Correspondence
Chemotherapy for Bladder Cancer
N Engl J Med 2003; 349:2272-2273December 4, 2003
- Article
To the Editor:
On the basis of their findings in a well-designed, randomized trial involving patients with muscle-invasive bladder cancer, Grossman et al. (Aug. 28 issue)1 conclude that neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), followed by radical cystectomy, improved survival, as compared with cystectomy alone. We want to point out some important considerations about the treatment received by patients in the control group (those treated with cystectomy alone).
First, 19 percent of patients in the cystectomy-alone group (30 of 154) did not undergo cystectomy according to the protocol, and no additional information about the alternative treatments given is provided. Although a similar proportion of patients in the chemotherapy group did not undergo surgery, they received at least M-VAC chemotherapy after transurethral resection. On the other hand, nearly two thirds of the patients had pathological stage T3 or T4a disease, and adjuvant cisplatin-and-doxorubicin–based chemotherapy should have been considered.2,3
In addition, the authors do not indicate whether the 77 patients in the cystectomy-alone group who died from bladder cancer received chemotherapy at the time of relapse. If they did, this fact might have substantially modified their survival in view of the results of M-VAC and other new chemotherapy regimens in patients with metastatic bladder carcinoma.4,5
5 ReferencesAlberto Muñoz, M.P.
José Ramón Barceló, Ph.D., M.D.
Guillermo López-Vivanco, Ph.D., M.D.
Hospital de Cruces, 48903 Barakaldo, Spain
amunoz@hcru.osakidetza. net 1
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 2003;349:859-866
Full Text | Web of Science | Medline2
Skinner DG ,Daniels JR ,Russell CA , et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective trial. J Urol 1991;145:459-464
Web of Science | Medline3
Stockle M ,Meyenburg W ,Wellek S , et al. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol 1995;153:47-52
CrossRef | Web of Science | Medline4
Sternberg CN ,Yagoda A ,Scher HI , et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response and relapse. Cancer 1989;64:2448-2458
CrossRef | Web of Science | Medline5
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 2000;18:3068-3077
Web of Science | Medline
To the Editor:
In their study evaluating neoadjuvant chemotherapy for locally advanced bladder cancer, Grossman et al. probably chose to prove an inordinately large improvement in median survival (50 percent) with a statistical power of only 80 percent and one-sided testing for one simple reason: to permit the use of a smaller sample. The result is a small study in which a two-sided P value of 0.05 is considered to indicate statistical significance, but it still does not definitively establish the role of neoadjuvant chemotherapy. It would have been preferable to adhere to the fundamentals of 90 percent power and two-sided statistics and to attempt to prove a more realistic 30 percent improvement in median survival. The frequency of follow-up after cystectomy and the systemic chemotherapy regimen received by patients in the cystectomy-alone group who had a relapse are not stated. It is possible that the patients in the cystectomy-alone group received inadequate follow-up. This suggests that they may not have received prompt and optimal chemotherapy on relapse, and a delay in chemotherapy may have affected their survival adversely.
Guru Sonpavde, M.D.
Anish Rawat, M.D.
Fahad Naveed, M.D.
Baylor College of Medicine, Houston, TX 77030
gurus@bcm.tmc. edu Author/Editor Response
Dr. Sonpavde and associates are correct in stating that, ideally, our study should have had greater statistical power to detect smaller differences. However, practicality often wins out, since it took 11 years to complete accrual for this study with its less stringent parameters. A one-sided test was specified because the hypothesis of interest is one-sided. Medical care would change only if the combined treatment were more effective than cystectomy alone. Identical follow-up instructions for the two treatment groups were specified in the protocol. Follow-up status for survival did not differ between the two groups.
Dr. Muñoz and associates raise several questions about patients who did not undergo cystectomy (30 patients in the group treated with cystectomy alone and 26 in the group treated with M-VAC and cystectomy). Of the 20 patients who did not undergo cystectomy as specified by the protocol for nonmedical reasons, 7 of the 10 randomly assigned to the cystectomy-alone group did undergo cystectomy outside the study, and 4 received M-VAC (neoadjuvant or adjuvant); 2 of the 10 randomly assigned to treatment with M-VAC and cystectomy underwent cystectomy outside the study, and 4 did not receive M-VAC. Another 36 patients did not undergo cystectomy for medical reasons (usually because of unresectable disease or nodal metastases). Sixteen of these patients were randomly assigned to neoadjuvant chemotherapy, but only nine received one full cycle or more of M-VAC. These data show that compliance with cystectomy (both within and outside the study) was similar in the two groups, and the M-VAC drop-in and drop-out rates may actually dampen the estimate of the true benefit of chemotherapy. The use of adjuvant therapy remains controversial and should not be considered the standard of practice.1
When patients had a relapse, physicians were encouraged to treat them according to current medical guidelines. We did not collect information on subsequent treatment for patients who had a relapse. The expected high rate of use of subsequent chemotherapy would potentially bias the results against the observed benefit of M-VAC, because patients who had not previously received chemotherapy might have been more likely to receive such therapy, and patients who had a relapse after receiving neoadjuvant chemotherapy might have had tumors that were more resistant to second-line treatment.
1 ReferencesH. Barton Grossman, M.D.
M.D. Anderson Cancer Center, Houston, TX 77030Cathy M. Tangen, Dr.P.H.
Southwest Oncology Group Statistical Center, Seattle, WA 981091
Juffs HG ,Moore MJ ,Tannock IF . The role of systemic chemotherapy in the management of muscle-invasive bladder cancer. Lancet Oncol 2002;3:738-747
CrossRef | Web of Science | Medline
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