Combined Radiation Therapy Research Articles

Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.

TPS766 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial (NCT04698915) is now enrolling. Clinical trial information: NCT04698915 .

Results of treatment of patients with nasopharyngeal cancer after superselective chemoembolization of tumor vessels

Background. Radiation therapy for locally advanced nasopharyngeal carcinoma (NC) has a high incidence of fatal complications, which leads to absolute contraindications to External Beam Radiation Therapy (EBRT). Chemoembolization of a nasopharyngeal tumor significantly reduces these risks and allows for EBRT. The aim of this study was to assess response rate after chemoembolization and EBRT. Objective. To evaluate the response rate in patients with locally advanced nasopharyngeal cancer treated with chemoembolization of tumor vessels and external beam radiation therapy in combination with chemotherapy. Methods. Prospective descriptive study was conducted. Patients with cT3–4, N0–2, M0 NC treated in April 2016 – March 2021 were enrolled. All patients had chemoembolization with doxorubicin’s microspheres followed by EBRT administrated once daily (2,0 Gy per fraction). Treatment response rate was assessed according RECIST 1.1 criteria in three weeks. Results. Twenty-one patients were identified. The median age was 47 years (IQR: 20–60). Tumors were staged as cT3N0M0 in 1 (4.8%) case, cT3N1M0 in 6 (28.6%) cases, cT3N2M0 in 5 (23.8%) cases, cT4N0M0 in 1 (4.8%) case, cT4N1M0 in 1 (4.8%) case and cT4N2M0 in 7 (33.4%) cases. There were the following histopathology types of NC: WHO type I (n = 1), WHO type II (n = 7) and WHO type III (n = 13). Fourteen (66.7%) patients had EBV-non-associated tumor and 7 patients were EBV-associated. Twenty (95.2%) patients had absolute contraindications to EBRT. All patients had chemoembolization. Complete response (CR) after chemoembolization was achieved in 3 (14.3%) patients, partial response (PR) was in 4 (19%) patients, stabilization was in 12 (57.1%), and progression was in 2 (9.6%) patients. All 21 patients had EBRT (median total dose 66 Gy [IQR: 60–72]).CR after EBRT was achieved in 17 (80%) patients and progression was in 4 (20%) patients. Conclusions. Chemoembolization provides acceptable response rate in patients with locally advanced NC and allows for EBRT. Further studies are needed to evaluate local control.

Endoscopic Excision of Hip Heterotopic Ossification, Plus Indomethacin and Radiation, Is Effective in Treating and Preventing Recurrence

To describe the clinical and patient-reported outcomes of heterotopic ossification (HO) excision as well as the results of a standardized HO prophylaxis protocol among a group of patients who previously underwent open or arthroscopic hip surgery. Patients who developed HO after index hip surgery and were subsequently treated with arthroscopic excision of HO and postoperative HO prophylaxis using 2 weeks of indomethacin and radiation were retrospectively identified. All patients were seen by a single surgeon and were treated with the same arthroscopic technique. Patients were also placed on a regimen of 2 weeks of indomethacin 50 mg and radiation therapy with 700 cGy in one fraction on the first postoperative day. Outcomes assessed included recurrence of HO and conversion to total hip arthroplasty by latest follow-up. Other outcomes included Modified Harris Hip Scores and Non-Arthritic Hip Scores, which were collected preoperatively and at 1-year and 2-year follow-up. There were 5 female and 9 male subjects, with an average age of 39 years (range 22-66) and average body mass index of 27.1 (19.1-37.5). Average follow-up time was 46 months (range 4-136). No patients had experienced HO recurrence by latest follow-up. Only 2 patients converted to total hip arthroplasty, one at 6 months and the other at 11 months postexcision. Average outcome scores improved by 2-year follow-up (average Modified Harris Hip Scores 52.8 improved to 86.5, average Non-Arthritic Hip Scores 49.4 improved to 83.8). Minimally invasive arthroscopic excision of HO and postoperative prophylaxis with combined indomethacin and radiation therapy effectively treats and prevents the recurrence of HO. Level IV, case series, therapeutic.

KRT13 is upregulated in pancreatic cancer stem-like cells and associated with radioresistance.

