Expanding Use of Oral Therapies Puts Challenges of Patient Compliance in Spotlight

Maurie Markman, MD

Until relatively recently, the use of oral antineoplastic therapy had been limited in routine oncologic care, largely restricted to hormonal treatments for breast cancer and a few cytotoxic agents such as capecitabine and etoposide. In recent years, however, an increasing number of targeted antineoplastic drugs with an oral method of delivery have been introduced into clinical practice.

This development is welcomed both for the overall convenience it offers patients and for the ability to continue treatment for prolonged periods while permitting patients a far greater opportunity to maintain their normal activities, including work. Further, since many advanced and metastatic cancers are increasingly and appropriately considered as very serious but chronic disease processes–with survival and treatment durations measured in years rather than weeks or months–the ability to optimize quality of life for these extended periods of time becomes critical.

In this context, enhancing an individual patient’s quality of life will likely include efforts to minimize the time spent receiving therapy, such as travel or periods away from work at the oncologist’s office for the patient and/or caregiver.

This effort becomes an absolutely essential component of an approach that recognizes the far longer duration of the routine disease management trajectory.

However, as we move into this new therapeutic paradigm, it is relevant that we consider unique aspects of this strategy that may substantially negatively impact outcomes, compared with an approach of systemic antineoplastic drug administration.

Table. Correlation of Outcomes With Compliance

Impact of adherence to imatinib therapy among 87 patients with CML

CCyR indicates complete cytogenetic response; CML, chronic myeloid leukemia; EFS, event-free survival; MMR, major molecular response.

Ibrahim AR et al. Blood. 2011;117(14):3733-3736.

In this regard, perhaps the most serious clinical concern with oral antineoplastic drug delivery is the fundamental issue of patient compliance with the physician-ordered drug regimen. The issue of compliance is not unique to the oncology arena and represents a major challenge for all areas of medicine. Fundamentally, many individuals do not like taking medicine and this can be particularly problematic in the setting of an individual who is (a) required to take many pills every day; (b) likely to continue therapy for prolonged periods of time (for life or until disease progression); (c) forced to cope with any unpleasant side effects that actually (or are perceived to) result from taking the medication; and (d) “feeling well” and not experiencing any direct benefit from taking the medication regularly.

Quantity, Size, and Shape of Oral Therapy

It is reasonable to expect that individuals required to take a number of pills every day or multiple times during a 24-hour period are likely to be far less willing to adhere to a prescribed regimen than if the patient only needs to take a single pill once a day. Further, if the pill is particularly large, has an unpleasant taste, or the patient has difficulty swallowing pills, one can certainly anticipate difficulties with adherence to the drug program.

While one might even speculate that liquid delivery of a medication (assuming reasonable taste) might be more acceptable in settings otherwise requiring multiple pills, accurately measuring the appropriate quantity for delivery will pose a significant challenge, as will the fact that a liquid form is likely to be far less convenient for individuals who do not want to be largely confined to a single location due to the difficulty associated with transport of the medication.

Unique Aspects of Generic Oral Medications

Although not currently a major issue with oral antineoplastic agents (except perhaps in the arena of hormonal therapy), it is increasingly recognized that there are clinically relevant concerns when any patented oral medication becomes generic and is available from several possible manufacturing sources. In a most provocative report, investigators studied the impact of a “change in appearance (shape or color)” of pills when employing a generic oral cardiovascular agent, in this case a beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin II-receptor blocker, or statin.¹

The study population (N = 11,513) comprised individuals who were discharged from the hospital with the diagnosis of a myocardial infarction. Of the patients included in this analysis, 29% had a change in the shape or color of the generic medication following discharge compared with the preadmission agent. The investigators found that, compared with individuals who did not have a change in their generic medication, patients who were prescribed a drug with a different color or shape were 34% and 66%, respectively, less likely to fully comply (“nonpersistent use”) with continuation of their medications.¹ The potential serious implications of these findings in the case of cardiovascular disease are clear.

In the case of generic antineoplastic agents, one can speculate that a given pharmacy may use generic drugs from several manufacturers.

If a patient is given the “correct drug” that looks different from that previously used, it is quite possible that, based on the cardiovascular agent experience, many patients will fail to appropriately take the critically important agent. The potential negative impact on outcome is clearly evident.

