Background We previously reported outcomes after hypofractionated postprostatectomy radiotherapy (HYPORT) with a median follow-up of 32 months. This was a primary citation supporting the fractionation selection for NRG-GU003, which showed noninferiority of HYPORT versus conventional radiotherapy. Methods One hundred sixty-one consecutive patients with biochemically recurrent prostate cancer after prostatectomy underwent HYPORT from 2003 to 2013 at a single academic institution using image guided intensity modulated radiation therapy, with the majority (154 of 161) receiving 65 Gy in 26 fractions. Results Median follow-up was 13.5 years. Forty-four patients (27.3%) experienced 58 late grade 3 to 5 toxicities (LTOX3) a median of 106 months after HYPORT. Fifty-five of 58 LTOX3 were genitourinary related. Higher-grade toxicities included 6 cystectomies and 3 deaths. At 2 years, only 2 patients had experienced an LTOX3. At 15 years, overall survival was 70%, freedom from biochemical recurrence was 52%, and the risk of LTOX3 was 34%. Conclusions Long follow-up is needed to fully capture severe toxicities after dose-escalated HYPORT. This should be considered prior to the broad adoption of similar regimens for this patient population with long survival potential.

Purpose: Elective nodal irradiation (ENI) in resectable pancreatic cancer remains undefined, although occult nodal disease is common. This study investigated the use of neoadjuvant stereotactic body radiation therapy (SBRT) for primary disease with ENI, with concurrent capecitabine therapy. Safety data for this protocol were previously reported. In this report, we provided an updated survival Methods and Materials: This is a prospective, single institution, phase 1A/B dose-escalation trial that enrolled patients with biopsyproven, resectable, pancreatic adenocarcinoma between 2014 and 2019 (NCT1918644). Patients were enrolled into 1 of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine (1650 mg/m2). All patients received ENI (5 Gy pound 5 fractions). Our initial report found no dose-limiting toxicities. Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier curves were employed for survival analysis. Results: Of 17 enrolled patients, 16 were evaluable (94.1%). Thirteen (76.5%) proceeded to surgery. The median follow-up was 28.0 (range, 1.7-71.9) months. Four patients (25.0%) received neoadjuvant chemotherapy, and 6 (37.5%) received adjuvant chemotherapy. Pathologic nodal involvement (69.2%) was associated with a higher risk of any relapse (P < .01) and distant metastasis (P = .02). Local failure occurred in 4 (25%) patients, with 2 of 4 of those failures occurring partially within the 25 Gy elective nodal field and 1 of 4 occurring in the 25 Gy elective nodal field and partially within the 35 Gy tumor field. The median overall survival (OS) and disease-free survival (DFS) were 31.1 (range, 2.3-73.6) months and 12.0 (range, 0.4-71.9) months, respectively. Three-year OS and DFS were 50% and 31.3% overall, and 61.5% and 38.5% for the surgical cohort. Patients with positive lymph nodes had worse median OS (23.9 vs 69.3 months; P = .002) and DFS (9.9 vs 58.9 months; P = .002). No further radiation-related toxicities were noted since the prior report. Conclusions: Neoadjuvant SBRT to the primary tumor with ENI and radiosensitizing chemotherapy is a feasible approach that may improve outcomes in patients with resectable and borderline pancreatic cancer, despite high rates of pathologic nodal involvement. Further investigation of this strategy is warranted in a larger cohort.

