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Originally published as JCO Early Release 10.1200/JCO.2008.16.7684 on May 12 2008 © 2008 American Society of Clinical Oncology.
Getting a Grip on Aromatase Inhibitor–Associated Arthralgias
Department of Medicine, Columbia University Medical Center, New York. NY 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,1 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.2-4 Among patients taking AIs, many discontinue as a result of arthralgias.5 The large adjuvant trials of AIs for breast cancer treatment6-8 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.9 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.10,11 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. Another strategy to address this issue is to gain a better understanding of the natural history of toxicities and to develop objective functional measures that can be used to characterize the syndrome. More importantly, these measures can provide tools for prospective toxicity assessments that can be used as outcome measures in prospective clinical trials. In this issue of the Journal of Clinical Oncology, Morales et al12 report results from a prospective study that evaluated women initiating treatment with AIs and tamoxifen. They show that the subjective symptoms of arthralgias and joint stiffness that have previously been reported are also associated with physiologic changes to the joint and functional impairments. The patients in this study were assessed with serial magnetic resonance imaging, measures of grip strength, and completed symptoms self-assessments. In a 6-month period, the majority of women taking AIs were more likely than those on tamoxifen to have an increase in tenosynovial changes as seen on magnetic resonance imaging, and a decrease in grip strength as measured by a simple to administer modified sphygmomanometer, and increased pain and stiffness as measured by questionnaire. Importantly, the objective, easy to reproduce, and inexpensive hand grip test was well correlated with the tenosynovial changes seen on magnetic resonance imaging. To perform the hand grip test, the patient is asked to squeeze the balloon of a modified sphygmomanometer three times with maximal force and the average value of three trials of each hand is recorded. This assessment has high inter-rater reliability and takes a minimal amount of time to administer.13 This has implications both in terms of patient monitoring, as well as for clinical trial designs, for future promising interventions to alleviate this important treatment-related adverse effect. With the identification and description of treatment-related toxicities, comes the opportunity to prevent or treat these symptoms, with the goal of improving both quality of life and adherence. Supportive care trials have, however, been plagued with the same criticisms related to the subjective, patient-reported assessments used to measure symptoms. Traditionally, the US Food and Drug Administration requires substantial evidence for reaching a conclusion that a drug will have an effect. PRO-based evidence of improved symptoms alone generally is not sufficient to substantiate a claim related to a patient's ability to function or the patient's psychological state. Rather, evidence that shows not only a change in symptoms, but how that change translates to other specific end points, such as the patients ability to perform activities, is required.14 It is also important to note that many women who develop arthralgias report improvement of their symptoms over time. The study by Morales et al, reported two time points after treatment initiation. We do not know yet what longer follow-up would show us. In addition, it is also important to recognize that while some of these changes reported were statistically significant, it is unclear that they have clinical significance. While all patients on AIs experienced a change from baseline, only two (16%) stopped taking AIs as a result of toxicity, and therefore while useful as a biomarker it is not clear if there is clinical application for these objective assessments. The exact mechanism of AI-related arthralgia and subsequent tenosynovial change is unclear, but may be related to estrogen deprivation. The development of AI-induced musculoskeletal disorders may be analogous to the development of hand and knee osteoarthritis at menopause.15 Studies of the incidence and prevalence of osteoarthritis in postmenopausal women with and without hormone replacement therapy have provided strong support for a protective effect of estrogens against osteoarthritis.16-19 Because estrogen replacement is not an option for these women, alternative approaches need to be explored. While research in this area is limited, one small pilot study evaluated the use of acupuncture to relieve symptoms of AI-associated arthralgias. In this study of 21 