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Purpose: The purpose of this study was to analyze the impact of prostate rectal spacers on sexual quality of life (QOL) following external beam radiation therapy (RT)., Methods and Materials: Patient- reported QOL was evaluated using the Expanded Prostate Cancer Index Composite (EPIC). Patients were pooled from two sources: a randomized controlled trial and a non-randomized cohort of patients from a single institution. Both cohorts used the same spacing product and QOL instrument. Analysis was limited to those with good baseline pre-treatment sexual QOL (EPIC >/= 60). Differences in QOL summary score and individual items were assessed compared with baseline and between treatment arms., Results: A total of 128 men had good baseline sexual function and were evaluated (64% with spacer and 36% without) with QOL data available for median 33 months (range: 2.5-69.4 months). Men without spacer were more likely to have declines in sexual function ( p < 0.0001), bother ( p = 0.0002), and sexual summary score ( p < 0.0001). A minimally important difference of 10 points (1xMID) and 20 point (2xMID) was more likely without rectal spacer [10 points: odds ratio 3.53, (95% confidence interval 1.11-11.2), p = 0.032; 20 points: odds ratio 3.29, (95% confidence interval 1.16-9.33), p = 0.025]. Seven of 13 QOL items were statistically superior with hydrogel (six of nine functional and one of four bother), while no items were statistically superior for control. At baseline, more men treated with hydrogel had erections sufficient for intercourse; however, when analyzed only by the men with best baseline erectile potential and excluding those with worse function, the benefit of rectal spacing was maintained with a higher likelihood of preservation of erections sufficient for intercourse in those treated with hydrogel., Conclusion: In this pooled analysis of QOL after prostate RT, the utilization of a hydrogel spacer was associated with better sexual QOL, less men with measurable declines in sexual QOL, and higher rates of adequate erectile function., Competing Interests: ZS – Augmenix has provided grant for dosimetric analysis unrelated to the current study. DH and SD-N as consultant for Augmenix unrelated to the current study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seymour, Pinkawa, Daignault-Newton, Bosch, Michalski, Gay and Hamstra.)

Purpose: To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer., Methods: Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death., Results: Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT ( P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006)., Conclusion: Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, we describe logistical, technical, and radiation safety considerations for implementing a radiopharmaceutical therapy program, with particular focus on the development of operating procedures for therapeutic administrations. Major steps for a center in the U.S. to implement a new radiopharmaceutical therapy (RPT) program are listed below, and then demonstrated in greater detail via examples for Lu-177-PSMA-617 therapy., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Automatic contouring algorithms may streamline clinical workflows by reducing normal organ-at-risk (OAR) contouring time. Here we report the first comprehensive quantitative and qualitative evaluation, along with time savings assessment for a prototype deep learning segmentation algorithm from Siemens Healthineers. The accuracy of contours generated by the prototype were evaluated quantitatively using the Sorensen-Dice coefficient (Dice), Jaccard index (JC), and Hausdorff distance (Haus). Normal pelvic and head and neck OAR contours were evaluated retrospectively comparing the automatic and manual clinical contours in 100 patient cases. Contouring performance outliers were investigated. To quantify the time savings, a certified medical dosimetrist manually contoured de novo and, separately, edited the generated OARs for 10 head and neck and 10 pelvic patients. The automatic, edited, and manually generated contours were visually evaluated and scored by a practicing radiation oncologist on a scale of 1-4, where a higher score indicated better performance. The quantitative comparison revealed high (> 0.8) Dice and JC performance for relatively large organs such as the lungs, brain, femurs, and kidneys. Smaller elongated structures that had relatively low Dice and JC values tended to have low Hausdorff distances. Poor performing outlier cases revealed common anatomical inconsistencies including overestimation of the bladder and incorrect superior-inferior truncation of the spinal cord and femur contours. In all cases, editing contours was faster than manual contouring with an average time saving of 43.4% or 11.8 minutes per patient. The physician scored 240 structures with > 95% of structures receiving a score of 3 or 4. Of the structures reviewed, only 11 structures needed major revision or to be redone entirely. Our results indicate the evaluated auto-contouring solution has the potential to reduce clinical contouring time. The algorithm's performance is promising, but human review and some editing is required prior to clinical use., (Copyright © 2022 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/β = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89], P= 0 . 009) on MVA. On Kaplan-Meier analysis, 36.25 Gy was associated with improved survival (p=0.034), with a five-year OS of 92% and 88%, respectively. Conclusions In a multi-institutional retrospective database of 2,214 IR patients treated with prostate SBRT, a prescription dose of 36.25 Gy/5 fx was associated with improved OS vs. 35 Gy/5 fx. Results are hypothesis-generating but do lend support to the current National Comprehensive Cancer Network (NCCN) guidelines that the minimum recommended dose for prostate SBRT is 36.25 Gy/5 fx., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Waters et al.)

