Use of Adjuvant Chemotherapy (ACT) for Muscle Invasive Bladder Cancer (MIBC)

Despite the fact that there is not enough evidence in favour of ACT, it is still much in use as some clinicians prefer the adjuvant approach. The advantages of ACT include more accurate pathological staging post-surgery, avoidance of overtreatment in patients with earlier stage disease and no delay in surgery, especially for patients who do not respond well to chemotherapy. The disadvantages include delay of chemotherapy due to prolonged post-operative recovery and difficulty in monitoring chemosensitivity of primary tumour as there is no measurable disease. As such, the panel feels the need to review the data and make recommendations.

To date, few published randomised trials have been performed comparing ACT and observation.12,13,14,15In addition, these trials had small sample size and methodological limitations including early termination of trials, poor patient accrual and lack of recommendations regarding salvage chemotherapy for relapse or metastases. Chemotherapy regimens also differed among the trials and a substantial number of patients randomized to the chemotherapy arm did not receive chemotherapy or had less than two courses of chemotherapy.

There was no statistically significant improvement in overall survival (OS) in the trials that reported statistical comparisons between trial arms. 12,13,15DFS defined as the time from cystectomy until evidence of disease recurrence, was significantly prolonged in the ACT groups comparedwith controls.12,13,15Results of the trials found that patients with more involved nodes were at higher risk of recurrence or death. 12,14Only one of the trials found, on subgroup analysis, that chemotherapy has benefit in time to progression and survival in patients with one lymph node involved.12A meta-analysis based on 491 patients from six trials found an overall hazard ratio for survival of 0.75 (95% CI 0.60-0.96, p=0.019), suggesting a 25% relative reduction in the risk of death for chemotherapy compared to that of control.16However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy on the results of this meta-analysis isnot clear. Although there is unlikely to be any level 1 evidence supporting the use of ACT, there is other evidence of benefit in health outcomes. 17

It is unclear, at the moment, whether immediate ACT is superior to chemotherapy at the time of relapse. Although there are a few long term survivors with chemotherapy at relapse, this is very rare. In the largest trial to date, which involved 284 patients but was unfortunately stopped early due to poor accrual, immediate adjuvant cisplatin-based combination chemotherapy led to a statistically significant improvement in the secondary endpoint of progression-free survival (PFS) but a non-significant decrease in the primary endpoint of death.18The estimated absolute difference in 5 year PFS and OS was 17.3% (46.8% versus 29.5%) and 5.9% (53.6% versus 47.7%) between the two arms respectively.

Although there is no level 1 evidence to support the routine use of ACT in patients with MIBC, there is data that suggests consistent benefit, including large community-based health outcome research studies.8In addition, as there is some evidence of a statistically significant benefit with regard to DFS, it is reasonable to discuss with patients for whom an improvement of DFS is important, especially for patients with extravesical extension and/or nodal involvement. Patients should be well informed of the scarce data available and the possible benefits and risks of chemotherapy must be discussed.

There is also no evidence that more modern or carboplatin-containing chemotherapy combinations are as effective in the adjuvant setting and that patients ineligible for cisplatin should not receive adjuvant chemotherapy.

There is no data on cost-effectiveness of these recommendations.

Recommendations for ACT in MIBC

The SCAN Workgroup voted 4 to 3 in support of the adoption of the ESMO guidelines20(Supplemental Table 1). Two workgroup members support the use of EAU guidelines while one member preferred case by case individualized discussion for high risk patients.

There is unanimous agreement among the workgroup members that cisplatin-based chemotherapy is not recommended for routine use due to its limited clinical data and evidence. However, as many patients are referred only after surgery, ACT should be considered in patients with high risk of relapse, namely, those with extravesical extension and/or node positive disease due to the possible improvement in DFS.