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Decipher is a genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials.A pre-specified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer-specific mortality (PCSM) and overall survival (OS) with Cox univariable (UVA) and multivariable analyses (MVA).GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). In the pooled cohort, on UVA, the GC was shown to be a prognostic factor for DM (per 0.1 unit; sHR 1.29, 95%CI 1.18-1.41, p0.001), PCSM (sHR 1.28, 95%CI 1.16-1.41, p0.001), and OS (HR 1.16, 95%CI 1.08-1.22, p0.001). On MVA, the GC (per 0.1 unit) was independently associated with DM (sHR 1.22, 95%CI 1.09-1.36), PCSM (sHR 1.23, 95%CI 1.09-1.39), and OS (HR 1.12, 95%CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT) but the absolute improvement in outcome varied by GC risk.This is the first validation of a gene expression biomarker on pre-treatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making.

Aim/objectives/background Timely, accurate, and effective communications are critical to quality in contemporary medical practices. Radiation oncology incorporates the science and technology of complex integrated radiation treatment delivery and the art of managing individual patients. Through written physical and/or electronic reports and direct communication, radiation oncologists convey critical information regarding patient care, services provided, and quality of care. Applicable practice parameters need to be revised periodically regarding medical record documentation for professional and technical components of services delivered. Methods The ACR-ASTRO Practice Parameter for Communication: Radiation Oncology was revised according to the process described on the American College of Radiology (ACR) Web site ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the American Society for Radiation Oncology (ASTRO). Both societies then reviewed and approved the document. Results This practice parameter addresses radiation oncology communications in general, including (a) medical record, (b) electronic, and (c) doctor-patient communications, as well as specific documentation for radiation oncology reports such as (a) consultation, (b) clinical treatment management notes (including inpatient communication), (c) treatment (completion) summary, and (d) follow-up visits. Conclusions The radiation oncologist's participation in the multidisciplinary management of patients is reflected in timely, medically appropriate, and informative communication with the referring physician and other members of the health care team. The ACR-ASTRO Practice Parameter for Communication: Radiation Oncology is an educational tool designed to assist practitioners in providing appropriate communication regarding radiation oncology care for patients.

Aim/objectives/background To standardize the practice of stereotactic body radiation therapy (SBRT), the American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) cooperatively developed the practice parameter for SBRT. SBRT is a treatment technique that delivers radiation dose to a well-defined extracranial target in 5 fractions or less and usually employs a higher dose per fraction than used in conventional radiation. Methods The ACR-ASTRO Practice Parameter for the Performance of Stereotactic Body Radiation Therapy was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. Results Given the complexities of SBRT, a separate document was created to develop a technical standard for the medical physics of SBRT (ACR-AAPM Technical Standard for Medical Physics Performance Monitoring of Stereotactic Body Radiation Therapy). Workflow, qualifications and responsibilities of personnel, specifications, documentation, quality control/safety/improvement, simulation/treatment, and follow-up were addressed in this practice parameter. Conclusions This practice parameter assists practitioners in providing safe and appropriate SBRT treatment and care for patients when clinically indicated. As technologies and techniques continue to evolve, this document will be reviewed, revised and renewed accordingly to a 5 year or sooner timeline specified by the ACR.

299 Background: Recently, an MMAI prognostic biomarker, ArteraAI Prostate, was trained and validated in localized prostate cancer to more accurately risk stratify patients for multiple endpoints compared to NCCN risk groups (Esteva et al., 2022). Prognostication within an NCCN risk group remains clinically important given the multiple treatment decisions required within each risk group (e.g., radiotherapy dose or hormone therapy use). Herein, we validated the MMAI biomarker in high-risk prostate cancer where an increasing number of therapeutic decisions is required. Methods: This study leveraged histopathology image and clinical data from patients with at least one high-risk feature (HRF; cT3-cT4, Gleason 8-10, PSA > 20 ng/mL, primary Gleason pattern 5) from six NRG/RTOG phase III randomized trials (n=1,088). Patients from two trials not part of the initial MMAI biomarker training/validation (RTOG 0521 [n=344] and 9902 [n=318]) and the MMAI validation cohort (RTOG 9202, 9408, 9413, and 9910 [n=426]) were included. Fine-Gray, cumulative incidence, and time dependent area under the curve (tdAUC) analyses were performed for time to distant metastasis (DM) and prostate cancer-specific mortality (PCSM) for standard clinicopathologic variables (age, PSA, Gleason score, T-stage, number of HRFs) and the MMAI model, as a continuous score (per standard deviation increase) and categorically by quartile. Death from other causes were treated as competing risks. Results: The analyzed cohort had a median follow-up of 10.4 years. Median PSA was 21 ng/mL, 60% had Gleason 8-10 disease, 37% had cT3-T4 disease, and 20% were African American. On univariable analysis, the MMAI model was significantly associated with DM (subdistribution hazard ratio [sHR] 2.05, 95% CI 1.74-2.43, p

ImportanceBladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches.ObjectiveTo evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis.Design, Setting, and ParticipantsThis prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020.ExposuresTrimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy.Main Outcomes and MeasuresMRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio.ResultsOf 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44).Conclusions and RelevanceHigher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

PURPOSE To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here. PATIENTS AND METHODS Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs). RESULTS A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( P = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( P = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( P = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; P = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; P = .0047) were associated with reduced IBR. CONCLUSION RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.

Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response.38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival.The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA.Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.

Purpose The American College of Radiology (ACR), American Brachytherapy Society (ABS), American College of Nuclear Medicine (ACNM), American Society for Radiation Oncology (ASTRO), Society of Interventional Radiology (SIR), and Society of Nuclear Medicine and Molecular Imaging (SNMMI) have jointly developed a practice parameter on selective internal radiation therapy (SIRT) or radioembolization for treatment of liver malignancies. Radioembolization is the embolization of the hepatic arterial supply of hepatic primary tumors or metastases with a microsphere yttrium-90 brachytherapy device. Materials and Methods The ACR -ABS -ACNM -ASTRO -SIR -SNMMI practice parameter for SIRT or radioembolization for treatment of liver malignancies was revised in accordance with the process described on the ACR website ( https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards ) by the Committee on Practice Parameters—Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards—Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters—Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with ABS, ACNM, ASTRO, SIR, and SNMMI. Results This practice parameter is developed to serve as a tool in the appropriate application of radioembolization in the care of patients with conditions where indicated. It addresses clinical implementation of radioembolization including personnel qualifications, quality assurance standards, indications, and suggested documentation. Conclusions This practice parameter is a tool to guide clinical use of radioembolization. It focuses on the best practices and principles to consider when using radioemboliozation effectively. The clinical benefit and medical necessity of the treatment should be tailored to each individual patient.

Aim/objectives/background The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for proton beam radiation therapy. Proton radiotherapy is the application of a high-energy proton beam to a patient in a clinical setting with therapeutic intent. Proton radiotherapy may permit improved therapeutic ratios with lower doses to sensitive normal structures and greater dose to target tumor tissues. Methods A literature search was performed to identify published articles regarding clinical outcomes, reviews, quality assurance methodologies, and guidelines and standards for proton radiation therapy. Selected articles are referenced in the text. The following recommendations are based on firsthand experiences of multiple clinical authorities who employ proton therapy and have been peer reviewed by experts at different practicing institutions. Results This practice parameter is developed to serve as a tool in the appropriate application of this evolving technology in the care of cancer patients or other patients with conditions where radiation therapy is indicated. It addresses clinical implementation of proton radiation therapy, including personnel qualifications, quality assurance standards, indications, and suggested documentation. Conclusions This practice parameter is a tool to guide technical use of proton therapy and does not assess the relative clinical indication of proton radiotherapy when compared with other forms of radiotherapy, but to focus on the best practices required to deliver proton therapy safely and effectively, when clinically indicated. Costs of proton treatments are high, and the economic costs of proton radiotherapy may also need to be considered.

PURPOSE: From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m(2) of 1,3 bis (2 chloroethyl)-1 nitrosourea on days 1–3 q8 weeks for 1 year. METHODS: Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. RESULTS: Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 mo vs. 13.1 mo (p=0.20) or PFS, with a median PFS time of 5.7 mo vs. 6.9 mo (p=0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio=1.16; p=0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 mo vs. 11.2 mo; p=0.34), anaplastic astrocytoma (MST: 69.8 mo vs 50.0 mo; p=0.91) or anaplastic oligodendroglioma (MST: 92.1 mo vs. 66.5 mo; p=0.33). CONCLUSION: Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

BACKGROUND PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival. METHODS CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients. RESULTS 42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models. CONCLUSIONS PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.

