Aromatase Inhibitors and Musculoskeletal Pain in ...

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FEATURE ARTICLE

Aromatase Inhibitors and Musculoskeletal Pain in Patients With Breast Cancer Loren Winters, MSN, APRN, BC, WHNP, OCN®, Karleen Habin, RN, and Joan Gallagher, EdD, APRN, BC, AOCN® Aromatase inhibitors are recommended for use by postmenopausal women who have estrogen receptor–positive early-stage breast cancer. They reduce local and distant recurrence more effectively than tamoxifen. Anastrozole (Arimidex®, AstraZeneca Pharmaceuticals LP), letrozole (Femara®, Novartis Pharmaceuticals Corporation), and exemestane (Aromasin®, Pfizer Inc.) inhibit aromatase activity, thus significantly decreasing estrogen production in tissues such as liver, muscle, and fat. Very low levels of estrogen may be one cause of musculoskeletal pain, a common side effect associated with the drugs. In the major adjuvant aromatase inhibitor clinical trials, 25% –30% of the patients enrolled experienced musculoskeletal pain. Although quality-of-life studies demonstrate that aromatase inhibitors are well tolerated overall, some women discontinue this treatment because of musculoskeletal pain. Little is known about how to predict, measure, or manage musculoskeletal pain caused by aromatase inhibition. Oncology nurses play an important role in the assessment and management of side effects related to cancer. This article provides an overview of the current knowledge about musculoskeletal pain in patients with breast cancer receiving aromatase inhibitor therapy.

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ecent clinical trials indicate that aromatase inhibitors (e.g., anastrozole, letrozole, exemestane) should be included in the adjuvant treatment of postmenopausal women with estrogen receptor–sensitive breast cancer. Most women with breast cancer are postmenopausal, and in these women, approximately 75% of tumors are endocrine sensitive (Anderson, Chatterjee, Ershler, & Brawley, 2002). The American Society of Clinical Oncology has recommended that optimal therapy for postmenopausal women with endocrine-sensitive breast cancer include an aromatase inhibitor (Winer et al., 2005). The National Comprehensive Cancer Network (2007) has provided guidelines on the use of aromatase inhibitors for adjuvant hormonal therapy in invasive breast cancer. Oncology nurses can anticipate that they will be caring for more patients receiving adjuvant therapy with aromatase inhibitors. Aromatase is the enzyme that converts androgens into estrogens. In postmenopausal women, estrogen is synthesized by the aromatase enzyme in peripheral tissues, rather than in the ovaries, and acts locally (Simpson, 2003) (see Figure 1). Aromatase inhibitors are orally active agents that cause near-complete inhibition of aromatase activity and, therefore, significantly deplete estrogen levels within two to four days of initiating therapy (Buzdar, Robertson, Eiermann, & Nabholtz, 2002; Lonning, 1996). By decreasing the concentration of endogenous estrogens to low levels, little of the hormone is left circulating (Buzdar, 2003), effectively starving estrogen-sensitive tumor cells.

At a Glance ✦ Aromatase inhibitors are indicated for the treatment of postmenopausal women with estrogen receptor–positive breast cancer, especially in patients with high-risk disease. ✦ Musculoskeletal pain induced by aromatase inhibitors may be a result of a reduction in systemic estrogen similar to but lower than a menopause effect. ✦ Nurses play an important role in the assessment, management, and education of patients experiencing musculoskeletal pain related to aromatase inhibitor therapy.

Loren Winters, MSN, APRN, BC, WHNP, OCN®, is a nurse practitioner in the Cancer Center, Karleen Habin, RN, is a nurse manager in breast care research, and Joan Gallagher, EdD, APRN, BC, AOCN®, is a preadmission testing area staff nurse, all at Massachusetts General Hospital in Boston. No financial relationships to disclose. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted September 2006. Accepted for publication February 9, 2007.) Digital Object Identifier: 10.1188/07.CJON.433–439

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Canada Clinical Trial Group (NCIC CTG) Intergroup Trial MA.17, following five years of tamoxifen, 5,157 patients were randomized to five years of letrozole or placebo (Goss et al., 2003). Letrozole reduced breast cancer recurrences and the incidence of new breast cancers (Goss et al., 2003). In the subset of axillary node– positive patients, overall survival was improved for those on letrozole (Goss et al., 2005). The Breast International Group (BIG) 1-98 Collaborative Group (2005) compared four arms consisting of (a) letrozole, (b) letrozole followed by tamoxifen, (c) tamoxifen, and (d) tamoxifen followed by letrozole in 8,010 patients. The study confirmed the positive results reported of letrozole in the NCIC CTG trial. In summary, the trials show that in postmenopausal women with estrogen-sensitive breast cancer, aromatase inhibitors should be included to achieve optimal adjuvant endocrine therapy. At the time this article was written, the optimal agent, sequence, and duration of aromatase inhibitor therapy were not yet determined but were being studied.

