Secondary Endpoint Utilization and Publication Rate among Phase III Oncology Trials.

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design. SIGNIFICANCE: In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes).

A Comprehensive Survey of 2024 Funding for Radiation Oncology Visiting Medical Student Electives.

Visiting electives provide an opportunity for medical students to engage with radiation oncology (RO) programs, likely influencing residency match outcomes. However, some student's out-of-pocket costs may be prohibitive, and in attempts to offset the financial burden of visiting electives, particularly for students underrepresented in medicine (URiM), some institutions offer scholarships. Here, we characterized the current domestic landscape of funded RO electives. Visiting electives were identified through the FREIDA and VSLO databases in April 2024. Funded elective availability and departmental characteristics were identified via internet search by two independent reviewers. Fisher's exact test was used to determine whether there was a difference in the distribution of scholarships across the US due to the small sample size. Ninety-two visiting electives were identified, with 40 programs offering URiM elective scholarships (43.5%). Twelve (30%) were funded specifically by RO departments, and 28 (70%) were part of broader institutional URiM scholarship initiatives. The median stipend provided was $2000 (IQR $500), range $1000-$5000. Analysis of scholarships by US census division and metro area revealed unequal distribution. Electives in New England, Mountain, and East North Central divisions had higher funding proportion compared to electives in the East South Central, West South Central, and Middle Atlantic divisions. Only 1/9 electives in New York City were funded compared with 4/6 in Los Angeles. Departments with funded electives had more faculty physicians and medical residents. In our review of the 2024 landscape, over 40% of RO electives offer financial support. However, we identified geographical disparities in the distribution of scholarships, highlighting the need for interventions to address unequal access to a wide array of training programs. Our study represents a valuable resource for students interested in RO and highlights the continued need to positively contribute to increasing diversity in the field. Future work exploring the impact of funded electives is needed.

Fallacy of attributing the U.S. firearm mortality epidemic to mental health.

BACKGROUND: Annual global data on mental disorders prevalence and firearm death rates for 2000-2019, enables the U.S. to be compared with comparable counties for these metrics. METHODS: The Institute for Health Metrics and Evaluation (IHME) Global Health Burden data were used to compare the prevalence of mental disorders with overall, homicide and suicide firearm death rates including homicides and suicides, in high sociodemographic (SDI) countries. RESULTS: Overall and in none of the nine major categories of mental disorders did the U.S. have a statistically-significant higher rate than any of 40 other high SDI countries during 2019, the last year of available data. During the same year, the U.S. had a statistically-significant higher rate of all deaths, homicides, and suicides by firearm (all p<<0.001) than all other 40 high SDI countries. Suicides accounted for most of the firearm death rate differences between the U.S. and other high SDI countries, and yet the prevalence of mental health disorders associated with suicide were not significantly difference between the U.S. and other high SDI countries. CONCLUSION: Mental disorder prevalence in the U.S. is similar in all major categories to its 40 comparable sociodemographic countries, including mental health disorders primarily associated with suicide. It cannot therefore explain the country's strikingly higher firearm death rate, including suicide. Reducing firearm prevalence, which is correlated with the country's firearm death rate, is a logical solution that has been applied by other countries.

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials.

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

Proportional Hazards Violations in Phase 3 Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

BACKGROUND: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHVs) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase 3 oncology trials and assess the utility of restricted mean survival time (RMST) and MaxCombo as additional analyses. METHODS: Clinicaltrials.gov and PubMed were searched to identify 2-arm, randomized, phase 3 superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. RESULTS: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 (23.8%; 95%CI 19.7%, 28.5%) comparisons. In multivariable analysis, non-OS endpoints (odds ratio [OR] 2.16 [95%CI 1.21, 3.87]; P=.009) were associated with higher odds of PHVs, and immunotherapy comparisons (OR 1.94 [95%CI 0.98, 3.86]; P=.058) were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) pre-specified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with RMST or MaxCombo, of which ten (71%) reported negative results. CONCLUSION: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting non-proportional hazards to be misinterpreted.

