Impact of immune, inflammatory and nutritional indices on outcome in patients with locally advanced cervical cancer treated with definitive (chemo)radiotherapy.

OBJECTIVE: Systemic immune, inflammatory, and nutritional indices are prognostic across multiple tumor sites. Comprehensive analysis of these markers in patients with locally advanced cervical cancer (LACC) treated with definitive (chemo)radiotherapy [(C)RT] is limited and may assist with future prognostication. METHODS: For this retrospective cohort study, patients with LACC treated with definitive (C)RT were identified from a comprehensive cancer center's clinicopathological database. Pre-treatment indices were derived including systemic immune-inflammation index (SII), platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), monocyte lymphocyte ratio (MLR), albumin to alkaline phosphatase ratio (AAPR) and prognostic nutritional index (PNI). Univariate analysis was performed for PFS and OS. ROC curves were analyzed to determine optimal cut points. PFS and OS were assessed by the Kaplan-Meier method and Log-Rank test. Multivariate analysis was performed using Cox regression. RESULTS: 196 patients were identified: median follow-up 7 years (IQR 2-11). Higher SII (≤700 vs >700; p = 0.01), higher PLR (≤ 250 vs >250; p < 0.001) and higher NLR (≤ 5 vs >5; p = 0.003) were associated with worse PFS. Higher SII (≤700 vs >700: p = 0.02), higher PLR (≤ 250 vs >250: p < 0.001) and higher NLR (≤ 5 vs >5; p = 0.01) were associated with worse OS. On multivariate analysis, SII, NLR and PLR were independently associated with PFS. SII and PLR were independently associated with OS. CONCLUSIONS: SII and PLR were independently associated with PFS and OS in patients with LACC treated with definitive (C)RT. NLR was independently associated with PFS. High inflammatory state is associated with shorter survival suggesting this as a target for interventions if validated in future studies.

Prospective validation of a machine learning model for applicator and hybrid interstitial needle selection in high-dose-rate (HDR) cervical brachytherapy.

PURPOSE: To Demonstrate the clinical validation of a machine learning (ML) model for applicator and interstitial needle prediction in gynecologic brachytherapy through a prospective clinical study in a single institution. METHODS: The study included cervical cancer patients receiving high-dose-rate brachytherapy using intracavitary (IC) or hybrid interstitial (IC/IS) applicators. For each patient, the primary radiation oncologist contoured the high-risk clinical target volume on a pre-brachytherapy MRI, indicated the approximate applicator location, and made a clinical determination of the first fraction applicator. A pre-trained ML model predicted the applicator and IC/IS needle arrangement using tumor geometry. Following the first fraction, ML and radiation oncologist predictions were compared and a replanning study determined the applicator providing optimal organ-at-risk (OAR) dosimetry. The ML-predicted applicator and needle arrangement and the clinical determination were compared to this dosimetric ground truth. RESULTS: Ten patients were accrued from December 2020 to October 2022. Compared to the dosimetrically optimal applicator, both the radiation oncologist and ML had an accuracy of 70%. ML demonstrated better identification of patients requiring IC/IS applicators and provided balanced IC and IC/IS predictions. The needle selection model achieved an average accuracy of 82.5%. ML-predicted needle arrangements matched or improved plan quality when compared to clinically selected arrangements. Overall, ML predictions led to an average total improvement of 2.0 Gy to OAR doses over three treatment fractions when compared to clinical predictions. CONCLUSION: In the context of a single institution study, the presented ML model demonstrates valuable decision-support for the applicator and needle selection process with the potential to provide improved dosimetry. Future work will include a multi-center study to assess generalizability.

Clinical implementation of 3D transvaginal ultrasound for intraoperative guidance of needle implant in template interstitial gynecologic high-dose-rate brachytherapy.

