Phase II study tests exercise, metformin in colorectal cancer survivors
Nearly 150,000 people are diagnosed with colorectal cancer every year in the United States, leading to approximately 50,000 deaths from the disease. Obesity and inactivity are well-established risk factors for developing the disease and may play a role in the recurrence and survival of those with established disease, recent research suggests.
To probe the suspected underlying molecular links connecting inactivity, obesity and cancer outcomes after treatment, Jeffrey Meyerhardt, MD, MPH (DFCI), Jennifer Ligibel, MD (DFCI), and their colleagues have just opened a randomized controlled trial for colorectal cancer survivors. The study will test how well exercise alone or in combination with metformin, a drug approved for treating type 2 diabetes, can reduce fasting insulin levels.
The study aims to enroll 200 patients who have completed standard therapy for stage I – III colorectal cancer, which accounts for about 80 percent of the diagnosed cases. Traditionally, surgery is the primary treatment for these patients, and some patients have additional chemotherapy or radiation. This study tests added approaches after standard treatment. Patients are eligible between two months and two years after ending treatment. Study participants also must exercise less than 120 minutes per week and not have diabetes.
"There is a fair amount of evidence that energy balance impacts the risk of developing colorectal cancer, and increasing evidence suggests that energy balance affects the outcomes of patients with colorectal cancer," said Meyerhardt, a gastrointestinal oncologist whose published research has identified exercise as a key factor in prognosis. Three observational studies (all led by Meyerhardt, who himself runs about five times a week) have found a 50 percent reduction in recurrence and mortality rate among colorectal cancer survivors who exercised the most — nine hours or more a week of average pace walking or the equivalent activity.
The connection between exercise and colon cancer may be partially related to two molecular networks involving insulin and insulin-like growth factor 1 (IGF-1), Meyerhardt said. In colorectal cancer cell cultures, both factors stimulate cell proliferation and block apoptosis. In colorectal cancer survivors, high levels of C-peptide (a marker of insulin levels) increases mortality rates, even for non-overweight and physically active men.
Metformin is one of the main therapeutic options for type 2 diabetes. It limits the glucose absorbed into the blood from food and the glucose made by the liver. The drug also controls glucose by boosting insulin sensitivity. Through complex signaling networks well known to cancer researchers, metformin also seems to inhibit the activation of the mammalian target of rapamycin (mTOR), which has been implicated in colorectal cancer tumorigenesis and is a target for the treatment of established disease.
No study has tested the combination of an exercise intervention with a drug impacting insulin sensitivity, Meyerhardt said. The 2x2 study design first randomizes participants to the exercise or control groups, and then randomizes each group to metformin or control. The main endpoint is the fasting insulin level after six months, but the study will also examine other biomarkers and how a supervised exercise program works to increase activity in people after colorectal cancer treatment.
People in the non-exercise intervention control group will be given educational material about the importance of a healthy lifestyle and encouraged to follow nutrition and activity guidelines of the National Cancer Institute and American Cancer Society. Previous studies have demonstrated the ineffectiveness of such material alone in changing behavior.
In a new spin on individualized cancer therapy, the exercise intervention offers a personal trainer specialized in working with cancer patients two times a week at the BodyScapes Fitness (formerly Fitcorp) gym in the Longwood Medical Area. Under the supervision of Nancy Campbell, MS (DFCI), participants will aim for a 10-to-20 percent increase in aerobic workouts each week until they reach the goal of 220 minutes of moderate intensity in three 45-minute gyms a week, mostly on their choice of bicycle, treadmill or elliptical trainer. Participants must complete 120 more minutes of unsupervised exercise each week on their own. At the end of six months, the study offers each person in the control group two personal training sessions plus a free pedometer.
Randomized Phase II Study of Exercise and Metformin in Colorectal Cancer Survivors
Jeffrey Meyerhardt, MD, MPH (DFCI)
Jennifer Ligibel, MD (DFCI)
Lee Jones, PhD (Duke University, North Carolina)
For eligibility criteria, go to NCT01340300 on ClinicalTrials.gov. To refer a patient to the trial, contact Laura Schockro at 617.632.5934, firstname.lastname@example.org, or Devin Wigler at 617.632.3687, email@example.com.