Sticking to It: Improving Outcomes by Increasing Adherence

Much of cancer research has focused on proving the efficacy of new interventions to reduce cancer mortality. However, it has become increasingly recognized that even in settings where efficacious treatments exist, many patients do not initiate these treatments, or they discontinue treatments prematurely. With the exponential increase in oral antineoplastic agents over the past decade and a large number of oral therapies in the pipeline, this is a problem that has enormous implications, because medication noncompliance is associated with treatment failure and increased health care expenditures. It is believed that to achieve maximal benefit from most treatments, patients need to initiate and continue their treatment as prescribed. Adjuvant endocrine therapy for breast cancer is the setting where adherence to antineoplastic agents has been the most studied. Depending on the population included and the methods used, noninitiation of endocrine therapy can range from 15% to 30%. Among the group that initiates, patients can either discontinue the medication or take the medication irregularly. Although there is a range, depending on the characteristics of the populations studied, as many as 50% of patients do not take the medication for the full 5-year duration as intended. The challenge until now has been to determine the impact of nonadherence on outcomes. Randomized trials suggest that taking hormone therapy for 5 years is better than for 2 years, and we now know that 10 years is better than 5 years, but it has not been easy to determine if taking the medications irregularly affects outcomes. Because most large adjuvant breast cancer trials have not collected information on endocrine therapy adherence, investigators have used pharmacoepidemiologic methodologies to understand the association between compliance and outcome. Although several observational studies suggest that early discontinuation of hormone therapy is associated with increased mortality, one cannot assume these associations are causal. Some patients may be at high risk for adverse outcomes because of the same factors that cause them to discontinue treatment early, such as poor performance status, negative psychological outlook, or noncompliant health behaviors. Assessing disease-free survival can help overcome this bias; however, this outcome is not often reliable in many tumor registries. This bias can be most clearly seen by examining the cardiovascular literature, where it was recognized that patients participating in placebo-controlled clinical trials who were noncompliant with the placebo had worse clinical outcomes than those who were adherent to the placebo. The Coronary Drug Project was a randomized controlled trial to evaluate mortality effect of lipid-lowering drugs. In patients randomly assigned to receive placebo, it was found that adherence to placebo was associated with a lower 5-year mortality rate (15% v 28%). Similarly, in the Beta Blocker Heart Attack Trial, patients adherent to the placebo had a mortality rate of 3.0% compared with a mortality rate of 7.0% among those nonadherent to the placebo. The study by Chirgwin et al that accompanies this editorial helps clarify this uncertainty. The Breast International Group (BIG) 1-98 trial was a large adjuvant hormonal therapy trial of more than 6,000 women designed to test the benefits of tamoxifen or letrozole alone or in sequence in postmenopausal women with hormone-sensitive breast cancer. Patients were followed prospectively, and disease-free survival was the primary end point. The investigators defined persistence as completing at least 54 of the 60 months of therapy. In this group of clinical trial patients, 19% stopped early for reasons other than progression and death. Importantly, this trial dispensed pills in drug packs, and information on compliance was recorded. Patients were classified as compliant if 80% of the pills were taken during the previous 6-month interval. If patients were compliant for 90% or more of these 6-month intervals, they were considered globally compliant. Only 5% of patients were globally noncompliant by this definition. Both persistence and global compliance were associated with increased disease-free survival, with hazard ratios reported as 1.61 and 1.45, respectively. One may wonder why anyone would not take a medication that could save their life. The reasons for nonadherence are multifactorial. Barriers to compliance include patient-, physician-, medication-, and system-related variables, and poor compliance is usually associated with a combination of these factors. Several observational studies have assessed predictors of endocrine therapy nonadherence. Common findings include extremes of age, race, increased number of comorbidities, prescriptions written by nonmedical oncologists, being single, number of total prescriptions, history of nonadherence to other chronic medications, insurance status, and higher out-of-pocket costs. Studies have also suggested that switching endocrine therapies is associated with increased discontinuation. BIG 1-98 reported a similar association among women randomly assigned to sequential therapy. The reasons for this are unclear but should alert practitioners to be observant that patients who switch therapies may be vulnerable to nonadherence.