652 Background: Radiation may have a role in management of patients with early-stage pancreatic cancer. However, the role of regional nodal irradiation (RNI) is not well defined despite the high frequency of occult nodal disease. The goal of this trial was to evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) to primary disease with RNI, combined with capecitabine as a neoadjuvant approach for patients with resectable pancreatic cancer. Updated survival analysis will be presented here. Methods: This is a prospective, single institution, phase IA/B dose-escalation trial that enrolled patients with biopsy-proven, resectable, pancreatic adenocarcinoma between 2014 – 2019 (NCT1918644). Patients were enrolled into one of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine. All patients received RNI 5 Gy x 5 fractions. Our initial report found no dose-limiting toxicities (Witt et al IJROBP 2020). Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier curves were employed for survival analysis. Results: Seventeen patients were enrolled on the protocol with sixteen evaluable (94.1%). Thirteen (76.5%) patients proceeded to surgery. Median follow up was 31.1 months (2.0 – 73.2). Among the evaluable patients, 63% were male, median age at diagnosis was 73 years (63 – 84), pre-treatment CA 19-9 149.5 U/mL (2.0 – 19358.0). The majority of patients had cT2-3 (94%) and cN0 (87.5%) disease. In patients who underwent resection, median time from radiation to surgery was 19.7 days (14.8 – 42.4), with median of 18 lymph nodes removed (11 – 27). Pathologically involved nodes were present in 69.2% of patients with a median of 2 nodes (1 – 10). Five patients (31.3%) received neoadjuvant chemotherapy, and ten (62.5%) received adjuvant chemotherapy. At the time of data cutoff, median overall survival was 31.1 months (2.3 – 73.6), and median locoregional control and distant metastasis free survivals were 32.8 months (4.0 – 59.5) and 15.3 months (0.4 – 73.6), respectively. No further radiation related toxicities were noted since the prior report. Conclusions: Neoadjuvant chemoradiation with SBRT and capecitabine to primary disease with RNI is feasible and provided a promising signal of durable local control in our study, despite high rates of pathological nodal involvement. Further investigation of this strategy is warranted in a larger cohort of patients. Clinical trial information: NCT1918644 .

Purpose: In this prospective phase 2 trial, we investigated the toxicity and patient-reported quality-of-life outcomes in patients treated with stereotactic body radiation therapy (SBRT) to the prostate gland and a simultaneous focal boost to magnetic resonance imaging (MRI)-identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk. Methods and Materials: Eligible patients included low-or intermediate-risk prostate cancer (Gleason score <= 7, prostate specific antigen <= 20, T stage <= 2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with any areas of high disease burden (MRI-identified prostate imaging reporting and data system 4 or 5 lesions) simultaneously escalated to 42.5 to 45 Gy and areas overlapping organs at risk (within 2 mm of urethra, rectum, and bladder) constrained to 36.25 Gy (n = 100). Patients without a pretreatment MRI or without MRI-identified lesions were treated to dose of 37.5 Gy with no focal boost (n = 14).Results: From 2015 to 2022, a total of 114 patients were enrolled with a median follow-up of 42 months. No acute or late grade 3+ gastrointestinal (GI) toxicity was observed. One patient developed late grade 3 genitourinary (GU) toxicity at 16 months. In patients treated with focal boost (n = 100), acute grade 2 GU and GI toxicity was seen in 38% and 4% of patients, respectively. Cumulative late grade 2+ GU and GI toxicities at 24 months were 13% and 5% respectively. Patient-reported outcomes showed no significant long-term change from baseline in urinary, bowel, hormonal, or sexual quality-of-life scores after treatment.Conclusions: SBRT to a dose of 40 Gy to the prostate gland with a simultaneous focal boost up to 45 Gy is well tolerated with similar rates of acute and late grade 2+ GI and GU toxicity as seen in other SBRT regimens without intraprostatic boost. Moreover, no significant long-term changes were seen in patient-reported urinary, bowel, or sexual outcomes from pretreatment baseline. (c) 2023 Elsevier Inc. All rights reserved.

