Adjunct Faculty, Research Investigator, Bastyr University, Seattle
Dr. Pantuso reports no financial relationships relevant to this field of study.
SUMMARY POINTS
- After six weeks of treatment with acupuncture, postmenopausal women with early-stage breast cancer demonstrated decreased aromatase inhibitor-associated joint pain.
- Women who received additional acupuncture treatments once weekly after the six-week intervention maintained pain improvements at 12 weeks.
- Acupuncture is well-tolerated, with bruising the most common adverse event.
SYNOPSIS: The authors of this randomized, controlled trial found that six weeks of acupuncture significantly reduced aromatase inhibitor-related joint pain in early stage breast cancer.
SOURCE: 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 2018;320:167-176.
Aromatase inhibitors (AI) are the standard treatment for hormone-sensitive breast cancers in postmenopausal women. AI therapy is an oral, self-administered daily therapy that is taken for five to 10 years.1 Patients who discontinue AI therapy have an increased risk of recurrence and mortality from breast cancer.1 AI-associated arthralgia occurs in 50% of women and is one of the main reasons for nonadherence and discontinuation of AI therapy.1 Previous studies investigating the efficacy of acupuncture treatment for reducing AI-associated joint pain have been difficult to evaluate because of small sample sizes and ineffective blinding. Hershman et al designed this study to further clarify whether the use of acupuncture demonstrated efficacy in treating musculoskeletal joint pain associated with AI therapy in early-stage breast cancer patients.
Participants were eligible to participate if they were women diagnosed with either primary invasive estrogen or progesterone receptor-positive carcinoma, were postmenopausal, or were premenopausal with use of a gonadotropin-releasing hormone agonist. The participants had to be taking a third-generation AI for more than 30 days with plans to continue for at least one additional year and have recovered from surgery and/or chemotherapy treatments. This study was conducted at 11 academic and community sites from March 2012 to February 2017. The participants also needed to score 0 to 1 on the Zubrod performance status scale (on a scale of 0 to 5). The Zubrod performance score measures the ability to perform activities of daily living in cancer patients. A score of 0 represents active and unrestricted activities, while increasing scores reflect decreased ability to perform activities of daily living. Eligible participants in this study had to score of 3 or higher on the Brief Pain Inventory Short Form (BPI-SF), which was associated with AI therapy. Exclusion criteria included diagnosis of severe bleeding disorder or latex allergy, previous acupuncture for joint symptoms, opioids, analgesics, topical analgesics, oral corticosteroids, and intramuscular or intra-articular steroids. Individuals were excluded if they had undergone joint pain treatment with any other medical or alternative or physical therapy within 28 days of registration. Any subjects with bone fractures or surgeries of affected hands, knees, or both within six months of study registration also were excluded.
A total of 226 patients were enrolled and randomly assigned in a 2:1:1 ratio to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57). Baseline participant characteristics were well matched, and the median AI time of use was 1.1 years. The true acupuncture and sham acupuncture groups had 12 visits that were 30-45 minutes in duration, twice per week, over six weeks followed by one visit per week for another six weeks. The true acupuncture group received acupuncture in accordance with a joint-specific protocol that was developed by a consensus of acupuncture experts and was tailored to as many as three of the patients’ most painful joints. Needles were re-stimulated manually one time during each session. Sham acupuncture visits involved use of a shallow needle insertion with short needles at non-acupuncture points. The waitlist group received no intervention for 24 weeks after randomization. All patients received 10 vouchers for true acupuncture visits at 24 weeks to be used before the 52-week visit. Twenty-one patients were not evaluated because they either had not filled out a baseline BPI or did not complete the six-week BPI measurement. There were reported protocol deviations that occurred in the study, with one patient in the sham group receiving true acupuncture for two visits and two patients in each of the true acupuncture and sham groups who did not receive treatment. The study participants denied undergoing any acupuncture treatments outside of the study.
