Search

BACKGROUND The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

Over a quarter of chemotherapy regimens now include oral agents. Individuals living with cancer are now responsible for administering this lifesaving therapy at home by taking every dose as prescribed. One type of oral chemotherapy, tyrosine kinase inhibitors (TKIs), is the current recommended treatment for chronic myeloid leukemia. This targeted therapy has markedly improved survival but comes with significant side effects and financial costs. In the study described in this protocol, the investigators seek to understand the dynamic nature of TKI adherence experienced by individuals diagnosed with CML. Using a mixed method approach in this prospective observational study, funded by the National Cancer Institute, we seek to describe subjects’ adherence trajectories over one year. We aim to characterize adherence trajectories in individuals taking TKIs using model-based cluster analysis. Next, we will determine how side effects and financial toxicity influence adherence trajectories. Then we will examine the influence of TKI adherence trajectories on disease outcomes. Additionally, we will explore the experience of patients taking TKIs by interviewing a subset of participants in different adherence trajectories. The projected sample includes 120 individuals taking TKIs who we will assess monthly for 12 months, measuring adherence with an objective measure (Medication Event Monitoring System- MEMS(®)). Identifying differential trajectories of adherence for TKIs is important for detecting subgroups at the highest risk of nonadherence and will support designing targeted interventions. Results from this study can potentially translate to other oral agents to improve care across different types of cancer.

Background While the importance of commensal microbes in vaginal health is well appreciated, little is known about the effects of gynecological cancer (GynCa) and radiation therapy (RT) on the vaginal microbiome (VM) of postmenopausal women. Methods We studied women with GynCa, pre‐ (N = 65) and post‐RT (N = 25) and a group of healthy controls (N = 67) by sequencing the V4 region of the 16S rRNA gene from vaginal swabs and compared the diversity and composition of VMs between the three groups accounting for potential confounding factors in multivariate analysis of variance. Results Comparisons of cancer vs healthy groups revealed that Lactobacillus and Bifidobacterium have significantly higher relative abundance in the healthy group, while the cancer group was enriched in 16 phylogroups associated with bacterial vaginosis (BV) and inflammation, including Sneathia, Prevotella, Peptoniphilus, Fusobacterium, Anaerococcus, Dialister, Moryella, and Peptostreptococcus. In our sample, RT affected the α‐diversity and correlated with higher abundance of typically rare VM species, including several members of the Lacnospiraceae family, a taxon previously linked to vaginal dysbiosis. In addition to cancer and treatment modalities, age and vaginal pH were identified as significant parameters that structure the VM. Conclusions This is among the first reports identifying VM changes among postmenopausal women with cancer. RT alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention., Vaginal microbial communities in postmenopausal women undergoing gynecologic cancer treatments have small but detectable differences compared to healthy controls, including higher diversity and abundance of opportunistic bacterial pathogens. Radiation therapy alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities (surgery and chemotherapy) are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention.

PURPOSE In oncology trials, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the standard tool for reporting adverse events (AEs), but it may underreport symptoms experienced by patients. This analysis of the NRG Oncology RTOG 1203 compared symptom reporting by patients and clinicians during radiotherapy (RT). PATIENTS AND METHODS Patients with cervical or endometrial cancer requiring postoperative RT were randomly assigned to standard 4-field RT or intensity-modulated RT (IMRT). Patients completed the 6-item patient-reported outcomes version of the CTCAE (PRO-CTCAE) for GI toxicity assessing abdominal pain, diarrhea, and fecal incontinence at various time points. Patients reported symptoms on a 5-point scale. Clinicians recorded these AEs as CTCAE grades 1 to 5. Clinician- and patient-reported AEs were compared using McNemar’s test for rates > 0%. RESULTS Of 278 eligible patients, 234 consented and completed the PRO-CTCAE. Patients reported high-grade abdominal pain 19.1% ( P < .0001), high-grade diarrhea 38.5% ( P < .0001), and fecal incontinence 6.8% more frequently than clinicians. Similar effects were seen between grade ≥ 1 CTCAE toxicity and any-grade patient-reported toxicity. Between-arm comparison of patient-reported high-grade AEs revealed that at 5 weeks of RT, patients who received IMRT experienced fewer GI AEs than patients who received 4-field pelvic RT with regard to frequency of diarrhea (18.2% difference; P = .01), frequency of fecal incontinence (8.2% difference; P = .01), and interference of fecal incontinence (8.5% difference; P = .04). CONCLUSION Patient-reported AEs showed a reduction in symptoms with IMRT compared with standard RT, whereas clinician-reported AEs revealed no difference. Clinicians also underreported symptomatic GI AEs compared with patients. This suggests that patient-reported symptomatic AEs are important to assess in this disease setting.

Objective Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment. Methods HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used. Results In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity. Conclusions Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Postmenopausal women often suffer from vaginal symptoms associated with atrophic vaginitis. Additionally, gynecologic cancer survivors may live for decades with additional, clinically significant, persistent vaginal toxicities caused by cancer therapies, including pain, dyspareunia, and sexual dysfunction. The vaginal microbiome (VM) has been previously linked with vaginal symptoms related to menopause (i.e. dryness). Our previous work showed that gynecologic cancer patients exhibit distinct VM profiles from healthy women, with low abundance of lactobacilli and prevalence of multiple opportunistic pathogenic bacteria. Here we explore the association between the dynamics and structure of the vaginal microbiome with the manifestation and persistence of vaginal symptoms, during one year after completion of cancer therapies, while controlling for clinical and sociodemographic factors. We compared cross-sectionally the vaginal microbiome in 134 women, 64 gynecologic patients treated with radiotherapy and 68 healthy controls, and we longitudinally followed a subset of 52 women quarterly (4 times in a year: pre-radiation therapy, 2, 6 and 12 months post-therapy). Differences among the VM profiles of cancer and healthy women were more pronounced with the progression of time. Cancer patients had higher diversity VMs and a variety of vaginal community types (CTs) that are not dominated by Lactobacilli, with extensive VM variation between individuals. Additionally, cancer patients exhibit highly unstable VMs (based on Bray-Curtis distances) compared to healthy controls. Vaginal symptoms prevalent in cancer patients included vaginal pain (40%), hemorrhage (35%), vaginismus (28%) and inflammation (20%), while symptoms such as dryness (45%), lack of lubrication (33%) and dyspareunia (32%) were equally or more prominent in healthy women at baseline. However, 24% of cancer patients experienced persistent symptoms at all time points, as opposed to 12% of healthy women. Symptom persistence was strongly inversely correlated with VM stability; for example, patients with persistent dryness or abnormally high pH have the most unstable microbiomes. Associations were identified between vaginal symptoms and individual bacterial taxa, including: Prevotella with vaginal dryness, Delftia with pain following vaginal intercourse, and Gemillaceaea with low levels of lubrication during intercourse. Taken together our results indicate that gynecologic cancer therapy is associated with reduced vaginal microbiome stability and vaginal symptom persistence.