PURPOSE: To demonstrate novel clinical implementation of a 3D transvaginal ultrasound (3DTVUS) system for intraoperative needle insertion guidance in perineal template interstitial gynecologic high-dose-rate brachytherapy and assess its impact on implant quality. METHODS AND MATERIALS: Interstitial implants began with preimplant 3DTVUS to visualize the tumor and anatomy, with intermittent 3DTVUS to assess the implant and guide needle adjustment. Analysis includes visualization of the implant relative to anatomy, identification of cases where 3DTVUS is beneficial, dosimetry, and a survey distributed to 3DTVUS clinicians. RESULTS: Seven patients treated between November 2021 and October 2022 were included in this study. Twenty needles were inserted under 3DTVUS guidance. The tumor and vaginal wall were well-differentiated in four and all seven patients, respectively. Patients with tumours below the superior aspect of the vagina are suited for 3DTVUS. Four radiation oncologists responded to the survey. There was general agreement that 3DTVUS improves implant and anatomy visualization and is preferred over standard 2D ultrasound guidance techniques. CONCLUSIONS: Based on qualitative feedback from primary users and a small preliminary patient cohort, 3DTVUS imaging improves tumor and vaginal wall visualization during gynecologic perineal template interstitial needle implant and is a powerful tool for implant assessment in an intraoperative setting.

Risk Stratification for Oropharyngeal Squamous Cell Carcinoma Using Texture Analysis on CT - A Step Beyond HPV Status.

Background and Purpose: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasingly prevalent. Despite the overall more favorable outcome, the observed heterogeneous treatment response within this patient group highlights the need for additional means to prognosticate and guide clinical decision-making. Promising prediction models using radiomics from primary OPSCC have been derived. However, no model/s using metastatic lymphadenopathy exist to allow prognostication in those instances when the primary tumor is not seen. The aim of our study was to evaluate whether radiomics using metastatic lymphadenopathy allows for the development of a useful risk assessment model comparable to the primary tumor and whether additional knowledge of the HPV status further improves its prognostic efficacy. Materials and Methods: 80 consecutive patients diagnosed with stage III-IV OPSCC between February 2009 and October 2015, known human papillomavirus status, and pre-treatment CT images were retrospectively identified. Manual segmentation of primary tumor and metastatic lymphadenopathy was performed and the extracted texture features were used to develop multivariate assessment models to prognosticate treatment response. Results: Texture analysis of either the primary or metastatic lymphadenopathy from pre-treatment enhanced CT images can be used to develop models for the stratification of treatment outcomes in OPSCC patients. AUCs range from .78 to .85 for the various OPSCC groups tested, indicating high predictive capability of the models. Conclusions: This preliminary study can form the basis multi-centre trial that may help optimize treatment and improve quality of life in patients with OPSCC in the era of personalized medicine.

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.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Changing Landscape of Radiation Therapy for Advanced Cervical Cancer With a Focus on Interstitial Brachytherapy: A Canadian Practice Patterns Survey.