PURPOSE/OBJECTIVE(S) Decipher is a prognostic 22-gene genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials. MATERIALS/METHODS Following a pre-specified and approved CTEP-CCSC analysis plan (NRG-GU-TS006), we obtained all available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability of GC for distant metastases (DM), and secondary was prostate cancer-specific mortality (PCSM) and overall survival (OS), with Cox multivariable analyses (MVA). RESULTS GC scores were obtained on 385 samples (n = 90 on 9202, n = 172 on 9413, and n = 123 on 9902), of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). On MVA, the GC (per 0.1 unit) was independently associated with DM (HR 1.24, 95% CI 1.11-1.39), PCSM (HR 1.27, 95% CI 1.13-1.43), and OS (HR 1.12, 95% CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. For categorical GC, on MVA, GC score ≥ 0.45 (representing the intermediate and high GC categories) had worse DM (HR 2.18, 95% CI 1.25-3.80), PCSM (HR 2.34, 95% CI 1.31-4.16), and OS (HR 1.45, 95% CI 1.03-2.04) outcomes as compared to those with low GC. Cumulative incidence of distant-metastasis at 10-years was 29% (95% CI 20-38%) for intermediate/high GC vs 13% (95% CI 7-18%) for low GC. For the subset with GC > 0.85, the threshold for inclusion in the intensification study of NRG GU009 (PREDICT-RT), at 5-years and 10-years DM was 29% (95% CI 7-52%) and 41% (95% CI 17-66%). GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT). CONCLUSION This is the first validation of any gene expression biomarker on pre-treatment biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT will further determine the optimal therapy based on GC score. NCT04513717.

PURPOSE/OBJECTIVE(S) Radiotherapy (RT) is an integral component of curative treatment of head and neck squamous cell carcinomas (HNSCC). Compromise of dysphagia/aspiration-related structures remains a clinically significant, and potentially life threatening, treatment complication. We hypothesized that treatment intensification might increase the long term risk of aspiration events, and investigated clinical factors contributing to this risk. MATERIALS/METHODS A single institution database of patients who received curative-intent RT for HNSCC from 1996 to 2018 was queried. Included patients had laryngeal/hypopharyngeal, oral cavity, or oropharyngeal cancers and did not experience locoregional failure. An aspiration event was defined as aspiration on modified barium swallow, or aspiration pneumonia, > 3 months after RT. 324 patients were eligible, with a median follow up of 42 months (range 4-195). Independent variables investigated included age, primary site, sex, T stage, N stage, overall stage, IMRT vs 3D RT, standard vs altered fractionation, prior vs never smoker, definitive vs post-operative RT, and the use of chemotherapy with RT. Univariate logistic regression was used to identify statistically significant risk factors and multivariate regression was then used to derive the final model. Kaplan Meier analysis was used to assess time to last aspiration event; significance was assessed via the log-rank test. RESULTS On univariate analysis patients who received chemotherapy (P = 0.007), were treated using 3D RT (P = 0.0009), or were prior smokers (P = 0.02) had a significantly increased risk of an aspiration event. No differences were seen with respect to age, sex, site, overall stage, T stage, N stage, postoperative vs definitive therapy, or fractionation. On multivariate analysis the use of chemotherapy [P = 0.004, OR 3.5 (95% CI 1.5 - 8.2)] and prior smoking [P = 0.03, OR 2.7 (95% CI 1.1 - 6.7)] remained significantly associated with increased risk, while use of IMRT significantly diminished risk [P = 0.001, OR 0.35 (0.19 - 0.35)]. In patients who received chemotherapy, the actuarial risk of aspiration via Kaplan Meier was 24% at five years, as opposed to 8% for RT alone (P = 0.007). Of the six patients who died secondary to aspiration pneumonia, five received chemotherapy with RT. CONCLUSION In this analysis the use of chemotherapy, prior smoking, and the use of 3D RT increased the odds of aspiration in patients receiving RT for HNSCC. Of note, use of chemotherapy increased this risk almost three-fold; this risk persisted long term, supporting the hypothesis that treatment intensification has a significant, persistent clinical impact on dysphagia-related structures. These data highlight the need to refine criteria for the use of chemotherapy with RT in the adjuvant setting, and support diminished dysphagia risk seen in de-intensification trials in HPV-associated oropharyngeal cancers.

