Annals of Oncology Advance Access originally published online on January 15, 2009
Annals of Oncology 2009 20(3):431-436; doi:10.1093/annonc/mdn646
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breast cancer |
Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer
Department of Gynaecology, Gynaecological Endocrinology and Oncology, Philipps-University of Marburg, Marburg, Germany
* Correspondence to: Dr V. Ziller, Department of Gynaecology, Gynaecological Endocrinology and Oncology, Philipps-University of Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Tel: +49-6421-5864400; Fax: +49-6421-5867070 E-mail: ziller{at}med.uni-marburg.de
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abstract |
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Background: The level of adherence of various pharmacological therapies in chronic diseases varies, but is predominantly low. With tamoxifen (TAM), 23% and 50% nonadherence after 1 and 4 years have been reported. Day-to-day clinical observation suggests that adherence may even be lower with aromatase inhibitors, but limited data exist on the situation in daily clinical routine. The aim of this study was to evaluate the rate of adherent patients in a randomly selected sample of postmenopausal women with primary breast cancer, who had been assigned to an adjuvant endocrine treatment with TAM or anastrozole (ANA).
Materials and methods: We investigated a random sample of 100 postmenopausal women with breast cancer (50 TAM and 50 ANA) who had received surgery for their primary breast cancer at our hospital in 2004/2005 and thereafter had been assigned to an adjuvant endocrine treatment. We evaluated the adherence rate with a detailed questionnaire and additionally carried out a retrospective prescription check of the hospital chart as well as calling the local physicians of our patients. A patient was counted as adherent with a self-reported tablet intake of 80% or more and if a medication possession ratio of 80% or more was achieved.
Results: Regarding the baseline characteristics, a significant difference in mean age was noticed in women on ANA versus TAM [65 (±3) and 72 (±3); P < 0.001]. All women on TAM and ANA reported to be adherent (100%). After controlling for prescriptions, only 40 (80%) and 27 (69%) of the women on TAM and ANA were still classified as adherent (P < 0.01 and P < 0.01 versus self-report). We found no significant correlation of adherence to any baseline characteristics or side-effects in a logistic regression model.
Conclusions: An important goal of any therapeutic intervention is to achieve comparable efficacy in routine clinical practice to that demonstrated in randomised clinical trials. However, a similar magnitude of adherence will be necessary in routine clinical practice to assure comparable clinical effects. Our results further support the data on suboptimal adherence of women with breast cancer on adjuvant TAM treatment. Here, we evaluated for the first time the patient reported and real-world adherence on adjuvant ANA and were able to show a similarly low adherence compared with TAM. More prospective studies are needed to increase our understanding of the underlying reasons for nonadherence in women with breast cancer.
Key words: adherence, anastrozol, breast cancer, endocrine treatment, tamoxifen
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introduction |
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Adherence with long-term oral medication in chronic disease is a challenge of increasing interest. It is well established that nonadherence to various medications and in various diseases lead to reduced efficacy and can be the most detrimental factor influencing clinical outcome [1, 2]. In Europe, breast cancer is the most common cancer in females and two-thirds of breast tumours occur in postmenopausal women aged 55 years and older [3]. A large proportion of breast cancer tumours are hormone responsive and as such oestrogen and its receptor have become the targets of choice for adjuvant treatment with the aim to prevent disease recurrence and prolong disease-free survival.
The antiestrogen tamoxifen (TAM) had been the standard in adjuvant therapy in postmenopausal women with hormone-sensitive (hormone receptor-positive) breast cancer (HR+ EBC) for 20 years. TAM therapy reduces breast cancer recurrence and mortality, but is also associated with an increased incidence of thromboembolic events and endometrial cancer, as well as other adverse events (AEs), including vaginal discharge, fluid retention, and hot flushes, which may increase the likelihood of therapy discontinuation [4].
TAM inhibits the action of oestrogen at the oestrogen receptor, whereas aromatase inhibitors (AIs) inhibit the aromatase enzyme that converts androgens to oestrogen [5]. With a different mechanism of action, the safety profile of AIs also differs in some respects, including a lower risk of some serious AEs, such as thromboembolic events and endometrial cancer [4, 6–9]. Several guidelines now advocate the use of AIs in the adjuvant setting for the management of postmenopausal women with HR+ breast cancer [10–12]. The third-generation AIs anastrozole (ANA), exemestane and letrozole, have been approved for the adjuvant treatment of HR+ breast cancer and are replacing TAM as initial adjuvant therapy (ANA and letrozole) or as adjuvant therapy following 2–3 years of TAM (ANA and exemestane) or the completion of 5 years of TAM (letrozole) [4, 6, 8, 9].