PURPOSE: To document the evolution of radical radiation therapy and interstitial brachytherapy (ISBT) utilization practice patterns across Canada, including use of imaging, technical details, and usage of anesthesia/analgesia, and to compare advanced (AC) versus nonadvanced (nAC) brachytherapy (BT) center practices. METHODS AND MATERIALS: All Canadian centers with BT services were identified. One gynecology radiation oncologist per center was sent a 64-item questionnaire regarding the center's practice for patients with cervical cancer. Centers were categorized based on availability of advanced BT expertise (AC) versus those referring patients to other centers for advanced BT techniques (nAC). Aggregate responses are reported and compared with practice patterns identified in our previous survey. Descriptive statistics were used to summarize data, and the Fisher exact test, Fisher-Freeman-Halton, or Mann-Whitney-Wilcox test was used for comparisons. RESULTS: Thirty-seven of 38 respondents completed the survey (response rate: 97.4%). Compared with 2015, there has been an increase in utilization of magnetic resonance imaging as the sole imaging modality for BT planning: 3 of 26 (11%) versus 12 of 37 (32%; P = .03). The number of centers with the ability to perform ISBT increased in 2020 compared with 2015 (26/37 [70%] vs 13/26 [50%], P = .710); this trend is likely due to an increase in use of hybrid (Vienna, Utrecht, Venezia) applicators (36% [2015] vs 84% [2020]; P = .175). Fifteen (40%) centers had the ability to perform perineal-ISBT (P-ISBT). Sixteen and 21 centers were identified as AC and nAC, respectively. All 16 AC centers had the ability to perform ISBT, compared with only 10 nAC centers (P < .001). A higher proportion of AC centers had fellowship-trained radiation oncologists performing brachytherapy, compared with nAC centers (94% vs 14%, P < .001). In terms of anesthesia, conscious sedation was the only available choice at low-patient-volume centers (8/37, 21%) performing intracavitary BT only. Those performing ISBT had choice of general, spinal, and epidural anesthesia. CONCLUSIONS: In Canada, high-quality, modern management radiation therapy practices are consistently offered to patients with cervical cancer. There is a trend toward increased utilization of ISBT. Accumulation of evidence toward the use of ISBT, increased utilization of high-quality imaging modalities such as magnetic resonance imaging, and availability of hybrid applicators are potential contributors for this upward trend.

Corrigendum: Development of a Machine Learning Model for Optimal Applicator Selection in High-Dose-Rate Cervical Brachytherapy.

[This corrects the article DOI: 10.3389/fonc.2021.611437.].

Development of a Machine Learning Model for Optimal Applicator Selection in High-Dose-Rate Cervical Brachytherapy.

Purpose: To develop and validate a preliminary machine learning (ML) model aiding in the selection of intracavitary (IC) versus hybrid interstitial (IS) applicators for high-dose-rate (HDR) cervical brachytherapy. Methods: From a dataset of 233 treatments using IC or IS applicators, a set of geometric features of the structure set were extracted, including the volumes of OARs (bladder, rectum, sigmoid colon) and HR-CTV, proximity of OARs to the HR-CTV, mean and maximum lateral and vertical HR-CTV extent, and offset of the HR-CTV centre-of-mass from the applicator tandem axis. Feature selection using an ANOVA F-test and mutual information removed uninformative features from this set. Twelve classification algorithms were trained and tested over 100 iterations to determine the highest performing individual models through nested 5-fold cross-validation. Three models with the highest accuracy were combined using soft voting to form the final model. This model was trained and tested over 1,000 iterations, during which the relative importance of each feature in the applicator selection process was determined. Results: Feature selection indicated that the mean and maximum lateral and vertical extent, volume, and axis offset of the HR-CTV were the most informative features and were thus provided to the ML models. Relative feature importances indicated that the HR-CTV volume and mean lateral extent were most important for applicator selection. From the comparison of the individual classification algorithms, it was found that the highest performing algorithms were tree-based ensemble methods - AdaBoost Classifier (ABC), Gradient Boosting Classifier (GBC), and Random Forest Classifier (RFC). The accuracy of the individual models was compared to the voting model for 100 iterations (ABC = 91.6 ± 3.1%, GBC = 90.4 ± 4.1%, RFC = 89.5 ± 4.0%, Voting Model = 92.2 ± 1.8%) and the voting model was found to have superior accuracy. Over the final 1,000 evaluation iterations, the final voting model demonstrated a high predictive accuracy (91.5 ± 0.9%) and F1 Score (90.6 ± 1.1%). Conclusion: The presented model demonstrates high discriminative performance, highlighting the potential for utilization in informing applicator selection prospectively following further clinical validation.

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.

Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002).

PURPOSE: Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS: In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS: Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56). CONCLUSION: The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

A real-world comparison of cisplatin vs cetuximab used concurrently with radiation in the treatment of locally advanced oropharyngeal carcinoma.

