Developing and validating multi-omics prediction models for late patient-reported dysphagia in head and neck radiotherapy.

Background and purpose. To investigate models developed using radiomic and dosiomic (multi-omics) features from planning and treatment imaging for late patient-reported dysphagia in head and neck radiotherapy.Materials and methods. Training (n = 64) and testing (n = 23) cohorts of head and neck cancer patients treated with curative intent chemo-radiotherapy with a follow-up time greater than 12 months were retrospectively examined. Patients completed the MD Anderson Dysphagia Inventory and a composite score ≤60 was interpreted as patient-reported dysphagia. A chart review collected baseline dysphagia and clinical factors. Multi-omic features were extracted from planning and last synthetic CT images using the pharyngeal constrictor muscle contours as a region of interest. Late patient-reported dysphagia models were developed using a random forest backbone, with feature selection and up-sampling methods to account for the imbalanced data. Models were developed and validated for multi-omic feature combinations for both timepoints.Results. A clinical and radiomic feature model developed using the planning CT achieved good performance (validation: sensitivity = 80 ± 27% / balanced accuracy = 71 ± 23%, testing: sensitivity = 80 ± 10% / balanced accuracy = 73 ± 11%). The synthetic CT models did not show improvement over the plan CT multi-omics models, with poor reliability of the radiomic features on these images. Dosiomic features extracted from the synthetic CT showed promise in predicting late patient-reported dysphagia.Conclusion. Multi-omics models can predict late patient-reported dysphagia in head and neck radiotherapy patients. Synthetic CT dosiomic features show promise in developing successful models to account for changes in delivered dose distribution. Multi-center or prospective studies are required prior to clinical implementation of these models.

Dysphagia in Head and Neck Radiotherapy: The Influence of Pharyngeal Constrictor Anatomy and Dosimetry.

The goal of this study was to identify which anatomical and dosimetric changes correlated with late patient-reported dysphagia throughout the course of head and neck chemo-radiotherapy treatment. The patient cohort (n = 64) considered oropharyngeal and nasopharyngeal patients treated with curative intent, exhibiting no baseline dysphagia with a follow-up time greater than one year. Patients completed the MD Anderson Dysphagia Inventory during a follow-up visit. A composite score was measured ranging from 20 to 100, with a low score indicating a high symptom burden; a score ≤60 indicated patient-reported dysphagia. The pharyngeal (PCM) and cricopharyngeal constrictor muscles (CPM) were contoured on a planning CT image and adapted to weekly cone-beam CT anatomy using deformable image registration and dose was accumulated using weighted dose-volume histogram curves. The PCM and CPM were examined for volume, thickness, and dosimetric changes across treatment with the results correlated to symptom group. Anatomical evaluation indicated the PCM thickness increased more during treatment for patients with dysphagia, with base of C2 vertebrae (p = 0.04) and superior-inferior middle PCM (p = 0.01) thicknesses indicating a 1.0-1.5 mm increase. The planned and delivered mean dose and DVH metrics to PCM and CPM were found to be within random error measured for the dose accumulation, indicating delivered and planned dose are equivalent. The PCM and CPM organs were found to lie approximately 5 mm closer to high dose gradients in patients exhibiting dysphagia. The volume, thickness, and high dose gradient metrics may be useful metrics to identify patients at risk of late patient-reported dysphagia.

Estimated absolute percentage of biopsied tissue positive for Gleason pattern 4 (eAPP4) in low dose rate prostate brachytherapy: Evaluation of prognostic utility in a large cohort.

