A retrospective study on the investigation of potential dosimetric benefits of online adaptive proton therapy for head and neck cancer.

PURPOSE: Proton therapy is sensitive to anatomical changes, often occurring in head-and-neck (HN) cancer patients. Although multiple studies have proposed online adaptive proton therapy (APT), there is still a concern in the radiotherapy community about the necessity of online APT. We have performed a retrospective study to investigate the potential dosimetric benefits of online APT for HN patients relative to the current offline APT. METHODS: Our retrospective study has a patient cohort of 10 cases. To mimic online APT, we re-evaluated the dose of the in-use treatment plan on patients' actual treatment anatomy captured by cone-beam CT (CBCT) for each fraction and performed a templated-based automatic replanning if needed, assuming that these were performed online before treatment delivery. Cumulative dose of the simulated online APT course was calculated and compared with that of the actual offline APT course and the designed plan dose of the initial treatment plan (referred to as nominal plan). The ProKnow scoring system was employed and adapted for our study to quantify the actual quality of both courses against our planning goals. RESULTS: The average score of the nominal plans over the 10 cases is 41.0, while those of the actual offline APT course and our simulated online course is 25.8 and 37.5, respectively. Compared to the offline APT course, our online course improved dose quality for all cases, with the score improvement ranging from 0.4 to 26.9 and an average improvement of 11.7. CONCLUSION: The results of our retrospective study have demonstrated that online APT can better address anatomical changes for HN cancer patients than the current offline replanning practice. The advanced artificial intelligence based automatic replanning technology presents a promising avenue for extending potential benefits of online APT.

A component method to delineate surgical spine implants for proton Monte Carlo dose calculation.

PURPOSE: Metallic implants have been correlated to local control failure for spinal sarcoma and chordoma patients due to the uncertainty of implant delineation from computed tomography (CT). Such uncertainty can compromise the proton Monte Carlo dose calculation (MCDC) accuracy. A component method is proposed to determine the dimension and volume of the implants from CT images. METHODS: The proposed component method leverages the knowledge of surgical implants from medical supply vendors to predefine accurate contours for each implant component, including tulips, screw bodies, lockers, and rods. A retrospective patient study was conducted to demonstrate the feasibility of the method. The reference implant materials and samples were collected from patient medical records and vendors, Medtronic and NuVasive. Additional CT images with extensive features, such as extended Hounsfield units and various reconstruction diameters, were used to quantify the uncertainty of implant contours. RESULTS: For in vivo patient implant estimation, the reference and the component method differences were 0.35, 0.17, and 0.04 cm3 for tulips, screw bodies, and rods, respectively. The discrepancies by a conventional threshold method were 5.46, 0.76, and 0.05 cm3 , respectively. The mischaracterization of implant materials and dimensions can underdose the clinical target volume coverage by 20 cm3 for a patient with eight lumbar implants. The tulip dominates the dosimetry uncertainty as it can be made from titanium or cobalt-chromium alloys by different vendors. CONCLUSIONS: A component method was developed and demonstrated using phantom and patient studies with implants. The proposed method provides more accurate implant characterization for proton MCDC and can potentially enhance the treatment quality for proton therapy. The current proof-of-concept study is limited to the implant characterization for lumbar spine. Future investigations could be extended to cervical spine and dental implants for head-and-neck patients where tight margins are required to spare organs at risk.

Onboard cone-beam CT-based replan evaluation for head and neck proton therapy.