Purpose: There is a vital need to train radiation therapy professionals in low- and middle-income countries (LMICs) to develop sustainable cancer treatment capacity and infrastructure. LMICs have started to introduce intensity modulated radiation therapy (IMRT), which is the standard of care in high-income countries, because of improved outcomes and reduced toxicities. This work reports the efficacy of a complementary asynchronous plus synchronous virtual-training approach on improving radiation therapy professions' self-confidence levels and evaluating participants' attitudes toward asynchronous and synchronous didactic hands-on learning in 3 LMICs., Methods and Materials: Training was provided to 37 participants from Uganda, Guatemala, and Mongolia, which included 4 theoretical lectures, 4 hands-on sessions, and 8 self-guided online videos. The 36-day training focused on IMRT contouring, site-specific target/organ definition, planning/optimization, and quality assurance. Participants completed pre- and postsession confidence surveys on a 0 to 10 scale, which was converted to a 5-point Likert rating scale to evaluate the training outcomes. The pros and cons of the 3 different training formats were compared., Results: The participants included 15 (40.5%) radiation oncologists, 11 (29.7%) medical physicists, 6 (16.2%) radiation therapists, and 5 (13.5%) dosimetrists. Approximately 50% had more than 10 years of radiation therapy experience, 70.8% had no formal IMRT training, and only 25% had IMRT at their institutions. The average experience and confidence levels in using IMRT at baseline were 3.2 and 2.9, which increased to 5.2 and 4.9 ( P < .001) after the theoretical training. After the hands-on training, the experience and confidence levels further improved to 5.4 and 5.5 ( P < .001). After the self-guided training, the confidence levels increased further to 6.9 ( P < .01). Among the 3 different training sessions, hands-on trainings (58.3%) were most helpful for the development of participants' IMRT skills, followed by theoretical sessions with 25%., Conclusions: After completing the training sessions, Uganda and Mongolia started IMRT treatments. Remote training provides an excellent and feasible e-learning platform to train radiation therapy professionals in LMICs. The training program improved the IMRT confidence levels and treatment delivery. The hands-on trainings were most preferred., (© 2023 The Authors.)

Purpose: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy. Treatment is frequently intensified by electively treating the pelvic lymph nodes (LNs) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy., Materials and Methods: National Cancer Database records of men diagnosed between 2008-2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±androgen deprivation therapy (72-86.4 Gy) with (15,175) or without (13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression., Results: Of the men, 53% received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (p <0.001). WPRT trended toward improved OS in all men with UIR-PCa and HR-PCa (HR: 0.95 [95% CI: 0.90-1.006], p=0.055). WPRT correlated with improved OS in men with Gleason 9 and 10 disease (HR: 0.87 [0.78-0.98], p=0.02) or risk of LN involvement ≥10% (HR: 0.93 [0.87-0.99], p=0.03)., Conclusions: Men with higher LN risk scores and Gleason grade benefited from WPRT. These results complement the recent POP-RT randomized trial in mostly positron emission tomography/computerized tomography-staged patients, demonstrating that a more heterogeneous population of men staged without functional imaging benefits from WPRT.

Purpose: The use of prostate fiducial markers and perirectal hydrogel spacers can reduce the acute and late toxic effects associated with prostate radiation therapy. These procedures are usually performed days to weeks before simulation during a separate clinic visit to ensure resolution of procedure-related inflammation. The purpose of this study was to assess whether same-day intraprostatic fiducial marker placement, perirectal hydrogel injection, and computed tomography (CT) and magnetic resonance imaging (MRI) simulation were feasible without adversely affecting hydrogel volume, perirectal spacing, or rectal dose. If feasible, performing these procedures on the same day as simulation would expedite the start of radiation therapy, improve patient convenience, and reduce costs., Methods and Materials: Twenty-one patients with clinically localized prostate cancer who were enrolled on a prospective clinical trial (NCT01617161) underwent same-day marker placement, hydrogel injection, and CT and MRI simulation, then underwent T2 MRI verification scans 3 to 4 weeks later. The MRI scans were fused to the CT planning scans by clinical target volumes (CTVs) to generate comparison treatment plans (70 Gy in 28 fractions). Hydrogel volume and symmetry, perirectal spacing, CTV dose, and organ-at-risk dose were evaluated., Results: Verification scans occurred a mean of 24.9 ± 4.6 days after simulation and 9.3 ± 4.9 days after treatment start. Prostate volume did not change between scans (median, 67.3 ± 22.1 cm 3 vs 64.1 ± 21.8 cm 3 ; P = .64). The median hydrogel change between simulation and verification was - 1.8% ± 4.5% (P = .27). No significant differences in perirectal spacing (midgland: 1.33 ± 0.45 cm vs 1.3 ± 0.7 cm; 1 cm superior: 1.25 ± 0.95 cm vs 1.43 ± 0.91 cm; 1 cm inferior: 1.16 ± 0.28 cm vs 1.41 ± 0.49 cm) were identified. No significant differences in rectal V66 (median 2.3 ± 2.18% vs 2.3 ± 2.28%; P = .99), V35 (median 14.79 ± 7.61 vs 14.67 ± 8.4; P = .73), or D1cc (65.7 ± 9.2 Gy vs 68.2 ± 9.0 Gy; P = .80) were found. All plans met CTV and organ-at-risk constraints., Conclusion: Same-day placement of intraprostatic fiducial markers, perirectal hydrogel, and simulation scans was feasible and did not significantly affect hydrogel volume, position, CTV coverage, or rectal dose., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Widespread implementation of automated treatment planning in radiation therapy remains elusive owing to variability in clinic and physician preferences, making it difficult to ensure consistent plan parameters. We have developed an open-source class library with the aim to improve efficiency and consistency for automated treatment planning in radiation therapy., Methods and Materials: An open-source class library has been developed that interprets clinical templates within a commercial treatment planning system into a treatment plan for automated planning. This code was leveraged for the automated planning of 39 patients and retrospectively compared with the 78 clinically approved manual plans., Results: From the initial 39 patients, 74 of 78 plans were successfully generated without manual intervention. The target dose was more homogeneous for automated plans, with an average homogeneity index of 3.30 for manual plans versus 3.11 for automated plans (P = .107). The generalized equivalent uniform dose (gEUD) was decreased in the femurs and rectum for automated plans, with a mean gEUD of 3746 cGy versus 3338 cGy (P ≤ 0.001) and 5761 cGy versus 5634 cGy (P ≤ 0.001) for the femurs and rectum, respectively. Dose metrics for the bladder and rectum (V6500 cGy and V4000 cGy) showed recognizable but insignificant improvements. All automated plans delivered for quality assurance passed a gamma analysis (>95%), with an average composite pass rate of 99.3% for pelvis plans and 98.8% for prostate plans. Deliverability parameters such as total monitor units and aperture complexity indicated deliverable plans., Conclusions: Prostate cancer and pelvic node radiation therapy can be automated using volumetric modulated arc therapy planning and clinical templates based on a standardized clinical workflow. The class library developed in this study conveniently interfaced between the plan template and the treatment planning system to automatically generate high-quality plans on customizable templates., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: The NCCN Guidelines for Prostate Cancer currently recommend several definitive radiotherapy (RT) options for men with unfavorable intermediate-risk (UIR) prostate cancer: external-beam RT (EBRT) plus androgen deprivation therapy (ADT) or EBRT plus brachytherapy boost with or without ADT. However, brachytherapy alone with or without ADT is not well defined and is currently not recommended for UIR prostate cancer. We hypothesized that men treated with brachytherapy with or without ADT have comparable survival rates to men treated with EBRT with or without ADT., Methods: A total of 31,783 men diagnosed between 2004 and 2015 with UIR prostate cancer were retrospectively reviewed from the National Cancer Database. Men were stratified into 4 groups: EBRT (n=12,985), EBRT plus ADT (n=12,960), brachytherapy (n=4,535), or brachytherapy plus ADT (n=1,303). Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances, and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios (HRs)., Results: Relative to EBRT alone, the following treatments were associated with improved OS: EBRT plus ADT (HR, 0.92; 95% CI, 0.87-0.97; P=.002), brachytherapy alone (HR, 0.90; 95% CI, 0.83-0.98; P=.01), and brachytherapy plus ADT (HR, 0.78; 95% CI, 0.69-0.88; P=.00006). Brachytherapy correlated with improved OS relative to EBRT in men who were not treated with ADT (HR, 0.92; 95% CI, 0.84-0.99; P=.03) and in those receiving ADT (HR, 0.84; 95% CI, 0.75-0.95; P=.004). At 10-year follow-up, 56% and 63% of men receiving EBRT and brachytherapy, respectively, were alive (P<.0001). IPTW was used to determine the average treatment effect of definitive brachytherapy. Relative to EBRT, definitive brachytherapy correlated with improved OS (HR, 0.90; 95% CI, 0.84-0.97; P=.009) on weight-adjusted MVA., Conclusions: Definitive brachytherapy was associated with improved OS compared with EBRT. The addition of ADT to both EBRT and definitive brachytherapy was associated with improved OS. These results suggest that definitive brachytherapy should be considered as an option for men with UIR prostate cancer.

