Authors

1. Garbee, Deborah PhD, APRN, ACNS-BC
2. Danna, Denise RN, DNS, NEA-BC, CNE, FACHE
3. Lemoine, Colleen APRN, MN, AOCN, RN-BC

Abstract

Review question/objective: The objective is to examine the evidence on the impact of side effects on adherence and persistence with oral anticancer agents in women diagnosed with early stage breast cancer. This review aims to answer the following question: What is the impact of side effects on adherence and persistence with oral anticancer agents in women diagnosed with early stage breast cancer?

Background: Breast cancer is the most common malignancy diagnosed in women both worldwide and in the United States.1-2 The International Agency for Research on Cancer1 estimated 1.67 million new cases of female breast cancer occurred in 2012 worldwide, accounting for 25% of all female cancers. The American Cancer Society2 estimates 232,670 new cases of female breast cancer will be diagnosed in the United States in 2014. Rates of breast cancer vary significantly across the world which is likely a function of true differences in incident rates, the absence of screening programs and limitations associated with the collection and reporting of cases.3 Based on available data, the lowest incidence of breast cancer reported is in Middle Africa and Eastern Asia and the highest incidence reported is in Western Europe. Since the mid-2000s, the incidence of breast cancer in the United States and the United Kingdom has been relatively stable;2,4 however, worldwide, there was a 20% increase in breast cancer incidence between 2008 and 2012.5 Bray et al.6 predict a global increase in breast cancer of two percent annually resulting in a projection of more than two million cases of female breast cancer diagnosed in 2030.

Breast cancer is also the leading cause of cancer deaths in females worldwide with an estimated 522,000 deaths globally in 2012.1 In the United States breast cancer is the second leading cause of cancer deaths in females and is expected to cause 40,000 female deaths in 2014.2 Mortality from breast cancer in women range from a low of six per 100,000 in Eastern Asia to a high of 20 per 100,000 in Western Africa.1 Higher mortality rates in less developed countries may be due to lack of screening and early detection programs, and to limited access to trained providers, treatment facilities and effective therapies.5-7

Treatment for breast cancer is based on stage and other tumor characteristics, such as hormone-receptor status and HER2/neu receptor status. In addition to surgery and radiation, early stage breast cancer treatment can include adjuvant treatment with chemotherapy, hormonal therapy and/or targeted therapy. The majority of adjuvant chemotherapy is administered intravenously; however, one agent, cyclophosphamide, is available in an oral formulation. Treatment with hormonal agents, which is accomplished almost exclusively through the use of oral agents, is the standard of care for women with hormone-receptor positive cancers, estimated to be 70-80% of all new breast cancer cases.8 At present, there are no oral targeted agents currently used to treat early stage breast cancer.

Oral anticancer agents are becoming increasingly more common in cancer treatment plans for both solid tumors and hematologic malignancies. In the past decade, more than two dozen oral anticancer agents have received approval by the US FDA.9 At present there are over fifty oral anticancer agents commercially available in the US, 11 of which are indicated for the treatment of breast cancer, although many are currently indicated for use in the more advanced breast cancer setting. The number of oral anticancer agents is likely to continue to increase as an estimated 25% of agents currently being investigated for oncology are orally administered.10

Compared to parenteral anti-cancer therapies, oral agents offer potential advantages including patient convenience, an increased sense of control and freedom, decreased time spent traveling to, and at, the health care provider site receiving treatment, and no discomfort associated with intravenous access.11-14 Despite the potential advantages oral anticancer therapy offers, there are also associated challenges, primarily monitoring for and managing side effects, and adherence and persistence with the treatment regimen.10-11, 15 Common side effects associated with oral anticancer agents include night sweats, hot flashes, vaginal dryness, decreased libido, arthralgia, myalgia, nausea or weight gain. The World Health Organization16 defines adherence as 'the extent to which a person's behavior - taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider.16^(p.3) This definition highlights the active role the patient has in agreeing with the healthcare provider's recommendations rather than "passively acquiescing" with the healthcare provider's advice. A more narrow definition specific to medication adherence is "the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen".17^(p.46)Persistence is the conforming to a recommendation of continuing treatment for the prescribed length of time and is defined as "the duration of time from initiation to discontinuation of therapy".17^(p.46)

Adherence is important because clinical benefits associated with medications cannot be derived by patients who do not take the medication. Compromised clinical response, development of drug resistance, disease progression, increased toxicity and death are all negative consequences that can occur from sub-optimal adherence. Poor persistence is also associated with compromised efficacy.16,18-25 Given the serious nature of cancer, it may not seem that suboptimal adherence and persistence would be problematic; however, studies have reported adherence rates as low as 20% and early discontinuation rates ranging from 17%-31%.26-27

The World Health Organization16 proposes five interacting dimensions of adherence: the social and economic dimension, the health care system dimension, the condition-related dimension, the therapy-related dimension, and the patient-related dimension. Within the therapy-related dimension, actual or perceived negative side effects are noted to influence adherence. A number of early studies yielded conflicting results about the impact of side effects on adherence in oncology patients.15

The expected increase in breast cancer globally and the significant effect of suboptimal adherence and persistence on patient outcomes makes it essential to fully characterize the impact side effects have on adherence and persistence in order to develop effective interventions. Systematic reviews have been conducted on adherence and persistence to oral anticancer therapies in other cancer populations but none has focused exclusively on the early stage breast cancer population.28-30 In addition, early studies reported conflicting results regarding the impact of side effects on adherence and persistence. Therefore, the aim of this review is to use early and more current publications to more clearly elucidate the impact side effects have on adherence and persistence to oral anticancer agents in women diagnosed with early stage breast cancer.