Initial studies of neoadjuvant classical MVAC showed a 23% absolute complete response improvement over cystectomy alone, however whilst there was a trend towards improved overall survival, this was not significant.r A subsequent 2005 meta-analysis of platinum-based neoadjuvant chemotherapy did demonstrate a statistically significant improvement in overall survival (see Kaplan-Meier curves below).r There has been further confirmation of this in a 2013 meta-analysis of chemotherapy in muscle invasive bladder cancer, which revealed an improvement in overall and disease free survival for both neoadjuvant and adjuvant treatment in separate analyses.r There has been no head-to-head trial of neoadjuvant and adjuvant chemotherapy.
Cisplatin-gemcitabine and ddMVAC regimens have been compared to classical MVAC in head-to-head trials in the advanced bladder cancer setting. Cisplatin-gemcitabiner and ddMVACrr were associated with no detriment in efficacy but much improved side effect profile. Similar trials in the neoadjuvant setting are lacking. The advantages that ddMVAC provide over classical MVAC include improved tolerability of the regimen and shorter duration of treatment, allowing quicker progression to cystectomy.
Kaplan-Meier curves for overall survivalr
© European Urology 2005
Blick et al retrospectively reviewed the records of 80 consecutive patients receiving a planned 3 or 4 cycles of ddMVAC neoadjuvantly for muscle invasive bladder cancer. Those eligible had T2-T4a disease, any nodal status, and no distant metastases. 75% of patients had cystectomy as definitive management; the remaining 25% underwent radical radiotherapy treatment.r
Complete (T0) pathological response was seen in 43% of those who underwent cystectomy. 2 year overall survival was 77% and 2 year disease free survival was 65%. Those who were node positive did considerably poorer than those who were node negative.
(A) Disease-free survival (B) Overall survivalr
Plimack et al conducted a phase 2 trial comparing the effects of ddMVAC with classical MVAC in the neoadjuvant setting utilising historical controls. 44 patients with T2-T4 (and either N0 or N1, but M0) bladder cancer with ECOG 0 or 1 were planned for 3 cycles of neoadjuvant ddMVAC which was completed 3 to 8 weeks prior to cystectomy. The primary outcome was pathological response, with secondary outcomes including safety parameters, side effect profile and survival.r
Complete (T0) pathological response was seen in 35% of evaluable patients (those who underwent cystectomy) compared to 38% seen in the Grossman et al trial using classical MVAC. Median follow up was too short to have meaningful survival results. The side effect profile was much more favourable; in particular 11% had a grade 3/4 neutropaenia compared with 54% in the standard MVAC trial.r