Lipid analysis showed that patients who received omega-3 fatty acid treatment had reduced triglyceride levels while those who received placebo did not. HDL, LDL, and C-reactive protein were similar between both treatment groups.1

The findings demonstrate that omega-3 fatty acids can substantially improve aromatase inhibitor–induced musculoskeletal symptoms; however, they are not superior to placebo. N. Lynn Henry, MD, PhD, and Jennifer J. Griggs, MD, MPH, from the University of Michigan Comprehensive Cancer Center in Ann Arbor, MI, proposed possible reasons for the surprising effect placebo had on symptom management in an editorial also published in the Journal of Clinical Oncology.1,3

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“The trial reported by Hershman et al is notable for the larger-than-expect placebo response that remains unexplained,” they wrote. “There are several potential factors that could have contributing to the findings.”3

Dr. Henry and Dr. Griggs suggest that contamination of the placebo, the placebo ingredients, and the natural history of the symptom complex may have contributed to the large symptom improvement in the placebo arm, but the most significant effect may have been a result of patient selection and the placebo effect.3

It is possible that patients opting to enroll onto this study were experiencing preexisting musculoskeletal pain unrelated to aromatase inhibitor use and the study was appealing to them because omega-3 fatty acids have low perceived toxicity, or patients who enrolled onto the study experienced symptom improvement solely because they expected to benefit from participating in a trial.3

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“Further understanding and perhaps harnessing the placebo effect could potentially enhance management of adverse events [associated with aromatase inhibitor use] without worsening the benefit-risk ratio,” Drs. Henry and Griggs said.3

Future studies are necessary to determine optimal strategies to define, prevent, and treat aromatase inhibitor–induced musculoskeletal pain, and the high prevalence of dyslipidemia “in this cohort suggests that more efforts are needed to manage long-term comorbidities in cancer survivors,” Dr. Hershman concluded.


  1. Hershman DL, Unger JM, Crew KD, et al. Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor–induced musculoskeletal pain: SWOG S0927. J Clin Oncol. May 4, 2015. [Epub ahead of print]. doi: 10.1200/JCO.2014.59.5595.
  2. Femara (letrozole) [prescribing information]. East Hanover, NJ. Novartis Pharmaceuticals Corporation.
  3. Henry NL, Griggs JJ. The power of the placebo in symptom management. J Clin Oncol. May 4, 2015. [Epub ahead of print]. doi: 10.1200/ JCO.2015.61.1004.