Chemotherapy for Invasive Bladder Cancer: Five Simple Rules Learned Over 30 Years

Invasive, clinically non-metastatic bladder cancer has a cure rate of only 50%, when all T stages are considered. The pattern of relapse is dominated by systemic spread, provided that optimal surgery is practiced. Occult metastases are thus most likely to be present at first presentation. For more than 30 years, therapeutic strategies have focused on the use of systemic chemotherapy before, during or after loco-regional therapy to produce cure. More aggressive surgery and more precise radiation techniques in addition to improved chemotherapy have also been tested to improve cure rates. Genetic analysis has focused on prediction and prognostication, without yet having a major impact on outcomes. New agents have been tested in the neoadjuvant and adjuvant setting, but have not yet proven superior to standard algorithms, such as neoadjuvant MVAC chemotherapy. Many studies have tested ineffective metastatic regimens in the neoadjuvant setting without success, giving rise to the maxim that ignoring logical rules of investigation will not advance clinical practice. Leveraging molecular prognostication and immune responsiveness of urothelial cancer may produce the next era of progress. Five simple rules are proposed to guide the development of future studies.