Pancreatic cancer is one of the most aggressive cancers and the seventh leading cause of cancer-associated death in the world. Radiation is performed as an adjuvant therapy as well as anti-cancer drugs. Because cancer stem-like cells (CSCs) are considered to be radioresistant and cause recurrence and metastasis, understanding their properties is required for the development of novel therapeutic strategies. To investigate the CSC properties of pancreatic cancer cells, we used a pancreatic CSC model, degron (++) cells, which have low proteasome activity. Degron (++) cells displayed radioresistance in comparison with control cells. Using Ribonucleic acid (RNA) sequencing, we successfully identified KRT13 as a candidate gene responsible for radioresistance. Knockdown of KRT13 sensitized the degron (++) cells to radiation. Furthermore, a database search revealed that KRT13 is upregulated in pancreatic cancer cell lines and that high expression of KRT13 is associated with poorer prognosis. These results indicate that a combination therapy of KRT13 knockdown and radiation could hold therapeutic promise in pancreatic cancer.

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment.

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention-a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies.

Calreticulin Upregulation in Cervical Cancer Tissues From Patients After 10 Gy Radiation Therapy

Understanding the immune response during radiation therapy (RT) in a clinical setting is imperative for maximizing the efficacy of combined RT and immunotherapy. Calreticulin, a major damage-associated molecular pattern that is exposed on the cell surface after RT, is presumed to be associated with the tumor-specific immune response. Here, we examined changes in calreticulin expression in clinical specimens obtained before and during RT and analyzed its relationship with the density of CD8+ T cells in the same patient set. This retrospective analysis evaluated 67 patients with cervical squamous cell carcinoma who were treated with definitive RT. Tumor biopsy specimens were collected before RT and after 10 Gy irradiation. Calreticulin expression in tumor cells was evaluated via immunohistochemical staining. Subsequently, the patients were divided into 2 groups according to the level of calreticulin expression, and the clinical outcomes were compared. Finally, the correlation between calreticulin levels and density of stromal CD8+ T cells was evaluated. The calreticulin expression significantly increased after 10 Gy (82% of patients showed an increase; P < .01). Patients with increased calreticulin levels tended to show better progression-free survival, but this was not statistically significant (P=.09). In patients with high expression of calreticulin, a positive trend was observed between calreticulin and CD8+ T cell density, but the association was not statistically significant (P=.06). Calreticulin expression increased after 10 Gy irradiation in tissue biopsies of patients with cervical cancer. Higher calreticulin expression levels are potentially associated with better progression-free survival and greater T cell positivity, but there was no statistically significant relationship between calreticulin upregulation and clinical outcomes or CD8+ T cell density. Further analysis will be required to clarify mechanisms underlying the immune response to RT and to optimize the RT and immunotherapy combination approach.

The content of VEGF, COX-2 and PGE-2 in the blood serum of patients with non-small cell lung cancer with different schemes of conformal radiotherapy in the dynamics of treatment

Background. Overcoming radioresistance is an important problem in radiation oncology. Therefore, the development of new approaches to modeling the radiosensitivity of tumors in cancer patients becomes relevant and important. Cyclooxygenase-2 (COX-2) inhibitors are new agents for radiomodification in various radiation therapy schemes, the use of which slows down angiogenesis by suppressing the activity of the COX-2 enzyme.&#x0D; Purpose. To determine the content of indicators of radioresistance: vascular endothelial growth factor (VEGF), COX-2, prostaglandin E-2 (PGE-2) in the blood serum of patients with non-small cell lung cancer (NSCLC) and changes in their levels with different schemes of radiation therapy (RT).&#x0D; Materials and methods. 36 patients with NSCLC were examined and treated, who were divided into four groups: RT (the first group – 16 patients), RT with the COX-2 inhibitor – ranselex (the second group – 9 patients), RT with ranselex and cisplatin (the third group – 5 patients ) and RT with cisplatin (fourth group – 6 patients). The patients received a course of radiation treatment using a Clinac 600C linear accelerator. The classical fractionation mode was used, the total focal doses were 60–66 Gy. Cisplatin was prescribed at 30 mg/m2 per week up to a total dose (SD) of 200 mg, the COX-2 inhibitor Rancelex® at a dose of 100 mg per day (active substance – celecoxib). The levels of VEGF, COX-2, and PGE-2 in the blood serum of patients with NSCLC were determined by enzyme-linked immunosorbent assay (ELISA) before and after treatment.&#x0D; Results. The level of the angiogenesis marker VEGF after treatment in the group with RT decreases by 1.46 times, in the group with the combined action of RT and ranselex – 2.4 times, in the group with the combined action of PT, ranselex and cisplatin – by 3.7 times, and in the group with the combined effect of RT and cisplatin, it decreases by 1.1 times. The greatest decrease in the level of VEGF is observed with RT in combination with ranselex and cisplatin, which indicates a more effective enhancement of the antiangiogenic effect.&#x0D; Conclusions. It has been proven that with various schemes of RT using the COX-2 inhibitor – ranselex and cisplatin in patients with NSCLC, there is a decrease in the radioresistance markers PGE-2 and COX-2, the angiogenesis marker – VEGF, which indicates that the effect of radiomodification on the angiogenesis process is most pronounced in the combined actions of RT and both radio modifiers. The use of COX-2 inhibitors as radiosensitizers in combination with RT provides a new opportunity to increase tumor radiosensitivity.

