Importance:The treatment of prostate cancer with radiotherapy is evolving. How quickly radiotherapy can be delivered, and the relative risks and benefits of such a treatment, is of significant public interest. Objective:To determine whether stereotactic body radiotherapy (SBRT) was superior to moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) in terms of patient-reported urinary irritative/obstructive and bowel quality of life and disease-free survival (DFS). Design, Setting, and Participants:NRG-GU005 was a phase-3, international, open-label, randomized clinical trial. The study was activated on November 16, 2017, and closed to accrual on June 8, 2022. Date of last follow-up was October 13, 2024. There were 136 centers in Asia, Canada, Europe, and the United States that accrued patients to the study. Patients with localized prostate cancer, clinical stage T1-T2b with Gleason 3 + 4 (grade group 2) and prostate-specific antigen (PSA) level less than 20 ng/mL or Gleason 3 + 3 (grade group 1) and PSA level 10 to 20 ng/mL were eligible. Intended accrual of 692 patients provided reductions of 8% and 10% in minimal clinically important decline (MCID) frequency for urinary-irritative/obstructive and bowel domains of the Expanded Prostate Cancer Index Composite-26 Item (EPIC-26) instrument at 2 years and greater than 80% power to detect a hazard ratio of 0.62 in DFS. Interventions:Patients were randomized 1:1 to receive SBRT (36.25 Gy in 5 fractions; n = 353) or MH-IMRT (70 Gy in 28 fractions or 60 Gy in 20 fractions; n  =345). Main Outcomes and Measures:Primary outcomes were the frequency of an MCID in the urinary irritative/obstructive and bowel domains of the EPIC-26 at 2 years and DFS at 3 years. Results:A total of 698 patients were randomized. Median age was 68 years; 3% were Asian, 13% Black, and 80% White. Median follow-up was 3.2 years (range, 0-6.5). At 2 years, there was no significant difference in the urinary-irritative domain (35.4% vs 33.7%, P = .68). Urinary incontinence at 1 and 2 years after treatment and sexual function at 1 year after treatment favored SBRT. Fewer grade 3 + 4 genitourinary adverse events occurred in the SBRT vs MH-IMRT group (0.6% vs 2.5%, P = .04). There were significantly fewer MCIDs with SBRT vs MH-IMRT in the bowel domain (34.9% vs 43.8%, P = .03). At 3 years, DFS for MH-IMRT was 92.1% (95% CI, 88.9%-95.2%) vs 88.6% for SBRT (95% CI, 85.2%-92.1%) (1-sided log-rank P < .001). Conclusions and Relevance:Stereotactic body radiotherapy using a modest dose prescription improved multiple quality-of-life domains but was not superior to MH-IMRT in terms of DFS. The rate of PSA failure was not significantly improved in the SBRT vs MH-IMRT group. Trial Registration:ClinicalTrials.gov Identifier: NCT03367702.

