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Originally published as JCO Early Release 10.1200/JCO.2005.92.001 on June 6 2005 © 2005 American Society of Clinical Oncology.
Bladder Cancer "Adjuvant-Lite": Tastes Great (works as well) and Less Filling (less toxic)?
Memorial Sloan-Kettering Cancer Center, New York, NY In this issue, Lehmann et al1 report that cisplatin plus methotrexate (CM) is not inferior to methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC) in the adjuvant treatment of patients with locally advanced bladder cancer after surgery. The report suggests a possible new standard of care. Do the data support this conclusion? To answer that question, a short review of pre-existing data and statistics is needed. One prerequisite for evaluating treatments in the perioperative setting is the demonstration of efficacy in advanced disease. The rationale has been that regimens meeting such a milestone may be incrementally more effective when the tumor is microscopic, exploiting the enhanced sensitivity of rapidly proliferating cells. This has been the evolution of treatment for transitional-cell carcinoma (TCC) of the bladder. In advanced disease, carefully conducted phase II studies showed transient partial responses with single agents in the 1970s; durable complete remissions were demonstrated when effective agents were combined in three- and four-drug combinations in the 1980s; and prospective randomized comparisons of these combinations provided evidence for survival benefits in the 1990s. In individual trials, methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) conferred a survival benefit compared with single-agent cisplatin and cisplatin, doxorubicin, and cyclophosphamide2,3; and cisplatin, methotrexate, and vinblastine (CMV) demonstrated a survival benefit compared with methotrexate and vinblastine.4 These results established M-VAC and CMV as treatment standards for patients with metastatic disease.
In the new millennium, adequately powered prospective randomized trials with sufficient follow-up of M-VAC and CMV as neoadjuvant therapy were reported, demonstrating survival benefits compared with no chemotherapy and establishing neoadjuvant chemotherapy as the standard management for patients with muscle-invasive disease. In the largest trial of neoadjuvant chemotherapy in TCC, 976 patients with clinical T2-4a disease were randomly assigned to neoadjuvant CMV versus no chemotherapy, combined with cystectomy, radiation therapy, or both as management of the primary tumor. The trial, which was powered to detect an absolute improvement in survival of 10% (from 50% to 60%), was initially reported as negative.5 However, with 7 years of follow-up, a significant reduction in the hazard ratio for death was observed for the chemotherapy-treated patients (hazard ratio = 0.85; 95% CI, 0.72 to 1.0; P = .048).6 In the second trial, INT 0080, 317 patients with clinical stage T2-4a TCC were randomly assigned to receive three cycles of neoadjuvant M-VAC followed by radical cystectomy or radical cystectomy alone.7 This trial was powered to detect a Given these results, why isn't the neoadjuvant approach practiced more widely? There are several reasons. First, the inaccuracies of clinical staging make the assessment of which patients are destined to metastasize and who, thus, need systemic therapy to achieve cure less precise. Second, the delay in definitive therapy in patients who do not respond to treatment raises concerns regarding compromise of curability. Third, the development of internal urinary reservoirs makes the objective of bladder preservation less tenable for the majority of patients. These factors have led many urologists and urologic oncologists to adopt a treatment policy in which the recommendation for chemotherapy is considered in the postoperative adjuvant setting, as opposed to the neoadjuvant setting. Unfortunately, the available data supporting an adjuvant approach are less compelling because, in large part, of deficiencies in trial design. At least five randomized trials have evaluated the role of postoperative chemotherapy in bladder cancer,8-12 of which the largest trial accrued 91 patients. The results suggested survival benefits in two trials, with no difference in the other three trials. Of those trials deemed to be positive, patients with pT3b-T4a and/or node-positive disease were randomly assigned to three cycles of M-VAC or M-VEC or no further treatment after cystectomy.9 Although 100 patients were required to detect a 35% improvement in disease-free survival, the trial was terminated after 49 patients were enrolled when an interim analysis showed a significant improvement in 3-year disease-free survival for the chemotherapy arm versus the no chemotherapy arm (63% v 13%, respectively; P = .0015). A follow-up report indicated an improvement in overall survival as well. This trial has been criticized because the results were not analyzed on an intent-to-treat basis; patients who were assigned to chemotherapy but did not receive treatment were included as controls, and treated patients included patients who were treated during the same interval but who did not undergo random assignment. In the second trial, patients with pT3-4 and/or node-positive TCC were randomly assigned to receive four cycles of cisplatin, doxorubicin, and cyclophosphamide or no further treatment after cystectomy.10 Although a significant difference in median survival was observed favoring chemotherapy compared with no