'Nonadherence May Be the Norm': Why Cancer Patients Don't Take Their Medications

Kate M. O'Rourke

Disclosures

October 24, 2016

Years ago, if you asked oncologists whether their cancer patients were taking their medicine, you might have heard overwhelmingly, "Of course; it's cancer." Nowadays, oncologists know better.

The World Health Organization estimates that half of medicines prescribed for long-term conditions are not taken as directed.[1] In an analysis of 48 studies published since 1990 that mostly assessed hormone-based therapy in breast cancer and targeted therapies in chronic myeloid leukemia (CML), adherence rates ranged from 14% to 100%.[2]

A combination of internal and external factors may reduce patient adherence to long-term therapies. New insight into why cancer patients don't take their drugs as prescribed comes from the global CML Advocates Network Adherence Survey, conducted by the CML Advocates Network, a global network of leukemia patient groups. Giora Sharf, cofounder of the network, presented the results at the 2016 European Society for Medical Oncology (ESMO) Congress.

Sharf pointed out that adherence is a complex and multifactorial issue, especially in medical conditions that require long-term therapy, such as chronic phase CML. Studies have shown that poor adherence is a critical factor for achieving molecular responses to the targeted therapies for CML.[3,4,5] In patients with CML treated with imatinib (Gleevec®) for years, poor adherence has been identified as the predominant reason for the inability to obtain adequate molecular responses.[4,5] Missing more than two to three daily doses each month can negatively affect response. While CML patients who take more than 90% of their drugs reach a major molecular response (MMR; one of the main goals of CML treatment), patients who take less than 90% of the drugs have only a 15% chance of an MMR.[3]

The CML Advocates Network Adherence Survey is an ongoing global effort involving 12 languages and 79 countries. The majority of patients were recruited through online patient associations. In France, Germany, and Italy, physicians recruited patients at consultations. So far, 2546 have completed the survey—2151 online and 395 on paper.

 
In the United States, roughly 35% of patients admitted to purposely missing a dose, and 65% missed doses accidentally.
 

Roughly half of the patients admitted missing a dose accidentally in the past year, and 20% chose to miss a dose on purpose. "The United States and Serbia were way above the global average of being nonadherent intentionally and unintentionally," said Sharf. In the United States, roughly 35% of patients admitted to purposely missing a dose, and 65% missed doses accidentally. For the overall survey population, the average number of doses missed per month was three. Using the validated eight-item Morisky Medication Adherence Scale, 33% of the patients were considered high adherers, 47% were classified as medium adherers, and 21% were considered low adherers.[6,7]

The primary reasons for accidental nonadherence was forgetting (41%) and interrupted routine (27%). Other factors included traveling (17%), being too ill (15%), and falling asleep (9%). The main reasons for choosing to miss a dose were not feeling well (35%) and reducing the side effects (26%). "Accidental missing is more linked to memory. Purposeful missing is more related to physical symptoms," said Sharf.

Almost 10% of patients claimed that their physician said it was okay to miss a dose, but through conversations with patients, the researchers identified a more complex picture. What happens, said Sharf, is that sometimes a patient asks a doctor if they can stop for a few days while they are on vacation, and in some cases the doctor will say it's okay. One or two months later, the patient has another reason to stop, but this time they don't ask their doctor because they think their doctor gave them permission.

Survey participants were less likely to be high adherers to nilotinib (Tasigna; 25%) than imatinib (36%) or dasatinib (Sprycel; 33%). This makes sense, as nilotinib is the only one of the three that has to be taken twice a day. "Nilotinib also has a schedule where you have to fast 2 hours before you take the drug and 1 hour after you take the drug. It is quite a challenge to patients, and that is an influence—without any question," said Sharf.

Patients with low adherence were more likely to take their medication two times per day and to take their medications in the evening. There was no difference in adherence by gender, but older patients were more adherent than younger patients. Individuals with low adherence were more worried about quality of life and long-term side effects, and were not clear on the consequences of missing their medication.

 
Adherence was strongly influenced by the doctor-patient relationship.
 

Adherence was strongly influenced by the doctor-patient relationship. Individuals in the high-adherence group were more likely to be very satisfied with information received from healthcare practitioners (69% vs 45%) and more likely to think their healthcare practitioner was very approachable (73% vs 53%). Only 5% of patients who perceived their healthcare practitioner as not approachable had higher adherence. Compared with low adherers, those with high adherence were more likely to discuss intentionally missing a dose with their doctors (85% vs 48%). The same pattern was seen for discussing accidental doses (83% vs 47%).

