Therapeutic Options in High-Risk Nonmuscle Invasive Bladder Cancer During the Shortage of Bacillus Calmette-Guérin

ABSTRACT

Bladder cancer is the second most common malignant tumor of the urinary tract and is the seventh most commoncancer among men worldwide and 17th among women. Seventy to eighty percent of bladder cancers arenonmuscle invasive bladder cancer (NMIBC) at the first diagnosis, and about 20%–25% of patients progress toinvasive bladder cancer. According to the EORTC (European Organisation for Research and Treatment of Cancer)risk classification study, patients with high-risk NMIBC (T1, high grade/G3, carcinoma in situ) have a 5-year recurrisk of up to 80% and a 50% chance of advance. Treatment options for high-risk NMIBC recommend BacillusCalmette-Guérin (BCG) intrabladder infusion therapy after transurethral resection of bladder tumor, and intrathecalbladder chemotherapy such as mitomycin C or epirubicin, or early radical bladder resection may also be consideredin recurrent high-risk patients. Among them, BCG intrathecal bladder infusion therapy has been demonstratedto reduce progression to mycoinvasive disease and has been used as a primary treatment for high risk NMIBCpatients. BCG intrathecal infusion therapy reported that less than 10%–20% of patients in the responding groupdeveloped myoinvasive disease, while 66% of the patients in the poor response group developed myoinvasivedisease. However, because BCG is made from Mycobacterium bovis, mass production is difficult due to a numberof factors, such as the strength, quality, purity, and potency of BCG vaccines that pharmaceutical companiesneed to control. Most of all, BCG vaccines are prone to bacterial contamination due to long incubation periodsand expensive specialized equipment. These factors eventually led to the closure of the Sanofi Institute for BCGvaccines in 2012, which continues the difficulties Merck has faced due to the lack of BCG supplies. BecauseBCG is a generic drug, the 2003 Medicare Modernization Act limited costs by up to 6% above the Medicareaverage selling price. Therefore, in 2016, Sanofi did not find any party to continue BCG’s manufacturing technologyand acquire the company, as a result, it announced that it will stop production in the United States, Canada,the United Kingdom, and France. In this article, we will discuss how to treat high-risk NMIBC patients underthese BCG deficiencies, along with some of the treatment options that can be implemented in cases of drugshortage.