Hypofractionated Radiotherapy Plus ICI for Bladder Cancer Limited by Toxicity

Sophia Kamran, MD, discusses potential toxicities limiting the addition of immunotherapy to trimodal therapy for patients with urothelial cancer.

Sophia Kamran, MD, a radiation oncologist at Massachusetts General Hospital and assistant professor of radiation oncology at Harvard Medical School, discusses potential toxicities limiting the addition of immunotherapy to trimodal therapy for patients with urothelial cancer.

Trimodal therapy combines trans-urethral resection with chemotherapy and radiotherapy. According to Kamran, hypofractionated radiotherapy delivers a larger dose of radiation to shorten the length of radiotherapy treatment by a week or multiple weeks. She says patients prefer to undergo hypofractionated radiation therapy for a shorter time with fewer trips to a radiation center, and in addition, it is more cost-effective.

However, early data have shown unacceptable toxicity risks when combined with immune checkpoint inhibitors (ICIs). This includes a phase 1 trial [NCT03620435] of trimodal therapy plus atezolizumab (Tecentriq) from McGill University in which 4 out of 8 patients with muscle-invasive bladder cancer developed grade 3 gastrointestinal toxicities, including 2 who had received a lower dose of atezolizumab.

The ongoing large phase 3 randomized SWOG NRG 1806 trial (NCT03775265), which is comparing trimodal therapy plus atezolizumab versus trimodal therapy with chemotherapy alone in patients with localized muscle-invasive bladder cancer, did not include hypofractionation for this reason. Kamran says this is an important area of research to determine whether hypofractionated radiation can be used safely with ICIs.


0:08 | Another challenge that we're running into, or just needs to be further investigated, is when we use ICIs—because we are now incorporating that into our treatment—whether or not we can safely hypofractionate treating the bladder when we use that. The reason why I bring that up is because hypofractionated radiation therapy, which really involves getting a larger dose of treatment per day of radiation so we can actually shorten the treatment duration overall by maybe a week, or a couple of weeks, just depending on what regimen you use. That has been very popular, particularly in the [United Kingdom], and it’s been used in the United States as well. However, there [have] been some early data showing that if you use hypofractionated radiation therapy in combination with these ICIs, some of the data [show] that there’s some unacceptable toxicity risks, particularly related to gastrointestinal toxicity.

1:05 | At this time, in that very large phase 3 randomized trial…SWOG NRG 1806, we do not allow for hypofractionation, so patients get the standard fractionations. It is kind of a prolonged treatment and we like hypofractionated radiation because patients like it better, they do not have to come in so many times to the radiation center, they can really shorten the duration, it's cost effective, etc. But, at this time, there needs to be a little bit more investigation because it just appears that there [are] some dose-limiting toxicities when you're combining the 2 in the hypofractionated setting.