Updated results of a randomized controlled trial of neoadjuvant cisplatin (C), methotrexate (M) and vinblastine (V) chemotherapy for muscle-invasive bladder cancer

Reviewer: Ryan Smith, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 20, 2002

Presenter: R.R. Hall
Presenter's Affiliation: MRC Clinical Trials Unit
Type of Session: Scientific

Background

Muscle-invasive bladder cancer continues to have a high rate of failure, with the majority with distant metastases. The use of chemotherapy, both in the adjuvant and neoadjuvant setting has been used to try to increase survival and decrease failure with mixed results. This is a randomized trial comparing a neoadjuvant regimen of cisplatin, vinblastine, and methotrexate to definitive treatment alone in muscle invasive bladder cancer. The results with shorter follow up have been previously published in Lancet 1999, 354, 533-40

Materials and Methods

976 patients were entered onto the study. All had T2 (G3) or T3-4a TCC <7cm
Arm 1-CMV x 3 cycles (cisplatin 100mg/m2 d2, methotrexate 30mg/m2 d1, 8, vinblastine 4mg/m2 d1, 8) followed by definitive therapy (radiation or cystectomy)
Arm 2-definitive therapy alone
Median FU of 4 years
Definitive therapy was not randomized and was by choice

Results

58% of the patients had T3 tumors
Type of definitive therapy was well-balanced between groups with approximately 40-45% receiving either surgery or radiation in both arms with approximately 10% receiving both surgery and radiation
80% of patients randomized to arm 1 received all 3 cycles of chemotherapy
OS at 7 years was 43% (CMV) vs. 37% (no CMV), p=.05
DFS at 7 years was 35% (CMV) vs. 29% (no CMV)
Metastatic free survival was 42% (CMV) vs. 34% (no CMV), p<.05
LR control was 34% (CMV) vs. 31% (no CMV)
There was no difference in the effect when comparing those patients who had surgery vs. those who underwent radiation therapy

Author's Conclusions

There is a likely survival benefit of approximately 6% with neoadjuvant CMV chemotherapy
This has not changed with longer follow up
There is no evidence of a difference in survival advantage of CMV between those treated with radiation or surgery

Clinical/Scientific Implications

Long term failure rate is relatively high in those patients with muscle invasive bladder cancer. The majority of patients fail distantly, and it has been postulated that up to 90% of patients have occult distant metastases at presentation. Although some studies have demonstrated increased DFS in patients treated with chemotherapy, this has not translated into a large gain in OS. Nor have these results been consistent. However, because of the high incidence of occult metastases, the high incidence of the development of eventual metastatic disease, and the increased DFS, most oncologists recommend chemotherapy as either a neoadjuvant or adjuvant treatment. The current study continues to support this practice, though it should be noted that the advantage achieved with chemotherapy is likely small. Although data comparing patients receiving cystectomy vs. those receiving radiation therapy was not presented, historical data has shown an advantage with surgery alone. Perhaps in a population treated definitively with surgery, this advantage of chemotherapy can be further exploited.

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