chemotherapy (4.3 v 2.4 years, respectively), the curves crossed at the 48% level, the ultimate accrual of 91 patients fell far short of the originally planned accrual goal, and the Wilcoxon analysis used favored early, rather than late, events. Is it reasonable to extrapolate the results from the neoadjuvant studies to the adjuvant setting? Many oncologists feel that it is, citing large trials in other malignancies that suggest no difference between these two approaches.13 Although no large trials have directly compared neoadjuvant and adjuvant therapy in bladder cancer, a trial reported by Millikan et al14 randomly assigned 140 patients to receive either two courses of neoadjuvant M-VAC followed by cystectomy plus three additional cycles of chemotherapy or initial cystectomy followed by five cycles of adjuvant chemotherapy. This small randomized trial suggested no difference in outcomes based on the sequence of administration of therapy. Another barrier to the widespread adoption of perioperative chemotherapy in bladder cancer has been concern regarding the toxicity associated with multiagent cisplatin-based regimens. The toxicities of M-VAC in advanced disease include febrile neutropenia, mucositis, hearing loss, renal impairment, and peripheral neuropathy; treatment-related deaths occur in 2% to 4% of patients. Over the last decade, several groups have designed studies in patients with metastatic disease to address whether the same anticancer effects can be achieved with fewer side effects. One study showed similar response rates, response durations, and survival with reduced toxicity for gemcitabine plus cisplatin compared with M-VAC.15 As a result, gemcitabine plus cisplatin has become a favored regimen in patients with advanced TCC. The trial reported by Lehmann et al1 in this issue extends this concept of similar efficacy with improved tolerability to the adjuvant setting. In this trial, M-VEC (M-VAC with epirubicin substituted for doxorubicin to minimize cardiotoxicity) was compared with CM as adjuvant therapy in patients with pT3a-4a and/or node-positive TCC of the bladder. A noninferiority design was chosen to establish CM as a less toxic regimen with comparable efficacy. The primary end point was progression-free survival, with the equivalence margin set at 0.15, and the upper bound of the hazard ratio was 1.5. The treatment arms were balanced with regard to baseline demographics and pathologic stage, and the number of patients completing all three cycles of chemotherapy was similar. The results showed a median time to progression of 49.7 months for patients treated with M-VEC compared with 43.4 months for CM-treated patients. The hazard ratio for recurrence of 1.131 (90% CI, 0.863 to 1.482) favored M-VEC, and the authors concluded that, "For the adjuvant indication of combination chemotherapy with curative intent in resected locally advanced bladder cancer, the current report provides evidence that the efficacy of the less toxic regimen of CM cannot be considered substantially inferior to the efficacy of M-VEC." Less filling and tastes great? Is less toxic really as effective? Have we established a new standard? Several questions remain. First, is the control regimen, adjuvant M-VEC, a standard of care? Second, what is known about CM, the experimental regimen, in advanced disease? Third, what is the basis for the statistical design and sample size to prove CM is not inferior? And finally, is CM less toxic than M-VEC? Even if we accept that adjuvant M-VAC/M-VEC is a standard of care, data to support CM as the experimental arm are limited. Unlike M-VAC and CMV, CM has not been shown to confer a survival benefit in patients with metastatic TCC. In a randomized trial of 108 patients comparing CM with single-agent cisplatin, CM was not superior to cisplatin alone.16 Because CM has not been shown to be superior to single-agent cisplatin and single-agent cisplatin is ineffective in the perioperative setting,17 the use of CM as the experimental arm is a leap of faith. Does the trial really show noninferiority? Before addressing this question, we must consider the question of superiority. To show an absolute difference in survival of 10% between the two groups would require the random assignment of approximately 1,000 patients.18 How can it be concluded that CM was noninferior when only 327 patients were accrued? Central to the noninferiority trial design is the equivalence margin, which is the degree of efficacy that the investigators are willing to give up for some decrement in toxicity. In this trial, an equivalence margin of 0.15 was chosen, with an upper bound of the hazard ratio at 1.5. In other words, the authors were willing to accept up to a 50% increase in the hazard of disease progression for a less toxic regimen. This seems excessive when the treatment objective is to prolong life and may exceed the benefit of even the most effective chemotherapy. On the basis of the actual accrual, the study met their primary end point, with an upper bound of the hazard ratio of 1.48; or, stated differently, the hazard of disease progression with CM could have been increased by up to 48% compared with M-VEC. Therefore, noninferiority is established only if the treating clinician is prepared to accept and offer to his or her patients a regimen (CM) that could have up to a 48% likelihood of being inferior to the alternative (M-VEC). To us, this risk seems too great, and a new standard of care is not established. Finally, was CM really