Purpose NRG/RTOG 1115 was a phase 3 trial evaluating the addition of orteronel, a CYP17A1 inhibitor, to radiation therapy (RT) plus androgen deprivation therapy (ADT) in men with high-risk prostate cancer. Methods and Materials The study was designed to evaluate overall survival for 900 men with high-risk prostate cancer (Gleason 9-10, prostate specific antigen (PSA) > 20, or clinical stage T2 or higher with Gleason ≥ 8). Patients were randomized 1:1 to standard of care (SOC) therapy (RT plus 2 years of ADT) or SOC plus 2 years of orteronel. RT entailed image guided conventionally fractionated dose-escalated external beam RT to the prostate and pelvis to 45 Gy using intensity modulated RT with either intensity modulated RT (to 79.2 Gy) or brachytherapy boost. Health-related quality of life (HRQOL) was measured using the Expanded Prostate cancer Index Composite (EPIC), Patient-Reported Outcome Measurement Information System (PROMIS) fatigue, and EQ-5D. Accrual was halted early because of discontinuation of orteronel development and the trial redesigned to focus on a composite biochemical failure endpoint. Results There were a total of 231 eligible randomized patients. Only 29% in the orteronel arm received ≥80% of the planned dose. With median follow-up of 6.2 years, the cumulative incidence of grade 3+ adverse events was higher on orteronel than on the standard arm (P < .001; hazard ratio [HR], 2.32; 95% CI, 1.52-3.47) with 5-year estimates of 59.0% and 35.1%, respectively. No significant differences in overall survival (P = .28; HR, 0.71; 95% CI, 0.39-1.32) or biochemical failure (P = .56; HR, 0.84; 95% CI, 0.47-1.51) were observed. Use of orteronel had a transient negative impact on all prostate cancer-specific QOL domains of the EPIC, but did not increase the magnitude of decline once RT started and had minimal impact on other HRQOL measures. Conclusions The addition of orteronel to RT and ADT did not result in significant improvement in any efficacy outcomes, although information was limited by poor drug tolerance and early termination of accrual, thus limiting statistical power.

Importance:Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective:To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants:This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention:Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures:The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results:Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance:In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration:ClinicalTrials.gov Identifier: NCT01711658.

ImportancePatients with locally advanced non–human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti–epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC.ObjectiveTo examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS).Design, Setting, and ParticipantsThis multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020.InterventionPatients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo).Main Outcomes and MeasuresThe primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS.ResultsOf the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84).Conclusion and RelevanceIn this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis.Trial RegistrationClinicalTrials.gov Identifier: NCT01711658

Purpose/Objective(s)RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis.Materials/MethodsThe study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred.Results231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance.ConclusionThe addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer.

6014 Background: Chemoradiation (CRT) with cis or anti-EGFR Ab has been shown to improve survival of patients with stage III-IV HNC. Since Lap, a dual EGFR and HER2 inhibitor, has shown effectiveness with CRT in a pilot non-HPV HNC cohort, the RTOG Foundation launched a phase II trial to test the hypothesis that adding Lap to the RT-cis for frontline therapy of stage III-IV Non-HPV HNC improves progression-free survival (PFS). Methods: Patients with stage III-IV carcinoma of the oropharynx (p16-negative), larynx, and hypopharynx, having Zubrod performance of 0-1, and meeting predefined blood chemistry criteria were enrolled after providing consent. Patients were randomized (1:1) to 70 Gy (6 weeks) + 2 cycles of CDDP (q3 weeks) plus either Lap (1500 mg daily, Arm A) or placebo (Arm B) starting 1 week prior to RT and concurrent with RT and for 3 months post RT. PFS was the primary endpoint. The protocol specified 69 PFS events (142 patients) for the final analysis based on HR = 0.65, 80% power, 1-sided alpha 0.20, and one interim efficacy and futility analysis at 50% information. PFS rates between arms for all randomized patients were compared by 1-sided log-rank test (1-sided alpha 0.1803). Overall survival (OS) was a secondary endpoint. Results: From 10/’12 to 04/’17, 142 patients were enrolled, of whom 127 were randomized, 63 to Arm A and 64 to Arm B. Arms A vs B, respectively, were similar in baseline patient characteristics, radiation delivery, completing ≥ 70 Gy (85.7% vs. 82.8%) and cisplatin delivery, completing 200 (±5%) mg/m 2 (65.1% vs 70.3%), but dissimilar in Lap/placebo delivery (median dose, 87000 mg vs. 125250 mg). Median follow-up was 4.1 years for surviving patients. The final analysis suggests no improvement in PFS of adding Lap to CRT (HR [A/B]: 0.91, 95% confidence interval CI 0.56-1.46; P= 0.34; 2-year rates: 50.6%, CI 37.5-63.7% vs. 56.2% CI 43.0-69.4%), or in OS (HR: 1.06, CI 0.61-1.86; P = 0.58; 2-year rates: 71.8% CI 60.1-83.5% vs. 76% CI 64.5-87.4%), death within 30 days of therapy (3.3% vs. 3.4%), and overall treatment-related grade 3-5 adverse event rate (86.7% vs. 84.7%). Grade 3-4 mucositis rates on Arm A and Arm B were 21.7% vs. 23.7%, all grade dysphagia and rash rates were 43.3% vs. 59.3%, and 13.3% vs. 6.8%, respectively. Conclusions: The addition of Lap to the radiation-cisplatin platform did not improve progression-free or overall survival in unselected non-HPV HN. Thus, dual EGFR, HER-2 inhibition does not appear to enhance the effects of chemoradiation. Although we showed that accrual to a non-HPV HN specific trial is feasible, new strategies must be investigated to improve the outcome for this poor prognosis HN population.

