Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation.

BACKGROUND: The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated cancers across Canada is limited. METHODS: We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression. RESULTS: We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of-tongue tumours and those with nodal involvement (p < 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (p < 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (p < 0.001). INTERPRETATION: Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012.

Radiogenomics: the search for genetic predictors of radiotherapy response.

'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation.

Effects of Androgen Deprivation Therapy on Prostate Cancer Outcomes According to Competing Event Risk: Secondary Analysis of a Phase 3 Randomised Trial.

BACKGROUND: Previous studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks. OBJECTIVE: To determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT. DESIGN, SETTING, AND PARTICIPANTS: An ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted. INTERVENTION: Short-term ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate-specific antigen (PSA), to stratify patients according to relative hazards for primary cancer-related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score. RESULTS AND LIMITATIONS: T2b, higher GS, and higher PSA were associated with an increased RR for cancer-related versus competing mortality events (a higher omega score); increased age and comorbidity were associated with a decreased omega score. Of 996 patients with low-risk/favourable intermediate-risk (FIR) disease, 286 (28.7%) had a high omega score (≥0.314). Of 768 patients with unfavourable intermediate-risk disease, 175 (22.8%) had a low omega score. The overall discordance in risk classification was 26.1%. Both standard criteria and omega score identified significant interactions for the effect of ADT on cancer-related events and late mortality in low- versus high-risk subgroups. Within the low-risk/FIR subgroup, a higher omega score identified patients in whom ADT significantly reduced cancer events and improved event-free survival. Limitations are the need for external/prospective validation and lower RT doses than contemporary standards. CONCLUSIONS: Stratification based on competing event risk is useful for identifying prostate cancer patients who selectively benefit from ADT. PATIENT SUMMARY: We analysed the effectiveness of androgen deprivation therapy (ADT) for localised prostate cancer among patients, defined by the relative risk (RR) for cancer versus noncancer events. Among patients with traditional low-risk/favourable intermediate-risk disease, those with a higher RR benefitted from short-term ADT.

Validation of the Head and Neck Patient Symptom Checklist as a nutrition impact symptom assessment tool for head and neck cancer patients.

PURPOSE: The purpose of this study was to test the validity of the Head and Neck Patient Symptom Checklist (HNSC). METHODS: Three hundred and sixty-eight treatment-naive individuals with head and neck cancer prospectively completed the HNSC and the Patient-Generated Symptom Global Assessment (PG-SGA). The predictive validity was determined by comparing the HNSC symptoms interference scores to the PG-SGA scores. Multivariate logistic regression was used to determine the HNSC symptoms scores associated with reduced dietary intake, ≥ 5 % weight loss over 6 months, and reduced functional performance (FP). RESULTS: HNSC sensitivity (79-98 %), specificity (99-100 %), positive predictive value (92-100 %), and negative predictive value (94-100 %) were excellent, and the Cronbach's alpha coefficient was 0.92. The multivariate logistic regression showed that advanced tumor stage, pain, loss of appetite (LOA), and difficulty swallowing significantly predicted dietary intake. Advanced tumor stage, LOA, and difficulty swallowing were also significant predictors of ≥ 5 % weight loss over 6 months. LOA, difficulty swallowing, feeling full, and lack of energy were significant predictors of reduced FP. CONCLUSIONS: The HNSC appears to be a valid tool for determining symptoms interfering with dietary intake of head and neck cancer (HNC) patients. This instrument may aid in early identification of symptoms that place HNC patients at risk for reductions in dietary intake, weight, and functional performance.

Metformin for Prevention of Anthropometric and Metabolic Complications of Androgen Deprivation Therapy in Prostate Cancer Patients Receiving Radical Radiotherapy: A Phase II Randomized Controlled Trial.