Background: Malnutrition is a common complication in children with cancer. Cancer treatment and malnutrition can disrupt gut microbiome diversity and composition. This study aims to compare the dietary intakes between children with solid tumors post-chemotherapy and healthy controls, and investigate associations between the dietary intakes and the gut microbiome. Procedure: Children (7-18 years) with solid tumors were recruited during year 1 after the completion of chemotherapy from Children’s Healthcare of Atlanta, Atlanta, Georgia. Healthy controls were recruited via flyers. Children completed the Block Kids Food Screener for dietary intakes in the past week. Fecal specimens were collected and processed for the gut microbiome. QIIME2 and Mann-Whitney U tests were conducted to answer the research questions. Results: Forty-nine children (25 cancers vs 24 controls) were analyzed. Two groups had no differences in age, race, sex, and body mass index. Children with solid tumors reported significantly higher mean daily intakes of macronutrients: calories, protein, fat, carbohydrate, and fiber, and antioxidant nutrients (vitamin E, vitamin C, and selenium) than controls. Children with adequate vitamin B6 had a higher Chao1 diversity index than children with inadequate or excessive intake (P = 0.0004). Children with excessive selenium intake had a trend of higher Pielou’s_e index than children with inadequate intake (P = 0.091). Conclusion: Children with cancer reported significantly higher intakes of macronutrients and antioxidant nutrients than healthy children, but no differences in major energy ratios. Macronutrients, particularly antioxidant nutrients, were associated with disruptions of the gut microbiome in children with solid tumors.

PURPOSE: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy. METHODS AND MATERIALS: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy–HNC. RESULTS: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to

Purpose/objective(s) Established risk factors for head and neck cancer recurrence include clinical and tumor features assessed prior to treatment. We report the first use of DNA methylation in peripheral blood before and after radiotherapy (RT) to further improve risk stratification. Materials/methods Peripheral blood samples were obtained from patients with non-metastatic squamous cell carcinoma (SCC) of the head and neck for methylation analysis, 1 week before initiation and 1 month after completion of RT. Patients were randomized to a discovery cohort or validation cohort. In the discovery cohort, associations between methylation change at 807,100 genomic sites (post-treatment minus pre-treatment) and progression-free survival (PFS) as well as overall survival (OS) were evaluated using Cox regression, adjusted for clinicopathologic covariates. A risk score (RS) was then constructed from methylation levels at the top associated sites, filtered for residing within regulatory elements of genes that are predominantly expressed in bone marrow, lymphoid tissue, or blood cells. The prognostic value of RS was separately assessed in the discovery cohort and validation cohort. Results Between December 2013 and September 2018, 115 patients enrolled in this study (Table) and consist of mostly males (72%) with locally advanced disease (91%). HPV negative status, oral cavity cancer, PEG tube insertion, and higher neutrophil count before RT were associated with shorter PFS and OS (P 10, P = 0.016) and OS (HR > 10, P = 0.017) in the discovery cohort, independent of the aforementioned risk factors. These findings were further replicated in the validation cohort where high RS also independently conferred poorer PFS (HR > 10, P = 0.002) and OS (HR 6.3, P = 0.015). Conclusion We successfully trained and validated a signature of DNA methylation in peripheral blood before and after RT that stratified outcomes among patients with head and neck SCC, implicating the potential for genomics-tailored consolidation treatment and surveillance. Efforts toward methylation analysis at additional post-treatment time points are ongoing.

Purpose NRG/RTOG 0841 assessed the feasibility of a depression screening procedure in patients receiving radiation therapy (RT). As a secondary endpoint, availability and barriers to psychosocial care data were collected in hopes of providing recommendations for improved psychosocial care among patients receiving RT. Methods and Materials Patients starting RT were prospectively recruited and assessed with self-reported distress screening tools. Patients exceeding a validated cutoff and a sample of patients who screened negative received the Structured Clinical Interview for DSM-IV (SCID) mood disorder modules via telephone. During that SCID evaluation, patients completed a validated scale ranking interview on barriers to psychosocial care and interest in various psychosocial intervention modalities. Results A total of 463 patients from 35 community-based and 2 academic RT oncology sites were recruited. Of the 455 eligible, 75 (16%) exceeded screening cutoffs for depressive symptoms. From this group, 78 patients completed the SCID; most were female (76%), white (88%), and had breast cancer (55%). Overall, the most common barriers to treatment, regardless of insurance, were costs (58%), daily responsibilities (44%), and physical health symptoms (38%). Patients from RT facilities without mental health services were significantly more likely to report difficulty with physical health problems, specifically serious illness and walking, compared with those treated at RT facilities with services (P = .013 and P = .039, respectively). Overall, there was interest in obtaining psychosocial services with face-to-face counseling at the cancer center and printed educational materials as the most commonly preferred interventions. Patients with difficult barriers to psychosocial interventions were significantly less interested in support away from the cancer center (P = .016), telephone and Internet counseling (P = .0062 & P = .011), and Internet support (P = .0048). Conclusion Radiation oncology patients are interested in obtaining psychosocial services but face barriers to access to mental health services including cost, debilitating symptoms, and time constraints that prevent adequate care.