Use of 3D planning of HDR brachytherapy in patients with cervical cancer

Background. Combined radiation therapy is the «gold standard» for the treatment of stages IIB-IVA of cervical cancer (cervical cancer). Given the data of statistical indicators of cervical cancer, the study of new approaches to treatment and implementation in clinical practice of modern technologies of radiation therapy of widespread cervical cancer is an extremely important area.&#x0D; Purpose – evaluate the benefits of using CT topometric preparation in planning brachytherapy for cervical cancer.&#x0D; Materials and Methods. 3D planning of brachytherapy of 24 patients with locally advanced cervical cancer (FIGO IIIB stage), who underwent a radical program of combined radiation therapy (remote radiation therapy with chemical modification with cisplatin followed by HDR-brachytherapy (High dose rate brachytherapy)).&#x0D; Results. The paper presents the results of the analysis of differences in brachytherapy planning according to orthogonal images and CT images. The analysis of the influence of the constitutional features of patients revealed that there are differences in the topographic anatomy of the pelvis depending on the surface area of the body. In patients with a body surface area of up to 1,65 m2 , a more intimate fit of the intestine to the target volume of irradiation was noted. No similar planning difficulties were found in patients with a body surface area above 1,65 m2 .&#x0D; Conclusions. The use of 3D images in the planning of intracavitary irradiation in patients with cervical cancer provides precision brachytherapy by simultaneously visualizing the irradiated volumes and spatial relationships of the anatomical structures of the pelvis, the introduced endostats and the corresponding volumetric dose distributions.

ACT-1 A PROSPECTIVE MULTICENTER PHASE I/IIA STUDY OF PREOPERATIVE NEOADJUVANT BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA

Abstract Background Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study. METHODS &amp; PATIENTS 15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection. RESULTS Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence. CONCLUSION Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.

Real-world treatment patterns and clinical outcomes in EGFR-mutant locally advanced lung adenocarcinoma: A multi-center cohort study

ObjectiveTo investigate the optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant locally advanced non-small cell lung cancer (LA-NSCLC). MethodsPatients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 were analyzed retrospectively, and were categorized into three groups according to the primary treatment: chemoradiotherpy (CRT) (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), and EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. ResultsA total of 104, 105, and 231 patients were categorized into groups 1, 2, and 3, respectively. After IPTW adjustment, the median PFS for each group was 12.4, 26.2, and 16.2 months (log-rank P < 0.001), and the median OS was 51.0, 67.4 and 49.3 months (log-rank P = 0.084), respectively. Compared with those in group 1, patients in group 2 had significantly improved PFS [adjusted hazard ratio HR (aHR), 0.40; 95% confidence interval (CI): 0.29, 0.54; P < 0.001] and OS (aHR, 0.61; 95% CI: 0.38, 0.98; P = 0.039). Patients in group 3 had prolonged PFS (aHR, 0.66; 95% CI: 0.50, 0.87; P = 0.003), but not OS (aHR, 0.90; 95% CI: 0.62, 1.32; P = 0.595). Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings. ConclusionsEGFR-TKIs after chemoradiation or combined with radiation alone correlated with the longest PFS and OS (versus CRT or TKIs alone) in patients with EGFR-mutant unresectable LA-NSCLC. Well-designed prospective trials were warranted.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Androgen deprivation therapy duration is significantly associated with Testosterone recovery in Japanese patients with prostate cancer.

