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PurposeWe report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up.Methods and materialsEligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen

Author(s): Hsu, I-Chow; Rodgers, Joseph P; Shinohara, Katsuto; Purdy, James; Michalski, Jeff; Roach, Mack; Vigneault, Eric; Ivker, Robert A; Pryzant, Rodger M; Kuettel, Michael; Taussky, Daniel; Gustafson, Gary S; Raben, Adam; Sandler, Howard M | Abstract: PurposeTo report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG.Methods and materialsPatients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method.ResultsOne hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA g10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3ngastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points.ConclusionsCombined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

PURPOSE Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer. PATIENTS AND METHODS The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT. RESULTS A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio [HR], 0.69; 90% CI, 0.49 to 0.97; one-sided P = .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23 v 16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided P = .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.77; 95% CI, 0.59 to 1.00; two-sided P = .053). CONCLUSION For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.

Purpose/Objective(s) Androgen suppression can improve outcomes when added to radiotherapy (RT) for intermediate risk prostate cancer, but no study to date has reported its utility in the context of contemporary, dose-escalated RT. Herein, the clinical outcomes of a phase III prospective trial evaluating the utility of total androgen suppression (TAS) combined with dose-escalated RT for patients with intermediate risk prostate cancer are reported. Materials/Methods Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of the following risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA value > 10 and ≤ 20 ng/mL. Patients with all three risk factors and ≥ 50% of biopsy cores positive were ineligible. After stratification by number of intermediate risk factors (single vs. multiple), RT boost modality, and baseline comorbidity (ACE-27 comorbidity index ≥ vs. Results The study completed its accrual objective. Between 2009 and 2016, 1538 patients were randomized. There were 750 eligible patients on Arm 1 and 742 on Arm 2 comprising the modified intent-to-treat population. 67% had a single intermediate risk factor. 88% were treated with EBRT with the remainder receiving EBRT plus brachytherapy boost. 33% had an ACE-27 score ≥ grade 2. With a median follow up of 6.2 years, 219 deaths occurred, 119 in Arm 1 and 100 in Arm 2, yielding 5-year overall survival estimates of 90% vs. 91%, respectively [HR 0.85 (95% CI 0.65-1.11); P = 0.22]. 193 patients experienced PSA failure, 125 in Arm 1 and 68 in Arm 2 [HR 0.52 (0.39-0.70); P Conclusion While the addition of TAS to dose-escalated RT did not improve overall survival for men with intermediate risk prostate cancer, significant improvements in rates of metastases, deaths due to prostate cancer, and PSA failures support the continued use of combination dose-escalated RT and TAS. Benefits will need to be weighed against the increased risk of adverse events and the patient reported outcomes analysis.

Objectives: We reviewed testosterone changes for patients who were treated with radiation therapy (RT) alone on NRG oncology RTOG 9408. Methods and materials: Patients (T1b-T2b, prostate-specific antigen

Purpose To report the biochemical control rate and clinical outcomes with real-time inverse planning (inverse optimization prostate seed implant [IO-PSI]) for favorable-risk (FR) and intermediate-risk (IR) prostate adenocarcinoma in a community practice setting. This analysis is an extended followup of our initial report, with favorable early biochemical control rate (biochemical nonevidence of disease) of 97% at 4 years. Methods and Materials Three hundred fifty-seven evaluable patients with FR and IR prostate cancer underwent real-time IO-PSI (iodine-125/145 Gy or palladium-103/120 Gy) between 2001 and 2013. Results With a median followup of 54 months (range, 24–110 months), the absolute biochemical failure free survival of disease was 96%. The 8-year actuarial probability of prostate-specific antigen failure-free survival for FR and IR cohorts was 92.4% and 87%, respectively. Late genitourinary and gastrointestinal toxicity remained low. Late Grade 2 and Grade 3 genitourinary toxicity was 19% and 1%, respectively. Late Grade 2 and 3 rectal bleeding rates were 1% and 0%, respectively. No difference in biochemical control was observed with preimplant short course androgen deprivation or between Gleason score 3 + 4 vs. 4 + 3 patients. No dosimetric parameter was predictive of biochemical failure. Patients with FR had a significantly decreased risk of failure (hazard ratio = 0.26; 95% confidence interval = 0.09–0.78; p = 0.02) compared with those with IR. Patients with a prostate-specific antigen nadir >0.4 ng/mL had an increased risk of failure (hazard ratio = 1.37; 95% confidence interval = 1.27–1.47; p Conclusions Our initial biochemical and clinical outcomes using real-time IO-PSI persisted with extended followup and support our original hypothesis for use of a reduced number of sources, needles, and total activity, suggesting that with IO, less is more.

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non–small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis–free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals – the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab – for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S. Electronic supplementary material The online version of this article (10.1186/s40425-019-0662-5) contains supplementary material, which is available to authorized users.

