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Background Previous studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown. Methods We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided. Results We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33–1.28) versus 1.32 (range: 0.86–2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol. Conclusions Despite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed. [ABSTRACT FROM AUTHOR]

Purpose: There currently are no established formal mentorship and training programs for radiation oncology (RO) trainees to learn trial design, creation, writing, or implementation. There only exists informal training on analyzing clinical trials in RO residency programs. The integration of a longitudinal formal training and mentorship program for clinical trialists-consisting of clinical trial education, design, mentorship, and implementation during the RO residency education-will give residents not only formal teaching in the subject but also strong tools and requisite mentorship in hopes to help them succeed as future academic physicians and leaders in the field of RO., Methods and Materials: We developed a clinical trial training pathway in 2018 at MD Anderson Cancer Center, proposing it as a pilot program. The "Fletcher-Cox Pathway" was accepted with a highly positive response by trainees and is now offered as a standard option to RO trainees at our institution., Results: With the guidance of their principal investigator, residents participating in this pathway design and submit a clinical trial for institutional review board review. In 2019, after implementation of the pilot program, 4 of the incoming 7 residents joined the pathway. The program continues, and the current cohort of trainees have received training in clinical trial design and worked with dedicated mentor(s) regarding clinical trial ideas; their studies are currently accruing patients., Conclusions: This pilot program has been viewed by trainees and mentors as successful; it highlights how a structured approach meets a clear need within RO training. We envision the creation of a national platform to increase access, whereby programs adopt this clinical trialist educational pathway, which ultimately leads to the development of a robust clinical trial community with communal resources. We hope that this not only improves and provides educational initiatives to all trainees but also initiates further collaboration., Competing Interests: None., (© 2024 The Authors.)

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Chemoradiation therapy (CRT) is the standard treatment for squamous cell carcinoma of the anus (SCCA). This study aimed to investigate the relationship between vaginal dosimetry and long-term patient-reported dyspareunia after treatment. We further aimed to use the anterior vaginal wall (AVW) as an organ at risk to define an actionable dosimetric clinical goal to decrease the risk of patient-reported dyspareunia., Methods and Materials: Women with SCCA treated with intensity modulated radiation therapy-based CRT were surveyed at least 2 years after successfully completing therapy. A Female Sexual Function Index (FSFI) pain subscore ≤4 was used to define dyspareunia. Dosimetric parameters were calculated for both the full vaginal canal and AVW. Multivariable linear regression models were created to identify predictors of FSFI pain subscore using backward selection to identify final variables include in the models. An actionable dosimetric predictor for dyspareunia was established using the Youden index method for cutoff optimization., Results: Of 184 women who were contacted, 90 (49%) returned completed surveys. Of those who completed surveys, 51 (56.7%) reported being sexually active, and 47 had dosimetric data available for review. Of sexually active respondents, 32 (68%) had an FSFI pain subscore ≤4. Multiple regression models were generated using the full vaginal canal and AVW as organs at risk, and both models showed similar predictive relationships with volumetric dose parameters emerging as the best dosimetric predictors for dysparenuia. Age over 65 years was also associated with higher FSFI pain subscores (eg, less pain with intercourse) in both models. AVW V35 Gy < 60% was identified as the optimal cutoff to reduce the risk of patient-reported dyspareunia., Conclusions: Increased dose to the vaginal canal is significantly associated with worse patient-reported dyspareunia following CRT for SCCA. Minimizing dose to the AVW to V35 Gy < 60% may reduce the risk of this quality of life-limiting toxicity. Further prospective evaluation is needed to validate these findings., Competing Interests: Joshua S. Niedzielski receives unrelated funding from Varian Medical Systems. Albert Koong is a stockholder in Aravive, Inc. All other authors have no disclosures to report., (© 2024 The Author(s).)

Purpose: Comorbidity is an independent predictor of mortality and treatment tolerance in head and neck cancer and should be considered with regard to treatment intensification. Multiple previously validated models can be used to evaluate comorbidity and propensity to benefit from intensive treatment, but they have not been directly compared., Materials and Methods: An online tool was developed and used to calculate the Charlson Comorbidity Index (CCI), Adult Comorbidity Evaluation-27 (ACE-27), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Geriatric 8 (G8), Cancer and Aging Research Group (CARG), and Generalized Competing Event (GCE) scores. To assess interrater variability, five evaluators independently calculated scores on a retrospective cohort of 20 patients. Correlation between models as well as age and performance status were calculated from a cohort of 40 patients., Results: The GCE and G8 models had an excellent (intraclass correlation coefficient and Fleiss' kappa ≥ 0.75) degree of interrater agreement. The CCI, ACE-27, CIRS-G, and CARG had a good (intraclass correlation coefficient and Fleiss' kappa 0.6-0.74) degree of interrater agreement. There was statistically significant correlation between models, especially with the CCI, ACE-27, and CIRS-G indices. Increased age was correlated with an increased CCI score and having moderate to severe comorbidity was correlated with the ACE-27 model. Except for the G8 model, the comorbidity indices were not associated with Eastern Cooperative Oncology Group performance status., Conclusion: We developed an online tool to calculate indices of comorbidity in patients with head and neck cancer with a high degree of reproducibility. Comorbidity is not strongly correlated with performance status and should be independently evaluated in patients.

