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Nonadherence to Adjuvant Tamoxifen Therapy in Women With Primary Breast Cancer

Ann H. Partridge, Philip S. Wang, Eric P. Winer, Jerry Avorn

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Division of Pharmacoepidemiology and Pharmacoeconomics, and Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Address reprint requests to Ann H. Partridge, MD, Dana-Farber Cancer Institute, 44 Binney St., D1210, Boston, MA 02115; email: ahpartridge{at}partners.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Although clinical trials have clearly demonstrated the benefits of tamoxifen in women with primary breast cancer, little is known about how this drug is actually used in the general population. We sought to estimate adherence and predictors of nonadherence in women starting tamoxifen as adjuvant breast cancer therapy.

Patients and Methods: Subjects were age 18 years or older initiating tamoxifen for primary breast cancer and enrolled in New Jersey’s Medicaid or Pharmaceutical Assistance to the Aged and Disabled programs during the study period, from 1990 to 1996 (N = 2,378). Main outcome measures were number of days covered by filled prescriptions for tamoxifen in the first year of therapy with the 4 years after tamoxifen initiation for a subset; predictors of good versus poor adherence.

Results: Twenty-three percent of patients missed taking tamoxifen on more than one fifth of days studied, although on average, patients filled prescriptions for tamoxifen for 87% of their first year of treatment. The youngest, oldest, nonwhite, and mastectomy patients had significantly lower rates of adherence; patients who had seen an oncologist before taking tamoxifen had significantly higher rates of adherence. Overall adherence decreased to 50% by year 4 of therapy.

Conclusion: The mean level of adherence to tamoxifen is high compared with other chronic medications. However, nearly one fourth of patients may be at risk for inadequate clinical response because of poor adherence. Because of the efficacy of tamoxifen therapy in preventing recurrence and death in women with early-stage breast cancer, further efforts are necessary to identify and prevent suboptimal adherence.

	INTRODUCTION

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CLINICAL TRIALS have documented the benefits of adjuvant tamoxifen in women with early-stage breast cancer. Adjuvant tamoxifen therapy reduces the risk of a systemic recurrence or a contralateral breast cancer by about 50% and results in a significant increase in overall survival for women with hormone receptor–positive breast cancer.^1–3

Side effects of tamoxifen include the development or worsening of menopausal symptoms and a small but significantly increased risk of thrombosis and endometrial cancer.^4–7 For most women with hormone receptor–positive early-stage breast cancer, the benefits of tamoxifen greatly outweigh the risks. To date, clinical trials have shown that the benefits of tamoxifen are greater with 5 years of therapy than with 1 or 2 years but that longer durations (beyond 5 years) provide no further advantage.^2,3,8 The standard recommendation for women with hormone receptor–positive breast cancer is 5 years of tamoxifen at a dose of 20 mg daily.⁹ There are no data to support lower doses or less frequent administration.

Adherence is the extent to which a patient’s behavior coincides with medical advice.¹⁰ Adherence to any intervention over long periods of time is largely determined by the individual’s perception of the risks, benefits, and costs of the intervention.¹¹ The psychosocial implications of taking medication on an ongoing basis and the logistic demands of such treatment must also be considered. Adherence rates for many chronic drug therapies have been shown to be strikingly low, often ranging between 40% and 50%.^12–14 Available data on adherence to tamoxifen are from limited study populations,^1,4,15–18 often as part of a clinical trial, and adherence as measured in a clinical trial can be a poor indication of how a medication will be taken in the general population.¹⁹ Overall adherence to adjuvant tamoxifen has been reported to range from 25% to 96%, although the assessment methodology often has not been reported.^1,4,15–18 In a group of 26 women with breast cancer, Waterhouse et al¹⁸ found that patient self-report and pill counts significantly overestimated the degree to which patients adhered to their tamoxifen regimen, compared with data recorded by a microelectronic monitoring device. In this study, when all dosing errors as measured by the microelectronic monitoring device were considered, 18 of 24 patients (75%) were less than 80% adherent with the tamoxifen regimen.

