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Purpose: To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer. Methods and Materials: In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor. Results: Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks. Conclusions: Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone. [Copyright &y& Elsevier]

: PurposeTo determine the feasibility and toxicity of delivering stereotactic radiosurgery to patients with locally advanced pancreatic cancer.: Methods and materialsPatients with Eastern Cooperative Oncology Group performance status ≤2 and locally advanced pancreatic cancer were enrolled on this Phase I dose escalation study. Patients received a single fraction of radiosurgery consisting of either 15 Gy, 20 Gy, or 25 Gy to the primary tumor. Acute gastrointestinal toxicity was scored according to the Radiation Therapy Oncology Group criteria. Response to treatment was determined by serial high-resolution computed tomography scanning.: ResultsFifteen patients were treated at 3 dose levels (3 patients received 15 Gy, 5 patients received 20 Gy, and 7 patients received 25 Gy). At these doses, no Grade 3 or higher acute gastrointestinal toxicity was observed. This trial was stopped before any dose-limiting toxicity was reached, because the clinical objective of local control was achieved in all 6 evaluable patients treated at 25 Gy.: ConclusionsIt is feasible to deliver stereotactic radiosurgery to patients with locally advanced pancreatic cancer. The recommended dose to achieve local control without significant acute gastrointestinal toxicity is 25 Gy. [Copyright &y& Elsevier]

Introduction: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80–0.91; p < 0.001) with longer OS versus CDR. Discussion and Conclusions: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real‐world results additionally provide an estimate of effect size of EDR for future prospective trials. [ABSTRACT FROM AUTHOR]

The article discusses research being done on non-small cell lung cancer (NSLC). It references the study "Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome," by A. Salem et al. in the 2018 issue. The variables considered include differential level of hypoxia observed in human tumor, efficacy of combining hypoxia-targeted approaches with radiotherapy (RT), concurrent chemotherapy with RT (CRT), chemotherapy or biologic agents, and hypoxia biomarkers.

Simple Summary: This survey study investigates long-term patient-reported quality of life for individuals with low-lying rectal cancers, particularly focusing on the potential impact that ostomies may have on overall, sexual, and urinary quality of life. The findings suggest that patients with ostomies may experience a worse quality of life, affecting various aspects of daily life and relationships. These insights may help to inform patient counseling and shared decision making in the context of evolving rectal cancer treatment paradigms where patients have increasing multidisciplinary options. Background: Despite the increasing utilization of sphincter and/or organ-preservation treatment strategies, many patients with low-lying rectal cancers require abdominoperineal resection (APR), leading to permanent ostomy. Here, we aimed to characterize overall, sexual-, and bladder-related patient-reported quality of life (QOL) for individuals with low rectal cancers. We additionally aimed to explore potential differences in patient-reported outcomes between patients with and without a permanent ostomy. Methods: We distributed a comprehensive survey consisting of various patient-reported outcome measures, including the FACT-G7 survey, ICIQ MLUTS/FLUTS, IIEF-5/FSFI, and a specific questionnaire for ostomy patients. Descriptive statistics and univariate comparisons were used to compared demographics, treatments, and QOL scores between patients with and without a permanent ostomy. Results: Of the 204 patients contacted, 124 (60.8%) returned completed surveys; 22 (18%) of these had a permanent ostomy at the time of survey completion. There were 25 patients with low rectal tumors (≤5 cm from the anal verge) who did not have an ostomy at the time of survey completion, of whom 13 (52%) were managed with a non-operative approach. FACTG7 scores were numerically lower (median 20.5 vs. 22, p = 0.12) for individuals with an ostomy. Sexual function measures IIEF and FSFI were also lower (worse) for individuals with ostomies, but the results were not significantly different. MLUTS and FLUTS scores were both higher in individuals with ostomies (median 11 vs. 5, p = 0.06 and median 17 vs. 5.5, p = 0.01, respectively), suggesting worse urinary function. Patient-reported ostomy-specific challenges included gastrointestinal concerns (e.g., gas, odor, diarrhea) that may affect social activities and personal relationships. Conclusions: Despite a limited sample size, this study provides patient-centered, patient-derived data regarding long-term QOL in validated measures following treatment of low rectal cancers. Ostomies may have multidimensional negative impacts on QOL, and these findings warrant continued investigation in a prospective setting. These results may be used to inform shared decision making for individuals with low rectal cancers in both the settings of organ preservation and permanent ostomy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PC) is known to be difficult to treat, even with standard-of-care chemotherapies. One emerging option for treating PC involves high-dose radiation therapy as a means to help control the growth and even destroy cancer cells. However, the pancreas is surrounded by many gastrointestinal organs and blood vessels; therefore, the implantation of a gold fiducial marker can help precisely target the pancreatic tumor. Our aim was to investigate whether implantation of fiducial markers through endoscopic ultrasound guidance is safe and feasible and to also document the radiation characteristics of this emerging high-dose radiation treatment option. Accurate delivery of stereotactic body radiotherapy (SBRT) to pancreatic tumors relies on successful EUS-guided placement of fiducial markers. The aim of this study is to report the technical feasibility and safety of EUS-guided fiducial placement and to evaluate the characteristics and technical benefit of SBRT in a cohort of patients with pancreatic cancer (PC). A retrospective chart review was performed for all (n = 82) PC patients referred for EUS-guided fiducial placement by a single endosonographer at a tertiary cancer center. Data regarding EUS-related technical details, SBRT characteristics, adverse events, and continuous visibility of fiducials were recorded and analyzed. Most patients included in the study had either locally advanced disease (32 patients, 39%) or borderline resectable disease (29 patients, 35%). Eighty-two PC patients underwent the placement of 230 fiducial markers under EUS guidance. The technical success rate of the fiducial placement was 98%. No immediate EUS-related adverse events were reported. The average time to the simulation CT after fiducial placement was 3.1 days. Of the 216 fiducial markers used for the SBRT delivery, 202 fiducial markers were visible on both the simulation CT and the cone beam CT scan. A median dose of 40cGY was given to all the patients in five fractions. Of these, 41% of the patients reported no SBRT-related toxicities during the follow-up. Fatigue and nausea were the most reported SBRT-related toxicities, which were seen in 35% of the patients post-SBRT. Our results demonstrate that EUS-guided fiducial placement is safe and effective in target volume delineation, facilitating SBRT delivery in PC patients. Further clinical trials are needed to determine the SBRT-related survival benefits in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate burnout in an academic radiation oncology program after the workforce shifted to working from home all or part of the time to better understand the impact of remote work and if it is sustainable after the COVID-19 virus abates.Methods and Materials: In May 2020, in the midst of work-safe policies in the state and stabilizing COVID-19 case numbers, the Qualtrics-based MiniZ burnout survey was amended to include questions related to COVID-19 and working from home and was emailed to all radiation oncology employees across 3 departments: radiation oncology, radiation physics, and experimental radiation oncology. Descriptive and χ2 statistics were calculated within Qualtrics using StatIQ to evaluate factors associated with burnout and positive work from home experience.Results: Five hundred seventy-five employees completed the survey. Aggregating 3 responses that indicate having some degree of burnout, the rate of burnout across the cohort was 32%. For the same survey questions administered a year earlier, burnout rate was reported to be 40%. In the current survey, radiation oncology faculty and therapists had the highest reported burnout rates, at 47% and 44%, respectively (P = .031). The majority of employees working from home at least part of the time reported the experience was positive (74%, 323/436), and feeling positive about working from home was associated with reduced burnout (P = .030). Qualitative data review suggested the main drivers of unfavorable work-from-home responses were child/family care issues and information technology issues.Conclusions: Burnout was not increased during the emerging COVID-19 period compared with pre-COVID data. The shift to working from home was positive for most of the workforce and a potential benefit in reducing burnout for many staff groups. Maintaining work-from-home options post COVID-19 may help reduce burnout long term. It is important to personalize options for those unable to work effectively from home and to resolve information technology challenges to ensure functionality. [ABSTRACT FROM AUTHOR]

