New in Bladder Cancer Treatment: An Effective, Accessible Chemotherapy Solution to the Global BCG Vaccine Shortages

The walls of the bladder are composed of an inner layer enveloped by a muscular outer layer.  "70% to 80% of bladder cancers are confined to the inner layer and are termed non-muscle invasive for the fact that they do not penetrate the muscular shell," says Dr. Leonard Gomella, chairman of the department of Urology at Thomas Jefferson University. He continues, "10-15% invade this shell and are termed muscle-invasive bladder cancers (MIBCs). The rest have spread beyond the bladder and are called metastatic bladder cancers."

Common Bladder Cancer Treatments

All bladder tumors, whether cancerous or benign, are initially managed with transurethral resection of bladder cancer (TURBT). TURBT uses specialized tools inserted into the bladder via the urethra. These tools remove and scrape the concerning tumors from the bladder walls. This procedure can be both diagnostic and therapeutic. It can tell physicians whether the tumor is cancerous or benign. In the case of NMIBCs, it is also a major step in the treatment as well.

Treatment of NMIBCs after TURBT, which can include chemotherapy or BCG vaccine, depends on the nature of the cancer. High-risk lesions necessitate further treatment while low-to-intermediate-risk lesions may be managed appropriately with TURBT alone. This risk depends on many factors, including tumor size, appearance under the microscope, and number of tumors, among others.

The Role of BCG Vaccine in Bladder Cancer Treatment

The BCG vaccine was originally developed as a vaccine against tuberculosis (TB). It was soon found to be effective against bladder cancers, which expanded its use. It is administered directly into the bladder.

"It is the standard of care for NMIBC ad is usually given as [initial] 6 weekly initial treatments followed by maintenance 3 doses every few months for 2-3 years. It is a very safe therapy with <5% chance of serious complications," notes Dr. Gomella.

A patient empties their bladder prior to receiving an infusion of the vaccine. They then hold the vaccine in their bladder for around 2 hours before urinating. This procedure may be repeated multiple times (usually once weekly for 6 weeks) before therapy is complete. Patients must take certain precautions prior to and after receiving each infusion. Additionally, the exact infusion protocol for BCG may differ between treating physicians. Studies have demonstrated that this therapy can eradicate bladder cancer in almost 70% of patients.

BCG Supply Shortages

The supply of the BCG vaccine has been hit with multiple setbacks for more than a decade. Articles, such as "cancer drug shortage sends patients on grim search," have been repeatedly covered in the news. And for good reason.

Firstly, only a few companies produce the vaccine in concentrations required to treat bladder cancers. These companies have experienced unexpected difficulties with their production. For example, mold from floods caused one factory, the main supplier of the vaccine for North America and Europe, to shut down in Canada. The company subsequently exited the BCG market altogether.

The remaining suppliers, including the pharmaceutical giant Merck, have scaled up their production in response to such setbacks. However, this has not been enough to counterbalance the shortage for now.

In the face of these tribulations, the leading medical bodies on bladder cancer have modified their guidelines. "Currently, patients with low-risk bladder disease do not receive any BCG therapy. Those with intermediate-risk NMIBC are recommended chemotherapy alternatives, while those with high-risk cancers are prioritized for BCG therapy. Even with such rationing, it is sometimes necessary to use only half or one-third of the normal BCG dose because of the shortages," related Dr. Gomella.

An Effective Chemotherapy Combination Alternative

Dr. Gomella stresses, "historically, chemotherapy monotherapy [using a single chemotherapy drug] has not been highly efficacious."

Therefore, a chemotherapy combination, consisting of gemcitabine and docetaxel, was investigated as an alternative to BCG more out of need than anything else shortly after worldwide shortages of the vaccine. However, it was logical to study such a combination since chemotherapy drugs have a track record of efficacy in treating bladder cancer that comes back after initial BCG treatment.

The Iowa research study reported outcomes for 312 patients treated for high-risk NMIBC over a decade. 174 patients were treated with BCG, while 138 were treated with the gemcitabine-docetaxel combination. The study aimed to compare the efficacy of the two regimens. Recurrence-free survival (RFS), which is the time patients live without their cancer coming back, was used as the main efficacy metric. For the BCG population, the RFSs at 6 months, 12 months, and 24 months were 76%, 71%, and 69% respectively. For the same time points, the RFSs for the chemotherapy group were 92%, 85%, and 81%. Beyond its superior efficacy, the chemotherapy combination interestingly also led to less treatment discontinuation as compared to BCG (2.9% vs. 9.2%).

Chemotherapy Alternative Still Carries Side Effects

The effectiveness of the chemotherapy combination is exciting. However, the treatment does carry side effects, which should be discussed. These percentages of patients who experienced side effects in the study were comparable between the two study arms (29.4% for the BCG group versus 52.2% for those in the chemotherapy group. Most of these side effects were mild and easily manageable. Only 4% and 1.4% of the patients experienced significant side effects in the BCG and chemotherapy groups respectively.

The most common side effects for those who received chemotherapy include:

• Bladder spasms
• Pain with urination
• Urinary frequency
• Urinary urgency
• Joint paints

What Does This Mean for the Future of Bladder Cancer Treatment?

While the chemotherapy combination offers a viable, effective alternative to BCG treatment, it needs to be considered within the limitations of the study. Although the study includes many patients, an overwhelming majority of them were white. Whether this treatment combination is just as effective in other racial and ethnic groups is, therefore, an open question. Additionally, the study was a retrospective analysis, meaning that it looked back in time. This means that it lacked the rigor of clinical trials, which are the ultimate mettle test for new treatment combinations.

These limitations will likely be addressed by the recently launched phase 3 BRIDGE clinical trial, which will pit the gemcitabine-docetaxel combination against the BCG vaccine in a controlled, rigorous manner. However, it will be years before the results from this trial are published.

Nonetheless, the Iowa study builds a good case for using the gemcitabine-docetaxel combination for patients who cannot get BCG therapy due to its global shortage.

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