Results from the long-awaited clinical trial testing neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy against the gold standard of cystectomy alone for locally advanced bladder cancer were hotly debated at the recent American Society of Clinical Oncology meeting.
The reason, in part, was that the results ran counter to findings from seven prior studies. A meta-analysis had shown no survival advantage with neoadjuvant chemotherapy for muscle-invasive bladder cancer. And some researchers found the trials study design, accrual rate, and associated toxic effects controversial.
The rationale behind using neoadjuvant (preoperative) MVAC was to help shrink the tumor. Investigators also thought it would be better tolerated than adjuvant (postoperative) therapy because patients would not be worn out from undergoing a radical cystectomy.
In the plenary session, Ronald B. Natale, M.D., acting medical director of Cedars-Sinai Medical Center in Los Angeles, reported a median survival of nearly 75 months for patients treated with neoadjuvant MVAC compared with 43 months for those treated with cystectomy alone, which represents a 2.5-year survival advantage for the MVAC trial arm. Pathological studies revealed that bladder cancer was completely eradicated in 38% of patients who received MVAC.
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Trial Design
The Southwest Oncology Group study employed a one-sided trial design, which means that the study only tested the hypothesis that patients improved with the addition of MVAC; it did not test whether patients could do worse with the regimen.
Some statisticians argue that a one-tailed study design is not rigorous enough for therapies that are toxic and can even cause death. But the National Cancer Institutes Cancer Therapy Evaluation Program statisticians approved the trial design, and many SWOG and American College of Surgeons Oncology Group trials employ that design.
Brent Blumenstein, Ph.D., chief statistician for SWOG, and now chief statistician for ACOSOG, defended one-tailed testing: "Its one thing to design a trial so that it is one-sided, but quite another to choose a one-sided test to reach statistical significance. If you are asking a clinical question [such as whether or not an added therapy is better than standard care], a one-sided design is reasonable."
At a podium debate at the ASCO meeting, Dean J. Bajorin, M.D., medical oncologist from Memorial Sloan-Kettering Cancer Center, New York, pointed out that the SWOG trial was the largest trial in bladder cancer ever performed in the United States. He noted that it satisfied CONSORT criteria, the standards for reporting clinical trials that consider patient eligibility, treatment, randomization, primary outcomes measures, stratification, and use of statistical methods. As for the one-sided trial design, Bajorin acknowledged that "the one-sided design is not optimal, but it is not wrong."
Cora N. Sternberg, M.D., medical oncologist at the Vincenzo Pansadoro Foundation in Rome, argued against adopting MVAC as the new standard of care. Her position proved especially provocative because she had previously pioneered the use of MVAC chemotherapy at Memorial Sloan-Kettering with Alan Yagoda, M.D., and Howard Scher, M.D.
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Accrual Numbers
The SWOG trial represented a milestone in cancer clinical trials because it was one of the first to depend on the cooperation of medical oncologists and urologists for accrual. In the end, that very strength led to one of the studys major drawbacks, namely, a patient accrual rate of approximately two patients per month over an 11-year period.
"There were numerous changes in practice over that period," Sternberg said.
Sternberg also took issue with the SWOG enrollees accounting for just 10% of all the patients in neoadjuvant chemotherapy trials in the literature. Recognizing it as the only trial to demonstrate a benefit, "its value is uncertain," she offered.
This issue was raised by other medical oncologists and urologists, many of whom pointed to a 900-patient, two-sided randomized trial conducted by the Medical Research Council/European Organization for Research and Treatment of Cancer and led by Reginald R. Hall, M.D., of the University of Newcastle. That trial showed that "neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy did not give the 10% improvement in 3-year survival that was judged necessary to put it into routine use" (published in the Lancet in 1999).
Toxicity
Bajorin acknowledged that, despite worries that neoadjuvant MVAC would be poorly tolerated, toxicity proved "better than anticipated." However, this finding was at odds with oncologists experiences with MVAC: Many report that patients tolerate the combination poorly. Urologists also have been reluctant to use MVAC because it makes patients so sick, instead looking for a chemotherapy regimen that is better tolerated.
Michael Jewett, M.D., professor and chair of urology at the University of Toronto, doubted that neoadjuvant MVAC would take hold. "Adjuvant chemotherapy flows much better. It is much easier to do the surgery and get your patient adjuvant chemotherapy without having to send the patient to a cancer center and risk not getting him back again," he said. Jewett thought that the survival advantage is too small to alter practice.
In the United States, "MVAC will disappear quicker than it is coming in," predicted James Montie, M.D., urologist at the University of Michigan, Ann Arbor. "Mucositis and neutropenia are much more profound with MVAC than competing regimens," he said. "My bias is that, if MVAC is useful, then perhaps you can extrapolate that gemcitabine/cisplatin will work similarly."
Meanwhile, Sternberg is chairing an international randomized phase III trial coordinated by EORTC that will compare the survival of patients with stage T3 or T4 or node-positive bladder cancer randomly assigned after radical cystectomy to either immediate chemotherapy (four cycles) or delayed chemotherapy at relapse (six cycles). Each institution will select one of the three different regimens: classical MVAC, high-dose MVAC with growth factors, or gemcitabine/cisplatin, which will be given in both the immediate and deferred treatment arms.
Some observers expressed fear that, on the heels of the SWOG findings, it might prove difficult to launch a trial, at least involving U.S. enrollees. But at grand rounds discussing the SWOG analysis at the American Urological Association annual meeting last month, Jewett said that "the consensus was that the trial should go on."
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