Radiation Dose Sensitivity of Subregions of the Larynx to Patient-Reported Swallowing Outcomes.

Purpose: To assess any correlation between swallowing dysfunction and radiation dose to 5 subregions of the larynx. Methods and Materials: A cohort of 136 patients with head and neck cancer, treated with either photon or proton radiation therapy, was assessed using an endpoint of patient-reported swallowing scores, evaluated with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 survey, within 1 month after treatment. Five subregions of the larynx were contoured, and dosimetric metrics were extracted for each subregion as well as the total larynx. Univariate and multivariate logistic regression statistical analyses were used to determine statistical correlation with the dose metrics and clinical variables. Univariate regression models were statistically compared using a non-nested model test. Results: Under univariate analysis, unilateral versus bilateral nodal irradiation (P = .004), concurrent chemotherapy (P = .007), and surgery (P = .015) were statistically significant predictors of poor swallowing score. Unilateral versus bilateral irradiation was statistically significant under multivariate analysis (P = .039). The epiglottis was the most predictive subregion of swallowing score, with a majority (21 of 25) of dosimetric variables being identified as statistically significant. The maximum dose to the epiglottis was the most significant dosimetric variable tested for poor swallowing score in both univariate (P = .003) and multivariate (P = .051) analyses. Comparison of univariate models indicated a general preference for epiglottic variables with the mean dose to the epiglottis being preferred at a statistically significant level in many cases. Conclusions: These results show the relatively increased sensitivity of the epiglottis compared with the rest of the larynx when considering patient-reported decrements in quality-of-life swallowing score and support both the inclusion of the epiglottis in standard larynx contours and the assessment of the epiglottis dose during plan evaluation. Our data suggest that keeping the mean and max doses to the epiglottis <20 to 37 Gy and <53 to 60 Gy, respectively, will reduce swallowing difficulties.

Impact of radiation dose distribution on nutritional supplementation needs in head and neck cancer radiotherapy: a voxel-based machine learning approach.

Objectives: To investigate the relationship between nutritional supplementation and radiation dose to the pharyngeal constrictor muscles and larynx for head and neck (HN) cancer patients undergoing radiotherapy. Methods: We retrospectively analyzed radiotherapy (RT) dose for 231 HN cancer patients, focusing on the pharyngeal constrictors and larynx. We defined nutritional supplementation as feeding tube utilization or >10% weight loss from baseline within 90 days after radiotherapy completion. Using deformable image registration (DIR), we mapped each patient's anatomical structures to a reference coordinate system, and corresponding deformations were applied to dose matrices. Voxel doses were utilized as features for ridge logistic regression models, optimized through 5-fold cross-validation. Model performance was assessed with area under the curve of a receiver operating curve (AUC) and F1 score. We built and compared models using 1) pharyngeal constrictor voxels, 2) larynx voxels, 3) clinical factors and mean regional dose metrics, and 4) clinical factors and dose-volume histogram metrics. Test set AUCs were compared among the models, and feature importance was evaluated. Results: DIR of the pharyngeal constrictors and larynx yielded mean Dice coefficients of 0.80 and 0.84, respectively. Pharyngeal constrictors voxels and larynx voxel models had AUC of 0.88 and 0.82, respectively. Voxel-based dose modeling identified the superior to middle regions of the pharyngeal constrictors and the superior region of larynx as most predictive of feeding tube use/weight loss. Univariate analysis found treatment setting, treatment laterality, chemotherapy, baseline dysphagia, weight, and socioeconomic status predictive of outcome. An aggregated model using mean doses of pharyngeal constrictors and larynx subregions had an AUC of 0.87 and the model using conventional DVH metrics had an AUC of 0.85 with p-value of 0.04. Feature importance calculations from the regional dose model indicated that mean doses to the superior-middle pharyngeal constrictor muscles followed by mean dose to the superior larynx were most predictive of nutritional supplementation. Conclusions: Machine learning modeling of voxel-level doses enables identification of subregions within organs that correlate with toxicity. For HN radiotherapy, doses to the superior-middle pharyngeal constrictors are most predictive of feeding tube use/weight loss followed by the doses to superior portion of the larynx.

A script-enabled interactive checklist document for efficient management of electronic devices in a busy multimodality radiotherapy clinic.

