Treatment adherence includes compliance with chemotherapy, radiotherapy and even surgery when they are recommended or prescribed. But for this article we focus on oral medications, following last week’s overview.
While the bulk of chemotherapy (I include any form of systemic therapy—conventional chemotherapy, hormonal therapy, biologic therapy, immunotherapy—under the broad rubric of chemotherapy) has been by parenteral, usually intravenous, infusion, there have always been at least a few agents that were administered orally. Oral cyclophosphamide (Cytoxan), diethylstilbestrol (DES), Megace (megestrol acetate), prednisone, levamisole to name a few. However, the past two decades have witnessed a veritable explosion in oral chemotherapy drugs. Over 25% of current chemotherapy is in the oral form and this figure is now approaching 50%—that is a real change. It is a blessing in terms of ease and logistics of administration and comfort for the patient, but it brings adherence to the forefront as an issue.
What is shocking is that the published statistics on the rates and circumstances of adherence for oral agents utilized in oncology do not differ substantially from what I described in last week’s article. I anticipated that for drugs that literally mean the difference between life and death that there would be an obsession with proper use, as compared, for example, to antihypertensive drugs, which are also important but primarily as prophylactic agents over time. Surprisingly, adherence remains a major problem in oncology as well.
The class of drugs most studied are the hormonal agents utilized for breast cancer—tamoxifen and aromatase inhibitors (anastrozole, exemestane and letrozole). Approximately 70% of breast cancer is hormone-sensitive and these drugs are prescribed for management of metastatic disease, adjuvant therapy (after surgery for localized disease), preventive therapy for those at high risk, and for ductal carcinoma-in-situ, a breast cancer precursor. I focus on its use for prevention or adjuvant therapy, not for metastatic disease, for three reasons. (1) Breast cancer is a common cancer and thus this is probably the most common scenario in which oral drugs are used. (2) These drugs are prescribed for five years in duration, frequently for 10 years, and therefore adherence is a major problem. (3) The use of hormonal therapy in these settings is highly efficacious so it is critical to ensure that adherence is maintained. Adjuvant therapy for hormone-sensitive breast cancer reduces mortality by over 20%, and its utilization as a preventive agent in high-risk women prevents 50% of breast cancer. A significant degree of non-adherence or early discontinuation of the drug can significantly reduce or eliminate these potential benefits.
Thus, it is surprising to learn that less than 50% of women finish all five years of the recommended treatment and thereby put themselves at risk for a major loss of benefit. This is worse for the aromatase inhibitors than tamoxifen because aromatase inhibitors have a worse panoply of side effects. Cost, family support, belief in drug efficacy, and other factors affect this rate. As mentioned last week, it is not easy for a physician to distinguish compliers from non-compliers. My own group’s studies in New York, Detroit and California have shown roughly 30% discontinuation rates by two to three years. More recently, our studies in Johannesburg have found discontinuation rates greater than 50% among B lack Africans with breast cancer by 18 months on tamoxifen, illustrating that adherence is a universal problem.
Another important oral anti-cancer drug is imatinib (Gleevec), used for gastrointestinal stromal tumors and chronic myelogenous leukemia. It has transformed these diseases from lethal cancers into chronic ones. However, cessation of its use leads to progression. One study in 2010 found that 26% of patients with CML were >90% adherent with their imatinib; other studies have confirmed these results and found even worse adherence. One study showed that a 75% adherence rate resulted in worse efficacy than a 90% adherence rate.
While the barriers to adherence are similar for oncology drugs and conventional drugs, one factor does stand out in the oncology realm. Side effects represent a more important obstacle to adherence for oncology than for other diseases. This has been a repetitive theme in studies exploring causes of nonadherence. Ironically, one of the benefits of oral drugs is that they usually have a superior toxicity spectrum versus intravenous medications. Nonetheless, they are still potent agents and cause some degree of side effects.
As with many problems in cancer care, the support of the physician and other healthcare workers and of the family are essential to dealing with these problems. As opposed to IV medications, it is too easy and tempting to avoid an oral medication that the patient knows may bring unpleasant consequences. One remedy is to replace the oral form of certain agents, when possible, and use the intravenous moieties. Thus, for the breast cancer regimen CMF, which includes Cytoxan (cyclophosphamide), intravenous cyclophosphamide has almost completely replaced the formerly common use of oral cyclophosphamide. Similarly, for a common regimen for colorectal cancer, a fluoropyrimidine (oral capecitabine or IV 5-fluorouracil) with IV oxaliplatin, I have come to prefer the IV 5FU when feasible as I have found patients infinitely creative in finding ways to screw up the taking of the capecitabine tablets, usually without my awareness.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
