ADHERENCE AND COMPLIANCE
Many patients who are given prescriptions for medications fail to take them as directed or for the length of time recommended. Adherence and compliance are a concern in the management of malignancies because oral chemotherapeutic agents are increasingly being developed and used in long-term management.427 Of the nearly 400 antineoplastic agents in various stages of development, nearly one-fourth are planned as oral agents.428 Clearly, the increasing percentage of cancer patients who are prescribed or will be prescribed oral therapies will affect current oncologic treatment patterns. Breast cancer survivorship is on a steady rise,427,428 and this cancer is no longer thought of as an acute illness but rather a chronic condition. Therefore, long-term therapies are being increasingly used. Foremost of these interventions is the oral administration of drugs in the outpatient setting, allowing patients to medicate themselves with appropriate dosages and scheduling.
This major advance in cancer treatment comes with new concerns: adherence and compliance. Although adherence and compliance are ultimately related, they are distinct parameters of therapy. Adherence defines the taking of medication as prescribed, whereas compliance more specifically addresses taking the medication for the full term recommended. Compliance is also often referred to as “persistence.”429,430 Some have called for the dismissal of the term compliance because it connotes an onus and dependence on the patients for their ultimate outcomes.431
Regardless of definitions and disparities, the ultimate measure of outcome is OS.432 Although developments in oncology have resulted in major advances in survivorship, many are dependent on long-term administration protocols. As such, the issue of adherence and/or compliance to therapies recommended has become the latest oncologic challenge. This also provides increased impetus for survivorship programs to assume a major role in the care of these patients, that is, follow-up with adherence and compliance.
Adherence and compliance are important for women who are prescribed AET. AET has been definitively demonstrated for more than 30 years to decrease both recurrence and mortality in ER+ patients.15,97,98 Five years of AET, with either tamoxifen or AIs, results in a greater than 30% reduction in breast cancer recurrence and increased OS.97,98,433 Despite the strong documentation of the effectiveness of AET, it is both surprising and disappointing to note the incredibly high rates of noncompliance to a 5-year regimen, which range from 30% to 70%.434 Less than 80% compliance at 2.5 years has been associated with increased mortality.14 Nearly 25% of patients discontinue AET within the first year, and 50% become noncompliant by Year 4,433,435 despite multiple trials that have shown higher recurrence rates and decreased survival.14,436,437
Another point of major concern is that women younger than age 45 years have a greater risk of recurrence owing to more aggressive, higher grade tumors, and yet this group is most likely to discontinue therapy.15 Multiple studies have noted this,435,438,439 yet the issue of age has not been adequately addressed. Patients who are premenopausal when their breast cancer is diagnosed have a higher recurrence rate and increased mortality than those diagnosed in the postmenopausal state.
The poor adherence and compliance to 5 years of AET presents a major challenge. Although this is a large enough issue, we now face new reports strongly supporting a 10-year regimen. Results from the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment Offers More (aTTom) trial have clearly demonstrated improved outcomes by doubling the 5-year recommendation for AET.198,440 The ATLAS trial concluded that recurrence and mortality were lowered in patients given an additional 5 years of tamoxifen. Ten-year recurrence rates decreased by 29% in 6846 patients. Similar findings were reported in aTTom, which followed 6934 women with early-stage breast cancer. Although AIs have been clearly demonstrated to decrease recurrence rates in postmenopausal women with breast cancer,189 their indications for extended length of therapy are less clear and are currently undergoing further investigation. These reports demonstrate the increasing need for adherence and compliance for AET maintenance. Extensions of AET must also take into consideration the long-term side effects of these therapies. Risks of PE were noted in the ATLAS trial as well as the development of endometrial cancer; however, the risk of mortality was lower than the mortality due to breast cancer itself.441,442 Long-term side effects of the AIs have yet to be determined. Particular attention must focus on bone health and osteoporosis as well as the CVD risk associated with AIs.126,443 Clearly, poor adherence and compliance result in less effective disease outcomes and increased mortality.444
AET is one of the most important recent advances in cancer treatment. As simple a treatment as it is, via oral administration, a large number of patients do not take advantage of this intervention. Numerous barriers to adherence and compliance have been identified. These barriers are multifactorial, complex, and often interrelated. Medication side effects are the primary reason for discontinuation of AET. Of patients receiving AET, 94% report mild to severe symptoms directly attributable to AET. These include hot flashes, bone and joint pain, muscle aches, mood swings, loss of libido, dyspareunia, and other menopause-related symptoms.445 Each year, more than 80,000 postmenopausal women begin the 5-year regimen with AIs in an effort to decrease recurrence.446 A major reason for the discontinuation of AIs is the development of incapacitating bone pain and arthralgias in a group that, because of age, has the comorbidity of arthritis.447 Strategies to encourage continuation of AIs include switching to different AIs and the promotion of exercise.448,449
Additional reasons cited for noncompliance include a poor understanding by the patient of the importance of taking the medication to offset recurrence and mortality.450 This has been attributed to inadequate communication by health care practitioners regarding risk vs benefit of the regimens and, in general, poor clinician-patient relationships.432 Patients who fail to understand the importance of their oral medications are likely not to take them as directed. Furthermore, as years of treatment progress and there are no overt symptoms of a malignancy or disease, patients may develop a sense of complacency, resulting in further noncompliance.431 Finally, the cost of medications may play a factor in noncompliance.15,431,432 Those with poor health care coverage or high copayments may not be able to afford the costs of oral agents for an extended time. Although most intravenous medications are a covered benefit, the same is not so for oral therapies. Oral parity legislation has been enacted by multiple states to guarantee payment for outpatient chemotherapy, putting it on par with infusion therapies. The federal government is considering such legislation but has failed to implement such a law. The American College of Surgeons Commission on Cancer’s Advocacy Committee (of which the senior author [BB] is a member) has been active in attempting to push oral parity legislation in Washington, DC. The unequal copay for oral anticancer agents needs correction, as does the poor adherence and compliance in patients with breast cancer receiving AET.
Practices to improve the dismal adherence and compliance rates for AET need to be developed. Interventions should involve a multifaceted approach, beginning with the attending physician and then extending to pharmacists and navigators. Pharmacists, in particular, have the opportunity to expand their scope of practice by actively participating in patient education regarding the importance of taking medications and appropriate scheduling. Navigators can play an important role as well. Regular telephone or texting conversations to check on a patient’s adherence can not only evaluate the patient for compliance but also serve as a motivator for the patient. Although it would appear intuitive that education for patient and family members about the importance of consistent oral therapy would improve compliance, this has not been fully validated. 432 Reminder letters and telephone calls have demonstrated only a minor increase in adherence rates.451 Other studies have noted no improvement in patients given additional education materials or increased support services.452,453 Going forward, technologic advances such as the widespread use of electronic medical records, sophisticated prescription bottles with built-in reminder timers, and effective pharmacy tracking systems may lead to further improvements. Simplified dosing regimens, as well as seamless access to refills, may also help improve compliance. Clearly, many women are not taking their AET as prescribed, and this remains an issue of major concern. Prescribed medications are useless if the patient does not take them. (See Sidebar: Barriers to Adherence and Compliance.)