Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer: A Systematic Review and Meta-analysis.

Importance: The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. Objective: To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. Data Sources: In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Study Selection: Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Data Extraction and Synthesis: Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Main Outcomes and Measures: Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. Results: In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. Conclusions and Relevance: This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

Analysis of wait times and costs during the peri-diagnostic period for non-small cell lung cancer.

PURPOSE: To determine the wait times and healthcare costs around the time of non-small cell lung cancer (NSCLC) diagnosis for a large, population-based cohort of patients. METHODS: Data on baseline demographics, diagnostic and staging tests, timelines of investigations, and frequency of physician visits and hospital admissions were obtained from a provincial cancer registry and health administrative databases for 2852 patients, who were diagnosed with NSCLC from 1996 to 2000 in Manitoba, Canada. Dates between investigations were used to determine wait times surrounding diagnosis and fee codes for physician and hospital services were used to estimate costs. RESULTS: The median wait times from chest x-ray to chest computed tomography (CT) scan and from CT scan to definitive histological diagnosis were 8 (inter-quartile range 1-25) and 18 (inter-quartile range 3-42) days, respectively. At least 25% of patients waited more than 55 days from initial suspicion on chest x-ray to final diagnosis of NSCLC. The mean cost per case of NSCLC diagnosis was $6,978 (in Canadian dollars) where the majority of expenses was attributed to hospital admissions and repeated physician visits before a diagnosis was confirmed. CONCLUSIONS: Despite clinical suspicion for NSCLC, a significant number of patients wait more than 8 weeks for a definitive diagnosis. Substantial costs are incurred by the Canadian universal healthcare system in the months surrounding diagnosis. Establishment of more efficient and cost-effective healthcare delivery in the peri-diagnostic time period may benefit the system as well as the patients.