PURPOSE: Develop an efficient, interactive, and instructive checklist document for the management of implanted electronic medical devices in a multimodality radiotherapy clinic. METHODS: The built-in scripting and interactivity of a popular commercial word processor was used to develop an interactive document that changes the information presented to the user based on drop-down selections. The interactivity and scripting were compatible with the radiation oncology information system (ROIS) which allows the document to be accessible by all team members and serve as a permanent record in a patient's electronic chart. RESULTS: The final interactive document, which was clinically deployed after beta testing with a group consisting of nurses and medical physicists, presents information and action plans to the user based on multiple departmental medical device decision trees that are specific to the combination of device, treatment modality, rhythm-pacing dependence for cardiac devices, and distance from the device to the treatment volume. CONCLUSION: A script-enabled interactive document was developed for a busy multimodality clinic, condensing multiple comprehensive departmental guidelines spanning multiple device types and treatment modalities into a single interactive checklist accessible within the ROIS. Given the wide accessibility of the commercial word processor, this approach could be adopted by other clinics to streamline their own respective workflows.

Treatment outcomes of single-fraction stereotactic radiosurgery for adenoid cystic carcinoma: a case series of 55 patients.

PURPOSE: This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. METHODS: Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). RESULTS: The median age was 60 years (range 21-85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. CONCLUSION: SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases.

Mean Oral Cavity Organ-at-Risk Dose Predicts Opioid Use and Hospitalization during Radiotherapy for Patients with Head and Neck Tumors.

BACKGROUND: Approximately 75% of all head and neck cancer patients are treated with radiotherapy (RT). RT to the oral cavity results in acute and late adverse events which can be severe and detrimental to a patient's quality of life and function. The purpose of this study was to explore associations between RT dose to a defined oral cavity organ-at-risk (OAR) avoidance structure, provider- and patient-reported outcomes (PROs), opioid use, and hospitalization. METHODS: This was a retrospective analysis of prospectively obtained outcomes using multivariable modeling. The study included 196 patients treated with RT involving the oral cavity for a head and neck tumor. A defined oral cavity OAR avoidance structure was used in all patients for RT treatment planning. Validated PROs were collected prospectively. Opioid use and hospitalization were abstracted electronically from medical records. RESULTS: Multivariable modeling revealed the mean dose to the oral cavity OAR was significantly associated with opioid use (p = 0.0082) and hospitalization (p = 0.0356) during and within 30 days of completing RT. CONCLUSIONS: The findings of this study may be valuable in RT treatment planning for patients with tumors of the head and neck region to reduce the need for opioid use and hospitalization during treatment.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC.

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. RESULTS: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012). CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. SIGNIFICANCE: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.

Clinicopathologic Factors and Their Association with Outcomes of Salivary Duct Carcinoma: A Multicenter Experience.

Purpose: This series reports long-term clinical outcomes of patients with salivary duct carcinoma (SDC), which is associated with a poor prognosis. Methods and Materials: Eighty-nine patients with SDC were treated with curative intent from February 5, 1971, through September 15, 2018. Kaplan-Meier and competing risk analyses were used to estimate locoregional control, distant metastasis-free survival (DMFS), progression-free survival, and overall survival (OS). Cox regression analyses of disease and treatment characteristics were performed to discover predictors of locoregional control, DMFS, and OS. Results: Median follow-up was 44.1 months (range, 0.23-356.67). The median age at diagnosis was 66 years (interquartile range, 57-75). Curative surgery followed by adjuvant radiation therapy was performed in 73 patients (82%). Chemotherapy was delivered in 26 patients (29.2%). The 5-year local recurrence and distant metastasis rates were 27% and 44%, respectively, with death as a competing risk. Distant metastasis was associated with lymph node-positive disease (hazard ratio [HR], 3.16; 95% confidence interval [CI], 1.38-7.23; P = .006), stage IV disease (HR, 4.78; 95% CI, 1.14-20.11; P = .033), perineural invasion (HR, 4.56; 95% CI, 1.74-11.97; P = .002), and positive margins (HR, 9.06; 95% CI, 3.88-21.14; P < .001). Median OS was 4.84 years (95% CI, 3.54-7.02). The 5-year OS was 42%. Reduced OS was associated with lymphovascular space invasion (HR, 3.49; 95% CI, 1.2-10.1; P = .022), perineural invasion (HR, 2.05; 95% CI, 1.06-3.97; P = .033), positive margins (HR, 2.7; 95% CI, 1.3-5.6; P = .011), N2 disease (HR, 1.88; 95% CI, 1.03-3.43; P = .04), and N3 disease (HR, 11.76; 95% CI, 3.19-43.3; P < .001). Conclusions: In this single-institution, multicenter retrospective study, the 5-year survival was 42% in patients with SDC. Lymphovascular space invasion, lymph node involvement, and higher staging at diagnosis were associated with lower DMFS and OS.

Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer.

INTRODUCTION: Intensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT. METHODS: We analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model. RESULTS: Median follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis. CONCLUSIONS: IMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.

Dosimetric predictors of pneumonitis in locally advanced non-small cell lung cancer patients treated with chemoradiation followed by durvalumab.

OBJECTIVES: The incidence and predictors of pneumonitis for patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) in the era of consolidation durvalumab have yet to be fully elucidated. In this large single institution analysis, we report the incidence of and factors associated with grade 2 + pneumonitis in NSCLC patients treated with the PACIFIC regimen. MATERIALS AND METHODS: We identified all patients treated at our institution with definitive CRT followed by durvalumab from 2018 to 2021. Clinical documentation and imaging studies were reviewed to determine grade 2 + pneumonitis events, which required the following: 1) pulmonary symptoms warranting prolonged steroid taper, oxygen dependence, and/or hospital admission and 2) radiographic findings consistent with pneumonitis. RESULTS: One-hundred ninety patients were included. The majority received 60 Gray (Gy) in 30 fractions with concurrent carboplatin and paclitaxel. Median number of durvalumab cycles received was 12 (IQR: 4-22). At a median follow-up of 14.8 months, 50 (26.3%) patients experienced grade 2 + pneumonitis with a 1-year cumulative incidence of 27.8% (95% CI: 21.9-35.4). Seventeen (8.9%) patients experienced grade 3 + pneumonitis and 4 grade 5 (2.1%). Dosimetric predictors of pneumonitis included ipsilateral and total lung volume receiving 5 Gy or greater (V5Gy), V10Gy, V20Gy, V40Gy, and mean dose and contralateral V40Gy. Heart V5Gy, V10Gy, and mean dose were also significant variables. Overall survival estimates at 1 and 3 years were 87.4% (95% CI: 82.4-92.8) and 60.3% (95% CI: 47.9-74.4), respectively. CONCLUSION: We report a risk of pneumonitis higher than that seen on RTOG 0617 and comparable to the PACIFIC study. Multiple lung and heart dosimetric factors were predictive of pneumonitis.

Long-Term Toxic Effects, Swallow Function, and Quality of Life on MC1273: A Phase 2 Study of Dose De-escalation for Adjuvant Chemoradiation in Human Papillomavirus-Positive Oropharyngeal Cancer.

PURPOSE: Patients with human papillomavirus oropharyngeal cancer are highly curable but risk significant long-term toxic effects with standard therapy. This study investigated a de-escalation strategy of decreased adjuvant radiation therapy and chemotherapy after transoral robotic surgery, and reports on long-term functional and quality of life (QOL) outcomes. METHODS AND MATERIALS: Eligible patients had a p16-positive oropharyngeal cancer and ≤10 pack-year smoking history and underwent surgery followed by treatment with either 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks with weekly docetaxel (15 mg/m2) if they had intermediate pathologic risk factors or 36 Gy in 1.8-Gy fractions twice per day over 2 weeks with the same chemotherapy if they had extranodal extension. Toxic effects, swallow function, and QOL were measured longitudinally. RESULTS: Seventy-nine patients (89.9% male) were treated and eligible for toxic effect and functional evaluation. Dry mouth was the most common grade 1 toxic effect at 1 year (55.6%), 2 years (53.3%), and 3 years (49.2%). The cumulative rates of grade 2 toxic effects at 1, 2, and 3 years were 1.4%, 6.7%, and 6.8%, respectively. There were only 2 grade 3 toxic effects at ≥1 year, including a grade 3 fatigue at 2.5 years, and a grade 3 superficial soft tissue fibrosis at 4 years. There were no grade 4 to 5 toxic effects. No patients were percutaneous endoscopic gastrostomy-dependent. Swallow function improved by 12 months posttreatment. QOL improved over time by all measurement tools and most patients returned to baseline level of function and QOL. CONCLUSIONS: De-escalated adjuvant therapy for select patients with human papillomavirus oropharyngeal cancer resulted in low rates of long-term toxic effects, excellent swallow outcomes, and preservation of global and xerostomia-related QOL.

