2023 Radiation oncology highlights.

Radiation oncology plays an important role in the local treatment of cancers. Understanding recent advances in the application of radiation therapy to solid tumors is important for all disciplines. The radiation oncology section editors for this journal have selected the following articles for their overall significance, relevance to surgical oncologists, and to illustrate important concepts within the practice of radiation oncology.

Automatic end-to-end VMAT treatment planning for rectal cancers.

BACKGROUND: The treatment planning process from segmentation to producing a deliverable plan is time-consuming and labor-intensive. Existing solutions automate the segmentation and planning processes individually. The feasibility of combining auto-segmentation and auto-planning for volumetric modulated arc therapy (VMAT) for rectal cancers in an end-to-end process is not clear. PURPOSE: To create and clinically evaluate a complete end-to-end process for auto-segmentation and auto-planning of VMAT for rectal cancer requiring only the gross tumor volume contour and a CT scan as inputs. METHODS: Patient scans and data were retrospectively selected from our institutional records for patients treated for malignant neoplasm of the rectum. We trained, validated, and tested deep learning auto-segmentation models using nnU-Net architecture for clinical target volume (CTV), bowel bag, large bowel, small bowel, total bowel, femurs, bladder, bone marrow, and female and male genitalia. For the CTV, we identified 174 patients with clinically drawn CTVs. We used data for 18 patients for all structures other than the CTV. The structures were contoured under the guidance of and reviewed by a gastrointestinal (GI) radiation oncologist. The predicted results for CTV in 35 patients and organs at risk (OAR) in six patients were scored by the GI radiation oncologist using a five-point Likert scale. For auto-planning, a RapidPlan knowledge-based planning solution was modeled for VMAT delivery with a prescription of 25 Gy in five fractions. The model was trained and tested on 20 and 34 patients, respectively. The resulting plans were scored by two GI radiation oncologists using a five-point Likert scale. Finally, the end-to-end pipeline was evaluated on 16 patients, and the resulting plans were scored by two GI radiation oncologists. RESULTS: In 31 of 35 patients, CTV contours were clinically acceptable without necessary modifications. The CTV achieved a Dice similarity coefficient of 0.85 (±0.05) and 95% Hausdorff distance of 15.25 (±5.59) mm. All OAR contours were clinically acceptable without edits, except for large and small bowel which were challenging to differentiate. However, contours for total, large, and small bowel were clinically acceptable. The two physicians accepted 100% and 91% of the auto-plans. For the end-to-end pipeline, the two physicians accepted 88% and 62% of the auto-plans. CONCLUSIONS: This study demonstrated that the VMAT treatment planning technique for rectal cancer can be automated to generate clinically acceptable and safe plans with minimal human interventions.

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

Prevalence, trends, and characteristics of trials investigating local therapy in contemporary phase 3 clinical cancer research.

BACKGROUND: Although most patients with cancer are treated with local therapy (LT), the proportion of late-phase clinical trials investigating local therapeutic interventions is unknown. The purpose of this study was to determine the proportion, characteristics, and trends of phase 3 cancer clinical trials assessing the therapeutic value of LT over time. METHODS: This was a cross-sectional analysis of interventional randomized controlled trials in oncology published from 2002 through 2020 and registered on ClinicalTrials.gov. Trends and characteristics of LT trials were compared to all other trials. RESULTS: Of 1877 trials screened, 794 trials enrolling 584,347 patients met inclusion criteria. A total of 27 trials (3%) included a primary randomization assessing LT compared with 767 trials (97%) investigating systemic therapy or supportive care. Annual increase in the number of LT trials (slope [m] = 0.28; 95% confidence interval [CI], 0.15-0.39; p < .001) was outpaced by the increase of trials testing systemic therapy or supportive care (m = 7.57; 95% CI, 6.03-9.11; p < .001). LT trials were more often sponsored by cooperative groups (22 of 27 [81%] vs. 211 of 767 [28%]; p < .001) and less often sponsored by industry (5 of 27 [19%] vs. 609 of 767 [79%]; p < .001). LT trials were more likely to use overall survival as primary end point compared to other trials (13 of 27 [48%] vs. 199 of 767 [26%]; p = .01). CONCLUSIONS: In contemporary late-phase oncology research, LT trials are increasingly under-represented, under-funded, and evaluate more challenging end points compared to other modalities. These findings strongly argue for greater resource allocation and funding mechanisms for LT clinical trials. PLAIN LANGUAGE SUMMARY: Most people who have cancer receive treatments directed at the site of their cancer, such as surgery or radiation. We do not know, however, how many trials test surgery or radiation compared to drug treatments (that go all over the body). We reviewed trials testing the most researched strategies (phase 3) completed between 2002 and 2020. Only 27 trials tested local treatments like surgery or radiation compared to 767 trials testing other treatments. Our study has important implications for funding research and understanding cancer research priorities.