"Communication between the patient and the doctor has a very important role in the patient being adherent," said Sharf. "When a patient tells you they are taking the drug every day, that is not always true; you have to go deeper and ask about issues that could affect adherence. Doctors have a central role in driving adherence." He said it is a joint responsibility between physician and patient.

According to many oncologists, including Daniel Mulkerin, MD, a medical oncologist at the University of Wisconsin Carbone Cancer Center, in Madison, managing oral anticancer agents requires a multidisciplinary approach. Oral anticancer agents are challenging for several reasons, including a narrow therapeutic index for many of them, the fact that the patient is responsible for treatment adherence, and the misperception that oral agents are safer than traditional chemotherapy.

The Carbone Cancer Center uses a standardized approach to patient education, based on the 2013 American Society of Clinical Oncology (ASCO) guidelines for the safe management of cancer agents.[8] In 2013, oral agents were added to these guidelines. Carbone, similar to some other centers, has expanded the involvement of pharmacy and the use of electronic chemotherapy order sets to address the issues raised by oral cancer agents.[9] An electronic medical record (EMR) tool reminds clinicians to monitor for toxicity and adherence. A call-back program helps assess the management of adverse effects and adherence to treatment using standardized tools.

"We have full scripts for adherence and toxicity monitoring for most of the 61 agents we define as oral chemotherapy," said Dr Mulkerin. Standardized counseling tools include questions, such as "How many doses have you missed in the past 2 weeks?"

According to Robin Zon, MD, a vice president at Michiana Hematology-Oncology, in South Bend, Indiana, having the manpower and getting reimbursed for the extra work involved in managing oral drugs are issues. "It takes multiple hours for one patient to get a prescription filled and get in a routine of taking it," said Dr Zon. "The problem is that nobody is paying for it." She said that what oncologists are reimbursed for managing oral drugs does not nearly cover the expenses involved in doing the work. She also believes that EMR prompts can be key in improving the management of cancer drugs.

At the 2016 ESMO meeting, Gerhardt Standhardt, executive director of Healthcare Compliance Packaging Council (HCPC) Europe, pointed out that packaging can be a driving factor in adherence. The HCPC is an organization dedicated to achieving demonstrable improvement in therapy adherence through the implementation of packaging-related initiatives. "As consumers, we look at packaging as trash, but it has a function," said Standhardt. "Packaging is the activity of temporarily integrating an external function and a product to enable the use of a product. Calendarizing is one way to improve adherence."

He highlighted examples of exemplary packaging, including that for the new multiple myeloma drug panobinostat (Farydak), which is calendarized. The calendarization helps with the tough-to-follow three-times-a-week schedule. "Three times a week is the most complicated regimen to adhere to," said Standhardt.

 
Nonadherence may be the norm, not the exception.
 

At the ESMO meeting, Rob Horne, PhD, director of the Center for Behavioral Medicine at University College London, pointed out that adherence rates vary among patients, within the same patient over time, and across treatments. Nonadherence may be the norm, not the exception.[10] Information is essential to enable adherence, but giving more information does not guarantee adherence. To result in action, information must either concur with the existing beliefs of the patient or their beliefs about medication adherence may need to be modified. Adherence is closely tied to specific beliefs and views about prescribed medication, about the necessity of the medication to maintain/improve current and future health, and concerns arising from beliefs about potential negative effects.

Dr Horne recently published a meta-analysis of 94 studies, showing that higher adherence was associated with stronger perceptions of necessity of treatment (odds ratio [OR], 1.742; 95% confidence interval [CI], 1.569-1.934; P<.0001) and fewer concerns about treatment (OR ,  0.504; 95% CI, 0.450-0.564; P<.0001).[11] The relationships remained significant when data were stratified by study size, the country in which the research was conducted, and the type of adherence measure used.

According to Dr Horne, people's evaluations of treatment are influenced by preexisting common-sense beliefs about illness and symptom experiences relative to expectations. Many patients do not have a clear common-sense rationale for why maintenance therapy is necessary, having a "'no symptoms, no problem' attitude."

In many countries, information leaflets provide a list of possible side effects, which increases patient concerns. According to Dr Horne, there is a need to communicate value (benefit) of a medication as well as the risk.

The information, said Dr Horne, should help patients balance risks against benefits so that they can make an informed choice about treatment.

Mr Sharf is a member of advisory boards: AbbVie, Gilead, Novartis, BMS, Pfizer, and Ariad. Dr Horne, Mr Standhardt, Dr Zon, and Dr Mulkerin have disclosed no relevant financial relationships.

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