Design and implementation of automated notification systems and an electronic whiteboard for radiation therapy planning monitoring.

PURPOSE: Radiotherapy (RT) treatment and treatment planning is a complex process prepared and delivered by a multidisciplinary team of specialists. Efficient communication and notification systems among different team members are therefore essential to ensure the safe, timely delivery of treatments to patients. METHOD: To address this issue, we developed and implemented automated notification systems and an electronic whiteboard to track every CT simulation, contouring task, the new-start schedule, and physician's appointments and tasks, and notify team members of overdue and missing tasks and appointments. The electronic whiteboard was developed to have a straightforward view of current patients' planning workflow and to help different team members coordinate with each other. The systems were implemented and have been used at our center to monitor the progress of treatment-planning tasks for over 2 years. RESULTS: The last-minute plans were relatively reduced by about 40% in 2023 compared to 2021 and 2022 with a p-value < 0.05. The overdue contouring tasks of more than 1 day decreased from 46.8% in 2019 and 33.6% in 2020 to 20%-26.4% in 2021-2023 with a p-value < 0.05 after the implementation of the notification system. The rate of plans with 1-3 day planning time decreased by 20.31%, 39.32%, and 24.08% with a p-value < 0.05 and the rate of plans with 1-3 day planning time due to the contouring task overdue more than 1 day decreased by 49.49%, 56.89%, and 46.52% with a p-value < 0.05 after the implementation. The rate of outstanding appointments that are overdue by more than 7 days decreased by more than 5% with a p-value < 0.05 following the implementation of the system. CONCLUSIONS: Our experience shows that this system requires minimal human intervention, improves the treatment planning workflow and process by reducing errors and delays in the treatment planning process, positively impacts on-time treatment plan completion, and reduces the need for compressed or rushed treatment planning timelines.

Volumetric changes of the parotid gland during IMRT based on mid-treatment imaging: implications for parotid stem cell sparing strategies in head and neck cancer.

BACKGROUND: To evaluate the change in parotid glands at mid-treatment during IMRT and the association between radiation dose to the parotid gland stem cell (PGSC) region and patient-reported xerostomia for patients with head and neck cancer (HNC). MATERIAL AND METHODS: Patients who were treated from 2006-2012 at our institution with patient-reported xerostomia outcomes available at least 9 months following RT were included. PG and PGSC regions were delineated and the dose was estimated from the treatment plan dose distribution, using contours from pre- and mid-treatment CT scans. The association between radiation dose and volumetric changes was assessed using linear regression. Univariable logistic regression, logistic dose-response curves, and receiver operating characteristics (ROC) were used to examine the relationship between radiation dose and patient-reported xerostomia. RESULTS: Sixty-three patients were included, most treated with 70 Gy in 33 fractions; 34 patients had mid-treatment CT scans. Both contralateral and ipsilateral PGs had considerable volume reduction from baseline to mid-treatment (25% and 27%, respectively, both p < .001), significantly associated with mean PG dose (-0.44%/Gy, p = .008 and -0.54%/Gy, p < .001, respectively). There was a > 5 Gy difference in mean PG and PGSC dose for 8/34 patients at mid-treatment, with 6/8 (75%) reporting severe xerostomia. Xerostomia prediction based on whole PG or PGSC region dose showed similar performance (ROC AUC 0.754 and 0.749, respectively). The corresponding dose-response models also predicted similar risk of patient-reported xerostomia with mean dose to the contralateral PG (32.5%) or PGSC region (31.4%) at the 20 Gy QUANTEC-recommended sparing level. CONCLUSIONS: The radiation dose to the PGSC region did not show stronger association with patient-reported xerostomia compared to that of whole PG, possibly due to considerable anatomical changes identified at mid-treatment. This shift in the size and position of the PG warrants adaptive planning strategies to evaluate the true benefit of parotid stem cell sparing.

Organ-at-risk dose prediction using a machine learning algorithm: Clinical validation and treatment planning benefit for lung SBRT.

