Preventing High-Risk Adenomas and Second Cancers in Colon Cancer Survivors
Name of the Trial
Phase III Double Blind Placebo-Controlled Trial of Eflornithine and Sulindac to Prevent Recurrence of High Risk Adenomas and Second Primary Colorectal Cancers in Patients with Stage 0-III Colon Cancer - Preventing Adenomas of the Colon with Eflornithine and Sulindac (PACES) (SWOG-S0820; NCT01349881). See the protocol summary.
Dr. Jason A. Zell, SWOG
Why This Trial Is Important
Colon cancer survivors face an increased risk of developing the disease again. After colon cancer surgery and adjuvant therapy (if needed), patients are monitored closely with blood and imaging tests and surveillance colonoscopies to detect new adenomas (lesions that may progress to cancer) or new colorectal tumors. Approximately 20 to 40 percent of colon cancer survivors go on to develop high-risk adenomas or second primary colorectal cancers.
“There are approximately 1.2 million colon cancer survivors in the United States,” Dr. Zell said. “These survivors face a risk of another primary colorectal cancer that is about 40 percent higher than what you would expect for the underlying population.”
Epidemiologic and experimental studies show that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of both adenomas and colon and rectal cancers. However, NSAIDs can cause serious side effects, including stomach and intestinal bleeding, so people should carefully consider the potential risks and benefits before deciding whether to use NSAIDs to prevent cancer.
Several small studies of the NSAID sulindac (Clinoril®) in people with an inherited condition called familial adenomatous polyposis (FAP) have shown that this drug is able to limit the number and size of adenomas in this very high risk population. These studies also showed that sulindac caused few side effects.
An experimental drug called eflornithine (DFMO) may also help prevent colorectal cancer. Eflornithine disrupts the polyamine synthesis pathway, a molecular pathway that is thought to be important in the development of colorectal and other cancers. Laboratory studies have shown that eflornithine irreversibly inhibits an enzyme in this pathway, thereby depleting polyamine metabolites and reducing levels of tumor promoting proteins influenced by those metabolites. In several small clinical studies, eflornithine has been found to reduce the polyamine content in colorectal tissue.
In a previous phase III trial, the combination of sulindac and eflornithine was studied in people who had already had adenomas removed within the preceding 5 years. In that study, the development of high-risk adenomas and multiple adenomas was reduced by more than 90 percent in people who took the combination compared with people who took the placebo. Based on these results and on other clinical and laboratory studies, doctors think this combination may also help prevent high-risk adenomas and second primary colorectal cancers in colon cancer survivors.
In the current phase III trial, people who have undergone curative surgery for stage 0-3 colon cancer, with or without adjuvant chemotherapy, will be randomly assigned to take sulindac and a placebo, eflornithine and a placebo, both sulindac and eflornithine, or two placebo pills for 36 months. Doctors will closely monitor all trial participants throughout the study to detect the recurrence of high-risk adenomas or the development of new colon or rectal cancers. After the 3-year intervention period, the participants will undergo annual follow-up for 5 years.
“This trial is unique in that it focuses on preventing the next high-risk adenoma or the next primary colorectal cancer in people who have already had colon cancer,” Dr. Zell said. “We should know by the end of the study if these agents, either alone or in combination, are effective in reducing high-risk adenomas and second primary tumors. Additionally, we have built in a follow-up period of 5 years so that, if we see an effect at the end of 3 years, we will be able to tell if that effect is durable.
“The current standard of care for colon cancer survivors is close monitoring. Our placebo arm, in which study participants will receive two inert placebos, is designed precisely in accordance with current national guidelines [on postoperative surveillance], and, if we really want to show any benefit of the intervention, we need to compare that to the current standard,” he explained.