Aromatase Inhibitors and Musculoskeletal Pain Note. Aromatase inhibitors are shown binding to aromatase (lower right), preventing the androgen substrate (red molecules) from binding and being converted to estradiol and estrone. This reduces the level of estrogen in the bloodstream of the patient with breast cancer. Insets on left, top to bottom, depict adipose tissue, adrenal cortex, and breast tumor.

Figure 1. Aromatase Inhibitors Shown Binding to Aromatase Note. Copyright Kevin A. Somerville/Phototake. All rights reserved. Reprinted with permission.

Researchers have reported on several large, randomized, adjuvant trials comparing aromatase inhibitors with tamoxifen and placebo. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial compared adjuvant anastrozole with tamoxifen in 9,366 patients (Baum et al., 2002). No difference was found between tamoxifen alone and the combination. At a median of five years of follow-up, participants taking anastrozole experienced a longer period of disease-free survival and a reduced incidence of contralateral breast cancer and distant metastases (Baum, 2005). A combined analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 8 and the Arimidex-Nolvadex 95 Trial conducted by the German Adjuvant Breast Cancer Group followed postmenopausal women who completed two years of tamoxifen and were randomized to either continue tamoxifen or switch to anastrozole (Jakesz et al., 2005). After a median follow-up of 28 months, a higher event-free survival rate and decreased risk of metastasis were found in the patients who switched to anastrozole and no significant difference in survival was found. The International Exemestane Study (IES) randomized 4,742 patients with breast cancer to tamoxifen or exemestane following two to three years of adjuvant tamoxifen (Coombes et al., 2004). At a median follow-up of 30.6 months, participants who were switched to exemestane experienced improved disease-free survival and reduced contralateral breast cancer compared with those receiving extended tamoxifen treatment. In the National Cancer Institute of 434

Quality-of-life studies from the adjuvant aromatase inhibitor trials reported no compromise in overall quality of life for patients receiving aromatase inhibitor therapy (Fallowfield, 2005; Fallowfield et al., 2004; Whelan et al., 2005). However, significant differences existed in certain domains of quality of life. In the ATAC trial, hot flashes and musculoskeletal pain were the adverse effects reported most often. Thirty percent of patients receiving anastrozole reported musculoskeletal problems, compared to approximately 24% of patients receiving tamoxifen (p < 0.001) (Baum et al., 2003). Fewer patients overall withdrew from anastrozole because of adverse effects when compared to those on tamoxifen or combination therapy. In the IES trial, those on exemestane experienced more arthralgia than those on tamoxifen (Coombes et al., 2004). In the NCIC CTG trial, 51% of patients in the letrozole group, compared with 47% in the placebo group, reported a worsening quality of life because of bodily pain. The difference between the groups was statistically significant (Whelan et al.). Of those receiving letrozole, 5% discontinued using the drug because of overall toxicity over five years of therapy, compared with 4% of those on placebo (Goss et al., 2005). Donnellan, Douglas, Cameron, and Leonard (2001) reported that in a sample of 77 patients with metastatic breast cancer taking anastrozole, 12 patients reported joint pain, and, of those, 4 patients discontinued treatment because of symptom severity. One small, randomized, single-blinded crossover study of 72 patients with metastatic breast cancer showed an 11% overall incidence of joint pain among those on anastrozole compared with 3% of those on letrozole (p = 0.025) (Thomas, 2003). Although studies are ongoing, no data have been published from randomized, double-blind comparative studies of aromatase inhibitors in the adjuvant setting (Berry, 2005).