Microglia are a major cellular component of gliomas, and abundant in the centre of the tumour and at the infiltrative margins. While glioma is a notoriously infiltrative disease, the dynamics of microglia and glioma migratory patterns have not been well characterized. To investigate the migratory behaviour of microglia and glioma cells at the infiltrative edge, we performed two-colour time-lapse fluorescence microscopy of brain slices generated from a platelet-derived growth factor-B (PDGFB)-driven rat model of glioma, in which glioma cells and microglia were each labelled with one of two different fluorescent markers. We used mathematical techniques to analyse glioma cells and microglia motility with both single cell tracking and particle image velocimetry (PIV). Our results show microglia motility is strongly correlated with the presence of glioma, while the correlation of the speeds of glioma cells and microglia was variable and weak. Additionally, we showed that microglia and glioma cells exhibit different types of diffusive migratory behaviour. Microglia movement fit a simple random walk, while glioma cell movement fits a super diffusion pattern. These results show that glioma cells stimulate microglia motility at the infiltrative margins, creating a correlation between the spatial distribution of glioma cells and the pattern of microglia motility., (© 2018 The Author(s).)

Purpose/objectives(s): Early-stage endometrial cancer patients are at higher risk of noncancer mortality than of cancer mortality. Competing event models incorporating comorbidity could help identify women most likely to benefit from treatment intensification., Methods and Materials: 67,397 women with stage I-II endometrioid adenocarcinoma after total hysterectomy diagnosed from 1988 to 2009 were identified in Surveillance, Epidemiology, and End Results (SEER) and linked SEER-Medicare databases. Using demographic and clinical information, including comorbidity, we sought to develop and validate a risk score to predict the incidence of competing mortality., Results: In the validation cohort, increasing competing mortality risk score was associated with increased risk of noncancer mortality (subdistribution hazard ratio [SDHR], 1.92; 95% confidence interval [CI], 1.60-2.30) and decreased risk of endometrial cancer mortality (SDHR, 0.61; 95% CI, 0.55-0.78). Controlling for other variables, Charlson Comorbidity Index (CCI) = 1 (SDHR, 1.62; 95% CI, 1.45-1.82) and CCI >1 (SDHR, 3.31; 95% CI, 2.74-4.01) were associated with increased risk of noncancer mortality. The 10-year cumulative incidences of competing mortality within low-, medium-, and high-risk strata were 27.3% (95% CI, 25.2%-29.4%), 34.6% (95% CI, 32.5%-36.7%), and 50.3% (95% CI, 48.2%-52.6%), respectively. With increasing competing mortality risk score, we observed a significant decline in omega (ω), indicating a diminishing likelihood of benefit from treatment intensification., Conclusion: Comorbidity and other factors influence the risk of competing mortality among patients with early-stage endometrial cancer. Competing event models could improve our ability to identify patients likely to benefit from treatment intensification., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Anaplastic gliomas, the most common and malignant of primary brain tumors, frequently contain activating mutations and amplifications in promigratory signal transduction pathways. However, targeting these pathways with individual signal transduction inhibitors does not appreciably reduce tumor invasion, because these pathways are redundant; blockade of any one pathway can be overcome by stimulation of another. This implies that a more effective approach would be to target a component at which these pathways converge. In this study, we have investigated whether the molecular motor myosin II represents such a target by examining glioma invasion in a series of increasingly complex models that are sensitive to platelet-derived growth factor, epidermal growth factor, or both. Our results lead to two conclusions. First, malignant glioma cells are stimulated to invade brain through the activation of multiple signaling cascades not accounted for in simple in vitro assays. Second, even though there is a high degree of redundancy in promigratory signaling cascades in gliomas, blocking tumor invasion by directly targeting myosin II remains effective. Our results thus support our hypothesis that myosin II represents a point of convergence for signal transduction pathways that drive glioma invasion and that its inhibition cannot be overcome by other motility mechanisms.