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Background Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes. Materials and Methods A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed; patients with BrM-BTC were identified, and clinical and molecular data were collected. Results Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis and 3.1 months after BrM diagnosis. Median time from primary diagnosis to diagnosis of BrM was 14.4 [range, 1.1-66.0] months. Median overall survival (OS) from primary diagnosis was 31.5 [2.9-99.8] months and median OS from BrM diagnosis was 4.2 [0.2-33.8] months. Patients who underwent BrM-directed therapy trended toward longer OS following BrM diagnosis than patients receiving supportive care only (median 6.5 vs 0.8 months, P = .060). The BrM-BTC cohort was enriched for BRAF (30%), PIK3CA (25%), and GNAS (20%) mutations. patients with BrM-BTC with BRAF mutations trended toward longer OS following BrM diagnosis (median 13.1 vs 4.2 months, P = .131). Conclusion This is the largest series of patients with BrM-BTC to date and provides molecular characterization of this rare subgroup of patients with BTC. Patients with BrM-BTC may be more likely to have BRAF mutations. With advances in targeted therapy for patients with BTC with actionable mutations, continued examination of shifting patterns of failure, with emphasis on BrM, is warranted.

Short course radiation-based total neoadjuvant therapy can improve disease-free survival for patients with high-risk locally advanced rectal cancer. Tumors that involve or threaten the circumferential resection margin have a particularly high risk of local recurrence. Intraoperative radiation therapy enables treatment escalation at the threatened or involved margin at the time of surgery.Patients with rectal adenocarcinoma treated with preoperative short course radiotherapy-based total neoadjuvant therapy and intraoperative radiation at the time of surgery were identified. All patients had a threatened or involved circumferential resection margin on magnetic resonance imaging at the time of diagnosis. Treatment details, radiation toxicities, postoperative complications and oncologic outcomes were recorded.Ten patients received intraoperative radiation after short course radiation-based total neoadjuvant therapy. All patients had an involved or threatened circumferential resection margin, 60% had extramural venous invasion, and 60% had positive lateral pelvic lymph nodes. Seven patients had negative surgical margins (≥ 2 mm), and 3 patients had an R1 resection with radial margins2 mm. The median [IQR] length of hospitalization after surgery was 11 [7-14] days. Three patients required readmission and 2 patients required reoperation due to complications including anastamotic leak and abscess. With a median follow up of 19.5 months postoperatively, no patient developed a pelvic recurrence, and 6 patients developed distant recurrences.The use of intraoperative radiation after a short course radiotherapy-based neoadjuvant therapy is safe and feasible. Further data are needed to determine whether the addition of intraoperative radiation improves local recurrence rates over preoperative radiation alone.

Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs).We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). Models were used to determine the association between demographic, tumor, treatment, and dosimetric data with PROs.One hundred twelve (45%) patients completed PROs. Median [interquartile range (IQR)] time from radiation completion to survey was 51 [37-85] months. The median scores [IQR] for FACT-G7, FIQoL, and LARS were 21 [15-24], 14 [11-16], and 32 [25-37], respectively. For men, median subscores [IQR] for ICIQ voiding and incontinence subscores were 5 [2-6] and 1 [1-3], respectively. For women, median subscores [IQR] for ICIQ voiding, incontinence, and filling were 1 [1-3], 5 [3-8], and 4 [2-5], respectively. Higher (better) FIQoL scores were associated with higher (better) FACT-G7 scores (β = 0.83; 95% confidence interval, 0.58-1.09; P.001), and higher (worse) LARS scores were associated with lower (worse) FACT-G7 scores (β = -0.22; 95% confidence interval, -0.31 to -0.13; P.001). A separate multivariable analysis revealed higher bowel bag D1% was associated with lower (worse) FIQoL (P = .001) and higher (worse) LARS (P = .003) scores. Higher bladder V40 Gy was associated with increased (worse) ICIQ voiding subscore (P = .001).Patients treated with modern chemoradiation for SCCA experience significant long-term bowel toxic effects with considerable effect on quality of life. Minimizing bowel hotspots and bladder V40 Gy may improve bowel and urinary function. Other interventions to reduce long-term toxic effects and improve quality of life are needed.

