Navigating the BCG Shortage: Real World Impact of Reduced-Dose Induction on Bladder Cancer Treatment

Bladder cancer ranks as one of the most common malignancies worldwide. It is associated with high rates of morbidity and mortality, as well as substantial healthcare costs. Approximately 82,000 cases of bladder cancer are diagnosed annually in the U.S., with about 17,000 deaths. The majority of bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBCa), localized to the bladder’s inner lining and accounts for about 75% of all bladder cancer cases​​. Treatment of NMIBCa often involves transurethral resection, a procedure to remove the cancerous tissues, followed by additional therapy to reduce the risk of recurrence. BCG (Bacillus Calmette-Guérin) treatment is a key adjuvant therapy used in NMIBCa. BCG is a weakened strain of Mycobacterium bovis (related to Mycobacterium tuberculosis, which causes tuberculosis) and is most widely known as a vaccine for tuberculosis. When used for bladder cancer, BCG is administered directly into the bladder through a catheter in a procedure called intravesical therapy. The exact mechanism by which BCG combats bladder cancer is not fully understood, but it is believed to work by stimulating the immune system to attack bladder cancer cells. It’s particularly effective in reducing the risk of recurrence and progression of high-grade NMIBCa, especially carcinoma in situ. BCG treatment is typically administered once a week for six weeks, known as induction therapy. Maintenance therapy, involving additional BCG treatments, may be given over a longer period to further reduce the risk of recurrence. BCG is generally considered effective and safe, but it can have side effects, such as irritation of the bladder, blood in the urine, mild flu-like symptoms, and, in rare cases, more serious complications. Despite these potential side effects, BCG remains a cornerstone in the management of non-muscle invasive bladder cancer due to its efficacy in reducing recurrence and progression of the disease.

The global shortage of BCG, has significantly impacted patient care. This shortage has been ongoing since 2014 and has led to the adoption of less optimal alternative therapies due to the inability to obtain BCG which has only one supplier in North America. In a new study published in the Journal Cancers by David Ostrowski, Raju Chelluri, Matthew Herzig, Leilei Xia, Brian Cortese, Daniel Roberson, Thomas Guzzo, Daniel Lee, and led by Professor S Bruce Malkowicz from the University of Pennsylvania Health System investigated the efficacy of reduced-dose induction BCG therapy compared to the standard full-dose regimen. The authors conducted a retrospective cohort analysis. It included adult patients diagnosed with intermediate- or high-risk NMIBCa, treated between 2015 and 2020. The inclusion criteria were carefully designed to ensure a focus on patients most likely to benefit from BCG therapy. Patients were categorized into two groups based on the BCG dosage received: the full-dose induction group and the reduced-dose induction group. The allocation to these groups was primarily dictated by the availability of BCG, reflecting the real-world impact of the drug shortage. The study employed propensity score matching, a statistical technique designed to balance the two groups on numerous covariates, thereby reducing potential biases and confounding factors. This approach enhances the comparability of the two cohorts, making the study’s findings more robust. The primary endpoint was the recurrence of bladder cancer within one year of treatment completion, with recurrence-free survival serving as a key metric for assessing treatment efficacy.

The authors reported that among the patients who received the reduced-dose induction BCG, 38.6% experienced a recurrence of bladder cancer within one year, compared to 33.7% in the full-dose group. This difference, while seemingly modest, was statistically significant and suggests that reduced-dose BCG is less effective than the full-dose regimen in preventing short-term recurrence of NMIBCa. Furthermore, they reported that recurrences in the reduced-dose group tended to occur earlier than in those who received the full dose. This early recurrence pattern raises concerns about the long-term efficacy and potential impact on overall survival and bladder preservation. The findings underscore the critical nature of the BCG dosage in NMIBCa management, especially in patients at intermediate or high risk of recurrence and progression.

The implications of these findings extend beyond the immediate clinical outcomes. In the face of ongoing BCG shortages, the new study challenges the prevailing assumption that a reduced dose could be an acceptable compromise to stretch limited BCG supplies. While dose reduction may seem like a pragmatic solution, the potential for increased recurrence rates and earlier recurrences cannot be overlooked. The authors highlighted the urgent need for alternative strategies in managing NMIBCa, especially in resource-constrained settings and the necessity for more research into alternative intravesical therapies, dose optimization, and novel treatment approaches. Moreover, the findings advocate for a more nuanced understanding of BCG therapy, encouraging clinicians to weigh the risks and benefits of dose alterations carefully.The study also has broader implications for healthcare policy and drug supply management. The BCG shortage is a stark reminder of the vulnerabilities in the global pharmaceutical supply chain and the need for proactive strategies to prevent and mitigate such shortages. It stresses the importance of coordinated efforts among healthcare providers, pharmaceutical companies, and policymakers to ensure the availability of essential drugs like BCG. In conclusion, Dr. Malkowicz  and colleagues provided crucial insights into the management of NMIBCa in the context of the BCG shortage. It highlights the potential risks associated with reduced-dose BCG therapy and calls for a reevaluation of treatment strategies amid drug scarcities. The findings emphasize the importance of maintaining the standard BCG dose when possible and exploring alternative treatments when not.