Numerous attempts have been made to develop a regimen superior to BEP for poor-prognosis germ cell tumors but none have been successful. Most recently, four cycles of BEP was compared with two cycles of BEP followed by two cycles of high-dose cyclophosphamide, etoposide, and carboplatin, but there was no difference in survival between the two arms. Earlier trials of higher dose cisplatin or long-term maintenance chemotherapy were similarly disappointing.
For good-risk patients, the goal of clinical trials has been to minimize treatment toxicity without sacrificing the therapeutic effectiveness. As noted above, no difference in outcome was seen when comparing three versus four cycles of BEP chemotherapy. However, attempts to eliminate bleomycin produced more ambiguous and usually disappointing results. A randomized controlled trial comparing three cycles of BEP with three cycles of EP reported lower OS (95% vs. 86%, P = .01) in the EP arm. Similarly, when three cycles of BEP was compared with four cycles of EP in a randomized trial in more than 260 patients, there were 6 relapses and 5 deaths in the bleomycin arm compared with 14 relapses and 12 deaths in the EP arm, but these differences were not statistically significant. Several other studies have compared bleomycin-containing regimens to etoposide and cisplatin and in every trial, the trend in survival has favored the bleomycin arm, but the differences have not usually been statistically significant.[13,14,15] These results have led to some controversy as to whether three cycles of BEP is superior to four cycles of EP.
Special Considerations During Chemotherapy
In most patients, an orchiectomy is performed before starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site (or on the basis of highly elevated serum tumor markers and radiological imaging consistent with an advanced-stage germ cell tumor) and chemotherapy has been initiated, subsequent orchiectomy is generally performed because chemotherapy may not eradicate the primary tumor. Case reports illustrate that viable tumor has been found on postchemotherapy orchiectomy despite complete response of metastatic lesions.
Some retrospective data suggest that the experience of the treating institution may impact the outcome of patients with stage III nonseminoma. Data from 380 patients treated from 1990 to 1994 on the same study protocol at 49 institutions in the European Organization for Research and Treatment of Cancer and the Medical Research Council were analyzed. Overall, 2-year survival for the 55 patients treated at institutions that entered fewer than 5 patients onto the protocol was 62% (95% confidence interval [CI], 48%-75%) versus 77% (95% CI, 72%-81%) in the institutions that entered 5 or more patients onto the protocol.
Similarly, a population-based study of testis cancer in Japan in the 1990s reported a significant association between survival and the number of testis cancer patients treated. Relative 5-year survival was 98.8% at high-volume hospitals compared with 79.7% at low-volume hospitals. After adjusting for stage and age, the hazard ratio for death in a high-volume hospital was 0.11 (95% CI, 0.025-0.495). Several other studies have reported similar findings.[19,20,21] As in any nonrandomized study design, patient selection factors and factors leading patients to choose treatment at one center versus another can make interpretation of these results difficult.