Background Although intensity-modulated radiation therapy (IMRT) is considered the standard of care for the treatment of squamous cell carcinoma of the anus (SCCA), few large series have reported oncologic outcomes and toxicities. In this retrospective report, we aim to describe outcomes and toxicities after IMRT-based chemoradiation (CRT) for the treatment of SCCA, evaluate the impact of dose escalation (>54 Gy), and compare concurrent fluoropyrimidine in combination with either mitomycin or with cisplatin as chemosensitizers. Methods Patients treated at The University of Texas MD Anderson Cancer Center between January 1, 2003 and December 31, 2018 with IMRT-based CRT were included. Median time to locoregional recurrence, time to colostomy, and overall survival were estimated using the Kaplan–Meier method. Results A total of 428 patients were included; median follow-up was 4.4 years. Three hundred and thirty-four patients (78.0%) were treated with concurrent cisplatin and fluoropyrimidine, and 160 (37.4%) with >54 Gy. Two- and 5-year freedom from locoregional failure, freedom from colostomy failure, and overall survival were 86.5% and 81.2%, respectively, 90.0% and 88.3%, respectively, and 93.6% and 85.8%, respectively. Neither dose escalation nor mitomycin-based concurrent chemotherapy resulted in improved outcomes. Mitomycin-based concurrent chemotherapy was associated with in approximately 2.5 times increased grade 3 or greater acute toxicity. Radiation dose >54 Gy was associated with approximately 2.6 times increased Grade 3 or greater chronic toxicity. Conclusions Our results suggest IMRT-based CRT with concurrent fluoropyrimidine and cisplatin is a safe and feasible option for patient with SCCA and may cause less acute toxicity. The role for radiation dose escalation is unclear and requires further study.

Purpose Quality assurance (QA) practices improve the quality level of oncology trials by ensuring that the protocol is followed and the results are valid and reproducible. This study investigated the utilization of QA among randomized controlled trials that involve radiotherapy (RT). Methods and Materials We searched ClinicalTrials.gov in February 2020 for all phase III oncology randomized clinical trials (RCTs). These trials were screened for RT-specific RCTs that had published primary trial results. Information regarding QA in each trial was collected from the study publications and trial protocol if available. Two individuals independently performed trial screening and data collection. Pearson’s Chi-square tests analyses were used to assess factors that were associated with QA inclusion in RT trials. Results Forty-two RCTs with RT as the primary intervention or as a mandatory component of the protocol were analyzed; the earliest was started in 1994 and one trial was still active though not recruiting. Twenty-nine (69%) trials mandated RT quality assurance (RTQA) practices as part of the trial protocol, with 19 (45%) trials requiring institutional credentialing. Twenty-one (50%) trials published protocol deviation outcomes. Clinical trials involving advanced radiation techniques (IMRT, VMAT, SRS, SBRT) did not include more RTQA than trials without these advanced techniques (73% vs. 65%, p=0.55). Trials that reported protocol deviation outcomes were associated with mandating RTQA in their protocols as compared to trials that did not report these outcomes (100% vs. 38%, p Conclusions There is a lack of RTQA utilization and transparency in RT clinical trials. It is imperative for RT trials to include increased QA for safe, consistent, and high-quality RT planning and delivery.

PURPOSE Local consolidative therapy (LCT) for patients with synchronous oligometastatic non–small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients. METHODS We identified all patients presenting between 2000 and 2017 with stage IV non–small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis. RESULTS Of 194 included patients, 121 received comprehensive LCT to all sites of disease with either surgery or radiation. TP53 mutations were identified in 40 of 78 (55%), KRAS in 32 of 95 (34%), EGFR in 24 of 109 (22%), and STK11 in nine of 77 (12%). At median follow-up of 96 months, median OS and PFS were 26 (95% CI, 23 to 31) months and 11 (95% CI, 9 to 13) months, respectively. On multivariable analysis, patients with EGFR mutations had lower mortality risk (hazard ratio [HR], 0.53; 95% CI, 0.29 to 0.98; P = .044) compared with wild-type patients, and patients with STK11 mutations had higher risk of progression or mortality (HR, 2.32; 95% CI, 1.12 to 4.79; P = .023) compared with wild-type patients. TP53 and KRAS mutations were not associated with OS or PFS. Among 71 patients with known EGFR mutational status who received comprehensive LCT, EGFR mutations were associated with lower mortality compared with wild-type (HR, 0.45; 95% CI, 0.22 to 0.94; P = .032). CONCLUSION When compared with wild-type patients, those with EGFR and STK11 mutations had longer OS and shorter PFS, respectively. EGFR mutations were associated with longer OS among oligometastatic patients treated with comprehensive LCT in addition to systemic therapy.

PURPOSE/OBJECTIVES: To estimate the effects of interfractional anatomic changes on dose to organs-at-risk (OARs) and tumors, as measured with cone-beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiotherapy (SBRT). MATERIALS/METHODS: We evaluated 11 patients with pancreatic cancer, whom were treated with SBRT (33–40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR datasets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface (TVI), duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms (DVHs) into a single DVH for comparison with the original planned dose. RESULTS: Four patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm(3)

Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.