// Matthias Holdhoff 1 , Gregory J. Cairncross 2 , Thomas M. Kollmeyer 3 , Ming Zhang 1 , Peixin Zhang 4 , Minesh P. Mehta 5 , Maria Werner-Wasik 6 , Luis Souhami 7 , Jean-Paul Bahary 8 , Young Kwok 5 , Alan C. Hartford 9 , Arnab Chakravarti 10 , Srinivasan Yegnasubramanian 1 , Bert Vogelstein 1 , Nickolas Papadopoulos 1 , Kenneth Kinzler 1 , Robert B. Jenkins 3 and Chetan Bettegowda 1 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 2 Charbonneau Cancer Institute at the University of Calgary, Calgary, AB, USA 3 Mayo Clinic, Rochester, MN, USA 4 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA 5 University of Maryland Medical Center, Baltimore, MD, USA 6 Thomas Jefferson University Hospital, Philadelphia, PA, USA 7 McGill University Health Centre, Montreal, QC, Canada 8 Centre Hospitalier de l’Universite de Montreal, Montreal University, Montreal, QC, Canada 9 Darthmouth-Hitchcock Medical Center, Lebanon, NH, USA 10 The Ohio State University, Columbus, OH, USA Correspondence to: Matthias Holdhoff, email: // Chetan Bettegowda, email: // Keywords : oligodendroglioma, chemotherapy, survival, genomics, co-deletion 1p/19q Received : October 01, 2016 Accepted : March 21, 2017 Published : March 31, 2017 Abstract Background: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of

Purpose To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO—100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes—twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale–Head and Neck Cancer and the Functional Assessment of Cancer Therapy–Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. Results Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy–Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. Conclusions While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.

Purpose Patients have reported sensations of seeing light flashes during radiation therapy, even with their eyes closed. These observations have been attributed to either direct excitation of retinal pigments or generation of Cherenkov light inside the eye. Both in vivo human and ex vivo animal eye imaging was used to confirm light intensity and spectra to determine its origin and overall observability. Methods and Materials A time-gated and intensified camera was used to capture light exiting the eye of a patient undergoing stereotactic radiosurgery in real time, thereby verifying the detectability of light through the pupil. These data were compared with follow-up mechanistic imaging of ex vivo animal eyes with thin radiation beams to evaluate emission spectra and signal intensity variation with anatomic depth. Angular dependency of light emission from the eye was also measured. Results Patient imaging showed that light generation in the eye during radiation therapy can be captured with a signal-to-noise ratio of 68. Irradiation of ex vivo eye samples confirmed that the spectrum matched that of Cherenkov emission and that signal intensity was largely homogeneous throughout the entire eye, from the cornea to the retina, with a slight maximum near 10 mm depth. Observation of the signal external to the eye was possible through the pupil from 0° to 90°, with a detected emission near 2500 photons per millisecond (during peak emission of the ON cycle of the pulsed delivery), which is over 2 orders of magnitude higher than the visible detection threshold. Conclusions By quantifying the spectra and magnitude of the signal, we now have direct experimental observations that Cherenkov light is generated in the eye during radiation therapy and can contribute to perceived light flashes. Furthermore, this technique can be used to further study and measure phosphenes in the radiation therapy clinic.

BACKGROUND/PURPOSE: Stratification of Gleason score (GS) into three categories (2-6, 7, and 8-10) may not fully utilize its prognostic discrimination, with Gleason Pattern 5 (GP5) previously identified as an independent adverse factor. MATERIALS/METHODS: Patients treated on RTOG 9202 (n = 1292) or RTOG 9902 (n = 378) were pooled and assessed for association of GS and GP5 on biochemical failure (BF), local failure (LF), distant metastasis (DM), and overall survival (OS). Fine and Gray’s regression and cumulative incidence methods were used for univariate and multivariate analyses. RESULTS: With median follow-up of 9.4 years, patients with GS 8-10 with GP5 had worse outcome than GS 4+4 for DM on both RTOG9202 (p=0.038) and RTOG9902 (p

This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this practice parameter should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or effective palliation of disease while minimizing untoward side effects and complications.