Purpose:The recently reported FLAME trial demonstrated a biochemical disease-free survival benefit to using a focal intraprostatic boost to multiparametric magnetic resonance imaging (mpMRI)-identified lesions in men with localized prostate cancer treated with definitive radiation therapy. Prostate-specific membrane antigen (PSMA)-directed positron emission tomography (PET) may identify additional areas of disease. In this work, we investigated using both PSMA PET and mpMRI in planning focal intraprostatic boosts using stereotactic body radiation therapy (SBRT). Methods and Materials:We evaluated a cohort of patients (n = 13) with localized prostate cancer who were imaged with 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-2-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/MRI on a prospective imaging trial before undergoing definitive therapy. The number of lesions concordant (overlapping) and discordant (no overlap) on PET and MRI was assessed. Overlap between concordant lesions was evaluated using the Dice and Jaccard similarity coefficients. Prostate SBRT plans were created fusing the PET/MRI imaging to computed tomography scans acquired the same day. Plans were created using only MRI-identified lesions, only PET-identified lesions, and the combined PET/MRI lesions. Coverage of the intraprostatic lesions and doses to the rectum and urethra were assessed for each of these plans. Results:The majority of lesions (21/39, 53.8%) were discordant between MRI and PET, with more lesions seen by PET alone (12) than MRI alone (9). Of lesions that were concordant between PET and MRI, there were still areas that did not overlap between scans (average Dice coefficient, 0.34). Prostate SBRT planning using all lesions to define a focal intraprostatic boost provided the best coverage of all lesions without compromising constraints on the rectum and urethra. Conclusions:Using both mpMRI and PSMA-directed PET may better identify all areas of gross disease within the prostate. Using both imaging modalities could improve the planning of focal intraprostatic boosts.

PurposeThe role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach.Methods and MaterialsPatients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT.ResultsA total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume.ConclusionsSBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

PURPOSE:This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer.METHODS AND MATERIALS:Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity.RESULTS:A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively.CONCLUSIONS:HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/β ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.

TPS874 Background: Colorectal cancer (CRC) is one of the few cancers in which aggressive local approaches to treat systemic metastases have resulted in clinical benefit. Despite these approaches 70-80% of patients (pts) with resectable metastatic disease will recur. The one-year recurrence rate for this population is ~40-50%. Immunotherapeutics have yet to be studied in this setting. To sensitize microsatellite stable (MSS) CRCs to immune therapies adjunctive therapies are required. Gross tumor microenvironments suppress systemic anti-cancer immune responses. Stereotactic body radiation therapy (SBRT) is commonly utilized to treat liver metastatic CRC, using very high doses of focused radiation to ablate tumors. This causes localized inflammation, a potential increase in immunogenic intra-tumoral and intra-lymphatic antigen release, and a rapid influx of responding immune cells. We hypothesize that radiotherapy-induced tumor necrosis, and surgical removal of the remaining immunosuppressive gross disease will enhance the immunogenicity of CRC and potentiate the effectiveness of PD-1 blockade. Methods: This is a single arm phase 1b investigator-initiated study (NCT02837263) to evaluate the use of pem in combination with ablative radiotherapy for the treatment of oligometastatic CRC. This study examines the sequential use of SBRT, then pem followed by resection of all known sites of disease and 6 months of adjuvant pem. Pts with MSS CRC with resectable liver metastatic disease who have received prior FOLFOX are eligible. The primary endpoints are safety/tolerability and the rate of cancer recurrence at 1 year. Secondary endpoints include time to disease recurrence, disease free survival and overall survival. This study is currently enrolling with a planned total accrual of 15 patients. Correlative studies examine PD-L1 status, tumor infiltrating lymphocytes, evidence of an abscopal effect, versican proteolysis as a novel immune biomarker, and the ability of multiparametric fluorodeoxyglucose (FDG) PET MR and fluorothymidine (FLT) PET CT to detect immune infiltration. Clinical trial information: NCT02837263.