Predicting early in treatment whether a tumor is likely to be responsive is a difficult yet important task to support clinical decision-making. Studies have shown that multimodal biomarkers could provide complementary information and lead to more accurate treatment outcome prognosis than unimodal biomarkers. However, the prognosis accuracy could be affected by multimodal data heterogeneity and incompleteness. The small-sized and imbalance datasets also bring additional challenges for training a designed prognosis model. In this study, a modular framework employing multimodal biomarkers for cancer treatment outcome prediction was proposed. It includes four modules of synthetic data generation, deep feature extraction, multimodal feature fusion, and classification to address the challenges described above. The feasibility and advantages of the designed framework were demonstrated through an example study, in which the goal was to stratify oropharyngeal squamous cell carcinoma (OPSCC) patients with low- and high-risks of treatment failures by use of positron emission tomography (PET) image data and microRNA (miRNA) biomarkers. The superior prognosis performance and the comparison with other methods demonstrated the efficiency of the proposed framework and its ability of enabling seamless integration, validation and comparison of various algorithms in each module of the framework. The limitation and future work was discussed as well.

Background: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy., Objective: To investigate treatment patterns and overall survival outcomes in this group of patients., Design Setting and Participants: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004-2016., Intervention: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery., Outcome Measurements and Statistical Analysis: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS)., Results and Limitations: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99-1.09; p  = 0.105). Definitive local treatment was associated with improved OS compared with ADT alone (RT alone, HR 0.54, 95% CI, 0.50-0.59, p  < 0.0001; ADT + RT, HR 0.48, 95% CI, 0.46-0.50, p  < 0.0001; surgery, HR 0.50, 95% CI, 0.42-0.59, p  < 0.0001)., Conclusions: This analysis demonstrates that the use of definitive local therapy, including surgery or RT ± ADT, is increasing and is associated with a 50% reduction in overall mortality compared with observation or ADT alone. While prospective validation is warranted, elderly men with high-risk disease eligible for definitive management should be counseled on the risks, including a possible compromise in OS, with deferring definitive management., Patient Summary: Elderly men are more often diagnosed with higher-risk prostate cancer but are less likely to receive curative treatment options than younger men. Our analysis demonstrates that for men ≥80 yr of age with high-risk prostate cancer, definitive local therapy, including surgery or radiation therapy and/or androgen deprivation therapy, is associated with a 50% reduction in overall mortality compared with observation or androgen deprivation therapy alone. We therefore recommend that life expectancy (ie, physiologic age) be taken into account, over chronologic age, and that elderly men with good life expectancy (eg, >5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy., (© 2022 The Authors.)