Purpose The Radiation Therapy Oncology Group 9804 study identified good-risk patients with ductal carcinoma in situ (DCIS), a breast cancer diagnosis found frequently in mammographically detected cancers, to test the benefit of radiotherapy (RT) after breast-conserving surgery compared with observation. Patients and Methods This prospective randomized trial (1998 to 2006) in women with mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm, compared RT with observation after surgery. The study was designed for 1,790 patients but was closed early because of lower than projected accrual. Six hundred thirty-six patients from the United States and Canada were entered; tamoxifen use (62%) was optional. Ipsilateral local failure (LF) was the primary end point; LF and contralateral failure were estimated using cumulative incidence, and overall and disease-free survival were estimated using the Kaplan-Meier method. Results Median follow-up time was 7.17 years (range, 0.01 to 11.33 years). Two LFs occurred in the RT arm, and 19 occurred in the observation arm. At 7 years, the LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001). Grade 1 to 2 acute toxicities occurred in 30% and 76% of patients in the observation and RT arms, respectively; grade 3 or 4 toxicities occurred in 4.0% and 4.2% of patients, respectively. Late RT toxicity was grade 1 in 30%, grade 2 in 4.6%, and grade 3 in 0.7% of patients. Conclusion In this good-risk subset of patients with DCIS, with a median follow-up of 7 years, the LF rate was low with observation but was decreased significantly with the addition of RT. Longer follow-up is planned because the timeline for LF in this setting seems protracted.

Background This collaborative practice parameter technical standard has been created between the American College of Radiology and American Brachytherapy Society to guide the usage of electronically generated low energy radiation sources (ELSs). It refers to the use of electronic X-ray sources with peak voltages up to 120 kVp to deliver therapeutic radiation therapy. Main Findings The parameter provides a guideline for utilizing ELS, including patient selection and consent, treatment planning, and delivery processes. The parameter reviews the published clinical data with regard to ELS results in skin, breast, and other cancers. Conclusions This technical standard recommends appropriate qualifications of the involved personnel. The parameter reviews the technical issues relating to equipment specifications as well as patient and personnel safety. Regarding suggestions for educational programs with regard to this parameter,it is suggested that the training level for clinicians be equivalent to that for other radiation therapies. It also suggests that ELS must be done using the same standards of quality and safety as those in place for other forms of radiation therapy.

Electron paramagnetic resonance (EPR) spectroscopy has been well established as a viable technique for measurement of free radicals and oxygen in biological systems, from in vitro cellular systems to in vivo small animal models of disease. However, the use of EPR in human subjects in the clinical setting, although attractive for a variety of important applications such as oxygen measurement, is challenged with several factors including the need for instrumentation customized for human subjects, probe, and regulatory constraints. This article describes the rationale and development of the first clinical EPR systems for two important clinical applications, namely, measurement of tissue oxygen (oximetry) and radiation dose (dosimetry) in humans. The clinical spectrometers operate at 1.2 GHz frequency and use surface-loop resonators capable of providing topical measurements up to 1 cm depth in tissues. Tissue pO2 measurements can be carried out noninvasively and repeatedly after placement of an oxygen-sensitive paramagnetic material (currently India ink) at the site of interest. Our EPR dosimetry system is capable of measuring radiation-induced free radicals in the tooth of irradiated human subjects to determine the exposure dose. These developments offer potential opportunities for clinical dosimetry and oximetry, which include guiding therapy for individual patients with tumors or vascular disease by monitoring of tissue oxygenation. Further work is in progress to translate this unique technology to routine clinical practice.

BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

Purpose Radiation therapy following resection of a brain metastasis increases the probability of disease control at the surgical site. We analyzed our experience with postoperative stereotactic radiosurgery (SRS) as an alternative to whole-brain radiotherapy (WBRT), with an emphasis on identifying factors that might predict intracranial disease control and overall survival (OS). Methods and Materials We retrospectively reviewed all patients through December 2008, who, after surgical resection, underwent SRS to the tumor bed, deferring WBRT. Multiple factors were analyzed for time to intracranial recurrence (ICR), whether local recurrence (LR) at the surgical bed or “distant” recurrence (DR) in the brain, for time to WBRT, and for OS. Results A total of 49 lesions in 47 patients were treated with postoperative SRS. With median follow-up of 9.3 months (range, 1.1-61.4 months), local control rates at the resection cavity were 85.5% at 1 year and 66.9% at 2 years. OS rates at 1 and 2 years were 52.5% and 31.7%, respectively. On univariate analysis (preoperative) tumors larger than 3.0 cm exhibited a significantly shorter time to LR. At a cutoff of 2.0 cm, larger tumors resulted in significantly shorter times not only for LR but also for DR, ICR, and salvage WBRT. While multivariate Cox regressions showed preoperative size to be significant for times to DR, ICR, and WBRT, in similar multivariate analysis for OS, only the graded prognostic assessment proved to be significant. However, the number of intracranial metastases at presentation was not significantly associated with OS nor with other outcome variables. Conclusions Larger tumor size was associated with shorter time to recurrence and with shorter time to salvage WBRT; however, larger tumors were not associated with decrements in OS, suggesting successful salvage. SRS to the tumor bed without WBRT is an effective treatment for resected brain metastases, achieving local control particularly for tumors up to 3.0 cm diameter.