Professor Jack Fowler passed away on December 1, 2016. He died peacefully at his home in London, in the arms of his beloved wife Anna, at the age of 91. Jack enjoyed a long and colorful professional career. Perhaps best known for his contributions to "fractionation" in radiation oncology, Jack was a prolific thinker, writer, and speaker over many decades. His academic career was launched strongly in physics at the University of London (BSc 1944, MSc 1946, PhD 1955) (Fig. 1) with contributions in radiation dosimetry and dose-rate effects but also in particle radiobiology and reduced oxygen effects of fast neutron radiation (he worked at the Medical Research Council Cyclotron Unit). However, Jack was intrigued by radiation biology early in his career and commenced tissue and animal experimentation on fractionation effects in normal tissues. Indeed, Jack earned his DSc 1974 in radiation biology and by mid-career was highly engaged in cancer biology, with subsequent interest in radiation fractionation schedules, tumor proliferation, and clinical outcomes. Jack served as director of the Gray Laboratory in Northwood, United Kingdom from 1969 to 1988, following Hal Gray and Oliver Scott in this leadership role. During Jack's tenure, the Gray Laboratory boasted a robust cadre of scientific talent, including Ged Adams, Adrian Begg, Julie Denekamp, Mike Joiner, Barry Michael, Fiona Stewart, Boris Vojnovic, Peter Wardman, George Wilson, and others. Significant contributions to tumor and normal tissue radiobiology emerged during this period, and Jack was integral to much of this work. The Gray Laboratory attracted many bright students, fellows, and faculty during this era, including Eli Glatstein, Lester Peters, Liz Travis, and others who interacted with Jack. With increasing focus on radiation fractionation, Jack was engaged in animal studies as well as consultation on design of human fractionation trials that attracted his interest during much of his latter career. Among the most influential of these liaisons came from the collaboration of Jack with Julie Denekamp and clinicians Stanley Dische and Michelle Saunders at the Mt. Vernon Hospital. The well-known Continuous Hyperfractionated Accelerated RadioTherapy (CHART) trial emerged from this productive collaboration and provided an enormously valuable foundation for much of today's knowledge of time–dose relationships in clinical radiation oncology. Soon after "retirement" from the Gray Laboratory, Jack joined the faculty as a visiting professor at the University of Wisconsin in Madison, where his contributions continued to flourish (Fig. 2, Fig. 3). Freed from administrative duties, Jack could focus his energies on reading, writing, teaching, and collaborating with researchers in Madison and across the globe. At Wisconsin, Jack worked closely and published broadly with a variety of clinicians, physicists, and statisticians (Dolores Buchler, Judith Stitt, Daniel Petereit, Bhudatt Paliwal, Bruce Thomadsen, Thomas "Rock" Mackie, Timothy Kinsella, Mark Ritter, Paul Harari, Richard Chappell, Mary Lindstrom, Minesh Mehta, Wolfgang Tome, and others) on clinical fractionation schedules (external beam and high dose rate), tumor cell proliferation, and overall treatment time. A charismatic teacher, he energized Madison's graduate school radiobiology curriculum and also held extended teaching engagements in Leuven (Belgium) and Umeå (Sweden) during this time frame.Fig. 3Jack Fowler, in his office at University of Wisconsin, circa 1992.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This was an enormously productive phase of Jack's career. His passion for linear-quadratic modeling and α/β analysis, combined with his ability to illuminate these concepts logically to colleagues, made Jack a coveted advisor, speaker, and analyst of clinical fractionation schedules across the globe. Fortunately, he enjoyed excellent health, loved to travel, and made his way around the world for various collaborations during this period. Although Jack was famous for devoting his undivided attention to any first-year student, he also loved interactions with other leading radiobiology and mathematical thinkers, including Howard Thames, Rod Withers, Eric Hall, Herman Suit, Bert van der Kogel, Emmanuel van der Schueren, Jolyon Hendry, David Brenner, Soren Bentzen, and many others throughout the years (Figure 4). Jack was a very prolific writer, with more than 550 papers listed on his curriculum vitae (several classic publications are referenced here) (1Fowler J.F. Stern B.E. Fractionation and dose-rate. Dose-time relationships in radiotherapy and the validity of cell survival curve models.Br J Radiol. 