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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4346-4349 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3777
Refining the Optimal Chemotherapy Regimen in Good Prognosis Germ Cell Cancer: Interpretation of the Current Body of KnowledgeErasmus University Medical Center Rotterdam and Rotterdam Cancer Institute, Rotterdam, the Netherlands The treatment of metastatic germ cell cancers with modern cisplatin-based chemotherapy results in a cure for approximately 70% to 80% of patients.1 Factors associated with treatment outcome include the extent of metastatic disease and serum levels of the ß-subunit of human chorionic gonadotropin, alpha fetoprotein, and lactate dehydrogenase.2 On the basis of these prognostic factors, clinical trials have focused on attempts either to decrease the toxicity of the standard four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with high possibility of cure, or to improve the curative results by intensifying therapy in patients with adverse risk factors.2 The standard BEP regimen comprises cisplatin 20 mg/m2 days 1 through 5 (100 mg/m2 per cycle), etoposide 100 mg/m2 days 1 through 5 (500 mg/m2 per cycle), and bleomycin 30 mg/week. Two of the efforts to decrease toxicity in good prognosis patients include the deletion of bleomycin (EP), and the reduction of the chemotherapy by one cycle (three cycles of BEP [3 BEP]). The European Organisation for Research and Treatment of Cancer (EORTC) investigated the relative merits of bleomycin by directly comparing four cycles of BEP with four cycles of EP in patients deemed to be good risk by the criteria used by the EORTC in the 1980s.3 The etoposide schedule in the study was based on the Royal Marsden Hospital regimen comprising 120 mg/m2 on days 1, 3, and 5 (360 mg/m2 per cycle). Four hundred nineteen patients were randomly assigned. More patients allocated to BEP achieved a complete response with chemotherapy alone or after postchemotherapy surgery (95% v 87%; P = .0075). In view of the low numbers of unfavorable treatment outcomes, no significant differences were detected in time to progression or survival. Although this study demonstrated that bleomycin contributes to the effectiveness of the BEP chemotherapy regimen, the dose of etoposide of 360 mg/m2 per cycle was less than is today considered standard EP chemotherapy. Two other studies have demonstrated that bleomycin adds to the effectiveness of the chemotherapy regimen.4,5 Both studies demonstrated superiority of the bleomycin-containing regimen, but the bleomycin was part of regimens that are now considered suboptimal. Taken together, these three studies have shown that bleomycin cannot be deleted if suboptimal chemotherapy is used, or when only three cycles are administered.6,7 Two randomized trials at Memorial Sloan-Kettering Cancer Center (New York, NY) examined the efficacy and toxicity of four cycles of EP. In these trials, etoposide was given at a dose of 500 mg/m2. Long-term follow-up of 214 patients treated with four cycles of EP (4 EP) revealed a progression-free survival of 82% after a median of 7 years, which was comparable with the results of the aforementioned studies investigating the role of bleomycin.8 A more exact interpretation of the data from these trials is hampered by the lack of uniform prognostic classification criteria in the 1980s. Consequently, complete response rates, progression-free survival, and overall survival figures could simply not be translated and compared among these trials. To reach consensus on one uniform prognostic model, the International Germ Cell Cancer Collaborative Group (IGCCCG) was established in 1994. Consensus was reached on one uniform model for both nonseminoma and seminoma using a risk classification in three prognostic categories.9 The proportion of patients falling in the good prognosis group is 60% for nonseminoma and 90% for seminoma. The progression-free and overall survival at 5 years in this category is 86% and 90%, respectively. The first trial in good prognosis patients according to the IGCCC criteria was conducted by the EORTC and the Medical Research Council. This study tested the reduction of the chemotherapy by one cycle, by random comparison of 3 BEP versus four cycles.10 To avoid a cumulative exposure of bleomycin above 300 mg, bleomycin was omitted in the fourth cycle (ie, 3 BEP plus one cycle of EP). The study methods were aimed to rule out a 5% decrease in the 2-year progression-free survival, requiring 774 patients. The study included an assessment of patient quality of life. A total of 812 patients were randomly assigned. The projected 2-year progression-free survival was 90.4% for three cycles and 89.4% for four cycles (difference, –1%; 80% CI, –3.8% to 1.8%). Hence, equivalence was claimed, since both bounds of the confidence limit were less than 5%. Frequencies of hematologic and nonhematologic toxicities were essentially similar, except for both acute and late sensory neuropathy, which was more frequent with four cycles. Quality of life 1 year after completion of treatment was identical. This study demonstrated that 3 BEP, with etoposide at 500 mg/m2 is sufficient therapy in good prognosis germ cell cancer by IGCCC criteria. For the purpose of better interpreting the results obtained by four cycles of EP in the two good prognosis trials, and allowing for meaningful intergroup comparisons, the Memorial Sloan-Kettering Cancer Center investigators have retrospectively assigned their patients to IGCCC criteria.9 Of the 214 patients treated with 4 EP, a total of 148 patients were deemed good risk by IGCCC criteria. Of these, 142 (96%) achieved a complete response, and the relapse proportion was 5%. A further report by the investigators comprised a total of 289 patients who had been treated with 4 EP and who met IGCCC criteria, of whom 269 (93%) obtained a complete response by chemotherapy alone and a further 5% who were rendered disease free by surgical resection of viable cancer remnants.11 Seventeen patients relapsed (6%), resulting in a 5-year progression-free survival of 94%. Therefore, by IGCCC criteria, these results appear virtually identical to those obtained in the EORTC/Medical Research Council study in IGCCC good-risk patients (Table 1). 