women treated with a 6-week course of acupuncture, improvement was reported in pain severity, pain-related functional outcomes, and physical well-being.20 This study was limited due to small samples sizes and lack of a control group. Ongoing randomized controlled studies are evaluating the efficacy of acupuncture, exercise, and herbal supplements to improve these symptoms. Future studies should incorporate objective measures of grip strength into the outcomes assessments. Many patients use complementary and alternative approaches to symptoms management and do not want to take additional pharmacologic treatments to control adverse effects from cancer treatment, therefore controlled trials of their safety and efficacy for symptoms management are warranted.21 Another approach may be to identify patients upfront who may have the highest risk for developing severe toxicities. In the study reported by Morales et al,12 three patients had tenosynovial changes at baseline that worsened after 6 months of AI therapy. One approach may be to assess patients with a history of arthritis for abnormalities of the synovium before the initiation of AI therapy. Patients with abnormalities may be offered tamoxifen or closely monitored for effects of therapy. With the increasing use of long-term AI therapy in the adjuvant setting, AI-induced arthralgia is becoming a major issue for cancer survivors and treating physicians. The majority of women who experience arthralgias continue with their treatment given the profound benefits associated with these medications. With a better understanding of the physiologic effects of these agents, we can develop targeted therapies or other interventions to manage this treatment-related adverse effect and improve both adherence and overall quality of life among breast cancer survivors. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on May 12, 2008 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. Fallowfield L, Fleissig A, Edwards R, et al: Tamoxifen for the prevention of breast cancer: Psychosocial impact on women participating in two randomized controlled trials. J Clin Oncol 19:1885-1892, 2001 3. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602-606, 2003 4. Partridge AH, LaFountain A, Mayer E, et al: Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 26:556-562, 2008 5. Dent S, DeVelentin T, Vanermeer 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 6. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 7. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 8. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 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. Varricchio CG, Sloan JA: The need for and characteristics of randomized, phase III trials to evaluate symptom management in patients with cancer. J Natl Cancer Inst 94:1184-1185, 2002 11. Basch E, Iasonos A, McDonough T, et al: Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: Results of a questionnaire-based study. Lancet Oncol 7:903-909, 2006[CrossRef][Medline] 12. Morales L, Pans S, Verschueren K, et al: Prospective study to assess short-term intra-articular and tenosynovial changes in the aromatase inhibitor–associated arthralgia syndrome. J Clin Oncol 26:3147-3152, 2008 13. Kaegi C, Thibault MC, Giroux F, et al: The interrater reliability of force measurements using a modified sphygmomanometer in elderly subjects. Phys Ther 78:1095-1103, 1998 14. Guidance for industry: Patient-reported outcome measures: Use in medical product development to support labeling claims: Draft guidance. Health Qual Life Outcomes 4:79, 2006[CrossRef][Medline] 15. Cecil RL, Archer BH: Arthritis of the menopause. JAMA 84:75-79, 1925 16. Nevitt MC, Cummings SR, Lane NE, et al: Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women: Study of Osteoporotic Fractures Research Group. Arch Intern Med 156:2073-2080, 1996 17. Hannan MT, Felson DT, Anderson JJ, et al: Estrogen use and radiographic osteoarthritis of the knee in women: The Framingham Osteoarthritis Study. Arthritis Rheum 33:525-532, 1990[Medline] 18. Spector TD, Nandra D, Hart DJ, et al: Is hormone replacement therapy protective for hand and knee osteoarthritis in women? The Chingford study. Ann Rheum Dis 56:432-434, 1997 19. Chlebowski RT, Johnson KC, Kooperberg C, et al: The Women's Health Initiative randomized trial of calcium plus vitamin D: Effects on breast cancer and arthralgias. J Clin Oncol 24:2s, 2006 (suppl; abstr LBA6)[CrossRef] 20. Crew K, Capodice J, Greenlee H, et al: Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients. J Cancer Surviv 1:283-291, 2007[CrossRef][Medline] 21. Navo MA, Phan J, Vaughan C, et al: An assessment of the utilization of complementary and alternative medication in women with gynecologic or breast malignancies. J Clin Oncol 22:671-677, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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