Background This study evaluated the association between health-related quality of life (HRQOL) and cognition in patients receiving memantine for prevention of cognitive dysfunction during whole-brain radiotherapy (WBRT). Methods Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine, 20 mg per day, within 3 days of initiating radiotherapy, for 24 weeks. The Functional Assessment of Cancer Therapy-Brain module (FACT-Br) and Medical Outcomes Scale-Cognitive Functioning Scale (MOS-C) were completed in coordination with serial standardized tests of cognitive function. Results Of the 508 eligible patients, 442 (87%) consented to participate in the HRQOL portion and contributed to baseline analyses. Evaluable patients at 24 weeks (n = 246) included surviving patients completing FACT-Br, MOS-C, and objective cognitive assessments (n = 146, 59%) and patients alive at time of missed assessment (n = 100, 41%). Baseline cognitive function correlated significantly with FACT-Br and MOS-C self-reports. All domains of objective cognitive function showed declines over time. Neither FACT-Br nor MOS-C differed between the treatment arms. Emotional and functional well-being subscales of the FACT improved over time while the remainder of the FACT-Br domains remained stable. MOS-C scores declined over time. Conclusion Baseline cognitive function correlated significantly with FACT-Br and MOS-C scores. No by-arm differences in HRQOL were observed despite differences in objective cognitive function. Patient attrition and poor testing compliance remain significant problems in studies of cognitive function of brain metastases patients and further effort is needed to improve compliance with testing and sensitivity of patient-reported measures.

BACKGROUND Human papillomavirus (HPV) infection has contributed to an increased incidence of squamous cell carcinoma of the head and neck (SCCHN). Fatigue is a major side effect of SCCHN and its treatment. However, to the authors' knowledge, the association between HPV and fatigue has not been examined to date, nor is it known whether HPV influences biological mechanisms of fatigue, including inflammation. METHODS Patients with SCCHN who were without distant metastasis were assessed at baseline (pre-radiotherapy) and 1 month and 3 months postradiotherapy. Fatigue was measured using the Multidimensional Fatigue Inventory. Peripheral inflammation was assessed by plasma C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor 2 (sTNFR2), and IL-6. Mixed effect models were used to examine associations. RESULTS A total of 94 patients who were newly diagnosed were enrolled; 53% had HPV-related tumors. Patients with HPV-unrelated tumors had higher fatigue and higher plasma CRP, sTNFR2, and IL-6 over time, especially at baseline and 3 months after intensity-modulated radiotherapy compared with those with HPV-related tumors (all P

Background Vaginal brachytherapy, a common treatment of endometrial cancer, is associated with high rates of vaginal stenosis. Recommendations for vaginal dilator use to minimize stenosis generally include 3 times per week for approximately 10 minutes per use. However, adherence rates range widely and are generally well less than 50%. Objectives The aims of this study were to assess feasibility of recruitment to a study of dilator use and test a theoretically driven enhanced educational program (EEP) to increase adherence. Methods Eligibility included women treated with postoperative vaginal brachytherapy for stage I to IIIc endometrial cancer. Patients were randomized to either nurse-delivered standard institutional instruction or EEP. Results Of eligible patients, 76% consented, 42 were randomized, and 69% completed the 6-month assessment. Mean age was 58.2 years; 48% were sexually active. There was no difference in adherence between arms. Overall, 20% and 8.3% were adherent to the prescribed use of 3 times per week, and 64% and 16% were adherent to use at least once per week at 6 weeks and 6 months, respectively. Adherence was greater among those motivated by vaginal health and having lower body mass index. Nonadherence was significantly higher among those who are college educated, in the EEP group, and with higher weight. Conclusions Feasibility of recruitment into a study of vaginal dilator use was high. Adherence was low, and there was no difference between groups. Adherence to vaginal dilator use requires novel interventions to test. Implications for practice Nursing education that includes how dilators may maintain vaginal health may improve use because it was a motivator for adherence in this study.

Radiation (RT) dose to the central nervous system (CNS) has been implicated as a contributor to treatment-related fatigue in head and neck cancer (HNC) patients undergoing radiation therapy (RT). This study evaluates the association of RT dose to CNS structures with patient-reported (PRO) fatigue scores in a population of HNC patients.At pre-RT (baseline), 6th week of RT, and 1-month post-RT time points, Multidimensional Fatigue Inventory (MFI-20) scores were prospectively obtained from 124 patients undergoing definitive treatment for HNC. Medulla, pons, midbrain, total brainstem, cerebellum, posterior fossa, and pituitary dosimetry were evaluated using summary statistics and dose-volume histograms, and associations with MFI-20 scores were analyzed.Maximum dose (Dmax) to the brainstem and medulla was significantly associated with MFI-20 scores at 6th week of RT and 1-month post-RT time points, after controlling for baseline scores (p0.05). Each 1Gy increase in medulla Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.026), and 0.25 (p=0.037), at the 6th week of RT and 1-month post-RT, respectively. Each 1Gy increase in brainstem Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.027), and 0.25 (p=0.037) at the 6th week of RT, 1-month post-RT, respectively. Statistically significant associations were not found between dosimetry for the other CNS structures and MFI-20 scores.In this analysis of PRO fatigue scores from a population of patients undergoing definitive RT for HNC, maximum dose to the brainstem and medulla was associated with a significantly increased risk of acute patient fatigue.

PURPOSE/OBJECTIVE(S) To report the PROs of a phase III randomized trial evaluating TAS combined with dose-escalated RT for patients with intermediate risk prostate cancer. MATERIALS/METHODS Eligible patients had intermediate risk prostate cancer defined as harboring ≥ 1 of these risk factors: clinical stage T2b-T2c, Gleason score 7, or PSA > 10 to ≤ 20 ng/mL. Patients were randomized to dose-escalated RT alone (Arm 1) or RT plus TAS (Arm 2) consisting of LHRH agonist/antagonist with oral antiandrogen for 6 months. Validated PROs included the Expanded Prostate Cancer Index Composite (EPIC-50) and Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue short form. PRO change scores, calculated for each patient as the follow-up score minus baseline score (at end of RT, 6, 12, and 60 months from start of RT) were compared between treatment arms using a two-sample t test. An effect size (ES) of 0.50 SD (standard deviation) of the baseline measure was considered clinically meaningful. For the PRO sample size, 200 patients per arm would provide 90% statistical power to detect an ES < 0.50 if the completion rate was only 60%. Mixed effect regression models were also utilized. Clinical outcomes are reported in a separate abstract. RESULTS Of the 402 initial planned subset of trial patients who completed baseline PROs, PRO compliance was approximately 96%, 89%, 86% and 87% at end of RT, 6, 12 and 60 months, respectively. There were no significant differences between these 402 patients and the remaining patients on this trial with respect to age, race, performance status, # risk factors, or comorbidity score. While EPIC urinary and bowel scores decreased significantly by the end of RT in both arms, no clinically meaningful differences between arms were detected over time. For the EPIC hormonal and sexual domains, however, there were clinically meaningful differences between the two arms with greater (P < 0.0001) deficits in the RT + TAS arm. These differences improved over time, with ∼50% resolution by one year after treatment and no clinically meaningful differences by 5 years between arms. PROMIS-fatigue scores increased from baseline in both arms and were significantly higher in arm 2 at the end of RT (P = 0.016), though slightly lower at 12 and 60 months. CONCLUSION The addition of TAS to dose-escalated RT demonstrated significant clinically meaningful declines in the EPIC hormonal and sexual domains, and increases in the PROMIS-fatigue scores, compared to RT alone. These scores gradually improved over time, with no clinically meaningful differences between arms in fatigue by one year, or in hormonal and sexual domains by 5 years. Beyond the clinical outcomes, these PRO results directly from patients provide added value to help patients make informed decisions among treatment options.