Menopause and Musculoskeletal Pain The hormone estrogen can affect overall response to pain. Estrogen is known to have an anti-inflammatory effect on body tissues, which is best illustrated by the observation that preg-

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nancy improves symptoms of rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease (Harnish, 2006). Changes in serum estrogen levels may affect the neurogenic pain response. Some studies suggest that high serum estrogen levels cause the body to release endorphins and enkephalins that can help dampen painful stimuli received by the brain (Felson & Cummings, 2005). Likewise, a decrease in estrogen level typically reduces the body’s ability to dampen pain (Zubieta et al., 2005). Researchers have suggested that because of a direct effect of estrogen on opioid pain fibers in the central nervous system, depleted estrogen levels might be a contributing factor in women with muscle and joint pain (Felson & Cummings). Menopause is defined as 12 months of amenorrhea after the final menstrual period and reflects complete ovarian follicular depletion and absence of ovarian estrogen secretion (Casper, 2006). Common symptoms include hot flashes, sleep disturbances, genitourinary symptoms, skin changes, and musculoskeletal pain. In a study of 251 premenopausal, perimenopausal, and postmenopausal women, joint or muscle pain was reported by 57% of the women but was not associated with menopausal status (Xu et al., 2005). Nineteen percent of the perimenopausal women and 9% of the postmenopausal women reported joint or muscle pain (Xu et al.). In Caucasian women, joint or muscle pain was prevalent during premenopause, perimenopause, and postmenopause, whereas in African American women, joint or muscle pain was prevalent only during premenopause (Xu et al.). An analysis of women in the United States ages 40–55 from different racial or ethnic groups showed that Caucasian women reported a significantly higher number of psychosomatic symptoms (e.g., stiffness, irritability, hot flashes) than women from other racial groups (Avis et al., 2001). African American women were significantly more likely to report vasomotor symptoms than Caucasian women (Avis et al.). A study of 427 premenopausal, perimenopausal, and postmenopausal women in gynecology clinics in Bangkok, Thailand, reported that the prevalence of menopausal symptoms such as muscle and joint pain was highest in the first two years after menopause and tended to decrease afterward (Sueblinvong, Taechakraichana, & Phupong, 2001). Joint or muscle pain is commonly reported by women during menopause, and studies have shown a difference in prevalence of symptoms with respect to race or ethnic background and years after menopause. Women who have undergone surgically induced menopause also seem to experience a greater incidence of joint pain. An association has been reported between hysterectomy, oophorectomy, and development or worsening of joint disease (Spector et al., 1991). However, more study is needed to determine the true prevalence of joint or muscle pain in the patients.

Musculoskeletal Disorders and Menopause Postmenopausal women are at risk for the development of painful musculoskeletal disorders such as arthritis and osteoporosis. In a population of more than 200,000 postmenopausal women without a prior diagnosis of osteoporosis, 40% were found to have osteopenia and 7% were found to have

osteoporosis indicated by dual energy x-ray absorptiometry testing (Siris et al., 2001). Female gender, early menopause, and primary or secondary amenorrhea are known risk factors for the development of osteoporosis (Dennison, Mohamed, & Cooper, 2006). Bone loss is known to contribute to arthralgias in menopausal women (Burstein, in press). In a study of 3,299 women with postmenopausal osteoporosis, 93% had skeletal pain (Scharla et al., 2006). Both rheumatoid arthritis and osteoarthritis are more common in women than in men. In a survey of 48,218 men and women older than age 55, women had a higher incidence of arthritis of the hip and knee, worse symptoms, and greater disability than men (Hawker et al., 2000). Women older than age 55 also have a higher incidence of osteoarthritis of the interphalangeal joints and thumb base (Brandt, 2005). Older adult onset rheumatoid arthritis, although significantly less prevalent than osteoarthritis, occurs in 2% of the population older than age 60, and in those patients, some studies have suggested a female predominance (Tutuncu & Kavanaugh, 2007). Some researchers have suggested that in patients with an autoimmune disease such as rheumatoid arthritis, changes in serum estrogen, such as those associated with menstrual cycle, pregnancy, or menopause, may affect the immune response (Cutolo et al., 2006). Furthermore, synovial cells from postmenopausal women have been shown to be able to express aromatase mRNA (Le Bail et al., 2001). Inflammatory cytokine production in the synovial fluid may cause increased activity of the aromatase enzyme and, therefore, increased estrogen synthesis in the synovial fluid. Research has indicated that because women have lower levels of circulating androgens than men, women may benefit less from the aromatase-mediated production of proinfl ammatory estrogens (Cutolo et al.). Although controversial, evidence suggests that exogenous estrogen may be useful in the treatment of osteoarthritis and rheumatoid arthritis (Fox, 2005; Nevitt et al., 1996; Spector, Nandra, Hart, & Doyle, 1997). In the United States, hormone replacement therapy has been used to treat menopause-associated joint pain. For the more than 16,000 postmenopausal women studied in the Women’s Health Initiative, estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms at year one (Barnabei et al., 2005). The Women’s Health Initiative showed that estrogen plus progestin therapy increased bone mineral density and reduced the risk of fracture (Cauley et al., 2003). Estrogen and progestin therapy are clearly contraindicated in women with a history of estrogen-sensitive breast cancer.