Intensity-modulated radiation therapy (IMRT) is a complex technique for the delivery of radiation therapy preferentially to target structures while minimizing doses to adjacent normal critical structures. It is widely utilized in the treatment of a variety of clinical indications in radiation oncology, including tumors of the central nervous system, head and neck, breast, prostate, gastrointestinal tract, and gynecologic organs, as well as in situations where previous radiation therapy has been delivered, and has allowed for significant therapeutic advances in many clinical areas. IMRT treatment planning and delivery is a complex process. Safe and reliable delivery of IMRT requires appropriate process design and adherence to quality assurance (QA) standards. A collaborative effort of the American College of Radiology and American Society for Therapeutic Radiation Oncology has produced a practice guideline for IMRT. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, physicist, dosimetrist, and radiation therapist. Factors with respect to the QA of the treatment planning system, treatment-planning process, and treatment-delivery process are discussed, as are issues related to the utilization of volumetric modulated arc therapy. Patient-specific QA procedures are presented. Successful IMRT programs involve integration of many processes: patient selection, patient positioning/immobilization, target definition, treatment plan development, and accurate treatment delivery. Appropriate QA procedures, including patient-specific QA procedures, are essential to ensure quality in an IMRT program and to assure patient safety.

Transperineal permanent brachytherapy is a safe and effective treatment option for patients with organ-confined prostate cancer. Careful adherence to established brachytherapy standards has been shown to improve the likelihood of procedural success and reduce the incidence of treatment-related morbidity. A collaborative effort of the American College of Radiology (ACR) and the American Brachytherapy Society (ABS) has produced practice parameters for LDR prostate brachytherapy. These practice parameters define the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, physicist and dosimetrist. Factors with respect to patient selection and appropriate use of supplemental treatment modalities such as external beam radiation and androgen suppression therapy are discussed. Logistics with respect to the brachytherapy implant procedure, the importance of dosimetric guidelines, and attention to radiation safety procedures and documentation are presented. Adherence to these parameters can be part of ensuring quality and safety in a successful prostate brachytherapy program.

Purpose To analyze 2 factors that influence timing of radiosurgery after surgical resection of brain metastases: target volume dynamics and intracranial tumor progression in the interval between surgery and cavity stereotactic radiosurgery (SRS). Methods and Materials Three diagnostic magnetic resonance imaging (MRI) scans were retrospectively analyzed for 41 patients with a total of 43 resected brain metastases: preoperative MRI scan (MRI-1), MRI scan within 24 hours after surgery (MRI-2), and MRI scan for radiosurgery planning, which is generally performed ≤1 week before SRS (MRI-3). Tumors were contoured on MRI-1 scans, and resection cavities were contoured on MRI-2 and MRI-3 scans. Results The mean tumor volume before surgery was 14.23 cm 3 , and the mean cavity volume was 8.53 cm 3 immediately after surgery and 8.77 cm 3 before SRS. In the interval between surgery and SRS, 20 cavities (46.5%) were stable in size, defined as a change of ≤2 cm 3 ; 10 cavities (23.3%) collapsed by >2 cm 3 ; and 13 cavities (30.2%) increased by >2 cm 3 . The unexpected increase in cavity size was a result of local progression (2 cavities), accumulation of cyst-like fluid or blood (9 cavities), and nonspecific postsurgical changes (2 cavities). Finally, in the interval between surgery and SRS, 5 cavities showed definite local tumor progression, 4 patients had progression elsewhere in the brain, 1 patient had both local progression and progression elsewhere, and 33 patients had stable intracranial disease. Conclusions In the interval between surgical resection and delivery of SRS, surgical cavities are dynamic in size; however, most cavities do not collapse, and nearly one-third are larger at the time of SRS. These observations support obtaining imaging for radiosurgery planning as close to SRS delivery as possible and suggest that delaying SRS after surgery does not offer the benefit of cavity collapse in most patients. A prospective, multi-institutional trial will provide more guidance to the optimal timing of cavity SRS.

