ADJUVANT CISPLATIN, VINBLASTINE AND METHOTREXATE CHEMOTHERAPY FOR BLADDER CANCER 499

12.

13.

14.

15.

16.

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muscle-invasive bladder cancer: long-term followup. J. Urol., 1 5 0 849, 1993.

Fair, W. R., Scher, H., Herr, H., Morse, M., Sogani, P., Bosh, G., Dershaw, D., Reuter, V., Curley, T. and Whitmore, W. F., Jr.: Neoadjuvant chemotherapy for bladder cancer: the MSKCC experience. Sem. Urol., 8 190, 1990.

Fossa, S. D., Harland, S. J., Kaye, S. B., Raghavan, D., Russell, J. M., Parmar, M. K. B., Uscinska, B. M., Wood, R. and the MRC Subgroup in Advanced Bladder Cancer: Initial combina- tion chemotherapy with cisplatin, methotrexate and vinblas- tine in locally advanced transitional cell carcinoma-response rate and pitfalls. Brit. J. Urol., 7 0 161, 1992.

Frassoldati, A., Federico, M., Barbieri, F., Brausi, M., Pollastri, C., Berri, G., Castagnetti, G., Palladini, P. P. and Silingardi, V.: Methotrexate, vinblastine, epidoxorubicin and cisplatin (M-VEC) in patients with locally advanced transitional blad- der cancer. Med. Oncol. Tumor Pharmacother., 8 99, 1991.

Paz-Ares, L., Lianes, P., Diaz-Puente, M., Rivera, F., Passas, J., Costas, P., Mendiola, C. and Co&s-Funes, H.: CMV front-line chemotherapy in transitional bladder carcinoma. Ann. Oncol., 4 147, 1993.

Kaufman, D. S., Shipley, W. U., Griffin, P. P., Heney, N. M., Althausen, A. F. and Efird, J. T.: Selective bladder preserva- tion by combination treatment of invasive bladder cancer. New Engl. J. Med., 3 2 9 1377, 1993.

Logothetis, C. J., Johnson, D. E., Chong, C., Dexeus, F. H., Ogden, S., von Eschenbach, A. and Ayala, A.: Adjuvant che- motherapy of bladder cancer: a preliminary report. J. Urol., 139 1207. 1988.

18. Skinner,-D.'G., Daniels, J. R., Russell, C. A, Lieskovsky, G., Boyd, S. D., Nichols, P., Kern, W., Sakamoto, J., Krailo, M. and Groshen, S.: The role of adjuvant chemotherapy following cys- tectomy for invasive bladder cancer: a prospective comparative trial. J. Urol., 1 4 5 459, 1991.

19. Stockle, M., Meyenburg, W., Wellek, S., Voges, G., Gertenbach, U., Thiiroff, J. W., Huber, Ch. and Hohenfellner, R.: 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., 1 4 8 302, 1992.

EDITORIAL COMMENT

The survival of patients with invasive bladder tumors treated with surgery alone has improved during the last 2 decades, partly due to refinements in preoperative staging and a marked decrease in sur- gical mortality. However, since the majority of deaths from bladder cancer are due to metastases, further improvements in survival required more effective chemotherapy. With the advent of multidrug cisplatin based combinations, long-term survival became possible for select patients with established metastases. The next question was how to integrate optimally chemotherapy with surgery.

Postoperative adjuvant chemotherapy is the preferred approach of many urological surgeons and medical oncologists because the deci- sion to recommend chemotherapy is based on pathological as Op- posed to clinical criteria, with the result that chemotherapy is likely to be administered to fewer patients who may not require it. Prop- nents also note the higher proportion of complete remissions and long-term cures in patients with nodal versus visceral sites,' and select clinical trials, randomized and nonrandomized, purporting to show a survival benefit.

This study is a randomized comparison of 4 cycles of postoperative CMV chemotherapy versus no chemotherapy in patients with stage p3b or p4 transitional cell carcinoma of the bladder. Patients ran- domized to no therapy were to receive chemotherapy at relapse. The chemotherapy was the most efficacious available a t the time the trial was designed, having been shown by these investigators to Produce a proportion of long-term cures, which is a prerequisite for improving survival (reference 8 in article).

