Researchers have demonstrated that a de-intensified treatment approach for familial adenomatous polyposis (FAP) significantly reduces duodenal polyp burden with more manageable side effects. This multicenter, single-arm, phase 2 trial, published in Gut online in May 2022, tested the efficacy of a once-weekly dose of erlotinib alone in patients with FAP, showing promising results in managing polyps while minimizing adverse effects.
FAP is a genetic cancer syndrome that predisposes patients to an increased risk of colorectal and duodenal adenomas and cancers. Without treatment, nearly 100% of FAP patients develop colorectal cancer, making regular endoscopic surveillance critical for early detection. Over 80% of FAP patients also develop polyps in the upper gastrointestinal tract, specifically in the duodenum, with a 5-12% risk of developing duodenal and periampullary cancers. Current prevention methods are not optimal, and many treatments carry significant morbidity.
Dr. Niloy Jewel J. Samadder, a gastroenterologist and hepatologist, emphasizes the urgency of improving cancer prevention strategies for FAP patients, especially in the small bowel, where treatment options remain limited. Previous research showed that combining sulindac and erlotinib resulted in a 69%-71% reduction in duodenal and colorectal polyps, but over 80% of patients experienced adverse effects.
To address these concerns, Mayo Clinic researchers tested a de-intensified regimen, giving patients a once-weekly oral dose of 350 mg of erlotinib for six months. Of the 46 participants, 42 completed the full six-month treatment. The goal was to reduce duodenal polyp burden with fewer side effects.
Results
Endoscopic evaluations at the start and after six months showed a nearly 30% reduction in the mean polyp burden, from 137.2 mm at baseline to 97.2 mm after treatment. Among the 42 participants who completed the treatment, 37 showed a decrease in polyp burden, and five showed an increase. Additionally, 85.7% of participants had the same Spigelman stage at baseline and endpoint, with five reporting a decrease in severity, from stage 3 to stage 2.
For those with severe duodenal disease (Spigelman stage 3 or higher), the mean reduction in duodenal polyp burden was 27%, indicating that the treatment was effective even for patients with more advanced disease.
Adverse Effects
While the once-weekly erlotinib regimen was expected to have fewer adverse effects than the prior combination therapy, the treatment still led to a significant rate of side effects. Grade 2 or 3 adverse effects were observed in 71.7% of participants, with the most common being an acneiform rash (56.5%), which was managed with topical cortisone and clindamycin. Other side effects included oral mucositis, diarrhea, and nausea. Four participants withdrew from the study due to adverse symptoms.
Despite these adverse effects, the treatment was generally well tolerated, and the benefits in reducing duodenal polyp burden were significant. Dr. Samadder described the study as an example of "precision cancer interception," highlighting its potential in reducing cancer risk for genetically predisposed patients.
Conclusion
The study suggests that erlotinib may offer a promising approach to preventing cancer in FAP patients, though further research is needed to evaluate its long-term effectiveness and minimize adverse effects. Despite the challenges, the results support continued exploration of erlotinib and other chemoprevention therapies as part of cancer prevention strategies for individuals with FAP. The treatment provided a meaningful reduction in polyp burden, offering hope for more effective and manageable cancer interception in the future.