Michael E. Williams, MD, ScM
Jonathan W. Friedberg, MD, MMSc
ADVANCES IN cancer treatment have been nothing short of breathtaking in recent years. Among the most important has been the advent of effective oral therapies, marking a significant change in the way many patients receive treatment and in the oversight required by the cancer care team. As with parenteral therapy, treatment compliance is essential to achieve the best outcome. Although solid tumor oncologists and those who treat myeloma or chronic myeloid leukemia (CML) have dealt with oral cancer treatment adherence for many years,1 those of us who manage patients with lymphoma and chronic lymphocytic leukemia (CLL) find ourselves on relatively new ground.
Continuous oral lymphoma and CLL therapy has become an important option for patients who can manage the prescribed regimens and recognize possible complications. Patients may select an oral treatment because of the appeal of prolonged remission, the perception that it is more convenient and may decrease the frequency of office visits, and to have a greater sense of control over their own cancer care. With this shift in cancer care, clinicians and patients must pay attention to the efficacy, value, and cost, as well as the convenience of and adherence to, oral cancer regimens.
The Lymphoma Research Foundation convened oral therapy workshops in 2015 and 2017, seeking to better understand the role oral therapies play in the treatment of lymphoma and CLL as well as the unique challenges with these regimens. Scientific and clinical knowledge gaps were identified and summarized in Lymphoma Research Foundation White Paper publications,2,3 including the implications of continuous therapy for the cancer care team, patient education, measurement of outcomes, monitoring for toxicities, and in the development of new therapeutic endpoints. The 2017 workshop,3 Adherence and Oral Therapies in Lymphoma and CLL, focused on the epidemiology and types of nonadherence (unintentional and intentional) as well as current methods of adherence assessment (eg, patient self-reporting, prescription refill rates, biologic testing, digital/electronic compliance monitoring), and barriers to accurately measuring adherence.
Lessons Learned From CML
THE ERA OF targeted oral anticancer treatment began 20 years ago with the tyrosine kinase inhibitor imatinib for chronic-phase CML. This agent provided durable remissions and markedly improved survival for the majority of patients. However, achieving the deep molecular remission needed to realize such positive outcomes requires at least 90% adherence to therapy—a level of compliance achieved by only about two-thirds of patients.4,5 Indeed, in a study by Marin et al,4 treatment adherence and achievement of major molecular response were the only independent predictors of outcome. As a corollary, loss of treatment response more commonly indicates noncompliance rather than biologic resistance to therapy.
Patients may find it a challenge to endure years of therapy expense and chronic toxicities. As a result, they may interrupt treatment or modify doses without disclosing this to the care team.”— Michael E. Williams, MD, ScM, and Jonathan W. Friedberg, MD, MMSc
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What factors may contribute to poor adherence? On the provider side of the equation, there’s often a false assumption that compliance is a given in the setting of cancer or a tendency to discount the effects of some grade 1/2 side effects associated with chronic therapy on the patient’s quality of life. Conversely, patients may find it a challenge to endure years of therapy expense and chronic toxicities, even if low grade. As a result, they may interrupt treatment or modify doses without disclosing this to the care team.6
Optimizing Adherence to Oral Therapy
THE LYMPHOMA RESEARCH Foundation workshop identified several themes relevant to optimization as well as a need for research into this complex patient care delivery challenge:
- Patients on oral therapy regimens generally receive less supervision and have less interaction with their health-care team. New models for providing care to patients on oral cancer therapies, which include more patient education, are needed.
- Patients utilizing medications to control other comorbidities such as hypertension or diabetes may experience polypharmacy issues including drug-drug interactions or may have additional difficulty adhering to complex regimens or drug administration schedules.
- Currently, there are no standardized methods for assessing adherence, and there is no uniform definition of adherence, nor a measure of adherence and ways in which it affects clinical outcomes and disease control.
- Based on experience with long-term treatment of other malignancies with oral therapies, such as CML, some side effects may not emerge until after years on the regimen.
- Because of the drug costs and often long duration of treatment required, oral therapies may lead to a financial burden due to high copays. The type and extent of insurance coverage the patient has may be a contributor to poor adherence.
The knowledge gap on long-term management and monitoring has led the National Cancer Institute to designate adherence to oral cancer therapies as a key research agenda item, offering research grant opportunities in the study of patient characteristics that are associated with adherence; studies on the psychological underpinnings of adherence including how mood disorders may affect adherence; and challenges for adherence in patients with physical limitations or disabilities or in those who live in areas where health-care resources are limited7 (https://grants.nih.gov/ grants/guide/pa-files/PA-17-060.html and https://grants.nih.gov/ grants/guide/pa-files/PA-17-061.html).
