1. Carlson, Robert H.

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Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Although duodenal adenocarcinoma is rare in the population, patients with FAP have more than a 100-fold lifetime risk of developing duodenal cancer, the second leading cause of death in FAP patients after colorectal cancer.

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Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful, but hopes have been placed on cyclooxygenase (COX)-2 inhibition.


Now, a double-blind, placebo-controlled trial has shown that treatment for six months with the COX-2 inhibitor sulindac combined with the tyrosine kinase inhibitor (TKI) erlotinib significantly reduced duodenal polyp burden and polyp number in patients with FAP, while the burden increased in the placebo group (JAMA 2016;315:1266-75).


But adverse events may limit the use of this combination at the doses used in this study.


Duodenal Polyp Burden

In the study, 92 patients with FAP were randomly selected to receive sulindac 150 mg twice daily and erlotinib 75 mg daily (46 patients), or placebo (also 46 patients) for six months. Mean patient age was 41 years, and 61 percent were women.


The trial was stopped prematurely by recommendation of the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority.


The change in total duodenal polyp burden, defined as the change in the median sum diameter of polyps, was significantly different between the placebo and sulindac-erlotinib groups at six months, the researchers reported. Over six months, the median duodenal polyp burden in the sulindac-erlotinib group decreased from 29.0 mm to 19.5 mm (median change, -8.5 mm), and in the placebo group increased from 23.0 mm to 31.0 mm (median change, 8.0 mm).


As percentages of change in duodenal polyp burden, the sulindac-erlotinib group had a 37.9 percent decrease from baseline versus a 30.6 percent increase from baseline in the placebo group.


And expressed as median duodenal polyp count, the sulindac-erlotinib group saw a decrease from 13.5 to 10.0, while the placebo group saw an increase from 10.5 to 17.0.


"Our study found the greatest reduction in polyp burden with sulindac-erlotinib treatment occurred in those with the greatest polyp burden, the patients we are most worried about in terms of duodenal cancer risk," said N. Jewel Samadder, MD, Assistant Professor in the Division of Gastroenterology and Hepatology at the Huntsman Cancer Institute, University of Utah Health Care, Salt Lake City, the first author of the study.


"That is why our trial is exciting, because the erlotinib-sulindac combination seems to have the greatest impact in those with higher polyp burdens," Samadder said.


TKI Rash Common

There was a high rate of grade-1 and grade-2 adverse events in the study, the most notable being erlotinib-induced acneiform rash in 87 percent and oral mucositis in 39 percent in the treatment group. But 20 percent of the placebo group also had rash. Rash was managed with topical cortisone and/or clindamycin therapy.


Only two participants experienced grade 3 adverse events-one case of oral mucositis in a treatment patient and one case of abdominal pain in a placebo patient. No grade 4 events were reported.


Samadder said the dosing of sulindac was based on prior chemoprevention studies, but the dosing of erlotinib was estimated from cancer treatment and lung cancer chemotherapy trials.


"Dose-ranging studies will be needed to determine if lower and/or less-frequent dosing of erlotinib could diminish these adverse effects, but retain efficacy," he said.


However, there was no correlation between total drug consumed and response, he said, indicating the study was conducted within the range of efficacy, even when participants reduced their dose.


Surgery vs. Side Effects

Samadder was asked whether the rate of adverse effects made the treatment impractical. "Patients who are at high risk for duodenal cancer and looking at surgery to remove part of their small intestine may find the trade-off between surgery and minimal side effects worth using the combination treatment," he said. "That said, we are now actively trying to determine what is the optimal dose at which polyp regression occurs and side effects can be minimized."


Samadder said a National Cancer Institute-funded clinical trial is starting in early Fall 2016, looking at once-weekly erlotinib for FAP polyp prevention. "Once-weekly erlotinib has been shown to be equally efficacious as daily dosing but with more tolerable side effects," he said.


The researchers noted several limitations to their study.


First, because the study measured polyp regression, it is not known if sulindac and erlotinib would be effective in preventing the emergence of new duodenal adenomas. Second, without long-term follow-up data, the durability of the effect of sulindac and erlotinib is not known, nor is the potential to develop resistance to either drug.


And, both sulindac and erlotinib can be associated with rare and serious adverse effects such as cardiotoxicity and interstitial lung disease, though no such effects were encountered in this study.


Also, this cohort was not sufficient in size to study the effects of erlotinib or sulindac alone, and the potential of synergistic activity led to the testing of the combination instead.


Finally, the authors noted studies terminated early for efficacy may overestimate the true effect size.


Nevertheless, they concluded, "our study suggests the possibility of an effective chemoprevention strategy for duodenal neoplasia in patients with FAP and supports the need for future longer-term studies to establish clinically meaningful outcomes."


Robert H. Carlson is a contributing writer.