The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives.RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives.There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09).Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

343 Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was >1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.

We investigated the stability of serrated gold coils (Visicoil) implanted within the prostate glands of patients undergoing definitive external beam radiotherapy for prostate cancer. Radiopaque Visicoils of diameter 0.75 mm and median length 3 cm (range 2–4 cm) were implanted, one into each lobe of the prostate glands of 30 patients planned for external beam treatment. The coils were visualized on CT simulation and again after 25 fractions of treatment (5WK). Data from 30 patients were studied, of whom 19 also received androgen ablation therapy. The average change in the distance between the two coils over five weeks of treatment was 0.8 mm (± 0.6 mm), with a maximum of 2.5 mm in one patient. Average residual errors (standard deviations) for the positions of individual coil segments after five weeks of therapy were only 0.7 mm LAT, 0.6 mm AP, and 0.4 mm SI. The average change in distance between the coils over five weeks compared favorably with published data regarding marker seed stability. Overall, less than a 2 mm margin (i.e., 2 standard deviations) would adequately compensate for positioning uncertainty of the coils in more than 95% of cases. PACS number: 87.55.kh

Purpose Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P =.81), biochemical failure (58% vs 54%; P =.82), local progression (11% vs 7%; P =.09), distant metastases (16% vs 14%; P =.42), or disease-free survival (22% vs 26%; P =.61). Conclusions NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

5078 Background: RTOG 9902 was a randomized controlled trial of the addition of adjuvant chemotherapy (CT; paclitaxel, oral etoposide, and estramustine x4 cycles) to 24 mo of androgen suppression (AS) and radiation (RT) for patients (pts) with high-risk CaP., beginning with an initial 4 mo of AS; RT began after 2 mo. 9902 accrued 397 pts and closed early due to excess toxicity. At a median follow-up of 9.2 years, there was no benefit to CT, but it is hypothesized that a subset analysis by post-RT PSA identifies pts that benefit from treatment intensification with CT. Methods: Post-RT PSA status was dichotomized at > 0.2 ng/mL within 1 mo of RT. Landmark analysis redefined starting times for disease-free survival (DFS), time to distant metastasis (TDM) and overall survival (OS) at 16 weeks post-RT (36 weeks post-randomization) when CT was planned to complete. Pts were excluded if they did not get RT or assigned CT, or experienced DFS events/lost to follow-up < 36 wks post-randomization. Hazard ratios (HR), 95% confidence intervals (CI), and PSA-by-treatment interaction were estimated by Cox or competing-risks regression. Results: 333 pts were analyzed: 190 without and 143 with CT. 37% of pts had a post-RT PSA ≤0.2, 34% > 0.2, and 29% no recorded PSA in the defined interval. CT was associated with improved DFS for pts with PSA > 0.2 (HR 0.59, 0.38-0.91), but not for those with PSA ≤0.2 (HR 0.94, 0.60-1.46; interaction p = 0.13). This association, for those with PSA > 0.2, persisted in those pts who received the full course of CT and trended in the same direction for pts receiving 1-3 cycles. CT was associated with a trend toward improved TDM in the PSA > 0.2 group (HR 0.56, 0.23-1.35) and not in the PSA≤0.2 group (HR 1.31, 0.36-4.70), based on 32 pts with metastases. OS did not show the same pattern (PSA > 0.2: HR 0.98, 0.55-1.77; PSA≤0.2: HR 0.57, 0.29-1.13). Conclusions: This analysis suggests that men with high-risk CaP and suboptimal response to AS+RT, as identified by post-RT PSA > 0.2, may benefit from adjuvant CT. Prospective trials using contemporary CT (e.g. docetaxel) will help optimize treatment for these men. NRG-GU002, recently activated, is addressing this issue.

