S0927:Omega3-Fatty Acid Supp in Treating Muscle&Bone Pain&Stiffness in Pts W/Stg I,II,III Brst Canc Rec'v Hormone Thpy

Study Overview
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Brief Summary
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RATIONALE: An omega-3 fatty acid-enriched nutritional supplement may help improve muscle and bone pain and stiffness caused by hormone therapy in patients with breast cancer. PURPOSE: This randomized phase III trial is studying omega-3 fatty acid supplements in treating muscle and bone pain and stiffness in patients with stage I, stage II, or stage III breast cancer receiving hormone therapy.

Detailed Description
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OBJECTIVES: Primary To assess whether omega-3-fatty acid as compared to placebo causes a reduction in worst joint pain and/or stiffness at 12 weeks, as measured by the modified Brief Pain Inventory (BPI), in women with early-stage breast cancer and aromatase inhibitor (AI)-associated arthralgia. Secondary To assess the proportion of patients who report improved versus deteriorated joint pain with omega-3-fatty acid versus placebo. To assess the proportion of patients who report improved versus deteriorated joint stiffness with omega-3-fatty acid versus placebo. To assess whether patients receiving omega-3-fatty acid compared to placebo have decreased analgesic use and increased AI adherence. To assess whether patients receiving omega-3-fatty acid compared to placebo have improved functioning, pain, and stiffness in the knees/hips (as measured by the Western Ontario and McMaster Universities Osteoarthritis, WOMAC) score. To assess whether patients receiving omega-3-fatty acid have improved functioning, pain, and stiffness in the hands (as measured by the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, M-SACRAH). To assess whether patients receiving omega-3-fatty acid compared to placebo have improved functional quality of life as measured by the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) Trial Outcome Index (TOI). To assess whether patients receiving omega-3-fatty acid report changes for the better versus worse compared to placebo as measured by the Global Rating of Change Scale. To identify minimally important change in the WOMAC, M-SACRAH, and the FACT-ES Trial Outcome Index (TOI) using a little better or a little worse responses on the patient-reported global rating of change in joint pain and joint stiffness. To assess whether patients receiving omega-3-fatty acid compared to placebo have an improved lipid profile as measured by triglycerides, HDL, and LDL. To assess the toxicity of omega-3-fatty acid compared to placebo in this setting. To assess whether there is a difference in serum-free and total estradiol levels before and after treatment with omega-3-fatty acid compared to placebo. To explore whether CYP19A1 genotype correlates with severity of joint symptoms or predicts response to omega-3-fatty acid. (exploratory) To explore changes in hormonal and inflammatory serum biomarkers, such as IL6, TNF-α, and CRP. To assess whether there is a relationship between change in serum docosahexaenoic acid (DHA) and EPA and resolution of joint symptoms. To establish a cohort of patients (placebo group) to better characterize the natural history of the syndrome. OUTLINE: This is a multicenter study. Patients are stratified according to prior osteoarthritis (yes vs no) and prior taxane use (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral omega-3-fatty acid twice daily (BID) or three times daily (TID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive oral placebo BID or TID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection at baseline and at 12 and 24 weeks for biomarker and DNA analysis. Patients complete the Brief Pain Inventory Short Form (BPI-SF), the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, the Modified-Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the FACT-ES Trial Outcome Index, and the Omega-3-fatty acid Dietary Intake questionnaires at baseline and at 6, 12, and 24 weeks.

Official Title
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S0927: A Randomized Placebo-Controlled Trial of Omega-3-Fatty Acid for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain and Stiffness In Women With Early Stage Breast Cancer, Phase III

Conditions
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Arthralgia, Breast Cancer, Pain

Intervention / Treatment
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* Dietary Supplement: omega-3 fatty acid
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary invasive adenocarcinoma of the breast Stage I, II, or IIIA disease No metastatic disease Must have undergone modified radical mastectomy or breast-sparing surgery and recovered Estrogen-receptor positive (ER+) and/or progesterone-receptor positive (PR+) Currently taking a third-generation aromatase inhibitor (AI) [e.g., anastrozole (Arimidex®), letrozole (Femara®), or exemestane (Aromasin®)] for ≥ 90 days prior to registration with plans to continue for ≥ 180 days after registration Must have completed the S092 Brief Pain Inventory (BPI)-Short Form within the past 14 days, and must have a worst pain/stiffness of ≥ 5 on the BPI (item #2) that has started or increased with AI therapy PATIENT CHARACTERISTICS: Postmenopausal Zubrod performance status 0-2 Willing to submit blood for serum-free estradiol, total estradiol, serum inflammatory markers (IL6, TNF-α, CRP), DHA and EPA, lipid profile (LDL, HDL, triglycerides), and DNA analysis (CYP19A1) Able to complete study questionnaires in English At least 5 years since other malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ of the breast or adequately treated stage I or II cancer from which the patient is currently in complete remission Patients must not have a known allergy to soy, given that the placebo is suspended in soybean oil PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 3 months since prior omega-3 fatty acid supplements and must agree to refrain from omega-3-fatty acid supplements from sources outside of this study More than 28 days since prior investigational agents No other medical therapy, alternative therapy, or physical therapy for joint pain/stiffness within the past 30 days Patients must not be on anticoagulation medication (i.e., heparin/warfarin) because of increased risk of bleeding within 28 days prior to registration Patients must not have a history of bone fracture or surgery of the afflicted knees and/or hands within 6 months prior to registration Patients must not be on narcotics within 14 days of registration Patients may have received corticosteroid treatment; however, the following criteria apply: Patients must not have received oral or intramuscular corticosteroids within the 28 days prior to registration Patients must not have received intra-articular steroids to the study, or any other, joint within 28 days prior to registration Patients must not have received topical analgesics (e.g., capsaicin preparations) to the study joint or any other analgesics (e.g., opiates, tramadol; with the exception of nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen) within 14 days prior to registration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral omega-3-fatty acid twice daily (BID) or three times daily (TID) for 24 weeks in the absence of disease progression or unacceptable toxicity. | Dietary Supplement: omega-3 fatty acid<br>* Given orally<br>|
| Placebo Comparator: Arm II<br>Patients receive oral placebo BID or TID for 24 weeks in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 12 Brief Pain Inventory (BPI) Worst Pain/Stiffness Score | Linear regression model-adjusted week 12 mean score by treatment group. Purpose: To assess the severity of pain Population: Patients with pain from chronic diseases or conditions such as cancer, osteoarthritis and low back pain, or with pain from acute conditions such as postoperative pain Responsiveness: Responds to both behavioral and pharmacological pain interventions Method: Self-report or interview Scoring: Higher scores indicate more pain Range: 0-10 | 12 weeks post-registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events That Are Possibly, Probably or Definitely Related to Study Drug | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 25 weeks | 
| Week 12 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Score | Linear regression model-adjusted week 12 mean score by treatment group The WOMAC measures five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). Higher scores indicate higher symptom burden. | 12 weeks post-registration | 
| Week 12 Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) Score | Linear regression model-adjusted week 12 mean score by treatment group. Higher scores represent higher symptom burden. Range is 0 to 100. | 12 weeks post-registration | 
| Week 12 Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) Score | FACT-ES measures physical, social and family, emotional, and functional well-being and endocrine symptoms. The FACT scaleshave five response levels (not at all to very much), where higher scores reflect better well-being and fewer symptoms. This scale provided a measure of the broader impact of join pain and stiffness symptoms. Score range is 0 to 220. | 12 weeks post-registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, arthralgia