Simple Summary: The ability of ultra-high dose rate FLASH radiation therapy (RT) to reduce normal tissue toxicity without affecting tumor response relative to conventional dose rate radiation therapy could fundamentally change the way we treat cancer. However, this field is still in its early stages, and the magnitude of the sparing effect between treatment centers differs greatly for reasons as yet unknown, which has put the robustness of the effect into question. In this study, we show that when similar irradiation beam parameter settings are used, the induced sparing effect is robust and reproducible across institutions. These settings should serve as a reference for further optimization of the FLASH effect. FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used. [ABSTRACT FROM AUTHOR]

Simple Summary: While anti-PD1 antibodies have demonstrated efficacy in some patients with metastatic anal cancer, these agents have no proven benefit for those with localized disease treated with chemoradiation. Difficulty procuring fresh tumor tissue required for RNA and protein expression analysis has limited extensive molecular profiling for this rare cancer. Our team utilized a novel digital spatial profiling technology on pretreatment anal cancer specimens to identify biomarkers associated with recurrence after chemoradiation. We observed that recurrent tumors had higher baseline expression of immune checkpoint biomarkers, higher MAPK signaling activation and higher PI3K/Akt signaling activation. These findings provide a rationale that supports future clinical trials with immunotherapy that seek to improve survival beyond chemoradiation for patients with localized squamous cell cancer of the anus. The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).Methods and Materials: We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the predicted cancer cell death to the actual cell death measured from corresponding resected tumors treated with neoadjuvant chemoradiation in a calibration cohort (n = 80) and prospective cohort (n = 25). After calibration, we applied the model to 2 separate cohorts for pathologic and clinical associations: targeted therapy cohort (n = 101), cetuximab/bevacizumab + radiosensitizing chemotherapy, and standard chemoradiation cohort (n = 81), radiosensitizing chemotherapy to 50.4 Gy in 28 fractions.Results: We established the relationship between pretreatment computed v nAUC to pathologically verified blood volume fraction of the tumor (r = 0.65; P = .009) and fractional tumor cell death (r = 0.97-0.99; P < .0001) in the calibration and prospective cohorts. On multivariate analyses, accounting for traditional covariates, nAUC independently associated with overall survival in all cohorts (mean hazard ratios, 0.14-0.31). Receiver operator characteristic analyses revealed discrimination of good and bad prognostic groups in the cohorts with area under the curve values of 0.64 to 0.71.Conclusions: This work presents a new mathematical modeling approach to predict clinical response from chemotherapy and radiation for PDAC. Our findings indicate that oxygen/drug diffusion strongly influences clinical responses and that nAUC is a potential tool to select patients with PDAC for radiation therapy. [ABSTRACT FROM AUTHOR]

Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, which is characteristic of cells with high level of secretory activity and implicated in a variety of disease conditions. In response to ER stress, the cell elicits an adaptive process called the unfolded protein response (UPR) to support cellular homeostasis and survival. However, prolonged and unsolvable ER stress also induces apoptosis. As the most conserved signaling branch of the UPR, the IRE1α–XBP1 pathway plays important roles in both physiological and pathological settings and its activity has profound effects on disease progression and prognosis. Recently, modulating this pathway with small molecule compounds has been demonstrated as a promising approach for disease therapy. In this review, we summarize a list of current investigational compounds targeting this pathway and their therapeutic features for treating human diseases. [ABSTRACT FROM AUTHOR]