The primary endpoint for this study was the Brief Pain Inventory-Worst Pain (BPI-WP) score at six weeks. A reduction of two points was considered clinically meaningful between the sham and true acupuncture groups and was not achieved. (See Table 1.) A significant improvement in worst pain was found at six weeks between the true acupuncture vs. sham acupuncture group and true acupuncture vs. waitlist groups. (See Tables 2 and 3.) The adjusted mean BPI-WP scores were 0.59 points lower (95% confidence interval [CI], 0.34-1.14; P = 0.04) in the true acupuncture group compared to the sham group through 24 weeks. This trend also was found between the true acupuncture group and the waitlist group, with the true acupuncture group scoring 1.23 points lower (95% CI, 0.66-1.80; P < 0.001).
Table 1: Baseline vs. Primary Endpoint BPI-WP Scores |
|||
Group |
Baseline Mean (range) |
6 Weeks Mean (range) |
12 Weeks Mean (range) |
|
True Acupuncture |
6.84 |
4.79 |
4.53 |
|
Sham Acupuncture |
6.55 |
5.48 |
5.04 |
|
Waitlist |
6.48 |
5.49 |
6.29 |
Table 2: Adjusted 6-week Mean BPI-WP Scores |
||
Groups |
Mean Fitted Difference (95% CI) |
P value |
|
True Acupuncture vs. Sham acupuncture |
0.92 (0.20 to 1.65) |
0.01 |
|
True Acupuncture vs. Waitlist |
0.96 (0.24 to 1.67) |
0.01 |
Table 3: Adjusted 12-week Mean BPI-WP Scores |
||
Groups |
Mean Fitted Difference (95% CI) |
P value |
|
True Acupuncture vs. Sham acupuncture |
0.73 (-0.07 to 1.53) |
0.08 |
|
True Acupuncture vs. Waitlist |
1.95 (1.19 to 2.70) |
< 0.001 |
Secondary endpoints that were measured and evaluated by several different instruments including the BPI, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) of the knees or hips, the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the Functional Assessment of Cancer Therapy Endocrine Symptoms (FACT-ES), and the PROMIS Pain Impact Short Form (PROMIS PI-SF). All secondary measurements were recorded at six, 12, 24, and 52 weeks.
The BPI measures of average pain, pain severity, and worst stiffness at six weeks were statistically significant between the true acupuncture and sham and waitlist groups. (See Table 4.) However, patients in the true acupuncture group had significantly improved pain interference compared to the sham acupuncture but not the waitlist group. (See Table 4.) At 12 weeks, compared to the sham group, the true acupuncture group had statistically significant improvements in average pain (0.79; 95% CI, 0.16-1.42; P = 0.02). This also was found between the true acupuncture and waitlist (1.38; 95% CI, 0.76-2.00; P = 0.003) groups. No significant difference was found between groups in measures of worst pain, pain interference, pain severity, or worst difference. At 12 weeks, the true acupuncture group had a significantly improved pain average on all BPI measures compared to the waitlist group (P ≤ 0.003).
Table 4: Secondary Outcomes – BPI at 6 Weeks |
||
Mean Fitted Difference (95% CI) |
P value |
|
Average Pain |
||
|
True Acupuncture vs. Sham Acupuncture |
0.60 (0.03 to 1.17) |
0.04 |
|
True Acupuncture vs. Waitlist |
0.71 (0.15 to 1.28) |
0.01 |
Pain Interference |
||
|
True Acupuncture vs. Sham Acupuncture |
0.73 (0.11 to 1.35) |
0.02 |
|
True Acupuncture vs. Waitlist |
0.63 (-0.03 to 1.29) |
0.06 |
Pain Severity |
||
|
True Acupuncture vs. Sham Acupuncture |
0.56 (0.00 to 1.11) |
0.05 |
|
True Acupuncture vs. Waitlist |
0.71 (0.15 to 1.28) |
0.01 |
Worst Stiffness |
||
|
True Acupuncture vs. Sham Acupuncture |
1.00 (0.19 to 1.81) |
0.02 |
|
True Acupuncture vs. Waitlist |
1.09 (0.26 to 1.92) |
0.01 |
At 12 weeks, the true acupuncture group had improved symptoms on the WOMAC and PROMIS-SF measures compared to the sham group. Between the true acupuncture group and the waitlist group, the true acupuncture group had improved symptoms on the M-SACRAH, WOMAC, FACT-ES, and PROMIS-SF measures at 12 weeks.
