Oral chemotherapeutic agents have been available for many years, and were traditionally cytotoxic drugs, such as cyclophosphamide, methotrexate, and mercaptopurine. In recent years, oral anticancer medications are being used more often in many types of cancer. Ongoing cancer research is focused on the development of new oral chemotherapies.1 Twelve new orally administered chemotherapeutic agents have been approved by the US Food and Drug Administration (FDA) in the past 22 months.2,3
The National Comprehensive Cancer Network (NCCN) has recognized the increasing use of oral chemotherapies as a growing concern, and has formulated “a multidisciplinary task force consisting of oncologists, nurses, pharmacists, and payor representatives to discuss the impact of the increasing use of oral chemotherapy.”1
Because of their efficacy and general acceptance by patients, there has been an increase in the number of patients with cancer who have been receiving oral therapies in the past few years. Oral chemotherapies are perceived by patients to be easier to use and safer, although this may not necessarily be true.1 Many oral chemotherapeutic agents have side-effect profiles that are similar to intravenous treatments and can involve complicated regimens, and difficult administration instructions.1,4 For instance, capecitabine is an oral prodrug of the parenteral medication fluorouracil, and therefore has side effects similar to fluorouracil, including diarrhea and hand-foot syndrome.1,5 Capecitabine must also be taken within 30 minutes of a meal, and the most common regimen requires the patient to take it twice daily for 14 days, then 7 days off.
Newer targeted agents may not have the same side effects as cytotoxic agents; however, they do come with their own side effects, and patients need to be aware of them. For example, enzalutamide and abiraterone may cause hot flashes, edema, diarrhea, and musculoskeletal pain, whereas the traditional parenteral chemotherapy could cause nausea, vomiting, hair loss, and diarrhea.6-8 Adherence to all medications used by patients at home is a well-known concern, and the literature indicates that this is also true for oral anticancer agents.4
During clinical trials, adherence to drug regimens tends to be higher than medication adherence in real-life outside of clinical trials because patients are aware that they are being observed during studies.1 In addition, clinical trials often use strict standards for medication adherence as inclusion criteria, which may overestimate real-life scenarios. It is very difficult to measure medication adherence, and it has been shown that the subjective measurements used by providers and nurses at clinic visits are not accurate for assessing adherence.4 In the general population, patients may not experience the same responses to therapy as those seen in clinical trials, because of a potential decrease in patient adherence to the treatment regimen. This has been shown in patients with chronic myeloid leukemia, a disease in which poor adherence to oral chemotherapy regimens leads to worse outcomes.9
At St. Luke’s Mountain States Tumor Institute (MSTI), the Oral Chemotherapy Service (OCS) follows patients who are taking oral chemotherapies at home and communicates with them at least once at every treatment cycle. This follow-up is done by a telephone call, during which the pharmacists assess the patient’s medication adherence and side effects. The MSTI OCS process has been described previously.10 As a result of this additional monitoring, it is hypothesized that the patients who fill their prescriptions through the MSTI OCS may have increased adherence to oral chemotherapy regimens compared with other patients, and they more closely resemble adherence seen in clinical trials.
This review aimed to evaluate how long patients continued to use their therapy compared with the duration of therapy seen in clinical trials.
Methods
This retrospective chart review included all new prescriptions for adult patients with cancer who received capecitabine, temozolomide, lenalidomide, abiraterone, or enzalutamide through the MSTI OCS between January 1, 2010, and December 31, 2013. These 5 medications were chosen after an evaluation of the top medications prescribed at the center in 2014.
The prescribing information for each drug was reviewed to collect the data reported in the respective clinical trials,5-7,11,12 and then the published primary studies were reviewed to obtain the duration of use for each drug.13-26 Prescriptions were excluded if they were written for off-label indications, had to be filled through a mail order or other pharmacies, or were never actually dispensed to the patient.
Data collected included the medication prescribed, the indication, dose, the date the prescription was written, the number of cycles received and the days per cycle, and the reason for discontinuation.
All the included prescriptions were reviewed to determine whether the medications prescribed were filled exclusively through the MSTI OCS, and if they were written for an FDA-approved indication. The duration of time patients continued to use the medication was then evaluated. In the case of temozolomide use in patients with glioblastoma who received concurrent radiation, the percentage of patients who completed therapy was compared.
Statistical Analysis
A Wilcoxon signed-rank test for a single sample was used to run statistical analysis for continuous data. The hypothesized median used in this analysis was the median duration reported in clinical trials for the drugs. For nominal data, a chi-square test was used. A power analysis was not completed, and therefore a sample size was not calculated; however, a P value of ≤.05 was considered to be significant.
Results
During the review period, 1105 new prescriptions were identified. A total of 356 prescriptions were written for off-label indications, 149 were sent to a mail order or other pharmacies, 152 were never dispensed to the patient, 45 patients received free medications from the manufacturer, and 36 prescriptions were found to not be initial treatments. This left 367 prescriptions that were prescribed according to FDA-approved indications and filled exclusively through the MSTI OCS (Figure).
The median durations of treatment reported in the clinical trials referenced in the prescribing information, and the median durations seen at MSTI during the review period are shown in the Table.
The most common reasons for medication discontinuation were disease progression, treatment completion, side effects, and patients moving to hospice care or to comfort measures.