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. In this analysis of 27,571 patients in the United States with unresected intrahepatic cholangiocarcinoma diagnosed between 2004 and 2018, use of liver radiotherapy remained constant despite growing evidence supporting that its use is associated with longer survival. Among patients who received liver radiotherapy, higher doses have been increasingly used; patients who received higher doses had longer survival than those receiving lower doses (median 23.7 vs 12.8 months, respectively). [ABSTRACT FROM AUTHOR]

Background: Oncology telemedicine was implemented rapidly after COVID‐19. We examined multilevel correlates and outcomes of telemedicine use for patients undergoing radiotherapy (RT) for cancer. Methods: Upon implementation of a telemedicine platform at a comprehensive cancer center, we analyzed 468 consecutive patient RT courses from March 16, 2020 to June 1, 2020. Patients were categorized as using telemedicine during ≥1 weekly oncologist visits versus in‐person oncologist management only. Temporal trends were evaluated with Cochran‐Armitage tests; chi‐squared test and multilevel multivariable logistic models identified correlates of use and outcomes. Results: Overall, 33% used telemedicine versus 67% in‐person only oncologist management. Temporal trends (ptrend < 0.001) correlated with policy changes: uptake was rapid after local social‐distancing restrictions, reaching peak use (35% of visits) within 4 weeks of implementation. Use declined to 15% after national "Opening Up America Again" guidelines. In the multilevel model, patients more likely to use telemedicine were White non‐Hispanic versus Black or Hispanic (odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.03–4.72; p = 0.04) or receiving ≥6 fractions of RT versus 1–5 fractions (OR = 4.49, 95% CI 2.29–8.80; p < 0.001). Model intraclass correlation coefficient demonstrated 43% utilization variation was physician‐level driven. Treatment toxicities and 30‐day emergency visits or unplanned hospitalizations did not differ for patients using versus not using telemedicine (p > 0.05, all comparisons). Conclusion: Though toxicities were similar with telemedicine oncology management, there remained lower uptake among non‐White patients. Continuing strategies for oncology telemedicine implementation should address multilevel patient, physician, and policy factors to optimize telemedicine's potential to surmount—and not exacerbate—barriers to quality cancer care. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide with slow progress in the development of effective therapies. The breakthrough IMbrave150 trial established atezolizumab plus bevacizumab as the standard of care first-line therapy for patients with unresectable/advanced HCC, demonstrating improved overall survival. Radiation therapy (RT) is a locoregional treatment that may prevent morbidity from tumor-related vascular compromise and associated liver failure. There is no documented evidence yet describing the safety and outcomes of combination RT and atezolizumab/bevacizumab. In the retrospective review of our experience, we identified 21 patients with advanced HCC who underwent liver-directed RT with atezolizumab/bevacizumab. From our findings, the treatment is well-tolerated, safe, and does not potentiate liver failure. There were uncommon autoimmune or GI bleeding events in some patients, mostly unrelated to RT. Post-RT absolute lymphocyte counts (ALC) improved more quickly with atezolizumab/bevacizumab than they did without, which may be a favorable treatment prognosticator. Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab. [ABSTRACT FROM AUTHOR]

• Two-thirds of all radiotherapy (RT) randomized controlled trials (RCTs) mandated RT quality assurance (RTQA). • Less than half of trials required institutional credentialing. • Clinical trials involving advanced radiation techniques were not associated with utilization of RTQA. • Half of radiotherapy RCTs published protocol deviation outcomes. • There is a need for greater use of RTQA in RCTs to ensure protocol-specified RT is being delivered safely. 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). 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. 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 < 0.001). 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. [ABSTRACT FROM AUTHOR]

Purpose: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron‐based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread‐out Bragg peak (SOBP) under FLASH conditions. Methods: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian‐like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low‐dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam‐shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm3 of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs. Results: The designed and fabricated devices were used to produce 10‐, 15‐, and 20‐mm diameter, circular field sizes and 10‐, 15‐, and 20‐mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high‐accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments. Conclusions: It is feasible to use synchrotron‐generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon. [ABSTRACT FROM AUTHOR]

Purpose: 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.Methods and Materials: 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 χ2 test and survival using Kaplan-Meier log-rank test.Results: Overall, 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

The article discusses the United States, the COVID-19 pandemic has caused profound changes in radiation oncology practices, including delays to treatment and reductions in patient volume, staff, and practice revenue. Topics include the first confirmed case of COVID-19 in the United States has recorded; and an analysis of Southwest Oncology Group Cancer Research Network trials showed a considerable decrease.

