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© 2001 American Society for Clinical Oncology
Neoadjuvant MVAC: The Long and Winding Road Is Getting Shorter and StraighterUniversity of Chicago Cancer Research Center, Chicago, IL IN THE EARLY 1980s, the late Alan Yagoda and a team of young investigators at Memorial Sloan-Kettering Cancer Center in New York revolutionized the treatment of metastatic bladder cancer.1,2 Inducing a 70% response rate, methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy was shown to be superior to cisplatin3 and to cisplatin, doxorubicin, and cyclophosphamide.4 It became the standard of care for metastatic disease, and oncologic logic dictated neoadjuvant trials.5 The preliminary trials showed promise, with pathologic complete remissions6,7 in 20% to 30% of patients. A plethora of phase II trials of neoadjuvant MVAC followed, and at a 1989 conference the consensus was that further phase II testing was not necessary, but rather phase III trials were strongly encouraged. Many attendees marshaled sufficient institutional and cooperative group resources to initiate and complete phase III trials. The largest trial was a joint effort of the United Kingdom’s Medical Research Council, the European Organization for the Research and Treatment of Cancer, and a number of other groups. Reported in 1996 and published in 1999, that 976-patient trial showed a marginal survival advantage (P = .075) after three cycles of neoadjuvant methotrexate, vinblastine, and cisplatin (MVC; without doxorubicin and with a higher cisplatin dose compared with MVAC) and definitive local therapy compared with definitive local therapy alone. The projected 5-year survival rate with neoadjuvant MVC was 52%. Meanwhile, Logothetis et al8 had elected to conduct a trial with a less difficult randomization, namely to neoadjuvant or postoperative adjuvant MVAC. In this issue of the Journal of Clinical Oncology, that neoadjuvant trial is reported in its final form by Millikan, Dinney, Swanson, Sweeny, Ro, Smith, Williams, and Logothetis (recently funded with the first Specialized Program of Research Excellence grant in bladder cancer).9 The authors convincingly argue that the expected survival would be only 20% to 30% given the high frequency of obstructive nephropathy, nonclassical histology, and high-stage disease. The study was designed to detect a 20% improvement (60% v 80%) in survival for two cycles of neoadjuvant and three cycles of postcystectomy adjuvant MVAC, compared with five cycles of adjuvant MVAC after radical cystectomy chemotherapy. This difference was not found; there was an equal number of deaths per arm and the surgical margin positivity rate was lower with neoadjuvant MVAC. There was an overall cancer-free survival rate of 58% of all patients after a follow-up of 6.8 years. Furthermore, 40% of patients given two cycles of neoadjuvant MVAC (25 of 63) had no evidence of muscle-invasive disease (the so-called no pathologic evidence of disease [p0] state). This achievement of a pathologic complete response is clearly a very good sign and has been noted repeatedly with neoadjuvant therapy. On the basis of these results, the M.D. Anderson Cancer Center group in Houston, TX, has adopted a preoperative chemotherapy approach as standard treatment for locally advanced bladder cancer. With the Medical Research Council and Millikan et al trials both suggesting benefit from neoadjuvant MV(A)C, the third trial to emerge from that 1989 meeting, a trial conducted by Natale et al10 for the Southwest Oncology Group (SWOG) and other United States cooperative groups, has been long awaited. SWOG 8710 (Intergroup 0080) was first presented at the plenary session of the 2001 Annual Meeting of the American Society of Clinical Oncology.10 It reported a 5-year survival rate of 57% after three cycles of neoadjuvant MVAC/cystectomy versus 42% with cystectomy alone (P = .04). With a median follow-up of 7.1 years, the median survival was nearly doubled by neoadjuvant MVAC (6.2 v 3.8 years). Furthermore, 37% of patients achieved the p0 state (nearly identical to that of the Millikan trial), which was associated with a high (> 90%) disease-free survival rate in that group. Importantly, there was no chemotherapy-associated mortality or increased surgical complications with neoadjuvant MVAC. The