Due to the fear generated by COVID-19 in Spring 2020, many patients postponed their scheduled outpatient visits. To differentiate those patients with prostate cancer (PCa) whose androgen deprivation therapy (ADT) injection treatment can be postponed, we investigated the characteristics of testosterone (T) recovery in Japanese patients after they received combined ADT and radiation therapy (RT). We included 81 patients with PCa treated with ADT and RT at Keio University Hospital from January 2013 to December 2018. T-recovery was defined as the time interval between the last ADT injection and 3-6months after T-normalization. The Kaplan-Meier method was used to estimate time to T-recovery. Cox proportional hazards models identified T-recovery predictors. The 50% cumulative incidence of T-recovery was 7.0months for the 6-short-term group (defined as patients having ≤6months of ADT therapy) versus 13.0months for the 6-long-term group (>6months of therapy) (p < 0.001). The incidence was 7.0months for the 12 short-term-ADT (ST) group versus 18.0months for the 12 long-term-ADT (LT) group (p < 0.001). Multivariate analysis revealed that a shorter duration of ADT was associated with a shorter time to T-recovery (hazard ratio, 0.253; 95% CI, 0.138-0.465; p < 0.001). No other factors were significant predictors of T-recovery. Androgen deprivation therapy duration is significantly associated with T-recovery in Japanese patients with PCa. If a patient undergoes ADT for more than 6 or 12months, it is possible to postpone their outpatient visits for 13 and 18months, respectively.

PMON324 Crooke Cell Corticotroph Adenoma: A rare but Real Possibility in Children

Abstract Background Cushing disease (CD) is uncommon in the pediatric population and is usually caused by benign pituitary corticotroph microadenomas. In some adults with CD, Crooke cell adenoma (CCA), a more aggressive histologic variant of corticotroph adenomas, has been described. CCA has rarely been reported in children as the etiology of CD and its course is not well described. Objectives To report a pediatric case of CCA, the youngest to our knowledge Case An 11-year-old African American female presented to the endocrinology clinic with concerns for diabetes, excessive weight gain and linear growth arrest. Workup for possible etiology showed: midnight salivary cortisol 0.924 (normal &amp;lt; 0.112 µg/dL), ACTH 119(6-48 pg/mL), morning cortisol 8.5 (normal &amp;lt; 1.8 µg/dL) post 1 mg dexamethasone mg/dL, consistent with the diagnosis of CD. Magnetic resonance imaging (MRI) showed a 4 mm pituitary microadenoma in the left anterior side of the adenohypophysis for which she underwent endoscopic endonasal transsphenoidal resection. Histopathologic examination revealed pituitary adenomatous tissue consisting of a uniform population of basophilic cells with granular cytoplasm, arranged in trabeculae and small nests with bundles encircling the nuclei, findings pathognomonic of CCA. Given persistence of hypercortisolemia, another transsphenoidal gross total resection of residual adenomatous tissue was performed 4 months later. This led to resolution of CD as evidenced by weight loss and linear growth. Twelve months following the second surgery, the patient experienced rapid weight gain and a decelerated linear growth accompanied by pubertal arrest. Another pituitary MRI showed a recurrent left sided adenoma (8×8×7 mm). Biochemical investigation this time again showed elevated midnight salivary cortisol and 24- hour urine free cortisol (UFC). In addition, AM cortisol was unsuppressed following 1 mg overnight dexamethasone administration. In response, repeat transsphenoidal gross total resection was performed, however residual microscopic disease in the cavernous sinus wall was highly suspected intraoperatively. A spine MRI did not show disseminated disease. Despite this, hypercortisolemia persisted both clinically and biochemically. The patient subsequently underwent proton beam radiation therapy in combination with adjuvant adrenolytic therapy with mitotane. The patient responded to these interventions with normalization of 24-hour UFC, resumption of linear growth, and pubertal progression. The treatment course was complicated by the development of isolated TSH deficiency requiring thyroid hormone replacement. Conclusion CCA is an aggressive entity described in the adult literature as a cause of CD. The current report adds to the limited pediatric cases of this disease. CCA can be equally aggressive in children and refractory to surgical treatment. Here, we show that it may respond to proton beam radiation and adrenolytic therapy. Pediatric endocrinologists should be aware of the rare occurrence of CCA in children and tailor treatment accordingly using a multi-disciplinary approach. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study

PurposeTo evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for...