Cancer patients are often regarded as highly motivated and compliant due to the seriousness of their disease but limited data are available investigating adherence in adjuvant treatment of breast cancer and especially regarding the use of AIs. Recent reports noted that about half of the patients stop their medication in the course of the 5-year adjuvant treatment with TAM and that a substantial proportion of patients on ANA do not reach the recommended adherence rates after the first year [13–17]. These studies were mainly carried out as health-care data-based analyses and do not provide evidence from daily clinical routine at a patient level.
The aim of the present study was to evaluate real-life adherence in a retrospective study in a sample of postmenopausal women with breast cancer on TAM or ANA, who had been treated for their primary breast cancer in our clinic from 2004 to 2006.
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materials and methods |
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The study was carried out as a combination of a retrospective analysis of patient files and an active part including patient self-reporting via a questionnaire and a prescription control.
We investigated a random sample of 100 postmenopausal women with breast cancer (50 TAM and 50 ANA) who had received breast cancer surgery in our hospital in 2004/2005 and thereafter had been assigned to an adjuvant endocrine treatment.
The random sample was taken out of a database of 258 patients using SPSS statistical package version 12.0.1.
Women were eligible for the study if treated in accordance with German breast cancer treatment guidelines [10] and the recommendation of the local interdisciplinary tumour board. Treatment had to have been started at least 12 and maximum 24 months before the patient interview.
We excluded patients who were not able to take their medication on their own initiative (for example dementia). Patients who were not accessible, not willing to participate, had died or did not fulfil inclusion criteria were documented but not analysed.
Adherence was evaluated via patient self-report with a detailed questionnaire. Questionnaires were sent to each patient after a first call and informed consent, answered by the patient and then queried in a second call. Additionally, prescriptions were counted from the hospital chart and by recall of prescription details from all local physicians involved in the treatment of the patient.
The study was conducted in accordance to the guidelines of the local ethics committee of the Philipps-University of Marburg.
definition of adherence
We defined adherence in drug therapy as the extent to which a patient adheres to a recommended dosage and intake interval. Adherence, as one aspect of compliance, was defined as the percentage of a prescribed dose that is actually taken in a certain time frame. For this study, the adherence rate in the first 12 months after therapy initiation was measured. We differentiated self-reported and prescription-controlled adherence. The prescription-controlled adherence is synonymous to the term ‘medication possession ratio’ (MPR) and indicates the quotient of recommended prescriptions to actual prescriptions. A patient was classified as adherent if a self-reported adherence and a MPR of 80% or more was achieved. The limit of 80% was chosen in accordance with the current literature [1, 2, 13, 18].
data collection
Data were collected via hospital medical records and patient self-reporting. Data collected from medical records included patients’ demographics, medical history, physical examination, histology, tumour staging and grading, HR status, and primary oncological treatment (surgery, radiation therapy, chemotherapy).
Self-reporting was carried out using an adherence questionnaire specifically designed to investigate how many tablets a patient had really taken (all, nearly all, more than half, about half, less than half, few, none) and how long the medication was taken for. In addition, tolerability of therapy was assessed with the menopause rating scale and a global quality-of-life scale [19]. Furthermore, patients recorded if they had any problems in receiving their prescriptions from their physicians.
study groups
To compare the prescription-controlled adherence rate with self-reported adherence and to find predictors for adherence, the three datasets of patient baseline documentation, medication intake, and prescription control were merged and subjects having missing data in any of the three sets were deleted. For TAM, there are 50 subjects and for ANA 39 subjects with a complete set of data for the evaluation.
primary and secondary analytic end points
The primary end point of the analysis was the proportion of patients classified as adherent. We further investigated patients’ characteristics, tolerability profile, and tumour-related variables and their correlation to adherence.
statistical analysis
To calculate relations between adherence and possible predictors, we used univariate logistic regression models to calculate odds ratios and their confidence intervals (CIs). P values were taken from the same univariate models.
Mostly ordinal variables, that is ordered categories, were transformed into binary variables for the analysis.
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results |
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Patients treated with ANA were significantly older than patients treated with TAM (mean age 72 years ANA versus 65 years TAM; P < 0.001) and more patients on TAM were currently working (23% TAM versus 2% ANA; P = 0.02).
Significantly more patients on TAM reported urinary tract problems (48% versus 23%; P < 0.03). No other patient characteristics, tumour-related variables, or side-effects showed significant differences between the two groups (Table 1).
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The median duration of treatment was 13.6 (±8.8) months for TAM and 16.6 (±5.4) months for ANA. Regarding self-reported adherence, 100% of the patients reported to be adherent. For TAM, nine subjects or 18% of all subjects reported that they took nearly all pills and 41 subjects or 82% reported that they took all pills. For ANA, five subjects or 13% of all subjects reported that they took nearly all pills and 34 or 87% reported that they took all pills.