PURPOSE: To determine whether a system to estimate Absolute Percentage of Biopsied Tissue Positive for Gleason Pattern 4 (eAPP4) is useful as a prognostication tool for patients with intermediate risk prostate cancer (IR-PCa) undergoing low dose rate prostate brachytherapy. METHODS: 497 patients with IR-PCa and known grade group 2 or 3 disease treated with low dose rate seed brachytherapy (LDR-BT) at a quaternary cancer centre were retrospectively reviewed. Prostate biopsies for each patient included Gleason grading with synoptic reporting that did not include percentage of pattern 4 disease found within the sample. Each core was assigned a grade grouping, however, and that was used with optimized estimates of percentage of pattern four disease to estimate eAPP4. Outcomes including cumulative incidence of recurrence (CIR), treatment of recurrent disease (RRX), and metastasis-free survival (MFS) were then reviewed and the prognostic value of eAPP4 evaluated. RESULTS: 428 (86%) patients had Gleason grade group 2 and 69 (14%) patients had Gleason grade group 3 disease. 230 (46%) patients had National Comprehensive Cancer Network (NCCN) favourable intermediate at baseline, while 267 (54%) of patients had NCCN unfavourable intermediate at baseline. Median follow-up was 7.3 (5.5-9.6) years. eAPP4 was predictive of CIR (p = 0.003), RRX (p = 0.003), or MFS (p = 0.001) events, while Gleason grade grouping alone was not. eAPP4 was strongest as a predictor for MFS when estimates of 30% (grade group 2) and 80% (grade group 3) were used [HR 1.07 (1.03-1.12); p = 0.001]. CONCLUSIONS: eAPP4 was strongly predictive of recurrence and metastasis-free survival in a large cohort of patients receiving LDR-BT treatment for IR-PCa. Treatment of future patients with IR-PCa could include the use of eAPP4 prognostication.

Do Dosiomic Features Extracted From Planned 3-Dimensional Dose Distribution Improve Biochemical Failure-Free Survival Prediction: an Analysis Based on a Large Multi-Institutional Data Set.

Purpose: The objective of this work was to investigate whether including additional dosiomic features can improve biochemical failure-free survival prediction compared with models with clinical features only or with clinical features as well as equivalent uniform dose and tumor control probability. Methods and Materials: This retrospective study included 1852 patients who received diagnoses of localized prostate cancer between 2010 and 2016 and were treated with curative external beam radiation therapy in Albert, Canada. A total of 1562 patients from 2 centers were used for developing 3 random survival forest models: Model A included only 5 clinical features; Model B included 5 clinical features, equivalent uniform dose, and tumor control probability; and Model C considered 5 clinical features and 2074 dosiomic features derived from the planned dose distribution of the clinical target volume and planning target volume with further feature selection to determine prognostic features. No feature selection was performed for models A and B. Two hundred ninety patients from another 2 centers were used for independent validation. Individual model-based risk stratification was examined, and the log-rank tests were performed to test statistically significant differences between the risk groups. The 3 models' performances were evaluated using Harrell's concordance index (C-index) and compared using one-way repeated-measures analysis of variance with post hoc paired t test. Results: Model C selected 6 dosiomic features and 4 clinical features to be prognostic. There were statistically significant differences between the 4 risk groups for both training and validation data sets. The C-index for the out-of-bag samples of the training data set was 0.650, 0.648, and 0.669 for models A, B, and C, respectively. The C-index for the validation data set for models A, B, and C was 0.653, 0.648, and 0.662, respectively. Although gains were modest, Model C was statistically significantly better than models A and B. Conclusions: Dosiomics contain information beyond common dose-volume histogram metrics from planned dose distributions. Incorporation of prognostic dosiomic features in biochemical failure-free survival outcome models can lead to statistically significant although modest improvement in performance.

Local Prostate Radiation Therapy and Symptomatic Local Events in De Novo Metastatic Prostate Cancer.

PURPOSE: Local prostate radiation therapy (LPRT) for low-burden metastatic prostate cancer (mPCa) improves overall survival and is the standard of care. The role of LPRT in reducing symptomatic local events (SLE) remains unclear. We aimed to identify SLE risk factors and to evaluate the association between LPRT and SLE in mPCa. METHODS AND MATERIALS: We conducted a retrospective, population-based cohort study of patients initially diagnosed with mPCa between 2005 and 2016 in a cancer registry. Patient, tumor, and treatment characteristics were obtained from chart review and the cancer registry. The coprimary endpoints were genitourinary (GU) and gastrointestinal (GI) SLE, identified by physician billing claims between 2004 and 2017 for diagnostic or therapeutic procedures potentially related to GU and GI SLE. The effect of LPRT on SLE was evaluated using both recurrent event (Andersen-Gill model) and time-to-first-event sequential landmark analyses. Risk factors for SLE were assessed by multivariable Cox regression. LPRT was defined as ≥40 Gy within 1 year of diagnosis. Metastatic burden was defined per the STAMPEDE trial. RESULTS: Of 1363 patients, 46 (3.4%) received LPRT. Median follow-up was 27.3 and 28.9 months in the control and LPRT groups, respectively. LPRT was associated with less recurrent GU SLE (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.17-0.67; P = .002), upper tract obstruction (HR, 0.20; 95% CI, 0.05-0.84; P = .03), and cystoscopy (HR, 0.38; 95% CI, 0.15-0.96; P = .04). Metastatic burden was not associated with SLE. CONCLUSIONS: LPRT in mPCa was associated with less recurrent GU SLE, specifically for upper tract obstruction and cystoscopy.

