OPEN ACCESS: EDITORIAL: Getting a Grip on Aromatase Inhibitor-Associated Arthralgias [
Journal of Clinical Oncology;
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In 2004, the American Society of Clinical Oncology reported its evaluation of the use of aromatase inhibitors (AIs) in the adjuvant treatment of postmenopausal breast cancer. While the panel endorsed the use of AIs at some point during adjuvant therapy for most patients with postmenopausal hormone receptor-positive breast cancer, it noted that many important unresolved issues around the use of AIs remain, specifically noting the unknown long-term risk of these agents. Not surprisingly, the use of medications on a larger scale in the community often uncovers toxicities not recognized in controlled clinical trials. This has been the case with AI-associated arthralgias and has become a particular concern because the success of AIs as adjuvant treatment depends on patients' ability and willingness to adhere to long-term treatment. Surprisingly, studies show that despite the known benefits of hormone therapy, 25% to 40% of women discontinue therapy early. Among patients taking AIs, many discontinue as a result of arthralgias.
The large adjuvant trials of AIs for breast cancer treatment reported large variability in reports of musculoskeletal disorders, with rates of patients on AIs ranging from 5% to 35%. In the community, the rate of AI-related arthralgia appears to be higher. In a survey of 200 patients with breast cancer on adjuvant AI therapy, more than 40% of women reported worsening or new-onset joint pain or stiffness after starting AIs. Among those with AI-related joint symptoms, about two thirds experienced moderate to severe symptoms. This variability reflects a critical issue with regard to clinical trial toxicity assessments and patient reported symptoms.
As we have seen with many agents over the past few years, such as cyclooxygenase 2 inhibitors, erythrocyte-stimulating agents, and bisphosphonates, late effects of cancer therapies are often not well characterized in clinical trials. When discovered, the presentation often leads to media-driven hysteria, distrust in the medical establishment, and discontinuation of effective therapies. Why might this be the case? Traditionally, clinical trials have relied on the National Cancer Institute Common Terminology Criteria of Adverse Events, which is limited by ambiguities in wording, poor validation with regard to subjective symptoms, and secondary interpretation by the clinician. There is mounting evidence that patient reported outcomes (PROs) provide significantly more toxicity and symptoms data than the traditional Common Terminology Criteria of Adverse Events. Studies have shown that there is poor agreement among raters of patient-reported toxicities as well as poor agreement among patients and raters of symptoms. In addition, clinical trials often only measure acute symptoms that develop during the initial phases of treatment, and very few mechanisms exist to evaluate long-term effects. To address this issue, novel studies have suggested that online patient self-reporting is a feasible strategy for long-term symptom monitoring. Because many new treatments are marketed as having a more favorable toxicity profile despite equal or near-equal efficacy, PROs are being incorporated into both industry-sponsored and cooperative group clinical trials.
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