The analysis of the MPR showed significantly lower adherence rates. For TAM, 40 of 50 subjects, that is 80% (95%CI 66% to 90%), were adherent as measured by the prescription control (P value = 0.003 self-report versus MPR). For ANA, 27 of 39 subjects, that is 69% (95%CI 52% to 82%), were adherent according to the prescription control (P value < 0.001 self-report versus MPR). The difference in MPR of TAM and ANA was not statistically significant (P = 0.36). (Figure 1)
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We found no statistically significant predictor for adherence as shown in Table 2 for TAM and Table 3 for ANA. Significantly more patients on ANA reported problems to receive their prescriptions from their physicians (23% ANA versus 0% TAM; P = 0.001).
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Women on adjuvant endocrine treatment for breast cancer are generally expected to be highly compliant as they are facing a serious life-threatening disease and as the treatment is effective, easy to use, and in general well tolerated. Our results indicated that there is a significant gap between patients' self-reported adherence and their MPR. These findings underline a clinically relevant decrease in adherence to TAM and ANA therapy as soon as after 12 months. This indicates that patient statements with regards to adherence, for whatever reasons, might not always reflect the reality, a problem which all physicians experience in their daily routine. The possible reduction in cancer outcome due to this inadherence is not known. A small study of Waterhouse et al. [15] reported similar findings for TAM. They investigated a comparison of self-reported adherence, classical pill count, and the use of a microelectronic monitoring device (MEMS). Similarly to our results, a significantly higher adherence was recorded by patient self-report compared with MEMS (16.7% versus 29% nonadherence at 3 months). Other previous studies evaluating adherence to TAM using self-reported evaluation or database claim methods found adherence rates ranging from 65% to 85% at different lengths of follow-up [14, 17, 20–24].
To our knowledge, our study is the first investigating adherence to an adjuvant endocrine treatment with ANA including patient self-reporting in combination with control of prescription refill. Previous reports evaluating adherence rates to ANA were only using database claims. In an analysis by Partridge et al. [13] using commercial health programme claims data, the mean adherence to ANA significantly decreased to 78%–86% in year 1 and to 62%–79% in year 3.
Our study results confirmed a comparable reduction of adherence for TAM and ANA in clinical practice after the first year of therapy, a fact, which emphasises the need to further investigate adherence in breast cancer patients.
In our study, patients reported good tolerability of the medication and we found no significant differences in side-effects of TAM versus ANA. The reason why a number of patients reported problems with receiving their ANA prescriptions from their local physicians was probably at least in part due to the fact that at the time of therapy initiation ANA was not yet a standard alternative to TAM with regard to local practice as well as to German treatment guidelines.
Factors that may influence adherence are numerous and complex and a high intra- and interindividual variation must be assumed [2].
Our study revealed no significant correlations to specific factors that were expected to influence adherence, such as side-effects. This is probably due to the relatively small sample size.
This study faces several other limitations. First, there is no gold standard in measuring adherence. The only way to assure adherence is the directly controlled application of a drug to the patient. Our method of measuring adherence combines self-reported patient-orientated subjective data with measuring MPR by prescription control, a fairly objective criteria. The calculation of the MPR by checking the filled prescriptions includes additional information on the drug supply of the patient. If the MPR is lower than recommended, it is impossible for the patient to be adherent. On the other hand, the medication received does not provide information about the real intake. Additionally, a further aspect which needs to be considered is the crudeness of the measurement as the prescribed package size defines the minimum time quotient which can be used. If a patient collects a package and terminates the medication shortly afterwards, the measured value overestimates the real intake. These factors underline that the magnitude of nonadherence might be by far greater than we believe to know today. Finally, our trial is a retrospective study. Groups were not prospectively randomised and the sample size was small.
One important factor influencing adherence might be the patient awareness and knowledge of disease [1, 2]. To further investigate and improve adherence in the adjuvant endocrine breast cancer treatment setting, we therefore initiated the COMPAS-trial. COMPAS is a monocentric, prospective, randomised, controlled parallel group study which was designed to evaluate the effects of an intervention including either a written or an oral patient information programme versus no intervention to improve adherence in the adjuvant endocrine treatment of breast cancer with an AI. COMPAS is open for recruitment until October 2008 and will until then include 180 patients. Another prospective study with a similar design is the PACT programme, a large, randomised trial investigating adherence to adjuvant ANA therapy, the reasons for and effects of nonadherence as well as the possible benefits of a regular written information and reminder service. This study is currently open for recruitment. Because of the apparent significant decrease of adherence of postmenopausal women with breast cancer to adjuvant treatment over time, the possibility of preventative measures needs to be further evaluated.
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Astra Zeneca (1266-P1-2005).
Received for publication June 24, 2008. Revision received August 28, 2008. Accepted for publication August 28, 2008.
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