Vitamin B12 for Aromatase Inhibitors Associated Musculoskeletal Symptoms in Breast Cancer
Keywords
Abstract
Description
According to the American Cancer Society, there were more than 250,000 new breast cancer cases in 2017. Incidence of breast cancer increases with age, with more than 75% of patients being postmenopausal at the time of diagnosis. In addition, hormone receptors (HR) are over expressed in the majority of breast cancer tumors in postmenopausal women.
Two classes of anti-endocrine therapies are used for treatment of HR-positive breast cancer: tamoxifen and the AIs, which can only be used to treat postmenopausal women because they are ineffective in women with functional ovaries. Joint pain is a significant AI-associated toxicity, affecting as many as 50% of patients. No factors associated with breast cancer treatment (such as chemotherapy) or co-morbid conditions (such as diabetes or body mass index) have been clearly shown to be predictive of the development of joint pain. The cause of AI-associated musculoskeletal symptoms remains elusive but some think it is associated with the direct effects of estrogen deprivation on bone, neurohormonal changes which result in change in pain sensitivity, and immune system changes that alter the circulating or local inflammatory cytokine concentrations.
Some studies report more than 20% of patients are no longer taking their AI chemotherapy regimen because of AI-associated joint pain. As many as 40,000 women are affected by this toxicity in the United States annually and up to 20,000 women discontinue AI therapy because of intolerable joint pain and muscle aches. The current treatment for AI associated musculoskeletal symptoms is limited to oral pain medications and exercise, but, neither intervention has optimal effects, and the long term use of oral pain medication is problematic. Improvement in the treatment of AI associated musculoskeletal symptoms is needed to improve compliance with therapy, and thereby lead to improved breast cancer outcomes and survivorship.
The study team conducted a pilot study (Campbell et al. Breast J, 2018) which suggested that vitamin B12 reduces pain and improves quality of life for participants taking aromatase inhibitors (AIs) who experienced AI-related musculoskeletal symptoms. This study aims to confirm these results in a phase III randomized prospective trial. If confirmed, Vitamin B12 would become a safe and cost-effective option for the treatment of AI-related musculoskeletal symptoms, leading to improved cancer outcomes and survivorship.
Dates
| Last Verified: | 06/30/2020 |
| First Submitted: | 12/17/2019 |
| Estimated Enrollment Submitted: | 12/17/2019 |
| First Posted: | 12/18/2019 |
| Last Update Submitted: | 07/01/2020 |
| Last Update Posted: | 07/06/2020 |
| Actual Study Start Date: | 07/31/2020 |
| Estimated Primary Completion Date: | 08/31/2021 |
| Estimated Study Completion Date: | 10/31/2022 |
Condition or disease
Intervention/treatment
Dietary Supplement: Study Medication Group (B12)
Other: Blood collection
Other: Brief Pain Inventory - Short Form survey
Other: FACT-ES Trial Outcome Index (Version 4)
Other: Questionnaire to Assess Adherence to Aromatase Inhibitors
Other: Demographics Questionnaire
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Active Comparator: Control - Standard of Care Day 0:
Baseline questionnaires: FACT-ES, BPI-SF, Assessment of AI Adherence, Demographics, CRF, and Supplemental Agents Reporting Form
Blood collection
Continue Usual Care
Day 45:
Repeat of baseline questionnaires with addition of vitamin B12 supplements form and investigational agent accountability record
Blood collection
Continue Usual Care
Day 90:
-Repeat of day 45 | |
| Experimental: Study Medication Group (B12) Day 0:
Baseline questionnaires: FACT-ES, BPI-SF, Assessment of AI Adherence, Demographics, CRF, and Supplemental Agents Reporting Form
Blood collection
Oral intake of Vitamin B12 Daily in the morning
Day 45
Repeat of baseline questionnaires with addition of investigational agent accountability record
Blood collection
Oral intake of Vitamin B12 Daily in the morning
Day 90:
-Repeat of day 45 without additional study drug intake. | Dietary Supplement: Study Medication Group (B12) Vitamin B12, orally, 2500 mcg, daily, for 90 days |
Eligibility Criteria
| Ages Eligible for Study | 19 Years To 19 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - Subjects must have histologically or cytologically confirmed estrogen receptor (ER) and/or progesterone receptor (PgR) positive invasive carcinoma of the breast (Stage I-III) with no evidence of metastatic disease (M0). - Subjects must have completed mastectomy or breast sparing surgery, and must have recovered from all side effects of the surgery. Patients should have recovered from all Grade 2 or higher side effects of chemotherapy and/or radiation therapy with the exception of alopecia and peripheral neuropathy. Concurrent bisphosphonate and trastuzumab therapies are allowed - Patients must have aromatase inhibitor (AI) associated musculoskeletal symptoms that began or increased after starting AI therapy. New musculoskeletal pain must not be due specifically to fracture or traumatic injury - Subjects must currently be taking one of the following aromatase inhibitor (AI) doses for at least 14 days prior to registration and plan to continue for at least an additional 180 days after registration: - Anastrozole (Arimidex) 1 mg daily OR - Letrozole (Femara) 2.5 mg daily OR - Exemestane (Aromasin) 25 mg daily - Patients must be post-menopausal, as defined by at least one of the following: --≥ 12 months since their last menstrual period OR - Prior bilateral oophorectomy OR - Previous hysterectomy with one or both ovaries left in place (or previous hysterectomy in which documentation of bilateral oophorectomy is unavailable) AND (unless ≥ 60 years of age) FSH values consistent with the institutional normal values for the post-menopausal state. - Performance status: Patients must have Zubrod performance status of 0-2 - Patients must have no known allergy or hypersensitivity to vitamin B12 - Patients must not have any contraindicated concurrent illnesses including: - History of alcohol or other substance abuse or dependence within 365 days prior to enrollment. - Chronic liver disease. - End stage renal disease. - Patients who are receiving treatment with narcotics, tramadol, gabapentin, and/or pregabalin must have been taking a stable dose for at least 30 days prior to registration. - Patients must be able to complete study questionnaires in English or Spanish, which will be given via an iPad or if unavailable or due to technical difficulties via paper copies. - Patients who are currently taking vitamin B12 or a multivitamin containing vitamin B12 will be able to participate in the study after having stopped taking the vitamin B12 or the multivitamin containing the B12 for two weeks. - Patients must be willing to submit blood samples for laboratory testing [to test for Serum Vitamin B12, CRP, homocysteine level, and MMA]. Baseline samples must be obtained prior to beginning protocol treatment. - All patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. - Subjects must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: - Subjects receiving any other investigational agents. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to vitamin B12 or other agents used in this study. - Subjects with uncontrolled intercurrent illness including, but not limited to chronic liver disease, end stage renal disease, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements |
Outcome
Primary Outcome Measures
1. Change in average joint pain according to the Brief Pain Inventory - Short Form (BPI- SF) [At baseline, day 45 (+/- 10 days), and at day 90 (+/- 10 days)]
Secondary Outcome Measures
1. Change in worst joint pain according to the BPI-SF [At day 90 (+/- 10 days)]
2. Quality of life (QOL) as measured by Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES) [At baseline, day 45 (+/- 10 days), and at day 90 (+/- 10 days)]
Other Outcome Measures
1. Serum inflammatory cytokine levels (C- reactive protein) [At baseline, day 45 (+/- 10 days), and at day 90 (+/- 10 days)]