Background: Combination treatment with radiotherapy can prime the immune system due and improve responses to PD-1 based immunotherapy. However, the optimal dose and schedule of combination therapy is still unclear. Although hypofractionated radiotherapy has been shown to be superior to traditional fractionation schedules, the immunostimulatory effects of this regimen may be limited by death of radiation sensitive T-cells. Here we examine the effects of heterogenous dose delivery on early T cell responses in a murine model of head and neck cancer. Methods: Dose delivery was validated for the SARRP irradiator using high spatial resolution radiochromic film absolute dosimetry. The nozzles size was selected to deliver either a uniform dose of 12 Gy or SORT using two abutted nozzles to deliver conventional (2Gy) and hypofractionated (12 Gy) dose regions. C3H/HeJ mice bearing SCCVII/SF xenografts (n=8/group) were irradiated with either a single fraction of a uniform dose of 12 Gy using the 1 × 1 cm2 nozzle to cover the entire tumor or SORT (2-12Gy) using 0.5 × 0.5 cm2 nozzle. To assess the effect on activation of T cells present within the tumor at the time of radiation, mice were sacrificed 24 hrs after treatment and the presence of T cell subsets and cytokines was determined by real-time PCR. Statistical differences were determined using a one-way ANOVA followed by a post-hoc Tukey T-Test. Results: Radiochromic film measurements indicated highly uniform dose profiles with sharp dose fall off region for 0.5 × 0.5 cm2 nozzle, allowing butting of high and low dose fields. Quantitative PCR revealed increases in CD8 gene expression in both treatment groups over sham-irradiated mice with a slight but significant increase in 2Gy-12Gy treated mice compared to mice treated with 12Gy (7 fold vs 5 fold). No statistical differences in FoxP3 gene expression were observed between the groups. Significant increases of IFN-γ gene expression were observed in SORT treated mice compared to mice irradiated with 12Gy. Mice treated with a uniform 12Gy dose showed a 13.75-fold increase in IFN-γ over sham irradiated mice. This increase was significantly larger in 2Gy-12Gy treated mice in which a mean 67 fold-difference over sham-irradiated mice was observed. In contrast, tumors treated with 12Gy had a significantly higher level of TGF-beta gene expression than mice treated with 12Gy-2GY compared to sham irradiated mice (10 fold vs 6 fold). Conclusion: Although increases in CD8 gene expression were observed in both treatment groups, this increase was not proportional to the large increase in IFN-γ observed in mice treated with a heterogenous dose, indicating enhanced T-cell survival and/or activation. Further study is needed to determine if early immune activation observed with heterogeneous dosing correlates to a sustained immune response and improved response to immunotherapy. Citation Format: Jennifer Mourtada, Adam Raben, James Keller, Neil Hockstien, Yan Yu, Bo Lu, Firas Mourtada. Early T cell responses are enhanced by heterogenous dose delivery in a murine model of head and neck cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-047.

To update the outcomes of an institutional clinical management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion.Between August 2003 and April 2014, 61 consecutive patients with ipsilateral node-positive squamous cell carcinoma of the tonsil without involvement of the base of the tongue or midline soft palate were treated at a community hospital-based cancer center with radiotherapy to the primary site and ipsilateral neck. Overall survival, disease-free survival and freedom from contralateral failure were calculated.Median follow up was 37.2months (range 4-121months). Freedom from contralateral nodal failure at 5years was 98% with one contralateral nodal failure noted. The patient underwent a salvage neck dissection and was treated with post-operative radiotherapy with no evidence of disease to date. 5-year overall survival (OS) was 92.4% and 5year disease-free survival (DFS) was 86.7%.This represents the single largest series reported from a community hospital-based cancer center in which lateralized tonsil cancers with N+ disease were treated with ipsilateral neck radiotherapy. In this carefully selected cohort of patients with well-lateralized tonsil cancers, the risk of contralateral nodal failure appears to be5%, suggesting that prophylactic radiation of the contralateral neck may not be necessary. Future planned studies will focus on prospectively selecting subgroups of patients eligible for treatment de-intensification as survivorship issues in excellent prognosis HPV positive patients are increasingly becoming relevant.

Purpose We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). Patients and Methods Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m2 once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray's test. Results In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. Conclusion When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.

To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival.Eligible patients were randomized into either an accelerated-fractionation arm or a standard-fractionation arm, and completed the Performance Status Scale for the Head and Neck (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from before treatment to 5 years after treatment.The results from the analysis of area under the curve showed that QOL/PS was not significantly different between the 2 arms from baseline to year after treatment (P ranged from .39 to .98). The results from general linear mixed models further supported the nonsignificant treatment effects until 5 years after treatment (P=.95, .90, and .84 for PSS-HN Diet, Eating, and Speech, respectively). Before treatment and after 1 year after treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than did p16-negative patients (P ranged from .0283 to.0001 for all questionnaires). However, QOL/PS decreased more significantly from pretreatment to the last 2 weeks of treatment in the p16-positive group than in the p16-negative group (P ranged from .0002 to.0001). Pretreatment QOL/PS was a significant independent predictor of overall survival, progression-free survival, and local-regional failure but not of distant metastasis (P ranged from .0063 to.0001).The results indicated that patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after 1 year of follow-up. Patients presenting with better baseline QOL/PS scores had better survival.

