Purpose/Objective(s) Five fraction salvage stereotactic body radiation therapy (SBRT) is a Delphi consensus recommendation for prostate re-irradiation, yet remains debatable and underutilized, and is associated with higher risk of treatment-related adverse events compared to primary radiotherapy. We hypothesized that intensification of hypo-fractionation delivering 2 fractions of 9 GY would be advantageous and here report the feasibility, toxicity, and preliminary outcomes of 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) directed salvage focal re-irradiation with this regimen. Materials/Methods From July 2022 to November 2023, 17 Men with isolated prostate cancer recurrence after definitive radiation were treated at single institution. All patients underwent 68Ga-PSMA PET/CT following biochemical recurrence by the phoenix criteria or a repeated PSA increase. Confirmation of recurrence was performed by prostate biopsy and multiparametric MRI in 53% and 35% of patients, respectively. Focal SBRT of 18 Gy in two fractions was delivered to the PSMA-avid disease and a 3-5mm margin in the prostate on alternate days with image guidance by fiducial markers. Placement of hydrogel spacer (29%) or endorectal balloon (71%) was mandated. Androgen deprivation therapy was given concurrently in 88% of patients for a median duration of six months (range = 4-21). Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 5. Results Median follow-up was 11.9 months (range = 3-18) with a median time between primary radiation treatment and salvage SBRT of 4.3 years (range = 0.6- 15.6). Median age was 73.1 (range = 66-89) and Prostate-specific antigen (PSA) level at reirradiation was 1.87 ng/ml (range = 0.02-7.1). At the end of follow up only one patient had a biochemical recurrence, which was confirmed by 68Ga-PSMA PET/CT. No patient developed acute or late gastrointestinal toxicity, and four patients (23.5%) did not have any adverse events. Rates of acute genitourinary (GU) toxicity grade 1 and 2 were 41.2% and 11.8%, respectively. Late grade 1 and 2 GU toxicity occurred in 41% and 35%, with cystitis as the leading toxicity followed by urinary incontinence. No grade 3 or 4 toxicities were reported. Conclusion With a short follow-up, PSMA-directed salvage focal reirradiation to the prostate using SBRT of 18 Gy in two fractions is feasible and has acceptable toxicity. No gastrointestinal toxicity was reported, as well as no high-grade toxicity of any type, with very favorable short term biochemical control in a selected cohort of patients.

Purpose/Objective(s)Gastro-intestinal (GI) side effects are dose limiting for pelvic & abdominal radiation therapy (RT). Advanced-age is hypothesized to be an aggravating factor in severe radiation toxicity, but this has not been well defined. We sought to quantify the effect of age on grade IV / V gastro-intestinal complications of RT by combining information from two US population-based databases.Materials/MethodsThe absolute number of complications was obtained by querying the National Inpatient Database (NIS) of the Healthcare Cost and Utilization Project, which contains discharge data from a 20% stratified sample of all US non-federal hospitals. Inclusion criteria were inpatient episodes between 2015-18, with listed diagnoses of both ‘Malignant neoplasm of rectum' (ICD-10-CM Code C20), and ‘Gastroenteritis and colitis due to radiation' (ICD-10-CM Code K52.0). A grade IV complication was defined as a hospitalization, alive on discharge; whereas grade V was defined as a hospitalization culminating in death. The relative age-distribution of patients with rectal cancer treated with RT was obtained from the SEER database. Relative toxicity incidence by age group was obtained by normalizing the absolute number of toxic events obtained from NIS with the age-distribution treatment data from SEER. Statistical techniques included best-fit linear regression and multivariate logistic regression.ResultsWithin the NIS database there were 31,878 hospitalizations with a listed diagnosis of rectal cancer (median age 63 years), of whom 290 had grade IV (median age 66) and 10 grade V (median age 76.5) radiation gastroenteritis / colitis. There were no grade 4 toxicities under the age of 20, and no grade 5 toxicities under the age of 70. After adjusting for the baseline age distribution of rectal cancer patients receiving radiation derived from SEER data, the relative risk (RR) of grade IV toxicity was 0.44 for subjects aged 20-39, and 0.53 for subjects aged 40-59 and 1.0 for 60-79 (the comparator). The RR for grade V toxicity was zero for <60, 1.0 for 60-79 (the comparator), and 1.26 for subjects aged 80-99. Best-fit linear regression line for grade IV toxicity was defined by [0.0084* age(yrs)* + 0.2], and for grade V toxicity by [0.024* age(yrs)* - 0.87]. On multivariate logistic regression, amongst all those with grade 4-5 radiation gastroenteritis / colitis, age was the only clinical predictor of death (dosimetric factors were not available).ConclusionWe demonstrate that the risk of acute severe radiation-induced bowel toxicity in rectal cancer patients rises linearly with age. Modelling demonstrates that the gradient is far steeper for grade V toxicity than grade IV toxicity. Importantly, our results facilitate the incorporated of age into existing NTCP models of bowel toxicity. Age-adjusted radiation dose constraints for the bowel should be adopted.