Another concern with generic oral antineoplastic agents is over the information that might be included in the labeling of one product compared with another. The rules and responsibilities of generic drug manufacturers are undergoing intensive review, but at the current time it remains possible for one generic agent to have listed in the package insert potential serious adverse events that are not included in written material provided with the same drug manufactured by another company.² Confusion among patients, their families, and possibly even the treating oncologist in this setting is potentially a serious matter.

Persistent Low-Grade Side Effects Take Toll

Frequently missing from discussions within the antineoplastic drug literature is the impact of persistent low-grade toxicities, particularly in the setting of long-term use.

While grade 1 emesis, mucositis, or stomatitis may be manageable if it lasts for a few days after each course of an every 3- to 4- week chemotherapy regimen, the situation would likely be quite different if the nausea occurred with each oral dose of an antineoplastic or the mouth sores never healed. And, it is likely data on the magnitude of this effect would be absent from many clinical trial reports.

Oral Drug Costs Create Barriers

While not in the scope of this commentary, the complex issues of the cost of oral medications, difficult billing and payment programs, co-pays, and the method of distribution of systemic versus oral antineoplastic medications are matters of increasing concern to patients and their families, as well as other interested parties including payers, employers, government regulators, and the biopharmaceutical industry and its investors.

In a recent report examining the issue of adherence to hormonal therapy among 10,302 women with early-stage breast cancer, investigators found a strong association between net worth (low, medium, high) and adherence to the prescribed regimen (P <.01).³ Further, this factor appeared to explain, at least in part, the previously documented impact of the patient’s race on adherence to hormonal treatment in this clinical setting.

Another well-documented example of the impact of cost on oral medication adherence is the experience with imatinib, the groundbreaking drug that has revolutionized the management of chronic myeloid leukemia and gastrointestinal stromal tumors. Remarkably, in contrast to what might have been predicted based on the increasing number of patients currently using this drug and the profit generated for the pharmaceutical company, the actual cost of the drug has increased rather substantially from the time the agent was initially introduced into the commercial market. It has been noted in the medical literature that the cost of the drug has unfortunately resulted in nonadherence among patients taking the agent despite its demonstrated tremendous clinical benefit.⁴

Moreover, the impact of nonadherence to imatinib on outcome should not be minimized. In one report, investigators attempting to evaluate the impact of nonadherence to long-term therapy with imatinib in chronic myeloid leukemia employed a microelectronic monitoring system to measure compliance.⁵ Of the 69 patients included in this series who had achieved a complete cytogenetic response and who achieved an adherence rate of >85% during follow-up, only 1.4% failed to maintain this clinical state for a minimum of 2 years. In rather striking contrast, of the 18 patients who achieved an adherence rate of ≤85% during this period, 36.3% were found to no longer be in a complete response by the 2-year mark (P = .0001).

A subset analysis (Table) led researchers to conclude that poor adherence “is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.”⁵

Strategies Needed to Address Issues

In the future, cancer therapy will surely increasingly rely on the availability of well-tolerated oral antineoplastic agents. It will be critical that the unique issues associated with the optimal utilization of this route of drug delivery are carefully considered. Just as has been demonstrated with all weight-losing diet experiences where the major factor associated with success is simply adherence to the diet,⁶ it is most unlikely that oral antineoplastic treatment will be effective in the absence of useful strategies designed to optimize adherence to the prescribed regimen.

References

1. Kesselheim AS, Bykov K, Avorn J, et al. Burden of changes in pill appearance for patients receiving generic cardiovascular medications after myocardial infarction: cohort and nested case-control studies. Ann Intern Med. 2014;161(2):96-103.
2. Duke JD, Kesselheim AS. The Food and Drug Administration’s role in promoting consistent labels for generic drugs. JAMA Intern Med. 2014;174(8):1213-1214.
3. Hershman DL, Tsui J, Wright JD, et al. Household net worth, racial disparities, and hormonal therapy adherence among women with early-stage breast cancer [published online February 17, 2015]. J Clin Oncol. 2015;33(9):1053-1059.
4. Kelley RK, Venook AP. Nonadherence to imatinib during an economic downturn. N Engl J Med. 2010; 363(6):596-598.
5. Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733-3736.
6. Pagoto SL, Appelhans BM. A call for an end to the diet debates. JAMA. 2013;310(7):687-688.