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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

  • Mina Shenouda
    Correspondence
    Address for correspondence: Mina Shenouda, Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, 1400 Hal Greer Boulevard, Huntington, WV 25701, USA
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV
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  • Renee Copley
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV
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  • Toni Pacioles
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV
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  • Yehuda Lebowicz
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV

    Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
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  • Muhammad Jamil
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV
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  • Sutoidem Akpanudo
    Affiliations
    Internal Medicine Department, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV

    Internal Medicine Department, Duke University, Durham, NC
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  • Maria Tria Tirona
    Affiliations
    Hematology Oncology Department, Marshall University, Joan C. Edwards School of Medicine, Edwards Comprehensive Cancer Center, Huntington, WV
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Open AccessPublished:June 17, 2021DOI:https://doi.org/10.1016/j.clbc.2021.06.007

      Abstract

      Background

      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.

      Keywords

      Introduction

      In postmenopausal women with hormone receptor-positive breast cancer (BC), aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment in terms of survival.
      • 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.
      ,
      • Coombes RC
      • Kilburn LS
      • Snowdon CF
      • et al.
      Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.
      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.
      • Lombard JM
      • Zdenkowski N
      • Wells K
      • et al.
      Aromatase inhibitor induced musculoskeletal syndrome: a significant problem with limited treatment options.
      ,
      • Niravath P
      Aromatase inhibitor-induced arthralgia: a review.
      AIA has been estimated to affect 45% to 60% of patients, many of whom report severe or continuous pain.
      • Mao JJ
      • Stricker C
      • Bruner D
      • et al.
      Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors.
      ,
      • Presant CA
      • Bosserman L
      • Young T
      • et al.
      Aromatase inhibitor-associated arthralgia and/or bone pain: frequency and characterization in non-clinical trial patients.
      AIA can be severe enough to cause AI noncompliance; it is implicated in 13% to 22% of AI therapy discontinuations at 12-month follow-up
      • Niravath P
      Aromatase inhibitor-induced arthralgia: a review.
      . Henry et al. reported an AI discontinuation rate of 32.4% within 2 years due to adverse effects; 24.3% specifically due to AIA.
      • 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.
      Noncompliance and early treatment cessation lead to a poorer prognosis
      • 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.
      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.
      • Gupta A
      • Henry NL
      • Loprinzi CL
      Management of aromatase inhibitor-induced musculoskeletal symptoms.
      However, despite a significant number of studies conducted to answer this question, it is still unclear to many physicians the optimal AIA management.
      • Nahm N
      • Mee S
      • Marx G
      Efficacy of management strategies for aromatase inhibitor-induced arthralgia in breast cancer patients: a systematic review.
      There appears to be an association between estrogen deficiency and increased pro-inflammatory cytokines.
      • Pfeilschifter J
      • Koditz R
      • Pfohl M
      • et al.
      Changes in proinflammatory cytokine activity after menopause.
      Estrogen was found to have anti-inflammatory properties by repressing the transcription of pro-inflammatory genes through estrogen receptors.
      • Santos RS
      • de Fatima LA
      • Frank AP
      • et al.
      The effects of 17 alpha-estradiol to inhibit inflammation in vitro.
      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,
      • Bowtell JL
      • Sumners DP
      • Dyer A
      • et al.
      Montmorency cherry juice reduces muscle damage caused by intensive strength exercise.
      • Howatson G
      • McHugh MP
      • Hill JA
      • et al.
      Influence of tart cherry juice on indices of recovery following marathon running.
      • Levers K
      • Dalton R
      • Galvan E
      • et al.
      Effects of powdered Montmorency tart cherry supplementation on acute endurance exercise performance in aerobically trained individuals.
      • Bell PG
      • Walshe IH
      • Davison GW
      • et al.
      Montmorency cherries reduce the oxidative stress and inflammatory responses to repeated days high-intensity stochastic cycling.
      • Kuehl KS
      • Perrier ET
      • Elliot DL
      • et al.
      Efficacy of tart cherry juice in reducing muscle pain during running: a randomized controlled trial.
      osteoarthritis,
      • Schumacher HR
      • Pullman-Mooar S
      • Gupta SR
      • et al.
      Randomized double-blind crossover study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee.
      and gout.
      • Zhang Y
      • Neogi T
      • Chen C
      • et al.
      Cherry consumption and decreased risk of recurrent gout attacks.
      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.
      • Chai SC
      • Davis K
      • Zhang Z
      • et al.
