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Arthralgia is a common and debilitating adverse effect experienced by patients with breast cancer who are being treated with aromatase inhibitors, often resulting in poor adherence. And premature treatment discontinuation can negatively impact disease-free and overall breast cancer survival. Limited data suggest utility of acupuncture for symptom relief. In this article, Drs. Hershman and Crew summarize findings from their recent randomized controlled trial using acupuncture to address this troubling side effect.
GUEST EDITOR
Jun J. Mao, MD, MSCE
Integrative Oncology is guest edited by Jun J. Mao, MD, MSCE, Laurance S. Rockefeller Chair in Integrative Medicine and Chief, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.
Overview of Arthralgias From Aromatase Inhibitors
Aromatase inhibitors are effective in the treatment and prevention of breast cancer in postmenopausal women.1,2 Recent evidence suggests there are benefits for young women with ovarian suppression3 and that the benefits may be better with extended hormonal therapy (10 rather than 5 years of treatment).4 However, the optimal benefits cannot be achieved if women do not take the medication regularly, and research has shown that a substantial number of women are nonadherent to this therapy.5
Joint pain and stiffness (arthralgias) are the most common side effects of aromatase inhibitors and the main reasons women discontinue these medications.6 Acupuncture is a traditional Chinese medicine treatment involving the insertion of fine, single-use, sterile needles in defined acupoints. Small studies have suggested symptom relief following acupuncture, although the results were inconclusive.7,8
Acupuncture for Arthralgias: Results of SWOG S1200
To address this issue, we conduced a randomized controlled trial to determine the effect of true acupuncture vs sham acupuncture or waitlist control on joint pain related to aromatase inhibitors among women with early-stage breast cancer (SWOG S1200).9 This was a multicenter trial that enrolled 226 patients: 110 were randomized to receive true acupuncture; 59, to sham acupuncture (which involved superficially inserting needles in nonacupoints); and 57, to waitlist control (which meant no treatment). Patients receiving true or sham acupuncture had twice-weekly sessions for 6 weeks followed by a once-weekly session for 6 more weeks.
Dawn Hershman, MD, MS
Katherine Crew, MD, MS
To maintain the intervention’s fidelity, the acupuncturists for both the true and sham arms were licensed with extensive experience. They completed online training with a combination of visual and video elements, received training manuals, as well as underwent in-person training, and there were also annual quality-assurance activities.
After 6 weeks, patients in the true acupuncture arm reported significantly lower BPI worst pain scores compared with those in the sham acupuncture and waitlist control arms. The mean BPI worst pain score for the true acupuncture arm was 0.92 points lower (on a scale of 0 to 10 points) than that for the sham acupuncture arm and 0.96 points lower than that for the waitlist control arm. These results were statistically significant. In addition, the acupuncture intervention resulted in statistically significant improvements in other secondary endpoints at 6 weeks, such as average pain, pain severity, and joint stiffness.
What was also interesting is that we followed patient symptoms for 24 weeks, which was 12 weeks after completing the intervention. We found that over time, patients randomized to receive acupuncture had a persistent improvement in joint symptoms compared with those in the other groups. A clinically meaningful reduction in the BPI score was 2 points. This study showed that the proportion of patients with a reduction of 2 or more points was significantly higher in the true acupuncture arm than in the sham acupuncture and waitlist control arms: 58% vs 33% and 31%, respectively. Acupuncture was well tolerated, and the most common side effect was mild bruising.9
Limitations of Acupuncture
There are several limitations to the uptake and use of acupuncture in the community. First, we know that only the methods used in the trial are effective. Results with these methods have been published,10 although there are no criteria for knowing which practitioners are knowledgeable about them. Patients may want to go to a licensed acupuncturist affiliated with a cancer program. Second, acupuncture is not routinely covered by health insurance. Therefore, financial factors may limit its access for some patients.
Other Treatment Options
Although acupuncture appears to be an option for some patients, others may not be interested in this approach. Several other interventions for arthralgias associated with aromatase inhibitors have been studied. For instance, a trial comparing 1 year of structured exercise with usual care found a significant reduction in joint pain among the group randomized to exercise.11 Another trial
Acupuncture may be an appropriate choice for some patients, but it is not for everyone.— Dawn Hershman, MD, MS, and Katherine Crew, MD, MS
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comparing duloxetine with placebo found a greater reduction in pain at 12 weeks among patients taking duloxetine.12 A large randomized trial comparing omega-3 fatty acids with placebo found a large improvement in pain in both groups but no difference between groups.13 However, a recent subset analysis found a strong improvement in aromatase inhibitor–related joint pain with omega-3 fatty acids among obese women with a body mass index over 30 kg/m2 compared with placebo.14
Conclusions and Future Directions
One would hope that by reducing the debilitating side effects of aromatase inhibitors, adherence to treatment may be increased and subsequent breast cancer outcomes improved. Acupuncture may be an appropriate choice for some patients, but it is not everyone. To better personalize interventions to reduce side effects, we may need to know more about the mechanisms of its toxicity and the biologic factors that contribute to it. ■
Dr. Hershman is Professor of Medicine and Epidemiology, Columbia University Medical Center, New York Presbyterian Hospital. Dr. Crew is Associate Professor of Medicine and Epidemiology, Columbia University Medical Center, New York Presbyterian Hospital, New York.
DISCLOSURE: Drs. Hershman and Crew reported no conflicts of interest.
SWOG S1200: Acupuncture for Arthralgias
- Multicenter trial of 226 patients
- Three treatment arms: true acupuncture, sham acupuncture, waitlist control
- Lower worst pain scores as well as improvement in joint symptoms reported with true acupuncture
REFERENCES
1. Early Breast Cancer Trialists’ Collaborative Group: Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 386:1341-1352, 2015.
2. Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): An international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-1048, 2014.
3. Prudence AF, Regan MM, Fleming GF, et al: Adjuvant ovarian function supression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.
4. Goss PE, Ingle JN, Pritchard KI, et al: Extending aromatase--inhibitor adjuvant therapy to 10 years. N Engl J Med 375:209-219, 2016.
5. Hershman DL, Kushi LH, Shao T, et al: Early discontinuation and non-adherence to adjuvant hormonal therapy in a cohort of 8900 early stage breast cancer patients. J Clin Oncol 28:4120-4128, 2010.
6. 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 34:2452-2459, 2016.
7. Crew KD, Capodice JL, 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.
8. Crew KD, Capodice JL, Greenlee H, et al: Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol 28:1154-1160, 2010.
9. Hershman DL, Unger JM, Greenlee H, et al: Effect of acupuncture vs sham acupuncture or waitlist control on joint pain related to aromatase inhibitors among women with early-stage breast cancer: A randomized clinical trial. JAMA 320:167-176, 2018.
10. Greenlee H, Crew KD, Capodice J, et al: Methods to standardize a multicenter acupuncture trial protocol to reduce aromatase inhibitor-related joint symptoms in breast cancer patients. J Acupunct Meridian Stud 8:152-158, 2015.
11. Irwin ML, Cartmel B, Gross CP, et al: Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol 33:1104-1111, 2015.
12. 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 36:326-332, 2018.
13. 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 33:1910-1917, 2015.
14. Shen S, Unger JM, Crew KD, et al: Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927). 2018 ASCO Annual Meeting. Abstract 10000. Presented June 3, 2018.