• SABR doses ≥40 Gy appear to be superior than lower doses. • Modified FOLFIRINOX use appears to be superior to gemcitabine-based regimens. • Combination of SABR ≥40 Gy and modified FOLFIRINOX demonstrated the best outcomes. • Future prospective studies should test this combination for unresectable pancreatic cancer. We aimed to report the long-term impact of modern chemotherapy and SABR dose regimens on oncologic outcomes of unresectable pancreatic adenocarcinoma (PA). We reviewed the treatment characteristics and outcomes of all patients who received multi-fraction SABR for unresectable PA between February 2007 and August 2018 at our institution. Time-to-events were calculated from date of diagnosis treating death as a competing risk. A total of 149 patients were identified. Median follow-up was 15 months (range: 5–47). Median SABR dose was 33 Gy (range: 20–45) delivered in 5 fractions in 143 patients, and 3 or 6 fractions in 6 patients. 107 patients (72%) received gemcitabine-based chemotherapy while 31 (21%) received modified FOLFIRINOX (mFFX). Median OS was 16 months (95% CI, 14–17), with a 1-year cumulative incidence of LF of 14%. The combination of SABR doses ≥40 Gy and mFFX (n = 21) showed a superior PFS and OS to the use of GEM-based chemotherapy with <40 Gy SABR doses (median PFS: 14 vs. 10 months, HR: 0.46, 95% CI: 0.29–0.71, P = 0.003; median OS: 24 vs. 14 months, HR: 0.36, 95% CI: 0.22–0.59, P = 0.002), with 1-year PFS and OS of 67% and 90% compared to 35% and 59% for those who received GEM-based chemotherapy with <40 Gy SABR doses, respectively. The use of mFFX and a SABR dose ≥40 Gy in 5 fractions may be superior compared to regimens that utilize gemcitabine-based chemotherapy or SABR doses <40 Gy. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy (RT) is prescribed for curative and palliative treatment for around 50% of patients with solid tumors. Radiation‐induced toxicities of healthy organs accompany many RTs and represent one of the main limiting factors during dose delivery. The existing RT planning solutions generally discard spatial dose distribution information and lose the ability to recognize radiosensitive regions of healthy organs potentially linked to toxicity manifestation. This study proposes a universal deep learning‐based algorithm for recognitions of consistent dose patterns and generation of toxicity risk maps for the abdominal area. Methods: We investigated whether convolutional neural networks (CNNs) can automatically associate abdominal computed tomography (CT) images and RT dose plans with post‐RT toxicities without being provided segmentation of abdominal organs. The CNNs were also applied to study RT plans, where doses at specific anatomical regions were reduced/increased, with the aim to pinpoint critical regions sparing of which significantly reduces toxicity risks. The obtained risk maps were computed for individual anatomical regions inside the liver and statistically compared to the existing clinical studies. Results: A database of 122 liver stereotactic body RT (SBRT) executed at Stanford Hospital from July 2004 and November 2015 was assembled. All patients treated for primary liver cancer, mainly hepatocellular carcinoma and cholangiocarcinoma, with complete follow‐ups were extracted from the database. The SBRT treatment doses ranged from 26 to 50 Gy delivered in 1–5 fractions for primary liver cancer. The patients were followed up for 1–68 months depending on the survival time. The CNNs were trained to recognize acute and late grade 3+ biliary stricture/obstruction, hepatic failure or decompensation, hepatobiliary infection, liver function test (LFT) elevation or/and portal vein thrombosis, named for convenience hepatobiliary (HB) toxicities. The toxicity prediction accuracy was of 0.73 measured in terms of the area under the receiving operator characteristic curve. Significantly higher risk scores (P < 0.05) of HB toxicity manifestation were associated with irradiation for the hepatobiliary tract in comparison to the risk scores for liver segments I–VIII and portal vein. This observation is in strong agreement with anatomical and clinical expectations. Conclusion: In this work, we proposed and validated a universal deep learning‐based solution for the identification of radiosensitive anatomical regions. Without any prior anatomical knowledge, CNNs automatically recognized the importance of hepatobiliary tract sparing during liver SBRT. [ABSTRACT FROM AUTHOR]

• Prospective cohort of 121 cancer patients tested for SARS-CoV-2 over 35 days. • Of 7 positive cases, 6 were admitted with 4 warranting intensive care, and 2 died. • RT was delayed in one-third of patients while awaiting RT-PCR test results. • With a dual PPE policy, newly quarantined employees decreased 6-fold per day. • Each patient was an exposure risk to 5 employees, most commonly RTTs (38%) The COVID-19 pandemic warrants operational initiatives to minimize transmission, particularly among cancer patients who are thought to be at high-risk. Within our department, a multidisciplinary tracer team prospectively monitored all patients under investigation, tracking their test status, treatment delays, clinical outcomes, employee exposures, and quarantines. Prospective cohort tested for SARS-COV-2 infection over 35 consecutive days of the early pandemic (03/19/2020–04/22/2020). A total of 121 Radiation Oncology patients underwent RT-PCR testing during this timeframe. Of the 7 (6%) confirmed-positive cases, 6 patients were admitted (4 warranting intensive care), and 2 died from acute respiratory distress syndrome. Radiotherapy was deferred or interrupted for 40 patients awaiting testing. As the median turnaround time for RT-PCR testing decreased from 1.5 (IQR: 1–4) to ≤1-day (P < 0.001), the median treatment delay also decreased from 3.5 (IQR: 1.75–5) to 1 business day (IQR: 1–2) P < 0.001]. Each patient was an exposure risk to a median of 5 employees (IQR: 3–6.5) through prolonged close contact. During this timeframe, 39 care-team members were quarantined for a median of 3 days (IQR: 2–11), with a peak of 17 employees simultaneously quarantined. Following implementation of a "dual PPE policy," newly quarantined employees decreased from 2.9 to 0.5 per day. The severe adverse events noted among these confirmed-positive cases support the notion that cancer patients are vulnerable to COVID-19. Active tracking, rapid diagnosis, and aggressive source control can mitigate the adverse effects on treatment delays, workforce incapacitation, and ideally outcomes. [ABSTRACT FROM AUTHOR]

