CTRI

The study will be conducted as a prospective observational study across a multiple centers in India. Initially the study will start at TMH and subsequently other centers will be included. The eligibility criteria for inclusion in the study are as follows: a clinical diagnosis of NSCLC with advanced (stage IV), the ability to read, write and speak in one of the following Indian languages (Hindi, Marathi, Gujarati, or Indian English)and provide a written informed consent to participate in the study; and no major disabling medical or psychiatric conditions that would substantially impair cognitive functioning . Patients will be instructed to complete the questionnaires themselves before the start of their treatment, before start of 4^th cycle of chemotherapy and 3-4 weeks after 6^th cycle of their chemotherapy during their clinic visits with the treating oncologist. In patients receiving oral TKI QOL will be evaluated at every 2 months, which is the regular follow up period. Patients who demonstrate difficulty in completing the questionnaires can seek assistance from pharmEDGE interviewers who are fluent in all Indian languages at any time during the study by dialing the help-line numbers that will be provided at the bottom of the study questionnaires. The interviewers will then assist the patientâ€™s by conducting the interview with them telephonically and recording their responses. Given that the objective of the study is to evaluate longitudinal changes in QOL within individual patients, we believe that a minimum sample size of 200 patients will be sufficient to evaluate meaningful differences in quality of life over the study time period. We expect that we will be able to recruit this number of patients in 1 year. This is an observational study where the main objective is to monitor changes in QOL within an individual patient, a sample size calculation is not warranted.

3.2.0 HRQOL Assessment

HRQOL will be measured using EORTC QLQ C-30/LC-13 which is validated and used commonly in various studies including randomized controlled trials and observational studies to measure quality of life. The questionnaire will be administered in an electronic format and will completed by patients during their clinic visit. The EORTC QOL Core Questionnaire (EORTC QLQ-C30) is a cancer-speciï¬c 30-item questionnaire used for assessing HRQOL and has been widely used in clinical trials. The scale includes 24 questions from nine multi item scales presenting various aspects of HRQOL, whereas the remaining six scales are single-item scales describing different cancer-relevant symptoms. The ï¬ve functional scales include questions that assess physical functioning, role functioning; emotional functioning, cognitive functioning, and social functioning. The nine symptoms scales assess fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and ï¬nancial difficulties and a global health status scale. In addition, EORTC features a speciï¬c lung cancer module (LC13) that includes 10 scales that address various symptoms such as dyspnea, coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, and pain in other parts. These instruments are translated and validated in 11 Indian languages (Bengali, English, Gujarati, Hindi, Kannada, Malayalam, Marathi, Punjabi, Tamil, Telugu, and Urdu).^13-16

Data Analyses

Patient characteristics will be summarized using descriptive statistics such as mean, median, or mode. Changes in HRQOL scores during the study will be calculated as the difference between baseline and last follow-up value and compared using the paired t test.Effect sizes will be calculated by dividing the changes in each HRQOL score by the standard deviation (SD) of that score estimated at baseline on the entire sample. To account for the hierarchical nature of the data (repeated measurements within patients) and to control simultaneously for the possible confounding effects of the different variables, multivariate multilevel linear models will be utilized. In this longitudinal analyses, which will evaluate factors associated with a decline in HRQOL measures, multilevel methods will allow to appropriately model within- and between-patient variability. Results from these multivariate models will be expressed in terms of standardized Î² parameters with the relative P value. Standardized Î² parameters indicate the changes over time in QoL measures with respect to baseline for patients. For the second objective Cox proportional hazards model will be used to assess the relative risk of survival in terms of the HRQOL instrument. The QLQ C-30 and LC-13 will be categorized according to their tertiles. The single-item symptom scales will be dichotomized. We will then evaluate the crude risk of survival separately for each scale, and then with variables such as age, gender, stages of cancer, treatment type, and duration of cancer. Continuous variables of the QLQ C-30

and LC-13 scales will be used to test linear trends. All analyses will be conducted using SAS, version 9.1 (SAS Institute Inc. Cary NC).