Review of Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

By Vadim S. Koshkin, MD, and Petros Grivas, MD, PhD

The standard of care for patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based combination neoadjuvant chemotherapy (NAC) followed by radical cystectomy and lymph node dissection. Patients with this disease are at a significant risk for both locoregional and distant recurrence following definitive local therapy. NAC has been shown to reduce this risk, mainly by targeting micrometastasis that may be present even at the time of diagnosis.

Two major randomized phase III clinical trials and a large meta-analysis provide level I evidence supporting the use of cisplatin-based NAC in MIBC based on overall survival (OS) advantage.

CMV and MVAC as standard NAC regimens

The first of these phase III trials randomized 976 patients with high-grade cT2-T4a N0-NX M0 bladder cancer to receive either CMV (cisplatin, methotrexate, vinblastine) chemotherapy for three cycles or no chemotherapy, followed by local therapy with either cystectomy or radiotherapy. Long-term follow-up revealed an OS advantage at 10 years for patients receiving NAC (36 versus 30 percent). There was a statistically significant 16 percent reduction in the risk of death (HR 0.84; 95% CI 0.72-0.99, p = 0.037) for patients receiving CMV prior to local therapy.

Another major trial initiated by SWOG (8710) used MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) as the NAC regimen prior to radical cystectomy. It included 317 patients enrolled from 1987 to 1998 with stage cT2-T4a muscle-invasive bladder cancer who were intended to undergo radical cystectomy. Patients were randomized 1:1 to receive either three cycles of MVAC (28-day cycle) followed by radical cystectomy or radical cystectomy alone.

Intention-to-treat analysis revealed median OS in the MVAC plus cystectomy group to be 77 months as compared to 46 months in the cystectomy group (p = 0.06). More patients in the MVAC plus cystectomy group had pathologic complete response (pT0) at the time of cystectomy compared to patients who only had cystectomy (38 percent versus 15 percent, p < 0.001). Pathologic complete response was associated with 85 percent disease-free status rate at five years.

Finally, a large meta-analysis of 10 randomized clinical trials of NAC, published in Lancet in 2003, included 2,688 patients and compared platinum-based NAC (one trial included carboplatin, the rest cisplatin) plus definitive local therapy (cystectomy or radiation) to definitive local therapy alone. The results confirmed the OS benefit of platinum-based combination NAC. The five-year OS was 50 percent for patients who received platinum-based NAC prior to definitive local therapy compared with 45 percent for patients who received definitive local therapy alone (HR 0.87; 95% CI 0.77-0.97). The absolute benefit in recurrence-free survival was 7 percent for patients who received platinum-based therapy prior to definitive therapy (HR 0.81; 95% CI 0.74-0.90).

Muscle-invasive urothelial carcinoma

But not all qualify

Despite this level I evidence, not all patients qualify for cisplatin-based NAC. Patients must be carefully screened for cisplatin “candidacy/eligibility,” based on “consensus” factors, including the absence of decreased renal function (GFR < 50-60 mL/min), ECOG PS ≥ 2, NYHA ≥ class III heart failure, grade ≥ 2 neuropathy, and significant hearing loss (benefit-risk discussion should take place). There is no proven benefit for non-cisplatin-based perioperative chemotherapy in bladder cancer outside the context of clinical trial. Therefore, patients who may not tolerate cisplatin should be referred for clinical trials or proceed directly to local therapy. Adherence to level I current evidence is important for optimal patient care.

Gemcitabine/cisplatin is alternative NAC regimen, while gene expression and immunotherapy may come into play

There is plenty of retrospective comparative effectiveness data suggesting that gemcitabine/cisplatin may substitute for MVAC as NAC regimen. However, no robust prospective data exists in the NAC setting. The SWOG 1314 trial, utilizing four cycles of either dose-dense MVAC or gemcitabine/cisplatin (NCT02177695), may help us select the proper regimen for an individual patient in the future, since it evaluates the predictive value of a gene expression score (COXEN) generated at the time of transurethral resection of bladder tumor (TURBT). It is worth noting that dose-dense MVAC given every two weeks (with less dose intensity of methotrexate and with use of growth factor support) has been replacing conventional MVAC due to lower toxicity and shorter duration of chemotherapy; this NAC regimen is given for three to four cycles. Gemcitabine/cisplatin is typically given on a 21-day cycle, over three to four cycles (four cycles correspond to 12 weeks, which was the duration of NAC in the SWOG 8710 trial).

Interestingly, there are many novel clinical trials, e.g. with neoadjuvant immunotherapy and chemotherapy combination (NCT02365766) or immunotherapy alone (NCT02736266) that may generate potentially more treatment options for bladder cancer patients. We designed such a trial, which may open in the near future at Cleveland Clinic.

Additional data suggest the predictive value of DNA repair gene mutations in response to NAC, and clinical trials are being designed to validate prospectively the utility of those findings. Referrals for appropriate clinical trials are critical for the development of new safe and effective therapies.

Dr. Koshkin is a fellow and Dr. Grivas is associate staff in the Hematology & Oncology Department.