To develop a framework for automated prediction of hepatobiliary (HB) toxicity after liver stereotactic body radiation therapy (SBRT). A newly recognized toxicity type, named central or HB liver toxicity, had been reported, manifestation of which strongly correlates with the dose delivered to portal vein (PV) during SBRT. We propose a novel framework for automated HB toxicity prediction by combining deep learning-based auto-segmentation, PV anatomy analysis and the previously reported HB toxicity model. For validation of the framework, an IBR approved representative database of 72 patients treated with SBRT from primary (37) and metastatic (35) liver cancer was assembled. Each case included a pre-treatment CT, manual segmentations of tumor and PV, approved treatment plan, and the record of acute and late post-treatment toxicities. Performance of the developed framework was evaluated by quantitative comparison against manual predictions of HB toxicity, as well as post-treatment toxicity follow-ups. The manual and automated predictions of HB toxicity were in agreement for 94% cases using either V BED10 30 ≥ 45 cc or V BED10 40 ≥ 37 cc dosimetric predictors. When compared to post-treatment follow-ups for primary liver cancer, the proposed automated framework made 86% and 83% correct predictions in comparison to 83% and 80% correct manual predictions using V BED10 30 ≥ 45 cc or V BED10 40 ≥ 37 cc, respectively. The proposed framework automates the HB toxicity prediction with the accuracy similar to manual analysis-based HB toxicity prediction. The strategy is quite general and extendable to the automated prediction of toxicities of other organs. [ABSTRACT FROM AUTHOR]

This prospective study aimed to determine the accuracy of radiation oncologists in predicting the survival of patients with metastatic disease receiving radiation therapy and to understand factors associated with their accuracy. This single-institution study surveyed 22 attending radiation oncologists to estimate patient survival. Survival predictions were defined as accurate if the observed survival (OS) was within the correct survival prediction category (0-6 months, >6-12 months, >12-24 months, and >24 months). The physicians made survival estimates for each course of radiation, yielding 877 analyzable predictions for 689 unique patients. Data analysis included Stuart's Tau C, logistic regression models, ordinal logistic regression models, and stepwise selection to examine variable interactions. Of the 877 radiation oncologists' predictions, 39.7% were accurate, 26.5% were underestimations, and 33.9% were overestimations. Stuart's Tau C showed low correlation between OS and survival estimates (0.3499), consistent with the inaccuracy reported in the literature. However, results showed less systematic overprediction than reported in the literature. Karnofsky performance status was the most significant predictor of accuracy, with greater accuracy for patients with shorter OS. Estimates were also more accurate for patients with lower Karnofsky performance status. Accuracy by patient age varied by primary site and race. Physician years of experience did not correlate with accuracy. The sampled radiation oncologists have a 40% accuracy in predicting patient survival. Future investigation should explore how survival estimates influence treatment decisions and how to improve survival prediction accuracy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs. [ABSTRACT FROM AUTHOR]

Purpose: Deep learning is an emerging technique that allows us to capture imaging information beyond the visually recognizable level of a human being. Because of the anatomic characteristics and location, on-board target verification for radiation delivery to pancreatic tumors is a challenging task. Our goal was to use a deep neural network to localize the pancreatic tumor target on kV x-ray images acquired using an on-board imager for image guided radiation therapy.Methods and Materials: The network is set up in such a way that the input is either a digitally reconstructed radiograph image or a monoscopic x-ray projection image acquired by the on-board imager from a given direction, and the output is the location of the planning target volume in the projection image. To produce a sufficient number of training x-ray images reflecting the vast number of possible clinical scenarios of anatomy distribution, a series of changes were introduced to the planning computed tomography images, including deformation, rotation, and translation, to simulate inter- and intrafractional variations. After model training, the accuracy of the model was evaluated by retrospectively studying patients who underwent pancreatic cancer radiation therapy. Statistical analysis using mean absolute differences (MADs) and Lin's concordance correlation coefficient were used to assess the accuracy of the predicted target positions.Results: MADs between the model-predicted and the actual positions were found to be less than 2.60 mm in anteroposterior, lateral, and oblique directions for both axes in the detector plane. For comparison studies with and without fiducials, MADs are less than 2.49 mm. For all cases, Lin's concordance correlation coefficients between the predicted and actual positions were found to be better than 93%, demonstrating the success of the proposed deep learning for image guided radiation therapy.Conclusions: We demonstrated that markerless pancreatic tumor target localization is achievable with high accuracy by using a deep learning technique approach. [ABSTRACT FROM AUTHOR]

Background: Oncologists use patients' life expectancy to guide decisions and may benefit from a tool that accurately predicts prognosis. Existing prognostic models generally use only a few predictor variables. We used an electronic medical record dataset to train a prognostic model for patients with metastatic cancer.Methods: The model was trained and tested using 12 588 patients treated for metastatic cancer in the Stanford Health Care system from 2008 to 2017. Data sources included provider note text, labs, vital signs, procedures, medication orders, and diagnosis codes. Patients were divided randomly into a training set used to fit the model coefficients and a test set used to evaluate model performance (80%/20% split). A regularized Cox model with 4126 predictor variables was used. A landmarking approach was used due to the multiple observations per patient, with t0 set to the time of metastatic cancer diagnosis. Performance was also evaluated using 399 palliative radiation courses in test set patients.Results: The C-index for overall survival was 0.786 in the test set (averaged across landmark times). For palliative radiation courses, the C-index was 0.745 (95% confidence interval [CI] = 0.715 to 0.775) compared with 0.635 (95% CI = 0.601 to 0.669) for a published model using performance status, primary tumor site, and treated site (two-sided P < .001). Our model's predictions were well-calibrated.Conclusions: The model showed high predictive performance, which will need to be validated using external data. Because it is fully automated, the model can be used to examine providers' practice patterns and could be deployed in a decision support tool to help improve quality of care. [ABSTRACT FROM AUTHOR]

