Compliance Inconsistent for Adjuvant Breast Cancer Therapy

DUBLIN, Jan. 22 -- Many women taking tamoxifen as adjuvant breast cancer therapy are halting it well before the optimal five-year therapeutic standard and not substituting an aromatase inhibitor, researchers here reported.

Among 2,816 women studied, 26.5% overall stopped tamoxifen without restarting it or an aromatase inhibitor within 180 days, said Thomas I. Barron, M.Sc., of Trinity College Dublin and St. James's Hospital here, and colleagues, online in advance of the March 1 issue of Cancer.

More than a fifth of women who started taking the hormonal treatment to prevent a recurrence of breast cancer stopped within a year, which is twice as high as has been reported in other studies.

Three years ago, Ann H. Partridge, M.D., of the Dana-Farber Cancer Institute in Boston reported in the Journal of Clinical Oncology that data from New Jersey's Medicaid program from 1990 to 1996 showed that, on average, patients filled prescriptions for tamoxifen for 87% of their first year of treatment. Overall adherence decreased to 50% by year four of therapy.

In the Irish study, more than a third of women stopped tamoxifen within 3.5 years. This rate is higher than even the five-year nonpersistence rates found in clinical trials (16% to 32%) or self-report studies (31%).

"These high rates of nonpersistence, especially in the early stages of treatment, are likely to have a negative impact on the therapeutic success of tamoxifen," the authors wrote. "Therefore, it is doubtful that the full benefits of tamoxifen, as demonstrated in randomized studies, will be achieved in clinical practice."

"This study demonstrates that persistence with tamoxifen cannot be assumed and raises concerns about persistence with other oral hormonal therapies for breast cancer and oral antineoplastics in general," they added. "Oncologists need to identify those at risk of nonpersistence and develop strategies to combat this barrier to treatment success."

The researchers examined the Irish national healthcare system prescribing database for all women over age 35 who started tamoxifen as initial hormonal therapy (no other hormonal therapy in the previous 12 months) from January 2001 and January 2004. The database included women who received free health services through the government with a disproportionate number being elderly or socially disadvantaged (20.4% ages 65 to 74, 31.2% over 75).

Tamoxifen nonpersistence was defined as 180 consecutive days without a filled prescription and no alternative hormonal therapy. Women were followed for an average of 2.7 years after their first tamoxifen prescription and for at least a year after their discontinuation data to identify subsequent hormonal therapy use.

Among the 26.5% who were nonpersistent with tamoxifen, only 1.2% switched to another hormonal therapy after a gap of at least 180 days, 5.1% restarted tamoxifen after a similar gap, and 20.2% stopped without restarting any hormonal therapy.

Only 31.4% of women stayed on tamoxifen through the end of follow-up. The cumulative nonpersistence rates were:

• 11.1% within 30 days (95% confidence interval 10.0% to 12.3%).
• 14.5% at 90 days (95% CI 13.2% to 15.9%).
• 22.1% by one year (95% CI 20.6% to 23.7%).
• 28.4% by two years (95% CI 26.6% to 30.3%).
• 35.2% at 3.5 years (95% CI 32.5% to 37.9%).

About a quarter of the women overall switched to another hormonal therapy within 180 days of discontinuing tamoxifen (25.4%; mean 1.5 years after tamoxifen initiation). The findings were:

• 20.9% switched to Arimidex (anastrozole).
• 3.7% switched to Femara (letrozole).
• 0.8% switched to Aromasin (exemestane).

About 16% of women in the database were lost to follow-up because of death, loss of eligibility for the healthcare system, or no prescription activity in the database during the 12 months following tamoxifen nonpersistence.

Women at the extremes of age or those with preexisting depression were most likely to stop tamoxifen early. The hazard ratios for nonpersistence were:

• 1.36 for age 35 to 44 compared age 45 to 54 (95% CI 1.01 to 1.83).
• 1.46 for age 75 and above compared with age 45 to 54 (95% CI 1.16 to 1.83).
• 1.41 for antidepressant use in the year preceding tamoxifen initiation (95% CI 1.18 to 1.70).
• 1.72 for the presence of Parkinson's disease or dementia (95% CI 1.24 to 2.39).

The reason for early discontinuation among younger women may be that they do not adjust well to the diagnosis of breast cancer or have more problems with side effects, the investigators suggested.

However, they said, "As younger women have the potential for a longer life expectancy, the negative consequences of nonpersistence with tamoxifen are significant, particularly as the benefits of five years of tamoxifen therapy have now been shown to extend to 15 years."

While the study was the first to report objectively measured rates of tamoxifen discontinuation, the database did not provide any diagnostic or staging information or differentiate between discontinuation by the patient or at the prescriber's direction.

The rates found in the study may be conservative, the investigators said, because patients who were prescribed tamoxifen but never filled even the first prescription would not have been included in the database. Also, some of the women may have filled their prescription but never taken the pills.