Outcomes and Patterns of Recurrence for Anaplastic Thyroid Cancer Treated With Comprehensive Chemoradiotherapy.

PURPOSE: Radiation therapy (RT) plays an important role in locoregional tumor control for anaplastic thyroid cancer (ATC). Due to its rarity, RT guidelines for ATC are lacking. We describe ATC patterns of nodal disease at presentation and progression and propose corresponding RT target volumes. METHODS AND MATERIALS: We identified all patients with ATC treated at our institution with definitive or adjuvant intensity modulated radiation therapy and concomitant chemotherapy from 2006 to 2020. We identified in-field, marginal, and out-of-field sites of locoregional recurrence and progression (LRR). RESULTS: Forty-seven patients met inclusion. Median follow-up was 6.6 months (interquartile range, 1.9-19.6). Nodal levels involved at presentation included: IB (2.1%), II (23.4%), III (21.3%), IV (21.3%), V (12.8%), VI (34%), and mediastinal (6.4%). All patients received elective nodal RT to levels II-IV and VI. RT volumes also included: IA (23.4%), IB (44.7%), V (87.2%), retropharyngeal/retrostyloid (RP/RS) (27.7%), and mediastinal 1 to 6 (53.2%). Cumulative incidence of LRR at 3- and 12-months was 26.1% (95% confidence interval, 15.9-42.8) and 35.7% (23.9-53.4). Isolated LRR risk at 3- and 12-months was 6.5% (2.2-19.8) and 8.9% (3.4-22.9). Fourteen (29.8%) patients experienced in-field LRR in the thyroid gland or postoperative tumor bed, II-IV, VI, and mediastinal 1 and 3A. Four (8.5%) patients had marginal LRRs, 3 of whom progressed in the mediastinum at 2, 3P, 4, and 6. Two (4.3%) patients experienced out-of-field LRRs. Throughout the pretreatment and follow-up period, no patients had disease at IA, and 1 (2.1%) patient each had disease at IB and RP/RS. No baseline or treatment characteristics, including RT dose (stratified by < or ≥66 Gy), were significant predictors of LRR on univariate analysis. CONCLUSIONS: Isolated LRR risk in patients with ATC treated with comprehensive RT and chemotherapy is low. Aggressive multimodality therapy should be reserved for willing, fit patients with no or limited distant disease burden. When treating comprehensively, complete inclusion of mediastinal levels 1 to 6 may be warranted to avoid marginal disease progression. Omission of levels I and RP/RS can be considered.

Oncologic Outcomes for Head and Neck Skin Malignancies Treated with Protons.

PURPOSE: Radiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. MATERIALS AND METHODS: We retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. RESULTS: The 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval [CI], 4.1%-30.3%), 4.4% (95% CI, 1.1%-17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%-95.5%), and 87.2% (95% CI, 75.7%-100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. CONCLUSION: IMPT is safe and effective in the treatment of skin malignancies of the H&N.

Ablative radiotherapy for ultracentral lung cancers: Dosimetric, geometric, and volumetric predictors of outcomes and toxicity.