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.

Feasibility and Acceptability of Implementing Site-Specific Patient-Reported Outcome Measure in Head and Neck Cancer Clinics: A Prospective Institutional Study.

Purpose: To assess the feasibility and acceptability of implementing the MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) module in cancer clinics and its effect on patient-reported experience. Methods: We conducted a prospective, longitudinal study at a tertiary cancer institution between September 2020 and August 2021. Patients with newly diagnosed head and neck (HN) cancer who were evaluated to receive radiation therapy with or without chemotherapy and could communicate in English were approached to participate. The primary outcome was feasibility and acceptability of the MDASI-HN implementation in the radiation oncology department assessed by patient and provider exit surveys. Secondary outcomes were patient-reported experience as recorded by a shortened Your Voice Matters survey (YVM) in 2 cohorts pre- and post-MDASI-HN implementation and symptom scores. Descriptive statistics were used for exit surveys and symptom scores. Mann-Whitney tests were used to assess differences in positive responses between pre- and postimplementation for each YVM question. Cochrane-Armitage tests were used to examine changes in patient-reported experience over time. Results: Fifty-one patients were enrolled in the postimplementation cohort and 29 (60%) responded to the exit survey. Eighty-nine percent of patients reported that MDASI-HN made it easier to remember symptoms, and 86% recommend its use in routine care. Four of the 5 radiation oncology HN providers (80%) responded to exit surveys; 75% felt the MDASI-HN provided clinically relevant information, improved communication with patients, and did not increase clinic time. The overall patient-reported experience was not affected by the implementation (P = .82). The probability of positive responses over time was significant (P = .025) in the clinic coordination domain for the postimplementation cohort. Conclusions: Implementation of MDASI-HN was feasible and acceptable by patients and providers. Although the overall patient-reported experience was not affected by implementation, some aspects improved as treatment progressed.

External beam radiation therapy treatment factors prognostic of biochemical failure free survival: A multi-institutional retrospective study for prostate cancer.

BACKGROUND AND PURPOSE: The goal of this work is to identify specific treatment planning and delivery features that are prognostic of biochemical failure-free survival (BFFS) for prostate cancer patients treated with external beam radiotherapy (EBRT). MATERIALS AND METHODS: This study reviewed patients diagnosed with localized prostate adenocarcinoma between 2005 and 2016, and treated with EBRT on a Varian linear accelerator at one of the four cancer centers in Alberta, Canada. BFFS was calculated using the Kaplan-Meier estimator. Patient demographics, tumor characteristics, and EBRT treatment planning and delivery factors, were collected for each patient. The patient cohort was split into a training dataset with patients from two centers and a validation dataset with patients from another two centers. A random survival forest was used to identify features associated with BFFS. RESULTS: This study included 2827 patients with a median follow-up of 6.4 years. The BFFS for this cohort collectively was 84.9% at 5 years and 69.3% at 10 years. 2519 patients from two centers were used for model training and 308 patients from two different centers were used for model validation. The prognostic features were Gleason score, prostate-specific antigen (PSA) at diagnosis, clinical T stage, CTV D99, pelvic irradiation, IGRT frequency, and PTV V98. Variables including bladder volume, dose calculation algorithm, PTV D99, age at diagnosis, hip prosthesis, number of malignancies, fiducial marker usage, PTV volume, RT modality, PTV HI, rectal volume, hormone treatment, PTV D1cc, equivalent PTV margin, IGRT type, and EQD2_1.5 were unlikely to be prognostic. A random survival forest using only the seven prognostic variables was built. The Harrell's concordance index for the model was 0.65 for the whole training dataset, 0.62 for out-of-bag samples of the training dataset, and 0.62 for the validation dataset. CONCLUSION: EBRT features prognostic of BFFS were identified and a random survival forest was developed for predicting prostate cancer patients' BFFS after EBRT.

Early Metabolic Changes in 1H-MRSI Predictive for Survival in Patients With Newly Diagnosed High-grade Glioma.

