Aromatase Inhibitor Adverse Effects: Are We Sweeping Them Under the Rug?
Authors: Polly Niravath, Mothaffar F. Rimawi, C. Kent Osborne
Journal: Journal of Clinical Oncology (2014)

With regard to the report, "Quality of Life in MAP.3:ARandomized,Placebo-ControlledTrialEvaluatingExemestane for Prevention of Breast Cancer," 1 we would like to offer additional perspective from a survivorship standpoint.Although we applaud the authors for investigating quality of life in the MAP.3 (Mammary Prevention 3) trial, we find it concerning that there is a developing trend among oncologists to conclude that aromatase inhibitor (AI) adverse effects are rather inconsequential, as we interpret the data very differently.For instance, studies that have looked specifically at AI-induced arthralgia estimated that 13% to 20% of patients prematurely discontinue AIs as a result of joint pain. 2,3This is consistent with the results of Maunsell et al, 1 which show that 15% of subjects discontinued exemestane because of any treatment-related toxicity, and the IBIS-II (International Breast Cancer Intervention Study II) results, which showed that 20% discontinued anastrozole because of adverse effects. 4n often-neglected adverse effect of AIs is atrophic vaginitis.In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, 18.5% of women taking anastrozole had vaginal dryness, compared with only 9.1% taking tamoxifen.Similarly, dyspareunia and loss of libido were significantly higher in the anastrozole arm, at 17.3% and 34%, respectively, as compared with 8.1% and 26.1% on the tamoxifen arms. 5In the Maunsell et al data, the Menopause-Specific Quality of Life Questionnaire-which asks about only three symptoms within the sexual subscale: vaginal dryness, avoiding intimacy, and decreased sexual desire-is used to evaluate vaginal symptoms.Among women who are not sexually active, or not familiar with the symptoms of vaginal dryness, many may inaccurately answer no to these questions.The well-validated Functional Assessment of Cancer Therapy-Endocrine Subscale adds specific items, such as vaginal irritation/itching, pain with intercourse, and vaginal bleeding/ spotting. 6In addition, frequent urinary tract infections or burning with urination may be other items that more clearly and accurately capture the symptoms of atrophic vaginitis.Similar to atrophic vaginitis, AI-induced arthralgia is likely also under-measured in large clinical trials, as our group was among the first to point out. 7This is reflected in the wide range of arthralgia seen in large AI clinical trials, where it is measured as anywhere between 5% and 35%. 7Arthralgia assessment is particularly challenging because of the lack of an accepted standard for its quantification in clinical trials.Large AI trials such as MAP.3, IBIS-II, and ATAC likely do not capture arthralgia appropriately because they use nonspecific measures such as the Menopause-Specific Quality of Life Questionnaire and the Medical Outcomes Study Short Form Questionnaire.Furthermore, as Maunsell et al 1 point out, many of the patients who have significant toxicities discontinue the AI, thus skewing the remaining population to reflect primarily those who are tolerating the medicines well.