OBJECTIVE: To quantify the clinical performance of a machine learning (ML) algorithm for organ-at-risk (OAR) dose prediction for lung stereotactic body radiation therapy (SBRT) and estimate the treatment planning benefit from having upfront access to these dose predictions. METHODS: ML models were trained using multi-center data consisting of 209 patients previously treated with lung SBRT. Two prescription levels were investigated, 50 Gy in five fractions and 54 Gy in three fractions. Models were generated using a gradient-boosted regression tree algorithm using grid searching with fivefold cross-validation. Twenty patients not included in the training set were used to test OAR dose prediction performance, ten for each prescription. We also performed blinded re-planning based on OAR dose predictions but without access to clinically delivered plans. Differences between predicted and delivered doses were assessed by root-mean square deviation (RMSD), and statistical differences between predicted, delivered, and re-planned doses were evaluated with one-way analysis of variance (ANOVA) tests. RESULTS: ANOVA tests showed no significant differences between predicted, delivered, and replanned OAR doses (all p ≥ 0.36). The RMSD was 2.9, 3.9, 4.3, and 1.7Gy for max dose to the spinal cord, great vessels, heart, and trachea, respectively, for 50 Gy in five fractions. Average improvements of 1.0, 1.4, and 2.0 Gy were seen for spinal cord, esophagus, and trachea max doses in blinded replans compared to clinically delivered plans with 54 Gy in three fractions, and 1.8, 0.7, and 1.5 Gy, respectively, for the esophagus, heart and bronchus max doses with 50 Gy in five fractions. Target coverage was similar with an average PTV V100% of 94.7% for delivered plans compared to 97.3% for blinded re-plans for 50 Gy in five fractions, and respectively 98.4% versus 99.2% for 54 Gy in three fractions. CONCLUSION: This study validated ML-based OAR dose prediction for lung SBRT, showing potential for improved OAR dose sparing and more consistent plan quality using dose predictions for patient-specific planning guidance.

Prolongation of radiotherapy duration is associated with inferior overall survival in patients with pediatric medulloblastoma and central nervous system primitive neuroectodermal tumors.

BACKGROUND: The importance of radiotherapy (RT) duration in medulloblastoma in the modern era of chemotherapy has not been well elucidated. The aim of this study was to determine the impact of RT treatment duration on overall survival (OS) in pediatric medulloblastoma and cenral nervous system neuroectodermal tumors (PNETs). METHODS: The National Cancer Database (NCDB) was queried to identify patients with newly diagnosed medulloblastoma and CNS PNETs diagnosed between 2004 and 2014. Patients were excluded if they had extraneural metastasis, did not receive standard craniospinal irradiation dose, had a nonstandard total dose outside of 54 or 55.8 Gy, did not receive adjuvant chemotherapy, or if the RT duration was outside of the expected range of 37 to 80 days. The Kaplan-Meier estimator was used to estimate the association between RT duration (≤45 days or >45 days) and OS. Multivariate Cox regression was used to assess other confounders of OS. RESULTS: Six-hundred twenty-five patients met inclusion criteria, of which 181 were assigned to the "RT long" (>45 days) cohort (29.0%) and 444 (71.0%) to the "RT short" group (≤45 days). The five-year OS for the "RT short" compared with "RT long" cohort was 82.2% versus 70.9%, respectively (log-rank, P < 0.0037). For average risk patients, the five-year OS was 84.6% versus 86.4% for "RT short" and "RT long," respectively (log-rank, P = 0.40). However, for high-risk patients, five-year OS was 77.7% versus 51.0% (log-rank, P < 0.0001) in the "RT short" and "RT long" cohorts. CONCLUSION: For patients with high-risk medulloblastoma and CNS PNETs, RT duration >45 days was associated with inferior OS.

Recommendations of megavoltage computed tomography settings for the implementation of adaptive radiotherapy on helical tomotherapy units.