Purpose To establish the safety and toxicity profile of daily gefitinib with radiation alone or with concurrent chemoradiotherapy in previously untreated patients with locally advanced squamous cell head and neck cancer (LAHNC). Patients and Methods Patients with intermediate-stage LAHNC were treated with concomitant boost radiation (RT) alone with escalating doses of daily gefitinib (250 or 500 mg; cohort I). Once a safety profile was determined with RT alone, patients with high-risk disease were then treated with daily gefitinib (250 or 500 mg), weekly cisplatin (CDDP; 30 mg/m2), and once-daily RT (cohort II). Patients also received post-RT gefitinib at 250 mg daily for a period of up to 2 years. Results Twenty-three patients were enrolled and assessable for toxicity. No dose-limiting toxicities (DLTs) were observed in patients treated in cohort I at either 250 or 500 mg of gefitinib daily with concomitant boost RT to 72 Gy. In patients receiving chemoradiotherapy and gefitinib (cohort II), DLTs included one grade 4 diarrhea and one grade 4 neutropenic fever. Fifteen patients started maintenance gefitinib, and eight (53%) experienced grade 1 to 2 acne-like skin rash and diarrhea, but no grade 3 or 4 toxicity occurred. Conclusion Gefitinib (250 or 500 mg daily) was well tolerated with concomitant boost RT or concurrent chemoradiotherapy with weekly CDDP. Protracted administration of gefitinib for up to 2 years at 250 mg daily was also tolerated well.

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

Background Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease. Objective We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase III trial. Design, setting, and participants A total of 1979 men with clinically localized (T1b–2b, prostate-specific antigen [PSA] Outcome measurements and statistical analysis The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA. Results and limitations Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81–1.42; p =0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death. Conclusions Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit. Patient summary We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit.

Purpose National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown. Patients and Methods The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models. Results Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment. Conclusion OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.

To compare dosimetric outcomes between two real-time prostate seed implantation (PSI) techniques to evaluate the impact of three-dimensional (3D) intraoperative computer planning on target coverage, conformality, and preset urethral and rectal dose constraints.One hundred and fourteen patients with clinically localized prostate cancer underwent ultrasound-guided transperineal PSI of the prostate with (125)I sources as monotherapy. From 1999 to 2001, 69 patients were implanted in real-time using a standard look-up nomogram (Group 1: NG-PSI). All patients were implanted with a modified peripheral loading technique in which 75-80% of the calculated total activity was delivered to the gland periphery, with the remaining 20-25% activity placed in the gland interior, to achieve a prescribed dose (PD) of 144 Gy to cover the gland with acceptable homogeneity. No preoperative or intraoperative planning was performed to set dose constraints to the urethra or anterior rectal wall. Dosimetric outcome from this group was compared with 45 patients subsequently implanted after 2001 using an intraoperative 3D computer planning system (Group 2: 3D-PSI). A similar modified peripheral loading technique was used as an option in the planning system. Preoperative dose constraints were placed on the urethra (V15035%), prostate (V10095% of PD; D90: 140-180 Gy), and rectal wall (V1101.5 cc) with real-time dosimetric feedback performed after peripheral loading. Manual dose optimization was performed to determine interior needle position and remaining number and placement of (125)I sources to adhere to urethral and rectal constraints and target coverage goals. Both groups underwent postimplant CT analysis to determine dosimetric outcome with regard toV100(prostate), D90(prostate), V150(urethra), and V110(rectum). Univariate and multivariate analysis was performed to determine variables impacting on dosimetric outcome.Analysis of preimplant and postimplant variables demonstrated no difference in the median preimplant gland volume (33 cc vs. 35 cc; p = 0.31), median mCi/seed strengths (0.4 vs. 0.45 mCi; p = 0.23), median V100 (94% vs. 94%), or median D90 at postimplant Day 30 (165 Gy vs. 160 Gy; p = 0.26) between Groups 1 and 2. However, for Group 2 (3D-PSI) the median total mCi implanted (26 vs. 33 mCi; p0.0001) and the median number of seeds implanted (67 vs. 83; p0.0001) were reduced substantially. The percent of patients exceeding a D90180 Gy was reduced from 29% in Group 1 to 16% in Group 2 (p = 0.08). A reduction was observed in the percent of patients receiving a D90140 Gy (14% Group 1 vs. 9% Group 2, p = 0.56). The median V150(urethra) for Group 2 was reduced dramatically with 3D-PSI compared with NG-PSI (63% vs. 17%; p0.0001). A V150(urethra)30% was observed in 88% in Group 1 compared with 29% in Group 2, p0.0001. Similarly, the median V110(rectum) for Group 1 was significantly higher than that in Group 2 (1.93 vs. 0.26 cc; p0.0001). The percent of patients with V110(rectum)1.5 cc in Group 1 and Group 2 was 57% and 13%, respectively (p0.0001).The adoption of 3D computer intraoperative dose planning and optimization for prostate seed implantation resulted in dramatic reductions in urethral and rectal wall doses, while consistently producing excellent target coverage with reduced dose variability above 180 Gy and below 140 Gy, compared with the use of a standard look-up nomogram. Additionally, the reduction in total mCi and number of seeds needed to achieve improved conformality was substantial and may have implications for cost savings.