“Recognition and avoidance of potential drug-drug interactions—a particular challenge when years of oral anticancer treatment is the expected course—are important priorities.”— Michael E. Williams, MD, ScM, and Jonathan W. Friedberg, MD, MMSc
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Next Steps
ALTHOUGH THE scope of the adherence challenge has been delineated, validated approaches to analysis and improvement in treatment compliance remain in evolution.8,9 Technologies such as Medication Event Monitoring Systems (MEMS) or mobile apps can supplement patient self-reporting,3,9 and nursing phone calls to patients within the first week of treatment initiation that include standardized toxicity management algorithms can enhance compliance.1 Recognition and avoidance of potential drug-drug interactions10—a particular challenge when years of oral anticancer treatment is the expected course—are important priorities.
The near term for molecularly defined subtypes of lymphoma and CLL is truly exciting, with the promise of less reliance on traditional cytotoxic chemotherapy via transition to oral targeted agents and immunotherapeutics in rational combinations. Ideally, they will be designed to achieve molecular remission as a therapeutic goal and to permit limited rather than lifelong treatment administration. To achieve such advances, research and new care models will be essential and should become a regular focus in our literature, our professional conferences, and our day-to-day practices. ■
DISCLOSURE: Dr. Williams is an advisor/consultant for AstraZeneca, Celgene, Takeda, Kite Pharma, Juno Therapeutics, TG Therapeutics, Gilead Sciences, Bristol-Myers Squibb, and Seattle Genetics; has received (institution) research funding from Celgene, Janssen, Pharmacyclics, Gilead Sciences, Allos Therapeutics, and Takeda; and travel acccommodations/expenses from Celgene, Takeda, and Janssen. Dr. Friedberg is a scientific advisory board member of Lymphoma Research Foundation and has received honoraria for data safety and monitoring committee activities from Bayer and Astellas.
Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO or The ASCO Post.
REFERENCES
1. Zerillo JA, Goldenberg BA, Kotecha RR, et al: Interventions to improve oral chemotherapy safety and quality: A systematic review. JAMA Oncol 4:105-117, 2018.
2. Lymphoma Research Foundation: Oral therapies in lymphoma: Opportunities and challenges in research and treatment: A Lymphoma Research Foundation White Paper. September 2015. Available at www.lymphoma.org/wp-content/uploads/2017/07/LRF-WHITE-PAPER-FINAL.pdf. Accessed May 15, 2018.
3. Lymphoma Research Foundation: Adherence and oral therapies in lymphoma and CLL: A Lymphoma Research Foundation White Paper. October 2017. Available at www.lymphoma.org/wp-content/ uploads/2018/03/6609-LRF-Oral-Therapies-White-Paper-Final2-Web-03_14.pdf. Accessed May 15, 2018.
4. Marin D, Bazeos A, Mahon FX, et al: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28:2381-2388, 2010.
5. Noens L, van Lierde MA, De Bock R, et al: Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood 113:5401-5411, 2009.
6. Mauro MJ: Adherence in the TKI era, or how to run the CML marathon. In: Adherence and oral therapies in lymphoma and CLL: A Lymphoma Research Foundation White Paper. October 2017. Available at www.lymphoma.org/wp-content/ uploads/2018/03/6609-LRF-Oral-Therapies-White-Paper-Final2-Web-03_14.pdf. Accessed May 15, 2018.
7. Nelson W: Utilization and adherence of oral anticancer agents: Perspectives and opportunities from the National Cancer Institute (NCI). In: Adherence and oral therapies in lymphoma and CLL: A Lymphoma Research Foundation White Paper. October 2017. Available at www.lymphoma.org/wp-content/ uploads/2018/03/6609-LRF-Oral-Therapies-White-Paper-Final2-Web-03_14.pdf. Accessed May 15, 2018.
8. Greer JA, Amoyal N, Nisotel L, et al: A systematic review of adherence to oral antineoplastic therapies. Oncologist 21:354-376, 2016.
9. Hall AE, Paul C, Bryant J, et al: To adhere or not to adhere: Rates and reasons of medication adherence in hematological cancer patients. Crit Rev Oncol Hematol 97:247-262, 2016.
10. Parsad S, Ratain MJ: Drug-drug interactions with oral antineoplastic agents. JAMA Oncol 3:736-738, 2017.