BACKGROUND: Ultracentral lung cancers arise near the proximal bronchial tree (PBT), trachea, or esophagus, and have been associated with worse outcomes and increased toxicity after radiotherapy. We sought to associate dosimetric and anatomic factors with oncologic outcomes and toxicities. METHODS: One-hundred ten patients treated with ablative, curative-intent radiotherapy for ultracentral, node-negative, non-small cell lung cancer were included. Dosimetric and geometric data obtained using custom software that calculated volumes of target structures and organs-at-risk and measured the shortest vector length between these volumes were associated with outcomes and toxicity. RESULTS: Common dose/fractionation schemes included 50 Gy in 5 fractions (57%), 60 Gy in 8 fractions (15%), and 48 Gy in 4 fractions (13%). Overall survival at 1, 2, and 5 years was 78%, 57%, and 32%, respectively. Factors significantly associated with death included endobronchial tumor, gross tumor volume (GTV) or planning target volume (PTV) contacting PBT, shorter distance from GTV to PBT or esophagus, volume of PBT receiving prescription dose, higher pericardium max dose, lung V20Gy, and mean lung dose. Local progression at 1, 2, and 5 years was 4%, 16%, and 21%. Factors associated with local progression were lower GTV minimum dose and higher GTV/PTV volume ratio. Acute and late grade 2 + toxicity was seen in 18% and 27%, respectively. Four patients (4%) had fatal toxicity. CONCLUSIONS: Lower GTV minimum dose and smaller volumetric PTV expansions may increase risk of local progression, and should be balanced against normal tissue doses including pericardium maximum dose, lung V20Gy, and mean lung dose.

Consensus Statement on Proton Therapy in Mesothelioma.

PURPOSE: Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons. METHODS: The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations. RESULTS: The Particle Therapy Cooperative Group Thoracic Subcommittee task group provides specific guidelines for the use of proton therapy for mesothelioma. CONCLUSIONS: This consensus report can be used to guide clinical practice, insurance approval, and future research.

Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx.

PURPOSE: De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273. METHODS AND MATERIALS: MC1273 is a prospective, phase 2 study evaluating adjuvant CRT to 30 to 36 Gy plus docetaxel for HPV+ OPSCC after surgery for high-risk patients. Matched standard-of-care control groups were retrospectively identified for patients treated with definitive CRT or adjuvant RT. Standardized costs were evaluated before radiation, during treatment (during RT), and at short-term (6 month) and long-term (7-24 month) follow-up periods. RESULTS: A total of 56 definitive CRT, 101 adjuvant RT, and 66 MC1273 patients were included. The CRT arm had more T3-4 disease (63% vs 17-21%) and higher N2c-N3 disease (52% vs 20-24%) vs both other groups. The total treatment costs in the CRT, adjuvant RT, and MC1273 groups were $47,763 (standard deviation [SD], $19,060], $57,845 (SD, $17,480), and $46,007 (SD, $9019), respectively, and the chemotherapy and/or RT costs were $39,936 (SD, $18,480), $26,603 (SD, $12,542), and $17,864 (SD, $3288), respectively. The per-patient, per-month, average short-term follow-up costs were $3860 (SD, $10,525), $1072 (SD, $996), and $972 (SD, $833), respectively, and the long-term costs were $978 (SD, $2294), $485 (SD, $1156), and $653 (SD, $1107), respectively. After adjustment for age, T-stage, and N-stage, treatment costs remained lower for CRT and MC1273 versus adjuvant RT ($45,450 and $47,114 vs $58,590, respectively; P < .001), whereas the total per-patient, per-month follow-up costs were lower in the MC1273 study group and adjuvant RT versus CRT ($853 and $866 vs $2030, respectively; P = .03). CONCLUSIONS: MC1273 resulted in 10% and 20% reductions in global costs compared with standard-of-care adjuvant RT and definitive CRT treatments. Substantial cost savings may be an added benefit to the already noted low toxicity and maintained quality of life of treatment per MC1273.

The Importance of Verification CT-QA Scans in Patients Treated with IMPT for Head and Neck Cancers.