A case of undifferentiated carcinoma of the bladder treated by combination therapy of surgery, local radiation, and immune checkpoint inhibitors.

Undifferentiated carcinoma of the bladder is a rare malignancy with a poor prognosis. We present the case of an 81-year-old woman complaining of bladder irritation. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a bulky bladder tumor, which was diagnosed as cT4aN0M0. A transurethral resection of the bladder tumor revealed pT2 or higher urothelial carcinoma. The patient underwent total cystectomy with an ileal conduit diversion. Histological examination revealed a primary undifferentiated bladder carcinoma with a sarcoma component, pT3aN0M0. Postoperative adjuvant chemotherapy with gemcitabine plus carboplatin was administered. However, this regimen was discontinued after one course due to significant myelosuppression. Four months after total cystectomy, a pelvic tumor with suspected local recurrence was detected on CT. The patient was diagnosed with recurrent undifferentiated carcinoma with a sarcoma component by a transperineal ultrasound-guided biopsy. Local radiation therapy and immunotherapy with immune checkpoint inhibitors were prescribed. After three courses of immunotherapy with pembrolizumab, the primary tumor disappeared. Upon continuing immune checkpoint inhibitor treatment, the patient has maintained a complete response without tumor recurrence in the following six months.

PL04 Presentation Time: 2:45 PM: A Randomized Phase III Trial Comparing Health-Related Quality of Life After Low Dose Rate or High Dose Rate Prostate Brachytherapy Boost Combined with External Beam Pelvic Radiotherapy

<h3>Purpose</h3> This randomized phase III trial compared health related quality of life (HRQOL) in urinary, bowel, and sexual domains in men with intermediate (IR) and high-risk (HR) prostate cancer treated with combined external beam radiation therapy (EBRT) and prostate brachytherapy (BT) using either low dose rate (LDR) or high dose rate (HDR). <h3>Materials and Methods</h3> Eligible men receiving pelvic EBRT (46 Gy/23F) combined with prostate BT were randomized to either an LDR (110 Gy) or HDR (15 Gy) boost. HDRBT preceded EBRT by 1 week while LDRBT followed. Time 0 for QOL evaluations was day 1 of any radiotherapy. The Expanded Prostate Cancer Index Composite (EPIC) questionnaire was used to evaluate HRQOL q3 months for the first year, q6 months to 3 years and then annually. The Mann-Whitney U test was used to compare mean EPIC scores for urinary, bowel and sexual summary domains. <h3>Results</h3> From 01/2014 to 01/2020, 191 men were randomized: 42% IR and 58% HR. Median age was 71 years. T stage was T1c/T2a:34%, T2b:28%, T2c:24% and T3:13%. 57% had Gleason 7, 13% Gleason 8 and 30% Gleason 9. 74% received ADT with at least 3 months neoadjuvant and for a median duration of 12 mo. Median follow-up was 48 mo. HDR patients had higher (better) HRQOL urinary domain scores at 3 mo. (79.0 vs. 69.4; p<.001) and 6 mo. (84.0 vs. 76.9; p<.001), and higher bowel domain scores at 3 mo. (87.0 vs. 82.1; p=.005) and 6 mo. (88.7 vs. 82.8; p=.023). Better bowel domain scores were sustained at 24, 36, and 48 mo. In contrast, HDR patients had worse HRQOL urinary domain scores at 1 mo. (73.6 vs. 80.7; p=.003). There was no statistically significant difference in HRQOL sexual domain scores between the two arms. <h3>Conclusions</h3> The effect of HDRBT on urinary and bowel domains was evident 1 mo. post implant but had recovered at 3 and 6 mo., while LDR patients were still experiencing significant QOL impact of their ongoing LDRBT. Although HDR patients sustained an advantage in long term bowel function compared to LDR, there was no difference in long term urinary QOL between the 2 types of BT after the acute phase subsided. The patient treatment experience of combined EBRT/BT is improved with HDR. Efficacy will be reported at 5 year minimum follow up.