We measured filled tamoxifen prescription rates in a population of women newly initiated on tamoxifen as adjuvant breast cancer therapy and identified clinical and demographic factors associated with poor adherence in this population.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Sources of Data
The study population was drawn from enrollees in the New Jersey Medicaid program and the New Jersey Pharmaceutical Assistance to the Aged and Disabled (PAAD) program for the period from January 1, 1990 to June 30, 1996. During the study period, an annual income below the poverty level was required for patients to be eligible for Medicaid benefits. In contrast, the New Jersey PAAD program provided drug coverage to a less indigent population, with income ceilings of $15,700 if single and $19,250 if married. Information on all filled prescriptions was extracted from the paid claims from these programs. Each record contained information on the tamoxifen dispensed, including dosage, quantity dispensed, and number of days supplied. We then linked drug use data with information on other health service use through Medicaid and Medicare to identify diagnoses and other clinical services used during the study period. We also linked the data with the New Jersey Cancer Registry to identify stage of breast cancer, when available. All personal identifiers were removed before analysis to protect the confidentiality of program participants, and local institutional review board approval was obtained.

During the study period, New Jersey’s Medicaid had no deductible or maximum benefit for drugs and charged no copayment for prescribed medications, ensuring complete ascertainment of drug use. New Jersey’s PAAD program had no deductible and no maximum benefit, but had a nominal $2 copayment for each prescription filled. Neither program had any formulary restrictions.

Study Subjects
We identified all women 18 years of age or older who were continuously enrolled in the New Jersey Medicaid program or New Jersey PAAD program and who filled a first prescription for tamoxifen during the years 1991 to 1995. The index date for a given study subject was defined as the first date of filling a prescription for tamoxifen. Subjects were required to have evidence of using services in the year before and after the index claim for tamoxifen. Subjects were also required to be active users of the drug programs as evidenced by filling at least one prescription for any drug during the year before and following their first tamoxifen prescription. Subjects who died during this period were excluded and women with known metastatic disease were excluded. To maximize the chance that women in the study had early-stage breast cancer, subjects were required to have had some type of potentially definitive breast cancer surgery (mastectomy, partial mastectomy, or if a breast biopsy only was performed, an axillary lymph node evaluation) in the year before the initiation of tamoxifen.

We defined other factors potentially related to adherence, including patient age, sex, race, socioeconomic status (defined by enrollment in Medicaid or PAAD), number and severity of comorbid diseases (as determined by the Charlson Comorbidity Index²⁰), and stage of breast cancer (ascertained from the New Jersey Cancer Registry). For the year before tamoxifen initiation, we also assessed use of other prescription medications, hormone replacement therapy, chemotherapy, radiation therapy, and oncologist care, as well as the number of outpatient visits, nursing home use, and days of acute hospitalization.

Definition of Adherence
Adherence was defined as the proportion of eligible days during the 365 days following a patient’s first tamoxifen prescription for which the patient had filled prescriptions for tamoxifen.^21–25 Eligible days were considered those days before any evidence of recurrence or new breast cancer, or an adverse event possibly related to tamoxifen. Evidence for recurrent disease or new primary breast cancer included use of another hormone or hormonal manipulation, new chemotherapy or radiation therapy (if > 60 days after the initiation of tamoxifen), any biopsy, or new breast cancer surgery. Evidence for adverse events potentially related to tamoxifen included evidence of thrombosis, pulmonary embolism, pancreatitis, hepatitis, liver failure and other liver abnormalities, or any endometrial pathology or surgery.

We used the quantity dispensed and the days’ supply data on all tamoxifen prescriptions filled during the eligible days for each patient to measure the number of days a patient had tamoxifen available during the period (days covered). This continuous outcome was used to dichotomize patients into two groups in categorical analyses, as follows: patients with 80% days covered were defined as adherent, whereas patients with less than 80% of eligible days covered were defined as nonadherent. An 80% cutoff was chosen because it is a rate frequently cited in the literature as achievable or acceptable.^1,18,26 Days in hospital were assumed to be days of full compliance; in the case of overlapping prescriptions, the number of days covered was not duplicated.

Long-Term Follow-Up
For the subset of subjects who began tamoxifen therapy in 1991, we obtained complete filled prescription data from January 1, 1991 through December 31, 1995. We then measured long-term drug use rates for the eligible subjects in this cohort.