10-12 These data have served to allow both 3 BEP and 4 EP to be considered standard treatment options for patients with metastatic good-risk germ cell cancer.8
The only randomized trial to directly compare 3 BEP and 4 EP was conducted by the French Federation of Cancer Centers Genito-Urinary Group from October 1993 to May 1999 with a total of 270 patients. The results were presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31 to June 3, 2003.13 As stated by the investigators, the study was underpowered to determine survival benefit. In addition, there was a risk of reaching false-positive conclusions by multiple end point testing. Conclusive interpretation of the data has lingered for several years. The final report of the study was recently published in Annals of Oncology,12 and in view of the importance of the topic, the Journal of Clinical Oncology has invited an Editorial on this report. The conclusion from the abstract of that study was that "both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients." In the French study, good risk was defined by the Institute Gustave Roussy prognostic model based on serum alpha fetoprotein and human chorionic gonadotropin levels.14 The study was originally designed to test for therapeutical equivalence, with an expected favorable response of 90% and not more than a 10% difference in the response proportions between the two treatment arms. For these purposes, 250 patients were needed. In view of the curative potential of chemotherapy in testicular cancer, a difference of between 5% and 9% would have been more appropriate. Moreover, response rates at the completion of chemotherapy do not take into account relapses after chemotherapy and cannot be considered optimal to test for therapeutical equivalence. To rule out a difference of 5% in the 2- or 3-year progression-free survival rate would have required 800 patients. In the alternative case that a difference in efficacy between the treatment groups would be observed and the investigators would change their objective by aiming to detect a difference of 10%, a total of 61 events would be required, translating into a total of 408 patients needed. Hence, the 270 patients recruited and 257 assessable for the efficacy analysis were insufficient to detect either superiority of one regimen or noninferiority. On the observation of numerical differences in favorable responses and relapses between the two treatment arms, the authors changed their primary objective and inadvertently increased the risk of obtaining false-positive results by analyzing multiple end points. The risk of multiple testing can be emphasized by the following computation: conducting three tests at 0.05 (5% risk of false-positive conclusion) increases the risk of a false-positive conclusion to 1 – (1 – 0.05)3 = 14%. At the American Society of Clinical Oncology meeting in 2003, data analyses were presented on favorable response, event-free survival (EFS) at 4 years, and progression-free survival at 4 years by retrospective assignment in good-risk disease according to IGCCC criteria. Eventually, the difference in EFS at 4 years by IGCCC criteria (252 patients) reached statistical significance in favor of 3 BEP, prompting the investigators to conclude in 2003 that 3 BEP was the standard of care regimen. At that time, the computation of events was also discussed. The investigators considered viable cancer found in residual tissue at postchemotherapy surgery an event, even in case of complete resection. In most trials in the past 20 years, patients rendered as having no evidence of disease by chemotherapy plus additional surgery were considered surgical complete responses and remained in the progression-free survival analysis. The French investigators also considered resection of mature teratoma (MT) during follow-up as relapse, whereas in other trials complete surgical resection of MT has not been considered an event. Since several cases of surgical complete responses and MT were reported on the 4 EP arm, there was a suggestion of more frequent events on 4 EP, whereas by using the general rules, the number of events was virtually identical in both arms. In the article by Culine et al,12 the authors have addressed these issues; no evidence of disease by chemotherapy plus surgery have been included in the favorable response category and MT relapses were not considered adverse events. Of the total 270 patients, eight did not receive protocol treatment and were excluded from any analyses. The 262 remaining patients were defined by the investigators to be the intent-to-treat population. Patient characteristics were reasonably well balanced, but were presented for