Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial

PURPOSE This phase III randomized trial ( NCT00954174 ) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION PC was not inferior to the active regimen PI and should be standard treatment for UCS.

Cardiovascular Safety Assessment in Cancer Drug Development

The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer‐specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real‐world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk‐benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early‐phase studies, and design of longitudinal multi‐institutional cardiotoxicity registries.

Unsatisfied Reporting Quality of Clinical Trials Evaluating Immune Checkpoint Inhibitor Therapy in Cancer

BackgroundMore and more immune-oncology trials have been conducted for treating various cancers, yet it is unclear what the reporting quality of immune-oncology trials is,and characteristics associated with higher reporting quality.ObjectiveThis study aims to evaluate the reporting quality of immune-oncology trials.MethodsThe PubMed and Cochrane library were searched to identify all English publications of clinical trials assessing immunotherapy for cancer. Reporting quality of immune-oncology trials was evaluated by a quality score with 11 points derived from the Trial Reporting in Immuno-Oncology (TRIO) statement, which contained two parts: an efficacy score of 6 points and toxicity score of 5 point. Linear regression was used to identify characteristics associated with higher scores.ResultsOf the 10,169 studies screened, 298 immune-oncology trial reports were enrolled. The mean quality score, efficacy score, and toxicity score were 6.46, 3.61, and 2.85, respectively. The most common well-reported items were response evaluation criteria (96.0%) and toxicity grade (98.7%), followed by Kaplan-Meier survival analyses (80.5%). Treatment details beyond progression (12.8%) and toxicity onset time and duration (7.7%) were poorly reported. Multivariate regression revealed that higher impact factor (IF) (IF &gt;20 vs. IF &lt;5, p &lt; 0.001), specific tumor type (p = 0.018 for lung, p = 0.021 for urinary system, vs. pan cancer), and a certain kind of immune checkpoint blocking agent (p &lt; 0.001 for anti-PD-1 or multiagents, vs. anti-CTLA-4) were independent predictors of higher-quality score. Similar independent predictive characteristics were revealed for high-efficacy score. Only IF &gt;20 had a significant high-toxicity score (p &lt; 0.001).ConclusionImmune-oncology trial reports presented an unsatisfied quality score, especially in the reporting of treatment details beyond progression and toxicity onset time and duration. High IF journals have better reporting quality. Future improvement of trial reporting was warranted to the benefit-risk assessment of immunotherapy.

Who Makes It All The Way? Participants Vs. Decliners, And Completers Vs. Drop-Outs, In A 6-Month Exercise Trial During Cancer Treatment. Results From The Phys-Can RCT

Purpose: To compare sociodemographic, health- and exercise-related characteristics of participants vs decliners, and completers vs drop-outs, in an exercise intervention during cancer treatment. Methods: Patients with newly diagnosed breast, prostate or colorectal cancer were invited to participate in a 6-month exercise intervention. Questionnaire, medical record and physical testing data were analyzed for between-group differences using independent t-tests and Chi2-tests. Results: Trial participants (n=577) were younger (59±12 yrs vs 64±11 yrs, p<.001), included more women (80% vs 75%, p=.012) and were scheduled for chemotherapy treatment (54% vs 34%, p<.001) compared to decliners (n=1391). A greater proportion had university education (60% vs 40%, p<.001), reported more anxiety (5.5±4.4 vs 4.3±3.7, p<.001), cancer-related fatigue, exercise self-efficacy (49.9±16.2 vs 45.0±20.1, p<.001), higher outcome expectations and less kinesiophobia (23.5±5.1 vs 24.5±5.0, p=.001) compared to decliners who completed baseline questionnaires (n=436). A greater proportion of participants were classified as ‘not physically active’, however, within the group who participated, more intervention completers were classified as ‘physically active’ at baseline compared to drop-outs. Completers also reported less kinesiophobia than drop-outs. Conclusion: Participants in a comprehensive exercise oncology trial differ in several sociodemographic, health and exercise-related aspects from those declining to participate, while differences between completers and drop-outs are less pronounced. A lack of health-enhancing exercise habits at baseline may be an incentive for accepting participation, while having such habits at baseline may increase the chances of completing exercise intervention trials. The findings provide useful insight for translating research results and planning future exercise interventions for cancer survivors.

The role of digital clinical measures in improving cancer care and research.

e13584 Background: From objectively assessing performance status to recording simple vital signs, the adoption of high quality digital clinical measures offers enormous possibilities for transforming cancer care & research. However, the development & deployment of high quality digital measures in oncology lags behind adoption in other therapeutic areas. At the time of submission, the DiMe library of digital endpoints reports 166 unique digital endpoints being used in industry sponsored trials of new medical products, but none are being used in an oncology trial. There are seven digital clinical measures working their way through the FDA qualification program, but none in oncology. During the pandemic, care for patients with cardiac and other chronic conditions transitioned out of the clinic & into the home powered not only by virtual visits, but high quality information from remote monitoring. A study of oncology care facilities worldwide reported 89% finding difficulty in delivering usual care due to the challenges of safely bringing patients into the clinic during COVID. Methods: From March to Sep 2020, cross-industry stakeholders at the Digital Medicine Society (DiMe), Elektra Labs, Genentech, Koneksa, Myokardia, Sage Bionetworks, Scripps Research, and the US Food & Drug Administration came together to synthesize best practices from the digital health field, breaking down silos to create ‘ The Playbook’, the comprehensive and accessible “how-to” guide to support all stakeholders working to advance the safe, effective, ethical, and equitable use of digital clinical measures to improve lives. In October 2020, DiMe -- a 501c3 non-profit dedicated to advancing digital medicine to improve lives -- convenened a pre-competitive collaboration of 44 participants from 29 organizations to drive the adoption of the best practices articulated in The Playbook. Results: The Playbook describes trans-industry consensus for best practices for developing and deploying digital clinical measures across patient care, clinical research, and public health, including for oncology. Conclusions: The clinical, technical, and operational best practices necessary to develop and deploy high quality digital clinical measures into cancer care & research have been established. There is no reason for their successful adoption in oncology to lag behind other therapeutic areas. The Playbook and additional resources to support implementation due for launch on April 30 are critical tools for the field of oncology.