Importance The role of epidermal growth factor receptor (EGFR) inhibition in chemoradation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. Objective To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. Design, Setting, and Participants A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. Interventions Patients were randomized to weekly concurrent cisplatin (50 mg/m 2 ), paclitaxel (25 mg/m 2 ), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m 2 on day 1 then 250 mg/m 2 weekly). Main Outcomes and Measures Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025. Results Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). Conclusions and Relevance The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. Trial Registration clinicaltrials.gov Identifier:NCT00566852

Importance Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined. Objectives To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected. Design, Setting, and Participants Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013. Interventions One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year. Main Outcomes and Measures Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events. Results Among 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo ( P = .49); an absolute difference of 5% (95% CI, −9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners. Conclusions and Relevance Among men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients. Trial Registration clinicaltrials.gov Identifier:NCT00931528

Background Our study is a prospective evaluation of unresectable malignant cancers of the head and neck treated with concomitant chemotherapy and radiotherapy (RT) using delayed accelerated fractionation (concomitant boost). Methods Between January 1988 and March 1995, 82 patients with unresectable cancers of the head and neck were enrolled in this phase II study. Of these, 52 patients were treated and followed for a minimum of 3 years and are the subject of this analysis. All patients had T4 lesions and were stage IV according to the American Joint Committee on Staging Criteria (AJCC). Patients received RT with accelerated fractionation to a total of 70 Gy in 6 weeks using a concomitant-boost technique. Concomitant cis platin (100 mg/M2) was given on days 1 and 22 of RT. Twenty-seven patients received mitomycin-C (7.5 mg/M2) on days 1 and 22, and 1 patient received mitomycin-C on day 1. In addition, 27 patients received adjuvant chemotherapy with cis platin and vinblastine. The mean follow-up was 45 months (range, 36–72 months). The minimum follow-up for surviving patients is 3 years. Results At 3 years, the local control rate was 58%. Three-year local control rates for paranasal sinus, nasopharynx, oropharynx, and larynx/hypopharynx were 78%, 78%, 64%, and 100%, respectively. For all patients, the distant-metastasis-free survival was 56%, and the overall survival rate was 36%. Patients with oral cavity cancers experienced worse overall survival versus other sites, 0% versus 47% (p = .03). Salivary cancers also showed worse survival versus other sites, 0% versus 47%, but was not statistically significant. Severe acute complications occurred in 34% of patients. Treatment-related toxicity also resulted in the death of 2 patients. Severe late complications occurred in 7% of patients. Conclusions Treatment of this poor prognostic group of patients with aggressive chemotherapy and RT produced surprisingly good local control and survival. © 1998 John Wiley & Sons, Inc. Head Neck20: 497–503, 1998.

This article reviews the indications, techniques, and results of brachytherapy in the treatment of non-small cell lung cancer (NSCLC) and selected chest neoplasms. Various isotopes and techniques are used to place radioactive sources directly into a tumor, tumor bed, or the chest. Brachytherapy techniques can be tailored to the clinical situation and can be in the form of permanent interstitial volume or planar implants (radioactive sources permanently imbedded into the tumor or tumor bed) or in the form of temporary interstitial or endoluminal implants (where radioactive sources irradiate a tumor bed over a certain length of time and then are removed). These treatments can be delivered over a short interval (high-dose rate [HDR]) or over a more protracted time (low-dose rate). HDR treatments can be used intraoperatively to deliver a large dose of radiation to a determined target area with selective sparing of surrounding normal structures. Different methods of delivering HDR intraoperative radiation are under investigation. Most reports on brachytherapy for chest malignancies are retrospective and come from a few single institutions. Most of the published data relate to the treatment of NSCLC, but other intrathoracic malignancies, such as malignant pleural mesothelioma and malignant thymoma, have been treated with brachytherapy. To our knowledge, no major randomized trials accurately assess or confirm these retrospective studies yet, complicating the interpretation of these results. Nevertheless, brachytherapy is of value in selected situations and offers the clinician and the patient an innovative method of delivering conformal high-dose radiation to a defined target with preferential sparing of normal surrounding structures. With continued innovations in the development of radioactive isotopes, computerized treatment planning and targeting, and source delivery, brachytherapy should continue to offer an attractive alternative and complement to conventional treatment approaches, and may offer patients improved local control and survival.

Purpose : Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival. Methods : There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38–82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients, had combined favorable prognostic factors (i.e. KPS ≤ 80, and ≤5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2–72 Gy) delivered in fractions of 1.8 Gy, 5 days per week. Results : Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35–59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity ≥grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (38) of patients with > 30% of lung volume receiving ≥25 Gy, versus 4% (123) of patients with ≤30% lung receiving ≥25 Gy ( P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (414) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% ( P = 0.03). Conclusions : Despite adverse prognostic criteria median survival is encouraging and may be higher than some combined modality approaches. Dose volume histogram parameters may be useful to determine the maximum dose for individual patients and thereby permit avoidance of toxicity.

Background: Thisstudywas conducted to evaluate quality of life in patients treated with primary radiotherapy (RT) for cancer of the base of tongue. Methods: From 1981 to 1990, 36 patients with primary squaradiotherapy. Ages ranged from 35 to 71 years (median, 58 years). T Stage was: T1, n = 11; T2, n = 14; T3, n = 10; T4, n = 1. Thirty-one patients (86%) had palpable cervical lymph node metastases at initial examination (N1, n = 16; N2, n = 11; N3, n = 4). Patients received external beam RT to their primary site and necks, followed by a brachytherapy boost to the tongue. Those with neck nodes also had a neck dissection. The median follow-up is 5 years (minimum, 3 years). Actuarial 5-year local control was 85%; regional control was 96%; distant metastases-free survival was 87.5%; and overall survival, 85%. Twenty-nine of the 30 long-term survivors completed (1) Memorial Symptom Assessment Scale (MSAS), (2) Functional Assessment of Cancer Therapy (FACT), (3) Performance Status Scale for Head and Neck Cancer(PSS), and (4) a sociodemographic and economic questionnaire. At the time of cancer diagnosis, 62% were employed full-time, and 21% were employed part-time; 83% were earning >$20,000/year, and 59% were earning >$60,000/year. Results: At follow-up, annual incomes were similar to those at initial examination. Of those who had been working full-time, 72% were still in full-time work, and of those who had been working part-time, 83% were still in part-time work. Average PSS scores were 90 for eating in public, 96 for understandability of speech, and 68 for normalcy of diet. On the MSAS, the following symptoms had prevalence: >30% xerostomia, difficulty swallowing, decreased energy, pain, worrying, insomnia, cough, drowsy, change In taste, and irritability. Scores on the FACT exceeded published values collected for a mixed cancer population. Conclusions: The overwhelming majority of patients achieved excellent functional status and quality of life and could maintain their prediagnosis earning potential and employment status after primary radiation for advanced base of tongue cancer.

