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Effect of Tart Cherry on Aromatase Inhibitor-Induced Arthralgia (AIA) in Nonmetastatic Hormone-Positive Breast Cancer Patients: A Randomized Double-Blind Placebo-Controlled Trial
Address for correspondence: Mina Shenouda, Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, 1400 Hal Greer Boulevard, Huntington, WV 25701, USA
Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WVHillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
Internal Medicine Department, Marshall University, Joan C. Edwards School of Medicine, Huntington, WVInternal Medicine Department, Duke University, Durham, NC
Aromatase Inhibitor induced Arthralgia (AIA) can cause noncompliance leading to decreased breast-cancer survival. Effective interventions for AIA are limited. Tart cherry (TC) showed beneficial effect on musculoskeletal pain. 48 patients (Pts) randomized to TC versus placebo over 6 weeks, TC (23pts) had 34.7% mean pain decrease versus 1.4% in Placebo (25pts). TC can improve AIA in nonmetastatic breast-cancer patients.
Methods
Randomized, placebo-controlled, double-blind trial. Eligible patients with NMHPBC on AI for at least 4 weeks were randomized to TC concentrate [50 tart cherries] vs. placebo (P) [syrup] in 1:1 model. Patients instructed to consume 1 Oz of concentrate in 8 Oz water daily for 6 weeks, and document their pain intensity at baseline, weekly and at study completion in a diary using Visual Analog Scale (VAS), with 0 mm indicating no pain, and 100 mm indicating highest pain.
Results
Sixty patients were enrolled. Two patients did not complete the study due to diarrhea, and 10 patients were noncompliant. Forty-eight patients were included in the final analysis. TC group (23 pts) had 34.7% mean decrease in pain compared to 1.4% in P group (25 pts). This difference was statistically significant (Mann-Whitney U Test, P = .034).
Conclusions
Tart cherry can significantly improve AIA in nonmetastatic breast cancer patient.
In postmenopausal women with hormone receptor-positive breast cancer (BC), aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment in terms of survival.
Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.
While AIs are associated with lower risk of thromboembolic events and endometrial cancer compared with tamoxifen, they are associated with greater rates of a musculoskeletal symptoms that is generally referred to as aromatase inhibitor induced arthralgia (AIA), which has been characterized in several reviews.
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.
emphasizing the importance of maintaining patients’ adherence to AI.
The current practice of AIA management includes the following options: nonsteroidal anti-inflammatory drugs (NSAIDs), exercise, yoga, vitamin D repletion, omega-3 fatty acids, acupuncture, duloxetine, or switching to another AI/ tamoxifen, among others. Gupta et al. provided a guidance for current evidence-based AIA interventions.
Tart cherries (TC) have high concentrations of bioactive compounds (eg, anthocyanins, hydroxycinnamates, Flavin-3-ols). Published literature suggests that cherry consumption may reduce musculoskeletal pain associated with exercise,
Furthermore, there is evidence that it may improve sleep, cognitive function as well as decrease the risk of several chronic inflammatory diseases including, arthritis, cardiovascular disease (CVD), diabetes, and cancer.
This study aimed to investigate whether TC consumption may improve AIA in nonmetastatic breast cancer patients.
Methods
Study Design and Participants
This is a 6-week, randomized, double-blind, placebo-controlled, single-institution, clinical trial conducted at Edward Comprehensive Cancer Center, Huntington, WV. Records of randomization were maintained at the clinical trials office. The treating physicians, physician assistants, nursing staff, and subjects were blinded to whether the subject is receiving placebo or TC concentrate. All subjects signed informed consent documents, and the study was approved by the Institutional Review Boards at Joan C. Edwards School of Medicine - Marshall University, Huntington, WV.
To be considered for the trial, each subject had to fulfill the following criteria: Female patient with nonmetastatic breast cancer; stage I-III; Age 18-90; all ethnic groups; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2; understands and willing to sign informed consent. Tumor must be Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive; received AI for a minimum of 4 weeks; developed musculoskeletal pain that was felt by the oncologist to be related to AI; and have a minimum of 6 weeks additional AI therapy planned. Subjects were not allowed to participate in this study if they reported any of the following: allergy to cherry, uncontrolled diabetes mellitus, or pregnancy.
