Are there feasible alternatives to BCG for the effective treatment of bladder cancer?
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The BCG shortage has caused significant concern among both patients and providers as they consider their options for the treatment of nonmuscle-invasive bladder cancer. Because low-risk patients do not need induction intravesical therapy, and AUA guidelines recommend either BCG or chemotherapy for intermediate-risk patients, those most at risk for undertreatment during a BCG shortage are high-risk patients, for whom BCG is the preferred treatment.
However, there are therapeutic alternatives. Mitomycin C (MMC) appears to be the best option, with a recent meta-analysis finding no difference in disease recurrence compared with BCG (RR = 0.95; 95% CI, 0.81-1.11). Although a sub-analysis restricted to studies with maintenance therapy favored BCG (RR = 0.79; 95% CI, 0.71-0.87), the overall comparison may be more pertinent to the current crisis. Importantly, meta-analyses have found no difference in the critical endpoints of cancer progression, cancer-specific mortality or all-cause mortality between MMC and BCG.
Most head-to-head studies of BCG and MMC used lower doses of MMC than are recommended today (40 mg in 20 mL) without optimized delivery. The SWOG 8795 study, with induction plus 1 year of maintenance therapy, demonstrated that 50 mg of TICE BCG improved RFS over MMC, but this was a low MMC dose of 20 mg in 20 mL.
Notably, TICE BCG (which is the only strain available in the U.S.) has been found to be less effective than other BCG strains, with lower 5-year RFS than both Connaught BCG (48% vs. 74%; P = .01) and RIVM BCG (36% vs. 54%). Further, most studies demonstrating superiority of BCG over MMC used nonTICE BCG strains. The Dutch Southeast Cooperative Urological Group trial of induction therapy alone found MMC at a dose of 30 mg in 50 mL conferred better RFS than 50 mg TICE BCG (57% vs. 36%; P = .01).
When faced with a shortage of a less-effective form of BCG (TICE), optimized MMC is likely an excellent alternative. Finally, intravesical chemotherapy is not the only additional therapy to consider. Radical cystectomy should be considered for patients with multiple high-risk features (ie, T1 with lymphovascular invasion, carcinoma in situ and/or variant histology).
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Jonathan L. Wright, MD, MS, FACS, is associate professor of urology at University of Washington School of Medicine and an associate member in epidemiology at Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance. He can be reached at email@example.com. Disclosure: Wright reports research grants from Altor Biosciences, Merck, Movember Foundation and Nucleix and royalties from UpToDate.
There is a reason why researchers have been unsuccessful in developing alternatives to BCG, despite decades of trying: immunotherapy with BCG is extremely effective. In most contemporary series, the response rates for carcinoma in situ are approximately 70% to 80%, and BCG prevents recurrences among about 55% of patients with papillary disease. Additionally, in head-to-head studies, BCG significantly reduces not only recurrences, but also bladder cancer deaths compared with chemotherapy.
The current primary alternative to BCG immunotherapy is intravesical chemotherapy. Chemotherapeutic agents mitomycin, gemcitabine and epirubicin uniformly fall short of BCG when evaluated in well-designed, randomized controlled studies. For example, in EORTC 30911, with 837 eligible patients and median follow-up of 9.2 years, time to first recurrence (P < .001), time to distant metastases (P = .046), OS (P = .023) and disease-specific survival (P = .026) were significantly longer with BCG compared with chemotherapy. Similarly, in the most often quoted study to claim that chemotherapy is equivalent to BCG, mitomycin was only as effective as BCG when no BCG maintenance therapy was used, which is clearly the wrong way to administer BCG. Taking all of this into account, whenever there is a shortage of BCG and alternatives are used, we are — by definition — using second-best therapy.
Certainly, in times of BCG shortage, we have to offer our patients therapy that is appropriate for their disease state. Immunotherapy for cancer has exploded in recent years, and its utility is unquestionable for urothelial bladder cancer. These findings have also made the community aware that BCG is most effective when used precisely with respect to administration dose, scheduling and duration of therapy.
Unfortunately, there has been a worldwide shortage of BCG, and many patients have no access to this agent. Faced with this situation, we must make sure we offer our patients alternatives — and they do exist, with certain caveats. Thus, it is important that all patients with NMIBC be appropriately counseled and provided detailed information regarding their risk for recurrence and progression, and understand the difference between the two. For patients with high-risk NMIBC (high-grade disease, especially T1HG or carcinoma in situ), every attempt must be made to administer BCG induction and maintenance therapy, even if at a lower dose. For patients with intermediate-risk (ie, low-grade) disease, intravesical chemotherapy, especially if optimized with hyperthermia or combination chemotherapy, is appropriate because these patients are at low risk for disease progression.
I urge regulatory bodies to also recognize this fact: Most data suggest that BCG from different parts of the world produces clinical benefits when used for bladder cancer. BCG in these countries often is administered to infants as prophylaxis against TB, so these strains are safe.
Thus, we do have an alternative to BCG: BCG itself.
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Ashish M. Kamat, MD, MBBS, is professor of urologic oncology surgery at The University of Texas MD Anderson Cancer Center. He also is president of the International Bladder Cancer Group and co-president of the International Bladder Cancer Network. He can be reached at firstname.lastname@example.org. Disclosure: Kamat reports research funding from Bristol-Myers Squibb, FKD Industries, Merck and Photocure; educational funding from CEC Oncology; advisory board/consulting fees from Abbott Molecular, Arquer, Asieris, AstraZeneca, BioClin Therapeutics, Bristol-Myers Squibb, Cepheid, Cold Genesys, Eisai, Ferring, FKD Industries, IBCG, Imagin Medical, MDxHealth, Medac, Merck, Pfizer, Photocure, Roivant Sciences, Sesen Bio, Theralase, TMC Innovation and US Biotest; and a pending patent for CyPRIT-Cytokine Panel for Response to Intravesical Immunotherapy.