Background Although the standard therapy for locally advanced hypopharyngeal cancer remains surgery and postoperative radiotherapy (RT), alternative treatment approaches include induction chemotherapy and RT. The purpose of this retrospective study was to compare the long-term outcome of these treatments performed in a single institution. Methods Twenty-six patients with advanced, resectable, squamous cell carcinoma of the hypopharynx were treated with induction chemotherapy and definitive RT (group I), reserving laryngectomy for salvage. The induction phase of therapy consisted of 2–3 cycles of cisplatin-based chemotherapy followed by conventional fractionated RT to doses of 66–70 Gy. The outcomes of this group of patients were compared with the outcomes of 30 patients with hypopharyngeal cancer who were treated at our institution with surgery and postoperative RT (group II). The median follow-up times of the surviving patients in groups I and II were 5 and 9 years, respectively. Results The local recurrence-free survival at 5 years from the completion of therapy for group I was 50%, compared with 69% for group II (p = .41). Among patients with T3–T4 primary tumors, the 5-year local control rates were 58% and 59% for groups I and II, respectively (p = .78). The likelihood of larynx preservation, free of local disease at 5 years for group I, was 52%. The 5-year neck recurrence-free survival for groups I and II were 47% and 69%, respectively (p = .66). Among patients with N2–N3 stage disease, the 5-year incidence of neck failure for groups I and II were 73% and 68%, respectively (p = .74). The 5-year distant metastases-free survival for groups I and II were 67% and 57%, respectively (p = .19). The 5-year disease-free survival rates for groups I and II were 30% and 42%, respectively (p = .9). The 5-year overall survival rates for groups I and II were 15% and 22%, respectively (p = .65). Conclusions Nonsurgical therapy for advanced-stage hypopharyngeal cancer provides survivorship comparable with that achieved with standard approaches of surgery and postoperative RT. However, despite the therapy, the outcome is poor. Future studies will need to explore new treatment strategies in an effort to improve upon the outcome for this group of patients. HEAD & NECK 1996;18:405–411 © 1996 John Wiley & Sons, Inc.

Purpose: The purpose of this study was to assess the feasibility of 103 Pd bracytherapy in the management of primary unresectable carcinoma of the pancreas. Methods and Materials: Between August 1988 and January 1992, 11 patients with biopsy-proven primary unresectable adenocarcinoma of the pancreas were treated with 103 Pd brachytherapy during laparotomy. The median age was 66 (range 57–70). The most common presenting symptoms were weight loss (eight patients), pain (six patients), and nausea/vomiting (four patients). Less common symptoms were jaundice (two patients), early satiety (two patients), and ascites (one patient). All patient underwent laparotomy and surgical staging. Eight patients had T3N0M0 disease, two patients had T3N1M0 disease, and one patient had T3N1M1 disease. The surgical procedure performed was biliary bypass in six patients, biopsy only in four patients, and gastric bypass in one patient. The average tumor dimension was 4.0 cm. The median activity, matched peripheral dose (MPD) and implanted volumes were 95.3 mCi, 124.4 Gy, and 33 cm 3 , respectively. The median initial dose rate was 0.21 Gy per hour. Five patients received postoperative external beam radiation therapy (median 45 Gy) and seven patients received chemotherapy postoperatively. The median follow-up was 7 months (range 1–19). Results: The median survival for the entire group of patients was 6.9 months. Ten of 11 patients have died, with 1 patient presently alive and receiving chemotherapy for metastatic disease to the liver, but without local progression radiographically. Five of 11 patients (45%) were locally controlled, defined as either a complete response or freedom from progression at the site of the implant as evaluated by computed tomography scan. In the other six patients, the median time to local progression was 6.9 months. Five patients developed distant metastases (four liver, one subcutaneous nodule). Two patients failed in regional sites (one omentum, one paraaortic lymph node). Four of 11 patients (36%) developed acute postoperative complications that included one gastric outlet obstruction, one duodenal perforation, and two with sepsis. One of 11 patients (9%) developed a late complication of radiation enteritis 5 months after implantation. The median survival for patients experiencing complications was 1.7 months as compared to 8.4 months for the patients who did not develop a complication ( p = 0.10). Pain relief was obtained in five out of six (83%) for the patients presenting with pain for a median duration of 24 weeks. Local control did not appear to be related to the MPD, dose rate, implanted volume, treatment with external beam irradiation, or the use of chemotherapy. Patients were more likely to develop a complication if the MPD was greater than 115 Gy (four out of six patients) as compared to those whose MPD was less than 115 Gy (one out of five patients) p = 0.12). Conclusions: Because there was no improvement in median survival over conventional modalities, and the complication rate was high; we do not recommend 103 Pd brachytherapy as a component of the treatment of unresectable adenocarcinoma of the pancreas.

e16614Background: Stereotactic body radiotherapy (SBRT) is an evolving and promising treatment modality for prostate cancer but without mature data compared with other definitive therapies. There i...