In this study, a total of 60 patients who fulfilled the inclusion criteria and were identified by themselves as well as their oncologist as having AIA were enrolled between May 2016 and August 2018. These patients were randomly assigned to receive TC concentrate vs. placebo in a 1:1 model.
Study subjects were instructed to do the following: Mix 1 ounce (2 tablespoons) of the concentrate in 8 ounces of water and consume daily. Refrain from using any new medication to alleviate the pain that is thought to be secondary to AI such as NSAIDS, duloxetine, etc. which were not allowed during the study period. Assess their pain intensity using Visual Analog Scale (VAS) at baseline (on first visit), weekly using home journal and at completion of study.
The TC concentrate was equivalent to 50 (Montmorency) TC, supplied from King Orchards, MI. (The TC dosing was based on the data presented by Kelly et al. who suggested that consumption of about 45 cherries a day has been shown to reduce circulating concentrations of inflammatory markers in healthy men and women.
) The control drink (placebo) was devoid of TC or its polyphenols, with similar color and flavor as the TC concentrate, and was supplied from “Torani.” The nutrient compositions of the TC concentrate are presented in Table 1. The TC concentrate and the syrup were supplied in bottles labeled A or B and dispensed by the clinical trials staff.
Table 1Nutrient Composition of Tart Cherry Serving Size: 30 ml (2 Tablespoons)
Tart cherry (473 ml)
Amount per serving
Energy (kcal)
70
Carbohydrate (g) sugar (g) 15
19
Protein (g)
<1
Fat (g)
0
Sodium (mg)
13
Ingredients: 100% Montmorency tart cherry juice concentrate.
The primary endpoint of the study was the pain score on VAS. This is a standard 100 mm VAS, with 0 mm indicating “no pain,” and 100 mm indicating “most severe pain.” The VAS has several benefits including: excellent reliability for acute pain; well-defined thresholds for meaningful change in pain intensity; it is quick to use and relatively easy to understand for most patients; it avoids the nonspecific use of descriptive words to describe pain and allows a meaningful comparison of measurements over time. VAS has shown to have ratio scale properties, which means that changes in VAS measurements represent actual percent differences between the measures.
Nevertheless, The VAS has few restrictions that are noted in the limitations of this study.
A 5 cc blood specimen was obtained to check for C-reactive protein (CRP) analysis twice, at the time of randomization, and at study completion.
Statistical Methods
Statistical analyses involving the outcome variables were performed using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY, USA) and R (R Core Team, 2020), Rcmdr (Fox J, Bouchet-Valat M, 2020) statistical packages. Descriptive statistics including mean, median, standard deviation, skewness and kurtosis were generated for the main outcome variable; pain score on the VAS for the treatment group and the control group. A variable describing the percentage change in pain rating at the end of the study as compared to the beginning of the study (baseline) was generated for each participant. This variable was evaluated for normality using a Q-Q plot, skewness, kurtosis and a Shapiro-Wilk test. These methods, including the Shapiro-Wilk test showed a significant departure from normality, W (48) = 0.83, P value < .001; therefore, comparisons between the TC and placebo groups were analyzed using Mann-Whitney U test.
A post hoc power analysis was performed using G-Power 3.0.10 (Faul, Erdfelder, Lang, & Buchner, 2007). The α was 0.05, the effect size, Cohen's d, was determined to be 0.61 (medium effect) and the actual power was calculated to be 0.66.
Results
A total of 60 patients were enrolled between May 2016 and August 2018. These patients were randomly assigned to receive TC concentrate vs. placebo in a 1:1 model. There was no interruption or discontinuation of AI therapy in both groups.
A total of 12 patients were excluded from the analysis; Ten patients were noncompliant with documenting their pain scale, and 2 patients (4%) developed diarrhea that was thought to be potentially related to TC and did not complete the study. A total of 48 patients were included in the final analysis. Out of the 48 patients who were enrolled in this clinical trial between May 2016 and August 2018, 23 patients received the TC concentrate (TC group), and 25 patients received the control syrup (Placebo group).
