This is a multicenter, observational, prospective study. The decision to prescribe treatment is fully separate from the decision to include a patient. Treatment will be prescribed as usual by the responsible oncologists, while the decision to include the patient in the study will be the responsibility of the participating pharmacist. Once included, the patient will be actively and prospectively followed up for 3 months, including 4 study visits to record information on sociodemographic variables, antineoplastic treatment and adherence, pharmaceutical care, clinical variables, and PROs (see below). Twelve months after inclusion of the last patient, we will record information on the progression status and dispensed prescriptions. The overall design is illustrated in figure. The study has been approved by the Ethics Committee for Research with Medicines from Galicia (Santiago de Compostela, Spain).

The study will be conducted by 6 Spanish hospitals with experience in managing patients with NSCLC.

The study will include men and women aged 18 years or older with a diagnosis of locally advanced or metastatic NSCLC, who are being treated or have been prescribed OCT for the management of NSCLC according to the standards and criteria of the participating centers, and who provide written informed consent. Patients will be excluded if, according to the investigator's judgment, they are unable to understand the questionnaires administered during the study or if the patient is currently included in a clinical trial.

Patients will be considered exposed to the intervention of interest if they are currently receiving or have been prescribed OCT. OCT should be prescribed in routine clinical practice and in accordance with the summary of product characteristics by the oncologist responsible for the management of patients who will not participate in the study as part of the research team.

There will be 4 visits during the active follow-up period of 3 months, at baseline, and every month until month 3 (Fig. 1); these visits could be substituted by telephone contact. At visit 1, at the time of the inclusion of the patient in the study, the pharmacist will record the following information: demographics including age, sex, race, studies, employment status, and tobacco use; disease-related variables such as date of diagnosis, disease stage at the time of diagnosis, histology, ECOG performance status, number and location of metastases, and biomarkers (specifically ALK, EGFR, EGFR-T790M, ROS-1, BRAF); and treatment-related variables including previous antineoplastic, concomitant medication, and OCTs, for the later recording of information posology and date of dispensation. At visit 1, the patient will complete the 3-level version of the EQ-5D (EQ-5D-3L),12 13-item lung cancer-specific questionnaire module of the EORTC Core Quality of Life Questionnaire (EORTC QLQ-LC13),13 and Brief Illness Perception Questionnaire (BIPQ).14 At visits 2, 3, and 4, the pharmacist will record information on the OCT pill count (i.e., dispensed and unused pills), treatment changes of concomitant medications and OCT, pharmaceutical care interventions, and use of resources (emergency department visits and admissions). During these visits, the patient will fulfill the 4-items Morisky Green Levine Medication Adherence Scale (MGLS-4)15 and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®), and the quality of life questionnaires, BIPQ, and Treatment Satisfaction with Medicines Questionnaire (SATMED-Q)16 will be self-administered again at visit 4. The final evaluation will take place 12 months after inclusion of the patient, and the pharmacist will record information on disease progression and dispensed OCT prescriptions. We will use the Spanish validated version of PROs, whose characteristics are briefly described below and that will be administered in a paper-based format.

Fig. 1.

Study periods and assessments.

BIPQ, Brief Illness Perception Questionnaire; EORTC QLQ-LC13, 13-item lung cancer-specific questionnaire module of the EORTC Core Quality of Life Questionnaire; EQ-5D-3L, 3-level version of the EQ-5D; MGLS-4, 4-items Morisky Green Levine Medication Adherence Scale; OCT, oral chemotherapy; PRO-CTCAE®, Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; PFS, progression-free survival; SATMED-Q, Treatment Satisfaction with Medicines Questionnaire.

(0.12MB).

The EQ-5D is a 5-item generic measure of quality of life that comprises 5 dimensions: movement, self-care, daily life activities, pain/discomfort, and anxiety/depression. We will administer the Spanish version of the EQ-5D 3-level version, where the degree of impairment in each dimension is evaluated as having no problems, some problems, or extreme problems.12 The instrument includes a Visual Analog Scale (EQ-5D VAS) to evaluate self-rated health from 0 (worst imaginable health status) to 100 (best imaginable health status).

The EORTC QLQ-LC13 comprises both a multi-item scale for evaluating dyspnea and single-item measures of lung cancer-associated symptoms such as pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis.13 The extent to which the patient has experienced these symptoms or problems during the past week is rated as ‘not at all,’ a ‘little,’ ‘quite a bite,’ or ‘very much.’