Purpose To review the outcomes of a prospective management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion. Methods and Materials Between August 2003 and June 2007, 20 patients who presented with squamous cell carcinoma of the tonsil, without involvement of the base of the tongue or midline soft palate, and with Stage N1-N2b disease were prospectively treated with radiotherapy to the primary site and ipsilateral neck. In addition, 18 patients received concurrent chemotherapy. The actuarial freedom from contralateral nodal and in-field progression was determined. Acute and late toxicity were prospectively evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3, and Radiation Therapy Oncology Group criteria. Results The nodal disease was Stage N1 in 4 patients, N2a in 3 patients, and N2b in 13 patients. At a median follow-up 19 months (range, 12–40), no in-field or contralateral nodal recurrences had been observed. The 2-year freedom from distant metastasis rate was 87.4%. The actuarial 2-year disease-free and overall survival rates were both 79.5%. Late Radiation Therapy Oncology Group grade 2 xerostomia occurred in 1 patient (5%). No late Grade 3 or greater toxicity was observed. No patient was feeding tube dependent at their last follow-up visit. Conclusion In carefully selected patients with node-positive, lateralized tonsillar cancer, treatment of the ipsilateral neck and primary site does not appear to increase the risk of contralateral nodal failure and reduces late morbidity compared with historical controls. Although the outcomes with ipsilateral radiotherapy in the present series were promising, these findings require longer follow-up and validation in a larger patient cohort.

The goal of this article is to review the various indications for the application of external beam radiotherapy in the management of thyroid cancer. This article includes a discussion of published literature to define risk variables that increase the risk of recurrence after surgery that might be mitigated by the use of radiation therapy. Clinical outcomes, recent technologic advances in treatment planning and radiation delivery, and potential morbidity associated with treatment are also reviewed.

LBA5002 Background: High-risk, localized prostate cancer (PCa) patients have a relatively poor prognosis. We hypothesized that the addition of adjuvant docetaxel and prednisone to long-term (24 month) AS and radiation therapy (RT) would improve overall survival (OS). Methods: RTOG 0521 opened December 2005 and closed August 2009 with targeted accrual of 600 cases. It was designed to detect improvement in 4-year OS from 86% to 93% with a 51% hazard reduction (HR = 0.49). Under a 0.05 1-sided type I error and 90% power, at least 78 deaths were required to analyze the OS endpoint. Patients had 1) Gleason (Gl) 7-8, any T-stage, and PSA > 20, or 2) Gl 8, ≥ T2, any PSA, or 3) Gl 9-10, any T-stage, any PSA. All had PSA ≤ 150. RT dose was 75.6 Gy. CT consisted of 6, 21-day cycles of docetaxel + prednisone starting 28 days after RT. Results: Of 612 enrolled, 50 were excluded for eligibility issues, leaving 562 evaluable. Median age = 66, median PSA = 15.1, 53% had Gl 9-10, 27% had cT3-4. Median follow-up = 5.5 yrs. 4-yr OS rates were 89% [95% CI: 84-92%] for the AS+RT arm and 93% [95% CI: 90-96%] for the AS+RT+CT arm (1-sided p = 0.03, HR = 0.68 [95% CI: 0.44, 1.03]). There were 52 centrally-reviewed deaths in the AS+RT arm and 36 in the AS+RT+CT arm, with fewer deaths both due to PCa/treatment (20 vs 16) and due to other causes/unknown (32 vs 20) in the AS+RT+CT arm. 5-yr disease-free survival rates were 66% for AS+RT and 73% for AS+RT+CT (2-sided p = 0.05, HR = 0.76 [95% CI: 0.57, 1.00]). There was 1, Gr 5 unlikely-related adverse event (AE) in the AS+RT arm and 2, Gr 5 possibly/probably-related AEs with AS+RT+CT. Conclusions: For high-risk, localized PCa, adjuvant CT improved the OS from 89% to 93% at 4 years. Toxicity was acceptable. This trial was designed with a short OS assessment period and additional follow-up is warranted to determine the long-term benefit of CT to the current standard of care of long-term AS+RT. This project was supported by grants U10CA21661, U10CA180868, U10CA180822, from the National Cancer Institute and Sanofi with additional support from AstraZeneca for Australian site participation. Clinical trial information: NCT00288080.

Purpose To report results of a phase II trial of high-dose-rate intra-operative radiation therapy (HDR-IORT) for malignant pleural mesothelioma (MPM). Methods and materials Seven patients had extrapleural pneumonectomy with IORT (EPP/IORT) and 6 patients had pleurectomy/decortication with IORT (PD/IORT) between 1994 and 1996. IORT was delivered with 192 Ir using a customized applicator with a remote afterloader. A median of 3 sites were treated to a median area of 143 cm 2 . A dose of 1500 cGy was prescribed at each site, with 1000 cGy delivered to the mediastinum. Postoperative external beam radiation therapy (EBRT) was given 3–5 weeks later. Median follow-up was 8 months (range, 1–84 months). Results Five patients developed local failure. Two-year local control and survival rates were 35% and 23%, respectively. Mortality was 2/13 (15%), 1 from each surgical group. Serious complications requiring further intervention occurred in 3/6 (50%) of the EPP/IORT group and 1/5 (20%) of the PD/IORT group. Conclusions HDR-IORT after EPP for MPM is prohibitively toxic and has been abandoned, while its use with PD remains in question.