The recent development of deep learning approaches has revoluted medical data processing, including semantic segmentation, by dramatically improving performance. Automated segmentation can assist radiotherapy treatment planning by saving manual contouring efforts and reducing intra-observer and inter-observer variations. However, training effective deep learning models usually Requires a large amount of high-quality labeled data, often costly to collect. We developed a novel semi-supervised adversarial deep learning approach for 3D pelvic CT image semantic segmentation. Unlike supervised deep learning methods, the new approach can utilize both annotated and un-annotated data for training. It generates un-annotated synthetic data by a data augmentation scheme using generative adversarial networks (GANs). We applied the new approach to segmenting multiple organs in male pelvic CT images. CT images without annotations and GAN-synthesized un-annotated images were used in semi-supervised learning. Experimental results, evaluated by three metrics (Dice similarity coefficient, average Hausdorff distance, and average surface Hausdorff distance), showed that the new method achieved comparable performance with substantially fewer annotated images or better performance with the same amount of annotated data, outperforming the existing state-of-the-art methods., (© 2021 IOP Publishing Ltd.)

Purpose: There is evidence of practice consolidation in US health care in recent years. To our knowledge, a detailed quantitative study of recent changes in radiation oncology practice size has not been performed. We aim to evaluate radiation oncology practice size changes between 2012 and 2020 in the United States., Materials and Methods: Using the Medicare Physician Compare Database, we identified practices employing radiation oncologists using their taxpayer identification number and individual radiation oncologists using their national provider identifier. We grouped individual radiation oncologists into categories by practice size (which includes the number of physicians of all specialties) and compared the number of radiation oncologists in each category between 2012 and 2020. Further analyses by US geographic census region, single-specialty practice, academic practice, and high- and low-population density areas were performed., Results: Between 2012 and 2020, the total number of practicing radiation oncologists increased by 9%, and the number of practices employing radiation oncologists decreased by 11.5%. The number of radiation oncologists in practices of size 1 to 2, 3 to 9, 10 to 24, and 25 to 49 decreased by 3.7%, 4.7%, 4.9%, and 2%, respectively, and the number of radiation oncologists in practices of size 50 to 99, 100 to 499, and 500+ increased by 1.4%, 2.1%, and 11.8%, respectively (all 500+ practices are multispecialty groups). The increase in practice size was significant in all regions, for single-specialty and multispecialty practices, academic and nonacademic practices, and for practices in high-, middle-, and low-population density areas (P < .05 for all comparisons). The proportion of single-specialty practices has decreased significantly (P < .001), and the proportion of academic practices increased significantly (P = .004). Additionally, the proportion of practices and physicians in high- and low-population density regions remained stable during this period (P > .05)., Conclusions: Our analysis suggests that practice size consolidation has occurred within the US radiation oncology workforce from 2012 to 2020. The impact of this consolidation on quality, cost, and patient access deserves further attention., (Copyright © 2021. Published by Elsevier Inc.)

Background: We present the first report comparing early toxicity outcomes with high-dose rate brachytherapy (HDR-BT) boost upfront versus intensity modulated RT (IMRT) upfront combined with androgen deprivation therapy (ADT) as definitive management for intermediate risk or higher prostate cancer., Methods and Materials: We reviewed all non-metastatic prostate cancer patients who received HDR-BT boost from 2014 to 2019. HDR-BT boost was offered to patients with intermediate-risk disease or higher. ADT use and IMRT target volume was based on NCCN risk group. IMRT dose was typically 45 Gy in 25 fractions to the prostate and seminal vesicles ± pelvic lymph nodes. HDR-BT dose was 15 Gy in 1 fraction, delivered approximately 3 weeks before or after IMRT. The sequence was based on physician preference. Biochemical recurrence was defined per ASTRO definition. Gastrointestinal (GI) and Genitourinary (GU) toxicity was graded per CTCAE v5.0. Pearson Chi-squared test and Wilcoxon tests were used to compare toxicity rates. P -value < 0.05 was significant., Results: Fifty-eight received HDR-BT upfront (majority 2014-2016) and 57 IMRT upfront (majority 2017-2018). Median follow-up was 26.0 months. The two cohorts were well-balanced for baseline patient/disease characteristics and treatment factors. There were differences in treatment sequence based on the year in which patients received treatment. Overall, rates of grade 3 or higher GI or GU toxicity were <1%. There was no significant difference in acute or late GI or GU toxicity between the two groups., Conclusion: We found no significant difference in GI/GU toxicity in intermediate-risk or higher prostate cancer patients receiving HDR-BT boost upfront versus IMRT upfront combined with ADT. These findings suggest that either approach may be reasonable. Longer follow-up is needed to evaluate late toxicity and long-term disease control., Competing Interests: Dr. Baumann reports other from Mevion Medical Systems, personal fees and other from Regeneron Pharmaceuticals Inc., personal fees and other from Sanofi S.A., outside the submitted work. The remaining authors have no conflicts to report., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

The COVID-19 crisis has resulted in a shortage of personal protective equipment (PPE). Adapting commercially available full-faced snorkel masks has been proposed as an alternative to narrow the gap in PPE. An advantage of the full-faced snorkel mask design is that it serves two critical purposes: eye and face protection, and high quality air filtration to protect against SARS-CoV-2. We performed quantitative testing on various full-faced snorkel masks with 3D printed adapters that accept commercially available particulate filters, and report on a design that passed Occupational Safety and Health Administration (OSHA) full-facepiece respirator standards., Competing Interests: The authors (Kyle Nicholson, Ashley Henke-Adams, Daniel M. Henke, Alexxai V. Kravitz, and Hiram A. Gay) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