BACKGROUND: This population-based retrospective study compares the efficacy of cisplatin (cis-RT) vs cetuximab (cetux-RT) with concurrent radiation as definitive treatment in patients with oropharyngeal carcinoma (OPC). METHODS: Patients with OPC treated in Alberta with cis-RT or cetux-RT between 2006 and 2016 were evaluated. Median disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan-Meier method. Multivariable analysis (MVA) was completed with a Cox proportional hazards model. RESULTS: Among 546 patients with OPC, 431 (78.9%) received cis-RT and 115 (21.1%) cetux-RT. Patients treated with cetux-RT were more likely to develop a recurrence after treatment compared to cis-RT (25% vs 15%, P = .01). On MVA, current smoking, human papillomavirus (HPV)-negative status, higher Charlson comorbidity index (CCI), T-stage, and cetux-RT predicted for worse DFS and OS. Outcomes in older patients with a higher CCI still favored cis-RT. CONCLUSIONS: Our data reaffirm results from randomized studies showing better survival outcomes with cis-RT compared to cetux-RT even among those who are >65 with CCI ≥3.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

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.

MRI-based interstitial brachytherapy for vaginal tumors: A multi-institutional study on practice patterns, contouring, and consensus definitions of target volumes.

PURPOSE: Interstitial brachytherapy (ISBT) can be effective for vaginal tumors due to its ability to deliver conformal treatment with 3D planning. As there is no consensus for 3D vaginal brachytherapy (BT) contouring, the goals of this study are to evaluate the variability in practices and contouring, and to develop consensus concepts on target definitions. METHODS: A survey/contouring study was conducted with 16 radiation oncologists from 10 Canadian academic centers. The study included three vaginal ISBT cases. Participants were provided staging, prebrachytherapy (pre-BT), and BT MRIs. Participants responded to a questionnaire and contoured on the provided images. Agreement between contours was analyzed. A meeting was held to develop consensus definitions of targets. RESULTS: Median ISBT experience was 3.5 years. All 16 participants regularly contour with MRI, whereas three also plan on MRI. For the three cases, there was variation into how CTVHR and CTVIR was defined. Kappa statistics showed higher agreement with bulky tumors (mean 0.59) as compared with small residual tumors (mean 0.29). For all cases, kappa was highest in pre-BT GTVres as compared with BT GTVres (mean 0.58, 0.46). Consensus concepts to define targets were developed. CONCLUSIONS: Variations exist in how ISBT targets are defined for vaginal tumors. Highest contouring variability was seen with small residual at BT. Contouring is more consistent on pre-BT MRI as compared with BT MRI suggesting a needle distortion effect. Consensus CTVHR and CTVIR definitions have been developed and further work is warranted to establish international standards.

The impact of inter-fraction changes for perineal template-based interstitial gynecologic brachytherapy implants.

PURPOSE: Perineal template-based interstitial gynecologic brachytherapy (ISBT) treatments are evaluated to determine whether adaptive inter-fraction re-planning is beneficial and necessary to meet the treatment aims of the American Brachytherapy Society (ABS) consensus guidelines for interstitial brachytherapy. Adherence to the EMBRACE II protocol is also assessed. MATERIAL AND METHODS: Ten patients receiving radical intent treatment for locally advanced or recurrent gynecologic malignancies underwent a three-fraction ISBT treatment with an ABS-recommended prescription regimen of 21 to 24 Gy. Clinical treatment plans were created according to a computed tomography (CT) acquired immediately post-implant. The first fraction was delivered on the same day as the implant (Day 1). The remaining two fractions were delivered on the next day (Day 2), at least six hours apart. Prior to treating on Day 2, a verification CT was acquired, permitting assessment of over-night changes. The Day 2 CT was used to evaluate deviations in 2-Gy-per-fraction equivalent dose (EQD2) from the clinically intended dosimetry for clinical target volume (CTV), bladder, rectum, and sigmoid. RESULTS: For all patients, the median (range) difference between the intended and the delivered dosimetry for the CTV D90% was 1.4 Gy10 (0.3-4.4 Gy10). For all normal tissues, the median (range) difference from the intended normal tissue dose was 2.6 Gy3 (0.1-15.5 Gy3). In all cases, the deviation from clinically intended dosimetry did not lead to a violation of recommended normal tissue dose guidelines. For two of 10 patients with large normal tissue differences (> 10 Gy3 from the intended dose), inter-fraction adaptive planning did improve the plan quality, but was not strictly required to meet the normal tissue dose planning aims. CONCLUSIONS: The implementation of perineal template-based ISBT treatment without inter-fraction adaptive planning can be delivered to comply with the ABS normal tissue dose guidelines and EMBRACE II limits for prescribed dose.