4007 Background: RTOG 0436 is a randomized Ph III trial evaluating cetuximab added to concurrent chemoradiation for patients (pts) undergoing non-operative management of esophageal carcinoma (EC). ...

LBA6 Background: RTOG 0436 is a randomized Ph III trial designed to evaluate the benefit of cetuximab added to the concurrent chemoradiation for patients undergoing non-operative management of esophageal carcinoma. Methods: Pts with biopsy-proven squamous cell or adenocarcinoma of the esophagus (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions ± weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2). Patients were stratified by histology, tumor size (< 5 cm vs > 5cm), and the status of celiac lymph nodal involvement. Overall survival (OS) was the primary endpoint, with a planned accrual of 420 pts to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided 0.025 alpha. An interim analysis of cCR was planned for the first 150 of each histology. Results: The study accrued 344 pts from 2008-2013 and 328 were eligible. Based on interim analyses, the study stopped accruing adeno pts in 5/2012 and SCC pts in 1/2013. Pts were well matched for pretreatment characteristics: 80% with T3/4 disease, 66% N1, and 19% with celiac nodal involvement. Incidence of grade 3/4/5 treatment (tx) related AEs was 45%, 22%, 4% in Arm 1 (cetuximab) and 49%, 17%, 1% in Arm 2 (no cetuximab). A cCR rate of 56% was observed in Arm 1 vs 59% in Arm 2 (p=0.72). No differences were seen in cCR between tx arms for either histology. The 12 and 24 mo OS rates for cCR pts were 79% and 58% vs 53% and 30% for those with residual disease (p

Purpose To evaluate the efficacy and morbidity of combined 3-dimensional conformal radiation therapy (3D-CRT) and brachytherapy for intermediate/unfavorable risk prostate cancer. Materials and Methods Between May 1996 and November 1997, 65 patients with intermediate/unfavorable risk prostate cancer were treated with 3D-CRT (50.4 Gy) followed by a transperineal permanent Pd-103 implant. Patients with one or two adverse prognostic features (PSA > 10 and Gleason ≥ 7) were classified as intermediate risk and unfavorable risk, respectively. Forty-seven patients (71%) had intermediate risk and 18 (29%) had unfavorable disease risk. The median age of this group was 65 years (range, 42–76 years), and the median pretreatment PSA level was 8.0 ng/ml (range, 1.7–42.0 ng/ml). The clinical stage of these patients was as follows: T1c, 36 (55%); T2a, 27 (42%); T2b/T3, 2 (3%). Fifteen patients (23%) had a Gleason ≤ 6, 41 patients (63%) were classified as Gleason 7, and 9 (14%) as Gleason ≥ 8. Fifty-two (80%) received neoadjuvant androgen deprivation (NAAD) for cytoreduction. The median follow-up was 36 months (range, 24–42 months). Results The PSA relapse-free survival rate at 3 years was 87%, with a median PSA value at last follow-up of 0.25 ng/ml. The relapse-free survival was 90% for those who had an initial PSA ≤ 10 ng/ml and 80% for patients who had an initial PSA > 10 ng/ml (p = 0.5). No difference in outcome was observed between patients with intermediate and unfavorable risk disease. Eight patients (13%) developed late Grade 2 rectal bleeding. Twenty-three patients (42%) required medication for urinary symptoms during the first 6 months after therapy. Three patients (5%) noted rare stress incontinence at last follow-up. Of the 44 patients who were potent prior to therapy, 17 (26%) developed erectile dysfunction (ED). Conclusion Although the follow-up is short, the early biochemical outcome of combined 3D-CRT and brachytherapy for intermediate/unfavorable risk prostate cancer is promising. While rectal toxicity is minimal, urinary side effects are more common. Further follow-up is necessary to fully evaluate the efficacy of this combined therapeutic approach. Int. J. Cancer (Radiat. Oncol. Invest.) 90:275–280, 2000. © 2000 Wiley-Liss, Inc.

To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI).Between 1989-1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45-80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scoresor =7. The median pretreatment PSA was 7 ng/mL (range: 1-58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level wasor =10.0 ng/mL and Gleason scoreor = 6; those with one and two adverse prognostic features (PSA10 ng/mL and Gleason score6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12-126 months).Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA10 ng/mL and Gleason score6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0. 4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication.Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI.

To evaluate the role of detailed pathologic features in predicting outcome for early-stage prostate cancer treated with I-125 brachytherapy. The pretreatment biopsy slides of 103 patients with T1/T2 and Gleason scores of 4–7 prostatic carcinoma, which was treated by transperineal I-125 implantation, were reviewed retrospectively by a single pathologist (P.B.G.). Biochemical tumor control rates [prostate-specific antigen (PSA) below 1.0] were correlated with pretreatment PSA, Gleason score, the amount of tumor in the biopsy samples, and the presence of perineural invasion.In Cox proportional-hazard, multivariate analysis, the strongest predictors of failure were pretreatment PSA above 10 ng/ml (P = 0.013) and the length of the biopsy specimen replaced by tumor (P = 0.15). The percent of biopsy tissue replaced by tumor (P = 0. 74), perineural invasion (P = 0.78), and Gleason score (P = 0.66) were less predictive of prognosis. It was concluded that pretreatment PSA is the strongest predictor of biochemical failure. Detailed assessment of pathological features on needle biopsy added little prognostic information beyond that of pretreatment PSA alone. Like all other prognostic parameters for prostate cancer, there is considerable overlap in pathologic features between those patients who will or will not be controlled biochemically. Radiat. Oncol. Invest. 6:170–174, 1998. © 1998 Wiley-Liss, Inc.