1963; 36: 163-173Crossref PubMed Scopus (44) Google Scholar, 2Fowler J.F. Bewley D.K. Morgan R.L. et al.Dose-effect relationships for radiation damage to organized tissues.Nature. 1963; 199: 253-255Crossref PubMed Scopus (10) Google Scholar, 3Denekamp J. Ball M.M. Fowler J.F. Recovery and repopulation in mouse skin as function of time after x-irradiation.Radiat Res. 1969; 37: 361-370Crossref PubMed Scopus (44) Google Scholar, 4Douglas B.G. Fowler J.F. The effect of multiple small doses of x rays on skin reactions in the mouse and a basic interpretation.Radiat Res. 1976; 66: 401-426Crossref PubMed Scopus (470) Google Scholar, 5Fowler J.F. Adams G.E. Denekamp J. Radiosensitizers of hypoxic cells in solid tumors.Cancer Treat Rev. 1976; 3: 227-256Abstract Full Text PDF PubMed Scopus (114) Google Scholar, 6Fowler J.F. The linear-quadratic formula and progress in fractionated radiotherapy.Br J Radiol. 1989; 62: 679-694Crossref PubMed Scopus (1749) Google Scholar, 7Fowler J.F. The phantom of tumor treatment—continually rapid proliferation unmasked.Radiother Oncol. 1991; 22: 156-158Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 8Fowler J.F. Lindstrom M.J. Loss of local control with prolongation in radiotherapy.Int J Radiat Oncol Biol Phys. 1992; 23: 457-467Abstract Full Text PDF PubMed Scopus (433) Google Scholar, 9Petereit D.G. Sarkaria J.N. Chappell R. et al.The adverse effect of treatment prolongation in cervical carcinoma.Int J Radiat Oncol Biol Phys. 1995; 32: 1301-1307Abstract Full Text PDF PubMed Scopus (246) Google Scholar, 10Fowler J.F. 21 years of biologically effective dose.Br J Radiol. 2010; 83: 554-568Crossref PubMed Scopus (392) Google Scholar). He published a book at the age of 89 on fractionation and overall treatment time in radiation oncology. He earned many awards and medals during his influential career. These include the Rontgen Prize of the British Institute of Radiology (1965), Breur Medal of the European Society for Radiotherapy and Oncology (1983), Juan del Regato Gold Medal (1984), Gold Medal of the Gilbert Fletcher Society (1986), Gold Medal of the American Society for Radiation Oncology (1995), and Radiation Research Society Failla Award (2002), among many others. A signature trait of Jack's was his remarkably upbeat, enthusiastic, and energetic style. Jack routinely met or beat deadlines, provided rapid and in-depth feedback to scientific queries, and made it very clear to colleagues that he was genuinely excited about "their" research. This style triggered widespread interest on the part of many to work with Jack. Radiation oncology clinicians around the world would contact Jack for advice on clinical fractionation questions and trial design. Jack always enjoyed immensely being an active life participant. He had a knack for learning as much or more about your region of the world than you knew yourself. He loved reading, theater, sports, dancing, wine and beer tasting, historic museums, and points of interest, to name a few. He was the father of seven children and grandfather to a cadre of grandchildren and great grandchildren. His wife since 1992, Anna Edwards Fowler, was a beautiful match and companion to Jack for almost 25 years. Anna and Jack brought great happiness and comfort to one another throughout the years. The breadth of the contributions made by Jack Fowler to the fields of radiation physics, biology, and oncology over 6 decades is compelling. In recognition, an endowed professorship in Jack's name was established at the time of his retirement from the University of Wisconsin in 2004 that serves to promote research, teaching, and collaboration in radiation oncology. The professorship also provides support for the annual Jack Fowler University of Wisconsin ESTRO and Radiation Research Society Awards to honor outstanding junior investigators. The discipline of radiation oncology was very fortunate to be blessed by this energetic and innovative researcher and collaborator. His willingness to listen, learn, inquire, analyze, rethink, and postulate new solutions rendered him a master teacher for generations. May the unwavering creativity and enthusiasm of Jack Fowler continue to inspire the very best in each of us.

