– Estrogen deprivation may be a factor

by Pam Harrison, Contributing Writer November 30, 2015

Patients receiving the aromatase inhibitor (AI) anastrozole had a higher incidence of carpal tunnel syndrome (CTS) compared with controls, an exploratory analysis has found, although few patients overall required surgical intervention to resolve it.

A total of 96 participants in the International Breast Cancer Intervention Study II (IBIS-II) developed CTS over a median follow-up of 6.4 years (3.4% in the anastrozole arm versus 1.6% of controls, odds ratio [OR] 2.16, 95% CI 1.40-3.33, P<0.001). The median time to CTS onset was 1.99 years (interquartile range [IQR] 0.95-3.05 years).

“With many patients with breast cancer taking AIs worldwide, adverse effects that can limit compliance are of growing importance,” lead author Francesco Spagnolo, MD, of the Queen Mary University of London, and colleagues wrote online in the Journal of Clinical Oncology. “We found that the use of anastrozole was associated with a higher incidence of CTS, with an excess incidence of 1.8% after treatment completion.”

Women in the active treatment arm also tended to have more severe disease, eight cases being severe among anastrozole patients compared with two cases in the placebo arm.

Indeed, the rate of severe CTS in the anastrozole arm was four times higher compared with rates in placebo patients, but this difference was not statistically significant.

Some 17 participants — 0.9% of those on active treatment — also reported CTS of moderate severity, compared with 10 controls (0.5%), but reports of mild symptoms were similar between the two treatment groups.

Only 1% of those who developed CTS reported receiving some sort of treatment for it, but the difference between the two treatment arms was still statistically significant at an OR of 2.21 (95% CI 1.11-4.39; P=0.024). Specifically, surgery was done significantly more often for women in the AI arm (0.9% versus 0.3%, OR 3.06, 95% CI 1.21-7.71, P=0.018).

The IBIS-II study was a double-blind, randomized, placebo-controlled trial in which women at increased risk of breast cancer were assigned to receive oral anastrozole at a dose of 1 mg per day or placebo for 5 years. A total of 3,864 women were randomized in roughly equal numbers to either treatment arm. Almost half of all women had used menopausal hormone replacement therapy (MHT) in the past.

Of the 38 women who had received some sort of treatment for CTS, 14 women were managed conservatively with either cortisone injections or a wrist splint or both, and the median time to resolution of symptoms was 1 year (IQR 0.27-2.07 years). There was no significant difference in time to resolution between the two treatment arms.

However, women in the anastrozole arm were almost 2.5 times more likely to discontinue treatment because of the onset of CTS or other adverse events (OR 2.44, 95% CI 0.80-8.885, P=0.08). Discontinuation rates due to adverse events were very modest in both arms (12 patients in the AI arm versus five from the placebo arm).

“Age, smoking, and prior MHT were not found to be risk factors for the development of CTS,” Spagnolo noted.

However, women who were either overweight (body mass index [BMI] from 25 to 30) or obese (BMI >30) were 78% more likely to develop CTS compared with normal-weight women (OR 1.78, 95% CI 1.07-2.96, P=0.02).

Similarly, patients who developed other musculoskeletal symptoms had a significantly higher risk of developing CTS (3.2%) compared with women who did not report any adverse musculoskeletal event (1.6%).

“Overall, the incidence of CTS with anastrozole was low (3.4%) and fewer than two of every 1,000 women discontinued treatment only because of the onset of CTS,” the investigators pointed out.

In fact, the majority of CTS symptoms reported in the AI group were of mild to moderate severity, with only one out of three patients requiring an intervention of any kind, they added.

Nevertheless, it has been hypothesized that estrogen deprivation — the main mechanism of action of all AIs — is likely responsible for the development of CTS and other musculoskeletal symptoms.

Limitations of the study include missing data on the severity and date of resolution of symptoms for a number of women and the fact that the diagnosis, management, and reporting of CTS were left to local investigators and were therefore heterogeneous.

However, with a median follow-up of more than 6 years, “we will have captured almost all of the treatment-related cases,” Spagnolo affirmed, “because most cases occur early in the treatment period.”

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 11.30.2015