Brain Metastases from Biliary Tract Cancer: Case Series and Clinicogenomic Analysis.

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.

Clinical Impact of Positive Surgical Margins in Gastric Adenocarcinoma in the Era of Preoperative Therapy.

BACKGROUND: Microscopically positive (R1) surgical margins after gastrectomy increase gastric cancer recurrence risk, but optimal management after R1 gastrectomy is controversial. We sought to identify the impact of R1 margins on recurrence patterns and survival in the era of preoperative therapy for gastric cancer. METHODS: Patients who underwent gastrectomy for adenocarcinoma during 1998-2017 at a major cancer center were enrolled. Clinicopathologic factors associated with positive margins were examined, and incidence, sites, and timing of recurrence and survival outcomes were compared between patients with positive and negative margins. RESULTS: Of 688 patients, 432 (63%) received preoperative therapy. Thirty-four patients (5%) had R1 margins. Compared with patients with negative margins, patients with R1 margins more frequently had aggressive clinicopathologic features, such as linitis plastica (odds ratio [OR] 7.79, p < 0.001) and failure to achieve cT downstaging with preoperative treatment (OR 5.20, p = 0.005). The 5 year overall survival (OS) rate was lower in patients with R1 margins (6% vs 60%; p < 0.001), and R1 margins independently predicted worse OS (hazard ratio 2.37, 95% CI 1.51-3.75, p < 0.001). Most patients with R1 margins (58%) experienced peritoneal recurrence, and locoregional recurrence was relatively rare in this group (14%). Median time to recurrence was 8.5 months for peritoneal dissemination and 15.7 months for locoregional recurrence. CONCLUSION: R1 margins after gastrectomy were associated with aggressive tumor biology, high incidence of peritoneal recurrence after a short interval, and poor OS. In patients with R1 margins, re-resection to achieve microscopically negative margins has to be considered with caution.

Localized Gastroesophageal Adenocarcinoma in the Elderly: Is Age a Factor Associated with Suboptimal Treatment?

INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Implementation and Assessment of an Informal Virtual Elective for Medical Student Radiation Oncology Exploration During the COVID19 Pandemic: a Brief Report.

Subspecialty exposure during medical school can be limited. Moreover, the COVID19 pandemic prevented most onsite elective medical student (MS) rotations during 2020. Therefore, we sought to create and assess the efficacy of an informal virtual elective (IVE) for MSs to explore radiation oncology (RO) at our institution. We created IVE activities including invitations to resident didactics, a faculty lecture series, and interactive virtual events with residents and faculty. MSs were offered RO resident and faculty mentors and the opportunity to deliver a lecture. Pre- and post-IVE evaluation surveys were sent to 27 4th year MSs. Surveys utilized importance ordering (1=most important; reported as median (interquartile range), free response, and Likert-type questions (5 = extremely, 1=not at all). Our IVE, held from July to October 2020, had a median of 11 students (range 7-18) attend each activity. Pre- and post-IVE surveys were completed by 22/27 (81%) and 20/27 (74%) MSs, respectively. In pre-IVE, MSs reported participating in the IVE for faculty/resident interaction (1.5 [1, 2]), networking (3 [2, 3]), and learning (4 [3-5]). In post-IVE, MSs reported benefit from faculty mentors (5 [4, 5]), delivering a presentation (5 [3-5]), and faculty lectures (4.5 [4, 5]). In post-IVE, MSs preferred a full onsite away elective (16, 80%) over an official virtual elective (1, 5%) or IVE (3, 15%). Overall, MSs reported that the IVE provided an adequate introduction to RO at our institution (4 [4, 5]). Alternative virtual elective experiences allow MSs to informally evaluate medical subspecialties and could be offered even if formal elective opportunities are available.

Ablative liver radiotherapy for unresected intrahepatic cholangiocarcinoma: Patterns of care and survival in the United States.