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.

BACKGROUND NRG-CC001 sought to evaluate the neuro-protective effects of avoiding the peri-hippocampal stem cell niche using intensity-modulated radiotherapy during WBRT. METHODS Patients with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+ Memantine (M) (30Gy in 10 fractions). Standardized NCF tests and the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) were obtained at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure defined using the reliable change index. Pre-specified secondary endpoints included patient-reported symptoms using the MDASI-BT. Time to NCF was reported as cumulative incidence (with death without NCF failure as a competing risk); between-arms differences were tested using Gray’s test. Deterioration at discrete time-points were tested using chi-square tests. MDASI-BT symptom burden, interference, and cognitive and neurologic burden were analyzed using mixed effects models and t-tests within the model using Hochberg’s multiplicity adjustment. RESULTS A total of 518 patients were randomized from 7/2016 to 3/2018. Median follow-up for alive patients was 12.1 mos, with no difference between arms in terms of toxicity, overall survival or intracranial progression-free survival. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.739, 95% CI: 0.577–0.945, p=0.0.016), with differences first noted at 4 mos in Trail Making Test Part-B (23.3% vs. 40.4% deteriorated, p=0.012). Age did not dilute treatment effect. HA-WBRT+M was associated with reduced cognitive symptom burden in an imputed model (estimate=-0.29, p=0.0425), and also reduced overall symptom burden (p< 0.0001) and interference (p< 0.0016) at 6 mos. CONCLUSIONS The addition of HA to WBRT+M preserved NCF and reduced patient reported cognitive symptom burden, overall symptom burden and symptom interference and should be considered standard of care for any patient fit enough to have WBRT. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

This pilot study examined whether a combined aerobic resistance exercise program reduced fatigue and the potential inflammatory and epigenetic mechanisms in patients with head and neck cancer (HNC) receiving intensity-modulated radiotherapy. The exercise group (N=12) received a 3-month supervised aerobic resistance exercise intervention that was initiated before a 6-week radiotherapy regimen; the control group (N=14) received standard care. Fatigue was measured using Multidimensional Fatigue Inventory-20; physical function measures included a 6-minute walk distance (6MWD), chair stands, bicep curls, and hand grip strength. Inflammatory markers and DNA methylation data were acquired using standardized protocol. Patients were mostly white (93%) and male (81%) with a mean age of 57 years. At the end of the intervention, the exercise group had a marginal decrease in fatigue compared with the control (−5.0 vs. 4.9; P = 0.10). The exercise group had a significantly greater improvement in 6MWD (29.8 vs. −55.5 meters; P = 0.04), and a marginally smaller decline in hand grip (−0.3 vs. −5.8 lbs; P = 0.05) at the end of the intervention than the control. No significant difference in inflammatory markers was observed between groups. Lower plasma interleukin (IL) 6, IL1 receptor antagonist, tumor necrosis factor α (TNFα), soluble TNF receptor II and C-reactive protein were significantly associated with increased 6MWD, chair stand, and bicep curl at the end of the intervention (p

INTRODUCTION AND OBJECTIVES:Salvage prostate bed radiotherapy (PBRT) results in about 70% 5 yr freedom from progression (FFP). A three arm randomized trial was designed to determine whether there a...

Despite initiatives to increase the enrollment of racial and ethnic minorities into cancer clinical trials in the National Cancer Institute National Cancer Clinical Trials Network (NCCTN), participation by Latino and African American populations remain low. The primary aims of this pilot study are (1) to develop a Cultural Competency and Recruitment Training Program (CCRTP) for physician investigators and clinical research associates (CRAs), (2) to determine if the CCRTP increases cultural competency scores among physician investigators and CRAs, and (3) to determine the impact of the CCRTP on minority patient recruitment into NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials. Sixty-seven CRAs and physicians participated in an in-person or online 4-h CRRTP training. Five knowledge and attitude items showed significant improvements from pre- to post-training. A comparison between enrolling sites that did and did not participate in the CCRTP demonstrated a pre to 1-year post-incremental increase in minority accrual to clinical trials of 1.2 % among participating sites. While not statistically significant, this increase translated into an additional 300 minority patients accrued to NCCTN clinical trials in the year following the training from those sites who participated in the training.

Background: Women with gynecological cancer (GynCa) undergoing radiation therapy (RT) are at increased risk for acute and long-term sexual dysfunction after treatment. The vaginal microbiome (VM) is the first line of defense against vaginal infection and sexually transmitted diseases. Compositions of VM between women with GynCa receiving RT and healthy women and associations between the VM and sexual dysfunction and vaginal adverse events are unknown. Methods: Using a longitudinal study design, VM, patient-reported sexual dysfunction and physician-reported vaginal adverse events data were collected from postmenopausal GynCa women receiving RT and healthy postmenopausal women. VM swabs from mid-vagina were used for DNA extraction and sequencing of the V3-V4 region of the 16S rRNA gene. Female Sexual Function Index (FSFI) was used to measure women's sexual dysfunction; the Common Terminology Criteria for Adverse Event (CTCAE) Reporting System was used to assess the severity of vaginal adverse events by physicians. All data were collected pre-RT, right after RT completion, 6- and 12-months post-RT. Group-based trajectory modeling was used to identify the sexual dysfunction trajectories. VM compositions were obtained using Qiime and associations with sexual dysfunction trajectories and vaginal adverse events were identified with univariate and multivariate analysis of variance in the R package vegan. Bacterial taxa characteristic for each trajectory group were identified using the LefSe pipeline. Results: Sixty-five patients with GynCa receiving RT and 69 healthy women participated. GynCa and healthy groups had no differences in age and race. VM communities were dominated by Lactobacillus, Prevotella, Dialister and Anaerococcus bacterial genera. We observed higher α-diversity in cancer than healthy patients, and in post-RT VMs than pre-RT. Three groups of sexual dysfunction trajectories were identified: low risk (17.4%), moderate risk (12.3%), and high risk (70.4%). Cancer and healthy women had no difference in sexual dysfunction trajectories. The VM compositions (Bray-Curtis Index) showed significant or marginal associations with vaginal pH (p=0.001), FSFI total score (p=0.001), all domains of FSFI (desire, arousal, lubrication, orgasm, pain, and satisfaction, all p Citation Format: Jinbing Bai, Despina Tsementzi, Pretesh Patel, Joseph Shelton, Mary Dolan, Jessica Arluck, Namita Khanna, Tony Y. Eng, Konstantinos T. Konstantinidis, Deborah Watkins Bruner. Vaginal microbiome associated with patient-reported sexual dysfunction and physician-reported vaginal adverse events in gynecologic cancer women across radiotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-362.