Purpose: With external beam radiation therapy, uncertainties in treatment planning and delivery can result in an undesirable dose distribution delivered to the patient that can compromise the benefit of treatment. Techniques including geometric margins and probabilistic optimization have been used effectively to mitigate the effects of uncertainties. However, their broad application is inconsistent and can compromise the conclusions derived from cross-technique and cross-modality comparisons. Methods and Materials: Conventional methods to deal with treatment planning and delivery uncertainties are described, and robustness analysis is presented as a framework that is applicable across treatment techniques and modalities. Results: This report identifies elements that are imperative to include when conducting a robustness analysis and describing uncertainties and their dosimetric effects. Conclusion: The robustness analysis approach described here is presented to promote reliable plan evaluation and dose reporting, particularly during clinical trials conducted across institutions and treatment modalities. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

Purpose The use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies, although concerns for broader adoption exist. Methods and materials From 2011 through 2013, 66 men were accrued to a phase 2 trial at 5 centers. SBRT consisted of 5 fractions of 7.4 Gy to a total dose of 37 Gy using conventional linear accelerators. Electromagnetic transponders were used for motion management. Health-related quality of life (HRQOL) was evaluated via the Expanded Prostate Cancer Index Composite 26 questionnaire. Acute and late toxicities were collected according to Common Terminology Criteria for Adverse Events, version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time. Results Median follow-up was 36 months. All men had low- or intermediate-risk disease. There have been 0 biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four percent and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6 to 12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling, the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL. Conclusions In this multi-institutional phase 2 clinical trial using continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects.