BACKGROUND: Single-institution studies have shown the oncologic benefit of ablative liver radiotherapy (A-RT) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, adoption of A-RT across the United States and its associated outcomes are unknown. METHODS: We queried the National Cancer Data Base for nonsurgically managed patients with ICC diagnosed between 2004 and 2018. Patients were labeled A-RT for receipt of biologically effective doses (BED10 ) ≥ 80.5 Gy and conventional RT (Conv-RT) for lower doses. Associations with A-RT use and overall survival were identified using logistic and Cox regressions, respectively. RESULTS: Of 27,571 patients, the most common treatments were chemotherapy without liver RT (45%), no chemotherapy or liver RT (42%), and liver RT ± chemotherapy (13%). Use of liver RT remained constant over time. Of 1112 patients receiving liver RT with known doses, RT was 73% Conv-RT (median BED10 , 53 Gy; median, 20 fractions) and 27% A-RT (median BED10 , 100 Gy; median, 5 fractions). Use of A-RT increased from 5% in 2004 to 48% in 2018 (Ptrend < .001). With a median follow-up of 52.3 months, median survival estimates for Conv-RT and A-RT were 12.8 and 23.7 months (P < .001), respectively. On multivariable analysis, stage III and IV disease correlated with a higher risk of death, whereas chemotherapy and A-RT correlated with a lower risk. CONCLUSIONS: Although A-RT has been increasingly used, use of liver RT as a whole in the United States remained constant despite growing evidence supporting its use, suggesting continued unmet need. A-RT is associated with longer survival versus Conv-RT. LAY SUMMARY: Bile duct cancer is a rare, deadly disease that often presents at advanced stages. Single-institution retrospective studies have demonstrated that use of high-dose radiotherapy may be associated with longer survival, but larger studies have not been conducted. We used a large, national cancer registry of patients diagnosed between 2004 and 2018 to show that liver radiotherapy use remains low in the United States, despite growing evidence that patients who receive it live longer. Furthermore, we showed that patients who received high-dose radiotherapy lived longer than those who received lower doses. Greater awareness of the benefits of liver radiotherapy is needed to improve patient outcomes.

Definitive Intensity-Modulated Chemoradiation for Anal Squamous Cell Carcinoma: Outcomes and Toxicity of 428 Patients Treated at a Single Institution.

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.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Using patient flow analysis with real-time patient tracking to optimize radiation oncology consultation visits.

PURPOSE: Clinical efficiency is a key component of the value-based care model and a driver of patient satisfaction. The purpose of this study was to identify and address inefficiencies at a high-volume radiation oncology clinic. METHODS AND MATERIALS: Patient flow analysis (PFA) was used to create process maps and optimize the workflow of consultation visits in a gastrointestinal radiation oncology clinic at a large academic cancer center. Metrics such as cycle times, waiting times, and rooming times were assessed by using a real-time patient status function in the electronic medical record for 556 consults and compared between before vs after implementation of the PFA recommendations. RESULTS: The initial PFA revealed four inefficiencies: (1) protracted rooming time, (2) inefficient communications, (3) duplicated tasks, and (4) ambiguous clinical roles. We analyzed 485 consult-visits before the PFA and 71 after the PFA. The PFA recommendations led to reductions in overall median cycle time by 21% (91 min vs 72 min, p < 0.001), in cumulative waiting times by 64% (45 min vs 16 min; p < 0.001), which included waiting room time (14 min vs 5 min; p < 0.001) and wait for physician (20 min vs. 6 min; p < 0.001). Slightly less than one-quarter (22%) of consult visits before the PFA lasted > 2 h vs. 0% after implementation of the recommendations (p < 0.001). Similarly, the proportion of visits requiring < 1 h was 16% before PFA vs 34% afterward (p < 0.001). CONCLUSIONS: PFA can be used to identify clinical inefficiencies and optimize workflows in radiation oncology consultation clinics, and implementing their findings can significantly improve cycle times and waiting times. Potential downstream effects of these interventions include improved patient experience, decreased staff burnout, financial savings, and opportunities for expanding clinical capacity.

Automation of radiation treatment planning for rectal cancer.