Table 2 details the baseline characteristics of the study sample. There were no significant differences in all but one of the baseline characteristics between the treatment and placebo groups, indicating that the 2 arms of the study sample were generally balanced. The only exception was in the histologic grade (P value = .013). A little Less than one half (45%) the patients in the treatment group had histologic grade 2, while a little more than one half of the placebo group (56%) had histologic grade 1.
For the treatment group (N = 23), the initial VAS pain score was 49.39 (mean), and at the end of study the VAS pain score was 32.13, P value = .001 (significant - using paired T-test). For the placebo group (N = 25), the initial VAS pain score was 44.20 (mean), and at the end of study the VAS pain score was 40.08, P value = .272 (not significant - using paired T-test)
At the end of the 6 weeks trial, the TC group had 34.7% mean decrease in pain compared to 1.4% in the placebo group. This difference was statistically significant (Mann-Whitney U Test, P = .034; Figure 1).
Figure 1Percent difference of pain scale in TC group (green) and placebo group (yellow) at the beginning and end of the trial.
Four out of 23 patients (17.4%) in the TC group had 100% decrease in pain, compared to 0% in the placebo group. Thirteen out of 23 patients (56.5%) in the TC group had >20% decrease in pain, compared to 7 out of 25 patients (28%) in the placebo group.
There was no statistically significant difference in the change in CRP in the TC group (mean = 0.00035) vs. the placebo group (mean = -0.00024; P = .084).
Discussion
To our knowledge, this is the first randomized controlled trial to study the potential benefit of TC on AIA in postmenopausal woman with nonmetastatic breast cancer.
The pathophysiology of AIA is not fully understood, but it is considered likely that estrogen deprivation is one of the key underlying mediators. Musculoskeletal symptoms of AIA are seen in 50% of women at the time of natural menopause.
Estrogen receptors are found in bone, cartilage, and synovial cells, and estrogen can reduce release of tissue necrosis factor (TNF) α and interleukin (IL)-1β involved in inflammatory arthritis.
At a cellular level, the underlying mechanism of AIA remains obscure. The levels of pro-inflammatory cytokines such as IL-6 and TNFα increase after menopause.
Bauml et al. suggested a possible underlying inflammatory mechanism based on the coexistence of arthralgia, fatigue, and insomnia among women taking AIs, which was associated with increased levels of inflammatory biomarkers (elevated CRP, eotaxin, MCP-1, and VDBP).
Inflammatory mediators like cytokines although likely to play a role, have not been consistently elevated in previous trials, suggesting that Local inflammatory molecules may play a role such as insulin-like growth factor I (IGF-1) which is high in AIA.
Arthralgia induced by endocrine treatment for breast cancer: a prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.
Despite substantial interest and research, no treatable target has been recognized that would suggest an effective management for AIA. Hence, there is still no clear uniform agreement on the best AIA management approach. The most commonly used treatment is NSAIDs, although there are no formal data testing their efficacy for AIA, and they are associated with potential adverse effects such as renal failure, gastrointestinal bleeding, and increased risk of cardiovascular events.
When NSAIDs fail to control AIA, patients may be switched from one AI to another or possibly to another therapy such as tamoxifen. Briot et al. reported that switching from one AI to another allowed 70% of patients to continue their treatment for over 6 months
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.
; although the underlying mechanism for this management strategy is not fully understood.
Other evidence-based AIA therapeutic options include the following: omega-3 fatty acids showed significant improvement in AIA especially in obese patients (body mass index ≥ 30 kg/m2), this was demonstrated in the SWOG S0927 trial and its post hoc analysis.
However, it is unclear whether these data are reproducible given the amount of supervised exercise provided. Yoga have demonstrated improved outcomes (balance, flexibility, perceived disability, pain, and quality of life) in a pilot study.