Megavoltage computed tomography (MVCT) image quality metrics were evaluated on an Accuray Radixact unit to recommend scan settings for the implementation of a consistent adaptive radiotherapy program. Megavoltage computed tomography image quality was evaluated and compared to a kilovoltage CT (kVCT) simulator using a commercial cone beam computed tomography image quality phantom. Megavoltage computed tomographies were acquired on the Accuray Radixact using fine, normal, and coarse pitches, with all available reconstruction slice thicknesses, each of which were reconstructed using standard and iterative reconstruction (IR). Image quality metrics (IQM) were evaluated using DoseLab: automatically and manually calculated spatial resolution, subject contrast, and contrast-to-noise ratio (CNR). Scanning time was 15.6 s/cm for fine, 8.1 s/cm for normal, and 5.6 s/cm for coarse pitch. Automatically evaluated spatial resolutions ranged from 0.39, 0.41, to 0.42 lp/mm for standard reconstruction and from 0.24, 0.21, to 0.18 lp/mm for soft-tissue IR, respectively, with general IR yielding values in between these. Spatial resolution for kVCT was measured to be at least 0.42 lp/mm. Contrast was consistent across MVCT settings with 8.1 ± 0.2%, while kVCT contrast was 10.27 ± 0.05%. CNR was calculated to be 3.3 ± 0.4 for standard reconstruction, 7.4 ± 0.4 for general IR, and 12.0 ± 1.9 for soft-tissue IR. It was found that increasing reconstruction slice thickness for a given pitch does not improve IQMs. Based on the consistency of contrast metrics across pitch values and the only slightly reduced spatial resolution using normal compared to fine pitch, we recommend the use of normal pitch with 2 mm slice thickness to maximize image quality for ART while limiting scanning time. Only for sites for which improved CNR is required and reduced spatial resolution is acceptable, soft-tissue IR is recommended.

Human papillomavirus, radiation dose and survival of patients with anal cancer.

Purpose: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS.Patients and methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 and 2014. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates.Results: We identified 5927 patients with tumor HPV status for this analysis, 3523 (59.4%) had HPV positive disease and 2404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR = 0.81 (95%CI: 0.68-0.96), p=.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR = 1.11 (95%CI: 0.86-1.43), p=.43). In the unmatched cohort, we found a significant improvement in OS with increasing radiation dose only for patients with locally advanced, HPV negative disease (p<.001). In those patients, significant improvement in OS compared to the group receiving 30-45 Gy was seen for increasing doses up to 55-60 Gy, but not beyond 60 Gy.Conclusion: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 55-60 Gy was associated with better OS, but only for patients with locally advanced, HPV negative disease.

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

The impact of dietary regimen compliance on outcomes for HNSCC patients treated with radiation therapy.

OBJECTIVE: To analyze nutritional factors and compliance with dietary recommendations for associations with overall survival (OS) and progression-free survival (PFS) in patients receiving definitive RT for laryngeal and oropharyngeal cancers. MATERIALS/METHODS: We identified 352 patients with non-metastatic laryngeal (146) and oropharyngeal (206) cancer treated with definitive RT between 2004 and 2013. Disease and patient characteristics, treatment information, sarcopenia based on muscle areas at L3 level on CT, compliance with the nutritional program, and clinical outcomes data were tabulated. Descriptive statistics, Kaplan-Meier survival analysis, and log rank tests were performed, and Cox regression models were used to examine predictors of OS and PFS. RESULTS: The median follow-up for the entire cohort was 22.86 months. The actuarial rates for OS were 91, 86, and 73% at years 1, 2, and 5, respectively. Of patients with abdominal CT prior to starting RT, 70.9% (112/158) were sarcopenic with a median muscle mass index of 48.2 (range 30.4-70.9) for males and 35.9 (range 24.6-53.2) for females. The majority (85.8%) of patients met with a dietitian during their course of RT and 62.6% of these patients were compliant with the nutritional program. Compliance with the nutritional program resulted in 27% (HR 0.73, 95% CI 0.43-1.26) protection from death (did not reach significance) and 31% (HR 0.69, 95% CI 0.50-0.94) significant protection from disease progression. Higher pretreatment BMI was associated with a lower risk of death (HR 0.94, 95% CI 0.90-0.99) and disease progression (HR 0.96, 95% CI 0.93-0.99). CONCLUSION: Laryngeal and oropharyngeal cancer patients treated with definitive RT who are compliant with regular dietetic counseling and contact appear to have improved outcomes. TRIAL REGISTRATION: Not applicable.