BACKGROUND: The purpose of this study was to evaluate the association of specific threshold values for changes in metabolic metrics measured from 1H magnetic resonance spectroscopic imaging (MRSI) to survival of patients with high-grade glioma treated with multimodality therapy. PATIENTS AND METHODS: Forty-four patients with newly diagnosed high-grade glioma were prospectively enrolled. Serial MRI and MRSI scans provided measures of tumor choline, creatine, and N-acetylaspartate (NAA). Cox regression analyses adjusted for patient age, KPS, and delivery of concurrent chemotherapy were used to assess the association of changes in metabolic metrics with survival. RESULTS: Median follow-up time for patients at risk was 13.4 years. Overall survival (OS) was longer in patients with ≤20% increase (vs. >20%) in normalized choline (p=0.024) or choline/NAA (p=0.024) from baseline to week 4 of RT. During this period, progression-free survival (PFS) was longer in patients with ≤40% increase (vs. >40%) in normalized choline (p=0.013). Changes in normalized creatine, choline/creatine, and NAA/creatine from baseline to mid-RT were not associated with OS. From baseline to post-RT, changes in metabolic metrics were not associated with OS or PFS. CONCLUSION: Threshold values for serial changes in choline metrics on mid-RT MRSI associated with OS and PFS were identified. Metabolic metrics at post-RT did not predict for these survival endpoints. These findings suggest a potential clinical role for MRSI to provide an early assessment of treatment response and could enable risk-adapted therapy in clinical trial development and clinical practice.

Comparing the M.D. Anderson Symptom and Dysphagia Inventories for Head and Neck Cancer Patients.

OBJECTIVES: Where patient-reported outcome measures (PROMs) may be administered at multiple patient visits, it is advantageous to capture these symptoms with as few questions as possible. In this study, the M.D. Anderson Head and Neck Symptom Inventory (MDASI-HN), and the M.D. Anderson Dysphagia Inventory (MDADI) is compared to determine if using the MDASI-HN alone would overlook symptoms identified with MDADI. METHODS: The MDASI-HN and the MDADI were completed by 156 patients, postradiotherapy for head and neck cancer (HNC). Associations between the two instruments were analyzed using correlation analysis, unsupervised machine learning, and sensitivity analysis. RESULTS: Little correlation was found between the two surveys; however, there was overlap between MDASI-HN dry mouth and many MDADI items, confirming that dry mouth is an important factor in difficulty swallowing, and patient QoL. Taking longer to eat (MDADI), was the most commonly reported item overall, with 85 (54%) patients rating it as moderate-severe. Dry mouth was the most endorsed MDASI-HN item (68, 44%). There were 51 patients missed by the MDASI-HN, reporting no moderate-severe symptoms, but reported one or more moderate-severe QoL impacts on MDADI. If patients who reported a score of 2 or higher on the MDASI-HN Dry Mouth item are flagged as requiring follow-up, the number of patients missed by MDASI-HN drops to 15. CONCLUSION: In an HNC clinic where MDASI-HN is routinely administered, assessment of symptoms and QoL might be enhanced by reducing the value at which MDASI Dry Mouth is considered moderate-severe to 2. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2388-2395, 2022.

Patient-Reported Outcomes-Guided Adaptive Radiation Therapy for Head and Neck Cancer.

