The timing of chemotherapy when given as an adjunct to surgery has continued to provoke much debate over several years with proponents for neoadjuvant chemotherapy justifying their position on the basis of clinical trials such as SWOG 8710r and meta-analysis results as published by the ABC meta analysis collaboration;r whilst proponents for adjuvant chemotherapy criticise these trials for slow accrual, low patient numbers and lack of use of cisplatin/gemcitabine regimens. Proponents for adjuvant chemotherapy may prefer to offer adjuvant chemotherapy to high-risk patients such as T3 and T4 and/or node positive tumours. Meta-analyses have also demonstrated survival advantage when adjuvant chemotherapy is used.
The evidence supporting this protocol is provided by a phase III multicentre randomised trial involving 317 patients with invasive TCC of the bladder comparing neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) followed by radical cystectomy vs. radical cystectomy alone over an 11 year period.r Between August 1987 and July 1998, 153 patients were randomised to receive three cycles of neoadjuvant MVAC followed by radical cystectomy and 154 patients to cystectomy alone. The median age range was 63 years (39-84) and ratio male: female was 4:1. The primary endpoint was median OS and secondary end point was tumour down staging.
Radical cystectomy is the gold standard in the treatment of invasive bladder carcinoma (stage T2-T4a). However, after radical cystectomy for locally advanced bladder cancer, there is a significant stage dependant rate of recurrence (56% among patients with pathological stage T3) most commonly as distant metastases, indicating that predominant cause is occult micrometastases at the time cystectomy.rrr
Neoadjuvant therapy with MVAC has shown a significant pathological down-staging to pT0 in 34-38% vs. 9-15% of patients at the time of cystectomy (p<0.001/p<0.01).rrr This down-staging has resulted in an improvement in OS, in the SWOG 8710 trial where 85% of patients with pT0 were alive at 5 years.r
Neoadjuvant therapy with three cycles of MVAC has significant and clinically meaningful improvement in survival (risk of death reduced by 33%) that appears to be strongly related to downstaging of tumour to pT0 (38% of patients who received MVAC followed by cystectomy compared with 15% of patients with cystectomy alone p<0.001).rrr The 5 year overall survival (OS) was 57% vs 43% and median OS was 77 months and 46 months respectively. However, this improvement in survival for patients with locally advanced bladder cancer was not statistically significant (p=0.06).
Kaplan-Meier curves for overall survivalr
© The New England Journal of Medicine 2003
The table below lists the toxicities found in the patient receiving neoadjuvant MVAC followed by radical cystectomyr
© New England Journal of Medicine 2003