      Effects of tart cherry juice on biomarkers of inflammation and oxidative stress in older adults.
      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.
      • Kelley DS
      • Rasooly R
      • Jacob RA
      • et al.
      Consumption of Bing sweet cherries lowers circulating concentrations of inflammation 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) 1519
      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.
      • Gallagher EJ
      • Liebman M
      • Bijur PE
      Prospective validation of clinically important changes in pain severity measured on a visual analog scale.
      ,
      • Bijur PE
      • Silver W
      • Gallagher EJ
      Reliability of the visual analog scale for measurement of acute pain.
      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.
      Table 2Patient Characteristics
      Patient GroupsTC GroupPlacebo GroupP Value
      Significant at P < .05.
      CharacteristicsPatients, n (%)Patients, n (%)
      Age (mean)61.30 (47.9)60.40 (52).71
      Age at menopause (mean)43.48 (47.9)46.28 (52).14
      Race.48
       White22 (95.7)25 (100.0)
       Black1 (4.3)0 (0.0)
      BMI (mean)31.96 (47.9)30.77 (52).606
      ECOG performance status.459
       Grade 017 (73.9)16 (64.0)
       Grade 1 or higher6 (26.1)9 (36.0)
      Clinical stage.849
       Stage 113 (56.5)15 (60.0)
       Stage 27 (30.4)8 (32.0)
       Stage 33 (13.0)2 (8.0)
      Tumor size (T).709
       T114 (60.9)16 (64.0)
       T27 (30.4)7 (28.0)
       T32 (8.7)1 (4.0)
       T40 (0.0)1 (4.0)
      Lymph node status.727
       Node positive4 (17.4)6 (24.0)
       Node negative19 (82.6)19 (76.0)
      Histologic grade.013
       01 (4.5)0 (0.0)
       18 (36.4)14 (56.0)
       210 (45.5)2 (8.0)
       33 (13.6)9 (36.0)
      Estrogen receptor (ER)NA
       Positive23 (100.0)25 (100.0)
       Negative0 (0.0)0 (0.0)
      Progesterone receptor (PR).099
       Positive22 (95.7)19 (76.0)
       Negative1 (4.3)6 (24.0)
      HER2/neo receptor1.00
       Positive3 (13.0)4 (16.0)
       Negative20 (87.0)21 (84.0)
      LVI.660
       Yes3 (13.0)2 (8.0)
       No20 (87.0)23 (92.0)
      Surgery.141
       Lumpectomy15 (65.2)11 (44.0)
       Mastectomy8 (34.8)14 (56.0)
      Hormonal therapy.544
       Anastrozole12 (52.1)18 (72.0)
       Letrozole9 (39.1)6 (24.0)
       Exemestane2 (8.7)1 (4.0)
      Chemotherapy.214
       Yes7 (30.4)12 (48.0)
       No16 (69.6)13 (52.0)
      Radiotherapy.971
       Yes13 (56.5)14 (56.0)
       No10 (43.5)11 (44.0)
      CRP (before study).087
       <0.2912 (52.2)7 (28.0)
       >0.2911 (47.8)18 (72.0)
      CRP (after study).571
       <0.2912 (52.2)11 (44.0)
       >0.2911 (47.8)14 (56.0)
      a Significant at P < .05.
      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 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.
      • Magliano M
      Menopausal arthralgia: fact or fiction.
      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.
      • Tan AL
      • Emery P
      Role of oestrogen in the development of joint symptoms?.
      Estrogen also plays a major role in joint integrity via its maintenance of collagen, cartilage, and bone health,
      • Richette P
      • Corvol M
      • Bardin T
      Estrogens, cartilage, and osteoarthritis.
      and its anti-nociceptive effects within the central nervous system.
      • Felson DT
      • Cummings SR
      Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation.
      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.
      • Pfeilschifter J
      • Koditz R
      • Pfohl M
      • et al.
      Changes in proinflammatory cytokine activity 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).
      • Bauml J
      • Chen L
      • Chen J
      • et al.
      Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia?.
      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.
      • Henry NL
      • Pchejetski D
      • A'Hern R
      • et al.
      Inflammatory cytokines and aromatase inhibitor-associated musculoskeletal syndrome: a case-control study.
      ,
      • Lintermans A
      • Vanderschueren D
      • Verhaeghe J
      • et al.
      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.
      • 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).
      ,
      • Johnsen SP
      • Larsson H
      • Tarone RE
      • et al.
      Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study.
      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
      • 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.
      ; 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.
      • 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).
      In the Hormones and Physical Exercise (HOPE) trial, combined aerobic and resistance exercise demonstrated efficacy for alleviating AIA symptoms.
      • Baglia ML
      • Lin IH
      • Cartmel B
      • et al.
      Endocrine-related quality of life in a randomized trial of exercise on aromatase inhibitor-induced arthralgias in breast cancer survivors.
      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.
      • Galantino ML
      • Desai K
      • Greene L
      • et al.
      Impact of yoga on functional outcomes in breast cancer survivors with aromatase inhibitor-associated arthralgias.
      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.
      • 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.
      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.
      • 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.
      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.
      • 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.
      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.
      • Kim TH
      • Kang JW
      • Lee TH
      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.
      • Halvorsen BL
      • Carlsen MH
      • Phillips KM
      • et al.
      Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States.
