Use of Neoadjuvant Chemotherapy (NACT) for Muscle Invasive Bladder Cancer (MIBC)

Use of Neoadjuvant Chemotherapy (NACT) for Muscle Invasive Bladder Cancer (MIBC)

The use of NACT has several advantages, including better tolerability of chemotherapy prior to surgery, assessment of chemosensitivity of primary tumour prior to resection, and chemotherapy is given when the burden of metastases is low. However, there are disadvantages and these include delayed surgery, which might compromise outcome in patients who do not respond to chemotherapy and over-treatment, which is a possibility as clinical staging has an accuracy of only 70%. Another problem with regard to the use of NACT is that its uptake is low as surgeons and urologists do not consistently refer to medical oncologists for NACT tobegiven.

Randomised controlled trials1-4and meta-analyses5,6have demonstrated the efficacy of NACT in MIBC. The MRC/EORTC randomized trial of neoadjuvant Cisplatin/Methotrexate/Vinblastine (CMV) chemotherapy showed a survival benefit, with a reduction of risk of death by 16% (HR 0.84, 95% CI 0.72-0.99,p=0.037, corresponding to an increase in 10-year survival from 30% to 36%) from CMV.3,4The SWOG/Intergroup trial also showed improved survival for patients given NACT.7After approximately 8.5 years of follow-up, there was a 25% reduction in the risk of death for patients treated with Methotrexate/Vinblastine/Doxorubicin/Cisplatin (MVAC) prior to cystectomy (HR 0.75, 95% CI 0.57-1.00,p=0.06). Another randomised trial, the Nordic Cystectomy 1 trial, using NACT with Doxorubicin and Cisplatin, found a statistically significant effect of chemotherapy in patients with stages T3-T4a (five-year survival, 52% versus 37% for chemotherapy and control, p=0.03).8

In the most recent meta-analysis with updated independent patient data published in 2005, there wasa significant survival benefit associated with platinum-based combination chemotherapy (HR 0.86, 95% CI 0.77-0.95, p=0.003), equivalent to a 5% absolute improvement in survival at 5 years. There was also a significant disease-free survival (DFS) benefit associated with platinum-based combination chemotherapy (HR = 0.78, 95% CI 0.71-0.86, p < 0.0001), equivalent to a 9% absolute improvement at 5 years.

The randomised trials that have shown survival benefit utilise cisplatin-based combination chemotherapy which mainly included CMV or MVAC for three cycles. Thus, the regimens of CMV or MVAC should be considered standards. Newer less toxic regimens (Gemcitabine/Cisplatin or dose-dense MVAC) have been shown to be equivalent in the more advanced metastatic setting9,10but further data on them are still unavailable and are unlikely to be available in the neoadjuvant setting. Although it is unlikely that there will be level 1 data on the use of Gemcitabine/Cisplatin in the neoadjuvant setting, the ease of use and the better tolerability of this regimen make it a suitable alternative chemotherapy combination. In addition, the use of Carboplatin in substitution for Cisplatin is not advocated.

There is no data on cost-effectiveness of these recommendations, but an unsystematic estimate has suggested that NACT is associated with an increased cost of USD $6,000/quality-adjusted life year (QALY) gained.11

Recommendations for NACT in MIBC

The SCAN Workgroup has voted 5 to 2 support of the adoption of the EAU guidelines (Supplementary Table 1). Two of the workgroup members support the use of the ESMO guidelines.

There is unanimous agreement among the working group members that cisplatin-based chemotherapy is the standard of care for NACT. The EAU guidelines recommend cisplatin-based combination chemotherapy, without specifying specific regimens. Although there is no evidence to suggest that the newer chemotherapy regimens are as effective as the older ones in the neoadjuvant setting, the workgroup members do not exclude the use of the newer chemotherapy regimens due to better toxicity profiles.

The majority of the workgroup members agree with the EAU guidelines that NACT is not recommended for patients with poor performance status and/or impaired renal function.