Statistical Analysis
The likelihood of 80% adherence to tamoxifen versus less than 80% adherence was estimated through unconditional logistic regression using the SAS logistic procedure (SAS Institute, Cary, NC).²⁷ Confidence intervals for the estimated odds ratios were used to judge the significance of differences. All potential determinants of nonadherence in the regression model were subject to a forward stepwise selection procedure with criteria for entry of P < .2.

	RESULTS

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Measurement of Adherence
There were 2,378 subjects who met study criteria (Table 1 lists characteristics of the study population). The population consisted of women with mean age of 75 years. The racial mix was representative of the U.S. population, and Medicaid recipients constituted more than one fourth of the study cohort. In the year before beginning tamoxifen, the women had a mean Charlson comorbidity index of 4.9, indicative of a moderate degree of comorbidity, and a rate of estrogen replacement therapy of 3%. Forty-six percent were seen by a medical oncologist at some point in the year before their first tamoxifen prescription, 60% had undergone a mastectomy, 14% received adjuvant radiation therapy, and only 7% underwent chemotherapy.

Relationship Between Patient Characteristics and Nonadherence
Predictors of nonadherence in univariate and adjusted models appear in Table 2. Nonadherence was associated with the extremes of age; patients less than 45 and 85 years old were the most nonadherent relative to 75- to 84-year-old patients (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.30 to 5.23 and OR, 1.87; 95% CI, 1.40 to 2.49, respectively). Nonwhite subjects were less adherent than white subjects (OR, 1.62, 95% CI 1.26 to 2.09). Women who had had a mastectomy rather than breast-conserving surgery were less adherent (OR, 1.64, 95% CI 1.33 to 2.02), and having seen an oncologist in the year before beginning tamoxifen therapy was independently associated with better adherence (OR, 0.80; 95% CI, 0.65 to 0.98). There was a tendency for higher Charlson score, reflecting increased comorbidity, to be associated with better adherence (OR, 0.96; 95% CI, 0.93 to 0.99). Type of drug program (Medicaid or PAAD); breast cancer stage at diagnosis; calendar year that the patient began tamoxifen therapy; use of other prescription medications; number of outpatient visits; nursing home use; days of acute hospitalization during the year before tamoxifen initiation; and history of estrogen replacement therapy, adjuvant chemotherapy, or radiation therapy were not associated with nonadherence. Type of drug program and nursing home use remained nonsignificant in an analysis restricted to patients 65 years old. When patients for whom stage was not available were excluded, results did not vary materially (21% of patients were defined as nonadherent, and stage remained not significantly associated with nonadherence).

View larger version (15K): [in this window] [in a new window]   Fig 1. Long-term adherence to adjuvant tamoxifen therapy in eligible patients from 1991 index year cohort.

	DISCUSSION

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Patients with cancer are thought to be highly motivated by the gravity of their disease, with too much to lose by being nonadherent.¹⁸ Yet, adherence is poor with other regimens well documented to reduce mortality or the risk of catastrophic outcomes (eg, statins after myocardial infarction, antihypertensive agents in patients with hypertension).^24,25,28 Adherence rates from studies of oncology patients range between 20% and 100%.²⁹

There are no data to support the efficacy of tamoxifen administered at lower doses or less frequent intervals than the standard recommendation. In an early dose-ranging study, the 19 women with metastatic breast cancer in the low-dose group, receiving 2, 4, or 8 mg/m² bid, did not do as well as the higher-dose groups.³⁰ Another group studied the effects of lower doses of tamoxifen on estrogen-related biomarkers, using doses of 20 mg daily, 10 mg daily, or 10 mg on alternating days.^17,31 For the two nonstandard dosing regimens, blood concentrations of tamoxifen and its metabolites were 60% and 80% lower, respectively, than those measured in the 20 mg daily dose group. Among doses, there were no significant concentration-response relationships observed for any of the biomarkers except platelet count. The authors conclude that a substantial reduction in tamoxifen blood levels, up to 80%, does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular (eg, lipid profile) or breast cancer risk (eg, insulin-like growth factor 1). It is unclear, however, whether these surrogate markers reflect antitumor actions in the breast, and there are no data available regarding the effect of lower doses on clinical efficacy.