Imaging of Drug-Related Pneumonitis in Oncology.

Clinical applications of novel anticancer agents in the past few decades brought marked advances in cancer treatment, enabling remarkable efficacy and effectiveness; however, these novel agents are also associated with toxicities. Among various toxicities, drug-related pneumonitis is one of the major clinical challenges in the management of cancer patients. Imaging plays a key role in detection, diagnosis, and monitoring of drug-related pneumonitis during cancer treatment. In the current era of precision oncology, pneumonitis from molecular targeted therapy and immune-checkpoint inhibitors (ICI) has been recognized as an event of clinical significance. Additionally, further advances of therapeutic approaches in cancer have brought several emerging issues in diagnosis and monitoring of pneumonitis. This article will describe the computed tomography (CT) pattern-based approach for drug-related pneumonitis that has been utilized to describe the imaging manifestations of pneumonitis from novel cancer therapies. Then, we will discuss pneumonitis from representative agents of precision cancer therapy, including mammalian target of rapamycin inhibitors, epidermal growth factor receptor inhibitors, and ICI, focusing on the incidence, risk factors, and the spectrum of CT patterns. Finally, the article will address emerging challenges in the diagnosis and monitoring of pneumonitis, including pneumonitis from combination ICI and radiation therapy and from antibody conjugate therapy, as well as the overlapping imaging features of drug-related pneumonitis and coronavirus disease 2019 pneumonia. The review is designed to provide a practical overview of drug-related pneumonitis from cutting-edge cancer therapy with emphasis on the role of imaging.

Analysis of Local Control Outcomes and Clinical Prognostic Factors in Localized Pelvic Ewing Sarcoma Patients Treated With Radiation Therapy: A Report From the Children's Oncology Group

To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy. Data for 101 patients treated with definitive radiation therapy (RT) or both surgery and radiation (S+RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks. The most common pelvic subsite was sacrum (44.6%). RT was used in 68% of patients and S+RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S+RT (P=.046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (P=.02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P=.06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P=.04). Multivariable analysis demonstrated RT alone (hazard ratio [HR], 5.1; P=.04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P=.02), and increasing volume per 100 mL (HR, 1.2; P=.01) were associated with a higher incidence of local recurrence. Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features.

National Trends in Utilization of Neoadjuvant Radiation for Pancreatic Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Neoadjuvant therapy (NAT) has been shown to improve clinical outcomes for patients (pts) with operable pancreatic adenocarcinoma (PDAC). The precise type of NAT used in the United States (US), such as chemotherapy alone or in sequence with external beam radiation therapy (RT), remains controversial. Our aim was to examine the use of neoadjuvant RT for pts who underwent pancreatectomy for PDAC in the US. <h3>Materials/Methods</h3> The National Cancer Database (NCDB) was queried for patients with localized PDAC who underwent pancreatectomy between 2009-2018. NAT was defined as receipt of chemotherapy and/or external beam RT prior to surgery at a dose 30-70 Gy, excluding palliative regimens. Center volumes were examined by surgical and RT cases/year. Comparisons and trends were made using the χ2 and Mann-Kendall tests. Logistic regression (LR) models were used to identify patient and institutional factors associated with receipt of neoadjuvant RT. <h3>Results</h3> A total 58,653 pts underwent pancreatectomy for PDAC and 13,223 (22.5%) received any NAT prior to surgery. Of these, 4,568 (7.8%) received RT; 4,453 (97.5%) of 4,568 received RT in combination with neoadjuvant chemotherapy and 115 (2.5%) of 4,568 received RT as the sole NAT. While the proportion of pts who received any NAT rose significantly from 13.5% in 2009-12 to 32.3% in 2016-18, the proportion of pts who received RT as a component of NAT rose only modestly from 6.8% in 2009-12 to 8.8% in 2016-18 (<i>p</i><0.001). Among the 4,568 pts who received neoadjuvant RT, administration of conventionally fractionated chemo-RT (25-28 fractions) declined from 62.4% in 2009-12 to 49.9% in 2016-18. Stereotactic body radiation therapy (SBRT) increased from 5.0% in 2009-12 to 25.9% in 2016-18 (<i>p</i><0.001). A total 598 unique centers treated the 4,568 pts who received neoadjuvant RT. The median pts treated annually per center was 3.2/year (IQR 6.9). Treating ≥7 pts/year qualified a center as being in the top tertile (67-100th percentile) for the use of neoadjuvant RT. In a multivariable LR model, pts with advanced age (OR 0.98, 95% CI 0.97-0.98), uninsured (0.64, 0.49-0.84), on Medicaid (0.74, 0.64-0.87), and treated at low surgical volume centers (0.80, 0.72-0.90) had decreased odds of receiving neoadjuvant RT. Pts treated in later years (2016-18: 1.57, 1.45-1.70) and with larger (cT3 or cT4) tumors (2.66, 2.49-2.84) had increased odds of receiving neoadjuvant RT. <h3>Conclusion</h3> Less than 10% of pts with operable PDAC received neoadjuvant RT over the last decade. The slight increase in the use of RT may have been due to the expanding role for surgery in patients with borderline and locally advanced PDAC. SBRT is gaining in popularity despite the absence of phase II/III trials confirming its safety/efficacy in the neoadjuvant setting. The routine use of neoadjuvant RT appears localized to a small number of high-volume academic centers, a finding that may change with the recent publication of the PREOPANC trial.