BACKGROUND: Patients with prostate cancer undergoing treatment with radical radiation therapy (RT) plus androgen deprivation therapy (ADT) experience a constellation of deleterious metabolic and anthropometric changes related to hypogonadism that are associated with increased morbidity and mortality. We assessed the effect of metformin versus placebo to blunt the adverse effects of ADT on body weight, waist circumference, and other metabolic parameters. METHODS AND MATERIALS: This phase 2, multicenter, randomized controlled trial (RCT) randomized normoglycemic men with locally advanced prostate cancer receiving radical RT and ADT (18-36 months) in a 1:1 ratio to receive metformin 500 mg by mouth 3 times a day (for 30-36 months) versus identical placebo. RESULTS: From December 2015 to October 2019, 83 men were randomized with median follow-up of 23 months. Baseline mean body mass Index (BMI) of the cohort was 30.2 (range 22.2-52.5). Change in mean weight relative to baseline was lower among men who received metformin compared with placebo at 5 months (-1.80 kg, P = .038), but was not significant with longer follow-up (1 year: +0.16 kg, P = .874). Although participants on ADT had increases in waist circumference in both study arms, metformin did not significantly reduce these changes (1 year: +2.79 cm (placebo) versus +1.46 cm (metformin), P = .336). Low-density lipoprotein (LDL) cholesterol was lower in the metformin arm (-0.32 mmol/L) compared with the placebo arm (-0.03 mmol/L) at 5 months (P = .022), but these differences were not significant with longer follow-up (1 year: -0.17 mmol/L vs -0.19 mmol/L, P = .896). There were no differences in HbA1C, triglyceride, high-density lipoprotein (HDL) cholesterol, and total cholesterol by study arm. CONCLUSIONS: Men receiving radical RT and ADT gained weight and had increases in waist circumference over time that metformin did not significantly mitigate. Although this study did not observe any preventive effect of metformin on the anthropometric and metabolic complications of ADT, metformin continues to be studied in phase 3 RCTs in this patient population to assess its potential antineoplastic effects.

Genomic Classifier Performance in Intermediate-Risk Prostate Cancer: Results From NRG Oncology/RTOG 0126 Randomized Phase 3 Trial.

PURPOSE: Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up. METHODS AND MATERIALS: After National Cancer Institute approval, biopsy slides were collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiation therapy without androgen deprivation therapy. RNA was extracted from the highest-grade tumor foci to generate the locked 22-gene GC model. The primary endpoint for this ancillary project was disease progression (composite of biochemical failure, local failure, distant metastasis, prostate cancer-specific mortality, and use of salvage therapy). Individual endpoints were also assessed. Fine-Gray or cause-specific Cox multivariable models were constructed adjusting for randomization arm and trial stratification factors. RESULTS: Two-hundred fifteen patient samples passed quality control for analysis. The median follow-up was 12.8 years (range, 2.4-17.7). On multivariable analysis, the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P = .04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P < .001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P = .01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P < .001). Ten-year distant metastasis in GC low-risk patients was 4% compared with 16% for GC high-risk patients. In patients with lower GC scores, the 10-year difference in metastasis-free survival rate between arms was -7%, compared with 21% for higher GC patients (P-interaction = .04). CONCLUSIONS: This study represents the first validation of a biopsy-based gene expression classifier, assessing both its prognostic and predictive value, using data from a randomized phase 3 trial of intermediate-risk prostate cancer. Decipher improves risk stratification and can aid in treatment decision-making in men with intermediate-risk disease.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Predictors of adherence to an exercise program for shoulder pain and dysfunction in head and neck cancer survivors.

PURPOSE: Achieving acceptable levels of adherence to exercise may be a challenge with head and neck cancer (HNC) survivors given the high morbidity associated with treatment. The purpose of the present trial was to identify the key predictors of adherence during our shoulder exercise rehabilitation trial. METHODS: Fifty-two HNC survivors were randomly assigned to a 12-week progressive resistance exercise training protocol (n = 27) or a standardized therapeutic exercise protocol (n = 25) that was prescribed to address shoulder pain and dysfunction. Baseline data were collected on standard demographic, medical, behavioral, symptom, psychosocial, and motivational variables from the theory of planned behavior. RESULTS: The exercise adherence rate for the trial was 91%. In multivariate analysis, the independent predictors of reduced adherence were undergoing a more extensive neck dissection procedure (ß = -0.361; P = 0.007) and reporting daily alcohol consumption (ß = -0.298; P = 0.031). Higher exercise adherence was achieved by HNC participants who had undergone nerve sparing neck dissection procedures and who were not regular drinkers. CONCLUSION: Excellent adherence to exercise was achieved in the trial despite high morbidity associated with HNC treatment. The high adherence achieved was likely due to the select and highly motivated sample of HNC survivors as well as to factors associated with trial design such as the support offered to participants. The findings of this trial need to be further explored and confirmed in a larger study that includes a more diverse sample of HNC survivors.