Background Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints. Methods We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards. Results Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasis-free survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively. Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophil-lymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively. Conclusions Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophil-lymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.

Local consolidative therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment paradigm. We investigated whether the biologically effective dose (BED) of consolidative radiation therapy (RT) to the primary tumor predicted for improved local control, progression-free survival (PFS), and overall survival (OS) among NSCLC patients presenting with oligometastatic disease.Patients presenting to a single institution (2000-2017) with stage IV NSCLC, ≤3 synchronous metastatic lesions at diagnosis, and treated with RT to the primary tumor were identified. Univariate and multivariable Cox proportional-hazards regression modeling were performed to identify factors associated with local recurrence-free survival (LRFS), PFS, and OS.One hundred twenty-four patients were identified meeting our inclusion criteria. With a median follow-up of 55.1 months, median PFS and OS for the entire cohort were 11.0 months and 25.3 months, respectively. The median BED (α/β = 10) of RT to the primary tumor was 74.3 Gy. On univariate analysis, increased BED to the primary tumor predicted for improved PFS (p 0.001) and LRFS (p = 0.01), with a median PFS of 8.5 vs 12.8 months and median LRFS of 23.4 vs 58.4 months between patients treated with BED 75 Gy and ≥75 Gy, respectively. Increased BED to the primary tumor was also associated with significantly improved OS (p = 0.02); patients treated with a BED of75 Gy demonstrated a median OS of 22.9 months vs 27.5 months if treated with BED ≥ 75 Gy. On multivariable analysis, primary site BED remained a significant predictor of OS (p = 0.02) and PFS (p = 0.002).We found that delivery of75 Gy BED RT regimens to the primary lesion in patients with synchronous oligometastatic NSCLC is associated with improved local control, PFS, and OS. These data support results of recent prospective trials and other ongoing prospective efforts to characterize therapeutic benefits associated with this management strategy.

Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients.In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χOverall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P.001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P.001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients.In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.

Purpose: Journal impact factor (IF) is often used to measure research quality and importance. We assessed trial factors associated with the publication of cancer trials in journals with higher IF and publications receiving higher citations. Materials and Methods: Cancer-specific phase III RCTs were screened through https://clinicaltrials.gov. We identified trials with published primary endpoints, along with their corresponding journal IF and relative citation ratio (RCR). Results: Seven-hundred ninety manuscripts were included in our study. Trials that met their primary endpoint were more commonly published in journals with higher IF (Median IF: positive trials 35.4 vs. negative trials 26.3, P < 0.001). Furthermore, trials that led to subsequent FDA drug approvals were also published in journals with higher IF (Median IF: 59.1 vs. 26.3 in trials not leading to FDA approvals, P < 0.001). When analyzing RCR, trial positivity (meeting primary endpoint) was not associated with increased citations on multivariable analysis (P = 0.56). Lastly, publications of trials leading to FDA approvals (P < 0.001), and publications of trials in journals with higher IF (P < 0.001) were associated with increased RCR. Conclusions: Positive trials are commonly published in journals with high IF, but do not necessarily lead to increased citations. Moreover, trials published in journals with higher IF are more likely to receive increased citations.

Financial conflicts of interest (FCOIs) could bias the potentially practice-changing oncologic randomized clinical trials (RCTs) of tomorrow. This investigation characterized the FCOIs of the principal investigators (PIs) of all currently accruing trials of the four (adult) cooperative groups of the National Clinical Trials Network. For this study, the PI list was first compiled, and each name was then searched in the CMS Open Payments database. For each transaction (general payments (GPs) or research funding (RF)), the amount/number/source of payments was recorded. Results showed that from 2014-2019, the 91 PIs collectively accepted nearly one-third of a billion dollars ($10 477 023 GPs and $320 096 233 RF). The mean and median GP was $6505 and $945 respectively, and $301 693 and $49 824 RF respectively. Multivariable Gamma regression analysis revealed that higher GP sums were associated with RCTs involving any type of systemic therapy, and higher RF sums with medical oncologist PIs, trials with phase III components, and RCTs involving radiotherapy (P < 0.05 for all). Both higher-volume GPs and RF were predicted by PIs having accepted payment(s) from the manufacturer of the drug utilized in their RCT (P < 0.001 GP, P = 0.008 RF). Taken together, the main message of this investigation is that FCOIs may be particularly high in PIs of phase III systemic therapy trials, especially if the PI accepted payments from the manufacturer of the drug utilized in their trial. Such RCTs should be thoroughly scrutinized by medical journals, the FDA, and insurance companies for potential “industry bias” that could influence the integrity of their conclusions. This article is protected by copyright. All rights reserved.

Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.

There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer.The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3-4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated.In the development cohort, 155 patients developed grade 3-4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.

