Dual-Drug Strategy Reduces Carpet of Polyps in FAP Patients

Pam Harrison

March 24, 2016

The high-risk polyp burden that characterizes familial adenomatous polyposis (FAP) can be significantly reduced using a novel combination of a nonsteroidal anti-inflammatory drug (NSAID) and an epidermal growth-factor receptor (EGFR) inhibitor, opening up the first really tenable treatment for this challenging disease, new research shows.

"FAP is an inherited condition and individuals who have severe colonic polyposis can be managed with a colectomy, but even after colectomy, there remains a risk that these polyps will go on to progress to cancer in the small intestine and in the duodenum in particular," study author Deborah Neklason, PhD, from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, told Medscape Medical News.

"So these findings are very important for this patient group. Our hope is that patients might receive reduced doses of both drugs, or at least a different dosing schedule, and still have a good effect with fewer side effects," she said.

The study was published online March 22 in JAMA.

Earlier studies showed that sulindac, a cyclooxygenase (COX-2) inhibitor, inhibits colorectal adenomatous polyps in patients with FAP, but the drug is not effective in the small intestine on its own.

Having observed that the combination of sulindac and an EGFR inhibitor reduced the development of small intestinal adenomas by 87% in a mouse model of FAP, the researchers set out to test the combination of sulindac and erlotinib (Tarceva), an EGFR inhibitor used in the treatment of non-small-cell lung cancer, in patients with FAP.

Patients had to be proven carriers of the germline mutation in the adenomatous polyposis coli (APC) gene that gives rise to the disease or had to have more than 100 adenomas in the large intestine at study entry. The latter group also had to have a family member with FAP. Patients with attenuated FAP or an APC genetic diagnosis alone were also included in the study.

Half of the 92 patients were randomized to active treatment, which consisted of sulindac 150 mg twice daily and erlotinib 75 mg once daily for 6 months, and half were randomized to placebo.

"The burden of duodenal adenomatous polyps was assessed by endoscopy with flexible video endoscopes," lead author Jewel Samadder, MD, also from the Huntsman Cancer Institute, explained.

Prior to the initiation of treatment and at the end of the 6-month study period, an expert endoscopist counted and mapped the number and size of polyps contained in a 10 cm segment of the duodenum.

The primary end point of the study was change in total duodenal polyp burden, determined by summing the diameters of all polyps counted at endoscopy before and after treatment.

After 6 months of treatment, there were 46 patients in each group in the intent-to-treat (ITT) analysis, and 37 patients in the combination group and 36 patients in the placebo group in the per protocol (PP) analysis.

Results at 6 Months

In the ITT analysis at 6 months, there was a median 8.5 mm decrease in the total duodenal polyp burden from baseline in the combination group, and a median 8.0 mm increase in the placebo group; the between-group difference was 19.0 mm (P < .001).

The total duodenal polyp burden was reduced by 37.9% from baseline in the combination group and increased by 30.6% from baseline in the placebo group; the between-group difference was 71.2% (P < .001).

In the PP analysis, reductions in the median total duodenal polyp burden were smaller. In the combination group, the median burden decreased from 19 mm at baseline to 14 mm at 6 months. In the placebo group, the median burden increased from 22 mm at baseline to 28 mm at 6 months. The between-group difference was 19.5 mm.

Between-group differences were seen in patients with classic and attenuated FAP. In the combination group at 6 months, between-group differences in total duodenal polyp burden was 20 mm less in patients with classic FPA and 18 mm less in patients with attenuated FAP (P < .001 for both).

The impact of the combination strategy was most pronounced in those with a high duodenal polyp burden at baseline.

Table. Chemopreventive Effect According to Baseline Polyp Burden in the Duodenum

Baseline Polyp Burden Median Reduction in Burden With the Combination, mm Median Between-Group Difference, mm P Value
Low (≤21 mm) 6.5 –9.1 .001
High (>21 mm) 13.3 –36.6 .001


Adverse Events

"Treatment with sulindac–erlotinib for a 6-month period was generally well tolerated," Dr Samadder observed.

However, grades 1 and 2 adverse events were more common in the combination group than in the placebo group, such as acne-like rash related to erlotinib (87% vs 20%; P <.001). (The rash was managed with the help of a topical steroid, clindamycin, or both).

Oral mucositis was also common in combination group, occurring in 39.1% of patients, as was diarrhea (in 26.0%) and nausea (in 23.9%).

Notably, 73% of patients in the combination group required a reduction in the dose of erlotinib, and only four patients had the full dose of erlotinib reinstated by study end point.

Despite receiving a reduced dose of erlotinib, "there was no correlation between total drug consumed and response, indicating that the study was conducted within the range of efficacy, even when participants reduced their dose," study authors observe.

Asked if the combination of sulindac and erlotinib is ready for use "across the board," Dr Neklason said there is still much to be learned about this novel strategy.

"We have some new proposals for clinical trials that we hope to start next year that will involve reduced dosing to see how low we can go," she said. "And we'll explore the possibility of dosing just once a week, or even cycle patients on and off these drugs when their polyps become problematic."

"We still need more studies, but I'm sure there are some physicians out there who have run out of options for some of their patients. I think those who are well versed in FAP high-risk patients will look at this as one of their options now," she commented.

High Colon Cancer Risk

They develop colons that are carpeted with polyps.

Elena Stoffel, MD, MPH, director of the Cancer Genetics Clinic at the University of Michigan Health System in Ann Arbor, told Medscape Medical News that although FAP accounts for only about 1% of all colorectal cancers, "the risk of FAP patients developing colon cancer is very, very high because they develop colons that are carpeted with polyps."

"At present, the best way to manage the colon cancer risk is surgical removal of the colon," she added.

However, Dr Stoffel reaffirmed that even after the colon has been removed, patients continue to develop polyps in their small intestine, and management of polyps in the small intestine is extremely challenging, requiring very invasive and potentially morbid surgery, including the Whipple procedure.

"The COX-2 inhibitors have been looked at but they require double the standard dose and, because of their potential to cause cardiac events, insurance won't cover the cost," she noted. Erlotinib is considered by most to be "cost-prohibitive" at the moment.

Nevertheless, she continued, "there are patients out there who break through celecoxib, who break through sulindac, and who are looking for some alternative to surgery. For those patients, I think erlotinib is a very reasonable thing to try before undergoing a potentially very morbid surgery."

Dr Stoffel was involved in another clinical trial evaluating another study agent for the same patient population, and has been in discussions with the University of Utah researchers to undertake a larger clinical trial using the same agents.

"We're still searching for a better treatment for FAP patients," Dr Stoffel said.

"But these data are very promising and they suggest that an approach that targets the EGFR pathway may be worth pursuing," she explained.

Patients in the current study are being followed for the next 2 years to determine whether the two-drug strategy prevents new duodenal polyps from forming and to quantify the duration of its effect.

This study was supported by the National Cancer Institute, the Huntsman Cancer Institute Cancer Center Support, and the Huntsman Cancer Foundation. Dr Samadder reports being a consultant for Cook Medical. Dr Stoffel has disclosed no relevant financial relationships.

JAMA. Published online March 22, 2016. Abstract


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