COLUMBUS, Ohio—Patients with cancer cachexia have been successfully treated in a small clinical trial with the oral administration of a high-calorie nutritional supplement combined with eicosapentaenoic acid (EPA), a polyunsaturated fatty acid derived from fish oil, Kenneth C. H. Fearon, FRCS, said at the Society for Nutritional Oncology Adjuvant Therapy (NOAT) annual congress.
This combination of supplements resulted in net weight gain rather than simple weight stabilization. “The dietary supplements are now the subject of a randomized trial of 80 patients,” said Dr. Fearon, a reader in surgery, Royal Infirmary of Edinburgh. His group’s goal is to address the metabolic changes that underlie the weight loss and muscle wasting of patients with cachexia while also providing them with conventional nutritional support.
“In a study of 20 cachectic patients with advanced pancreatic cancer, patients were asked to drink two cans per day of an oral supplement combined with EPA,” Dr. Fearon said. The EPA was in the form of mixed marine triglycerides. Each 8-oz can of the oral supplement contained 310 kcal, 16 g of protein and 1.09 g of EPA. Drinking two cans a day, therefore, resulted in a dietary increase of about 600 kcal, 32 g of protein, and 2 g of EPA. The total fat increase was 6.5 g.
This drink was an addition to the patient’s diet and did not take the place of other calories. The oral supplement is not commercially available.
After 3 weeks of taking this supplement, average weight gain was 1 kg. “The patients dramatically increased their lean body weight,” Dr. Fearon said. He emphasized that water retention was not responsible for the weight gain. After 7 weeks, average weight gain was 2.5 kg. “Patients noted a significant trend of increase in appetite,” he said.
The nutritional supplement also seemed to inhibit the hypermetabolism that is a frequent component of cachexia. By arresting anorexia and metabolic change, it led to a reversal of cachexia.
“This type of result has never been achieved before with oral supplements,” Dr. Fearon said. NOAT president Daniel Nixon, MD, agreed. “This is the very first time lean body mass has been put back on a cachectic patient,” he said during the question period.
A Multifactorial Problem
Cachexia, which means poor condition in Greek, is characterized by weight loss, anorexia, early satiety, fatigue, anemia, and edema. Body fat mass is reduced 85%, and muscle protein is reduced 75%.
“Cachexia differs from simple starvation, however, in that non-muscle mass is relatively unaffected,” Dr. Fearon said. In simple starvation, muscle mass and non-muscle mass waste similarly. The weight loss of cachexia is caused by increased energy expenditure, reduced food intake, or a combination of the two.
“Cachexia is a multifactorial problem that needs a multifactorial approach,” Dr. Fearon said. “The precise metabolic alterations that underlie weight loss and muscle wasting are poorly understood,” he said. “The dominant mechanism in cachexia, which seems to vary among patients and tumor types, is a raging question in medical science,” he added.
In animal models, the action of cytokines has been implicated in the development of cachexia. The University of Edinburgh group hypothesizes that the metabolic abnormalities seen in cachexia are caused by pro-inflammatory cytokines interacting with neuroendocrine catabolic factors. The cytokines may be produced by the tumor cells themselves or by the tumor host. However, investigators have been unable to target one dominant cytokine.
An acute-phase protein response (APPR) is a biomarker for the production of pro-inflammatory cytokines and for the hypermetabolism seen in cachexia. Earlier studies by Dr. Fearon’s group showed that an APPR is a useful predictor of survival in patients with unresectable pancreatic cancer. The group hypothesized that the metabolic disturbances associated with an APPR might be a worthwhile therapeutic target (Falconer JS et al: Cancer 75:2077-2082, 1995).
“Fifty years of research had shown that giving cachectic patients more food to eat failed to reverse weight loss,” Dr. Fearon said. His group set out to improve the efficacy of conventional nutritional food support.
A Series of Experiments
In one experiment, he said, the group gave fish oil capsules to 18 pancreatic cancer patients who had lost, on average, 16% of their body weight. The capsules, known as MaxEPA, contained EPA and docosahexaenoic acid(Drug information on docosahexaenoic acid). The administration of 12 g/day of MaxEPA was shown to stabilize weight loss or even result in weight gain in the majority of patients (Wigmore SJ et al: Nutrition 12(suppl 1):S27-S30, 1996).
After this experiment, the University of Edinburgh group hypothesized that EPA was the anticachectic agent in fish oil. It appears that EPA acts, in part, by downregulating the pro-inflammatory cytokine release and the APP response.
The group then did another series of experiments showing that patients who received high-purity EPA for a month had a significant decrease in their levels of serum C-reactive protein, an acute-phase protein.
The next step, the one that resulted in the current experiment, was to give additional calories along with the EPA in order to facilitate weight gain.