Capecitabine
Capecitabine is FDA approved for the treatment of patients with metastatic colorectal cancer, metastatic breast cancer, or Duke’s C colon cancer.5 There were 54, 71, and 29 prescriptions, respectively, filled at the MSTI OCS for these indications. The only indication that showed a longer duration of therapy at MSTI compared with that reported in clinical trials was metastatic breast cancer. Patients receiving capecitabine for metastatic colorectal cancer showed no difference in treatment duration, and patients with Duke’s C colon cancer had a significantly shorter duration of treatment than those treated in clinical trials.
Temozolomide
Temozolomide is FDA approved for use, concomitantly with radiation therapy, for the treatment of patients with glioblastoma multiforme; as maintenance therapy; and for patients with refractory anaplastic astrocytoma.11 There were 72 prescriptions written for glioblastoma—46 concurrently with radiation and 26 as maintenance regimens—and 1 prescription was written for anaplastic astrocytoma.
The only indication that had a longer duration of therapy than reported in clinical trials was glioblastoma, as maintenance therapy. Patients who received temozolomide for glioblastoma concurrently with radiation had no significant difference in the percent completing therapy compared with those reported in clinical trials. Only 1 prescription was for anaplastic astrocytoma, resulting in insufficient data for a statistical evaluation.
Lenalidomide
Lenalidomide is FDA approved for the treatment of patients with multiple myeloma; transfusion-dependent anemia caused by myelodysplastic syndromes associated with 5q deletion; or mantle-cell lymphoma.12 There were 55 prescriptions written for lenalidomide for all indications—45 for multiple myeloma, 8 for myelodysplastic syndromes, and 2 for mantle-cell lymphoma.
Patients with multiple myeloma at MSTI did not continue lenalidomide therapy as long as patients in clinical trials. There were too few patients with myelodysplastic syndrome or mantle-cell lymphoma arms to allow for statistical evaluation.
Enzalutamide and Abiraterone
The only FDA-approved indication for enzalutamide and for abiraterone is the treatment of patients with metastatic castration-resistant prostate cancer.6,7 Each of these 2 medications reported data from 2 clinical trials in their respective prescribing information; therefore, results from the MSTI OCS were compared with the 2 medians reported. A total of 20 prescriptions for enzalutamide and 65 for abiraterone were included in the analysis.
Patients who received prescriptions for enzalutamide or for abiraterone continued to use the drugs for a significantly shorter duration than that reported in their clinical trials.
Discussion
The goal of this study was to consider alternate ways of determining the benefits of more direct and intensive management of patients who receive oral therapies for cancer. In the past, the success of a directed management program has been measured as a function of various measures of medication adherence, such as Medication Event Monitoring Systems caps,4,27-29 tracking refill/dispensing rates,4,27,28,30,31 and patient interviews/questionnaires.4,27,28,32
The problem with most medication adherence measures is that they do not always relate directly to taking the medication itself. Some patient-reported measures have ways to get around them through patient-directed mechanisms, such as pill dumping or filling in dosing charts. Nonpatient-reported measures, such as refill rates, do not confirm whether a patient is actually taking the medication.
The other issue is that we do not know what a given adherence rate in oncology translates to in terms of desired outcomes with cancer.28 Therefore, it was our hypothesis that the best way to evaluate the true benefit of an oral chemotherapy management program was to look at the outcomes and compare them with the primary outcomes of the clinical trials that led to the FDA approval of the medications.
Limitations
Several limitations should be taken into consideration. The patients evaluated in this review included only those who were prescribed a medication for an FDA-approved indication. The study had no exclusion criteria based on patient parameters; therefore, these patients are a fair representation of the general population. Patients were not matched to the exclusion and inclusion criteria of the clinical trials, which might have influenced the results. Because no calculations of sample size were done, and the sample sizes for each indication varied greatly, there is a risk for type II error.
Other potential confounders may be that the intended duration of treatment and patient populations were not consistent with those in the clinical trials for all medications evaluated. Patients with multiple myeloma who received lenalidomide were included pre- and posttransplantation, which might have swayed the results toward a shorter duration of treatment. For the other medications evaluated, the regimen durations were the same as those in the clinical trials.
As for patients who recieved enzalutamide or abiraterone, the analysis period only included a short time after the approval of these 2 medications. Some of the patients included could have been waiting for the approval of these medications, and thus had disease progression in the interim—the results might have been skewed because of the severity of disease in these patients compared with those in clinical trials.
Conclusion
Adherence to oral medication regimens can be difficult to measure. This review showed that the additional monitoring and counseling performed by the MSTI OCS pharmacists resulted in similar or prolonged durations of therapy compared with those reported in clinical trials of capecitabine and temozolomide; however, this was not the case for lenalidomide, abiraterone, or enzalutamide. Because it is difficult to measure patient adherence in the real-world setting, if patients are continuing to use their medication for as long as or longer than patients in clinical trials, it is speculated that these patients will have similar outcomes as those included in the clinical trials. Further analysis of the utility of this type of measure for the success of a program is encouraged.
Author Disclosure Statement
Dr Mancini is on the Speaker’s Bureau of Millennium and a consultant for Taiho. Dr Hogue and Dr Ineck have no conflicts of interest to report.
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