Management algorithm for HIV-associated parotid lymphoepithelial cysts.

We report an evidence-based management algorithm for benign lymphoepithelial cysts (BLEC) of the parotid glands in HIV patients based on long-term outcomes after radiation therapy. From 1987 to 2013, 72 HIV-positive patients with BLEC of the parotid glands treated at our institutions were identified and their medical records were reviewed and analyzed. The primary endpoint of our study was to determine a dose response in HIV patients with BLEC. In group A (≤18 Gy), which received a median dose of 10 Gy (8-18), overall response (OvR), complete response (CR), partial response (PR), and local failure (LF) was experienced by 7, 7, 0, and 93 %, respectively. In group B (≥22.5 Gy), which received a median dose of 24 Gy (22.5-30), OvR, CR, PR, and LF was experienced by 88, 65, 23, and 12 %. Logistic regression revealed that higher dose (≥22.5 Gy) predicted for cosmetic control (p = 0.0003). Multiple regression analysis revealed higher dose predicted for cosmetic control (p = 0.0001) after adjusting for confounding variables (age, gender, race, HAART use, BLEC duration, and fractionation size). No patients in either group experienced RTOG grade ≥3 toxicities. A radiation dose of 24 Gy delivered in 12-16 fractions of 1.5-2 Gy per fraction provides long-term cosmetic control in HIV-positive patients with BLEC of the parotid glands.

Association of tumor growth rate with overall survival and recurrence among patients with laryngeal squamous cell carcinoma.

BACKGROUND: Delay in time to treatment initiation (TTI) is associated with worsened survival outcomes in laryngeal squamous cell carcinoma (LSCC). It is unclear whether this is due to tumor growth or an increased risk of metastatic disease. METHODS: This retrospective cohort study at one academic center included patients with LSCC who underwent radiotherapy/chemoradiotherapy between 2005 and 2017. We examined the association between tumor growth rate (TGR) and survival outcomes. RESULTS: Among 105 patients (mean age, 63.8 ± 11.1 years; 72% male), the threshold between "slow-growing" and "fast-growing" tumors was >0.036 mL/day (survival) and >0.082 mL/day (recurrence). Faster growth was associated with worse overall survival (OS) (hazard ratio, 1.97; 95% confidence interval [CI], 0.94-4.13) and increased recurrence (odds ratio, 9.10; 95% CI, 2.40-34.4). CONCLUSIONS: TGR >0.036 mL/day during TTI was associated with decreased OS, and >0.082 mL/day was associated with increased recurrence. Tumor measurement in patients experiencing delay may identify those who could benefit from escalated therapy.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Clinical Assessment of a Novel Ring Gantry Linear Accelerator-Mounted Helical Fan-Beam kVCT System.

PURPOSE: To assess clinically relevant image quality metrics (IQMs) of helical fan beam kilovoltage (kV) fan beam computed tomography (CT). METHODS AND MATERIALS: kVCT IQMs were evaluated on an Accuray Radixact unit equipped with helical fan beam kVCT to assess the capabilities of this newly available modality. kVCT IQMs were evaluated and compared to a kVCT simulator and linear accelerator-based cone beam CTs (CBCT) using a commercial CBCT image quality phantom. kVCTs were acquired on the Accuray Radixact for all combinations of kVp and mAs in fine mode using a 440-mm field of view (FOV). Evaluated IQMs were spatial resolution, overall uniformity, subject contrast, contrast-to-noise ratio (CNR), and effective slice thickness. Imaging dose was assessed for planar kV imaging. RESULTS: On this kVCT system spatial resolution and contrast were consistent across all settings with 0.28 ± 0.03 lp/mm and 9.8% ± 0.7% (both 95% confidence interval). CNR strongly depended on selected mode (views per rotation) and body size (mA per view) and ranged between 7.9 and 34.9. Overall uniformity was greater than 97% for all settings. Large FOV was not found to substantially affect the IQMs whereas small FOV affected IQMs due to its effect on pitch. Technique-matched CT simulator scans were comparable for uniformity and contrast, while spatial resolution was higher (0.43 ± 0.06 lp/mm), and CNR was between 4% (140 kVp) and 51% (100 kVp) lower. For kV-CBCT, spatial resolutions ranging from 0.37 to 0.44 lp/mm were achieved with comparable contrast, CNR, and uniformity to kVCT. All kVCT scans exhibit imaging artifacts due to helical acquisition. Clinical acquisitions of megavoltage (MV) CT, kV-CBCT, and kVCT on the same patient showed improved and comparable image quality of kVCT compared to MVCT and kV-CBCT, respectively. CONCLUSIONS: Helical fan beam kVCT allows for daily image guidance for localization and setup verification with comparable performance to existing kV-CBCT systems. Scan parameters must be selected carefully to maximize image quality for the desired tasks. Due to the large effective slice thicknesses for all parameter combinations, kVCT scans should not be used for simulation or planning of stereotactic procedures. Finally, improved image quality over MVCT has the potential to greatly improve manual and automated adaptive monitoring and planning.

