Combination therapy with sulindac and erlotinib reduced the burden of duodenal polyps in a preliminary study involving 92 patients with familial adenomatous polyposis (FAP), which was reported online March 22 in JAMA.
At present, surgery – including repeated polypectomies, duodenectomy, and the Whipple procedure – are the standard of care for advanced neoplasia of the duodenum, but they are associated with marked morbidity and mortality. “Our study suggests the possibility of an effective chemoprevention strategy for duodenal neoplasia in patients with FAP,” said Dr. N. Jewel Samadder of the Huntsman Cancer Institute and the department of gastroenterology at the University of Utah, Salt Lake City, and his associates.
Dr. N. Jewel Samadder
Given the preliminary nature of this study, especially the relatively small study population and the relatively short (6-month) follow-up, further research is crucial. It will be particularly important to determine whether this decline in the burden of duodenal polyps translates into more definitive, clinically meaningful endpoints such as preventing the formation of new polyps and preventing malignant transformation. Optimal dosing, treatment resistance, and long-term adverse effects also must be investigated further, the investigators noted.
They assessed the effects of 6 months of combination therapy using the cyclooxygenase inhibitor sulindac (150 mg twice daily) plus the epidermal
growth factor receptor (EGFR) inhibitor erlotinib (75 mg daily), compared with matching placebos, in a single-center randomized double-blind study. The study was halted after an interim analysis showed the clear superiority of active treatment over placebo.
The primary outcome was change in duodenal polyp burden as detected on endoscopy, defined as the total number and diameter of all polyps in a 10-cm segment of the duodenum. The sulindac-erlotinib group showed a median decrease of 8.5 mm in polyp burden at 6 months, while the placebo group showed a median 8-mm increase. This represents a 37.9% decrease in polyp burden with active treatment and a 30.6% increase with placebo, Dr. Samadder and his associates said (JAMA. 2016 Mar 22. doi: 10.1001/jama.2016.2522).
These results remained consistent in a subgroup analysis comparing patients with classic FAP against those with attenuated FAP, in a subgroup analysis comparing patients with a low initial polyp burden against those with a high initial polyp burden, and in a subgroup analysis involving only the 81 patients with a confirmed germline mutation in the adenomatous polyposis coli (APC) gene.
However, the rate of adverse events associated with active treatment was high. An acneform rash developed in 87% of participants taking sulindac-erlotinib and oral mucositis developed in 39%. Nineteen patients withdrew from the study, including five who reported adverse events or possible allergic reactions to active treatment, and 54% required a dose reduction of sulindac, erlotinib, or both. “Dose-ranging studies will be needed to determine if lower and/or less-frequent dosing could diminish these adverse effects but retain efficacy,” the investigators said.