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The clinical importance of patient adherence to therapy.


Incredible advances in cancer treatments have been made over the last decade. Many more patients are cured or gain worthwhile remissions and life extension, and chemoprevention is now a real possibility. The availability and affordability of many of these novel drugs are major issues; however, the fact that many patients prescribed these drugs do not take them, is arguably an even larger problem.

When any new drug is discovered, the ultimate goal is to develop an orally administered formulation, as there is a perception that patients prefer oral administration over intramuscular or intravenous routes for reasons of convenience. Many cytotoxic chemotherapy and endocrine therapies are therefore given orally, as are other drugs used in women with breast cancer, such as bisphosphonates. Oral administration is also associated with significant reductions in healthcare costs, but there are many examples to illustrate how non-adherence and suboptimal adherence can compromise safety.


Although poor adherence with treatment is widely accepted, many people are shocked that patients with life-threatening diseases do not adhere to the treatment regimens prescribed. Yet non-adherence is found in all medical conditions across all age groups, ethnic, socioeconomic and educational groups, with estimates varying from 20% to 80%. Complex behavioural processes underpin why a patient chooses not to take their medicine; it is often not just a failure to follow instructions but sometimes an active reasoned decision. Patients' expectations about the value of therapy, their attitudes, intentions and experiences when they take a drug, all impact on their behaviours.

Non-adherence can influence the effectiveness of treatment at a variety of stages from the very start of the treatment process. For example, 20% of prescriptions are never filled, and patients may never take their drugs, or they take them irregularly or give themselves a 'holiday', especially when they are experiencing side effects. Patients may struggle with timings of doses when they are taking other medications or need to take medicines with or without food; this can be a particular problem for older patients with comorbidities and polypharmacy. Such patients may also have problems opening containers, swallowing tablets or seeing the instructions well enough to read them. Furthermore, many drugs have side effects that can be intolerable for some patients over long periods of time. For example, although not life-threatening, side effects such as hot flushes, vaginal dryness, sexual problems and arthralgias have a considerable impact on quality of life when drugs are used in the long term. In the adjuvant setting, when patients see no obvious benefit from the drug, it can be easy to understand why they may not adhere. Yet poor adherence is not restricted to the adjuvant setting, being observed at all stages of the disease trajectory in breast cancer, including chemoprevention and advanced disease.

Poor adherence may have a variety of consequences. The most obvious is that the patient fails to obtain the maximum benefit, and mortality increases. In addition, clinicians may conclude that the tumour is non-responsive and unnecessarily increase the dose or switch to another drug. When non-adherence is due to side effects, these will remain unrecognised and underestimated, so that ameliorative interventions that could reduce the side effects and thus improve adherence are never developed. Healthcare costs may increase as a result.

Adherence in patients with breast cancer

In a retrospective cohort study of 1633 women in Scotland between 1992 and 2003, adherence was calculated from the encashed prescriptions and survival analysed to determine the effect on all-cause mortality [1]. Persistence was modest, with only 49% of patients who were followed for 5 years or more continuing therapy to 5 years. Adherence <80% was associated with poorer survival [hazard ratio (HR): 1.10 (95% confidence interval 1.001 to 1.21)], increasing the risk of relapse and death. In the TAMOPLAC and International Breast Cancer Intervention Study (IBIS-I) chemoprevention studies, blood results showed that 38% of participants had stopped taking their tablets, or took them infrequently, by 5 years [2]. In NSABP study P-1, at median follow-up of 54 months, blood results showed that 23.7% of patients had discontinued tamoxifen and 19.7% had stopped taking paclitaxel [3].

In the MAP.3 study, in which exemestane was compared with placebo, pill counts showed that 30% of patients missed pills on more than 10% of the study days in the first 6 months of the trial and a further 14% missed taking pills on about one-fifth of the study days examined [4]. Women from ethnic minority groups had particularly poor adherence compared with white American women. In contrast, fewer than 5% of the 207 women in the cognitive cohort of the IBIS-II study of anastrozole versus placebo reported taking drug holidays over 24 months [5].

As the half-lives of aromatase inhibitors are much shorter than those of the selective estrogen receptor modulators (SERMs) (exemestane 27 hours; letrozole and anastrozole 2 days; tamoxifen 14 days), the occasional missed dose may be more crucial for the aromatase inhibitors than for tamoxifen.

Adjuvant setting

In the adjuvant setting, the recommended treatment duration of at least 5 years could be problematic as side effects are more than a transient inconvenience. One study in the US showed that 25% of patients failed to take tamoxifen more than 20% of the time during the first year. By the fourth year, adherence was only 40% [6]. The situation is no better in the real world outside of trials, with healthcare plan surveys showing a continuous decline in prescription filling and suboptimal adherence for aromatase inhibitors over 3 years [7].

In many self-report studies, patients have admitted to low persistence. For example, a pharmacy database study of 2816 women in the community found that 22.1% of patients completely stopped taking their medicine in the first year, with the cumulative rate of non-persistence reaching 35.2% at the end of 3.5 years of follow-up [8].

Metastatic setting

Patients in the metastatic setting might be expected to be more adherent, but evidence does not support that supposition. In an in-depth interview study of patients with early and advanced breast cancer, 50% of patients admitted to choosing not to take their tablets or frequently forgetting to take them, primarily due to side effects [9]. Interestingly, almost one-quarter of the patients expressed a preference for intramuscular fulvestrant over oral aromatase inhibitors, with 43% of these explaining it was to ensure adherence [10].