Patient acceptance ofthe randomization was extremely high, since 55 of 56 seen during the 7 years (8 patients per year) were accrued. Of the patients 88% received 4 cycles. Comparing the chemotherapy versus nonchemotherapy treated patients, recurrence was noted in 52% versus 80%. with median intervals to recurrence of 17 and 11

median interval to recurrence was 37 versus 12 months (p = 0.01). Of the 19 patients with recurrence in the no chemotherapy group alone 15 (78%) received chemotherapy but only 10 (53%) received 4 or more cycles. However, when all patients were considered no survival ben- efit was observed.

The question is whether the data, including this study, supporting the use of adjuvant chemotherapy are conclusive and whether adju- vant chemotherapy should be considered a standard of care. The preferred clinical trial design to test the hypothesis of whether che- motherapy offers a survival benefit for patients with invasive blad- der cancer is a prospective comparison of patients randomized to receive or not receive treatment. The number of patients required to show a benefit with a predetermined power is based on the proba- bility of the event of interest occurring, in this case interval to relapse and overall survival, the "effectiveness" of the chemotherapy in decreasing that probability, and the interval during which that event is expected to occur. Fewer patients are required to show a benefit if the end point occurs frequently, the end point occum early and the chemotherapy is curative. This study was designed to detect a 30% difference in freedom from progression and an improvement in overall survival, for which it was estimated that 80 patients (40 per arm) would be required for a power of 0.90 at p = 0.05. Only 55 patients were enrolled and the reasons for termination were not clearly stated. In retrospect, the investigators were overly optimistic with respect to the efficacy of the chemotherapy regimen. Were the trial designed today, a more realistic estimate of the net benefit would be a 10 to 15% increment in survival, which is also clinically important but which would require approximately 400 patients to show a survival benefit with suflicient power.2 To date, none of the trials using combination chemotherapy reported to date included this number of patients (references 18 and 19 in article).3

In retrospect, the investigators were overly optimistic with regard to the rate of accrual despite the high rate of acceptance of the study. Even if one accepts the planned 30% improvement in survival as realistic, the study would have taken 10 years to complete. Given this long interval, it is likely that changes in medical practice would have occurred that would influence patient management. Examples affecting this trial include the availability of hematopoietic growth factors,4 which clearly decrease toxicities, and the identification of new active agents. This study and 2 other trials using combination chemotherapy

showed a delay in the interval to progression for chemother- apy treated patients (references 18 and 19 in articlel.3 All were terminated before reaching the planned accrual goal. Furthermore, the treatment of patients a t progression was not clearly stated in 2 studies (references 18 and 19 in article) and in 1 (reference 19 in article) the patients did not receive chemotherapy at relapse. The latter trial did not include a survival comparison. However, a benefit for chemotherapy treated patients would be expected, since those with relapse did not receive treatment. The present study clearly states that patients were to receive treatment at relapse, and a proportion were successfully salvaged. The absence of a survival benefit is probably due to this successful salvage therapy.

Given the response proportions observed with combination chemo- therapy in advanced disease, it is not surprising that postoperative chemotherapy can result in a significant delay in interval to progres- sion. Presented in this fashion, it is not unreasonable to offer treat- ments to patients with a high risk of recurrence. However, clinical practice based on small sample sizes can be hazardous and mislead- ing. Although the authors are meticulous in the comparison of pa- tient demographics and pathological parameters between the che- motherapy and nonchemotherapy treated patients, they could not have known about other prognostic factors that, if unequally distrib- uted between the 2 groups, may have produced the same outcomes independent of the chemotherapy administered. Two examples in- clude the proportion of tumors within each group that express the Rb protein,5.6 and the proportion of tumors that stain positive for p53, which in most cases represents a mutated gene product.7 These findings can significantly alter the prognosis of patients with stages Tis and T1 disease, as well as muscle infiltrating tumors.8 An im- balance in any of these factors may have explained the results.

The authors are to be congratulated for the meticulous conduction of a randomized trial in a difficult patient population who typically do not tolerate full doses of chemotherapy. Patient compliance and enrollment were excellent, which is a tribute to the treating team. It is clear. however, that future trials in this population will q u i r e a

months, res rnve ly . Considering the entire group of patients the multicenter approach, since the reported &sults to date leave many

500 ADJWANT CISPLATIN, VINBLASTINE AND METHOTREXATE CHEMOTHERAPY FOR BLADDER CANCER

questions unanswered and limit our ability to extrapolate the results to all patients with invasive disease.