An evaluation of the Clarity 3D ultrasound system for prostate localization.

The purpose of this study is to evaluate the accuracy and precision of the Clarity 3D ultrasound system to track prostate gland positional variations due to setup error and organ motion. Seventeen patients (n = 17) undergoing radical external beam radiation therapy for localized prostate cancer were studied. Subsequent to initial reference ultrasound and planning CT scans, each patient underwent seven repeat weekly tracking CT and ultrasound (US) scans during the course of treatment. Variations in the location of the prostate between reference and tracking scans were measured. Differences reported by CT and ultrasound scans are compared. Ultrasound tracking was initially performed clinically by a group of trained general users. Retrospective prostate localization was then performed by a trained dedicated user upon the original raw data set and also a reduced data set derived from the original by an expert user from Resonant Medical. Correlation accuracy between ultrasound and CT shifts acquired and delineated by a pool of trained general users was deemed unacceptable for radiotherapy purposes. A mean discrepancy between CT and US localizations of greater than 10 mm, with a 5 mm or greater discrepancy rate of nearly 90%, was observed. Retrospective analysis by a dedicated user of both the original and Resonant Medical reduced data sets yielded mean CT-Us discrepancies of 8.7 mm and 7.4 mm, respectively. Unfortunately, the 5 mm or greater CT-US discord rate for these retrospective analyses failed to drop below 80%. The greatest disparity between CT and ultrasound was consistently observed in the superior-inferior direction, while greatest agreement was achieved in the lateral dimension. Despite an expert reanalysis of the original data, the Clarity ultrasound system failed to deliver an acceptable level of geometric accuracy required for modern radiotherapy purposes.

Feasibility of Implementing Cancer-Specific Community-Based Exercise Programming: A Multi-Centre Randomized Trial.

BACKGROUND: There is growing recognition of the importance of reporting preliminary work on the feasibility of a trial. The present study aimed to assess the feasibility of (1) a proposed fitness testing battery, and (2) processes related to the implementation of cancer-specific exercise programming in a community setting. METHODS/DESIGN: A randomized controlled implementation feasibility trial was performed in advance of a large-scale implementation study. Eligible participants within 18 months of a cancer diagnosis were randomized to immediate or delayed community-based exercise at YMCA locations in Calgary and Edmonton, Canada for an 8-week period. The primary outcome for the trial was the feasibility of the physical fitness testing battery, defined as a 70% or greater completion rate across the 24-week study period. The Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework was used to evaluate processes related to implementation of the exercise program across the two sites. RESULTS: Eighty participants were recruited, 73 (91%) completed the 8-week trial, and 68 (85%) completed the 16- and 24-week follow-ups. Sixty participants (75%) completed the full physical fitness test battery at each time point, and 59 (74%) completed the patient-reported outcome measures. Statistically significant between-group differences were found in favor of the exercise group for functional aerobic capacity, upper and lower extremity strength, and symptoms. Differences were found between the sites, however, in completion rates and processes related to program implementation. DISCUSSION: Findings suggest the need for minor adaptations to the physical fitness battery and outcome measures to better fit the community context. While findings support feasibility, context-specific challenges related to implementation processes were identified.

Conventional Versus Hypofractionated Radiation for High-Risk Prostate Cancer Patients (CHIRP): 24-Month Patient-Reported Outcomes of the Randomized Phase 2 CHIRP Trial.

