Alternatives to Standard BEP x 3 in Good-Prognosis Germ Cell Tumors—You Bet Your Life Craig Nichols, Christian Kollmannsberger
Affiliations of authors: Robert W Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR (CN); British Columbia Cancer Agency, Division of Medical Oncology, Vancouver Cancer Centre, University of British Columbia, Vancouver, BC, Canada (CK)
Correspondence to: Craig Nichols, MD, FACP, Robert W Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan St, Portland, OR 97213 (e-mail: email@example.com).
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 high-quality 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 x 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 x 3 is difficult precisely because in the modern era with the brief 9-week schedule, low cumulative doses, and modern supportive care, BEP x 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, etoposide-induced 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 x 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 x 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 x 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 x 3 (eg, advanced age, substantial renal insufficiency, 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 standard BEP x 3 was the superior regimen and that further investigation of this issue was not warranted; standard BEP x 3 has thus become the recommended therapy for good-prognosis disseminated germ cell tumors throughout Europe and in Canada.
The thorough article by Grimison et al. (1), with the careful attention to long-term follow-up, in our view, should bring an end to clinical investigations of alternatives to BEP x 3 for good-prognosis disseminated germ cell tumors. Short of a discovery of a breakthrough biological concept and therapy, any potential gains are too small and potential losses (ie, lives) too great to justify these investigations. Dr Lawrence Einhorn called for such clinical trial restraint in this arena in 1993 in discussing the comparative trial of cisplatin and etoposide to an experimental alternative of carboplatin and etoposide (10). He closed his editorial entitled "Curable neoplasms and the ethics of clinical trials" with "The dictum of ‘do no harm’ also applies to regimens that might be inferior to standard therapy." The dictum remains relevant.
There may be lessons in this saga for other clinical investigators who toil at these lofty heights of treatment efficacy. In early-stage Hodgkin lymphoma, we believe that clinical investigations continue to ask questions aimed at reducing relatively trivial toxic effects and run the risk of reducing the therapeutic gain. In the HD13 trial of the German Hodgkin Lymphoma Study Group study for early-stage good-prognosis disease (11), patients were randomly assigned to two cycles of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD x 2) plus 30 Gy involved-field radiation vs the same radiation following either two cycles of doxorubicin (Adriamycin), bleomycin, vinblastine (ABV x 2); two cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD x 2); or two cycles of doxorubicin (Adriamycin) and vinblastine (AV x 2). The group has closed two arms early (ABV x 2 and AV x 2) because of increased failures. Again, the standard arm of ABVD x 2 plus involved-field radiation was remarkably effective (at 5 years: failure-free survival = 93%, overall survival = 97%). It is hard to image a toxicity question that would be compelling enough to forgo this well-tolerated 2-month outpatient chemotherapy regimen and to jeopardize the years of clinical trial gains that have resulted in meaningful reductions in radiation dose and field size and meaningful reductions in chemotherapy duration from four cycles of ABVD to two cycles.
At some point, it is time to declare victory and wait patiently for a blockbuster new concept to emerge. Until then, we should develop consist policies and guidelines for treating patients with good-prognosis germ cell tumors and teach the world to deliver these remarkable and, ultimately, fairly simple cures in a safe and consistent manner. Currently, our biggest gains will come from improved efforts to deliver, effectively and broadly, these safe and well-defined therapies.
1. Grimison PS, Stockler MR, Thomson DB, et al. Comparison of two standard chemotherapy regimens for good-prognosis germ cell tumors: updated analysis of a randomized trial. J Natl Cancer Inst (2010) 102 begin_of_the_skype_highlighting (2010) 102 end_of_the_skype_highlighting(16). xxx–xxx.
2. Einhorn LH, Williams SD, Loehrer PJ. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol (1989) 7(3):387–391.[Abstract]
3. De Wit R, Stoter G, Kaye SB, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol (1997) 15(5):1837–1843.[Abstract/Free Full Text]
4. Loehrer PJ, Johnson D, Elson P, et al. Importance of bleomycin in favorable prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group Trial. J Clin Oncol (1995) 13(2):470–476.[Abstract/Free Full Text]
5. Horwich A, Sleijfer DT, Fossa SD, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol (1997) 15(5):1844–1852.[Abstract/Free Full Text]
6. De Wit R, Roberts T, Wilkinson PM, et al. Equivalence of 3 or 4 cycles of BEP chemotherapy administered on a 3 or 5 day schedule in good prognosis germ cell cancer, a randomized study of the European Organisation for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol (2001) 19(6):1629–1640.[Abstract/Free Full Text]
7. Culine S, Kerbrat P, Kramar A, et al. Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-cell tumors: a randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP). Ann Oncol (2007) 18(5):917–924.[Abstract/Free Full Text]
8. Krege S, Beyer J, Souchon R, et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): Part II. Eur Urol. (2008) 53(3):497–513.[CrossRef][Web of Science][Medline]
9. Wood L, Kollmannsberger C, Jewett M, et al. Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J (2010) 4(2):e19–e38.[Medline]
10. Einhorn LH. Curable neoplasms and the ethics of clinical trials. J Clin Oncol (1993) 11(4):593–595.[Web of Science][Medline]
11. Klimm B, Diehl V, Pfistner B, Engert A. Current treatment strategies of the German Hodgkin Study Group (GHSG). Eur J Haematol Suppl (2005) 75(Suppl 66):125–134.
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