A positron emission tomography radiomic signature for distant metastases risk in oropharyngeal cancer patients treated with definitive chemoradiotherapy.

BACKGROUND AND PURPOSE: Disease recurrence and distant metastases (DM) are major concerns for oropharyngeal cancer (OPC) patients receiving definitive chemo-radiotherapy. Here, we investigated whether pre-treatment primary tumor positron emission tomography (PET) features could predict progression-free survival (PFS) or DM. METHODS AND MATERIALS: Primary tumors were delineated on pre-treatment PET scans for patients treated between 2005 and 2018 using gradient-based segmentation. Radiomic image features were extracted, along with SUV metrics. Features with zero variance and strong correlation to tumor volume, stage, p16 status, age or smoking were excluded. A random forest model was used to identify features associated with PFS. Kaplan-Meier methods, Cox regression and logistic regression with receiver operating characteristics (ROC) and 5-fold cross-validated areas-under-the-curve (CV-AUCs) were used. RESULTS: A total of 114 patients were included. With median follow-up 40 months (range: 3-138 months), 14 patients had local recurrence, 21 had DM and 38 died. Two-year actuarial local control, distant control, PFS and overall survival was 89%, 84%, 70% and 84%, respectively. The wavelet_LHL_GLDZM_LILDE feature slightly improved PFS prediction compared to clinical features alone (CV-AUC 0.73 vs. 0.71). Age > 65 years (HR = 2.64 (95%CI: 1.36-5.2), p = 0.004) and p16-negative disease (HR = 3.38 (95%CI: 1.72-6.66), p < 0.001) were associated with poor PFS. A binary radiomic classifier strongly predicted DM with multivariable HR = 3.27 (95%CI: 1.15-9.31), p = 0.027, specifically for patients with p16-negative disease with 2-year DM-free survival 83% for low-risk vs. 38% for high-risk patients (p = 0.004). CONCLUSIONS: A radiomics signature strongly associated with DM risk could provide a tool for improved risk stratification, potentially adding adjuvant immunotherapy for high-risk patients.

Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials: Analysis of RTOG 9811 and RTOG 0529.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation.

Validating the SumMean 18F-FDG PET Textural Feature as a Prognostic Marker in an Independent Cohort of Locally Advanced Non-Small Cell Lung Cancer Patients Undergoing Concurrent Chemoradiation Therapy.

