Bladder cancer breakthrough

O’Donnell began studying chemotherapy combinations that could maximize efficacy while minimizing toxicity. Sticking to that approach over two decades, he has devised an astonishing six new intravesical chemotherapy treatments, giving urologists an unprecedented number of new options to save bladders and keep patients cancer-free.

The centerpiece of that body of work is a regimen of sequential doses of two low-cost generics: gemcitabine and docetaxel (gem/doce) (pictured above). In 2015, O’Donnell and his UI colleagues published the first study of the therapy’s effectiveness. They described their success using gem/doce to treat 45 patients who had failed multiple courses of BCG. Two years after treatment, 34% of those patients—patients who otherwise would have been advised to have their bladders removed—were cancer-free.  

Urologists at leading cancer centers across the country, including Johns Hopkins, Harvard, and MD Anderson, were now turning to Iowa to learn about using gem/doce after BCG failures. At the same time, bladder cancer patients from around the world were traveling to UI Holden Comprehensive Cancer Center after learning about O’Donnell’s groundbreaking work.

As the UI program refined and improved the gem/doce regimen, O’Donnell began recommending the new therapy to most of his patients as a first-line therapy in place of BCG, which was often in short supply because of manufacturing problems. When BCG supplies went into a critical, long-term, worldwide shortage in 2019, the UI bladder cancer program weathered the disruption because it had already moved beyond sole reliance on BCG.

O’Donnell believes all programs should strive to do the same, and the UI program is paving the way for them.

“We have the most advanced early-stage bladder cancer program in the world,” he says.

“Everyone knows what gem/doce is now,” Packiam says. “And almost everyone is using it or wants to use it.”

To date, all the studies reporting on gem/doce outcomes have been retrospective, analyzing past patient data, and most of that data has come from UI Hospitals & Clinics patients. A UI study directly comparing gem/doce to BCG, published in in JAMA Network Open in February 2023, was also a retrospective analysis of UI patient data, and it showed that gem/doce was better than BCG in preventing recurrence of high-risk cancer in a population of 312 patients. In early 2023, however, a group of cancer research centers launched the BRIDGE clinical trial, a highly anticipated nationwide study that will recruit 870 NMIBC patients and conduct the first prospective, controlled, randomized comparison of BCG and gem/doce. 

“There’s already a huge waiting list of centers eager to get started,” says Packiam, who along with O’Donnell helped develop the study’s protocol. “There’s a lot of excitement about this trial.” 

Packiam serves as the UI’s principal investigator for the study, and he’s also one of the trial’s designated advocates, recruiting new centers and helping them get the protocol up and running. 

“If this trial shows the results that we think it will, that gem/doce is as effective as BCG, it has the potential to completely change how we’ve treated NMIBC since before 1980,” Packiam says. 

The BRIDGE trial likely won’t be completed for seven or eight years. Packiam is ready now to start moving bladder cancer care into its next era, building on the success of the UI program’s preceding 20 years of discovery. He already sees two promising directions that he is passionate about following.

The first is continuing the UI’s early work to personalize NMIBC care through genomics. With multiple treatments available, patients will receive better care if their doctors know in advance which therapy will likely work best for them.

“We’re looking at new biomarkers—in the urine, in the blood, or in the tumor—to predict if a patient is going to respond better to a particular treatment,” Packiam says. “I don’t think any other center is as well-equipped as we are to do that. We have the most experience and a huge bio bank of specimens.” 

His second passion is the development of a treatment-agnostic framework that clinicians can use to design care plans that optimize quantity and quality of life. 

“We can do all these new things to save a bladder,” Packiam says. “But will the bladder be functional? What will the patient’s quality of life look like, even after the cancer is gone? I think we’re in the best position to look at that new question, and I’m very interested in leading the charge.”

As O’Donnell surveys the bladder cancer program that Williams challenged him to build,  he sees it on a trajectory even he couldn’t have imagined back in 2000. 

“This is what you want your career to turn into,” he says. “You want it to take on a life of its own.” 

To illustrate the driving force that led to that, O’Donnell recalls a conversation that could have been lifted straight from the script of a TV medical melodrama. 

In 2013, he had run out of options for a patient who had a small tumor in his bladder. The best available treatments—including gem/doce—had failed to kill the cancer cells. The only realistic choice left was radical cystectomy. 

The patient refused. 

“He wanted a better choice,” O’Donnell says. “He looked me in the eye and said, ‘I have a tumor the size of a postage stamp, and you’re telling me I have to lose my bladder? No. Come up with something else.’” 

To most ears, that might have sounded like an unreasonable demand. For O’Donnell, it was a rallying cry. 

“A lot of the work I do is the direct result of heroic patients who stood up for what they believed in and put their trust in me to try something new,” he says. 

O’Donnell responded by devising another novel intravesical chemotherapy combination—valrubicin and docetaxel—that, to his knowledge, had never been used to treat NMIBC. 

It worked. The patient kept his bladder and a year later was cancer-free. O’Donnell has since used that regimen to treat dozens of patients who otherwise would have had no choice but to opt for a cystectomy. 

With that kind of inspiration, along with the generosity of the John and Carol Walter Family Foundation and other donors who support his program’s research, O’Donnell considers it his duty to keep pushing against the boundaries of what is possible. 

“If you believe in the motto of this institution—Changing Medicine, Changing Lives—you have to put your money where your mouth is,” O’Donnell says. “Otherwise you’re just doing the same thing as everybody else. Who wants to be average?”