PURPOSE: To identify which patient-reported outcomes (PROs) may be most improved through adaptive radiation therapy (ART) with the goal of reducing toxicity incidence among head and neck cancer patients. METHODS: One hundred fifty-five head and neck cancer patients receiving radical VMAT (chemo)radiotherapy (66-70 Gy in 30-35 fractions) completed the MD Anderson Symptom Inventory, MD Anderson Dysphagia Inventory (MDADI), and Xerostomia Questionnaire while attending routine follow-up clinics between June-October 2019. Hierarchical clustering characterized symptom endorsement. Conventional statistical approaches indicated associations between dose and commonly reported symptoms. These associations, and the potential benefit of interfractional dose corrections, were further explored via logistic regression. RESULTS: Radiotherapy-related symptoms were commonly reported (dry mouth, difficulty swallowing/chewing). Clustering identified three patient subgroups reporting: none/mild symptoms for most items (60.6% of patients); moderate/severe symptoms affecting some aspects of general well-being (32.9%); and moderate/severe symptom reporting for most items (6.5%). Clusters of PRO items broadly consisted of acute toxicities, general well-being, and head and neck-specific symptoms (xerostomia, dysphagia). Dose-PRO relationships were strongest between delivered pharyngeal constrictor Dmean and patient-reported dysphagia, with MDADI composite scores (mean ± SD) of 25.7 ± 18.9 for patients with Dmean <50 Gy vs. 32.4 ± 17.1 with Dmean ≥50 Gy. Based on logistic regression models, during-treatment dose corrections back to planned values may confer ≥5% decrease in the absolute risk of self-reported physical dysphagia symptoms ≥1 year post-treatment in 1.2% of patients, with a ≥5% decrease in relative risk in 23.3% of patients. CONCLUSIONS: Patient-reported dysphagia symptoms are strongly associated with delivered dose to the pharyngeal constrictor. Dysphagia-focused ART may provide the greatest toxicity benefit to head and neck cancer patients, and represent a potential new direction for ART, given that the existing ART literature has focused almost exclusively on xerostomia reduction.

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 from Dose-Reduced Radiotherapy to the Prostate in Elderly Patients with Localized Prostate Cancer.

Radical treatment of localized prostate cancer in elderly patients may lead to unacceptable treatment-associated toxicities that adversely impact quality of life without improving survival outcomes. This study reports on a cohort of 54 elderly (>70 years) patients that received 4000-5000 cGy of palliative external beam radiotherapy (EBRT) as an alternative to androgen deprivation therapy (ADT). The primary outcome of interest was the period of ADT-free survival, and secondary outcomes included overall survival (OS) and metastases-free survival (MFS). Kaplan-Meier regression was used to estimate survival outcomes. Thirty-six (67%) patients achieved a break in ADT post-radiotherapy, with a median time to ADT reinitiation of 20 months. Common Terminology Criteria for Adverse Events (CTCAE) were limited to low-grade gastrointestinal (GI) or genitourinary (GU) toxicities, with no skin toxicities observed. Grade 1 GI toxicity was observed in 9 (17%) patients, and grades 1 and 2 GU toxicities were observed in 13 (24%) and 3 (6%) patients, respectively, with no higher-grade toxicities reported. Five-year MFS and OS were 56% and 78%, respectively. In summary, the treatment regimen was well-tolerated and achieved durable ADT-free survival in most patients. Dose-reduced EBRT appears to be a viable alternative to ADT in elderly patients with localized prostate cancer.

Excessive waitlists and delays to treatment with low-dose-rate brachytherapy predict an increased risk of recurrence and metastases in intermediate-risk prostatic carcinoma.

PURPOSE: It has previously been shown that increased wait times for prostatectomy are associated with poorer outcomes in intermediate-risk prostatic carcinoma (PCa). However, the impact of wait times on PCa outcomes following low-dose-rate brachytherapy (LDR-BT) are unknown. METHODS AND MATERIALS: We retrospectively reviewed 466 intermediate-risk PCa patients that underwent LDR-BT at a single comprehensive cancer center between 2003 and 2016. Wait times were defined as the time from biopsy to LDR-BT. The association of wait times with outcomes was evaluated using Cox and Fine-Gray regression in both univariate and multivariate models. RESULTS: Median (interquartile range) follow-up and wait time for all patients were 8.1 (6.3-10.4) years and 5.1 (3.9-6.9) months, respectively. Among NCCN unfavourable intermediate-risk (UIR) patients (n = 170; 36%), increased wait times predicted both a greater cumulative incidence of recurrence [MHR = 1.01/month of wait time (95% CI: 1.00-1.03); P = 0.044] and metastases [MHR = 1.04/month of wait time (95% CI: 1.02-1.06); P < 0.001] in multivariate modeling. In NCCN favourable intermediate-risk (FIR) patients, there was no significant association between wait time and recurrence or metastases risk. Among all intermediate-risk patients, wait time was associated with an increase in the incidence of metastases [MHR = 1.03/month of wait time (95% CI: 1.02-1.05); P < 0.001], but not recurrence in multivariate models. There was no association between wait time and overall survival in the UIR, FIR, or all intermediate-risk cohorts. CONCLUSIONS: Resource constraints within this center's public healthcare system have contributed to waitlists exceeding 5-months in length. This study finds that patients with UIR PCa experience a 1% increase in the risk of recurrence and 4% increase in the risk of metastases with each additional month of delay in definitive disease management. Preventing such extended management delays in LDR-BT may improve disease-related outcomes in patients with PCa.