In locally advanced head and neck squamous-cell carcinoma (LA-HNSCC), clinical complete response (cCR) at the primary site, assessed by clinical examination, after induction chemotherapy predicts for a low relapse risk after subsequent chemoradiotherapy. Prior studies showed a cCR rate of 77% with induction nanoparticle albumin-bound (nab)-paclitaxel given with cisplatin and 5-fluorouracil (APF). The primary aims of this non-randomized phase 2 trial were to determine the cCR rate after induction nab-paclitaxel and cisplatin (Arm 1) and after nab-paclitaxel monotherapy (Arm 2). Eligibility required LA-HNSCC, T2-T4 stage classification, and suitable (Arm 1) or unsuitable (Arm 2) candidates for cisplatin. Arm 1 patients received nab-paclitaxel and cisplatin, then cisplatin with radiation. Arm 2 patients received nab-paclitaxel, then cetuximab with radiation. The primary endpoint was cCR after two cycles of induction chemotherapy. Each arm enrolled forty patients. cCR at the primary site occurred in 28 patients (70%) after nab-paclitaxel and cisplatin and in 8 patients (20%) after nab-paclitaxel monotherapy. The overall clinical response rate was 98% after nab-paclitaxel and cisplatin and 90% after nab-paclitaxel monotherapy. In subset analyses, cCR rates by T stage classifications (T2, T3, T4) were 54, 86, and 69% after nab-paclitaxel and cisplatin, and 14, 11, and 26% after nab-paclitaxel. cCR rates by human papillomavirus status (p16 positive oropharynx vs other) were 72 and 64% after nab-paclitaxel and cisplatin and 35 and 9% after nab-paclitaxel. The cCR rate after nab-paclitaxel and cisplatin was similar to APF; however, the cCR rate after nab-paclitaxel monotherapy was lower. The trial was registered at ClinicalTrials.gov NCT02573493 on October 9, 2015.

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known., Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery., Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020., Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73)., Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival., Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival., Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.

Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC., Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684)., Results: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients., Conclusions: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical., (©2020 American Association for Cancer Research.)

Purpose: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit., Methods and Materials: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed., Results: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines., Conclusions: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: The optimal treatment strategy for patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) of the base of the tongue (BOT) has not been sufficiently studied., Objective: To investigate the rate of and risk factors for occult contralateral nodal disease in patients with HPV-related BOT OPSCC undergoing transoral surgery and bilateral neck dissections., Design, Setting, and Participants: This retrospective case series reviewed the medical records of patients with HPV-related BOT OPSCC who underwent transoral surgery and bilateral neck dissections from January 1, 2002, through December 31, 2018, at the tertiary care center of Washington University School of Medicine in St Louis. Patients had a median follow-up of 30.0 months (interquartile range, 11.0-60.4 months). Patients with recurrent disease or multiple synchronous OPSCC primary tumors were excluded for a total of 89 patients. Data were analyzed from January 1 through June 1, 2019., Main Outcomes and Measures: The primary outcome was the rate of contralateral occult nodal disease. Secondary outcomes were potential risk factors for contralateral occult nodal disease and regional recurrence rates., Results: Eighty-nine patients were included in the series, of whom 81 (91.0%) were men. The mean (SD) age was 60 (9) years. Overall, 34 patients (38.2%) had pathologic contralateral nodal metastases. Seventy patients had no clinical evidence of contralateral nodal disease. Of these 70, occult nodes were identified in 15 (21.4%). Risk of contralateral disease was higher when the primary tumor crossed midline (odds ratio, 6.23; 95% CI, 1.71-22.77). Of the 55 patients with no occult disease identified, only 2 (3.6%) received radiotherapy to the contralateral neck, and no regional recurrence of disease was noted., Conclusions and Relevance: Given the rate of occult contralateral nodal disease of 21.4%, it appears that contralateral elective neck dissection or radiotherapy should be recommended in patients with HPV-related BOT OPSCC. Patients with a pathologically negative result of contralateral neck dissection may not benefit from radiotherapy to that nodal basin. Future prospective investigations should evaluate functional and oncologic outcomes of contralateral elective neck dissection compared with elective radiotherapy in the contralateral neck for HPV-related BOT OPSCC.

Purpose: Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created., Methods and Materials: Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy., Results: Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients., Conclusions: These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Better biomarkers are needed for human papillomavirus (HPV)-negative oropharyngeal cancer (OPC) to identify patients at risk of recurrence. Lymphopenia and an elevated ratio of neutrophils to lymphocytes (NLR) have been associated with poor disease outcomes in a number of solid tumors., Objective: To test the hypothesis that postradiotherapy lymphopenia and elevated NLR are associated with poor clinical outcomes., Design, Setting, and Participants: This single-institution retrospective analysis included patients with HPV-negative OPC treated from January 1, 1997, through January 4, 2017. Median follow-up was 37 months (range, 2-197 months). A total of 108 patients with HPV-negative OPC and at least 1 complete blood cell count 2 to 12 months after the start of radiotherapy were included. Data were analyzed from August 26 to September 7, 2017., Interventions: Surgery followed by radiotherapy vs definitive radiotherapy, with or without chemotherapy., Main Outcomes and Measures: Absolute lymphocyte (ALC) and absolute neutrophil (ANC) counts were tested as variables affecting locoregional control, recurrence-free survival, and overall survival., Results: Of a total of 108 patients included in the analysis (87.0% male; mean age, 56 years [range, 35-84 years]), 57 received surgery followed by postoperative radiotherapy and 51 received definitive radiotherapy. During treatment, 67 of 79 patients (84.8%) had grades 3 to 4 lymphopenia and 17 of 79 (21.5%) had grade 4 lymphopenia. The ANC recovered by 6 months after radiotherapy, but ALC remained depressed to 1 year after radiotherapy. Posttreatment lymphopenia and elevated NLR were associated with worse recurrence-free and overall survival. The estimated 3-year LRC in patients with and without grades 3 to 4 lymphopenia at 3 months after radiotherapy start was 73% vs 82% (hazard ratio [HR], 0.58; 95% CI, 0.19-1.8); estimated 3-year recurrence-free survival, 36% vs 63% (HR, 0.45; 95% CI, 0.23-0.87); and estimated 3-year overall survival, 34% vs 64% (HR, 0.45; 95% CI, 0.23-0.88). In multivariable analysis, an association with worse overall survival was found for definitive radiotherapy (HR, 3.3; 95% CI, 1.6-7.1) and grades 3 to 4 lymphopenia (HR, 2.6; 95% CI, 1.3-5.5) at 3 months after radiotherapy., Conclusions and Relevance: Lymphopenia and NLR as early as 3 months after treatment start may serve as biomarkers of clinical outcomes in patients with HPV-negative OPC. These patients may benefit from adjuvant treatment intensification or closer surveillance.