PURPOSE: To understand how verification computed tomography-quality assurance (CT-QA) scans influenced clinical decision-making to replan patients with head and neck cancer and identify predictors for replanning to guide intensity-modulated proton therapy (IMPT) clinical practice. PATIENTS AND METHODS: We performed a quality-improvement study by prospectively collecting data on 160 consecutive patients with head and neck cancer treated using spot-scanning IMPT who underwent weekly verification CT-QA scans. Kaplan-Meier estimates were used to determine the cumulative probability of a replan by week. Predictors for replanning were determined with univariate (UVA) and multivariate (MVA) Cox model hazard ratios (HRs). Logistic regression was used to determine odds ratios (ORs). P < .05 was considered statistically significant. RESULTS: Of the 160 patients, 79 (49.4%) had verification CT-QA scans, which prompted a replan. The cumulative probability of a replan by week 1 was 13.7% (95% confidence interval [CI], 8.82-18.9), week 2, 25.0% (95% CI, 18.0-31.4), week 3, 33.1% (95% CI, 25.4-40.0), week 4, 45.6% (95% CI, 37.3-52.8), and week 5 and 6, 49.4% (95% CI, 41.0-56.6). Predictors for replanning were sinonasal disease site (UVA: HR, 1.82, P = .04; MVA: HR, 3.64, P = .03), advanced stage disease (UVA: HR, 4.68, P < .01; MVA: HR, 3.10, P < .05), dose > 60 Gy equivalent (GyE; relative biologic effectiveness, 1.1) (UVA: HR, 1.99, P < .01; MVA: HR, 2.20, P < .01), primary disease (UVA: HR, 2.00 versus recurrent, P = .01; MVA: HR, 2.46, P = .01), concurrent chemotherapy (UVA: HR, 2.05, P < .01; MVA: not statistically significant [NS]), definitive intent treatment (UVA: HR, 1.70 versus adjuvant, P < .02; MVA: NS), bilateral neck treatment (UVA: HR, 2.07, P = .03; MVA: NS), and greater number of beams (5 beam UVA: HR, 5.55 versus 1 or 2 beams, P < .02; MVA: NS). Maximal weight change from baseline was associated with higher odds of a replan (≥3 kg: OR, 1.97, P = .04; ≥ 5 kg: OR, 2.13, P = .02). CONCLUSIONS: Weekly verification CT-QA scans frequently influenced clinical decision-making to replan. Additional studies that evaluate the practice of monitoring IMPT-treated patients with weekly CT-QA scans and whether that improves clinical outcomes are warranted.

Modeling the Impact of Cardiopulmonary Irradiation on Overall Survival in NRG Oncology Trial RTOG 0617.

PURPOSE: To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non-small cell lung cancer. EXPERIMENTAL DESIGN: We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification. RESULTS: Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89). CONCLUSIONS: The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

Comparative analysis of acute toxicities and patient reported outcomes between intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngeal cancer.

BACKGROUND AND PURPOSE: IMPT improves normal tissue sparing compared to VMAT in treating oropharyngeal cancer (OPC). Our aim was to assess if this translates into clinical benefits. MATERIALS AND METHODS: OPC patients treated with definitive or adjuvant IMPT or VMAT from 2013 to 2018 were included. All underwent prospective assessment using patient-reported-outcomes (PROs) (EORTC-QLQ-H&N35) and provider-assessed toxicities (CTCAEv4.03). End-of-treatment and pretreatment scores were compared. PEG-tube use, hospitalization, and narcotic use were retrospectively collected. Statistical analysis used the Wilcoxon Rank-Sum Test with propensity matching for PROs/provider-assessed toxicities, and t-tests for other clinical outcomes. RESULTS: 46 IMPT and 259 VMAT patients were included; median follow-up was 12 months (IMPT) and 30 months (VMAT). Baseline characteristics were balanced except for age (p = 0.04, IMPT were older) and smoking (p < 0.01, 10.9% IMPT >20PYs, 29.3% VMAT). IMPT was associated with lower PEG placement (OR = 0.27; 95% CI: 0.12-0.59; p = 0.001) and less hospitalization ≤60 days post-RT (OR = 0.21; 95% CI:0.07-0.6, p < 0.001), with subgroup analysis revealing strongest benefits in patients treated definitively or with concomitant chemoradiotherapy (CRT). IMPT was associated with a relative risk reduction of 22.3% for end-of-treatment narcotic use. Patients reported reduced cough and dysgeusia with IMPT (p < 0.05); patients treated definitively or with CRT also reported feeling less ill, reduced feeding tube use, and better swallow. Provider-assessed toxicities demonstrated less pain and mucositis with IMPT, but more mucosal infection. CONCLUSION: IMPT is associated with improved PROs, reduced PEG-tube placement, hospitalization, and narcotic requirements. Mucositis, dysphagia, and pain were decreased with IMPT. Benefits were predominantly seen in patients treated definitively or with CRT.