BACKGROUND Angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS Among patients taking ACEIs/ARBs in the UW data set, a significant 3‐fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2‐fold–increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06‐7.82; P < .001). CONCLUSIONS The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487–95 . © 2016 American Cancer Society .

Purpose: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy.Methods and Materials: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of >= 50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching.Results: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses).Conclusions: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer. (C) 2016 Elsevier Inc. All rights reserved.

Objective This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. Methods 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. Results Bowel QoL data at 3 years revealed no significant difference among regimens (p = 0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p = 0.343) although, for all patients combined, a significant decline was observed from the baseline (p = 0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p = 0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. Conclusions Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94–4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer

e15017 Background: Induction chemoradiation therapy (CRT) followed by esophagectomy has recently gained wider acceptance as the preferred treatment for locoregionally advanced esophageal cancer. However, CRT has the potential to further debilitate patients and may complicate resection given the resulting inflammation and fibrosis that occurs in the surgical field. Controversy exists as to whether or not these potential effects have a negative impact on perioperative outcomes. Methods: We performed a retrospective review of 163 patients treated for primary esophageal cancer with potentially curative esophagectomy between January 2009 and June 2013 at our institution. Data including preoperative patient characteristics and perioperative outcomes was obtained from our prospectively collected and maintained database. Comparisons were made between patients who received induction therapy followed by surgery (n = 90) and surgery alone (n = 73). Results: All but two patients in the induction cohort received combined CRT. Induction therapy was successfully completed in 83 patients (92%). Preoperative characteristics varied significantly between cohorts, including age, nutritional status, and cardiovascular comorbidity. In comparing CRT plus surgery vs. surgery alone, no significant differences were noted in overall morbidity (39% vs. 52%, p=0.114), pulmonary complications (14% vs. 22%, p=0.225), or anastomotic leak rate (14% vs. 10%, p=0.473). Thirty-day (1% vs. 3%, p=0.587) and 90-day mortality (4% vs. 3%, p=0.692) were similar. In the CRT group, 25 patients (28%) had a pathologic complete response. Shorter mean LOS (9 days vs. 12 days, p=0.079) and more frequent discharge to home (96% vs. 83%, p=0.015) favored the induction cohort. Conclusions: Morbidity and mortality was similar in patients who did or did not receive CRT prior to esophagectomy in the present series. Patients in the CRT cohort were discharged home more often and a trend toward shorter LOS was noted. However, these patients tended to be younger and in better health prior to treatment. This study supports the hypothesis that induction CRT does not worsen perioperative outcomes in properly selected patients.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The recently published Prostate Cancer Intervention versus Observation Trial (PIVOT) did not identify differences in prostate cancer-specific mortality or all-cause mortality among patients with low-risk disease managed conservatively vs those managed definitively; however, recently published data suggest that older men may harbour more aggressive disease than is identified at biopsy owing to sampling error and undergrading. Whether older men with apparent low-risk disease are placed at risk of prostate cancer-specific mortality when managed conservatively remains unknown. The study used population-level data to show that non-curative approaches for older men with low-risk prostate cancer do result in an increased risk of prostate cancer-specific mortality. Differences between our study and the PIVOT trial include the fact that we included a larger sample size, analysed the data using an 'as-treated' approach, and included a healthier cohort of men as evinced by lower 4-year all-cause mortality estimates in our study than in the PIVOT. Our results suggest that older men with apparent low-risk prostate cancer are at risk of undergrading, which probably explains the differences in prostate cancer-specific mortality observed between men managed conservatively vs those managed definitively. Our study suggests that alternative approaches to excluding occult, high grade prostate cancer are needed in such men.