PURPOSE: In this study, we report the 24-month patient-reported outcomes of the randomized phase 2 CHIRP trial that compared conventional and hypofractionated radiation therapy (RT) in the treatment of high-risk prostate cancer. METHODS AND MATERIALS: Men with high-risk localized prostate cancer were randomized to either conventional (78 Gy/39 fractions) or hypofractionated RT (68 Gy/25 fractions). All patients received pelvic nodal RT and adjuvant androgen deprivation therapy. Quality of life (QoL) data were collected through the expanded prostate cancer index composite and the short-form 12 (SF-12) health-related QoL questionnaire at baseline and at 3, 6, 12, 18, and 24 months posttreatment. We assessed change from baseline to account for differences in baseline comorbidities. Independent t test was used to identify differences between the 2 groups. RESULTS: Ninety-six participants were included in the QoL analysis, 49 in the hypofractionation arm and 47 in the standard fractionation arm. Urinary and sexual scores were similar between the 2 arms at all time points. Bowel bother scores exhibited a consistent trend favoring the standard arm from 3- to 18-months posttreatment and were statistically significant at 12 months (P = .016). SF-12 physical component scores showed a consistent trend favoring the hypofractionation arm from 6- to 18-months posttreatment and were statistically significant at 18 months (P = .017). At 24 months, there were no significant differences in QoL scores between the 2 groups. CONCLUSIONS: At 24 months post-RT, there were no major differences in patient-reported QoL between standard and hypofractionated RT. Early statistically significant differences in bowel bother and SF-12 physical component scores were no longer present at 24 months.

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126.

PURPOSE: External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. METHODS AND MATERIALS: The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. RESULTS: In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. CONCLUSIONS: Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

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

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity.

PURPOSE: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. METHODS AND MATERIALS: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. RESULTS: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10-5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10-5). CONCLUSIONS: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial.

Androgen deprivation therapy (ADT) used for prostate cancer (PCa) management is associated with metabolic and anthropometric toxicity. Metformin given concurrent to ADT is hypothesized to counteract these changes. This planned interim analysis reports the gastrointestinal and genitourinary toxicity profiles of PCa patients receiving ADT and prostate/pelvic radiotherapy plus metformin versus placebo as part of a phase 2 randomized controlled trial. Men with intermediate or high-risk PCa were randomized 1:1 to metformin versus placebo. Both groups were given ADT for 18-36 months with minimum 2-month neoadjuvant phase prior to radiotherapy. Acute gastrointestinal and genitourinary toxicities were quantified using CTCAE v4.0. Differences in ≥ grade 2 toxicities by treatment were assessed by chi-squared test. 83 patients were enrolled with 44 patients randomized to placebo and 39 randomized to metformin. There were no significant differences at any time point in ≥ grade 2 gastrointestinal toxicities or overall gastrointestinal toxicity. Overall ≥ grade 2 gastrointestinal toxicity was low prior to radiotherapy (7.9% (placebo) vs. 3.1% (metformin), p = 0.39) and at the end of radiotherapy (2.8% (placebo) vs 3.1% (metformin), p = 0.64). There were no differences in overall ≥ grade 2 genitourinary toxicity between treatment arms (19.0% (placebo) vs. 9.4% (metformin), p = 0.30). Metformin added to radiotherapy and ADT did not increase rates of ≥ grade 2 gastrointestinal or genitourinary toxicity and is generally safe and well-tolerated.

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer.

PURPOSE: Hypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation. METHODS AND MATERIALS: After giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis. RESULTS: From 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116). CONCLUSIONS: HFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.

Comparison of dose statistics for bladder wall and rectum wall vs whole organs for VMAT prostate treatment.

Dose-wall histograms (DWHs) have been used as alternatives to dose-volume histograms (DVHs) for hollow organs, with the rationale that the dose delivered to the interior of a hollow organ would be unrelated to the level of radiation damage. The purpose of this study is to conduct a statistical comparison of dose statistics for both walled and solid structure contours for both bladder and rectum in the treatment of intermediate risk prostate cancer with volumetric arc therapy (VMAT). Ten intermediate risk prostate cases were randomly selected. Rectum and bladder were first contoured as solid structures, and then the corresponding wall structures were generated using either a slice-by-slice cropping (2D method), or with a full 3D cropping tool (3D method). Each case was then inverse planned using a 2-arc VMAT technique. Two plans per case were created, 1 with a hypofractionated treatment and 1 with a standard fractionated treatment. DVHs were calculated for solid structure contours, and DWHs were calculated for the walled structure contours generated using 2D and 3D contouring tools. A nonparametric Spearman statistic correlation test was used to compare a large number of relevant dose histogram points, and to establish the relationship between dose statistics for walled and solid structures. Several notable relationships were observed. Maximum rectal dose was strongly correlated between the solid structure and both the 2D-generated (Spearman's correlation rs = 0.988, p < 0.01) and 3D-generated (rs = 0.952 p< 0.01) wall structures. This indicates that the rectal hot spot occurred in or near the wall for all cases, suggesting that both structure types give similar maximum dose information for rectum. Maximum bladder dose was not significantly correlated between solid structures and the 2D (rs = 0.596, p= 0.069) and 3D-generated (rs = 0.681, p= 0.03) counterparts. This suggests that the maximum dose is not consistently in or near the bladder wall. This favors the use of bladder wall contours when considering bladder toxicity, with the maximum dose to the wall potentially being more relevant radiobiologically. This analysis was extended to many other relevant points on the rectum and bladder histogram curves. Where correlations are strong, equations of best-fit are presented. This work establishes several statistically-significant relationships between bladder and rectum DVHs and DWHs for VMAT irradiation of intermediate-risk prostate cancer. This information may be used to inform contouring requirements for clinical trial design as well as for standard patient care.