PURPOSE: Quality assurance computed tomography (QACT) is the current clinical practice in proton therapy to evaluate the needs for replan. QACT could falsely indicate replan because of setup issues that would be solved on the treatment machine. Deforming the treatment planning CT (TPCT) to the pretreatment CBCT may eliminate this issue. We investigated the performance of replan evaluation based on deformed TPCT (TPCTdir) for proton head and neck (H&N) therapy. METHODS AND MATERIALS: Twenty-eight H&N datasets along with pretreatment CBCT and QACT were used to validate the method. The changes in body volume were analyzed between the no-replan and replan groups. The dose on the TPCTdir, the deformed QACT (QACTdir), and the QACT were calculated by applying the clinical plans to these image sets. Dosimetric parameters' changes, including ΔD95, ΔDmean, and ΔD1 for the clinical target volumes (CTVs) were calculated. Receiver operating characteristic curves for replan evaluation based on ΔD95 on QACT and TPCTdir were calculated, using ΔD95 on QACTdir as the reference. A threshold for replan based on ΔD95 on TPCTdir is proposed. The specificities for the proposed method were calculated. RESULTS: The changes in the body contour were 95.8 ± 83.8 cc versus 305.0 ± 235.0 cc (p < 0.01) for the no-replan and replan groups, respectively. The ΔD95, ΔDmean, and ΔD1 are all comparable for all the evaluations. The differences between TPCTdir and QACTdir evaluations were 0.30% ± 0.86%, 0.00 ± 0.22 Gy, and -0.17 ± 0.61 Gy for CTV ΔD95, ΔDmean, and ΔD1, respectively. The corresponding differences between the QACT and QACTdir were 0.12% ± 1.1%, 0.02 ± 0.32 Gy, and -0.01 ± 0.71 Gy. CTV ΔD95 > 2.6% in TPCTdir was chosen as the threshold to trigger QACT/replan. The corresponding specificity was 94% and 98% for the clinical practice and the proposed method, respectively. CONCLUSIONS: The replan evaluation based on TPCTdir provides better specificity than that based on the QACT.

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy.

BACKGROUND: Perioperative chemotherapy (POC) is one standard approach for the treatment of resectable cancers of the stomach and gastroesophageal junction (GEJ), whereas there has been growing interest in preoperative therapies. The objective of the current study was to compare survival between patients treated with preoperative chemoradiotherapy and adjuvant chemotherapy (PCRT) with those receiving POC using a large database. METHODS: The National Cancer Data Base was queried for patients diagnosed between 2004 and 2013 with American Joint Committee on Cancer clinical group stage IB to stage IIIC (excluding T2N0 disease) adenocarcinoma of the stomach or GEJ. Patients treated with definitive surgery and POC with or without preoperative radiotherapy of 41 to 54 Gy were included. Overall survival (OS) was defined from the date of definitive surgery and estimated using the Kaplan-Meier method. A total of 14 patient and treatment variables were used for propensity score matching (PSM). RESULTS: A total of 1048 patients were analyzed: 53.2% received POC and 46.8% received PCRT. The primary tumor site was the GEJ in 69.1% of patients and stomach in 30.9% of patients. The median age of the patients was 60 years, and the median follow-up was 25.8 months. The use of PCRT was associated with a greater pathologic complete response rate of 13.1% versus 8.2% (P = .01). POC was associated with a decreased risk of death in unmatched groups (hazard ratio [HR], 0.83; P = .043). Using PSM cohorts, POC decreased the risk of death with a median OS of 45.1 months versus 31.4 months (HR, 0.70; P = .016). The 2-year OS rate was 72.9% versus 62.5% and the 5-year OS rate was 40.7% versus 33.1% for POC versus PCRT, respectively. Survival favored POC in PSM gastric (HR, 0.41; P = .07) and GEJ (HR, 0.77; P = .08) patient subgroups. CONCLUSIONS: The addition of preoperative radiotherapy to POC appears to be associated with an increased risk of death in patients with resectable gastric and GEJ cancers.

Survival outcomes by high-risk human papillomavirus status in nonoropharyngeal head and neck squamous cell carcinomas: A propensity-scored analysis of the National Cancer Data Base.

