Aromatase inhibitors (AIs) are the standard treatment for postmenopausal women with hormone receptor–positive breast cancers. One of the most common side effects of AIs is joint pain; it is also the most frequently cited reason for nonadherence and discontinuation before completion of the prescribed treatment course. Nonadherence and, in particular, discontinuation, can lead to increased rates of breast cancer mortality. The prevalence of AI-induced arthralgias is about 50%, and there are several interventions, including switching to a different AI, that can increase adherence. The healthcare professional plays a part in fostering adherence by communicating the side effects of AIs to patients before the initiation of treatment, as well as explaining the strategies for addressing these side effects, should they occur.
Introduction
Adjuvant endocrine therapy is the standard of care for women with estrogen receptor– and progesterone receptor–positive breast cancers. Endocrine therapies include aromatase inhibitors (AIs), such as the nonsteroidal compounds letrozole and anastrozole and the steroidal compound exemestane. All three AIs have comparable benefits and side effect profiles. The selective estrogen receptor modulator tamoxifen has anticancer activity in pre- and postmenopausal women. While AIs only have anticancer activity in postmenopausal women, they are superior to tamoxifen at reducing the risk of recurrence and improving overall survival.[1-3]
AIs and tamoxifen require long-term daily self-
administration of oral medications for 5 years, and in some cases, 10 years. However, up to 28% of women in clinical trials, and as many as 73% in community practice settings, prematurely discontinue these drugs.[4-6] AI adherence in particular is suboptimal, ranging from 50% to 91% over 5 years of therapy,[6] and only 40% to 60% of women complete the recommended course of AIs.[7-9] A consequence of nonadherence and discontinuation is an increase in breast cancer mortality.[8-10]
Medication “adherence” is synonymous with medication “compliance.” Adherence is measured over time and reported as a percentage.[11] The preference for “adherence” over “compliance” is due to the former term’s less harsh and judgmental connotations regarding patients’ behavior.[12] Persistence is the duration of time from initiation to discontinuation of therapy, and is a continuous variable referring to the duration of treatment.[11,12] Persistence is a specific aspect of adherence.
There are several ways to measure adherence. One method is to review prescription refill data and the medication possession ratio (MPR). The MPR is the ratio of total days of medication divided by the entire duration of days that the drug is prescribed for, with adherence defined as > 80%.[8] Another method of measuring adherence is to use patient-reported data, which may take into account behaviors and experiences. The most straightforward and reliable way to measure adherence is to ask the patient if she is taking the medication.
Risk Factors Leading to Treatment Nonadherence and Discontinuation
There are many independent risk factors for treatment nonadherence and discontinuation, including adverse effects; disease stage; use of chemotherapy (ie, taxanes); comorbidities; demographic features such as age, lower socioeconomic status, and race; and psychosocial factors such as quality of life, emotional distress, attitude toward therapy, and perception of self-efficacy.[13-16]
Adverse effects are the most common reason for nonadherence to and discontinuation of endocrine therapy. A survey of 538 women with early-stage breast cancer receiving endocrine treatments found that 18% of women discontinued therapy within 5 years, and 94% of them experienced adverse effects. Among those who discontinued AIs, two-thirds reported that they “did not like the adverse effects.”[15] Importantly, about 25% of the women in this study discontinued treatment without consulting a medical provider, thus missing an opportunity for guidance or shared decision making.
Adverse Effects of Endocrine Therapy
The adverse effects of endocrine therapy include hot flashes, vaginal dryness, dyspareunia, osteoporosis, and arthralgia/myalgia. For many of these side effects, there are proven interventions, including venlafaxine or gabapentin for hot flashes; vaginal moisturizers, dehydroepiandrosterone, the intravaginal laser MonaLisa Touch, and minimal doses of intravaginal estrogens for dyspareunia or vaginal dryness; and vitamin D and calcium supplementation, bisphosphonates, and denosumab for osteoporosis and osteopenia. Here, we will focus on arthralgia and myalgia, because mitigating these symptoms can prove especially challenging.
Arthralgia and myalgia are the most common side effects of AI treatment and contribute the most to nonadherence and discontinuation. The prevalence of AI-induced arthralgia is 50% (range, 20% to 73%).[17] Some studies combine data on arthralgia and myalgia, referring to the two together as ‘musculoskeletal symptoms.’[18] We have followed this practice here, using the term ‘AI-induced arthralgia’ to encompass myalgia as well. In one study of women with early-stage breast cancer receiving an adjuvant AI, more than half of those who discontinued treatment reported grade 2/3 arthralgia as the reason.[19]
The primary criteria defining AI-induced arthralgia are:
• Joint pain develops or worsens while a patient is taking an AI.
• If the AI is stopped for 3 weeks, the joint pain goes away. When the AI is subsequently restarted, the joint pain returns.[20]
Minor criteria include:
• The joints are affected symmetrically.
• The patient complains of pain in the hands or wrists, carpal tunnel syndrome, and/or decreased grip strength.
• Joint stiffness is worse in the morning.
• Exercise improves symptoms.