In this study, reliable predictors of nonadherence were few and included demographic factors including age (< 45 years and 85 years), and being nonwhite, as well as having had a mastectomy and not having seen an oncologist before initiation of tamoxifen therapy. Adherence to oral antineoplastic agents among individuals more than 85 years old has not been evaluated previously. Adherence among the elderly may be more heavily influenced by polypharmacy for multiple comorbidities, as well as psychosocial issues including decreased social support and increasing incidence of memory problems.³² These factors may account for our finding and that of other investigators that older patients, 85 years, may be less adherent.²⁵ The finding of decreased adherence among the youngest group in our cohort, women less than 45 years old, is a concern. Younger women with early-stage breast cancer may have less of a sense of vulnerability than older women. Several studies indicate that younger women do not adjust to breast cancer as well as older women,^33–36 and this may affect their adherence. In addition, the benefit of tamoxifen in premenopausal women was debated until the early 1990s. The fact that only in the past several years has tamoxifen been demonstrated to have a clear benefit for premenopausal women³ may have influenced adherence rates of younger women. For these reasons, younger women may have been more likely to discontinue tamoxifen because of nonserious side effects.

Race seems to influence both access to health services and adherence to therapy among patients who are already in the system.³⁷ It is unclear why nonwhite patients had significantly lower adherence rates than white women in our study, and this raises important questions for further study. Our finding of decreased adherence among patients who had undergone a mastectomy rather than breast-conserving surgery may reflect differences in women who choose different surgical approaches. It has been well documented that mastectomy rates vary as a result of a range of patient and physician characteristics.^38,39

Better adherence among subjects who had seen a medical oncologist before initiating tamoxifen therapy may reflect several factors, including a woman’s increased ability or desire to see an oncologist, increased vigilance, increased fear of disease recurrence, characteristics of the primary care physician, issues prompting referral to an oncologist, or unmeasured risk factors. The finding that adherence became progressively worse in this cohort with each passing year is not surprising. Several studies have revealed that adherence may decline over time, particularly in the setting of chronic medications.^37,40–42

Analysis of large databases offers the ability to document all healthcare service use, including prescription refill rates, to assess adherence. This method virtually eliminates any distortion caused by patient recall or the desire to give socially acceptable answers.⁴³ Previous studies have reported a high degree of reliability and validity of Medicaid prescription data.^43–46 However, the limitations of this claims-based information must be considered.⁴⁷ Claims-based databases, including those used in this study, are often limited to specific patient populations (eg, the elderly or the poor), and thus may not fully reflect adherence behavior in other segments of the general population of women taking tamoxifen. Although we attempted to identify patients who may have stopped taking tamoxifen on the recommendation of their doctor, some physician recommendations to discontinue tamoxifen could not be captured through such data.²⁵ If a patient had evidence of recurrent or new breast cancer, or evidence of adverse events possibly caused by tamoxifen, her adherence data were censored on the date when evidence first appeared in the database. There are likely to be occasional instances when a procedure or medication change that triggered censoring was not detected immediately, and such patients would have been assumed to be nonadherent for a somewhat longer period of time. Further limitations of this study include the exclusion of patients who died in the first year, omitting many of the sickest subjects, and the exclusion of the most nonadherent subjects, those who never filled even one prescription for tamoxifen, making this a conservative estimate of nonadherence.

This is the largest study to date of the use of any oral antineoplastic agent outside a clinical trial setting. The large number of subjects made it possible to evaluate several possible predictors of nonadherence. In light of the efficacy of tamoxifen therapy in preventing recurrence and death in women with early-stage breast cancer, further efforts are necessary to detect and address suboptimal adherence, particularly in vulnerable populations such as the elderly and the poor. These results provide insight into potential nonadherence to oral antineoplastic agents in general. Future studies focusing on adherence to oral antineoplastic agents would likely reveal that adherence in typical care settings is dramatically worse than that seen in clinical trials.¹⁹ Given the growing number of new oral agents for the treatment of cancer, attention to adherence will be increasingly important.

	NOTES

 
This research was supported in part by a Training Grant in Epidemiology and Prevention of Breast Cancer through the U.S. Department of Defense (DAMD17-00-1-0165), a research grant from the National Institute on Aging (R03-AG18395), and the NCI Specialized Program of Research Excellence (SPORE) in breast cancer at the Dana-Farber Cancer Institute.

	REFERENCES

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Submitted July 12, 2002; accepted November 1, 2002.

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