e24097 Background: Women with gynecological cancer (GynCa) reported an increased risk for acute and long-term sexual dysfunction across cancer treatments, especially radiation therapy (RT). However, limited data exist on the course of sexual dysfunction across RT and its risk factors are unknown. This study sought to characterize women’s sexual dysfunction trajectories and identified risk factors of persistent sexual dysfunction. Methods: Using a longitudinal study design, patient-reported sexual dysfunction, demographic and clinical data were collected. Women receiving RT for GynCa older than 18 years or age, race, and BMI matched healthy controls were enrolled. Female Sexual Function Index (FSFI) was used to assess women’s sexual dysfunction. Patients completed all the questionnaires pre-RT, at the end of RT, 6- and 12-month post-RT. Group-based trajectory modeling was used to identify trajectories of sexual dysfunction and risk factors of persistent sexual dysfunction. Results: Eighty-two patients were analyzed, including 36 GynCa patients receiving RT and 46 healthy post-menopausal women, comprising of 33 Blacks, 44 Whites, and 5 others. Three trajectory groups of sexual dysfunction (total FSFI score) were identified: low risk (17.4%), moderate risk (12.3%), and high risk (70.4%). All three trajectory groups were significantly different from each other (p

PURPOSE: NRG CC001, a phase III trial of WBRT plus memantine with or without hippocampal avoidance, sought to evaluate the neuro-protective effects of avoiding the hippocampus using intensity-modulated radiotherapy. METHODS: Adult patients with brain metastases were stratified by RPA class and receipt of prior radiosurgery/surgery and randomized to WBRT+memantine (WBRT+M) versus hippocampal-avoidant WBRT+memantine (HA-WBRT+M) (30Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months. The primary endpoint was time to NCF failure, defined as decline on at least one of the following tests using the reliable change index: Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence was used to estimate time to NCF failure (death without NCF failure was treated as competing risk) with between-arms differences tested using Grays test. To detect an 11% absolute reduction in 6-month NCF failure, 382 analyzable patients were required for 90% power with two-sided =0.05. Due to possible non-compliance, the sample size was increased by 25% (510 patients). RESULTS: From July 2016 to March 2018, 518 patients were randomized. Median age was 61.5 years. Median follow-up for alive patients was 6.1 months. Treatment arms did not differ in grade3 toxicity, overall survival, intracranial progression, or baseline NCF. Time to NCF failure was significantly longer in favor of HA-WBRT+M (p=0.012). The 6-month NCF failure rates were 69.1% (95% CI:61.8–75.3%) vs. 58.0% (95% CI:50.2–64.9%) for WBRT+M vs. HA-WBRT+M, respectively. After adjusting for stratification factors, HA-WBRT+M (hazard ratio (HR)=0.73, 95%CI:0.56–0.94, p=0.016) and age 61 years (HR=0.61, 95%CI:0.46–0.81, p=0.0006) remained significant. CONCLUSION: Preliminary analysis confirms that conformal avoidance of the neuro-regenerative hippocampal stem cell compartment during WBRT preserves neurocognitive function while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

PurposeThere is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.Methods and materialsNRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test.ResultsThe study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity.ConclusionsThis study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Cancer pain relief is often inadequate because of poor adherence to pain medication, especially for black patients.The purpose of this study is to describe factors related to adherence to around-the-clock opioids among 110 black patients being treated for cancer pain.Sociodemographic, clinical, symptoms, and social support data were collected at baseline; pain and adherence data were collected at 30 days. Associations between these variables and opioid adherence measured by Medication Event Monitoring System were estimated using multiple regression.Mean age was 56 (±10.1), the majority were women (63%) and college educated (56%). Mean pain severity at baseline equaled 4.6 (±2.3). Mean dose adherence was 60% (±28.5), while mean schedule adherence was 33.0% (±31.0). In adjusted analysis, 26% of the variance in dose adherence was explained by recent chemotherapy, changes in pain, concerns about nausea, and doctors' focus on cure versus pain control (P0.001); 27% of the variance in schedule adherence was explained by recent chemotherapy, changes in pain, symptom burden, and concerns about doctors focus on cure versus pain control (P0.001).Findings confirm pain medication adherence is poor and pain was not well relieved. Multiple factors influence adherence to around-the-clock opioids. Clinicians need to partner with patients by providing a personalized pain treatment plan including an in-depth assessment of treatment choices and adherence.

Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient’s perspective.

Purpose: A meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. Methods and materials: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. Results: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (

BACKGROUND: NRG CC001, a phase III trial of WBRT+memantine (WBRT+M) with or without Hippocampal Avoidance (HA), sought to assess the neuro-protective effects of lowering the radiation dose received by the hippocampus. METHODS: Patients (pts) with brain metastases were stratified by RPA class and prior radiosurgery/surgery and randomized to either WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months (mos.). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module and analyzed using mixed effects models and t-tests. RESULTS: From 7/2016 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted HR=0.74, p=0.02) due to lower risk of deterioration in executive function at 4 mos. (p=0.01); and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted for lower NCF failure risk (HR=0.60, p=0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p=0.036); difficulty speaking (p=0.049); and problems remembering things (p=0.013) at 6 mos. favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Treatment arms did not significantly differ in toxicity; intracranial progression or overall survival. CONCLUSIONS: While achieving similar intracranial control and survival; Hippocampal Avoidance during WBRT+M for brain metastases better preserves NCF and patient-reported symptoms. Supported by UG1CA189867 (NCORP) and DCP from the NCI.

Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted.

Purpose A preliminary report of patient reported outcomes (PROs) between men receiving high-dose radiation therapy (RT) on RTOG 0126, a phase III dose-escalation trial treated with either 3-dimensional conformal RT (3D-CRT) or intensity modulated RT (IMRT).

BACKGROUND: Cost can be a major issue in therapeutic decision-making, and in particular for patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: The specific aim of this analysis was to evaluate the costs and outcomes of patients treated on Radiation Therapy Oncology Group (RTOG) 94-10, Medicare Part A and Part B costs from all for patients treated from 1991 to 1996 on RTOG 94-10, a phase III trial showing a survival benefit for concurrent chemoradiation (STD RT) over sequential (RT day 50) chemoradiation in LA-NSCLC with intermediate outcome for concurrent twice daily radiation and chemotherapy (HFX RT). 26-month expected costs for each arm of the trial in 1996 dollars were determined, with Kaplan Meier sampling average estimates of survival probabilities for each month and mean monthly costs. The analysis was performed from a payer’s perspective. Incremental cost-effectiveness ratios were calculated comparing RT on day 50 and HFX RT to the STD RT. RESULTS: Of the 610 patients entered, Medicare cost data and clinical outcomes were available for 92 patients. In this subset, compared to STD RT, RT on day 50 proved less costly but resulted in reduced survival at 1 year. In addition, HFX RT cost slightly more than STD RT but was less effective in this cohort of patients. CONCLUSIONS: In patients with Medicare insurance and with significant toxicity burden, RT on day 50 is the least expensive but also least effective treatment in this subset of patients treated on RTOG 94-10.

Xerostomia (dry mouth) is a common, often permanent, and debilitating morbidity of radiotherapy (RT) for head-and-neck malignancies (1,2). Patients with severe xerostomia have thick secretions, difficulty in swallowing and speaking, and are at high risk for oral infection and dental caries (3). This symptom burden impairs the quality of life (QoL) of many head-and-neck cancer survivors for months, even years, after treatment (4). It is well established that the main cause of RT-induced xerostomia is irradiation of parotid glands—the major salivary glands producing ~60% of total saliva (1). Recent clinical studies indicate that intensity-modulated radiotherapy (IMRT) provides a significant advantage in sparing the parotid glands and reducing xerostomia. However, even with the new technology, 17%–30% of patients treated with IMRT still develop permanent xerostomia. There is substantial heterogeneity in parotid gland injury after radiation (5–7). In the clinic, radiation-induced xerostomia is assessed using patient-based or physician-based grading systems. For example, the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) established a morbidity scale to evaluate post-RT salivary glands. Specifically, salivary gland toxicity was divided into two categories: acute (≤3 months after RT) toxicity and late (>3 months after RT) toxicity. Physicians assign a score of grade 1 (slight dryness) to grade 4 (necrosis or fibrosis) for acute or late salivary toxicity (8). Such subjective measures of radiation toxicity are prone to intraobserver and interobserver variability. In recent years, many groups have been investigating imaging technologies to evaluate parotid gland injury induced by radiation. Studies using computed tomography (CT), magnetic resonance imaging (MRI), MR sialography, and single-photon emission computed tomography scintigraphy have shown some degree of success in assessing the severity of parotid gland injury and documenting normal tissue response to RT (9–17). However, the high cost, the technical complexity, and the need for dedicated imaging expertise (CT, MRI, or nuclear medicine) preclude their use in routine clinical assessment of xerostomia. The concept of ultrasound imaging to evaluate parotid gland injury is especially attractive because ultrasound is safe, portable, widely available, easy to use, and cost effective. In particular, because parotid glands are superficial structures wrapping around the mandible, they are readily amenable to ultrasound examination. Ultrasound, therefore, is the standard imaging modality in the assessment of salivary gland diseases such as neoplasms, Sjogren syndrome, sialadenitis, and sialolothiasis. However, there is limited information in the literature about evaluation of radiation-induced parotid gland injury or xerostomia using ultrasound (9). Previously, we have proposed an ultrasound technology based on quantitative analysis of echo-intensity histogram to assess RT-associated parotid gland injury (18). A family of sonographic features was derived from the echo histogram to quantify the echogenicity and heterogeneity of parotid glands, which is used to assess the morphologic and architectural integrity of post-RT parotids. In a pilot study of 12 patients, we demonstrated the clinical feasibility of using these echo histogram features in evaluating parotid gland toxicity after RT (18). Another appealing factor of ultrasound histogram evaluation of RT-related parotid gland toxicity is that it could eliminate variations in subjective radiologic interpretations of ultrasound images. To further explore this ultrasound technology in the evaluation of RT-induced parotid gland injury, we embarked on this clinical study. The primary objective was to determine the diagnostic accuracy of echo-intensity histogram parameters in the assessment of RT-induced parotid gland injury. In addition, we compared the quantitative ultrasound examination with radiologists’ evaluation of acute and late toxicities of RT to parotid glands. Special emphasis was placed on acute toxicity for patients within 3 months of cancer treatment. We want to emphasize the importance of developing safe and easy ultrasound technology to detect acute toxicity because early detection of parotid gland injury could enable early interventions to minimize long-term morbidity.

Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs).The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models.Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P.001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P.001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088).Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia.

Purpose Missing data are a significant problem in clinical trials, particularly for quality of life (QOL), which cannot be obtained retrospectively. The purpose of this study was to evaluate the feasibility of an electronic web-based strategy for QOL data collection in a cooperative group radiation oncology trial setting. Methods and materials Radiation Therapy Oncology Group (RTOG) 0828 was a prospective National Cancer Institute cooperative group companion study of RTOG-0415, a randomized study of conventional versus hypofractionated radiation. Forty-nine English-speaking patients with favorable risk prostate cancer who enrolled on RTOG-0415 consented to using web-based technology for completing QOL. In RTOG-0415, using paper forms, the 6-month QOL compliance rate was 52%. The purpose of RTOG-0828 was to test the feasibility of a web-based strategy with the goal of increasing the 6-month QOL completion rate by 25% (from 52% to 77%) for a relative improvement of ~50%. The web-based tool used in this study was VisionTree Optimal Care (VTOC; VisionTree Software, Inc, San Diego, CA), a Health-Insurance-Portability-Accountability-Act secure, online technology that allows real-time tracking and e-mail reminders. The primary endpoint was the 6-month compliance rate for the validated QOL instrument, Expanded Prostate Index Composite. Results The QOL completion rate at baseline was 98%. Compared with the prior 52% QOL completion rate at 6 months using paper forms, the QOL web-based completion rate at 6 months was 90% (2-sided P value Conclusions This RTOG study suggests that a web-based strategy to collect QOL appears to be feasible in the cooperative group radiation oncology trial setting and is associated with an increase in the 6-month QOL compliance rate compared with the prior method of using paper forms. The RTOG plans to further test this strategy in a head-and-neck cancer trial across all participating RTOG sites.