AI-induced arthralgia tends to occur soon after initiating treatment with an AI, with a median onset of 1.6 months (range, 0.4 to 10 months).[20] The mechanism(s) of AI-induced arthralgia are not entirely understood.[21] MRI findings show tenosynovitis with enhancement and thickening of the tendon sheaths, consistent with an inflammatory process.[22]
Our Approach to Maximizing Treatment Adherence to AI Therapy
In clinical practice, the biggest challenge of treating hormone receptor (HR)-positive breast cancer patients is helping them maintain adherence and complete the prescribed course of AI treatment. Some of the questions that clinicians often struggle with include: How do you know that the patient receiving an AI is experiencing AI-induced arthralgia, and what distinguishes it from osteoarthritis? What are the proven interventions for AI-induced arthralgia? Finally, what is the role of the healthcare provider in increasing adherence and decreasing discontinuation rates? Our experience mirrors the literature.[23]
Before starting AI therapy, weight management and increasing physical activity should be part of the routine care of every woman with breast cancer. Obesity increases breast cancer mortality, and increasing physical activity (ie, from being sedentary), though not proven, may decrease breast cancer mortality. Increasing physical activity has a wealth of benefits beyond breast cancer, and may mitigate AI-induced arthralgia. It is beyond the scope of this article to discuss the ‘teachable moment’[24] and the ways to effect behavior modification. However, three points are worth mentioning. The first point is that women receiving AIs desire information from their oncology provider about AI-induced arthralgia, and are more likely to increase physical activity if their oncologists recommend it.[25] Second, if AI-induced arthralgia occurs, despite maintaining optimal physical activity, there are approaches to mitigate it. Finally, it should be noted that there is a placebo effect in all intervention trials. For example, as many as 50% of women reported improvements in joint pain while receiving a placebo in a randomized placebo-controlled trial of omega-3 fatty acids for AI-induced arthralgias.[26] From the patient’s point of view, it doesn’t matter whether it’s a therapeutic effect of an intervention or the placebo effect, as long as it relieves the joint pain.
KEY POINTS
- It should be established that a patient’s joint pain is caused by her aromatase inhibitor (AI) and not related to other causes. The most effective way is to note what happens to the joint pain when the AI is stopped for about 2 to 4 weeks. If joint pain resolves, then rechallenge with the same AI. If joint pain reoccurs, causality is proven.
- One of the simplest and most effective methods of maintaining adherence in a patient who experienced AI-induced joint pain is to switch her to another AI. About 30% of women will stay on the second AI for a median of 14 months. Some women are intolerant of all three AIs and are then switched to tamoxifen.
- There are many trials of interventions to mitigate the pain of AI-induced arthralgia. Many of these are flawed methodologically, and are of low to moderate quality. Higher doses of vitamin D3 and omega-3 fatty acids are ineffective. However, there is recent evidence for duloxetine that shows both statistically significant and clinically meaningful reductions in AI-induced arthralgia.
- Healthcare providers have a role in increasing adherence and decreasing discontinuation rates. Adherence, in part, depends on good physician/patient communication with regard to the risks and benefits of treatments, and available alternatives.
Typically, we start endocrine treatment with the nonsteroidal compound anastrozole. If the patient has any preexisting arthritis, we note the sites of joint pain. As discussed previously, we describe the relatively rapid onset of AI-associated joint pain, and its typical pattern of affecting the joints symmetrically. To assess adherence, we directly ask the patient if she is taking her medication.[27]
If new joint symptoms appear while a patient is taking an AI, do not respond to over-the-counter medications, and are of sufficient magnitude to affect activities of daily living, we recommend stopping the AI for 2 to 4 weeks. If the joint pain persists, it is not likely related to the AI. If the joint pain improves, we recommend a rechallenge with the same AI. If the joint pain reoccurs, then a causal relationship between the particular AI and the joint pain is established.
One of the simplest and most effective interventions is switching from one AI to another or to tamoxifen[28,29]; about one-third of women who switch to another AI can tolerate the second AI for a median of nearly 14 months (range, 3 to 39 months).[30] For example, we would switch to the steroidal compound exemestane if anastrozole causes intolerable side effects. If exemestane results in joint pain, and rechallenge provokes the same joint pain, we would typically try tamoxifen in women for whom there are no absolute contraindications to this drug.
There are several recent systematic reviews of other interventions, including high-dose vitamin D3, omega-3 fatty acids, duloxetine, acupuncture, aerobic and resistance exercise training, yoga, and tai chi.[18,31] Many of the intervention trials have methodological problems, including small sample sizes, the inclusion of only retrospective or prospective cohorts, the use of different entry criteria for baseline level of joint pain, and the use of different instruments to measure the primary endpoint of joint pain, as well as secondary endpoints.
The results of acupuncture trials and exercise interventions, as well as studies on vitamin D3, are mixed.[18] Higher doses of omega-3 fatty acids in randomized controlled trials were shown to be ineffective at reducing AI-induced arthralgia.[18] Recently, the results of a randomized placebo-controlled trial of duloxetine showed statistically and clinically significant reductions in joint pain in women receiving AIs.[32] At Mount Sinai, there is an ongoing randomized controlled trial of hypnosis for women with AI-induced arthralgia. We encourage eligible patients to enroll in this trial. The uptake of the trial is high because it uses a nondrug intervention. We also often refer women with AI-induced arthralgia for acupuncture, despite the mixed trial results.
