• Aromatase inhibitor-associated arthralgias were equally reduced by omega-3 fatty acids and soybean-corn oil placebo in breast cancer patients.
• Triglyceride levels were reduced by omega-3 fatty acids and not by placebo, but there were no differences in LDL or HDL cholesterol or CRP.

The arthralgias that reduce quality of life and treatment compliance in breast cancer patients on aromatase inhibitors (AI) decrease by more than 50% with 12 weeks of fish-oil omega-3 fatty acids (O3-FAs), according to findings published online in the Journal of Clinical Oncology.

But women who received a placebo reported almost the same clinical benefits as women in the O3-FA arm, although the placebo did not lower serum triglycerides.

O3-FAs inhibit the conversion of arachidonic acid to prostaglandin and leukotrienes, resulting in reduced inflammation, and they have been studied in rheumatoid arthritis and other inflammatory conditions for the past 2 decades.

AI-related arthralgia — possibly related in part to estrogen deprivation — is more prevalent than previously reported, noted the study, led by medical oncologist Dawn L. Hershman, MD, MS, of Columbia University Medical Center, in New York City. In a cross-sectional survey of 200 consecutive postmenopausal women receiving adjuvant AI therapy for breast cancer, 94 (47%) reported AI-related joint pain, and 88 (44%) reported joint stiffness, with the bulk of the symptoms reported in the hands and knees. Such side effects can lead to early cessation of treatment.

The researchers conducted a multicenter randomized, controlled trial (SWOG S0927) of 262 AI-treated women with early-stage (I-III) hormone-sensitive breast cancer who were recruited between February 2012 and February 2013. The patients (mean age 59.2, 87% white) had a worst joint pain/stiffness score >5 of 10 on the Brief Pain Inventory-Short Form (BPI-SF). They were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. There were no notable imbalances in characteristics, although fewer black women were allocated to the treatment arm.

The trial defined clinically significant change as >2-point drop in BPI-SF score from baseline. Patients also completed assessments of quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain and stiffness at baseline and also at weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. The baseline rate of unfavorable lipid levels in these AI patients was surprisingly high, the authors noted.

Of the 249 patients evaluable, 122 were in the treatment arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo.

In a linear regression, with adjustment for the baseline score, osteoarthritis, and taxane use, the adjusted 12-week BPI-SF scores did not differ by arm. In multivariable analysis, adjusted week-12 BPI worst pain scores were 0.17 points lower on average (implying slightly less pain) in the O3-FA arm than in the placebo arm (95% CI -0.79 to 0.44, P=0.58). A 2-point change from baseline was achieved in 61% of women receiving O3-FAs and 57% of women receiving placebo. Similar results were seen with regard to pain interference and the global rating of change scales.

Triglyceride levels decreased in patients on O3-FAs but remained the same for those on placebo (P=0.01). No differences were seen between the two groups in high- or low-density lipoprotein cholesterol or C-reactive protein levels.

“This larger-than-expected placebo effect may have been a result of the natural history of arthralgia, which can improve over time. It is also possible that the placebo contained ingredients (soy/corn oil) that were active in reducing arthralgia,” the authors wrote. They referred to two randomized trials of other interventions for arthralgia (acupuncture, exercise) that reported no placebo effect.

Noting that there are no proven therapies for the treatment or prevention of AI-induced arthralgia, the authors called for the determination of optimal approaches to define, treat, and prevent this adverse effect. Furthermore, “the high prevalence of unfavorable lipid profiles in this cohort suggests that more efforts are needed to manage long-term comorbidities in cancer survivors,” they concluded.

Commenting on the larger-than-expected placebo effect in this study in an accompanying editorial, N. Lynn Henry, MD, PhD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor, Mich., and an associate noted that placebo response rates have been as high as 30% to 50% in studies of the pharmacologic management of cancer treatment emergent toxicities. “…the placebo response is related to the expectations and perceptions of the treated patient and can be heightened if there is a supportive patient-provider relationship,” they wrote. “Conversely, the placebo effect can be abolished if a patient is told that the intervention is ineffective.”

They noted that the effect may have been partly due to the independent use of O3-FA supplements in the control group (contamination), potentially estrogenic ingredients in the soy-containing placebo itself, the natural history of AI-related musculoskeletal symptoms, and patient selection. The study drug, perceived as tolerable and beneficial on multiple fronts, could have attracted patients with pain that may have been less likely a treatment-emergent toxicity than in those enrolled in other trials.

“That is, it is possible that patients enrolling onto this study had pre-existing musculoskeletal pain that was not related to the AI and that the study was appealing because of the low perceived toxicity of the drug under study,” they wrote.

Another possibility is that patients enrolled in SWOG S0927 experienced improvement in symptoms simply because of participation in a clinical trial and the expectation that they would benefit.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 05.05.2015