Dec. 08, 2022
Researchers at Mayo Clinic have shown that a de-intensified treatment option for patients with familial adenomatous polyposis (FAP) reduces duodenal polyp burden with more manageable adverse side effects. Results of the multicenter, single-arm, phase 2 trial were published to Gut online in May 2022.
FAP is a genetic cancer syndrome. Therefore patients with this germline mutation have an increased risk of colorectal and duodenal adenomas and cancer. If untreated, patients with FAP have a nearly 100% risk of developing colorectal cancer. Patients' colorectal risk is monitored endoscopically until further treatment is needed.
More than 80% of patients with FAP develop upper gastrointestinal polyposis in the duodenum, and 5% to 12% of these patients will be diagnosed with duodenal and periampullary cancers. Currently, there is not an optimal approach to prevent duodenal carcinomas, and existing approaches can be associated with significant morbidity.
"There really is an urgent need to improve cancer prevention strategies for patients with FAP," says Niloy Jewel J. Samadder, M.D., a gastroenterologist and hepatologist at Mayo Clinic Comprehensive Cancer Center in Arizona. "We need to learn how to delay or interrupt FAP-associated cancers, including in the small bowel."
Previous research noted some success in treating FAP with a combination of sulindac and erlotinib. This approach showed a 69% to 71% reduction in duodenal and colorectal polyp burden, but more than 80% of patients observed adverse events.
Reducing duodenal polyp burden with fewer side effects
Researchers at Mayo Clinic sought to reduce duodenal polyp burden and limit adverse side effects with a once-weekly dose of erlotinib alone. Forty-six participants self-administered 350 mg of erlotinib by mouth once each week for six months. Of those, 42 completed the entire six-month intervention.
"We hoped to see significantly reduced duodenal polyp burden at six months and for the therapy to be better tolerated with fewer adverse effects," says Dr. Samadder.
Duodenal poly burden
Endoscopic evaluations were performed within 30 days of starting treatment, and six months after treatment started to assess duodenal polyp burden. The mean polyp burden at start of the trial was 137.2 mm.
In the follow-up evaluation, mean polyp burden had reduced by nearly 30% to 97.2 mm. Of the patients who completed the entire treatment regimen, 37 showed decreased duodenal polyp burdens and five showed increased burdens.
Researchers also assessed Spigelman stage, which is commonly used to assess severity of duodenal disease in FAP, before and after treatment. Most participants (85.7%) had the same stage at baseline and endpoint, while five reported a decreased Spigelman stage from 3 to 2 at baseline and endpoint, respectively.
Participants with severe duodenal disease, identified as Spigelman score 3 or higher, observed similar results to the study group at large. Thirty-two patients had severe disease and had a mean duodenal polyp burden decrease of 27%. Similar results were seen across genders, across ages and among those with and without adverse effects.
The previous combination treatment was associated with a high rate of adverse effects in the form of a rash. Once-weekly erlotinib was still associated with a higher rate of adverse effects than hypothesized. Grade 2 or 3 adverse effects were reported in 71.7% of participants. While the treatment was generally well tolerated, four participants did withdraw due to the symptoms.
An acneiform rash — the most common adverse effect — occurred in 56.5% of participants. It was managed by topical cortisone and clindamycin therapy. Other adverse effects included oral mucositis, diarrhea and nausea.
"This was a great example of precision cancer interception," says Dr. Samadder. "We want to continue to learn how we can reduce the cancer risk for patients who are genetically predisposed."
This study shows the need for further investment in evaluating the use of erlotinib and other chemoprevention therapies for cancer prevention in patients with FAP. While adverse effects were still reported and may inhibit clinical application, they were generally well tolerated and associated with a decrease in duodenal polyp burden.
For more information
Samadder NJ, et al. Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis. Gut. In press.
Refer a patient to Mayo Clinic.