Arthralgia is a common and debilitating side-effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation.We conducted a randomised controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed 10 EA/SA treatments over 8 weeks using a manualised protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary end-point was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims.Of the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (-2.2 versus -0.2, p=0.0004) and at Week 12 (-2.4 versus -0.2, p0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (-2.0 versus 0.2, p=0.0006) and Week 12 (-2.1 versus -0.1, p=0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (-2.3, -1.5 respectively) and Week 12 (-1.7, -1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events.Compared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.

Purpose To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. Methods and Materials The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. Results Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P P =.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity ( P =.099). Acute G2+ toxicity was associated with late G3+ toxicity ( P =.005). With dose–volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race ( P =.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity ( P =.034). Conclusions Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a clinically meaningful reduction in late G2+ GI toxicity with IMRT. The occurrence of acute GI toxicity and large (>15%) volumes of rectum >70 Gy are associated with late rectal toxicity.

Vascular comorbidities (VC) (hypertension, diabetes, and hyperlipidemia) are known factors related to erectile dysfunction (ED) in men. However, no data are yet available for the effects of VC on ED incidence after prostate cancer radiotherapy (XRT).To investigate the influence of VC on post-XRT ED incidence and to further characterize ED incidence by racial groups.ED incidence.We reviewed 732 charts of patients (267 Caucasian and 465 African American [AA]) who received prostate XRT (external beam radiotherapy and/or brachytherapy) with or without hormone therapy between 1999 and 2010. The number of pre-XRT VC (0, 1, 2, or 3) was determined by medical history and medication list. ED (defined by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history) was determined pre-XRT as well as 1, 2, and 4 years post-XRT.ED incidence progressively increased from 22% pre-XRT to 58% 4 years post-XRT (P 0.01). Additionally, ED incidence significantly increased with number of VC-4-year incidence between patients with 1 vs. 0 (P = 0.02), 2 vs. 0 (P 0.01), 3 vs. 0 (P 0.01), 3 vs. 1 (P 0.01), and 3 vs. 2 (P = 0.04) VC (2 vs. 1 VC was nonsignificant). Compared with the Caucasian patients, ED incidences were slightly higher for the AA group with 0, 1, 2, and 3 comorbidities at 4 years follow-up (but statistically nonsignificant).The number of VCs have a significant effect on development of post-XRT ED. Pre- and post-XRT ED appear to be independent of race when number of VCs are considered. Our results can be used to guide physicians in counseling patients on the incidence of ED by number of VC and as preliminary data for prospective efforts aimed at reducing post-XRT ED.

Summary Objectives This study is to identify symptom clusters for head and neck (HNC) patients treated with concurrent chemoradiotherapy. Patients and methods A secondary data analysis of 684 HNC patients treated on the Radiation Therapy Oncology Group (RTOG) 0129 trial comparing different RT fractionation schedules with concurrent chemotherapy was used to examine clusters. Treatment-related symptoms were measured by clinicians at three time-points during and after chemoradiotherapy using the National Cancer Institute Common Toxicity Criteria v2.0. Exploratory factor analysis was applied to identify symptom clusters, which was further verified by confirmatory factor analysis. Coefficients of congruence and alpha coefficients were employed to examine generalizability of cluster structures over different time-points and in different subgroups. Results Two clusters were identified. The HNC specific cluster is composed of radiodermatitis, dysphagia, radiomucositis, dry mouth, pain, taste disturbance, and fatigue. The gastrointestinal (GI) cluster involves nausea, vomiting, and dehydration. With the exception of patients 65 years old or older, diagnosed with larynx cancer, or with stage III cancer, the two clusters were generalizable to different subgroups defined by age, gender, race, education, marital status, history of tobacco use, treatments, primary sites, disease stages, and tube feedings, as well as to the three symptom assessment time-points. Conclusions The data provides preliminary support for two stable clusters in patients with HNC. These findings may serve to inform the symptom management in clinical practice. Moreover, the findings necessitate future research to examine the generalizability of identified clusters in the late symptom phase or other treatment modalities, and to understand the underlying biological mechanism.

The gut microbiome plays a critical role in maintaining children’s health and in preventing and treating children’s disease. Current application of the gut microbiome in childhood cancer is still lacking. This study aimed to systematically review the following: (1) alternations in the gut microbiome throughout cancer treatment trajectories in children, (2) the associations between the gut microbiome and gastrointestinal (GI) symptoms and psychoneurological symptoms (PNS), and (3) the efficacy of therapeutic interventions in the gut microbiome in children with cancer. PubMed, EMBASE, the Cochrane Library, and the American Society of Clinical Oncology abstract were searched. Eligible studies included all study types in which the gut microbiome was primarily reported in children with cancer. The Mixed Methods Assessment Tool was used to evaluate the methodology quality of included studies. Seven studies met our eligibility criteria, including two cohort studies, two case-control studies, and three randomized controlled trails. The findings showed that the diversity estimates of the gut microbiome in children with cancer were lower than those of healthy controls both pre- and post-treatment. Children with cancer showed a significantly lower relative abundance of healthy gut microbiome (e.g., Clostridium XIVa and Bifidobacterium) during and after cancer treatment. No adequate literature was identified to support the associations between dysbiosis of the gut microbiome and GI symptoms/PNS. The use of prebiotics (fructooligosaccharides) and probiotics (Bifidobacterium or Lactobacilli) appears to improve the microenvironment of the gut around 1 month (4–5 weeks) during chemotherapy rather than at the beginning of treatment. Data also suggest that both prebiotic and probiotic interventions decrease clinical side effects (e.g., infection and morbidity risk) in children with cancer. This study adds to the evidence that dysbiosis of the gut microbiome can be improved using prebiotic and probiotic supplementations in children with cancer. More well-designed experimental studies are needed to confirm this conclusion. Further studies are needed to examine the associations between the gut microbiome and GI symptoms/PNS in childhood cancer.

