The use of chemotherapy as adjuvant or neoadjuvant treatment of localized, invasive transitional cell carcinoma (TCC) of the uroepithelium remains controversial, with no clear consensus in the literature. Survival of patients with invasive bladder TCC treated with cystectomy alone is overestimated in large series due to the inclusion of patients with recurrent but superficial TCC. The long-term survival rate with invasive cancer is less than 50%, and primarily dependent upon clinical stage.[1,2] Patients with invasive bladder TCC treated with trimodality bladder-preservation therapy instead of cystectomy appear to have comparable survival,[3,4] although the two approaches have never been compared in randomized trials.
The poor survival after local treatment for TCC, usually due to distant recurrence, has provided impetus for studies of systemic treatment before or after local treatment. Multiple randomized studies have been attempted, some with clear results, but many with either an ambiguous outcome or failure due to lack of accrual. Drs. Sonpavde and Lerner have comprehensively reviewed the clinical trials that have been carried out, particularly for neoadjuvant chemotherapy.
Chemotherapy in TCC
Using metastatic disease as a springboard for the evaluation of different chemotherapy regimens, experts in TCC have concluded that the current standard of care is GC (gemcitabine [Gemzar]/cisplatin) or MVAC (methotrexate/vinblastine/doxorubicin [Adriamycin]/cisplatin).[5,6] For the many patients with metastatic TCC and suboptimal renal function or other medical comorbidities, no clear treatment paradigm exists. Since carboplatin(Drug information on carboplatin) is inferior to cisplatin(Drug information on cisplatin) in the treatment of TCC, taxane-based regimens such as gemcitabine(Drug information on gemcitabine)/paclitaxel might be the most appropriate alternatives in nephron-challenged individuals.[7-9]
The majority of adjuvant or neoadjuvant chemotherapy trials have utilized cisplatin-based regimens as well. As Drs. Sonpavde and Lerner point out, the adjuvant trials have been small and inconclusive, or have failed to accrue sufficient patients. The ongoing European Organisation for Research and Treatment of Cancer (EORTC) study offers some hope that we may yet benefit from a large, definitive trial of adjuvant chemotherapy in TCC, but the hope is fading due to difficulty with accrual.
Clinical Trials in Neoadjuvant Chemotherapy for TCC
Four large published investigations of neoadjuvant chemotherapy in TCC have been considered at length individually, and as core components of numerous meta-analyses: the EORTC/Medical Research Council (MRC) trial, the Southwest Oncology Group (SWOG) trial, and the Nordic Cystectomy I and II trials.[10-13] Although improvements in pathologic complete response were observed, it is important to note that not one of these trials demonstrated a statistically significant survival benefit to neoadjuvant chemotherapy.
The largest trial was the EORTC/MRC study, which initially demonstrated a trend toward improvement in survival with CMV chemotherapy (cisplatin/methotrexate/vinblastine) compared to no chemotherapy among 976 patients. In a 2002 update, the investigators reported a statistically significant benefit of 5.5% after longer follow-up, though the findings have not been published.
Meta-analyses combining data from these and other smaller studies suggest a small but statistically significant benefit to neoadjuvant chemotherapy. Proponents of neoadjuvant treatment such as Drs. Sonpavde and Lerner point to the meta-analayses as proof of benefit, but the clinical significance of the small statistical finding remains dubious. In patients treated with bladder-preservation therapy, a Radiation Therapy Oncology Group (RTOG) randomized trial demonstrated that there was no benefit to neoadjuvant CMV chemotherapy.