SAN DIEGO -- A combination of the targeted agent difluoromethylornithine (DFMO) at a low dose and sulindac, a non-steroidal anti-inflammatory drug (NSAID), reduces the risk of recurrent colorectal adenomas, an early sign of colon cancer, by up to 95 percent with less toxicity than with chemotherapy, researchers report.
“There is a great hope that we will be able to prevent colon cancer effectively using this method. We had not been able to do this before due to the high toxicity of available therapies. Difluoromethylornithine is a targeted agent that represents a new treatment paradigm,” said Frank Meyskens, M.D., director of the Cancer Center at the University of California at Irvine.
In earlier studies, Meyskens’s team had established a safe and well-tolerated dose of DFMO that was 1/50th of what would typically be used to treat advanced cancers. By combining this reduced dose of DFMO with sulindac researchers believed they could achieve a significant clinical effect with reduced toxicity.
For the current study, researchers enrolled 375 patients who had a history of at least one colorectal polyp within the previous five years. Patients were randomly assigned to either a combination of 500 mg of daily DFMO and 150 mg of the NSAID sulindac, or placebo. Patients were followed for three years to measure adenoma recurrence.
Overall, the combination treatment reduced the risk of a recurrent adenoma from 41.1 percent in the placebo group to 12.3 percent with treatment, a 70 percent reduction.
When researchers measured advanced adenomas only, the rate was 8.5 percent in the placebo group compared with 0.7 percent in the treatment group, a 92 percent reduction.
For adenomas larger than one centimeter, the rate was 7 percent in the placebo group compared with 0.7 percent in the treatment group, a 90 percent reduction. Among patients who had previously had more than one adenoma, the rate of subsequent adenomas was 13.2 percent in the placebo group compared with 0.7 percent in the treatment group, a 95 percent reduction.
The rate of reduction was so pronounced that the trial’s independent data and safety monitoring board stopped the trial early.
An analysis of side effects and toxicity found no difference between the treatment and placebo groups. There was no difference in side effects requiring an overnight hospitalization, gastrointestinal side effects, cardiovascular side effects, or hearing loss between the two groups.
“These are important findings, but they are not ready for prime time yet. What we have shown here is that there is value in testing these agents at lower doses and in combination to determine if we can achieve the same effect without the damaging side effects,” Meyskens said.
Marked efficacy of difluoromethylornithine plus sulindac in reducing recurrent colorectal adenomas in patients with prior adenomas: results of a randomized, placebo-controlled double-blind phase III trial: Abstract LB-142
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 27,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is the only journal worldwide dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.