Ignoring Level 1 Evidence in Invasive Bladder Cancer: Is Ignorance Bliss?

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Derek Raghavan, MD, PhD

Until someone shows (for the first time) that there really is an overall survival benefit from the use of adjuvant chemotherapy after cystectomy [for invasive bladder cancer], our only proven approach is the use of neoadjuvant treatment with MVAC or CMV.

Derek Raghavan, MD, PhD

I’ve been part of the uro-oncology community for more than 30 years and have been proud to be involved in a good number of well-powered, enthusiastically subscribed randomized clinical trials. These have dated back to a time before randomization was necessarily the fashion.

I have had the pleasure of helping to design or simply participating in randomized studies that proved: (a) a survival benefit from MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) compared to cisplatin for metastatic bladder cancer, (b) GCT (gemcitabine, cisplatin, paclitaxel) doesn’t offer a major benefit over GC (gemcitabine, cisplatin) for metastatic bladder cancer, (c) continuous androgen blockade is superior to intermittent androgen blockade for metastatic prostate cancer if survival is the key endpoint, and (d) bleomycin confers a survival benefit when added to vinblastine/cisplatin for patients with advanced testis cancer, among others.

I have even sunk to the depths of meta-analysis, a poor man’s randomization surrogate, to show the modest benefits of maintaining combined androgen blockade compared to monotherapy in advanced prostate cancer. Thus, my portfolio of approaches used in clinical practice is heavily dominated by evidence-based strategies, at least for first-line therapy.

This is why something that I see increasingly in the management of invasive bladder cancer puzzles me.

Neoadjuvant Data

In the early 1980s, Dr. Mark Soloway and I, working independently, demonstrated anticancer efficacy of neoadjuvant single-agent cisplatin for patients with invasive bladder cancer, but a randomized trial that Dr. David Wallace and I reported did not show a survival benefit. We figured that the early survival data from our phase II studies might simply have reflected the impact of CT scanning with associated stage migration.

Soon thereafter, multicenter working parties conceived two important randomized trials, testing the survival benefit of either neoadjuvant MVAC before cystectomy or CMV (cisplatin, methotrexate, vinblastine) before either cystectomy or radiotherapy for invasive, clinically nonmetastatic bladder cancer. Both studies showed a survival benefit, although the first report of the CMV trial showed only a 5% hike in survival, which was less than the desired 10% in the initial design. As a result, we recorded it as a “negative” study in the interim report.1

However, it was clear that the MVAC trial showed an increment in median survival of 3 years and an absolute survival increment of 7%.2 The most recent (final) report of the CMV trial confirmed the impact of neoadjuvant combination chemotherapy with a reduction in hazard ratio of 16% and an overall survival benefit of 7%.3 As if that wasn’t enough, our meta-analysis of all of the published data reached the same conclusion.4

Despite this wealth of level 1 evidence to confirm the survival benefits of neoadjuvant CMV or MVAC chemotherapy prior to surgery or radiotherapy, four surveys over the past 10 years have shown that less than 25% of patients are treated according to this strategy.5-8 One could reasonably discount the first two reports as they reflected time periods when the mature randomized data had not yet been published, but the two more recent studies show little improvement.

Puzzling Practice

So why is potentially lifesaving treatment withheld? Most of my colleagues in the world of urology seem pretty up to date with the literature.  Perhaps they think they can avoid chemotherapy by doing a radical cystectomy first and applying adjuvant chemotherapy for particularly tough tumors. That really can’t be the explanation because no well-powered, randomized trial has ever shown an overall survival benefit for that strategy. The closest to a positive result came from the Stanford group, which showed an improved disease-free interval, but the Data and Safety Monitoring Committee closed the study at that point, and no overall survival benefit was shown.

The European Organisation for Research and Treatment of Cancer (EORTC) attempted to answer this important question, but the study closed prematurely because of lack of accrual. Our team at the University of Southern California, under the leadership of Dr. Don Skinner and Dr. Richard Cote, and in collaboration with the Southwest Oncology Group (SWOG), assessed the utility of p53 mutation as a predictor of outcome in a trial that compared adjuvant MVAC to observation after radical cystectomy for patients with p53-mutant urothelial cancer.9 While the study had some problems of execution, and fewer events than anticipated in design, it was quite clear that there was no difference in outcome for p53-positive and p53-negative cases. More importantly, there was no difference in survival between the two treatment groups—thus, nothing to support the routine use of adjuvant MVAC in this contemporary study.

Proven Approach

Patients with bladder cancer are generally very much inclined to take the advice of their clinicians and, as such, are rather different from some other groups of patients with urologic malignancy. Urologists, the gatekeepers of bladder cancer, have a huge influence on their patients with this disease, with respect to both the choice of primary therapy and the role of adjunctive treatments, and even regarding therapies at the time of relapse.

Until someone shows (for the first time) that there really is an overall survival benefit from the use of adjuvant chemotherapy after cystectomy, our only proven approach is the use of neoadjuvant treatment with MVAC or CMV. While gemcitabine/cisplatin has been shown to be approximately equivalent to MVAC in patients with metastatic disease, that similarity has never been confirmed in a well-powered randomized trial for the neo-adjuvant or adjuvant setting. One must remember that in an underpowered study comparing two treatments, a nonsignificant P value may simply reflect the fact that the sample size is too small to show the existence of a true difference in survival; it doesn’t necessarily mean that the outcomes are the same.

So now what? I guess I will go and write a paper on this topic for a urology journal. Let’s hope, for our patients’ sake, that somebody reads it. ■

Disclosure: Dr. Raghavan is on the President’s Advisory Board of Sanofi Aventis and is an occasional consultant for Gerson Lehrman.


1. Hall R, Sylvester R, Raghavan D, et al, for International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet 354:533-540, 1999.

2. 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.

3. Griffiths G, Hall R, Sylvester R, et al, for International Collaboration of Trialists: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 Trial. J Clin Oncol 29:2171-2177, 2011.

4. Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 361:1927-1934, 2003.

5. David KA, Milowsky MI, Ritchey J, et al: Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: A report from the National Cancer Data Base. J Urol 178:451-454, 2007.

6. Miles BJW, Fairey AS, Eliasziw M, et al: Referral and treatment rates of neoadjuvant chemotherapy in muscle-invasive bladder cancer before and after publication of a clinical practice guideline. Can Urol Assoc J 4:263-267, 2010.

7. Porter MP, Kerrigan MC, Donato BM, et al: Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol 29:252-258, 2011.

8. Raj GV, Karavadia S, Schlomer B, et al: Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer. Cancer 117:276-282, 2011.

9. Stadler W, Lerner SP, Groshen S, et al: A phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on P53 status. J Clin Oncol 29:3443-3449, 2011.