Reasons for non-adherence

Non-adherence may seem irrational to scientists but health psychology offers some explanations. Simplistically, if the positive outcomes of a behaviour are distal and difficult to detect, then the patient is less likely to repeat that behaviour. In addition, if negative outcomes are proximal, they become associated with the behaviour and reduce the likelihood that the patient will continue with that behaviour. In other words, the positive effects of pill taking--that is, prevention of breast cancer and reduction of recurrence--are not observed, while side effects such as nausea, hair loss, hot flushes and arthralgia are experienced quickly. The patient thus perceives negative rewards for taking their pills but with no obvious positive benefit.

Health cognition models also provide clues, as beliefs and perceptions influence interpretation of information about disease and treatment, and effect on behaviour. In patients with chronic health problems, the core beliefs that underpin adherence are perceived necessity and concerns about harms: high necessity beliefs are associated with high adherence and high harms concerns are associated with low adherence [11]. A study from the UK showed that patients engage in implicit cost-benefit analyses that influence their adherence with tamoxifen [12].


Adherence is a major issue that is not sufficiently considered by many oncologists and clinical scientists. Some data from clinical trials may be compromised by the absence of any data regarding adherence. The adverse events that threaten quality of life and influence adherence need appropriate monitoring and amelioration. Factors associated with suboptimal adherence, such as ethnicity, age and health beliefs, need to be recognised, and interventions to improve adherence must be developed. At the very least, good communication about the true therapeutic aims of drugs and how they work, as well as checks to ensure that patients understand dosing schedules, is absolutely vital.

Post-presentation discussion

Participant: Do you think that some patients perceive they have side effects after reading the instructions and information in patient information leaflets?

Lesley Fallowfield: That is an interesting question, because the detail given in patient information could be enough to make someone think twice about taking medicines as simple as paracetamol or aspirin. Unfortunately, many of the side effects mentioned in these leaflets have been compiled from case report forms completed by physicians for clinical trials, which report any occurrence of any event at any time during the study period. Patient-reported outcomes collected from quality-of-life questionnaires would actually be of more value. However, physicians could discuss side effects and offer ameliorative interventions at the outset of treatment to encourage patients to make better decisions about adherence and persistence.

Louis Weiner[dagger]: Your data raise questions regarding the appropriateness of oral medications for patients with severe or life-threatening illnesses. Have any pharmacoeconomic analyses determined whether oral agents actually do provide cost savings to society?

Lesley Fallowfield: The results of such studies would differ from country to country depending on the funding with a particular healthcare system, but your question raises a number of interesting issues. Non-adherence results in a massive waste of scarce resources, not only in terms of the drugs themselves but also in relation to the loss of benefit to the patient and the increased risk of recurrence or death, which will incur additional costs to the healthcare system. These must be taken into account in any pharmacoeconomic analysis of the impact of suboptimal adherence.


[1.] McCowan C, Shearer J, Donnan PT et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer, 2008, 99, 1763-1768.

[2.] Fallowfield L, Fleissig A, Edwards R et al. Tamoxifen for the prevention of breast cancer: psychosocial impact on women participating in two randomized controlled trials. J Clin Oncol, 2001, 19, 1885-1892.

[3.] Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst, 1998, 90, 1371-1388.

[4.] Moy B, Richardson H, Johnson D et al. NCIC CTG MAP.3 : enrolment and study drug adherence of ethnic minority women in a breast cancer prevention trial. Breast Cancer Res Treat, 2007, 106, S141-S142 (Abstr. 3048).

[5.] Jenkins VA, Ambroisine LM, Atkins L et al. Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II). Lancet Oncol, 2008, 9, 953-961.

[6.] Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol , 2003, 21, 602-606.

[7.] Partridge AH, LaFountain A, Mayer E et al. Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol, 2008, 26, 556-562.

[8.] Barron TI, Connolly R, Bennett K et al. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer, 2007, 109, 832-839.

[9.] Fallowfield L, Atkins L, Catt S et al. Patients' preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol, 2006, 17, 205-210.

[10.] Atkins L, Fallowfield L. Intentional and non-intentional non-adherence to medication amongst breast cancer patients. Eur J Cancer, 2006, 42, 2271-2276.

[11.] Horne R, Weinman J. Patients' beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. J Psychosom Res, 1999, 47, 555-567.

[12.] Grunfeld EA, Hunter MS, Sikka P, Mittal S. Adherence beliefs among breast cancer patients taking tamoxifen. Patient Educ Couns, 2005, 59, 97-102.

Correspondence to: Lesley Fallowfield, Cancer Research UK Sussex Psychosocial Oncology Group Sussex Health Outcomes Research and Education in Cancer (SHORE-C) Brighton & Sussex Medical School, University of Sussex Falmer BN1 9QG, UK


[dagger] Department of Oncology, Georgetown University Medical Centre, Washington DC, USA
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Article Details
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Title Annotation:Feature Article
Author:Fallowfield, Lesley
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Jun 1, 2009
Previous Article:An oncologist's perspective on having breast cancer.
Next Article:Psychological issues that may affect breast cancer trial recruitment.

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