American College of Radiology and American Society for Radiation Oncology Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS). SRS is a safe and efficacious treatment option of a variety of benign and malignant disorders involving intracranial structures and selected extracranial lesions. SRS involves a high dose of ionizing radiation with a high degree of precision and spatial accuracy. A quality SRS program requires a multidisciplinary team involved in the patient management. Organization, appropriate staffing, and careful adherence to detail and to established SRS standards is important to ensure operational efficiency and to improve the likelihood of procedural success. A collaborative effort of the American College of Radiology and American Society for Therapeutic Radiation Oncology has produced a practice guideline for SRS. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, neurosurgeon, and qualified medical physicist. Quality assurance is essential for safe and accurate delivery of treatment with SRS. Quality assurance issues for the treatment unit, stereotactic accessories, medical imaging, and treatment-planning system are presented and discussed. Adherence to these practice guidelines can be part of ensuring quality and patient safety in a successful SRS program.

Background We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. Patients and methods Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m2 weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. Results Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9–57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1–69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. Conclusions This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291.

The major indications for radical radiation therapy of prostate cancer for both early-stage and locally advanced disease are discussed. Important issues in the interpretation of long-term treatment series are reviewed. The outcomes of therapy are analyzed for both early-stage and locally advanced disease, including alternative therapeutic strategies. On the basis of this review of the literature, current treatment recommendations delineate patients most likely to benefit from radiation therapy as opposed to alternative therapeutic modalities.

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.

Purpose: To assess the robustness of immobilization using open-face mask technology for linac-based stereotactic radiosurgery (SRS) with multiple non-coplanar arcs via repeated CBCT acquisition, with comparison to contemporaneous optical surface tracking data. Methods: 25 patients were treated in open faced masks with cranial SRS using 3–4 non-coplanar arcs. Repeated CBCT imaging was performed to verify the maintenance of proper patient positioning during treatment. Initial patient positioning was performed based on prescribed shifts and optical surface tracking. Positioning refinements employed rigid 3D-matching of the planning CT and CBCT images and were implemented via automated 6DOF couch control. CBCT imaging was repeated following the treatment of all non-transverse beams with associated couch kicks. Detected patient translations and rotations were recorded and automatically corrected. Optical surface tracking was applied throughout the treatments to monitor motion, and this contemporaneous patient positioning data was recorded to compare against CBCT data and 6DOF couch adjustments. Results: Initial patient positions were refined on average by translations of 3±1mm and rotations of ±0.9-degrees. Optical surface tracking corroborated couch corrections to within 1±1mm and ±0.4-degrees. Following treatment of the transverse and subsequent superior-oblique beam, average translations of 0.6±0.4mm and rotations of ±0.4-degrees were reported via CBCT, with optical surface tracking in agreement to within 1.1±0.6mm and ±0.6-degrees. Following treatment of the third beam, CBCT indicated additional translations of 0.4±0.2mm and rotations of ±0.3-degrees. Cumulative couch corrections resulted in 0.7 ± 0.4mm average magnitude translations and rotations of ±0.4-degrees. Conclusion: Based on CBCT measurements of patients during SRS, the open face mask maintained patient positioning to within 1.5mm and 1-degree with >95% confidence. Patient positioning determined by optical surface tracking agreed with CBCT assessment to within 1±1mm and ±0.6-degree rotations. These data support the use of 1–2mm PTV margins and repeated CBCT to maintain stereotactic positioning tolerances.

2054Background: The randomized multicenter RTOG 9402 trial showed a significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (R...

The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100–200 to 1,200 mg every 1–2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95–1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73–1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17–2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3–4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.

The purpose of this study was to assess the usefulness of the Eppendorf 'Kistograph' as a device for measuring pO(2) in tumor and normal tissues of the laboratory mouse. To determine the appropriate calibration and electrode condition, nitrogen bubbling time was changed, and the current during calibration was recorded. Reproducibility of pO(2) measurements was tested in the series of human xenografts and murine isoplants at different time points or in the same tumor in successive determinations. pO(2) values obtained with the Eppendorf 'Histograph' were compared to those obtained with a manually controlled needle-type electrode manufactured by the Diamond-General Company. The pO(2) values after 9 min of nitrogen bubbling were closer to the expected values than those after 3 min bubbling. The current during nitrogen bubbling in calibration declined following the pO(2) measurement by an amount corresponding to 0.8 mm Hg. Good reproducibility of pO(2) measurement was shown in i) pO(2) values in the same cell line at different time points and ii) pO(2) values in two or three consecutive measurements in related regions within the same tumor. The Eppendorf 'Histograph' and the Diamond-General device showed no significant differences in pO(2) distribution in either subcutaneous tissue or MCaIV tumors. In conclusion, results of the Eppendorf 'Histograph' were consistent and reproducible and were similar to those obtained by the Diamond-General set-up.