Howard I. Scher Solid Tumor Service Memorial Sloan-Kettering Cancer Center New York, New York

1. Scher, H. I.: Chemotherapy for invasive bladder cancer: neoad- juvant versus adjuvant. Semin. Oncol., l?: 555, 1990.

2. Dalesio, 0.: Neoadjuvant chemotherapy in invasive bladder can- cer. Trial design and statistics. Prog. Clin. Biol. Res., 353: 57, 1990.

3. Stiickle, M., Meyenburg, W., Wellek, S., Voges, G. E., Rossmann, M., Gertenbach, U., Thiiroff, J. W., Huber, C. and Hohenfellner, R.: Adjuvant polychemotherapy of nonorgan- confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J. Uml., 16% 47, 1995.

4. Gabrilove, J. L., Jakubowski, A., Scher, H., Sternberg, C., Wong, G., Grous, J., Yagoda, A., Fain, El, Moore, M. A. and Clarkson, B.: Effect of granulocyte colony-stimulating factor on neutro- penia and associated morbidity due to chemotherapy for tran- sitional-cell carcinoma of the urothelium. New Engl. J. Med., 318 1414, 1988.

5. Cordon-Cardo, C., Wartinger, D., Petrylak, D., Dalbagni, G., Fair, W. R., Fuks, Z. and Reuter, V. E.: Altered expression of the retinoblastoma gene product: prognostic indicator in blad- der cancer. J. Natl. Cancer Inst., 84: 1251, 1992.

6. Lagothetis, C. J., Xu, H.J., Ro, J. Y., Hu, S. X, Sahin, A,, Ordonez, N. and B e n d i d , W. F.: Altered expression of retino- blastoma protein and known prognostic variables in locally advanced bladder cancer. J. Natl. Cancer Inst., 84: 1256,1992.

7. Cordon-Cardo, C., Dalbagni, G., Saez, G. T., Oliva, M. R., Zhang, Z. F., Rosai, J., Reuter, V. E. and Pellicer, A.: p53 mutations in human bladder cancer: genotypic versus phenotypic patterns. Int. J. Cancer, 66: 347, 1994.

8. Esrig, D., Elmajian, D., Groshen, S., Freeman, J. A., Stein, J. P., Chen, S. C., Nichols, P. W., Skinner, D. G., Jones, P. A. and

Cote, R. J.: Accumulation of nuclear p53 and tumor progres- sion in bladder cancer. New Engl. J. Med., 331: 1259, 1994.

REPLY BY AUTHORS

This commentary is thoughtful and balanced. We would add only a few points of clarification. The study was closed because the free- dom from progression end point was reached with fewer patients than originally anticipated (for example, there was almost a 3-fold improvement in the median time to relapse in the adjuvant CMV arm). As discussed, the statistical model did not account for the possible salvage of cases of recurrent or metastatic disease. Such long-term salvage of advanced cases was only documented in 1993 (reference 9 in article). In our trial the long-term survival of some patients with relapse made the survival end point unobtainable as originally developed. It is important to recognize that entering more patients in this circumstance would not necessarily produce a differ- ence in survival. For example, the national adjuvant trial for stage I1 testicular cancer showed a marked difference in freedom from pro- gression yet no difference in survival in a large cohort of patients.

Statistical significance for freedom from progression was reached with 54 patients entered, perhaps suggesting that the original esti- mates of anticipated differences were reasonable. What would have happened if there was no salvage of relapsing cases, as initially anticipated? If one makes the plausible assumption that those pa- tients would have had brief survival after relapse, we might still have found ourselves closing this study with 54 patients to prevent the ethical dilemma of continuing a study in which the adjuvant CMV arm showed improvement in survival as well as freedom from progression. Although many studies in cancer research are justly criticized for limited accrual, in our study statistical differences were observed with fewer than the anticipated number of patients. Nev- ertheless, we strongly endorse the concept that conclusions are more safely drawn with large numbers of patients. I t is for this reason that we have been so circumspect in our conclusions. Furthermore, we support the suggestion that multicenter trials be developed to test the value of adjuvant chemotherapy in patients with more limited stage disease. If such large scale trials are to be developed, prudence dictates tha t the same drug schedule, dose intensity and treatment duration should apply.