However, these trials had a limitation of no blinded placebo-controlled arms, it is reasonable however to recommend exercise and physical activity in breast cancer patients with AIA. A single-institution randomized controlled trial (n = 38) of true acupuncture vs. sham acupuncture reported significant improvements in pain severity and pain-related interference between groups at 6 weeks.
Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer.
These findings were confirmed in a larger, multi-institutional trial that enrolled 226 women with AIA where more than half the patients in the true acupuncture arm experienced a clinically meaningful response to pain.
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.
Results from the SWOG S1202 clinical trial support consideration of a short course of duloxetine in symptomatic patients to assess improvement in AIA and tolerance of duloxetine.
Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202.
A systematic review of systematic reviews conducted by Kim et al. assessed the effectiveness of different AIA therapeutic options. They found that various interventions including acupuncture, pharmacologic agents, vitamin D, yoga, exercise therapy, omega-3 fatty acids, herbal medicine, and exercise, have been used for AIA and their clinical effectiveness has been assessed in systematic reviews. Their research showed that acupuncture was the intervention most widely studied. However, the confidence level for each review was limited; hence they could not provide a favorable recommendation for reducing pain in patients with AIA.
Therapeutic options for aromatase inhibitor-associated arthralgia in breast cancer survivors: A systematic review of systematic reviews, evidence mapping, and network meta-analysis.
TC have high concentrations of bioactive compounds (eg, anthocyanins, hydroxycinnamates, Flavin-3-ols), and a higher amounts of antioxidants compared to many other foods per portion size like red wine, dark chocolate, and orange juice, placing TC among the top 15 highest antioxidant containing foods.
Seeram et al. reported that the aglycone cyanidin from TC has comparable anti-inflammatory activities to ibuprofen and naproxen when comparing COX-I and COX-II inhibition activities.
Published literature suggests that consumption of cherries may reduce the risk of several chronic inflammatory diseases including arthritis, cardiovascular disease, diabetes, and cancer. Furthermore, there is evidence that cherry consumption may improve sleep, cognitive function, and recovery from pain after strenuous exercise.
TC consumption was linked to positive effect in osteoarthritis and gout. Schumacher et al. reports that the WOMAC score for osteoarthritis improved significantly during the TC treatment and did not change during placebo treatment. There were significant improvements in pain and function scores, during the TC treatment with no change during the placebo treatment. However, the change in WOMAC score was not statistically different between treatment.
Zhang et al. conducted a large prospective study on patients with preexisting gout, where cherry intake was associated with a 35% lower risk of recurrent gout attacks. This risk reduction was independent of other risk factors including genetics, sex, race, education, purine intake, alcohol consumption, as well as use of anti-gout medications and diuretics.
TC juice is generally safe and well tolerated. Potential adverse effects of TC include abdominal discomfort and diarrhea, due to its relatively high sorbitol content. It might also affect weight and blood glucose. Chai et al. found that daily integration of TC or control drink into diet did not significantly affect the total carbohydrate, fat, and protein intakes. TC consumption was not associated with a significant increase in body weight, body mass index, insulin, and insulin resistance index compared to control drink.
In the current study, only 2 out of the 30 study participant who received TC (6.7%) reported diarrhea as a side effect and they did not complete the study.
We acknowledge that there are several limitations to this research; hence the results of our study should be interpreted cautiously. Among those limitations, the small sample size. Even so TC intake showed a statistically significant reduction in AIA compared to placebo, which may imply that replicating this study on a bigger patient population may show a stronger benefit for TC in clinical practice. Another limitation, the possibility of under or over reporting of pain which is subjective and may vary according to several factors; patients were instructed to maintain their prestudy life routine and refrain from significant changes including pain medication intake, to decrease this limitation. Furthermore, a prior history of AIA interventions was not collected during this trial. One more concern that the positive effect of TC on AIA in the current study may be related to a potential estrogenic effect of TC. Even though the estrogen level was not checked in the current study participants, there is no clear evidence in the literature that TC significantly increases serum estrogen. However, further studies may be needed to confirm that. An additional concern, TC in this study were supplied from one location (King Orchards in Michigan), hence there is a concerned about the reproducibility of the study results if TC are obtained from another vendor. Lastly, the VAS was used to objectively assess the pain scale, which has potential few restrictions including the following: a possible lack of objective measure of clinically meaningful improvement in pain; Dworkin et al. suggested that pain level decreased with the intervention but were not able to evaluate whether this translated into improved patient reported functional outcomes and treatment compliance.