Impact of Smoking on Outcomes of HPV-related Oropharyngeal Cancer Treated with Primary Radiation or Surgery.

PURPOSE: Tobacco exposure is known to affect the biological behavior of human papilloma virus (HPV)-positive oropharyngeal carcinoma (OPC) with intermediate outcomes relative to tumors that are HPV associated with no smoking exposure and smoking-related HPV-negative tumors. We aim to evaluate the impact of smoking on the outcomes of patients with HPV-associated locally advanced OPC when stratified by treatment modality. METHODS AND MATERIALS: A retrospective chart review was undertaken for 352 patients with known p16-overexpressing locally advanced OPC who were managed with curative-intent therapy from 2006 to 2015. The impact of smoking status on overall survival (OS) and recurrence-free survival were compared using the Kaplan-Meier method. RESULTS: Of the 352 patients, 67.6% (n = 238) were managed with primary chemoradiation therapy (CRT) and 32.4% (n = 114) with primary surgery ± adjuvant therapy. The median smoking pack-year was 15. Twenty-seven percent of patients were active smokers at the time of presentation, with 40.3% identifying as former smokers and 32.7% having never smoked. Median follow-up for surviving patients was 4.2 years. Current smokers had a significantly worse relapse-free survival and OS compared with never and former smokers (P = .03 and P = .0001, respectively), with outcomes significantly worsening with increasing smoking exposure. The 5-year OS for more than 10, 20, and 30 pack-year smoking history was 73.2%, 64.7%, and 59.1%, respectively. Current smokers managed with CRT had a 5-year OS of 64.2% compared with former and never smokers (93.1% and 78.2%, respectively). For current smokers managed primarily by surgery the 5-year OS was 57.6% compared with former and never smokers (69.6% and 73.5%, respectively). CONCLUSIONS: Current smokers and those with higher smoking exposure had poorer outcomes irrespective of their primary modality of treatment. Although not the specific focus of the study, definitive CRT appeared to at least be equivalent to surgery with respect to disease outcomes for patients with HPV-associated oropharyngeal cancer, regardless of smoking status.

Framework for the quantitative assessment of adaptive radiation therapy protocols.

BACKGROUND: Adaptive radiation therapy (ART) "flags," such as change in external body contour or relative weight loss, are widely used to identify which head and neck cancer (HNC) patients may benefit from replanned treatment. Despite the popularity of ART, few published quantitative approaches verify the accuracy of replan candidate identification, especially with regards to the simple flagging approaches that are considered current standard of practice. We propose a quantitative evaluation framework, demonstrated through the assessment of a single institution's clinical ART flag: change in body contour exceeding 1.5 cm. METHODS: Ground truth replan criteria were established by surveying HNC radiation oncologists. Patient-specific dose deviations were approximated by using weekly acquired CBCT images to deform copies of the CT simulation, yielding during treatment "synthetic CTs." The original plan reapplied to the synthetic CTs estimated interfractional dose deposition and truth table analysis compared ground truth flagging with the clinical ART metric. This process was demonstrated by assessing flagged fractions for 15 HNC patients whose body contour changed by >1.5 cm at some point in their treatment. RESULTS: Survey results indicated that geometric shifts of high-dose volumes relative to image-guided radiation therapy alignment of bony anatomy were of most interest to HNC physicians. This evaluation framework successfully identified a fundamental discrepancy between the "truth" criteria and the body contour flagging protocol selected to identify changes in central axis dose. The body contour flag had poor sensitivity to survey-derived major violation criteria (0%-28%). The sensitivity of a random sample for comparable violation/flagging frequencies was 27%. CONCLUSIONS: These results indicate that centers should establish ground truth replan criteria to assess current standard of practice ART protocols. In addition, more effective replan flags may be tested and identified according to the proposed framework. Such improvements in ART flagging may contribute to better clinical resource allocation and patient outcome.