ImportancePrimary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity).ObjectivesTo assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity.Design, Setting, and ParticipantsThis cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020.Main Outcomes and MeasuresThe main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity.ResultsOf 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P χ2 = 18.7; P P = .003).Conclusions and RelevanceThis cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.

This cohort study assesses the relative stability of median and mean survival time estimates reported in cancer clinical trials.

BACKGROUND Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low-grade glioma. Despite favorable survival, location makes treatment difficult and local progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades. METHODS Clinical characteristics were abstracted for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3- to 6-month intervals were examined with age-appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan-Meier blindness-free survival (BFS) curves, calculated as time-to-bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first-line salvage treatment) or chemotherapy (CT) and evaluated using the log-rank test. RESULTS Thirty-eight patients with a median follow-up of 8.5 years (range, 2-17 years) were identified. Median age at diagnosis was 3 years (interquartile range

Purpose Pediatric patients with rhabdomyosarcoma (RMS) are treated with multimodal therapy, often with radiation therapy (RT) as part of local therapy. We report on the efficacy and patterns of failure after proton beam therapy (PBT) for RMS. Methods and Materials Between January 2006 and February 2017, patients with RMS were enrolled in a prospective institutional review board–approved registry protocol for pediatric patients undergoing PBT. Demographics, clinical characteristics, and treatment related outcomes were reviewed. Results Ninety-four RMS patients were treated with a combination of chemotherapy (CT) and PBT. The majority of patients had head and neck (49%) and genitourinary (30%) primaries. Median tumor size was 4.1 cm (range, 1.0-16.5 cm); 33 patients (35%) had primary tumors >5 cm. Median cyclophosphamide equivalent dose was 14.4 g/m2 (range, 0-30.8 g/m2). Median time from CT initiation to RT initiation was 13 weeks (range, 1-58 weeks). With median follow-up of 4 years, 4-year overall survival (OS) was 71%, and 4-year progression-free survival (PFS) was 63%. Thirty patients (32%) experienced relapse (13% with local failure [LF]). Four-year local control (LC) was 85% overall; 4-year LC rates were 100% for low-risk, 85% for intermediate-risk, and 55% for high-risk patients (P = .02). Tumor size predicted LC (P = .007), with 7% versus 33% LF rate by tumor size (≤5 cm vs >5 cm). Delayed RT delivery (≥13 weeks from initiation of CT) predicted worse LC (P = .01). Increased tumor size predicted both inferior PFS (P = .02) and OS (P = .01). Delayed RT delivery predicted both inferior PFS (P = .04) and OS (P = .03). Conclusions PBT provides LC comparable to prior studies using photon RT. Inferior LC, PFS, and OS rates were observed for patients with larger tumors and those treated with delayed RT. This finding supports ongoing prospective efforts to dose-escalate treatment of tumors >5 cm; however, these data call into question the optimal timing of local therapy, particularly for patients treated with reduced-dose cyclophosphamide.

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (D...

The purposes of this study were to develop and integrate a colorectal model that incorporates anatomical variations of pediatric patients into the age-scalable MD Anderson Late Effects (MDA-LE) computational phantom, and validate the model for pediatric radiation therapy (RT) dose reconstructions.Colorectal contours were manually derived from whole-body non-contrast computed tomography (CT) scans of 114 pediatric patients (age range: 2.1-21.6 years, 74 males, 40 females). One contour was used for an anatomical template, 103 for training and 10 for testing. Training contours were used to create a colorectal principal component analysis (PCA)-based statistical shape model (SSM) to extract the population's dominant deformations. The SSM was integrated into the MDA-LE phantom. Geometric accuracy was assessed between patient-specific and SSM contours using several overlap metrics. Two alternative colorectal shapes were generated using the first 17 dominant modes of the PCA-based SSM. Dosimetric accuracy was assessed by comparing colorectal doses from test patients' CT-based RT plans (ground truth) with reconstructed doses for the mean and two alternative models in age-matched MDA-LE phantoms.When using all 103 PCA modes, the mean (min-max) Dice similarity coefficient, distance-to-agreement and Hausdorff distance between the patient-specific and reconstructed contours for the test patients were 0.89 (0.85-0.91), 2.1 mm (1.7-3.0), and 8.6 mm (5.7-14.3), respectively. The average percent difference between reconstructed and ground truth mean and maximum colorectal doses for the mean (alternative 1, 2) model were 6.3% (8.1%, 6.1%) and 4.4% (4.3%, 4.7%), respectively.We developed, validated and integrated a colorectal PCA-based SSM into the MDA-LE phantom and demonstrated its dosimetric performance for accurate pediatric RT dose reconstruction.