To assess QOL after treatment with SBRT for low-intermediate risk prostate cancer and to correlate these changes with plan dosimetry. From January 2011 to June 2013, 68 men were treated at 5 institutions on an institutional review board–approved trial with a primary QOL endpoint. SBRT used 5 fractions of 7.4 Gy to 37 Gy over 15 to 19 days. The clinical target volume was the prostate with a 3-mm planning target volume (PTV) and 2-mm action level. Daily bladder and bowel preparations were used. Dosimetric goals mirrored RTOG 0126 after α/β correction (bioeffective dose 3 Gy) with urethral constraints based on high-dose-rate monotherapy. QOL was evaluated by EPIC 26 with mean changes examined by paired t test. A minimally detectable decline (MDD) in QOL was defined as 7, 6, 5, and 11 points for urinary incontinence (UI), urinary obstructive (UO), bowel (BS), and sexual (SS) domains. Receiver operating characteristic (ROC) curves were used to assess associations between dosimetry and MDD or greater changes in QOL. Median follow-up was 24 months (range 20-46). EPIC summary domains are in the table. There was not a statistically significant mean change for urinary QOL at any time. Significant mean BS changes were observed at 6 and 12 months but only the decline at 12 months met the threshold for an MDD. Mean declines in SS were observed at all times but only reached an MDD at 24 months. Despite no changes in mean urinary scores a detectable change in UI by MDD was seen in 17% and 18% at 6 and 24 months. At 6 months 41% had an MDD for UO with only 19% at 24 months. Bowel MDD was 33% at 6 months and 23% at 24 months. An MDD for SS was seen in 39% at 6 and 43% at 24 months. By ROC curve analysis Vrectum ≥100% was associated with BS MDD at 6 (P=.049) and 24 months (P=.03) as was rectal absolute V90% (P=.02) and absolute V50% (P=.02) at 24 months. Absolute bladder volumes receiving 10 to 37 Gy were associated with MDD for UI at 24 months (P=.01-.03). Neither PTV nor urethral mean or max doses were associated with urinary QOL. No doses predicted sexual MDD. Prostate SBRT with real time tracking and urethral constraints led to no mean changes in urinary QOL; but absolute bladder dose/volumes correlated with the minority experiencing UI changes. Average bowel QOL decreased at 6 to 12 months but resolved by 24 months. Rectal V90-100 correlated with MDD. Electromagnetic transponder guided SBRT has minimal changes in QOL at 2 years. Nevertheless, optimized radiation planning may improve both urinary and bowel QOL.Poster Viewing Abstracts 2517; Table 1EPIC Domain Scores [Mean (Median) (IQR)]Baseline6 monthP value*12 monthP value*24 monthP value*UI94 (100) (92-100)94 (100) (92-100).792 (100) (86-100).594 (100) (92-100).8UO94 (100) (91-100)92 (94) (86-100).392 (100) (86-100).394 (100) (92-100).9Bowel95 (100) (92-100)93 (96) (90-100).0488** (96) (80-100).00796 (96) (95-100).3Sexual63 (67) (42-92)54 (58) (31-79).0158 (63) (41-83).0350** (58) (19-77).01*Paired t test comparing to baseline **Mean change met MDD from baseline Open table in a new tab

______________________________ Al Introduction ____________________________ 1 Acknowledgments _________________________ 2 Formation of the scarps ____________________ 3 Dimensions of the scarps _________________ 4 Description of the scarps ____________________ 5 China Mountain scarp __________________ 5 Tobin scarp __________________________ 7 Pearce scarp __________________________ 7 Sou Hills scarp ________________________ 15 Stillwater scarp ______________________ 16 Profiles of the scarps ______________________ 19 Page Recurrence of faulting ______________________ A21 Patterns of recurrent faulting ________________ 27 Sizes of the earthquakes as determined from scarp dimensions __________________________ 27 Characteristics of faulting, and some tectonic implications ___________________________ 28 Eastward tilting of range blocks _____________ 28 En echelon pattern of scarps and regional extension __________________________ 30 Tectonic implications ____________________ 31 References _____________________________ 32

A comprehensive Code of Ethics for the members of the American Association of Physicists in Medicine (AAPM) is presented as the report of Task Group 109 which consolidates previous AAPM ethics policies into a unified document. The membership of the AAPM is increasingly diverse. Prior existing AAPM ethics polices were applicable specifically to medical physicists, and did not encompass other types of members such as health physicists, regulators, corporate affiliates, physicians, scientists, engineers, those in training, or other health care professionals. Prior AAPM ethics policies did not specifically address research, education, or business ethics. The Ethics Guidelines of this new Code of Ethics have four major sections: professional conduct, research ethics, education ethics, and business ethics. Some elements of each major section may be duplicated in other sections, so that readers interested in a particular aspect of the code do not need to read the entire document for all relevant information. The prior Complaint Procedure has also been incorporated into this Code of Ethics. This Code of Ethics (PP 24-A) replaces the following AAPM policies: Ethical Guidelines for Vacating a Position (PP 4-B); Ethical Guidelines for Reviewing the Work of Another Physicist (PP 5-C); Guidelines for Ethical Practice for Medical Physicists (PP 8-D); and Ethics Complaint Procedure (PP 21-A). The AAPM Board of Directors approved this Code or Ethics on July 31, 2008.