Introduction: Squamous cell carcinoma (SqCC) is the second most common histology of primary bladder cancer, but still very limited information is known about its treatment outcomes. Most bladder cancer trials have excluded SqCC, and the current treatment paradigm for localized SqCC is extrapolated from results in urothelial carcinoma (UC). In particular, there is limited data on the efficacy of definitive chemo-radiotherapy (CRT). In this study, we compare overall survival outcomes between SqCC and UC patients treated with definitive CRT., Materials/methods: We queried the National Cancer Database (NCDB) for muscle-invasive (cT2-T4 N0 M0) bladder cancer patients diagnosed from 2004 to 2013 who underwent concurrent CRT. Propensity matching was performed to match patients with SqCC to those with UC. OS was analyzed using the Kaplan-Meier survival method, and the log-rank test and Cox regression were used for analyses., Results: 3332 patients met inclusion criteria of which 79 (2.3%) had SqCC. 73.4% of SqCC patients had clinical T2 disease compared to 82.5% of UC patients. Unadjusted median OS for SqCC patients was 15.6 months (95% CI, 11.7-19.6) versus 29.1 months (95% CI, 27.5-30.7) for those with UC (P < 0.0001). On multivariable analysis, factors associated with worse OS included: SqCC histology [HR: 1.53 (95% CI, 1.19-1.97); P = 0.001], increasing age [HR: 1.02 (95% CI, 1.02-1.03); P < 0.0001], increasing clinical T-stage [HR: 1.21 (95% CI, 1.13-1.29); P < 0.0001], and Charlson-Deyo comorbidity index [HR: 1.26 (95% CI, 1.18-1.33); P < 0.0001]. Seventy-seven SqCC patients were included in the propensity-matched analysis (154 total patients) with a median OS for SqCC patients of 15.1 months (95% CI, 11.1-18.9) vs. 30.4 months (95% CI, 19.4-41.4) for patients with UC (P = 0.013)., Conclusions: This is the largest study to-date assessing survival outcomes for SqCC of the bladder treated with CRT. In this study, SqCC had worse overall survival compared to UC patients. Histology had a greater impact on survival than increasing T-stage, suggesting that histology should be an important factor when determining a patient's treatment strategy and that treatment intensification in this subgroup may be warranted.

Background: Small cell carcinoma of the bladder (SCCaB) is a rare tumor without a standard treatment algorithm. Treatment patterns and survival outcomes from the National Cancer Database (NCDB) may provide insight into optimal treatment strategies., Objective: To investigate the relationship between overall survival (OS) and treatment strategy., Design, Setting, and Participants: This was an observational study of treatment-naïve patients who received treatment from 2004 to 2013. Patients with cT1-4aN0M0 SCCaB were identified from the NCDB, a hospital-based tumor registry that captures >70% of incident cancer cases in the USA., Intervention: Treatment strategies included local therapy alone, chemotherapy (CT), radiation therapy (RT), chemoradiation therapy (CRT), radical cystectomy (RC), and RC plus chemotherapy (RC+C)., Outcome Measurements and Statistical Analysis: OS was analyzed as a function of treatment modality adjusting for patient, demographic, and tumor-related factors. The Kaplan-Meier survival method, and the log-rank test and Cox regression were used for univariable and multivariable analyses., Results and Limitations: We identified 856 patients with median follow-up of 18.3 mo. The median OS for the entire cohort was 20.7 mo (95% confidence interval [CI] 18.3-23.2) and estimated 3-yr and 5-yr OS were 37.5% and 28.2%, respectively. The most common treatment modality was CT (225 patients; 26.3%) followed by CRT (203 patients; 23.7%) and RC+C (201 patients; 23.5%). The median OS was 18.4 mo (95% CI 15.2-21.5) for CT, 34.1 mo (95% CI 22.5-45.8) for CRT, and 32.4 mo (95% CI 20.8-44.1) for RC+C. OS did not significantly differ between CRT and RC+C (p=0.42). On multivariable analysis, the best OS was associated with CRT (hazard ratio [HR] 0.41, 95% CI 0.32-0.53; p<0.0001) and RC+C (HR 0.45, 95% CI 0.34-0.59; p<0.0001)., Conclusions: RC+C and CRT are associated with better OS compared to monotherapy among patients with SCCaB., Patient Summary: Small cell carcinoma of the bladder is a rare and highly aggressive cancer. According to National Cancer Database data, radical cystectomy plus chemotherapy and chemoradiation therapy are associated with better overall survival compared to monotherapy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Acute pain during weekly radiotherapy (RT) to the head and neck is not well characterized. We studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT., Materials and Methods: We prospectively collected weekly patient-reported outcomes from 122 head and neck cancer patients during RT. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophageal and throat pain and clinical as well as dosimetric variables., Results: In multivariate analysis, age was significantly associated with both types of pain, leading to odds ratio (OR) = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophageal and throat pain, respectively. For throat pain, sex (OR = 4.12; p = 0.010), with females at higher risk, and fractional organ at risk (OAR) mean dose (OR = 3.30; p = 0.014) were significantly associated with throat pain., Conclusions: A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal and throat pain. Younger patients who received RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain.

