UI study of alternative treatment for bladder cancer offers effective solution to critical drug shortage
A chemotherapy regimen developed at the University of Iowa for the treatment of high-risk cases of non-muscle invasive bladder cancer (NMIBC) has shown promising signs of effectiveness and tolerability at a time when urologic oncologists are in dire need of an alternative to the drug that is used as the standard treatment, which is in short supply worldwide.
The study, which was conducted by a team of researchers in the UI Department of Urology, analyzed follow-up data from the cases of 107 UI Hospitals & Clinics patients with high-risk NMIBC who were treated with gem/doce instead of BCG from 2013 to 2021. The analysis revealed that 82% of those patients remained cancer-free two years after treatment. Less than 4% of those patients were unable to tolerate a complete course of treatment.
“These results for patients treated with gem/doce are significantly better than what we’ve seen in historical data for BCG, which is the current gold standard,” says Vignesh T. Packiam, MD, clinical assistant professor of urology and lead author of the study. “Historically, two-year cancer-free rates for BCG are about 60 to 65%. Some modern series of BCG show efficacy in the 80 to 85% range, which is on par with the gem/doce results in our study.”
Packiam says that in the context of the ongoing, long-term shortage of BCG, the results point to gem/doce as “an effective and readily available alternative.”
One of Iowa’s most-diagnosed cancers
The National Cancer Institute estimates that about 81,000 new cases of bladder cancer will be diagnosed in the U.S. in 2022. In its annual report on cancer, the Iowa Cancer Registry of the UI College of Public Health estimates that bladder cancer will rank sixth among the most-diagnosed new cancers in Iowa this year.
NMIBC is an early form of bladder cancer and accounts for about 75% of all new bladder cancer cases. In NMIBC, the tumor cells are situated in the mucosa, which is the innermost layer of the bladder wall. About 25% of all NMIBC cases are considered high-risk, meaning the tumor cells are much more likely to grow beyond the mucosa and into the bladder’s muscle layer. From there the cancer has the potential to take root and spread to other areas of the body.
For nearly five decades, the conventional therapy for high-risk NMIBC has been surgical removal of the tumor followed by intravesical BCG to kill any tumor cells that remain in the bladder. An intravesical treatment is administered directly into the bladder through a catheter, as opposed to an intravenous treatment, which is administered via the blood stream.
Since 2011, manufacturing challenges have limited the available supply of BCG. That situation worsened in 2017 when one of the major manufacturers of the drug stopped producing it, leaving many health care providers unable to provide the established standard of care for their NMIBC patients or offer effective alternative therapies. Single-agent chemotherapy regimens have been studied extensively and are well-known to treat cancer less effectively than BCG, but without a supply of BCG, urologists have been forced to use those suboptimal treatments.
of all new bladder cancer cases are NMIBC
of all NMIBC cases are considered high-risk
O’Donnell began using intravesical gemcitabine in his practice after reading studies that reported modestly favorable outcomes and low toxicity when the drug was used to treat NMIBC. The initial results in his patients looked promising, O’Donnell says, but one-year cancer-free rates were under 20%. He began searching for drugs to pair with gemcitabine that would boost the overall effectiveness in killing cancer cells while keeping levels of toxicity low.
That work led eventually to the development of the gem/doce regimen, which soon became the primary treatment at UI Holden Comprehensive Cancer Center for NMIBC patients for whom BCG had failed—effectively rescuing about 50% of patients who otherwise would have needed to have their bladders removed.
The cost of the treatment was an additional benefit for Holden patients: Both drugs used in the regimen are low-cost generics.
Leading cancer centers adopt innovative UI alternative
With the onset of the global BCG shortage, the next step in the development of gem/doce was to apply it as first-line therapy in place of BCG, an effort that culminated in this most recent study published by Packiam and the UI team. Although the regimen has been used at Holden for more than a decade, and UI Department of Urology researchers first reported on their results using the treatment for BCG failures in 2014, Packiam says this latest study is a significant milestone toward replacing BCG.
“A lot of patients don’t have access to BCG, and before this study was published, a lot of these patients really didn’t have an effective alternative,” Packiam says. “Now, for the first time in almost 50 years, we have what appears to be a viable alternative.”
Since O’Donnell began his work on alternative chemotherapy approaches to treat NMIBC, urologic oncologists at some of the nation’s leading cancer centers, including Harvard University, Johns Hopkins University, and MD Anderson, have introduced the regimen to their patients.
Earlier this year, Packiam co-authored an article published in AUA News that reported the results of a survey of North American urologic oncologists in which 71% of the 198 respondents confirmed that they had prescribed gem/doce for NMIBC in the previous year. The authors estimated that at least 1,300 NMIBC patients are now receiving the UI-pioneered regimen annually.
Continuing work to help more NMIBC patients
Packiam says investigations into the efficacy of the gem/doce regimen will continue. Potential areas of study include its use in treating intermediate-risk NMIBC. And because this study was a retrospective analysis, verifying the value of the regimen will require prospective studies, many of which are already being planned at multiple institutions, including a large randomized prospective study comparing gem/doce and BCG.
The UI team is also studying other promising multi-agent chemotherapy treatments for NMIBC and working on identifying biomarkers that will help physicians decide which of multiple treatments would most likely benefit an individual NMIBC patient.
Along with Packiam and O’Donnell, the UI Department of Urology research team included Ian McElree; Ryan L. Steinberg, MD; Alex C. Martin, MD; Jordan Richards, MD; Sarah L. Mott; Paul T. Gellhaus, MD; and Kenneth G. Nepple, MD.
The study was funded in part by the John & Carol Walter Family Foundation and the UI Carver College of Medicine.