Vitamin D Supplementation Viable for Reducing Pain during Breast Cancer Therapy

High serologic vitamin D levels may reduce local infl ammation, conferring a potentially protective effect against common causes of therapy discontinuation. Supplementation with vitamin D may reduce musculoskeletal pain and fatigue among women starting adjuvant aromatase inhibitor (AI) therapy for breast cancer treatment. The addition of 30,000 IU/ week of vitamin D3 to letrozole therapy resulted in fewer reports of musculoskeletal pain compared with placebo in a trial of 147 women (Abstract 9000).

During Monday’s Patient and Survivor Care Oral Abstract Session, Qamar J. Khan, MD, of the University of Kansas Medical Center, presented the results of the phase III randomized, placebocontrolled, double-blind VITAL study.

The ability of clinicians to reduce pain, fatigue, and other issues often associated with cancer therapy could have important implications for improving compliance. Notably, Dr. Khan said, around 50% of women taking adjuvant AIs for breast cancer report new or worsening musculoskeletal pain, and 18% to 30% report fatigue.

“These are significant causes of women prematurely discontinuing therapy,” Dr. Khan said.

Fewer Reported Musculoskeletal Events For the study, 147 evaluable women with stage I to III breast cancer were enrolled to receive letrozole therapy plus a standard dose of vitamin D (600 IU) plus calcium (1,200 mg) daily.

Patients were then randomly assigned to receive an additional 30,000 IU/week of vitamin D3 or placebo. Patients were assessed at baseline and again at weeks 12 and 24 for vitamin D levels using a 25-hydroxyvitamin D test and symptom questionnaires.

Three patients, all in the placebo arm, discontinued therapy early due to musculoskeletal pain. In the vitamin D arm, blood levels rose from 22 ng/mL at baseline to 53 ng/mL at week 12 and 57 ng/ mL at week 24. In the placebo arm, blood vitamin D levels increased from 25 ng/ mL at baseline to 32 ng/mL at week 12 and 31 ng/mL at week 24 (Figure).

According to Dr. Khan, serologic vitamin D levels below 20 ng/mL are considered deficient for bone health. In fact, part of the rationale for the study is that a syndrome similar to musculoskeletal pain associated with use of AIs has been observed in patients with severe vitamin D deficiency. Additionally, vitamin D deficiency is common among women with breast cancer who have musculoskeletal symptoms, as well as among women undergoing adjuvant chemotherapy despite supplementation.

A higher proportion of women in the placebo arm (51%) experienced a protocol- defined musculoskeletal event compared with 37% in the vitamin D arm, as evaluated with the Simple Descriptive Pain Intensity Scale (p = 0.069). However, using the quantitative Brief Pain Inventory, 61% of patients in the placebo arm and 38% in the vitamin D arm reported a musculoskeletal event (p = 0.008).

The study also evaluated the incidence of an adverse quality-of-life event as a secondary endpoint, and found a signifi- cantly higher percentage of women in the placebo arm (72%) reported a musculoskeletal event and fatigue compared with 42% in the vitamin D arm (p < 0.001).

Remaining Questions

The mechanism of action defining the benefit of vitamin D in this setting is unclear, Dr. Khan said. However, it is likely that AIs induce estrogen deprivation, thereby slowing local production of calcitriol (1,25-dihydroxycholecalciferol), which is important in limiting joint infl ammation. As a result, stimulating higher doses of calcidiol (25-hydroxycholecalciferol)—a prehormone produced in the liver as a result of hydroxylation of vitamin D, which is converted to calcitriol in the kidney— may have benefit, Dr. Khan said. Even less clear, according to Discussant Karen M. Mustian, PhD, MPH, of the University of Rochester Medical Center, is how long it takes for nutritional supplementation to provide benefi t, and how sustainable the benefit is.

The former is a crucial component of nutritional supplementation, Dr. Mustian said, because a lag in treatment benefit might still cause some women to discontinue therapy.

The phase III VITAL trial was designed only to evaluate subjects at baseline, 12 weeks, and 24 weeks, with primary and secondary endpoints evaluated upon study completion, so answering these questions is difficult, Dr. Khan said.

However, patients in the study taking the additional vitamin D achieved high and presumably protective levels of serologic vitamin D at 12 weeks and appeared to maintain that level until study completion.

This leveling off suggests that it may be feasible to load the body to suffi- cient vitamin D levels and then maintain that benefit long term.