Purpose: Elderly patients with muscle invasive bladder cancer can pose a therapeutic dilemma, given multiple comorbidities which may preclude surgery. In this registry based analysis we investigated treatment patterns and survival outcomes in this group of patients., Materials and Methods: We queried the National Cancer Database for muscle invasive (cT2-T4aN0M0) bladder cancer in patients 80 years old or older who were diagnosed from 2004 to 2013. Patients included in study underwent transurethral resection of bladder tumor followed by radical cystectomy, radical cystectomy plus chemotherapy, radiation therapy alone, chemotherapy alone, chemoradiation or no treatment. We performed Kaplan-Meier, log rank and multivariate Cox proportional hazards regression and propensity score matching., Results: A total of 9,270 patients were identified with a median followup of 12.8 months. Median overall survival in patients treated with radical cystectomy alone was 23.2 months (95% CI 19.8-26.6), which was superior to that of chemotherapy alone or radiation therapy alone (p <0.0001). Those treated with chemoradiation had a median overall survival of 27.3 months (95% CI 25.0-29.7), which did not statistically differ from that of radical cystectomy alone (p = 0.39). Surgery plus chemotherapy showed the longest median overall survival of 34.5 months (95% CI 22.2-46.7, vs chemoradiation and radical cystectomy alone p <0.0001). On multivariate analysis and propensity score matching the best overall survival was seen in patients treated with surgery plus chemotherapy and there was no difference in overall survival between chemoradiation and radical cystectomy alone., Conclusions: In elderly patients with muscle invasive bladder cancer chemoradiation is an alternative definitive treatment strategy with survival equal to that of surgery alone and superior to that of chemotherapy alone or radiation therapy alone. If a patient was able to receive neoadjuvant or adjuvant chemotherapy with surgery, additional survival was observed in this nonrandomized study., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies, although concerns for broader adoption exist., Methods and Materials: From 2011 through 2013, 66 men were accrued to a phase 2 trial at 5 centers. SBRT consisted of 5 fractions of 7.4 Gy to a total dose of 37 Gy using conventional linear accelerators. Electromagnetic transponders were used for motion management. Health-related quality of life (HRQOL) was evaluated via the Expanded Prostate Cancer Index Composite 26 questionnaire. Acute and late toxicities were collected according to Common Terminology Criteria for Adverse Events, version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time., Results: Median follow-up was 36 months. All men had low- or intermediate-risk disease. There have been 0 biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four percent and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6 to 12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling, the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL., Conclusions: In this multi-institutional phase 2 clinical trial using continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects., (Copyright © 2017. Published by Elsevier Inc.)

Background: We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL., Methods and Materials: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain., Results: A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P > .1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC >60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P < .05)., Conclusions: The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe acute dysphagia commonly results from head and neck radiotherapy (RT). A model enabling prediction of severity of acute dysphagia for individual patients could guide clinical decision-making. Statistical associations between RT dose distributions and dysphagia could inform RT planning protocols aiming to reduce the incidence of severe dysphagia. We aimed to establish such a model and associations incorporating spatial dose metrics. Models of severe acute dysphagia were developed using pharyngeal mucosa (PM) RT dose (dose-volume and spatial dose metrics) and clinical data. Penalized logistic regression (PLR), support vector classification and random forest classification (RFC) models were generated and internally (173 patients) and externally (90 patients) validated. These were compared using area under the receiver operating characteristic curve (AUC) to assess performance. Associations between treatment features and dysphagia were explored using RFC models. The PLR model using dose-volume metrics (PLR standard ) performed as well as the more complex models and had very good discrimination (AUC = 0.82) on external validation. The features with the highest RFC importance values were the volume, length and circumference of PM receiving 1 Gy/fraction and higher. The volumes of PM receiving 1 Gy/fraction or higher should be minimized to reduce the incidence of severe acute dysphagia., Competing Interests: Conflicts of interest: None.

Purpose: For high-risk prostate cancer (HR-PCa) in men with a life expectancy of at least 10 years, the National Comprehensive Cancer Network recommends radiation therapy (RT) plus androgen deprivation therapy (ADT) with category 1 evidence or radical prostatectomy (RP) as an acceptable initial therapy. Randomized evidence regarding which therapy is optimal for disease control is lacking for men with HR-PCa. We performed a propensity-score-matched comparison of outcomes for men with localized HR-PCa treated with primary RT or RP., Methods and Materials: The medical records of patients with localized HR-PCa who were treated at our institution between 2002 and 2011 were reviewed. Patient and disease characteristics, treatment details, and outcomes were collected. A combination of nearest-neighbor propensity score matching on age, Adult Comorbidity Evaluation-27 comorbidity index, prostate-specific antigen, biopsy Gleason scores, and clinical T-stage as well as exact matching on prostate-specific antigen, biopsy Gleason scores, and clinical T-stage was performed. Outcomes were measured from diagnosis. Multivariate Cox proportional hazards regression was used to compare metastasis-free and overall survival., Results: A total of 246 patients were identified with 62 propensity-score-matched pairs. ADT was administered to 6.5% and 80.6% of patients receiving RP and RT, respectively. Five-year rates of metastasis for RP and RT were 33% and 8.9%, respectively ( P  = .003). Overall survival was not different. Delay of salvage therapy was longer for patients undergoing primary RT ( P  < .001). Findings were similar when only those patients who did not receive ADT were compared., Conclusions: At our institution, treatment with primary RT resulted in superior metastasis-free survival over RP. This was not accompanied by an improvement in OS.