Purpose : Minimal literature exists with 10-year data on neck control in advanced head and neck cancer. The purpose of this study is to determine long-term regional control for base of tongue carcinoma patients treated with primary radiation therapy plus neck dissection. Methods and Materials : Between 1981–1996, primary radiation therapy was used to treat 68 patients with squamous cell carcinoma of the base of tongue. Neck dissection was added for those who presented with palpable lymph node metastases. The T-stage distribution was T1, 17; T2, 32; T3, 17; and T4, 2. The N-stage distribution was N0, 10; N1, 24; N2a, 6; N2b, 11, N2c, 8; N3, 7; and Nx, 2. Ages ranged from 35 to 77 (median 55 years) among the 59 males and nine females. Therapy generally consisted of initial external beam irradiation to the primary site (54 Gy) and neck (50 Gy). Clinically positive necks were boosted to 60 Gy with external beam irradiation. Three weeks later, the base of tongue was boosted with an Ir-192 interstitial implant (20–30 Gy). A neck dissection was done at the same anesthesia for those who presented with clinically positive necks, even if a complete clinical neck response was achieved with external beam irradiation. Neoadjuvant cisplatin-based chemotherapy was administered to nine patients who would have required a total laryngectomy if their primary tumors had been surgically managed. The median follow-up was 36 months with a ranged from 1 to 151 months. Eleven patients were followed for over 8 years. No patients were lost to follow-up. Results : Actuarial 5- and 10-year neck control was 96% overall, 86% after radiation alone, and 100 after radiation plus neck dissection. Pathologically negative neck specimens were observed in 70% of necks dissected after external beam irradiation. The remaining 30% of dissected necks were pathologically positive. These specimens contained multiple positive nodes in 83% despite a 56% overall complete clinical neck response rate to irradiation. Regional failure occurred in only two patients, neither of whom underwent adjuvant neck dissection. Symptomatic neck fibrosis (RTOG grade 3) was not observed. Actuarial 5- and 10-year local control was 88% and 88%, disease-free survival was 80% and 67%, and overall survival was 86% and 52%. Conclusion : For base of tongue cancer, most patients can obtain long-term regional control with no severe complications after definitive radiation therapy, plus neck dissection for those who present with lymphadenopathy. Complete clinical regression of palpable neck metastases after irradiation poorly correlates with pathologic outcome. Our current policy is to include neck dissection at the time of implantation for patients who present with palpable neck metastases. We realize that this therapeutic approach may overtreat some patients, but we are reluctant to change our policy in light of these excellent outcomes.

9525 Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p

PURPOSE: To compare the prostate-specific antigen (PSA) relapse-free survival outcome and incidence of late toxicity for patients with early-stage prostate cancer treated at a single institution with either three-dimensional conformal radiotherapy (3D-CRT) or transperineal permanent implantation (TPI) with iodine-125 seeds. MATERIALS AND METHODS: Patients with favorable-risk prostate cancer, defined as a pretreatment PSA of less than or equal to 10.0 ng/mL, Gleason score of 6 or lower, and stage less than or equal to T2b, were selected for this analysis. Between 1989 and 1996, 137 such patients were treated with 3D-CRT and 145 with TPI. The median ages of the 3D-CRT and TPI groups were 68 years and 64 years, respectively. The median dose of 3D-CRT was 70.2 Gy, and the median implant dose was 150 Gy. Prostate-specific antigen relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up times for the 3D-CRT and TPI groups were 36 and 24 months, respectively. RESULTS: Eleven patients (8%) in the 3D-CRT group and 12 patients (8%) in the TPI group developed a biochemical relapse. The 5-year PSA relapse-free survival rates for the 3D-CRT and the TPI groups were 88% and 82%, respectively (P = .09). Protracted grade 2 urinary symptoms were more prevalent among patients treated with TPI compared with 3D-CRT. Grade 2 urinary toxicity, which was manifest after the implant and persisted for more than 1 year after this procedure, was observed in 45 patients (31%) in the TPI group. In these 45 patients, the median duration of grade 2 urinary symptoms was 23 months (range, 12 to 70 months). On the other hand, acute grade 2 urinary symptoms resolved within 4 to 6 weeks after completion of 3D-CRT, and the 5-year actuarial likelihood of late grade 2 urinary toxicity for the 3D-CRT group was only 8%. The 5-year actuarial likelihood of developing a urethral stricture (grade 3 urinary toxicity) for the 3D-CRT and TPI groups was 2% and 12%, respectively (P CONCLUSION: Both 3D-CRT and TPI are associated with an excellent PSA outcome for patients with early-stage prostate cancer. Urinary toxicities are more prevalent for the TPI group and subsequently resolve or improve in most patients. In addition to evaluating long-term follow-up, future comparisons will require detailed quality-of-life assessments to further determine the impact of these toxicities on the overall well-being and quality of life of the individual patient.