the entire 270 patient population, rather than the eventual 262 intent-to-treat population. It is not clear from the article why an additional five patients (one on 3 BEP and four on 4 EP) were excluded from the efficacy analysis. Of 131 eligible patients on 3 BEP, six were treatment failures at completion of protocol treatment and a further six relapsed for a total of 12 events (91% event free), which is identical to the 12 events reported in the intent-to-treat analysis (4-year EFS, 91%). Of 126 eligible patients on 4 EP, three patients experienced failure of protocol treatment and an additional 14 relapsed, for a total of 17 events (87% event free). The number of events reported in the intent-to-treat analysis of 130 patients, however, is 20 (4-year EFS, 86%), which means that three of four patients on 4 EP, who for undocumented reasons were not included in the efficacy analysis, had an event. Retrospective assignment of patients into the IGCCC classification identified six patients (four on 3 BEP and two on 4 EP) who fulfilled criteria for poor prognosis disease. The 4-year EFS in the 128 patients on each arm with IGCCC good prognosis disease was 93% on 3 BEP and 86% on 4 EP. None of the EFS and overall survival analyses reached statistical significance, except for a borderline P value of .052 for 4-year EFS by IGCCC criteria. In view of the posthoc nature of this analysis, as well as the multiple end point testing, this result cannot be considered conclusive. When these EFS rates are added to those previously reported results by 3 BEP and 4 EP (Table 1), there is no indication that there are clinically meaningful differences in the efficacy of the two regimens. Although the study was underpowered to detect superiority of one regimen over the other, the sample size did allow the observation of differences in toxicity. There was an unexpected difference in neurological toxicity (any grade) in favor of 4 EP; 16% on BEP versus 5% on EP (P = .006). 3 BEP also resulted in significantly greater frequency of Raynaud's phenomenon (29% v 8%; P = .0001). Pulmonary toxicity was observed in 9% of patients on 3 BEP, mostly grade 1% and 6% on 4 EP, which was not significant. No toxic deaths occurred. These observations provide important information. First, the data on minor pulmonary toxicity add to other recent data that 3 BEP, with a cumulative dose of bleomycin of 270 mg, bear a minor risk of bleomycin-induced pneumonitis and the risk of bleomycin-associated death has become less than 0.2%.10 This risk can possibly be even further reduced by withholding bleomycin in patients older than 40, those who have impaired renal function, or those patients who are heavy cigarette smokers—factors that are all associated with an increased risk of bleomycin toxicity.15-19 In these patients, the preferred choice of 4 EP is obvious. Second, this direct randomized study of 3 BEP versus 4 EP provides the important information that the addition of bleomycin to 3 EP causes greater incremental neurologic toxicity than the addition of a fourth cycle of EP in the EP regimen. Many physicians treating testicular cancer patients prefer 3 BEP because they thought that this regimen was less neurotoxic. The evidence is now otherwise. Of equal importance is the significant greater skin toxicity of bleomycin. The difference in toxicity is similar to that observed in the study of the EORTC of 4 BEP versus 4 EP that showed skin toxicity (any grade) in 39% of patients receiving BEP versus 5% on EP (P < .001), and late Raynaud's phenomenon occurred in 8% versus 0%, respectively (P < .001). Hence, it is clear that bleomycin clinically significantly contributes to the chemotherapy toxicity. Raynaud's phenomenon is considered to reflect vascular damage. Arteriograms have documented diffuse narrowing in the hands of these patients.20 Also, late cardiovascular toxicity appears to be associated with the development of Raynaud's phenomenon.21 Late cardiovascular disease is well documented in testis cancer survivors after platinum-based chemotherapy.22-24 Most of the patients in these studies have been treated with cisplatin, vinblastine, and bleomycin or BEP; thus, the combined use of bleomycin and cisplatin. Databases on platinum-based chemotherapy without bleomycin are too small to detect meaningful differences in the occurrence of late cardiovascular toxicity. Nuver et al25 recently reported on acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. In 65 patients receiving BEP chemotherapy, the intima-media thickness of the carotid artery and plasma Von Willebrand levels, being a marker of endothelial damage, both increased significantly after treatment. These changes are likely to indicate chemotherapy-induced vascular damage. The same group of investigators is currently conducting a similar study, in which both patients receiving 3 BEP, as well as patients scheduled to receive 4 EP are included. This study may provide important information for our understanding of the possible contribution of bleomycin in the cardiovascular toxicity of this chemotherapy. For the time being, both 3 BEP and 4 EP can still be considered standard regimens, which yield excellent long-term efficacy results in IGCCC good risk germ cell cancer. However, it may very well be differences in acute and late toxicity inflicted by this chemotherapy that eventually identifies a winner. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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