The Brief Illness Perception Questionnaire (Brief IPQ) is a 9-item questionnaire that assesses cognitive and emotional representations of illness.14 It comprises 5 items on the cognitive representation of illness perception (consequences, timeline, personal control, treatment control, and identity), 2 items on emotional representation (concern and emotions), 1 item on illness comprehensibility, and 1 item on the perceived cause of illness, in which respondents list the 3 most important causal factors in their illness. The first 8 items are rated on a scale from 0 (minimum) to 10 (maximum), and summing up produced the total score ranges from 0 to 80.

The MGLS-4 includes 4 questions with elements of forgetfulness and symptom severity, which are answered in a yes/no format. The score ranges from 0 to 4, with 0 indicating perfect adherence and a score equal to or greater than 1 indicating some degree of non-adherence.15

The SATMED-Q is a self-administered tool with 17 items that evaluates treatment satisfaction in six dimensions: treatment effectiveness, convenience of use, impact on daily activities, medical care, global satisfaction, and undesirable side effects.16 A global score for satisfaction with drug treatment can be obtained by summing the scores of all domains, with scores ranging from 0 to 68, with higher scores indicating higher satisfaction.

PRO-CTCAE is a PRO measurement system developed by the National Cancer Institute of the USA to evaluate symptomatic toxicity in patients in cancer clinical trials. It comprises 124 items representing 78 symptomatic toxicities drawn from the CTCAE. The investigator evaluated the attributes of frequency, severity, interference, amount, and presence/absence (each symptomatic adverse event was assessed by 1–3 attributes depending on the symptom), and 21 toxicities were selected for this study.

Sample size has been calculated assuming a finite population (N=19 141 cases of NSCLC estimated for Spain17), maximum data variability among the participants (p=q=0.5), and a precision error of 10% with a 95% level of confidence. The maximum variability criterion is generally assumed when the final objective is to estimate the proportions.

We applied the following formula18:

Where N is the size of the study population (N=19 141); Zα is 95% of the normal distribution (Zα=1.96); p=q=0.5; e is the precision error (10%).

Under these assumptions, and considering a 10% of losses, the sample size is 106 subjects (18–22 patients/hospital).

The primary outcome is the percentage of treatment adherence that will be calculated based on the pill count as follows: the difference between the number of pills dispensed minus the number of unused pills will be divided by the number of days of treatment multiplied by the number of pills/day prescribed by the oncologist; this quotient will be multiplied by 100 to obtain the percentage of adherence. Those with a percentage adherence >80% will be primarily categorized as adherent. The percentage of treatment adherence will be presented using the mean and standard deviation and the median and interquartile range.

Secondarily, adherence based on a cut-off value of 90% for the pill count will be also calculated. Treatment adherence will be also calculated based on the proportion of days covered (PDC) and the MGLS-4. PDC will be calculated as the number of days the patient was covered by the drug based on the prescription fill date and days of supply divided by the number of days of the treatment period (counted as the number of the index prescription date until the end of the study, study discontinuation, or death); the resultant quotient be multiplied by 100. Patients will be considered adherent if the PDC is ≥80%. Patients will be considered adherent according to the MGLS-4 if the score is 0. The proportion of adherent patients according to dichotomous criteria for each cut-off point of the pill count, PDC, and MGLS-4 will be presented using absolute and relative frequencies with the corresponding 95% confidence interval.

The adherence results will be reported for the overall sample and the following subgroups: first- and second-generation EGFR-TKIs (Erlotinib, Afatinib, and Gefitinib), third-generation EGFR-TKIs (osimertinib), and ALK inhibitors (Alectinib, Crizotinib, and Lorlatinib).

To analyze the impact of patients' and treatment characteristics on adherence, bivariate analyses will be performed using the different cut-off points for adherence to pill count, PDC, and MGLS-4, quantitative variables will be compared using the Student’s t-test or a non-parametric test, and qualitative variables will be compared using the chi-square test. To evaluate the potential relationship between adherence and some PROs, such as health-related quality of life, disease perception, treatment satisfaction, toxicity perception, and health resource utilization, bivariate analyses will be performed in a similar manner. Agreement between the 3 measures of adherence will be evaluated using Fleiss' kappa index. Finally, to evaluate the impact of adherence (i.e., being treatment adherent as defined above) on treatment efficacy as evaluated by progression-free survival, we will be using the Kaplan–Meir method and compare it with the log-rank test and univariate Cox regression analysis.

Statistical analyses will be performed using IBM SPSS Statistics 26.0 or a subsequent version. All comparisons will be considered significant if p<.05.