Purpose Conventional radiotherapy (C-RT) treatment schedules for patients with prostate cancer typically require 40 to 45 treatments that take place from > 8 to 9 weeks. Preclinical and clinical research suggest that hypofractionation—fewer treatments but at a higher dose per treatment—may produce similar outcomes. This trial was designed to assess whether the efficacy of a hypofractionated radiotherapy (H-RT) treatment schedule is no worse than a C-RT schedule in men with low-risk prostate cancer. Patients and Methods A total of 1,115 men with low-risk prostate cancer were randomly assigned 1:1 to C-RT (73.8 Gy in 41 fractions over 8.2 weeks) or to H-RT (70 Gy in 28 fractions over 5.6 weeks). This trial was designed to establish (with 90% power and an α of .05) that treatment with H-RT results in 5-year disease-free survival (DFS) that is not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] < 1.52). Results A total of 1,092 men were protocol eligible and had follow-up information; 542 patients were assigned to C-RT and 550 to H-RT. Median follow-up was 5.8 years. Baseline characteristics were not different according to treatment assignment. The estimated 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3% (95% CI, 83.1 to 89.0) in the H-RT arm. The DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority criterion that required that DFS outcomes be consistent with HR < 1.52 was met (P < .001). Late grade 2 and 3 GI and genitourinary adverse events were increased (HR, 1.31 to 1.59) in patients who were treated with H-RT. Conclusion In men with low-risk prostate cancer, the efficacy of 70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions over 8.2 weeks, although an increase in late GI/genitourinary adverse events was observed in patients treated with H-RT.

Purpose Vaginal stenosis (VS) is a recognized complication of pelvic and vaginal radiation therapy (RT). Methods and materials A 26-item survey assessing the signs/symptoms, risk factors, diagnosis, prevention, treatment, and impact of VS on women's sexual health was distributed to radiation oncologists. Descriptive statistics were calculated. Chi-square tests examined differences in categorical responses. Results A total of 233 (10.5%) participants completed the entire survey. Twelve percent, 21%, and 68% report treating gynecologic (GYN) tumors only, non-GYN pelvic tumors only, or both, respectively. Regarding risk factors, 78% believed that VS can be caused by pelvic RT alone, 91% by vaginal brachytherapy alone, and 98% by combined pelvic RT and vaginal brachytherapy. Approximately one-half of respondents felt that being postmenopausal and having a hysterectomy before radiation therapy were risk factors for VS, whereas the other half felt that these were not risk factors. All respondents agreed that VS is a clinical diagnosis. Respondents indicated that VS symptoms include dyspareunia, vaginal pain, dryness, and/or bleeding (100%, 90%, 85%, and 72%, respectively); 65% indicated all 4. The most commonly recommended treatment for VS is vaginal dilator use. Radiation oncologists who treat GYN-only versus non-GYN cancers were more likely to perform a vaginal examination, to distribute written instructions regarding vaginal dilator use ( P = .002), to have vaginal bleeding reported after RT ( P = .001), and to refer patients to a sexual counselor ( P = .007). Most providers (73%) expressed willingness to participate in prospective research on the diagnosis and treatment of VS. Conclusions This is the first large-scale survey of radiation oncologists' perceptions and practices regarding VS. There is agreement among providers regarding the signs/symptoms of VS and strategies for its prevention/treatment using vaginal dilators. Further prospective and observational research is needed. This survey shows a willingness on the part of providers to take part in prospective research regarding the diagnosis, impact, and treatment of VS on women's sexual health.

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.

Purpose The objective of this study was to determine the patient- and treatment-related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. Methods and Materials We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at the Hospital of the University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients’ charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. Results The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2–3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 ( p = 0.013), 3.96 ( p = 0.008), and 0.17 ( p = 0.032) respectively. Conclusion Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings.

Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT.The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data.The primary end point was improved erectile function, as measured by the IIEF.The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving ≤ 120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase.This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer.

Purpose The specific aim of this analysis was to evaluate the feasibility of performing a cost-effectiveness analysis using Medicare data from patients treated on a randomized Phase III clinical trial. Methods and Materials Cost data included Medicare Part A and Part B costs from all providers—inpatient, outpatient, skilled nursing facility, home health, hospice, and physicians—and were obtained from the Centers for Medicare & Medicaid Services for patients eligible for Medicare, treated on Radiation Therapy Oncology Group (RTOG) 9111 between 1992 and 1996. The 47-month expected discounted (annual discount rate of 3%) cost for each arm of the trial was calculated in 1996 dollars, with Kaplan-Meier sampling average estimates of survival probabilities for each month and mean monthly costs. Overall and disease-free survival was also discounted 3%/year. The analysis was performed from a payer's perspective. Incremental cost-effectiveness ratios were calculated comparing the chemotherapy arms to the radiation alone arm. Results Of the 547 patients entered, Medicare cost data and clinical outcomes were available for 66 patients. Reasons for exclusion included no RTOG follow-up, Medicare HMO enrollment, no Medicare claims since trial entry, and trial entry after 1996. Differences existed between groups in tumor characteristics, toxicity, and survival, all which could affect resource utilization. Conclusions Although we were able to test the methodology of economic analysis alongside a clinical trial using Medicare data, the results may be difficult to translate to the entire trial population because of non-random missing data. Methods to improve Medicare data capture and matching to clinical trial samples are required.

Importance Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences. Objective To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer. Design, Setting, and Participants The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions. Main Outcomes and Measures Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively. Results With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy and 47% and 35% with 70.2 Gy, respectively (both P P = .006 [HR, 1.39; 95% CI, 1.10-1.77] and P = .003 [HR, 1.59; 95% CI, 1.17-2.16], respectively). Conclusions and Relevance Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy. Trial Registration clinicaltrials.gov Identifier:NCT00033631

ObjectiveA meta-analysis was conducted to determine the influence of gender, race, and marital status on overall survival (OS) in Radiation Therapy Oncology Group nonoperative non-small cell lung cancer trials.Materials and MethodsData from 1365 patients treated on nine prospective Radiation Therapy Oncology Group studies activated during the 1990s were analyzed. Impact of gender, marital status, and race was considered in the Cox proportional hazards models. Age, Karnofsky performance status, weight loss, stage, histology, location of primary tumor, biologic equivalent dose, deviation from protocol dose, and education level were adjusted in the model. A two-sided p value