Highlights • Demonstrate that IMPT with feedback guided breath hold and CT-on-rail guidance is a robust treatment approach for liver tumor cases. • Investigate the dosimetric impact of interactional anatomy change and breath hold uncertainties with breath hold for IMPT. • Investigate the treatment planning technique for liver patients with IMPT. Abstract Purpose To evaluate the effect of setup uncertainties including uncertainties between different breath holds (BH) and inter-fractional anatomical changes under CT-guided BH with intensity-modulated proton therapy (IMPT) in patients with liver cancer. Methods and materials This retrospective study considered 17 patients with liver tumors who underwent feedback-guided BH (FGBH) IMRT treatment with daily CT-on-rail imaging. Planning CT images were acquired at simulation using FGBH, and FGBH CT-on-rail images were also acquired prior to each treatment. Selective robust IMPT plans were generated using planning CT and re-calculated on each daily CT-on-rail image. Subsequently, the fractional doses were deformed and accumulated onto the planning CT according to the deformable image registration between daily and planning CTs. The doses to the target and organs at risk (OARs) were compared between IMRT, planned IMPT, and accumulated IMPT doses. Results For IMPT plans, the mean of D 98% of CTV for all 17 patients was slightly reduced from the planned dose of 68.90 ± 1.61 Gy to 66.48 ± 1.67 Gy for the accumulated dose. The target coverage could be further improved by adjusting planning techniques. The dose–volume histograms of both planned and accumulated IMPT doses showed better sparing of OARs than that of the IMRT. Conclusions IMPT with FGBH and CT-on-rail guidance is a robust treatment approach for liver tumor cases. [ABSTRACT FROM AUTHOR]

Highlights • Severe lymphopenia during chemoradiation therapy was associated with poor survival outcomes. • Lymphocyte recovery after chemoradiation could not mitigate the poor long-term outcomes brought by high-grade lymphopenia. • Lymphocyte recovery ability was not different between patients with or without severe lymphopenia. • Lymphocyte recovery was only associated with baseline lymphocyte count. Abstract Introduction Radiation-induced lymphopenia (RIL) during therapy is associated with poor prognosis but is often temporary and resolves after treatment completion in esophageal cancer. How lymphocyte recovery contributes to prognosis is unknown. Methods We reviewed 755 patients with stage I-III esophageal carcinoma who received concurrent chemoradiation therapy (CRT) with or without surgery in 2004–2015. Complete blood counts were obtained before, during, and at first follow-up after CRT. Lymphopenia was graded per the Common Terminology Criteria for Adverse Events v4.03 during CRT (G) and as recovery after CRT (G r). Clinical factors and lymphopenia grade were tested for association with survival in univariable and multivariable Cox proportional hazard regression analyses. Results During CRT, 294 patients (38.9%) had G4 lymphopenia; by the first follow-up, 406 patients (53.8%) had recovered (G r 0-1). Relative to patients with G0-3 lymphopenia during CRT, G4 lymphopenia independently predicted worse OS in multivariable analyses. However, lymphocyte recovery was not associated with a better prognosis. Patients with G4 lymphopenia during CRT and recovery (G r 0-1) afterward still had poorer 5-year OS rate than patients with G0-3 during CRT without recovery (G r 2-4) afterward (36.6% vs. 51.9%, HR = 1.40, 95% CI 1.04–1.89, P = 0.027). Moreover, the lymphocyte recovery ability (post-CRT ALC divided by pre-CRT ALC) was not affected by lymphopenia grade during CRT (0.66 in G0-3 vs. 0.65 in G4, p = 0.473). Among patients with G4 lymphopenia during treatment, lymphocyte recovery was only associated with pre-CRT lymphocyte counts. Conclusion Lymphocyte count recovery after CRT does not alter the poor long-term outcomes brought about by high-grade lymphopenia during CRT. [ABSTRACT FROM AUTHOR]

Purpose: Tumor hypoxia contributes to radiation resistance. A noninvasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia-targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by 18F-EF5 PET with clinical outcomes after radiation therapy remains limited.Methods and Materials: Our study prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment 18F-EF5 PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dichloroacetate followed by repeated 18F-EF5 PET. The hypoxic subvolume of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with a hypoxic subvolume ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess the correlation between imageable hypoxia and clinical outcomes after treatment.Results: At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while dichloroacetate did not result in a significant change under our protocol conditions. Tumors with imageable hypoxia had a higher incidence of local recurrence at 12 months (30%) than those without (0%) (P < .01).Conclusions: Noninvasive hypoxia imaging by 18F-EF5 PET identified imageable hypoxia in about 40% of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia. [ABSTRACT FROM AUTHOR]

Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells' demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine's complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of escalated dose radiation therapy (EDR, defined as doses >50.4 Gy in 28 fractions [59.5 Gy BED]) on overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) of patients with unresectable extrahepatic cholangiocarcinoma (EHCC). Methods: A consecutive cohort of 80 patients who underwent radiotherapy for unresectable EHCC from 2001 to 2015 was identified. Demographic, tumor, treatment, toxicity, and laboratory variables were collected. The maximal RT doses ranged from 30 to 75 Gy (median 50.4 Gy, at 1.8‐4.5 Gy/fraction). Gross tumor volume (GTV) coverage by maximal dose in EDR group ranged from 38% to 100%. Kaplan–Meier method was used to estimate OS, FFLP, and FFDP. Univariate and multivariate Cox regression models were analyzed. Results: After radiotherapy, median OS, FFLP, and FFDP were 18.7, 22.6, and 24.3 months, respectively. There was no significant difference in OS or FFLP between patients who received EDR to portions of the GTV and patients who did not. On multivariate analysis, bigger GTV, age, and ECOG performance status were independently associated with shorter OS. Local progression on chemotherapy prior to RT was independently associated with shorter FFLP. High baseline neutrophil/lymphocyte ratio (>5.3) was independently associated with shorter FFDP. Toxicity grades were similar in EDR and lower doses except lymphopenia which was higher in EDR (P = 0.053). Conclusions: EDR to selective portions of the GTV may not benefit patients with unresectable EHCC despite having acceptable toxicity. New methods to improve local control and survival for unresectable EHCC are needed. We have investigated the role of escalated radiation dose in treatment of unresectable extrahepatic cholangiocarcinoma. Escalated dose radiation therapy did not significantly improve overall survival or local control. [ABSTRACT FROM AUTHOR]

Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Neoadjuvant chemoradiation (nCRT) can reduce tumor infiltrating lymphocytes. We examined absolute lymphocyte count (ALC) nadir during nCRT for esophageal cancer (EC) and pathologic complete response (pCR). Materials and methods Patients with stage I–IVA EC (n = 313) treated 2007–2013 with nCRT followed by surgery were analyzed. ALC was obtained before, during/weekly, and one month after CRT. pCR was defined as no viable tumor cells at surgery. High ALC was defined as nadir of ≥0.35 × 103/μL (highest tertile). Comparison of continuous and categorical variables by pCR was assessed by ANOVA and Pearson’s chi-square. Univariate/multivariate logistic regression was used to assess predictors of pCR and high ALC nadir. Results Eighty-nine patients (27.8%) achieved a complete pathological response (pCR). For patients with pCR, median ALC nadir was significantly higher than those without (0.35 × 103/μL vs 0.29 × 103/μL, p = 0.007). Patients maintaining high ALC nadir had a higher pCR rate (OR1.82, 95%CI 1.08–3.05, p = 0.024). Predictors of high ALC included treatment with proton therapy vs. IMRT (OR4.18, 95%CI 2.34–7.47, p < 0.001), smoking at diagnosis (OR2.80, 95%CI 1.49–5.25, p = 0.001), early stage I–II disease (OR2.33, 95%CI 1.32–4.17, p = 0.005), and SCC histology (OR3.70, 95%CI 1.01–14.29, p = 0.048). Mean body dose (MBD) was inversely related to high ALC nadir (OR0.77 per Gy, 95%CI 0.70–0.84, p < 0.001). Conclusion A higher ALC level during nCRT is associated with a higher rate of pCR for esophageal cancer patients undergoing trimodality therapy. [ABSTRACT FROM AUTHOR]

Two decades following the creation of the Office of Cancer Complementary and Alternative Medicine at the National Cancer Institute, the status of complementary and alternative medicine (CAM) research within oncology remains opaque. To better understand the landscape of CAM studies in oncology, we identified CAM-related phase III randomized controlled trials (RCTs) through ClinicalTrials.gov and compared these CAM trials to all non-CAM oncologic RCTs. Pearson χ2 testing was used to compare proportions across groups; all tests were two-sided. Comparing the 25 identified CAM RCTs with 739 non-CAM RCTs, CAM studies were more likely to be sponsored by a cooperative group (64.0% vs 28.6%, P < .001) and less likely to be industry funded (8.0% vs 76.5%, P < .001). CAM trials disproportionately excluded disease-related outcomes as endpoints (8.0% vs 84.6%, P < .001), were unsupported by prior early-phase data (55.0% vs 96.1%, P < .001), and did not meet the primary endpoint (8.7% vs 53.0%, P < .001). Given the observed relationship between encouraging pilot data and subsequent phase III trial success, we contend that future CAM RCTs may yield more promising findings if better supported by appropriately designed and well-characterized early-phase signals. [ABSTRACT FROM AUTHOR]

The article discusses strategy to enhance clinical trial enrollment at MD Anderson Cancer Center satellite community campuses. It mentions that academic medical centers conducted oncologic clinical research trials, which limited trial access for the majority of cancer patients. It mentions implementation of a two-part approach to improve screening and enrollment among HAL radiation oncology patients.

With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract: Wound healing is characterized by the production of large amounts of protein necessary to replace lost cellular mass and extracellular matrix. The unfolded protein response (UPR) is an important adaptive cellular response to increased protein synthesis. One of the main components of the UPR is IRE1, an endoplasmic reticulum transmembrane protein with endonuclease activity that produces the activated form of the transcription factor XBP1. Using luciferase reporter mice for Xbp1 splicing, we showed that IRE1 was up‐regulated during excisional wound healing at the time in wound healing consistent with that of the proliferative phase, when the majority of protein synthesis for cellular proliferation and matrix deposition occurs. Furthermore, using a small molecule inhibitor of IRE1 we demonstrated that inhibition of IRE1 led to decreased scar formation in treated mice. Results were recapitulated in a hypertrophic scar mouse model. These data help provide a cellular pathway to target in the treatment of hypertrophic scarring and keloid disorders. [ABSTRACT FROM AUTHOR]

