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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3797-3799 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9529
Aromatase Inhibitors and Arthralgias: A New Frontier in Symptom Management for Breast Cancer SurvivorsDana-Farber Cancer Institute, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA Aromatase inhibitors (AIs) have become widely used as adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer. Although the optimal schedule and duration remain unclear, current guidelines endorse the inclusion of AI treatment at some point during adjuvant therapy for most postmenopausal women with estrogen receptor–positive breast cancer.1 Because of the incidence and demographics of breast cancer, hundreds of thousands of breast cancer patients throughout the world will start AI therapy each year. As a class, AIs are generally safe drugs and are reasonably well tolerated by most patients. They have been studied in very large adjuvant trials with careful documentation of both toxicity and patient compliance. The majority of symptoms associated with aromatase inhibition are related to the profound estrogen deprivation that arises as a consequence of AI therapy. These symptoms include hot flashes, night sweats, vaginal dryness, and sexual dysfunction. A particular concern among postmenopausal women has been bone health, including osteopenia, osteoporosis, and osteoporotic fracture, all of which are accelerated by AIs.2 Serial monitoring of bone mineral density and supplemental calcium, vitamin D, and exercise are recommended to minimize loss of bone density in women receiving AI therapy.2,3 Given that AI treatment has become more common, clinical experience has suggested another unique musculoskeletal adverse effect of AI therapy: arthralgias. Arthralgia is defined as pain in one or more joints, and is distinguished from arthritis, which suggests inflammation of the joint caused by structural damage, infection, autoimmunity, or metabolic conditions. Arthralgias may be difficult to gauge in older breast cancer patients with early-stage breast cancer owing to the high prevalence of degenerative joint disease and of nonspecific muscle and joint aches. In patients with stage IV breast cancer, the frequency of bone metastases also confounds easy measurement of drug-associated musculoskeletal symptoms. The pivotal trials of AIs as treatment for metastatic breast cancer documented musculoskeletal complaints in 4% to 13% of women receiving AI therapy. The first report linking AI therapy to arthralgia was a letter to the editor of the Journal of Clinical Oncology (JCO) in 2001, describing a series of patients with metastatic breast cancer treated with AI therapy in the United Kingdom.4 Among 77 women starting AI therapy for metastatic breast cancer, 16% developed new joint pains, mostly of moderate grade, prompting one in four of these women to stop AI therapy because of symptoms. In each case, cessation of AI therapy resolved the joint pain. The most common sites of joint pain were hands, knees, hips, back, and shoulders. The seminal studies of adjuvant AI therapy such as the Arimidex, Tamoxifen, Alone or in Combination, Breast International Group 1-98, Intergroup Exemestane Study, and National Cancer Institute of Canada trial MA17, captured data on adverse effects of AI and tamoxifen as treatment-related toxicity. Bone and joint symptoms were categorized in a variety of different ways in the toxicity reporting of the major adjuvant AI trials, including classification as arthritis, joint pain, or musculoskeletal disorders, to name several examples.5 Estimates for the incidence of musculoskeletal problems in these trials range from 5% to 36% among patients receiving AI therapy, and from 4% to 29% among women taking tamoxifen. These broad ranges reflect both the variety of definitions of arthritis, arthralgia, and bone pain, and the potentially confounding effect of widely prevalent nonspecific bone symptoms. Formal surveys of patients continuing protocol treatment in the adjuvant AI trials showed comparable global quality of life among women taking either AI or tamoxifen/placebo therapies, suggesting that whatever musculoskeletal symptoms patients were experiencing, they had on average a modest impact on day-to-day function and activity.6-8 Nonetheless, growing clinical experience suggests that AI therapy can be associated with a particular clinical syndrome of arthralgias, and breast cancer specialists are becoming more familiar with these symptoms. Typical sites of discomfort include the hands (fingers and wrists), arms, knees, and feet, pelvic and hip bones, and back. In our experience, patients describe stiffness, achiness, or pain that is usually symmetric, may be associated with mild thickening of the soft tissues (for instance, rings do not fit as before), and is temporally associated with onset of AI therapy. Symptoms may be most noticeable on awakening, and often improve with morning activities. Patients frequently make gestures such as squeezing or flexing their joints to show affected areas, and often mention that they feel they have "aged" abruptly. The true prevalence of such symptoms among breast cancer survivors is not known, and thus the report from Crew et al9 at Columbia University in this issue of JCO is most welcome. These investigators asked postmenopausal women receiving AI therapy to complete a self-administered questionnaire that focused on joint pain and stiffness. The findings resonate with the words of patients in our breast cancer clinics: nearly half (47%) describe AI-associated joint pain or stiffness, either originating or worsening during AI treatment. Although the majority of patients described mild to moderate symptoms, nearly one fourth had symptoms rated as severe. Adjuvant taxane therapy, which also can cause musculoskeletal symptoms, seemed to increase the risk of arthralgias. Joint symptoms prompted patients to try pharmacologic interventions, both conventional analgesics such as acetaminophen or nonsteroidal anti-inflammatory agents, and nonconventional supplements. Most women reported some relief with these interventions. The survey has a number of methodologic challenges. Patients who had already discontinued AI treatment because of symptoms—arguably those most affected by the adverse effects of AI therapy—would not be captured in a cross-sectional survey. Furthermore, symptomatic patients may be more interested in participating