      Ou et al. found that TC concentrate has higher inhibitory actions than did other types of processed TC.
      • Ou B
      • Bosak KN
      • Brickner PR
      • et al.
      Processed tart cherry products–comparative phytochemical content, in vitro antioxidant capacity and in vitro anti-inflammatory activity.
      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.
      • Seeram NP
      • Momin RA
      • Nair MG
      • et al.
      Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries.
      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.
      • McCune LM
      • Kubota C
      • Stendell-Hollis NR
      • et al.
      Cherries and health: a review.
      • Bell PG
      • McHugh MP
      • Stevenson E
      • et al.
      The role of cherries in exercise and health.
      • Alba CM
      • Daya M
      • Franck C
      Tart cherries and health: current knowledge and need for a better understanding of the fate of phytochemicals in the human gastrointestinal tract.
      Cherry consumption was linked to significant reduction in exercise-induced muscle pain in 8 out of 9 studies,
      • Bowtell JL
      • Sumners DP
      • Dyer A
      • et al.
      Montmorency cherry juice reduces muscle damage caused by intensive strength exercise.
      • Howatson G
      • McHugh MP
      • Hill JA
      • et al.
      Influence of tart cherry juice on indices of recovery following marathon running.
      • Levers K
      • Dalton R
      • Galvan E
      • et al.
      Effects of powdered Montmorency tart cherry supplementation on acute endurance exercise performance in aerobically trained individuals.
      • Bell PG
      • Walshe IH
      • Davison GW
      • et al.
      Montmorency cherries reduce the oxidative stress and inflammatory responses to repeated days high-intensity stochastic cycling.
      • Kuehl KS
      • Perrier ET
      • Elliot DL
      • et al.
      Efficacy of tart cherry juice in reducing muscle pain during running: a randomized controlled trial.
      ,
      • Bell PG
      • Stevenson E
      • Davison GW
      • et al.
      The effects of montmorency tart cherry concentrate supplementation on recovery following prolonged, intermittent exercise.
      ,
      • Connolly DA
      • McHugh MP
      • Padilla-Zakour OI
      • et al.
      Efficacy of a tart cherry juice blend in preventing the symptoms of muscle damage.
      but were not different from placebo in one study that involved water polo athletes.
      • McCormick R
      • Peeling P
      • Binnie M
      • et al.
      Effect of tart cherry juice on recovery and next day performance in well-trained Water Polo players.
      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.
      • Schumacher HR
      • Pullman-Mooar S
      • Gupta SR
      • et al.
      Randomized double-blind crossover study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee.
      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.
      • Zhang Y
      • Neogi T
      • Chen C
      • et al.
      Cherry consumption and decreased risk of recurrent gout attacks.
      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.
      • Chai SC
      • Davis K
      • Zhang Z
      • et al.
      Effects of tart cherry juice on biomarkers of inflammation and oxidative stress in older adults.
      Supplementation with cherry products did not alter fasting or randomly sampled blood glucose and fasting insulin in healthy study participants.
      • Kelley DS
      • Rasooly R
      • Jacob RA
      • et al.
      Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women.
      Consumption of extracts from both sweet and TC prevented alloxan-induced diabetes in rats.
      • Lachin T
      Effect of antioxidant extract from cherries on diabetes.
      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.
      • Dworkin RH
      • Turk DC
      • Wyrwich KW
      • et al.
      Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
      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.
      • Bauml J
      • Chen L
      • Chen J
      • et al.
      Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia?.
      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.
      • Howatson G
      • McHugh MP
      • Hill JA
      • et al.
      Influence of tart cherry juice on indices of recovery following marathon running.
      ,
      • Bell PG
      • Walshe IH
      • Davison GW
      • et al.
      Montmorency cherries reduce the oxidative stress and inflammatory responses to repeated days high-intensity stochastic cycling.
      ,
      • Schumacher HR
      • Pullman-Mooar S
      • Gupta SR
      • et al.
      Randomized double-blind crossover study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee.
      ,
      • Kelley DS
      • Rasooly R
      • Jacob RA
      • et al.
      Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women.
      ,
      • Dimitriou L
      • Hill JA
      • Jehnali A
      • et al.
      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.
      • Jacob RA
      • Spinozzi GM
      • Simon VA
      • et al.
      Consumption of cherries lowers plasma urate in healthy women.
      In contrast, other studies did not show a statistically significant effect of TC on plasma CRP.
      • McCormick R
      • Peeling P
      • Binnie M
      • et al.
      Effect of tart cherry juice on recovery and next day performance in well-trained Water Polo players.
      ,
      • Kent K
      • Charlton K
      • Roodenrys S
      • et al.
      Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia.
      ,
      • Vargas AJ
      • Ashbeck EL
      • Thomson CA
      • et al.
      Dietary polyamine intake and polyamines measured in urine.
      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.

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