Senescence is considered a contributor to radiation resistance. The mechanisms underlying radiation-induced senescence are poorly understood. The programmed cell death network comprises the apoptosis, autophagy and programmed necrosis pathways. The programmed cell death network's physiological role is the removal of unwanted, infected or damaged cells. We hypothesized that the programmed cell death network plays a critical role in irradiation (IR)-induced senescence, and hence modulation of the network will determine the outcome of cancer cells following irradiation. We developed a novel experimental model system of IR-induced senescence in NCI-H460 (NSCLC cell line). Subsequently, we performed a siRNA screen of programmed cell death genes, using IR-induced senescence as an endpoint, based upon the CellTiter glo assay - a reduction in the extent of senescence response to IR indicated the corresponding gene functions as a positive mediator of senescence. Results were validated both genetically and pharmacologically. Further experiments explored the putative targets' substrates and functions. We found that IR of NCI-H460 cells induced prominently cellular senescence, as evident by morphological and biochemical changes (including SA-β-gal staining). Subsequently we identified several hits in the siRNA screen. The top hit was a specific serine protease with known pro-apoptotic activity, yet not previously linked to senescence. We demonstrated that knock down of the serine protease mitigated the IR induced reduction in cell number/metabolic state, the increase in cell size characteristic of cellular senescence and the increase in SA-β-gal staining. The serine protease's critical role in IR-induced senescence was further validated using a pharmacological inhibitor. Potential substrates of the serine protease were identified, including a cytoskeletal protein whose cleavage following IR was mediated by the serine protease. We have revealed a serine protease as a critical mediator of IR-induced senescence. Based upon the serine protease's substrates, for the first time we are able to postulate the basis for the morphological changes seen during IR senescence. This serine protease is a potential new target for radiation sensitization. * The abstract contains unpublished data. The precise identity of the substrates and proteins will be disclosed at the meeting.

PURPOSE/OBJECTIVES:The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy.MATERIALS AND METHODS:Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes.RESULTS:Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002).CONCLUSIONS:Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT.

Many patients with upper-abdominal malignancies suffer from a characteristic syndrome of severe lower back pain radiating to the epigastrium, thought to be caused by involvement of the celiac plexus. Contemporary approaches (opioids, celiac blocks, systemic chemotherapy) are often inadequate. We hypothesized that ablative radiation delivered to the celiac plexus would alleviate pain levels. We performed a single-institution prospective clinical trial to evaluate a novel therapeutic approach: stereotactic radiation therapy focused on the celiac plexus. Eligibility criteria included typical celiac-pain syndrome, significant pain despite opioid usage (Numerical Rating Scale, NRS > 4/10), prognosis > 8 weeks, ECOG 0-3. Evaluable patients were defined as those completing treatment per protocol and completed at least one post-treatment visit. Exclusion criteria included previous abdominal RT. The anterolateral aspect of the aorta from D12 to L2 was used as a surrogate marker for the celiac plexus; primary tumor was irradiated according to physicians’ discretion. Radiation dose was originally 9 Gy*5, and later amended to a single fraction 25 Gy, both using VMAT. A dose-painting technique was used to limit dose to duodenum. The primary endpoint was pain-relief 3 weeks post-treatment, measured using NRS. Secondary endpoints included pain at 6 weeks, analgesic use, toxicity (CTCAE v4.03), and pain interference with seven daily activities as evaluated by the ‘Brief Pain Inventory' (BPI) instrument before and after radiation therapy. Analgesic use was not restricted. Twenty-one subjects were evaluable: 2 received 9Gy*5, 19 received 25Gy*1. The median age was 65 (range 37-83 years) with a Median ECOG of 1, 86% had pancreatic cancer. Median volume of celiac plexus was 30.8 cc, median dose to celiac plexus was 25 Gy. All patients reported decreased celiac pain: median pain level prior to RT was 6/10 (IQR 5-7.5) and reduced to 2.3/10 NRS score (IQR 0.9-3.3) (p <0.0005 compared to baseline) at 3 weeks (primary endpoint), and to 1.8/10 (IQR 0-3) (p <0.0005 compared to baseline) at 6 weeks’ post-treatment. 76% of patients reported a significant decrease of pain at primary endpoint (two point decrease), and in one third of patients the celiac pain had been eliminated entirely during follow-up. Toxicity was minimal and limited to grade 1-2 (2 patients reported mild worsening of pain immediately following treatment, some limited nausea/vomiting). Median daily morphine equivalent dose consumption decreased (NS). A significant improvement was noted in all evaluated measures of quality of life. Celiac plexus radiosurgery is well tolerated, substantially decreases pain, and improves quality of life amongst patients with advanced upper-GI cancer. An international multicenter phase II trial is currently accruing.