in a symptom assessment study, potentially contributing to artificially high rates of symptom frequency and intensity. Recall bias may enrich the likelihood of reported symptoms. However, the reported incidence seems credible. It is not surprising that a questionnaire focused on bone and joint problems would reveal more widespread symptomatology than suggested by adverse effect or toxicity monitoring in adjuvant trials. The observation that so many women had already decided by themselves to intervene to relieve these symptoms lends credence to arthralgias as a major patient concern. Emerging data from other sources also suggest a high prevalence of AI-associated arthralgias. A chart review of 50 patients in Ottawa found that 22% had discontinued adjuvant AI therapy because of toxicity, for reasons including self-reported arthralgias, arthritis, and myalgias.10 In a prospective study of 40 women beginning adjuvant AI therapy, 20% developed arthralgias rated as grade 2 or 3, without evidence for other autoimmune disorders.11 Neither the cause, nor the time course, nor the treatment for AI-associated arthralgias is well understood. Investigators have suggested that estrogen deprivation contributes to joint discomfort.12 Classic case reports in the oncology literature of postchemotherapy rheumatism, arising in breast cancer patients with chemotherapy-induced menopause, support the relationship between declines in estrogen levels and joint symptoms.13 However, the pathophysiological mechanisms linking a low estrogen milieu and joint pain are not clear. Magnetic resonance imaging among patients with marked AI-associated joint pain in their hands disclosed tenosynovial thickening without laboratory stigmata of autoimmune dysfunction.14 How does this new information help breast cancer patients and clinicians? First, awareness of AI-associated arthralgias remains modest, and it is clearly important for doctors and patients to appreciate this common adverse effect of these widely used drugs. Patients may better cope with symptoms that are understood to be linked to their cancer treatments. Second, bone and joint symptoms in breast cancer patients require thoughtful review and evaluation. Breast cancer patients are at risk for inflammatory or osteoarthritis, normal "aches and pains," and metastatic cancer. The time course of onset, the presence or absence of joint swelling, erythema, warmth or pain, asymmetric symptoms, involvement of joints outside of the hands/feet (where cancer rarely spreads), and other constitutional findings may lead clinicians toward appropriate evaluations for other causes of joint pain. In our clinical experience, extensive rheumatologic evaluation (such as measurement of erythrocyte sedimentation rate, rheumatoid factor, or antinuclear antibody) has not been informative when the clinical history and examination lacked other suggestions of rheumatologic illness, although more research in this area is needed. AI-associated arthralgias are a new frontier in supportive care for cancer patients, and clearly warrant rigorous clinical trials to evaluate whether common analgesics or other novel treatments may improve symptoms. Anecdotal experience suggests that regular exercise may mitigate some symptoms in some patients. For patients with disabling or debilitating symptoms, discontinuation of AI therapy is reasonable, and if the diagnosis is accurate, such discontinuation is effective for alleviating pain, usually within weeks. At present, it is not clear if AI-associated arthralgias are a so-called class effect common to all AIs, or whether different AIs might carry more or less risk. Rechallenging patients with a different AI might identify a better-tolerated drug. Tamoxifen, which generally is not associated with arthralgias, is an effective adjuvant endocrine therapy should AI treatment prove intolerable. AI-associated arthralgias have emerged as a major patient concern in adjuvant breast cancer therapy, and it is hoped that additional studies will clarify the cause, and eventually treatment, for this common malady. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Harold J. Burstein, Eric P. Winer Data analysis and interpretation: Harold J. Burstein, Eric P. Winer Manuscript writing: Harold J. Burstein, Eric P. Winer Final approval of manuscript: Harold J. Burstein, Eric P. Winer REFERENCES
1. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone-receptor positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005 2. Chien AJ, Goss PE: Aromatase inhibitors and bone health in women with breast cancer. J Clin Oncol 24:5305-5312, 2006 3. Hillner B, Ingle JN, Chlebowski R, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 4. Donnellan PP, Douglas SL, Cameron DA, et al: Aromatase inhibitors and arthralgias. J Clin Oncol 19:2767, 2001 5. Burstein HJ: Aromatase inhibitor associated arthralgia syndrome. Breast 16:223-234, 2007[CrossRef][Medline] 6. Fallowfield L, Cella D, Cuzick J, et al: Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant breast cancer trial. J Clin Oncol 22:4261-4271, 2004 7. Whelan TJ, Goss PE, Ingle JN, et al: Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931-6940, 2005 8. Fallowfield LJ, Bliss JM, Porter LS, et al: Quality of life in the intergroup exemestane study: A randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 24:910-917, 2006 9. Crew KD, Greenlee H, Capodice J, et al: Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25:3877-3883, 2007 10. Dent S, DeValentin T, Vandermeer L, et al: Long-term toxicities in women with early stage breast cancer treated with aromatase inhibitors: Data from a tertiary care center. Breast Cancer Res Treat 100:S190, 2006 (suppl 1; abstr 4057) 11. Azria D, Lamy PJ, Belkacemi Y, et al: Letrozole-induced arthralgia is not consistent with an autoimmune disease resembling Sjögren's syndrome: Preliminary results of a multicentric prospective trial. Breast Cancer Res Treat 100:S25, 2006 (suppl 1; abstr 106) 12. Felson DT, Cummings SR: Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 52:2594-2598, 2005[CrossRef][Medline] 13. Loprinzi CL, Duffy J, Ingle JN: Postchemotherapy rheumatism. J Clin Oncol 11:768-770, 1993[Abstract] 14. Morales L, Pans S, Paridaens R, et al: Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: Associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat [epub ahead of print on October 24, 2006] Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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