PURPOSE: Analyses from the ACRIN6668/RTOG0235 trial data identified the SumMean textural feature, calculated from 18-fluorodeoxyglucose positron emission tomography for tumors with a metabolic tumor volume >93 cm3, as a predictor of overall survival (OS) for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy. Here, we validated that finding in a completely independent patient cohort from a single institution. METHODS AND MATERIALS: We identified patients with LA-NSCLC who underwent staging 18-fluorodeoxyglucose positron emission tomography and received definitive chemoradiation therapy at our institution between 2007 and 2018. Primary tumors were segmented semiautomatically, and SumMean score was calculated for each tumor and categorized according to the previously proposed cutoff of 0.018. In patients with metabolic tumor volume >93 cm3, SumMean was evaluated as a predictor of progression-free survival (PFS) and OS using log rank and Cox proportional hazards testing. RESULTS: One hundred forty-eight patients met inclusion criteria, and 34 had large tumors (>93 cm3). Twelve (35%) had high SumMean, and 22 (65%) had low SumMean. SumMean was not significantly associated with other clinical variables. Median PFS for patients with large tumors and low SumMean was 5.8 months, compared with 41.1 months for patients with large tumors and high SumMean (log rank P = .022). Median OS for patients with large tumors and low SumMean was 15.0 months; median OS was not reached for patients with large tumors and high SumMean (log rank P = .014). In multivariable analysis, high SumMean was an independent predictor of improved OS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.94; P = .041) and PFS (hazard ratio, 0.30; 95% confidence interval, 0.10-0.86; P = .026). CONCLUSIONS: We externally validated SumMean as a prognostic marker for patients with LA-NSCLC treated with chemoradiation therapy in an independent patient cohort. Future studies will explore potential mechanisms for this association and how textural features may help guide treatment decisions.

Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer.

BACKGROUND: Proton therapy is a promising advancement in radiation oncology especially in terms of reducing normal tissue toxicity, although it is currently expensive and of limited availability. Here we estimated the individual quality of life benefit and cost-effectiveness of proton therapy in patients with oropharyngeal cancer treated with definitive radiation therapy (RT), as a decision-making tool for treatment individualization. METHODS AND MATERIALS: Normal tissue complication probability models were used to estimate the risk of dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis for 33 patients, comparing delivered photon intensity-modulated RT (IMRT) plans to intensity-modulated proton therapy (IMPT) plans. Quality-adjusted life years (QALYs) lost were calculated for each complication while accounting for patient-specific conditional survival probability and assigning quality-adjustment factors based on complication severity. Cost-effectiveness was modeled based on upfront costs of IMPT and IMRT, and the cost of acute and/or long-term management of treatment complications. Uncertainties in all model parameters and sensitivity analyses were included through Monte Carlo sampling. RESULTS: The incremental cost-effectiveness ratios (ICERs) showed considerable variability in the cost of QALYs spared between patients, with median $361,405/QALY for all patients, varying from $54,477/QALY to $1,508,845/QALY between individual patients. Proton therapy was more likely to be cost-effective for patients with p16-positive tumors ($234,201/QALY), compared to p16-negative tumors ($516,297/QALY). For patients with p16-positive tumors treated with comprehensive nodal irradiation, proton therapy is estimated to be cost-effective in ≥ 50% of sampled cases for 8/9 patients at $500,000/QALY, compared to 6/24 patients who either have p16-negative tumors or receive unilateral neck irradiation. CONCLUSIONS: Proton therapy cost-effectiveness varies greatly among oropharyngeal cancer patients, and highlights the importance of individualized decision-making. Although the upfront cost, societal willingness to pay and healthcare administration can vary greatly among different countries, identifying patients for whom proton therapy will have the greatest benefit can optimize resource allocation and inform prospective clinical trial design.

Using Statistical Measures and Density Maps Generated From Chest Computed Tomography Scans to Identify and Monitor COVID-19 Cases in Radiation Oncology Rapidly.