Radiation therapy for deep periocular cancer treatments when protons are unavailable: is combining electrons and orthovoltage therapy beneficial?

Deep periocular cancers can be difficult to plan and treat with radiation, given the difficulties in apposing bolus to skin, and the proximity to the retina and other optic structures. We sought to compare the combination of electrons and orthovoltage therapy (OBE) with existing modalities for these lesions. Four cases-a retro-orbital melanoma (Case 1) and basal cell carcinomas, extending across the eyelid (Case 2) or along the medial canthus (Cases 3-4)-were selected for comparison. In each case, radiotherapy plans for electron only, 70% electron and 30% orthovoltage (OBE), volumetric-modulated arc therapy (VMAT), conformal arc, and protons were compared. Dose-volume histograms for planning target volume coverage and selected organs at risk (OARs) were then calculated. The V90% coverage of the planning target volume was >98% for electrons, VMAT, conformal arc and proton plans and 90.2% and 89.5% in OBE plans for Cases 2 and 3, respectively. The retinal V80% was >98% in electron, VMAT and proton plans and 79.4%; and 87.1% in OBE and conformal arcs for Case 2 and 91.3%, 36.4%, 56.9%, 52.4% and 43.7% for Case 3 in electrons, OBE, VMAT, conformal arc and proton plans, respectively. Protons provided superior coverage, homogeneity and OAR sparing, compared with all other modalities. However, given its simplicity and widespread availability, OBE is a potential alternative treatment option for moderately deep lesions where bolus placement is difficult.

Comparison of patient-reported acute urinary and sexual toxicity scores in a 6- versus 2-fraction course of high-dose-rate prostate brachytherapy monotherapy.

INTRODUCTION: To identify differences in acute urinary and sexual toxicity between a 6-fraction and 2-fraction high-dose-rate brachytherapy monotherapy regimen and correlate dosimetric constraints to short-term toxicity. METHODS: A single institution retrospective study of 116 men with prostate cancer treated with HDR monotherapy from 2010 to 2015 was conducted. Eighty-one men had 7.25 Gy × 6-fractions and 35 men had 13.5 Gy × 2-fractions. Patients had two CT-planned implants spaced 1-2 weeks apart. Patient baseline characteristics, International Prostate Symptom Scores (IPSS) and Sexual Health Inventory for Men (SHIM) scores were collected pre-treatment and 3, 6 and 12 months post-implantation. Mixed effect modelling was undertaken to compare baseline, 1-6 month and 7-12 month scores between groups. Poisson regression analysis was performed to correlate dosimetric constraints with acute toxicity. RESULTS: There was no difference between baseline and post-implantation IPSS scores between 6-fraction and 2-fraction groups. SHIM scores for men treated with 6-fractions had a steeper decline at 1-6 months, but resolved at 7-12 months. Pre-treatment alpha-blocker use correlated with worse short-term acute urinary toxicity. Worsened SHIM score correlated with increasing age, diabetes mellitus and androgen-deprivation therapy. In a dosimetric analysis of outcomes, prostate V150 dose and bladder wall (D01.cc, D1cc, D2cc) dose correlated with increased IPSS score. CONCLUSION: No increased acute genitourinary or sexual dysfunction has been observed in men when transitioning from 6-fraction to 2-fraction HDR monotherapy. A dosimetric correlation was found between the V150 and bladder wall doses for acute urinary toxicity. Future research should continue to standardize and validate dose constraints for prostate HDR monotherapy patients.