Radical cystectomy (RC) is considered the standard treatment for muscle-invasive bladder cancer (MIBC). However, the 5-year survival rate of patients with MIBC remains low at approximately 50%. To improve the oncological outcome, guidelines recommend cisplatin-based neoadjuvant chemotherapy for the treatment of patients with MIBC.[3, 4] Unfortunately, neoadjuvant chemotherapy is not widely used in routine clinical practice.
What is the cause of this discrepancy between clinical guidelines and routine practice? This might be caused by, at least in part, a short survival benefit provided by cisplatin-based neoadjuvant chemotherapy while patients have to endure severe toxicity. The second point might be a considerable delay to RC. It is well known that an interval of longer than 12 weeks between initial diagnosis of MIBC and RC results in a worse oncological outcome. The reported neoadjuvant regimens include at least three courses of chemotherapy whose response rates are approximately 70%.[3, 4] Thus, a number of patients are at risk of delay for RC because of severe toxicity, as well as at risk of disease progression. In addition, adverse effects associated with cisplatin-based regimens are problematic, particularly in elderly patients with a high prevalence of cardiovascular disease and renal dysfunction. This particular cohort of elderly patients with MIBC is rapidly increasing in size in Japan, which is also the case in Western countries.
To achieve a better outcome, the chemotherapy regimen should be less toxic and RC should be carried out immediately after the best response induced by neoadjuvant chemotherapy. To address these issues, we need to remind ourselves that there is no evidence that clearly supports the superiority of a cisplatin-based regimen against a carboplatin-based one in a neoadjuvant setting. The use of carboplatin instead of cisplatin in a neoadjuvant setting is supported by Steve Nicholson, who previously stated that “The perception that carboplatin-based combinations are inferior to cisplatin-based combinations is probably incorrect.”
Based on this situation, we designed a novel strategy including neoadjuvant gemcitabine plus carboplatin (GCarbo) chemotherapy (Fig. 1) followed by immediate RC.[8, 9] We knew from our preliminary study that this combination of chemotherapy was less toxic than gemcitabine plus cisplatin while preserving an identical antitumor effect. In addition, we knew that the duration of the antitumor effect of GCarbo was short, and the maximum response could be obtained immediately after the second course.
Our prospective single-arm study showed the safety and effectiveness of the GCarbo neoadjuvant chemotherapy followed by immediate RC. We enrolled 116 patients with histologically-proven MIBC, 44% of whom were ineligible for cisplatin. All participants received two courses of GCarbo chemotherapy. RC with pelvic lymph node dissection was carried out approximately within a month after the cessation of chemotherapy. The RC specimens of 28 (24.1%) patients were stage pT0. Over a median follow-up period of 41 months, the overall survival and disease-free survival rates were 89.7% and 86.3%, respectively (Fig. 2). No patient showed grade 3 or 4 gastrointestinal toxicity or renal function impairment because of the chemotherapy. We then confirmed the safety and effectiveness of GCarbo neoadjuvant chemotherapy in cisplatin-unfit patients using propensity score matching analysis. Most importantly, both neoadjuvant chemotherapy and RC were carried out by a urologist, which facilitated the shorter interval between diagnosis and RC. We believe that the shorter interval between diagnosis and RC is also beneficial for those who do not respond to chemotherapy.
To date, a number of clinical trials including molecular-target agents in neoadjuvant setting have failed to prove effectiveness. We need to keep in mind that the definitive therapy for MIBC is RC. Patients with MIBC should not be exhausted before definitive therapy. There is a possibility that neoadjuvant GCarbo could be beneficial, especially in cisplatin-unfit patients.