Combination Radiation Therapy and Selective TLR9 Agonist Improves Local Control in a Murine Model of HPV-Related HNSCC

<h3>Purpose/Objective(s)</h3> As novel immunotherapies emerge, it has become increasingly evident that personalized treatment combinations are necessary to improve outcomes in head and neck squamous cell carcinomas (HNSCC). Toll-like receptors (TLR) play a critical role in the activation of professional antigen presenting cells (APC). Given the increasing appreciation of the role of APC and B-cells in HPV+ HNSCC, we sought to evaluate the therapeutic role of selective TLR agonists in combination with radiation therapy (RT). <h3>Materials/Methods</h3> For human tumor RNA sequencing studies, we analyzed data from the TCGA and a separate independent validation cohort of HNSCC patients, cumulatively totaling nearly 600 patients. Single cell RNA sequencing (scRNA-seq) databases were analyzed using Seurat v4.0. For murine studies, wild type C3H mice were injected subcutaneously with 5 × 10⁵ cells of AT-84-E7-OVA syngeneic squamous cell carcinoma into the right flank. TLR agonists were administered intratumorally in 25 uL per published schedules for: TLR4 (MPLA-SM, 1 mg/ml), TLR7 (1V270, 2 mg/ml), and TLR9 (ODN 1826, 2 mg/ml). Control mice received PBS. Mice receiving RT were treated with 12 Gy in 1 fraction. Cell surface markers in the tumor draining lymph node (TDLN) and tumor were analyzed by flow cytometry. <h3>Results</h3> Treatment with TLR4, TLR7, and TLR9 agonists decreased the size of the primary tumor in our murine model of HPV+ HNSCC, with a B cell selective TLR9 agonist exhibiting the greatest therapeutic benefit. When analyzing transcriptomes of HPV- tumors, we found no correlation between high TLR4/7/9 expression and outcomes, however, in HPV+ tumors, among TLRs 4/7/9, only TLR9 had a significant correlation with overall survival (HR 0.38, P = 0.008). In an independent cohort of HPV+ HNSCC patients, the correlation between OS and high TLR9 expression was maintained. scRNA-seq of human HNSCC TILs revealed heterogeneity in TLR9 expression among various immune cells. In the TDLN, TLR9 agonist were shown to decrease the relative proportion of B cells and trended towards increased proportions of CD4+ T cells, which had decreased expression of CD44. In comparison, in the tumor, we observed increased CD8+ T cell infiltration but decreased proportions of B cells with TLR9 agonists. When evaluating TLR9 agonists in conjunction with RT, we found that the combination treatment led to the largest therapeutic benefit. <h3>Conclusion</h3> In HPV+ HNSCC, transcriptional analysis revealed a significant correlation between high TLR9 expression and overall survival. Concordantly, the combination of RT and TLR9 agonists lead to a significant reduction in the primary tumor, which may be driven by dynamic changes in B cell phenotype or migration patterns and CD8+ T cell tumor infiltration. These findings support the further investigation into the use of TLR9 agonists in combination with radiation therapy for the treatment of HPV+ HNSCC.