and quickly return to full and productive activities with few long-term physical sequelae of their treatment. The primacy of BEP × 3 for treatment of good-prognosis disseminated germ cell tumors is now well embedded in emerging guidelines for the management of testicular cancer in both Europe and Canada (8,9). The results of the last 20 years of attempts to improve upon standard BEP, with consistent failure of alternative regimens to maintain the curative potential of BEP × 3, should call into question any deviations from the precise doses and schedule of this regimen in routine clinical practice. There is now sufficient evidence to say that deviation from standard BEP × 3 is a potentially life-threatening decision and, therefore, requires a corresponding life-threatening reason to drop bleomycin or to extend the 21-day schedule or to tinker with the etoposide dose. In addition, in terms of routine clinical practice, there must be a compelling medical reason to use etoposide and cisplatin for four cycles rather than BEP × 3 (eg, advanced age, substantial renal insuffi ciency, demonstrable clinically significant pulmonary compromise), and these two regimens should not be viewed as equally effective options. This question has been addressed formally by a randomized trial conducted in France (7), in which it was concluded that