Determining Clinical Patient Selection Guidelines for Head and Neck Adaptive Radiation Therapy Using Random Forest Modelling and a Novel Simplification Heuristic.

PURPOSE: To determine which head and neck adaptive radiotherapy (ART) correction objectives are feasible and to derive efficient ART patient selection guidelines. METHODS: We considered various head and neck ART objectives including independent consideration of dose-sparing of the brainstem/spinal cord, parotid glands, and pharyngeal constrictor, as well as prediction of patient weight loss. Two-hundred head and neck cancer patients were used for model development and an additional 50 for model validation. Patient chart data, pre-treatment images, treatment plans, on-unit patient measurements, and combinations thereof were assessed as potential predictors of each objective. A stepwise approach identified combinations of predictors maximizing the Youden index of random forest (RF) models. A heuristic translated RF results into simple patient selection guidelines which were further refined to balance predictive capability and practical resource costs. Generalizability of the RF models and simplified guidelines to new data was tested using the validation set. RESULTS: Top performing RF models used various categories of predictors, however, final simplified patient selection guidelines only required pre-treatment information for ART predictions, indicating the potential for significant ART process streamlining. The simplified guidelines for each objective predicted which patients would experience increases in dose to: brainstem/spinal cord with sensitivity = 1.0, specificity = 0.66; parotid glands with sensitivity = 0.82, specificity = 0.70; and pharyngeal constrictor with sensitivity = 0.84, specificity = 0.68. Weight loss could be predicted with sensitivity = 0.60 and specificity = 0.55. Furthermore, depending on the ART objective, 28%-58% of patients required replan assessment, less than for previous studies, indicating a step towards more effective patient selection. CONCLUSIONS: The above ART objectives appear to be practically achievable, with patients selected for ART according to simple clinical patient selection guidelines. Explicit ART guidelines are rare in the literature, and our guidelines may aid in balancing the potential clinical gains of ART with high associated resource costs, formalizing ART trials, and ensuring the reproducibility of clinical successes.

Novel imaging classification system of nodal disease in human papillomavirus-mediated oropharyngeal squamous cell carcinoma prognostic of patient outcomes.

BACKGROUND: Matted nodes in human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPC) is an independent predictor of distant metastases and decreased overall survival. We aimed to classify imaging patterns of metastatic lymphadenopathy, analyze our classification system for reproducibility, and assess its prognostic value. METHODS: The metastatic lymphadenopathy was classified based on radiological characteristics for 216 patients with HPV-mediated OPC. Patient outcomes were compared and inter-rater reliability was calculated. RESULTS: The presence of ≥3 abutting lymph nodes with imaging features of surrounding extranodal extension (ENE), one subtype of matted nodes, was associated with worse 5-year overall survival, overall recurrence-free survival, regional recurrence-free survival, and distant recurrence-free survival (p ≤ 0.03). Other patterns were not significantly associated with outcome measures. Overall inter-rater agreement was substantial (κ = 0.73). CONCLUSION: One subtype of matted nodes defined by ≥3 abutting lymph nodes with imaging features of surrounding ENE is the radiological marker of worst prognosis.

Analysis of outcomes after non-contour-based dose painting of dominant intra-epithelial lesion in intra-operative low-dose rate brachytherapy.

PURPOSE: To compare the outcomes of patients with intermediate risk prostate cancer (IR-PCa) treated with low-dose rate I-125 seed brachytherapy (LDR-BT) and targeted dose painting of a histologic dominant intra-epithelial lesion (DIL) to those without a DIL. METHODS: 455 patients with IR-PCa were treated at a single center with intra-operatively planned LDR-BT, each following the same in-house dose constraints. Patients with a DIL on pathology had hot spots localized to that region but no specific contouring during the procedure. RESULTS: 396 (87%) patients had a DIL. Baseline tumor characteristics and overall prostate dosimetry were similar between patients with and without DIL except the median number of biopsy cores taken: 10 (10-12) vs 12 (10-12) (p = 0.002).19 (5%) and 18 (5%) of patients with and 1 (2%) and 0 (0%) of those without DIL experienced CTCAE grade 2 and 3 toxicity respectively. Overall, toxicity grade did not significantly correlate with presence of DIL (p = 0.10).Estimated 7-year freedom from biochemical failure (FFBF) was 84% (95% confidence interval: 79-89) and 70% (54-89) in patients with and without a DIL (log-rank p = 0.315). In DIL patients, cox regression revealed location of DIL ("Base" vs "Apex" HR: 1.03; 1.00-1.06; p = 0.03) and older age (70 vs 60 HR: 1.62; 1.06-2.49; p = 0.03) was associated with poor FFBF. CONCLUSIONS: Targeting DIL through dose painting during intraoperatively planned LDR-BT provided no statistically significant change in FFBF. Patients with DILs in the prostate base had slightly lower FFBF despite DIL boost.