A 52-year-old patient with a family history of prostate cancer is screened for prostate cancer on the basis of his prostate-specific antigen (PSA) level. The initial value is 10.2 ng/mL, which is confirmed as 11 ng/mL on repeat testing. Clinically, he is found to have no prostate abnormalities on digital rectal examination (T1c). Prostate ultrasound and biopsy reveal two cores that are 90% positive with a Gleason score of 4 + 3 = 7. The options of surveillance, radiation treatment, or surgery are discussed, and the patient elects to undergo radical prostatectomy. Final pathology confirms an adenocarcinoma with a Gleason score of 7 (4 + 3) that extensively involves the left gland. The tumor margins are negative, and there is no seminal vesicle involvement. However, one obturator node is positive (one of 14 pelvic lymph nodes) for adenocarcinoma, making his pathologic staging pT2cN1M0. Initial postoperative PSA obtained 2 months after surgery is found to be undetectable.

Since delivered dose is rarely the same with planned, we calculated the delivered total dose to ten prostate radiotherapy patients treated with rectal balloons using deformable dose accumulation (DDA) and compared it with the planned dose. The patients were treated with TomoTherapy using two rectal balloon designs: five patients had the Radiadyne balloon (balloon A), and five patients had the EZ-EM balloon (balloon B). Prostate and rectal wall contours were outlined on each pre-treatment MVCT for all patients. Delivered fractional doses were calculated using the MVCT taken immediately prior to delivery. Dose grids were accumulated to the last MVCT using DDA tools in Pinnacle3 TM (v9.100, Philips Radiation Oncology Systems, Fitchburg, USA). Delivered total doses were compared with planned doses using prostate and rectal wall DVHs. The rectal NTCP was calculated based on total delivered and planned doses for all patients using the Lyman model. For 8/10 patients, the rectal wall NTCP calculated using the delivered total dose was less than planned, with seven patients showing a decrease of more than 5% in NTCP. For 2/10 patients studied, the rectal wall NTCP calculated using total delivered dose was 2% higher than planned. This study indicates that for patients receiving hypofractionated radiotherapy for prostate cancer with a rectal balloon, total delivered doses to prostate is similar with planned while delivered dose to rectal walls may be significantly different from planned doses. 8/10 patients show significant correlation between rectal balloon anterior-posterior positions and some VD values.

PURPOSE:The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08.METHODS AND MATERIALS:468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria.RESULTS:In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation.CONCLUSIONS:High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

242 Background: Long term quality of life after diagnosis of prostate cancer (PC) is an important factor in determining treatment success and satisfaction. Here we investigate the quality of life in a rural cohort of individuals treated for PC within a single institution. Methods: The Expanded Prostate Cancer Index Composite (EPIC) and the Medical Outcomes Short-Form 36 (SF 36) were completed by a rural population based cohort diagnosed with prostate cancer between January of 2005 and December of 2010, enrolled in a population based biorepository. Medical records were interrogated electronically for information such as age at treatment, stage, CCI, and first course of treatment. Results: Of the 173 individuals within the cohort, we received 95 completed survey instruments. No differences in age group, stage at treatment, or treatment type between individuals who completed the survey and those who did not were observed. Median summary score for the sexual domain was 10 (min -6 max 77), median summary score for urinary domain was 85 (min 36 max 100), and median summary score for the bowel domain was 95 (min 68 max 100). Median physical health score was 80 (min 20 max 100) and median general health score was 67 (min 20 max 100). Overall satisfaction score was 75 (min 25 max 100). Scores for bowel and urinary function were not significantly associated with treatment, age, CCI, or stage at diagnosis. For the sexual domain, individuals with hormonal treatment scored worse than other treatments (ttest p=0.05). Overall physical health was associated (anova, p<=0.05) with treatment, age, CCI, and stage. In a multivariate model only treatment and an interaction term with treatment and CCI were significant. Satisfaction score varied with treatment, individuals who received radiation treatment had a higher mean satisfaction score (87 vs 68 for the other groups ANOVA p=0.03). Conclusions: The treatment for prostate cancer affected an individual's quality of life in the domains of physical function, and sexual health. Treatment also affected satisfaction score regardless of age or stage at diagnosis.