The authors also found that patients in the true acupuncture group were more likely to believe they were receiving true acupuncture than those patients in the sham acupuncture group (68% vs. 36%; P < 0.001).
Bruising was the most common adverse event reported and was more common in the true acupuncture group. There was one episode of presyncope in the true acupuncture group and one episode in sham group. No grade 3 or higher adverse events were reported.
COMMENTARY
AI-associated arthralgia is a major side effect, leading to non-adherence to AI medication, which subsequently increases the risk of mortality. Other research has shown that 159 minutes of exercise per week with both aerobic (119 minutes) and strength training has demonstrated benefit in reducing AI-associated arthralgia at 12 months in a study of 121 postmenopausal, estrogen receptor-positive breast cancer survivors taking AIs.2 The Hershman et al study investigating the effects of acupuncture on reducing AI-associated arthralgia adds to the evidence of previous, although methodologically variable, studies demonstrating benefit.3,4
The study had several strengths, including the fact that it was randomized, multicenter, and controlled for both sham and waitlist arms. Also, there were more participants enrolled in this study compared to previous studies.The addition of the waitlist control group controlled for the sham acupuncture effect that has been seen in previous studies. In previous studies evaluating the effectiveness of acupuncture, the study design used the sham acupuncture group as the control group, and sham acupuncture has been found to have an effect. Because sham acupuncture has demonstrated an effect, including a waitlist group is important for assessing the effectiveness of the true acupuncture group. The authors also published a separate trial protocol prior to this study that defined which acupuncture points were used.
Limitations included a lack of consensus on the best measurement for AI-induced arthralgias. Although the BPI-SF was used in previous studies, it may not be the best measurement device. The BPI-WP was used as the primary outcome because it previously has been demonstrated that a reduction of two points on the BPI-WP is clinically meaningful. The authors also mentioned that there was a lack of blinding in the waitlist control group as well as issues with masking the sham acupuncture group. Another factor that was not discussed in this study was the amount of exercise that the participants were performing on a regular basis.
The authors also reported that the outcomes of this study were similar to previous investigations of pain control interventions, with a between-group difference of 0.92 points for true and sham acupuncture groups and 0.96 points for true acupuncture vs. waitlist control. AI-associated arthralgia is a common side effect and the benefit of AI therapy decreases with non-adherence. Patients experiencing AI-associated arthralgia should be counseled to exercise at least 150 minutes per week, and the addition of acupuncture may provide further benefit.2 As seen in this study and in previous studies, patients noticed an improvement in AI-associated symptoms at six weeks after two acupuncture visits per week.3 In a previous study conducted by Mao et al, early-stage breast cancer patients experiencing fatigue and psychological distress on AI therapy who were treated by electroacupuncture had significant improvements in fatigue and psychological distress in a 12-week trial.4
Bottom Line
Recommending acupuncture to reduce arthralgia associated with AI use in early-stage breast cancer patients, in addition to 150 minutes of weekly exercise, is clinically sound, with some possible, although small, benefits, and minimal adverse effects. The most successful protocol supported by the literature is 12 acupuncture treatments within six weeks. Since techniques vary among acupuncturists, referring patients to an acupuncturist willing to use the acupuncture treatment in the study protocol may demonstrate the most benefit.
REFERENCES
- Brockway JP, Shapiro CL. Improving adherence to endocrine therapy in women with HR positive breast cancer. Oncology 2018;32:235-237.
- Irwin ML, Cartmel B, Gross CP, et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol 2015;33:1104-1111.
- 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 2010;28:1154-1160.
- Mao JJ, Xie SX, Farrar JT, et al. A randomized trial of electro-acupuncture for arthralgia related to aromatase inhibitor use. Eur J Cancer 2014;50:267-276.
The authors of this randomized, controlled trial found that six weeks of acupuncture significantly reduced aromatase inhibitor-related joint pain in early stage breast cancer.
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