What is the adjuvant therapy for muscle-invasive bladder cancer (MIBC)?

From the Guidelines

Adjuvant chemotherapy is recommended for patients with muscle-invasive bladder cancer (MIBC) who have undergone radical cystectomy, particularly those with pathologic T3/T4 disease or node-positive disease, with the preferred regimen being cisplatin-based combination chemotherapy, specifically gemcitabine plus cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) 1.

Key Considerations

• The choice between GC and ddMVAC should be based on patient tolerance and potential side effects, with GC being a reasonable alternative to ddMVAC based on category 1 evidence showing equivalence to conventional MVAC in the setting of advanced disease 1.
• For GC, the typical regimen is cisplatin 70 mg/m² on day 1 and gemcitabine 1000 mg/m² on days 1 and 8, repeated every 21 days for 4 cycles 1.
• For ddMVAC, the regimen includes methotrexate 30 mg/m² on day 1, vinblastine 3 mg/m² on day 2, doxorubicin 30 mg/m² on day 2, and cisplatin 70 mg/m² on day 2, repeated every 14 days with G-CSF support for 4 cycles 1.
• Treatment should begin within 90 days of surgery when possible.
• For cisplatin-ineligible patients (those with poor renal function, hearing loss, or poor performance status), immunotherapy with nivolumab or pembrolizumab may be considered.

Rationale

• Adjuvant therapy improves overall survival by eliminating micrometastatic disease that may be present after surgery, reducing the risk of recurrence by approximately 30% 1.
• Regular monitoring for side effects, including myelosuppression, nephrotoxicity, and neuropathy, is essential during treatment.
• Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy on a higher level of evidence data, with ddMVAC being preferred over standard MVAC based on category 1 evidence showing DDMVAC to be better tolerated and more effective than conventional MVAC in advanced disease 1.

From the FDA Drug Label

INDICATIONS Cisplatin Injection is indicated as therapy to be employed as follows: ... Advanced Bladder Cancer Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments, such as surgery and/or radiotherapy. The FDA drug label does not answer the question about adjuvant therapy for muscle invasive bladder cancer, as it only mentions cisplatin as a single agent for advanced bladder cancer that is no longer amenable to local treatments. 2

From the Research

Adjuvant Therapy for Muscle Invasive Bladder Cancer

• The use of adjuvant chemotherapy (ACH) in muscle-invasive bladder cancer (MIBC) has been investigated in several studies, with the goal of improving survival outcomes in patients treated with radical cystectomy (RC) 3, 4, 5.
• A systematic review and network meta-analysis of randomized clinical trials found that ACH was associated with significantly better progression-free survival (PFS) and overall survival (OS) than RC alone, with a pooled hazard ratio (HR) of 0.64 (95% CI, 0.49-0.85) for PFS and 0.79 (95% CI, 0.68-0.92) for OS 5.
• The gemcitabine/cisplatin/paclitaxel (GCP) combination was found to be the only ACH regimen associated with significant improvement in both PFS (HR, 0.38; 95% CrI, 0.25-0.58) and OS (HR, 0.38; 95% CrI, 0.22-0.65) in a network meta-analysis 5.
• However, other studies have found that the benefit of ACH in MIBC is still unclear, with some trials showing no significant difference in OS or disease-free survival between patients who received ACH and those who did not 4.
• Neoadjuvant chemotherapy (NAC) has also been investigated as a treatment option for MIBC, with studies showing that it can improve OS and PFS in patients with locally advanced disease 3, 6, 7.
• A systematic review and pooled meta-analysis found that neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with improved OS and PFS compared to gemcitabine and cisplatin, although treatment toxicity was greater with ddMVAC 7.

Treatment Options

• Neoadjuvant cisplatin-based chemotherapy, such as ddMVAC or gemcitabine and cisplatin, may be considered as a treatment option for patients with MIBC who are fit for cisplatin 3, 6, 7.
• Adjuvant chemotherapy, such as the GCP combination, may also be considered as a treatment option for patients with MIBC who have undergone RC 5.
• However, the optimal ACH regimen for MIBC is still unclear, and further studies are needed to establish the most effective treatment strategy 4, 5.