PURPOSE: To develop an automated workflow for rectal cancer three-dimensional conformal radiotherapy (3DCRT) treatment planning that combines deep learning (DL) aperture predictions and forward-planning algorithms. METHODS: We designed an algorithm to automate the clinical workflow for 3DCRT planning with field aperture creations and field-in-field (FIF) planning. DL models (DeepLabV3+ architecture) were trained, validated, and tested on 555 patients to automatically generate aperture shapes for primary (posterior-anterior [PA] and opposed laterals) and boost fields. Network inputs were digitally reconstructed radiographs, gross tumor volume (GTV), and nodal GTV. A physician scored each aperture for 20 patients on a 5-point scale (>3 is acceptable). A planning algorithm was then developed to create a homogeneous dose using a combination of wedges and subfields. The algorithm iteratively identifies a hotspot volume, creates a subfield, calculates dose, and optimizes beam weight all without user intervention. The algorithm was tested on 20 patients using clinical apertures with varying wedge angles and definitions of hotspots, and the resulting plans were scored by a physician. The end-to-end workflow was tested and scored by a physician on another 39 patients. RESULTS: The predicted apertures had Dice scores of 0.95, 0.94, and 0.90 for PA, laterals, and boost fields, respectively. Overall, 100%, 95%, and 87.5% of the PA, laterals, and boost apertures were scored as clinically acceptable, respectively. At least one auto-plan was clinically acceptable for all patients. Wedged and non-wedged plans were clinically acceptable for 85% and 50% of patients, respectively. The hotspot dose percentage was reduced from 121% (σ = 14%) to 109% (σ = 5%) of prescription dose for all plans. The integrated end-to-end workflow of automatically generated apertures and optimized FIF planning gave clinically acceptable plans for 38/39 (97%) of patients. CONCLUSION: We have successfully automated the clinical workflow for generating radiotherapy plans for rectal cancer for our institution.

Linguistic Biases in Letters of Recommendation for Radiation Oncology Residency Applicants from 2015 to 2019.

We aimed to investigate whether implicit linguistic biases exist in letters of recommendation (LORs) for applicants to radiation oncology (RO) residency. LORs (n = 487) written for applicants (n = 125) invited to interview at a single RO residency program from the 2015 to 2019 application cycles were included for analysis. Linguistic Inquiry and Word Count (LIWC) software was used to evaluate LORs for length and a dictionary of predetermined themes. Language was evaluated for gender bias using a publicly available gender bias calculator. Non-parametric tests were used to compare linguistic domain scores. The median number of the LORs per applicant was 4 (range 3-5). No significant differences by applicant gender were detected in LIWC score domains or gender bias calculator (P > 0.05). However, LORs for applicants from racial/ethnic backgrounds underrepresented in medicine were less likely to include standout descriptors (P = 0.008). Male writers were less likely to describe applicant characteristics related to patient care (P < 0.0001) and agentic personality (P = 0.006). LORs written by RO were shorter (P < 0.0001) and included fewer standout descriptors (P = 0.014) but were also more likely to include statements regarding applicant desirability (P = 0.045) and research (P = 0.008). While language was globally male-biased, assistant professors were less likely than associate professors (P = 0.0064) and full professors (P = 0.023) to use male-biased language. Significant linguistic differences were observed in RO residency LORs, suggesting that implicit biases related to both applicants and letter writers may exist. Recognition, and ideally eradication, of such biases are crucial for fair and equitable evaluation of a diverse applicant pool of RO residency candidates.

Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial.

BACKGROUND: The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. METHODS: This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0-2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60-70 Gy in ten fractions or 52·5-67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. FINDINGS: 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2-24·6), median progression-free survival was 22·7 months (95% CI 10·4-not reached; 1-year progression-free survival 64% [95% CI 48-85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. INTERPRETATION: Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. FUNDING: Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.

Chemotherapy Versus Chemotherapy Plus Chemoradiation as Neoadjuvant Therapy for Resectable Gastric Adenocarcinoma: A Multi-institutional Analysis.

OBJECTIVE: We compare neoadjuvant chemotherapy (CT) to neoadjuvant chemotherapy plus chemoradiation (CRT) for patients with gastric adenocarcinoma (GA). SUMMARY OF BACKGROUND DATA: The optimal neoadjuvant therapy regimen for resectable GA is not defined. METHODS: Utilizing data from 2 high-volume cancer centers, we analyzed patients who underwent surgery for localized GA from 1/1/2000-12/31/2017. Standard CT regimens were used according to treatment period. We compared propensity matched cohorts based on age, sex, race, histology, and clinical stage. RESULTS: Four-hundred five patients (age 62 ± 12 year, 58% male, 56% White) were analyzed. 231 (57%) received CRT and 174 (43%) received CT. Groups differed based on histopathologic characteristics including preoperative stage (p = 0.013). To control for these differences, propensity matched cohorts of 113 CT and 113 CRT patients were compared. CRT had similar frequencies of microscopically negative resections to CT (93% vs 91%, p = 0.81), but higher rates of complete pathologic response (15% vs 4%, p = 0.003) and lower pathologic stage (p = 0.002). Completion of intended perioperative therapy occurred in 63% of CT and 91% of CRT patients (p < 0.001). Median DFS was 45mo (95%CI: 20-70) in the CT group and 113mo (95%CI: 75-151) in the CRT group (p = 0.018). Median OS was 53mo (95%CI: 30-77) versus 120mo (95%CI: 101-138); p = 0.015. CONCLUSIONS: In this multi-institutional comparison of neoadjuvant CT and CRT for resectable GA, CRT is associated with higher rates of completed perioperative therapy, higher rates of complete pathologic response, lower pathologic stage, and improved survival.Level of Evidence: Level III.