Objectives This study aimed to evaluate quantitative and qualitative screening measures for anomalous computed tomography (CT) scans in cancer patients with potential coronavirus disease 2019 (COVID-19) as an automated detection tool in a radiation oncology treatment setting. Methods We identified a non-COVID-19 cohort and patients with suspected COVID-19 with chest CT scans from February 1, 2020 to June 30, 2020. Lungs were segmented, and a mean normal Hounsfield Unit (HU) histogram was generated for the non-COVID-19 CT scans; these were used to define thresholds for designating the COVID-19-suspected histograms as normal or abnormal. Statistical measures were computed and compared to the threshold levels, and density maps were generated to examine the difference between lungs with and without COVID-19 qualitatively. Results The non-COVID-19 cohort consisted of 70 patients with 70 CT scans, and the cohort of suspected COVID-19 patients consisted of 59 patients with 80 CT scans. Sixty-two patients were positive for COVID-19. The mean HUs and skewness of the intensity histogram discriminated between COVID-19 positive and negative cases, with an area under the curve of 0.948 for positive and 0.944 for negative cases. Skewness correctly identified 57 of 62 positive cases, whereas mean HUs correctly identified 17 of 18 negative cases. Density maps allowed for visualization of the temporal evolution of COVID-19 disease. Conclusions The statistical measures and density maps evaluated here could be employed in an automated screening algorithm for COVID-19 infection. The accuracy is high enough for a simple and rapid screening tool for early identification of suspected infection in patients treated with chemotherapy and radiation therapy already receiving CT scans as part of clinical care. This screening tool could also identify other infections that present critical risks for patients undergoing chemotherapy and radiation therapy, such as pneumonitis.

Who Benefits the Most From Adjuvant Durvalumab After Chemoradiotherapy for Non-small Cell Lung Cancer? An Exploratory Analysis.

PURPOSE: Adjuvant durvalumab is now recommended for most patients with locally advanced non-small cell lung cancer after concurrent chemoradiotherapy. Herein, we explore the clinical factors that may be associated with the benefit from adjuvant durvalumab. METHODS AND MATERIALS: Patients with non-small cell lung cancer who were treated with definitive concurrent chemoradiotherapy at our institution between August 2013 and May 2019 were included in this analysis. Clinical and treatment characteristics were tested for associations with progression-free survival (PFS) in Cox models. Interaction terms were added to the PFS Cox models to explore factors that may modulate the effects of adjuvant durvalumab. PFS and overall survival (OS) rates were estimated using the Kaplan-Meier method, and comparisons between patient subgroups were performed using log rank testing. RESULTS: A total of 105 patients met the eligibility criteria. Thirty-five patients (33%) received adjuvant durvalumab. Treatment with durvalumab was associated with significant improvement in PFS (1-year PFS: 67% vs 39%; log rank P = .006) and OS (1-year OS: 88% vs 76%; log rank P = .041). Exploratory analyses identified the neutrophil-to-lymphocyte ratio (NLR) after radiation therapy (RT) as a factor that may be associated with a benefit from durvalumab. For patients with post-RT NLR exceeding the cohort's median value of 4.3, receipt of adjuvant durvalumab was not associated with a significant PFS improvement (1-year PFS: 45% vs 36%; log rank P = .702). For patients with post-RT NLR <4.3, durvalumab receipt was associated with improved PFS (69% vs 41%; P = .009). High mean RT doses delivered to the heart and esophagus were associated with high post-RT NLR. CONCLUSIONS: We identified low NLR after chemoradiotherapy as a factor that may be associated with a benefit from adjuvant durvalumab. Validation studies are warranted.

Clinical Review of Proton Therapy in the Treatment of Unilateral Head and Neck Cancers.

Radiotherapy is a common treatment modality in the management of head and neck malignancies. In select clinical scenarios of well-lateralized tumors, radiotherapy can be delivered to the primary tumor or tumor bed and the ipsilateral nodal regions, while intentional irradiation of the contralateral neck is omitted. Proton beam therapy is an advanced radiotherapy modality that allows for the elimination of exit-dose through nontarget tissues such as the oral cavity. This dosimetric advantage is apt for unilateral treatments. By eliminating excess dose to midline and contralateral organs at risk and conforming dose around complex anatomy, proton beam therapy can reduce the risk of iatrogenic toxicities. Currently, there is no level I evidence comparing proton beam therapy to conventional photon radiation modalities for unilateral head and neck cancers. However, a growing body of retrospective and prospective evidence is now available describing the dosimetric and clinical advantages of proton beam therapy. Subsequently, the intent of this clinical review is to summarize the current evidence supporting the use of proton beam therapy in unilateral irradiation of head and neck cancers, including evaluation of disease site-specific evidence, unique challenging clinical scenarios, and ongoing clinical trials.

NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.