Evaluation of Musculoskeletal Pain Musculoskeletal disorders are a significant health problem. Arthritis is a leading cause of disability in the United States and is a term used to describe more than 100 different types of conditions that affect the joints and connective tissues (Centers for Disease Control and Prevention, 2005). The terminology that is available and used to describe the pain associated with aromatase inhibitors can be confusing. Healthcare providers are challenged to differentiate aromatase inhibitor drug-related arthritis and arthralgia from preexisting or new connective tissue disease. The NCIC CTG and IES trialists used the National


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Cancer Institute’s (1999) Common Toxicity Criteria for Adverse Events to identify and grade joint pain. Arthralgia is defi ned as mild, moderate, or severe joint pain, whereas arthritis is defi ned as mild, moderate, or severe pain in the joints with erythema, inflammation, or swelling (National Cancer Institute). Both are graded by how the pain interferes with function. Use of an algorithm may be helpful for the diagnosis of musculoskeletal complaints (Cush & Lipsky, 2006) and to assess new onset joint pain in patients using aromatase inhibitors. However, further study is needed to determine whether an algorithm intended for use in primary care will help to differentiate between arthritis and drug-induced arthralgia in patients with breast cancer receiving aromatase inhibitors.

Cancer Treatments and Musculoskeletal Pain Oncology nurses who care for patients with breast cancer are familiar with treatment-related adverse effects of drugs such as taxanes, bisphosphonates, and colony-stimulating growth factors. Taxanes cause arthralgia and myalgia in 75% of patients (Rowinsky et al., 1993). Reports of aching hips, thighs, and shoulders are referred to as myalgia or arthralgia (Martin, 2004). A variety of medications have been used to prevent and treat this side effect, but as of 2006, little evidence supports the efficacy of the medications. Pegfi lgrastim (Neulasta®, Amgen Inc.), a long-acting growth factor used in adjuvant chemotherapy protocols to help prevent treatment-induced neutropenia, is known to cause myalgia and arthralgia as part of a flu-like syndrome (Wilkes & Barton-Burke, 2005), which usually is managed successfully with over-the-counter analgesics. Alendronate (Fosamax®, Merck & Co., Inc.) and risedronate (Actonel®, Procter & Gamble Pharmaceuticals, Inc.), two drugs used to treat osteoporosis, have been associated with cases of severe bone pain (Wysowski & Chang, 2005). Patients on aromatase inhibitors with bone density loss often are given bisphosphonates to reduce the risk of fractures. Further study is needed to determine how a patient’s experience with other cancer treatment-related musculoskeletal pain influences the ability to tolerate aromatase inhibitor therapy.

Management of Musculoskeletal Pain No evidence-based practices are available to treat musculoskeletal pain caused by aromatase inhibitors in patients with breast cancer. Clinically, oncologists might choose to prescribe analgesics, allow for a treatment break, discontinue the drug, switch to tamoxifen, or try another aromatase inhibitor. Oncology nurses should consider a care plan for patients starting on aromatase inhibitor therapy (see Figure 2) and be prepared to explore the use of anti-inflammatories, acetaminophen, and supportive measures such as complementary and alternative medicine (CAM) or exercise programs. Women with breast cancer and people with arthritis have reported frequent use of CAM (Lengacher et al., 2002; Quandt et al., 2005). Patients with breast cancer use CAM to relieve symptoms and side effects (Lengacher et al., 2006). In one survey of 2,022 breast cancer survivors, tamoxifen or anastrozole therapy was as436

• Review the patient’s understanding of the goal of therapy and expected side effects. • Identify risk factors or cofactors that may contribute to musculoskeletal pain such as age, menopausal symptoms, weight, lifestyle, history of osteoarthritis or rheumatoid arthritis, chemotherapy side effects, or medications such as bisphosphonates. • Assess severity of pain using a validated grading system such as the Common Toxicity Criteria or a 0–10 pain scale. • Examine affected joints and muscles for tenderness, swelling, warmth, and redness. • Document onset, location, character, intensity, and relieving and exacerbating factors of pain at baseline and during treatment. • Explore the effect of pain on quality of life. • Consider adjuvant approaches to joint and muscle pain management such as using heat or ice, over-the-counter analgesics, or acupuncture. • Promote lifestyle adjustments such as controlling weight, eating a healthy diet, and exercising regularly. • Follow up with patients regarding results of interventions and compliance. • Explore reasons for drug discontinuation.