As healthcare providers, we tend to underestimate the role we play in maintaining adherence and reducing discontinuation. It is important to remember that adherence depends to a considerable degree on good physician/patient communication, as well as on the strength of the therapeutic relationship; good communication should include clear and careful explanations of risks, benefits, and alternatives to treatment.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
References:
1. Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2014;32:2255-69.
2. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28:509-18.
3. Early Breast Cancer Trialists’ Collaborative Group, Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771-84.
4. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805-16.
5. Kuba S, Ishida M, Nakamura Y, et al. Persistence and discontinuation of adjuvant endocrine therapy in women with breast cancer. Breast Cancer. 2016;23:128-33.
6. Murphy CC, Bartholomew LK, Carpentier MY, et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134:459-78.
7. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120-8.
8. Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126:529-37.
9. Chirgwin JH, Giobbie-Hurder A, Coates AS, et al. Treatment adherence and its impact on disease-free survival in the Breast International Group 1-98 trial of tamoxifen and letrozole, alone and in sequence. J Clin Oncol. 2016;34:2452-9.
10. Gotay C, Dunn J. Adherence to long-term adjuvant hormonal therapy for breast cancer. Expert Rev Pharmacoecon Outcomes Res. 2011;11:709-15.
11. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11:44-7.
12. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59:56-66.
13. Hershman DL, Kushi LH, Hillyer GC, et al. Psychosocial factors related to non-persistence with adjuvant endocrine therapy among women with breast cancer: the Breast Cancer Quality of Care Study (BQUAL). Breast Cancer Res Treat. 2016;157:133-43.
14. Wouters H, van Geffen EC, Baas-Thijssen MC, et al. Disentangling breast cancer patients’ perceptions and experiences with regard to endocrine therapy: nature and relevance for non-adherence. Breast. 2013;22:661-6.
15. Aiello Bowles EJ, Boudreau DM, Chubak J, et al. Patient-reported discontinuation of endocrine therapy and related adverse effects among women with early-stage breast cancer. J Oncol Pract. 2012;8:e149-e157.
16. Farias AJ, Du XL. Association between out-of-pocket costs, race/ethnicity, and adjuvant endocrine therapy adherence among Medicare patients with breast cancer. J Clin Oncol. 2017;35:86-95.
17. Beckwee D, Leysen L, Meuwis K, Adriaenssens N. Prevalence of aromatase inhibitor-induced arthralgia in breast cancer: a systematic review and meta-analysis. Support Care Cancer. 2017;25:1673-86.
18. Roberts K, Rickett K, Greer R, Woodward N. Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early breast cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;111:66-80.
19. Moscetti L, Agnese Fabbri M, Sperduti I, et al. Adjuvant aromatase inhibitor therapy in early breast cancer: what factors lead patients to discontinue treatment? Tumori. 2015;101:469-73.
20. Niravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol. 2013;24:1443-9.
21. Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat. 2008;111:365-72.
22. Lintermans A, Laenen A, Van Calster B, et al. Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data. Ann Oncol. 2013;24:350-5.
23. Gallicchio L, Calhoun C, Helzlsouer K. A prospective study of aromatase inhibitor therapy initiation and self-reported side effects. Support Care Cancer. 2017;25:2697-705.
24. Bluethmann SM, Basen-Engquist K, Vernon SW, et al. Grasping the ‘teachable moment’: time since diagnosis, symptom burden and health behaviors in breast, colorectal and prostate cancer survivors. Psychooncology. 2015 Jun 8. [Epub ahead of print]
25. Nyrop KA, Callahan LF, Rini C, et al. Aromatase inhibitor associated arthralgia: the importance of oncology provider-patient communication about side effects and potential management through physical activity. Support Care Cancer. 2016;24:2643-50.
26. Hershman DL, Unger JM, Crew KD, et al. Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor-induced musculoskeletal pain: SWOG S0927. J Clin Oncol. 2015;33:1910-7.
27. Stewart M. The validity of an interview to assess a patient’s drug taking. Am J Prev Med. 1987;3:95-100.
28. Briot K, Tubiana-Hulin M, Bastit L, et al. Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (Articular Tolerance of Letrozole) study. Breast Cancer Res Treat. 2010;120:127-34.
29. Kwan ML, Roh JM, Laurent CA, et al. Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer. Cancer Causes Control. 2017;28:557-62.
30. Henry NL, Azzouz F, Desta Z, et al. Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol. 2012;30:936-42.
31. Yang GS, Kim HJ, Griffith KA, et al. Interventions for the treatment of aromatase inhibitor-associated arthralgia in breast cancer survivors: a systematic review and meta-analysis. Cancer Nurs. 2017;40:E26-E41.
32. Henry NL, Unger JM, Schott AF, et al. Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202. J Clin Oncol. 2018;36:326-32.