Promoting Career Selection Through a Comprehensive Enrichment Experience: A Review of the Canadian Radiation Oncology Summer Studentship.

PURPOSE: The impact that early clinical exposure to radiation oncology has on medical students' understanding of oncology and career choice is understudied. This study aims to review the experience and outcomes of medical students who participated in the Canadian Association of Radiation Oncology-Canadian Radiation Oncology Foundation 6-week summer studentship. METHODS AND MATERIALS: Medical students who participated in the nationally funded studentship from 2014 to 2018 were asked to fill out a survey after completing the program. The survey asked about student experience related to radiation oncology before the studentship, student satisfaction with the studentship (scale of 1-5; 5 = outstanding, 3 = meets expectations, 1 = unsatisfactory), and student willingness to recommend it to other students (scale of 1-10; 1 = strongly disagree, 5 = neutral, 10 = strongly agree). The effect of studentship on interest in the specialty was assessed (scale of 1-10; 1 = strongly disagree, 5 = neutral, 10 = strongly agree), including intent to direct their career toward radiation oncology. Match rates to radiation oncology residency are reported for students who participated in the studentship from 2013 to 2016. RESULTS: All 31 students responded to the survey. Overall, the program was highly rated: inclusion of a broad range of clinical problems (mean = 4.6/5); opportunity to learn assessment, investigation, and management (mean = 4.2/5); and overall educational value (mean = 4.8/5). Poststudentship, most students reported an increased interest in oncology (76%, n = 22/29), and specifically radiation oncology (83%, n = 24/29). They would highly recommend this program to another medical student (mean = 9.8/10). The average percentage of these students entering a radiation oncology career (30.5%) each year was higher than national residency match rates in radiation oncology (0.7%). CONCLUSIONS: Clinical exposure to radiation oncology through a nationally funded Canadian Association of Radiation Oncology-Canadian Radiation Oncology Foundation summer studentship positively affected medical student interest in oncology. This study suggests a potential effect of the studentship program on career selection of radiation oncology.

Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.

BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

Changes in Ultraviolet Radiation Exposure to the Ocular Region: A Population-Based Study.

In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy for UVR exposure in the ocular region using a population-based cancer registry. Overall, 74,053 cases of eyelid basal cell carcinoma (BCC) and 7890 cases of melanoma over a 26-year period (1982-2007) were analyzed. The incidence of eyelid basal cell carcinoma and uveal melanoma remained stable, whereas other cutaneous areas demonstrated an increase in the rates. A comparability test demonstrated that BCC incidence trends were significantly different between the eyelid versus both chronically exposed (males p = 0.001; females p = 0.01) and intermittently exposed skin (males and females, p = 0.0002), as well as the skin of the face (males p = 0.002; females p = 0.02). Similarly, melanoma trends were significantly different between the UM group versus both chronically exposed cutaneous melanoma (CM) (males p = 0.001; females p = 0.04) and intermittently exposed CM (males p = 0.005), as well as facial skin CM (males and females p = 0.0002). The discrepancy of cancer incidence between tumors in the peri-ocular region versus the rest of the body suggests that the peri-ocular region might have a different or unique exposure pattern to ultraviolet radiation.