Disease Site Specialization in the Academic Radiation Oncology Workforce: Evidence of Gender Differences.

PURPOSE: Because some stakeholders within medicine seek to diversify and attain greater workforce equity, it is critical to understand gender-based divisions within specialization. Radiation oncology (RO) has one of the smallest proportions of women representation of all specialties, and to our knowledge, no prior studies have investigated gender differences in all the disease site specializations within RO. Thus, we analyzed the relationship between gender and disease site(s) treated in academic RO (ARO). METHODS AND MATERIALS: Faculty gender and disease site(s) treated by faculty from ARO departments were collected via publicly available department websites in January 2020. X2 analyses were conducted to assess differences between the proportions of women faculty treating each disease site. RESULTS: Of 1337 ARO faculty, 408 (30.5%) were identified as women. Breast, gynecology, and pediatrics had the largest proportions of women faculty (all >40%; P < .001). A majority (53%; P < .001) of women ARO faculty treated breast. Genitourinary, thoracic, and head and neck had the smallest proportions of women faculty (all <25%; P < .001). Women ARO faculty were twice as likely to treat breast and gynecologic malignancies compared with men faculty (risk ratio [RR] with 95% CI, 2.01 [1.75-2.50]; P < .001 and RR [95% CI], 2.06 [1.72-2.79]; P <.001, respectively). Men ARO faculty were 3 times more likely to treat genitourinary cancer compared with women faculty (RR [95% CI], 0.40 [0.34-0.48]; P < .001). There was no difference in the mean number of disease sites treated between women and men ARO faculty (2.63 vs 2.53; P = .29). CONCLUSIONS: Gender differences in disease site specialization were observed in ARO. Future research into the drivers of disease site selection should be explored.

Anesthetic Oxygen Use and Sex Are Critical Factors in the FLASH Sparing Effect.

Purpose: Ultra High Dose-Rate (UHDR) radiation has been reported to spare normal tissue, compared with Conventional Dose-Rate (CDR) radiation. However, important work remains to be done to improve the reproducibility of the FLASH effect. A better understanding of the biologic factors that modulate the FLASH effect may shed light on the mechanism of FLASH sparing. Here, we evaluated whether sex and/or the use of 100% oxygen as a carrier gas during irradiation contribute to the variability of the FLASH effect. Methods and Materials: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary postradiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female), skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: Neither supplemental oxygen nor sex affected time to ulceration in CDR irradiated mice. In the UHDR group, skin damage occured earlier in male and female mice that received 100% oxygen compared room air and female mice ulcerated sooner than male mice. However, there was no significant difference in time to ulceration between male and female UHDR mice that received room air. Oxygen measurements showed that tissue oxygenation was significantly higher when using 100% oxygen as the anesthesia carrier gas than when using room air, and female mice showed higher levels of tissue oxygenation than male mice under 100% oxygen. Conclusions: The skin FLASH sparing effect is significantly reduced when using oxygen during anesthesia rather than room air. FLASH sparing was also reduced in female mice compared to male mice. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

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.

Tratamiento del cáncer mamario metastásico / Metastasic breast cancer treatment

En los Estado Unidos se diagnostican cada año aproximadamente 150.000 nuevos casos de cáncer mamario y la mayoria de las pacientes tarde o temprano secumben a la enfermedad. De cada diez mujeres con riesgo, una llega a sufrir este tipo de cáncer, que casi siempre se presenta como enfermedad localizada a un seno (sin compromiso de los ganglios axilares) en el momento del diagnóstico. Un infortunado 10 por ciento de las pacientes presenta ya esta enfermedad metatástica. Muchas mujeres con cáncer mamario se someten a tratamiento quirúrgico primario aparentemente exitoso, sólo para sufrir una "recaida" más tarde. La quimioterapia combinada y las manipulaciones hormonales apropiadas han prolongado la sobrevida de muchas mujeres. La radioterapia dirigida específicamente al sitio del tumor y la resección quirúrigica también puede ser benéricas para determinadas pacientes con cáncer mamario metastásico.