Purpose: SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years., Methods and Materials: Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds., Results: The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02)., Conclusions: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Little is known about treatment outcomes for T4 oropharyngeal squamous cell carcinoma (OPSCC), particularly in the era of human papillomavirus (HPV)-related disease., Objective: To evaluate oncologic outcomes for T4 OPSCC treated with primary surgical and nonsurgical therapies., Design, Setting, and Participants: Retrospective cohort study of 131 patients from a single academic hospital, who were treated for T4a or T4b OPSCC (with any N stage and without distant metastatic disease at presentation) between 1998 and 2012 and had a minimum 2-year follow-up (the median follow-up time was 34.6 months). This study was conducted between January 1, 1998, and November 1, 2012., Interventions: Sixty-nine patients underwent nonsurgical therapy, 47 (68%) of whom had p16-positive tumors. Nonsurgical treatment paradigms included induction chemotherapy followed by chemoradiotherapy (n = 36 [54%]), concurrent chemoradiotherapy (n = 29 [43%]), and induction chemotherapy followed by radiation therapy alone (n = 2 [3%]). Sixty-two patients underwent surgical treatment, 50 (81%) of whom had p16-positive tumors. Fifty-seven surgical patients (92%) received adjuvant therapy., Main Outcomes and Measures: Overall survival (OS) was the primary outcome measure. Secondary outcome measures included disease-specific survival (DSS), disease-free survival (DFS), 2-year gastrostomy and tracheostomy tube rates, and major complication rates., Results: Significant baseline differences between the surgical vs nonsurgical groups included age (mean 59.8 vs 55.4 years [P = .005]), sex (male, 95% vs 84% [P = .04]), body mass index (<18.5 [calculated as weight in kilograms divided by height in meters squared], 3% vs 16% [P = .02]), and smoking history of 10 or more pack-years (48% vs 77% [P = .003]). For p16-positive patients, Kaplan-Meier estimates of OS, DSS, and DFS were significantly higher for surgically treated patients than for the nonsurgical group (χ(2)(1) = 7.335 for log-rank P = .007, χ(2)(1) = 8.607 for log-rank P = .003, and χ(2)(1) = 7.763 for log-rank P = .005, respectively). For p16-negative patients, Kaplan-Meier estimates of OS and DSS were higher for the surgical group but did not reach statistical significance (χ(2)(1) = 2.649 for log-rank P = .10 and χ(2)(1) = 2.077 for log-rank P = .15, respectively), while estimates of DFS were significantly higher for patients treated with primary surgery (χ(2)(1)= 3.869 for log-rank P = .049. In a multivariable Cox survival analysis, p16-positive immunohistochemical status had a significant positive association with OS (hazard ratio [HR], 0.55; 95% CI, 0.32-0.95 [P = .03]), DSS (HR, 0.45; 95% CI, 0.22-0.92 [P = .03]), and DFS (HR, 0.55; 95% CI, 0.32-0.95 [P = .03]), and nonsurgical treatment had a significant negative association with OS (HR, 2.79; 95% CI, 1.51-5.16 [P = .001]), DSS (HR, 3.38; 95% CI, 1.59-7.16 [P = .002]), and DFS (HR, 2.59; 95% CI, 1.51-4.45 [P = .001])., Conclusions and Relevance: Primary surgical treatment may be associated with improved outcomes in patients with T4 OPSCC. p16 Immunohistochemical status remains a strong prognostic indicator even in patients with locally advanced disease.

Purpose: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation., Methods and Materials: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months., Results: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption., Conclusions: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this article is to review the history of permanently implanted brachytherapy sources and to establish methods of identifying radon sources and discussing appropriate management., Conclusion: There are likely thousands of people bearing radon seeds that continue to emit radiation decades after implantation. They can be identified by clinical history and emission of characteristic x-rays. Surgical removal of these sources is rarely warranted.

Background: Prostate cancer is the second leading cause of cancer death in men, and early detection is essential to reduce mortality and increase survival. delta-Catenin is a unique beta-catenin superfamily protein primarily expressed in the brain but is upregulated in human prostatic adenocarcinomas. Despite its close correlation with the disease, it is unclear whether delta-catenin presents the potential in prostate cancer screening because it is an intracellular protein. In this study, we investigated the hypothesis of delta-catenin accumulation in the urine of prostate cancer patients and its potential pathways of excretion into extracellular milieu., Methods: Prostate cancer cell cultures, human tissue biopsies, and voided urines were characterized to determine extracellular delta-catenin accumulation and co-isolation with exosomes/prostasomes., Results: We identified delta-catenin in culture media and in the stroma of human prostate cancer tissues. In PC-3 cells in culture, delta-catenin was partially co-localized and co-isolated with raft-associated membrane protein caveolin-1 and glycosylphosphatidylinositol-anchored protein CD59, suggesting its potential excretion into extracellular milieu through exosome/prostasome associated pathways. Interference with endocytic pathway using wortmannin did not block prostasome excretion, but delta-catenin overexpression promoted the extracellular accumulation of caveolin-1. delta-Catenin, caveolin-1, and CD59 were all detected in cell-free human voided urine prostasomes. delta-Catenin immunoreactivity was significantly increased in the urine of prostate cancer patients (P < 0.0005)., Conclusions: This study demonstrated, for the first time, the extracellular accumulation of delta-catenin in urine supporting its potential utility for non-invasive prostate cancer detection., (2008 Wiley-Liss, Inc.)