A Phase II Trial of Cytoreduction, Gastrectomy, and Hyperthermic Intraperitoneal Perfusion with Chemotherapy for Patients with Gastric Cancer and Carcinomatosis or Positive Cytology.

BACKGROUND: Current national guidelines do not include hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for gastric cancer, and there are no completed clinical trials of cytoreduction, gastrectomy, and HIPEC from the US. METHODS: Patients with gastric adenocarcinoma and positive peritoneal cytology or carcinomatosis who had completed systemic chemotherapy and laparoscopic HIPEC underwent cytoreduction, gastrectomy, and HIPEC with 30 mg mitomycin C and 200 mg cisplatin. The primary endpoint was overall survival (OS), with a secondary endpoint of postoperative complications (NCT02891447). RESULTS: We enrolled 20 patients from September 2016 to March 2019. Six patients had positive cytology only and 14 had carcinomatosis. All patients were treated with systemic chemotherapy with a median of eight cycles (range 5-11 cycles) and at least one laparoscopic HIPEC. The median peritoneal carcinomatosis index at cytoreduction/gastrectomy/HIPEC was 2 (range 0-13). After surgery, the 90-day morbidity and mortality rates were 70% and 0%, respectively. Median length of hospital stay was 13 days (range 7-23 days); median follow-up was 33.5 months; median OS from the date of diagnosis of metastatic disease was 24.2 months; and median OS from the date of cytoreduction, gastrectomy, and HIPEC was 16.1 months. 1-, 2-, and 3-year OS rates from the diagnosis of metastatic disease were 90%, 50%, and 28%, respectively. CONCLUSIONS: Survival rates for patients with gastric adenocarcinoma and peritoneal disease treated with cytoreduction, gastrectomy, and HIPEC are encouraging; our early results are similar to those of recent prospective registry studies. Multi-institutional and cooperative group trials should be supported to confirm survival and safety outcomes.

Determinants of Survival for Patients with Neoadjuvant-Treated Node-Negative Gastric Cancer.

BACKGROUND: This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0). METHODS: Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis. RESULTS: The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences). CONCLUSIONS: Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.

Chemotherapy Versus Chemotherapy Plus Chemoradiation as Preoperative Therapy for Resectable Gastric Adenocarcinoma: A Propensity Score-Matched Analysis of a Large, Single-Institution Experience.

BACKGROUND: We compared oncologic outcomes of patients who received neoadjuvant chemotherapy (CT) with those of patients who received neoadjuvant chemotherapy plus chemoradiation (CRT) for resectable gastric adenocarcinoma. METHODS: We compared oncologic and survival outcomes of patients who received CT or CRT for gastric adenocarcinoma at our institution between July 1995 and July 2018. We analyzed propensity score-matched cohorts based on age, sex, race, tumor histologic characteristics, and clinical stage. RESULTS: We identified 440 patients (mean age 61 ± 12 years, 62% male, 55% white); 345 (78%) received CRT, and 95 (22%) received CT. The propensity score-matched cohorts included 65 patients who received CT and 65 who received CRT. The CRT group had similar frequencies of R1 resection margins to the CT group (7.7% vs. 6.2%, p = 0.75) but significantly higher frequency of pathologic complete response (27.7% vs. 1.5%, p < 0.001). The CRT group had lower pathologic stages (p = 0.002). Median disease-free survival was 50.9 months (95% confidence interval [CI]: 4.7-97.2) in the CT group and 122.1 months (95% CI: 69.0-175.1) in the CRT group (p = 0.07). Median overall survival was 70.7 months (95% CI: 23.9-117.5) in the CT group and 122.1 months (95% CI: 68.7-175.4) in the CRT group (p = 0.21). CONCLUSIONS: Compared with CT, CRT for resectable gastric adenocarcinoma is associated with higher rates of pathologic complete response and subsequent lower final pathologic stage, but survival differences are not significant. Ongoing investigation is necessary to better determine the optimal neoadjuvant therapy and identify patients who receive optimal benefit from CRT. LEVEL OF EVIDENCE: III.