Accelerating prostate stereotactic ablative body radiotherapy: Efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT).

BACKGROUND: Prostate stereotactic ablative radiotherapy (SABR) regimens differ in time, dose, and fractionation. We report an update of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL), efficacy, and toxicity. METHODS: Men with intermediate risk prostate cancer were randomized to 40 Gy in 5 fractions delivered every other day (EOD) versus once per week (QW). Primary outcome was proportion of patients experiencing a minimally clinically important change (MCIC) in acute bowel QOL using EPIC. Secondary outcomes were toxicity, biochemical failure (BF), other QOL domains, and the rate of salvage therapy. FINDINGS: 152 men from 3 centers were randomized; the median follow-up was 62 months. Results are described for EOD versus QW. Acute bowel and urinary QOL was reported previously. Late changes in QOL were not significantly different between the two arms. There were 1 (1.3%) vs 3 (2.7%) late grade 3 + GI toxicities (p = 0.36) and 5 (6.7%) vs 2 (2.7%) late grade 3 GU toxicities (p = 0.44). Two and 5 patients had BF (5-year failure rate 3.0 vs 7.2%, p = 0.22); 0 and 4 patients received salvage therapy (p = 0.04). 5-Year OS and CSS was 95.8% and 98.6% with no difference between arms (p = 0.49, p = 0.15). 3 patients in the QW arm developed metastases. INTERPRETATION: Although we previously reported that weekly prostate SABR had better bowel and urinary QOL compared to EOD, the updated results show no difference in late toxicity, QOL, BF, or PSA kinetics. Patients should be counseled that QW SABR reduces short-term toxicity compared to QW SABR.

Volumetric changes in pharyngeal structures following head and neck cancer chemoradiation therapy.

OBJECTIVES/HYPOTHESIS: To determine the volumetric changes in pharyngeal structures in patients with head and neck squamous cell carcinoma (HNSCC) treated with curative chemoradiation therapy (CRT). Patients treated with CRT for esophageal carcinoma (EC), where pharyngeal structures were not part of the radiation treatment fields, were controlled for dysphagia-associated weight loss. We hypothesize that tissue volume alteration is a contributing factor of post-CRT dysphagia. STUDY DESIGN: Case series. METHODS: This study measured pre- and 1-year posttreatment volumes of the base of tongue (BOT), parapharyngeal spaces, posterior pharyngeal constrictors (PCs), and retropharyngeal space (RPS) in patients undergoing CRT for HNSCC or EC treated January 1, 2012 to December 31, 2015. All HNSCC patients were treated to doses of 66 to 70 Gy in 30 to 33 fractions using intensity-modulated radiotherapy techniques. RESULTS: Our cohort included 49 HNSCC and 11 EC patients. Within the HNSCC cohort, the PCs volume increased 1.55 cm3 (95% confidence interval [CI]: 0.77 to 2.34 cm3 , P = .0002), RPS increased 1.22 cm3 (95% CI: 0.67 to 1.77 cm3 , P < .0001), and BOT decreased 2.29 cm3 (95% CI: -0.20 to 4.79 cm3 , P = .070). The EC cohort showed no significant volumetric changes for any anatomic space, with combined PCs and RPS volume changes statistically less than the HNSCC cohort (P = .031). There was no difference in mean body mass index reduction between groups (P = .10). CONCLUSIONS: Volumetric changes following CRT may play a role in posttreatment dysphagia. Our findings support loss of physiologic function from posterior pharynx tissue thickening combined with reduced pharyngeal constriction capacity, and BOT atrophy secondary to radiation effects contribute to dysphagia. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:597-602, 2020.