Figure 2. Care Plan for Patients With Breast Cancer Starting Aromatase Inhibitor Therapy

sociated with the use of homeopathic therapies (Buettner et al., 2006), but little evidence supports its efficacy. Preliminary evidence exists suggesting that acupuncture may be an effective adjunctive treatment for arthritis-related pain (Berman et al., 2004; Vas et al., 2004). The efficacy of using supplements such as chondroitin and glucosamine to reduce arthritis pain is controversial. Braham, Dawson, and Goodman (2003) suggested that up to 8–12 weeks of treatment with 2 g daily of glucosamine is necessary to obtain benefit. Although some evidence supporting the use of chondroitin and glucosamine for joint pain has been identified (Soeken, 2004), the Glucosamine/Chondroitin Arthritis Intervention Trial, a multicenter, double-blind, placebo and celecoxib controlled study, showed that these agents, either alone or in combination, did not reduce pain effectively in patients with osteoarthritis pain in the knee (Clegg et al., 2006). Exercise is part of the nonpharmacologic treatment of joint pain related to osteoarthritis (Lane & Thompson, 1997). It has been shown to reduce pain and improve physical function in those with osteoarthritis of the knee (Fransen, McConnell, & Bell, 2003). Research also has shown exercise to be an important self-care intervention in patients with breast cancer undergoing adjuvant therapy (Markes, Brockow, & Resch, 2006; McNeely et al., 2006). Aromatase inhibitor therapy is associated with significantly greater osteoporotic fractures and bone mineral density loss (Perez & Weilbaecher, 2006). Exercise reduces bone loss in postmenopausal women (Kemmler et al., 2004) and should be recommended to patients with breast cancer receiving aromatase inhibitors along with adequate calcium and vitamin D intake. More research is needed to determine whether a lifestyle adjustment such as exercise can reduce joint pain severity directly or by its impact on weight control and metabolic effect.


Implications for Research The goal of adjuvant endocrine therapy is to prevent cancer recurrence by providing treatments with as few side effects as possible (Tobias, 2004). Aromatase inhibitors generally are believed to be well tolerated. Quality-of-life subprotocols from the ATAC, NCIC CTG, and IES trials report better overall tolerability with an aromatase inhibitor compared with tamoxifen (Fallowfield, 2005; Fallowfield et al., 2004; Whelan et al., 2005). Perhaps, clinicians underreport symptoms associated with endocrine therapy (Fellowes, Fallowfield, Saunders, & Houghton, 2001). The three major trials of aromatase inhibitors use different instruments to report on quality of life; therefore, a direct comparison within this family of drugs is not possible (Fallowfield). Musculoskeletal pain associated with aromatase inhibitor therapy can be a challenge to patients and oncology nurses. Knowledge about what causes aromatase inhibitor-related muscle and joint pain is limited. Endocrine therapy trials identify the problem but provide little guidance on how to predict which patients may experience toxicity. Factors such as concomitant musculoskeletal disorders, menopausal state and symptoms, and history of pain from other cancer-related treatments may influence women’s ability to tolerate aromatase inhibitors. Without a thorough assessment and patient education regarding side effects, quality of life and compliance may be compromised. The data from three major clinical trials show that optimal adjuvant endocrine therapy for postmenopausal women with estrogensensitive breast cancer should include an aromatase inhibitor. Most breast cancer survivors with invasive estrogen-dependent tumors will be placed on an aromatase inhibitor at some point in their treatment. Those patients will need oncology nurses to provide guidance on how to manage menopausal symptoms and treatment-associated side effects. Research has shown that nursing interventions can reduce symptom burden and improve quality of life in patients undergoing chemotherapy (Given et al., 2002). The development of nursing interventions in the management of aromatase inhibitor–related pain in patients with breast cancer is an exciting and important area for future nursing research. Author Contact: Loren Winters, MSN, APRN, BC, WHNP, OCN®, can be reached at [email protected], with copy to editor at CJONEditor@ons .org.

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