Purpose: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. Materials and Methods: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. Results: We identified a strong positive association between the XBP1 gene signature and estrogen receptor–positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. Conclusion: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: We examined the impact of intensity modulated radiation therapy (IMRT) on hospitalization rates in the Surveillance, Epidemiology, and End Results (SEER)-Medicare population with anal squamous cell carcinoma (SCC).Methods and Materials: We performed a retrospective cohort study using the SEER-Medicare database. We identified patients with nonmetastatic anal SCC diagnosed between 2001 and 2011 and treated with chemoradiation therapy. We assessed the relation between IMRT and first hospitalization by use of a multivariate competing-risk model, as well as instrumental variable analysis, using provider IMRT affinity as our instrument.Results: Of the 1165 patients included in our study, 458 (39%) received IMRT. IMRT use increased over time and was associated more with regional and provider characteristics than with patient characteristics. The 3- and 6-month cumulative incidences of first hospitalization were 41.9% (95% confidence interval [CI], 37.3%-46.4%) and 47.6% (95% CI, 43.0%-52.2%), respectively, for the IMRT cohort and 46.7% (95% CI, 43.0%-50.4%) and 52.1% (95% CI, 48.4%-55.7%), respectively, for the non-IMRT cohort. IMRT was associated with a decreased hazard of first hospitalization compared with 3-dimensional radiation techniques (hazard ratio, 0.70; 95% CI, 0.58-0.84; P=.0002). Instrumental variable analysis suggested an even greater reduction in hospitalizations with IMRT after controlling for unmeasured confounders. There was a trend toward improved overall survival with IMRT, with an adjusted hazard ratio of 0.77 (95% CI, 0.59-1.00; P=.05).Conclusions: The use of IMRT is associated with reduced hospitalizations in elderly patients with anal SCC. Further work is warranted to understand the long-term health and cost impact of IMRT, particularly for patient subgroups most at risk of toxicity and hospitalization. [ABSTRACT FROM AUTHOR]

Purpose: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. Materials and Methods: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. Results: We identified a strong positive association between the XBP1 gene signature and estrogen receptor–positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. Conclusion: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose To further explore the correlation of central biliary tract (cHBT) radiation doses with hepatobiliary toxicity (HBT) after stereotactic body radiation therapy (SBRT) in a larger patient dataset. Methods We reviewed the treatment and outcomes of all patients who received SBRT for primary liver cancer (PLC) and metastatic liver tumors between July 2004 and November 2015 at our institution. The cHBT was defined as isotropic expansions (5, 10, 15, 20 and 25 mm) from the portal vein (PV). Doses were converted to biologically effective doses by using the standard linear quadratic model with α / β of 10 (BED 10 ). HBT was graded according to the Common Terminology Criteria for Adverse Events v4.03. Results Median follow-up was 13 months. Out of the 130 patients with complete follow-up records analyzed, 60 (46.1%) had liver metastases, 40 (30.8%) had hepatocellular carcinoma (HCC), 26 (20%) had cholangiocarcinoma (CCA) and 4 (3.1%) patients other PLC histologies. Thirty-three (25.4%) grade 2+ and 28 (21.5%) grade 3+ HBT were observed. Grade 3+ HBT was seen in 13 patients (50%) with CCA, 7 patients (17.5%) with HCC and 7 (11.7%) patients with liver metastases. SBRT doses to the cHBT were highly associated with HBT, but only for PLC patients when analyzed by histological subtype. The 15 mm expansion from the PV (cHBT 15 ) proved to be an appropriate surrogate for the cHBT. The strongest cHBT 15 dose predictors for G3+ HBT for PLC were the V BED10 40 ⩾37 cc ( p < 0.0001) and the V BED10 30 ⩾ 45 cc ( p < 0.0001). Conclusion SBRT doses to the cHBT are associated with occurrence of HBT only in PLC patients. Limiting the dose to the cHBT to V BED10 40 < 37 cc and V BED10 30 < 45 cc when treating PLC patients with SBRT may reduce the risk of HBT. [ABSTRACT FROM AUTHOR]

The benefits of radiotherapy for inoperable biliary tract cancer remain unclear due to the lack of randomized data. We evaluated the impact of radiotherapy on survival in elderly patients using the SEER-Medicare database. Patients in the SEER-Medicare database with inoperable biliary tract tumors diagnosed between 1998 and 2011 were included. We used multivariate logistic regression to evaluate factors associated with treatment selection, and multivariate Cox regression and propensity score matching to evaluate treatment selection in relation to subsequent survival. Of the 2343 patients included, 451 (19%) received radiotherapy within 4 months of diagnosis. The use of radiotherapy declined over time, and was influenced by receipt of chemotherapy and patient age, race, marital status, poverty status, and tumor stage and type. Median survival was 9.3 (95% CI 8.7-9.7) months among patients who did not receive radiation and 10.0 (95% CI 9.1-11.3) months among those who received radiation, conditional on having survived 4 months. In patients who received chemotherapy ( n = 1053), receipt of radiation was associated with improved survival, with an adjusted hazard ratio of 0.82 (95% 0.70-0.97, P = 0.02). In patients who did not receive chemotherapy ( n = 1290), receipt of radiation was not associated with improved survival, with an adjusted hazard ratio of 1.09 (95% 0.91-1.30, P = 0.34). Propensity-scored matched analyses showed similar results. Despite the survival benefit associated with the addition of radiotherapy to chemotherapy, the use of radiation for unresectable biliary tract cancers has declined over time. [ABSTRACT FROM AUTHOR]

The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer. [ABSTRACT FROM AUTHOR]

Purpose: To identify prognostic biomarkers in pancreatic cancer using high-throughput quantitative image analysis.Methods and Materials: In this institutional review board-approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT (18)F-fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162 robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy.Results: The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6).Conclusion: Quantitative analysis identified novel (18)F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy. [ABSTRACT FROM AUTHOR]