The VAS attempts to assign a single value to a complex, multidimensional experience. Some patients will have trouble deciding how to choose a single number to represent their pain sensation. In addition, they often have no real concept of what “worst pain” means because every experience of pain is different. Thus, the VAS may have a ceiling at the upper-most end, which can potentially conceal variation in the intensity of severe pain. There is also disagreement about what amount of change in the VAS is necessary for it to be considered an acceptable improvement in pain from the patient's perspective.
CRP is a marker of systemic inflammation, and it was found to be elevated in women with moderate to severe AIA.
CRP was used in this study to assess whether the effect of TC on AIA is related to its anti-inflammatory property. There was no statistically significant difference in the change in CRP in the TC group compared to the placebo group in the current study. Several studies investigated the effects of consuming cherries on markers of inflammation including plasma CRP, which was found to be decreased in several studies.
Influence of a montmorency cherry juice blend on indices of exercise-induced stress and upper respiratory tract symptoms following marathon running—a pilot investigation.
Plasma CRP was also decreased by approximately 25% within 5 hours of a bolus of 45 fresh Bing cherries compared with baseline values, although it did not attain significance.
The discrepancy in TC effect on plasma CRP level in not fully understood. However, it may be related to the level of inflammation in each study population.
Conclusions
TC can be a viable and relatively safe option for the management of aromatase inhibitor induced arthralgia in nonmetastatic breast cancer patients.
Future directions: Further studies are needed to replicate these results and determine whether AIA reduction using TC would increase compliance with AI therapy, potentially improve survival and quality of life outcomes in this population. This can be considered while using a longer duration and/ or higher dose of TC. It would also be interesting to correlate Levels of inflammatory biomarkers in responders vs. nonresponders in the intervention group and compare the levels between intervention and placebo group.
Clinical Practice Points
•
What is already known about this subject?
Aromatase inhibitors (AI) are the standard treatment for hormone receptor‐positive breast cancer in postmenopausal women. About half of patients (pts) taking AI suffer Aromatase Inhibitor Arthralgia (AIA) which can cause noncompliance. Suboptimal AI adherence is associated with decreased survival. Effective AIA interventions are limited. In clinical trials, tart cherry (TC) showed beneficial effect on musculoskeletal pain associated with osteoarthritis, gout, and strenuous exercise. The flavonoids and anthocyanins in TC reportedly exert an anti-inflammatory effect that may lessen adverse effects of estrogen deficiency. This trial aimed to investigate whether TC can reduce AIA in nonmetastatic hormone positive breast cancer (NMHPBC) pts.
•
What are the new findings?
TC can be a viable and relatively safe option for the management of aromatase inhibitor induced arthralgia in nonmetastatic breast cancer patients.
•
How might it impact on clinical practice in the foreseeable future?
AIA reduction using TC could increase compliance with AI therapy, potentially improve survival and quality of life outcomes in this population.
Disclosure
This clinical trial was supported by a grant from the Cherry Marketing Institute, Dewitt, Michigan. The authors otherwise declare that there is no conflict of interest.
Acknowledgments
Lora Maynard; Barbara Payne; Christina Cole.
This work was supported by a grant from the Cherry Marketing Institute , Dewitt, Michigan. This study was granted the 2019 Conquer Cancer Foundation ASCO Merit Award.
References
Coates AS
Keshaviah A
Thurlimann B
et al.
Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.
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.
Arthralgia induced by endocrine treatment for breast cancer: a prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.
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.
Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer.
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.
Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202.
Therapeutic options for aromatase inhibitor-associated arthralgia in breast cancer survivors: A systematic review of systematic reviews, evidence mapping, and network meta-analysis.
Influence of a montmorency cherry juice blend on indices of exercise-induced stress and upper respiratory tract symptoms following marathon running—a pilot investigation.
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