consistently good survival results of the three studies are impressive and add to the credibility of each.9-11 The Millikan trial probably had the largest fraction of truly poor-risk patients, since the investigators selectively excluded T2 (muscle-invasive only) disease. Surgery alone can achieve only a 50% to 60% cure rate in the absence of node positivity.12 So how does neoadjuvant MVAC continue on its long and winding road forward? First, advanced-stage (T3/T4) nonmetastatic bladder cancer is rare. A major center, such as M.D. Anderson, was only able to accrue 11 to 12 patients per year; only cooperative group trials can be readily recommended in the future. Second, the most obvious follow-up to this trial would be to build on the neoadjuvant approach. Both SWOG and M.D. Anderson have judged it superior in patient tolerance and efficacy. The difficult trials of "upfront" randomization to chemotherapy or no chemotherapy have been completed. For example, the Eastern Cooperative Oncology Group attempted to compare adjuvant MVAC to paclitaxel plus carboplatin but had to close the trial because of insufficient accrual. It should now be considerably easier for patients and physicians to enter patients onto trials in locally advanced bladder cancer. Using MVAC followed by cystectomy as the new standard of care will allow clinical trialists to ask other critical questions, such as how to increase the p0 rate or how to further decrease the 40% to 50% death rate. Although others will disagree,12 I would maintain the MVAC for three cycles/cystectomy neoadjuvant approach and begin to focus on adding new drugs or combinations in the postoperative setting (such as gemcitabine or one of the taxanes). Third, the molecular markers that predict the achievement of the p0 state need to be defined.13 The Millikan et al9 trial will also lend support to the multicenter phase III adjuvant trial in which patients with p1 or p2 disease after cystectomy are being randomized to observation or adjuvant MVAC if the tumor is p53-positive (University of Southern California; R. Cote, MD, principal investigator). In conclusion, the weight of the available medical evidence suggests that neoadjuvant MVAC should be used for this uncommon stage of bladder cancer. The way forward on this long and winding road is clearer, thanks to these investigators. REFERENCES 1. Yagoda A: Phase-II trials in patients with urothelial tract tumors: Memorial Sloan-Kettering Cancer Center. Cancer Chemother Pharmacol 11: S9-S12, 1983 (suppl) 2. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 133: 403-407, 1985[Medline]
3.
Saxman SB, Propert KJ, Einhorn LH, et al: Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 15: 2564-2569, 1997 4. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8: 1050-1055, 1990[Abstract]
5.
Herr HW, Bajorin DF, Scher HI: Neo-adjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: Ten-year outcome. J Clin Oncol 16: 1298-1301, 1998 6. Splinter TAW, Scher HI, Denis L, et al: The prognostic value of the pT-stage of the primary tumor after chemotherapy for patients with invasive bladder cancer. J Urol 147: 606-608, 1992[Medline] 7. Vogelzang NJ, Moormeier JA, Awan AM, et al: Methotrexate, vinblastine, doxorubicin and cisplatin followed by radiotherapy or surgery for muscle-invading bladder cancer: The University of Chicago experience. J Urol 149: 753-757, 1993[Medline] 8. Logothetis C, Swanson D, Amato R, et al: Optimal delivery of perioperative chemotherapy: Preliminary results of a randomized, prospective trial of preoperative and postoperative chemotherapy for invasive bladder carcinoma. J Urol 155: 1241-1245, 1996[Medline]
9.
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 10. Natale RB, Grossman HB, Blumenstein B, et al: SWOG 8710 (INT-0080): Randomized phase III trial of neoadjuvant MVAC + cystectomy versus cystectomy alone in patients with locally advanced bladder cancer. Proc Am Soc Clin Oncol 20: 2a, 2001 (abstr 3) 11. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet 354: 533-540, 1999[Medline]
12.
Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19: 666-675, 2001 13. Cote RJ, Esrig D, Groshen S, et al: p53 and treatment of bladder cancer. Nature 385: 123-125, 1997[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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