Omega Fatty Acid Changes Tied to Lower Proliferation Rate in Early Prostate Cancer

A short-term randomized study of active surveillance for prostate cancer showed that fish oil supplementation was associated with a reduction in a biomarker of disease progression.

During a year of follow-up, prostate biopsies showed about a 15% decrease in the Ki-67 index in patients who received fish oil capsules enriched for omega-3 fatty acids and low in omega-6. The index increased by 24% in men who did not receive the supplements. Secondary endpoints related to tumor characteristics did not change significantly between the randomized groups.

The findings support continued investigation of the fish oil intervention in phase III trials of prostate cancer, concluded William Aronson, MD, of the David Geffen School of Medicine at the University of California Los Angeles (UCLA), and colleagues in the Journal of Clinical Oncology.

“Patients in the trial were compliant with the intervention, which was well tolerated,” the authors stated. “Moreover, obtaining serial same-site prostate biopsy tissue is feasible for future biomarker intervention trials. On the basis of the underlying antiprostate cancer mechanisms of a high omega-3, low omega-6 diet with FO [fish oil] supplements, future trials are warranted evaluating this intervention in varying stages of prostate cancer.”

The trial met the primary endpoint (effect on Ki-67 index), but interpretation of the results should include recognition of certain limitations, according to the authors of an accompanying editorial. The magnitude of benefit was associated with wide confidence intervals (and a lower boundary of 2%), and the dietary intervention was not controlled.

“Instead, patients received monthly dietary counseling from a professional dietitian which resulted in a notable shift in habits, generally, in a positive direction,” noted Nazli Dizman, MD, and Andrea Necchi, MD, both of San Raffaele University in Milan. “This counseling resulted in a statistically significant reduction in participant’s total daily calorie intake and total fat and saturated fat consumption, with notable decreases in protein and carbohydrate intake.”

“Hence, the dietary changes prompted by the intervention in this study appear to have extended well beyond the intended shifts in the ratio of omega-6 and omega-3 fatty acid intervention, rendering it challenging to attribute the results of the study solely to the omega-6 and omega-3 fatty acid intervention,” they said.

The trial highlights the feasibility and complexity of dietary intervention trials, Dizman and Necchi continued.

“To better understand the mechanisms underlying the link between diet and outcomes and offer patients with prostate cancer evidence-based dietary guidance, continuous efforts through well-designed dietary intervention trials with robust translational correlatives will be essential,” they concluded.

Aronson’s group noted that patients with all stages of prostate cancer have demonstrated interest in dietary strategies and supplements that may help delay disease progression. To date, no specific clinical guidelines have provided recommendations.

Among previous studies of dietary interventions, the MEAL trial showed no effect of increased vegetable intake on prostate cancer progression during active surveillance. The CANARY study showed no impact of “healthy diet patterns” on upgrading of cancer during 7.8 years of follow-up.

Studies involving preclinical models have shown that lowering omega-6 and raising omega-3 fatty acids delayed prostate cancer progression, but epidemiologic studies have yielded mixed results, the authors noted. A cross-sectional study nested within a phase II study of men on active surveillance showed that higher omega-3 levels correlated with less clinical upgrading on prostate biopsies. A short-term pre-prostatectomy study showed that a low-fat diet supplemented with fish oil was associated with a decrease in the Ki-67 index cell-cycle progression score.

Following up the preclinical and clinical studies, Aronson and colleagues conducted the CAPFISH-3 trial, a 1-year prospective randomized study involving 100 men with grade group 1 or 2 prostate cancer on active surveillance at UCLA. Participants had a mean age of about 64; they were randomly assigned to no dietary intervention or to dietary counseling to reduce intake of dietary omega-6 and increase omega-3 intake, combined with daily fish oil supplements. The primary endpoint was change in Ki-67 index at 1 year based on prostate biopsies.

The results showed that the group assigned to the intervention had a reduction in biopsy-specific Ki-67 index from 1.34% at baseline to 1.14% at 1 year. During the same time the Ki-67 index increased in the control group, from 1.23% at baseline to 1.52% a year later. The results translated into a between-group difference of 31% (95% CI 2-52%, P=0.043).

Secondary endpoints did not differ between the groups, including upgrading or downgrading, maximal tumor length, or Decipher genomic classifier score. Testosterone and PSA levels also did not differ significantly between the groups. Serum triglycerides declined significantly in the intervention group versus the control group (P=0.016), but other lipid parameters did not differ between groups, nor did weight or BMI. With respect to cytokine activity, colony-stimulating factor-1 declined in the intervention versus control group (P=0.017).

Four patients in the intervention group withdrew because of adverse events related to fish oil, such as grade 2 flatulence, grade 2 diarrhea, and grade 1 loose stools.