The hazard ratio (HR) is used routinely to quantify the treatment effect for time-to-event end points in oncology trials, but its use requires that there be proportional hazards in the treatment arms. Non-proportional hazards are observed frequently in cancer immunotherapy trials due to the long-term survival and delayed clinical effect. Although values of HR are quoted in such trials, they are not valid measures of outcome. Reports of parallel group randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors with overall survival data were eligible. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. Twenty-five RCTs totaling 12 870 patients were included in this study. Overall survival was used as primary or coprimary end point in 18 trials (72%). In all trials, there was agreement between the ratio of RMST or RMTL and the reported HR about the direction of treatment effect. Estimates of HR provided larger estimates of treatment effect than the ratio of RMST or RMTL in all these trials. The estimated HR and RMST-based measures were in agreement regarding the statistical significance of the effect in all but two trials. Ratio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.

Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) were released in 2003 and have been used widely to report toxicity in publications or presentations describing cancer clinical trials. Here we evaluate whether guidelines for reporting toxicity are followed in publications reporting randomized clinical trials (RCTs) for cancer. Phase III RCTs evaluating systemic cancer therapy published between 2011 and 2013, were reviewed to identify eligible studies, which stated explicitly that CTCAE v3.0 was used to report toxicity. Each AE term and its grade were located in CTCAE v3.0 to determine if they fell within the guidelines provided in the explanatory file. A total of 166 publications were included in this analysis. Criteria from CTCAE v3.0 were frequently used incorrectly. For example, CATEGORY names such as Metabolic were misreported as AEs in 19 trials, and inappropriate grades for AEs assigned frequently. For example, febrile neutropenia was graded 1 or 2 in 35 of 91 studies (38 %), but the minimum grade for this toxicity is 3. Alopecia was graded 3 or more in 19 of 77 studies (25 %), but the maximum is only grade 2. The present study provides evidence of poor reporting of toxicity in clinical trials. The study provides a lower estimate for the misuse of AE terms and grades, and implies that other AE terms and grades that conform to CTCAE v3.0 guidelines may have been assigned incorrectly. Inaccurate reporting of toxicity in clinical trials can lead clinicians to make inappropriate treatment decisions.

Purpose: Treatment decisions in clinical oncology are guided by results from phase III randomized clinical trials (RCTs). The results of subgroup analyses may be potentially important in individualizing patient care. We investigated the appropriateness of the use and interpretation of subgroup analyses in oncology RCTs on the basis of the CONSORT statement requirements. Methods: Phase III RCTs published between January 1, 2011, and December 31, 2013, were reviewed to identify eligible studies of solid tumor treatments. Information related to the subgroup analyses included prespecification, number, subgroup factors, interaction test use, and claim of subgroup difference. Results: A total of 221 publications reporting data on 184,500 patients were analyzed. One hundred eighty-eight (85%) RCTs were reported with subgroup analyses. Of those, 146 (78%) trials were reported with at least six subgroups. For the majority of trials with subgroup analyses (173; 92%), the actual number of subgroup analyses conducted cannot be determined. Only 59 (31%) RCTs were reported with fully prespecified subgroups and only 64 (34%) trials were reported with interaction tests. In addition, 102 (54%) RCTs were reported with claims of subgroup differences. Of those, only 18 claims of RCTs (18%) were based on significant interaction test results. Conclusion: The reporting of subgroup analyses in contemporary oncology RCTs is neither uniform nor complete; it requires improvement to ensure consistency and to provide critical information for guiding patient care. Major problems include testing of a large number of subgroups, subgroups without prespecifications, and inadequate use of interaction tests.

Case reports, retrospective analyses, and observational studies have linked the use of cisplatin to increased risk of second cancers, especially life-threatening secondary leukemia. We therefore performed a systematic review and meta-analysis to evaluate the risk of second cancers associated with receipt of cisplatin-based chemotherapy in randomized controlled trials (RCTs). We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant RCTs comparing cisplatin- versus non-cisplatin-containing chemotherapy with data on second cancers. We extracted data about study characteristics and second cancers, especially leukemia/ myelodysplasia. The primary and secondary outcomes were the odds ratios (ORs) for all second cancers and for secondary leukemia/ myelodysplasia, respectively. We identified 28 eligible trials with 7403 patients. Second cancers were reported in 143 patients, including 75 patients in the cisplatin arm and 68 in the non-cisplatin arm (raw event rates of 1.91 and 1.96%, respectively). The pooled OR for risk of all second cancers associated with cisplatin-based chemotherapy was 0.95 (95% confidence interval (CI): 0.67–1.33, P = 0.76). Secondary leukemia/ myelodysplasia was reported in 14 patients on cisplatin arms and in 6 patients on non-cisplatin arms of 11 eligible RCTs with 2629 patients (raw event rates of 1.09 and 0.45%, respectively; pooled OR = 2.34, 95%CI 0.97–5.65, P = 0.06). Cisplatin was not associated with a significantly increased risk of second cancers compared with non-cisplatin-based chemotherapy. There is a non-significant trend to increased risk of leukemia/ myelodysplasia and the absolute risk was low. The concern about risk of second cancers should not influence decisions to use an efficacious regimen containing cisplatin.