less toxic than M-VEC? Here, as well, the data are not convincing. Although the frequency of grade 3 neutropenia and alopecia was higher on the M-VEC arm, the rates of grade 4 neutropenia, febrile neutropenia, infection, and treatment-related deaths were similar. Information regarding other toxicities was not provided, and quality-of-life end points were not addressed prospectively in the study design. Notably, the toxicity observed with M-VAC/M-VEC in patients with metastatic disease has not been encountered to the same degree in the perioperative setting, and those toxicities that are encountered can be reduced substantially with hematopoietic growth factors and antiemetics, which were supportive measures that were not available when M-VAC was originally designed. The investigators set out with the noble goal of defining a less toxic alternative adjuvant regimen for locally advanced TCC of the bladder. Unfortunately, the question of whether CM is equivalent to the three- and four-drug regimens of CMV and M-VEC (M-VAC) with respect to survival remains open. At present, on the basis of a survival benefit demonstrated in randomized comparative trials, neoadjuvant cisplatin-based combination chemotherapy followed by definitive treatment of the primary tumor is the current standard of care for patients with muscle-invasive bladder cancer. Patients who do not receive neoadjuvant therapy should be considered for enrollment onto clinical trials. The utility of adjuvant chemotherapy in bladder cancer remains controversial. To address this issue, the European Organization for Research and Treatment of Cancer is randomly assigning 1,344 patients with pT3-4 and/or node-positive disease to postoperative cisplatin-based chemotherapy or a similar regimen at the time of relapse. Convinced of the benefit of adjuvant chemotherapy, the Cancer and Leukemia Group B (CALGB)/Clinical Trial Support Unit is seeking to define an optimal treatment by randomly assigning 800 patients to either gemcitabine plus cisplatin or doxorubicin plus gemcitabine followed by paclitaxel plus cisplatin (CALGB 90104) More answers will only become available if we support these efforts. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Acknowledgment We thank Nandita Mitra, PhD, for her statistical review and comments. REFERENCES
1. Lehmann J, Retz M, Wiemers C, et al: Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: Results of a randomized, multicenter, phase III trial J Clin Oncol 23: 4963-4974, 2005 2. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 10: 1066-1073, 1992[Abstract] 3. Logothetis CJ, Dexeus F, Sella A, et al: A prospective randomized trial comparing CISCA to MVAC chemotherapy in advanced metastatic urothelial tumors. J Clin Oncol 8: 1050-1055, 1990[Abstract] 4. Mead GM, Russell M, Clark P, et al: A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: Results and a report on prognostic factors in a Medical Research Council study—MRC Advanced Bladder Cancer Working Party. Br J Cancer 78: 1067-1075, 1998[Medline] 5. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial—International collaboration of trialists. Lancet 354: 533-540, 1999[CrossRef][Medline] 6. Hall R: Updated results of a randomised controlled trial of neoadjuvant cisplatin (C), methotrexate (M) and vinblastine (V) chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 21: 178a, 2002 (abstr 710)
7. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349: 859-866, 2003 8. Bono AV, Benvenuti C, Reali L, et al: Adjuvant chemotherapy in advanced bladder cancer: Italian Uro-Oncologic Cooperative Group. Prog Clin Biol Res 303: 533-540, 1989[Medline] 9. Stockle M, Meyenburg W, Wellek S, et al: Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): Improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy—Results of a controlled prospective study. J Urol 148: 302-306, 1992[Medline] 10. Skinner DG, Daniels JR, Russell CA, et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 145: 459-464, 1991[Medline] 11. Studer UE, Bacchi M, Biedermann C, et al: Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: Results of a prospective randomized trial. J Urol 152: 81-84, 1994[Medline] 12. Freiha F, Reese J, Torti FM: A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 155: 495-499, 1996[CrossRef][Medline] 13. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672-2685, 1998[Abstract]
14. Millikan R, Dinney C, Swanson D, et al: Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 19: 4005-4013, 2001
15. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18: 3068-3077, 2000 16. Hillcoat BL, Raghavan D, Matthews J, et al: A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol 7: 706-709, 1989[Abstract] 17. Advanced Bladder Cancer Meta-Analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 361: 1927-1934, 2003[CrossRef][Medline] 18. Bajorin DF: Plenary debate of randomized phase III trial of neoadjuvant MVAC plus cystectomy versus cystectomy alone in patients with locally advanced bladder cancer. J Clin Oncol 19: 17S-20S, 2001 (suppl 18)[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50% improvement in median survival with the combined approach. With a median follow-up of almost 9 years, a 21-month difference was observed for chemotherapy-treated patients versus patients who did not receive chemotherapy (77 v 46 months, respectively; P = .06). The absolute survival benefit at 5 years was 14%, and the hazard ratio for survival was 0.75 (95% CI, 0.57 to 1.0), favoring the neoadjuvant arm. 
