MCW Cancer Investigators Evolve Clinical Trial Design Evaluate Outcomes that Matter to Patients

Clinician with Male PatientSystemic therapy for cancer—treatment that can target cancer cells throughout the entire body—has greatly evolved in recent years, advancing in various methods like chemotherapy, immunotherapy, and hormone therapy. Given the rapid development of these systemic treatments, some oncologists believe the role of radiation therapy (RT) is diminishing, especially for treating gastrointestinal (GI) malignancies. Negative results from recent clinical trials only reinforce this belief, as many studies have failed to show that RT, a localized treatment, is beneficial to patients with GI cancers.

Authors of a new Journal of Clinical Oncology study are challenging this viewpoint, asserting that many GI cancer studies are sub-optimally designed, and don’t evaluate the impact of RT on outcomes that matter to patients. After an in-depth analysis of recent trials, the research team discovered the primary endpoint for most RT studies was overall survival (OS), a difficult outcome to achieve. In contrast, systemic therapy trials had lower success thresholds that made it easier to demonstrate their benefits.

“Our striking revelation was that in GI cancer studies, the bar you have to reach to declare success of a modality is set much higher for radiation therapy than it is for systemic therapy. This imbalance in standards poses a significant challenge for radiation therapy, potentially leading to its exclusion from standard of care treatments, despite its proven efficacy in reducing symptoms, improving quality of life, and reducing the need for chemotherapy cycles,” said William Hall, MD, professor of Radiation Oncology and Surgery.

In the study, Dr. Hall and the research team reviewed 65 clinical trials approved by the GI Steering Committee, which encompasses major cancer research consortia such as ALLIANCE, SWOG, ECOG, and NRG. They discovered the most common primary endpoints in systemic therapy trials were disease-free survival (DFS), progression-free survival (PFS), or event-free survival (EFS); and only 32% had OS as a primary endpoint. When it came to RT studies, all but two trials had OS as a primary endpoint.

“The primary endpoint is extremely critical because it dictates if a trial is going to be seen as successful for an intervention, or if a trial will fail to demonstrate an improvement in that particular metric,” explained Dr. Hall. “We feel confident that RT is beneficial to patients, but it hasn’t been able to demonstrate success for reasons I think are relatively clear when you look at the design of the trials. Oncologists see these results and think RT doesn’t work, then present a narrative that it should be excluded or dialed back for treatment of GI cancers. And that’s just not the case.”

Changing the Paradigm: MCW Clinical Trials Use Patients-Centered Endpoints

In light of their study results, authors encourage the medical community to carefully consider the design of future GI cancer trials so patients don’t miss out on important therapeutic options, like RT. While it may not improve OS, RT has proven effective for reducing symptoms, improving quality of life (QOL), and reducing the number of chemotherapy cycles needed (which reduces toxicity and cost). When caring for patients with GI cancer, Dr. Hall says many prefer to have these benefits over prolonging survival.

“RT is very helpful for a multitude of things patients care about, in some cases more than OS. There are other primary endpoints—like QOL or chemo-free intervals—that could be used in RT trials and would demonstrate significant benefit to patients,” he said. “That’s exactly what we’re aiming to do with our trial portfolio at MCW. We’re changing this paradigm by asking: What factors matter most to patients and how do we make those factors the primary endpoint to benefit patients treated with RT?”

Dr. Hall and Dr. Carrie Peterson are following this strategy in the investigator-initiated trial MR-ENHANCE that tests a new method of real-time, adaptive MRI-based RT in patients with advanced rectal cancer; the primary goal of the phase 1 study is to understand the side effect profile of novel ways to preserve a patients’ rectum and avoid a major surgery. It’s also applied in the national JANUS Rectal Cancer Trial, which compares two chemotherapy regimens after long-course RT in patients with advanced rectal cancer. Dr. Hall, National Co-Principal Investigator (PI) and lead MCW PI of the study, noted that the trial uses clinical complete response (cCR) as its primary endpoint, “representing a substantial change in rectal cancer management.”

Dr. Hall and the radiation oncology team are also using this patient-centered framework in clinical trials for other cancers, like the phase 2 PROMETHEAN prostate cancer study that focuses on improving QOL symptoms.

“In clinical trials, the bar for success should be set at a level that reflects the diverse benefits radiation therapy can offer to patients beyond just prolonging survival. At MCW, we’re not talking the talk, we’re walking the walk by offering innovative studies with endpoints we feel confident will be improved by radiation therapy, and that are meaningful to patients.”

Read the full study in Journal of Clinical Oncology.