BACKGROUND: The prognostic relevance of human papillomavirus (HPV) status in patients with nonoropharyngeal (OPX) squamous cell cancer (SCC) of the head and neck is controversial. In the current study, the authors evaluated the impact of high-risk HPV status on overall survival (OS) in patients with non-OPX SCC using a large database approach. METHODS: The National Cancer Data Base was queried to identify patients diagnosed from 2004 through 2014 with SCC of the OPX, hypopharynx (HPX), larynx, and oral cavity (OC) with known HPV status. Survival was estimated using Kaplan-Meier methods; distributions were compared using log-rank tests. Propensity score-matching and inverse probability of treatment weighing (IPTW) methods were used; cohorts were matched based on age, sex, Charlson-Deyo score, clinical American Joint Committee on Cancer (AJCC) group stage, treatments received, and anatomic subsite. Propensity analyses were stratified by group stage of disease. RESULTS: A total of 24,740 patients diagnosed from 2010 through 2013 were analyzed: 1085 patients with HPX, 4804 with laryngeal, 4,018 with OC, and 14,833 with OPX SCC. The percentages of HPV-positive cases by disease site were 17.7% for HPX, 11% for larynx, 10.6% for OC, and 62.9% for OPX. HPV status was found to be prognostic in multiple unadjusted and propensity-adjusted non-OPX populations. HPV positivity was associated with superior OS in patients with HPX SCC with a hazard ratio (HR) of 0.61 (P < .001 by IPTW), in patients with AJCC stage III to IVB laryngeal SCC (HR, 0.79; P = .019 by IPTW), and in patients with AJCC stage III to IVB OC SCC (HR, 0.78; P = .03 by IPTW). CONCLUSIONS: Positive high-risk HPV status appears to be associated with longer OS in multiple populations of patients with non-OPX head and neck disease (HPX, locally advanced larynx, and OC). If prospectively validated, these findings have implications for risk stratification.

Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx.

BACKGROUND: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx. METHODS: Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history. RESULTS: A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease. CONCLUSIONS: Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation.

Chemotherapy with or Without Definitive Radiation Therapy in Inoperable Pancreatic Cancer.

BACKGROUND: The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. METHODS: Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2-4, N0-1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ≥ 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. RESULTS: 13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with hazard ratio of 0.79 (95% confidence interval 0.76-0.83) compared with CT alone. CONCLUSIONS: In our series, addition of definitive radiotherapy to CT was associated with better OS when compared with CT alone in LAPC. Definitive radiotherapy should remain a treatment option for LAPC, but optimal selection criteria remain unclear.

Health care disparities among octogenarians and nonagenarians with stage II and III rectal cancer.

BACKGROUND: Octogenarians and nonagenarians with stage II/III rectal adenocarcinomas are underrepresented in the randomized trials that have established the standard-of-care therapy of preoperative chemoradiation followed by definitive resection (ie, chemoradiation and then surgery [CRT+S]). The purpose of this study was to evaluate the impact of therapies on overall survival (OS) for patients with stage II/III rectal cancers and determine predictors of therapy within the National Cancer Data Base (NCDB). METHODS: In the NCDB, patients who were 80 years old or older and had clinical stage II/III rectal adenocarcinoma from 2004 to 2013 were queried. Kaplan-Meier analysis, log-rank testing, logistic regression, Cox proportional hazards regression, interaction effect testing, and propensity score-matched analysis were conducted. RESULTS: The criteria were met by 2723 patients: 14.9% received no treatment, 29.7% had surgery alone, 5.0% underwent short-course radiation and then surgery (RT+S), 45.3% underwent CRT+S, and 5.1% underwent surgery and then chemoradiation (S+CRT). African American race and residence in a less educated county were associated with not receiving treatment. Male sex, older age, worsening comorbidities, and receiving no treatment or undergoing surgery alone were associated with worse OS. There was no statistical difference in OS between RT+S, S+CRT, and CRT+S. Interaction testing found that CRT+S improved OS independently of age, comorbidity status, sex, race, and tumor stage. In the propensity score-matched analysis, CRT+S was associated with improved OS in comparison with surgery alone. CONCLUSIONS: A significant portion of octogenarians and nonagenarians with stage II/III rectal adenocarcinomas do not receive treatment. African American race and living in a less educated community are associated with not receiving therapy. This series suggests that CRT+S is a reasonable strategy for elderly patients who can tolerate therapy. Cancer 2017;123:4325-36. © 2017 American Cancer Society.

Proton Radiotherapy for Midline Central Nervous System Lesions: A Class Solution.

OBJECTIVE: Midline and central lesions of the brain requiring conventional radiotherapy (RT) present complex difficulties in dose avoidance to organs at risk (OAR). In either definitive or adjuvant settings, proper RT coverage of these lesions involves unnecessary treatment of large volumes of normal brain. We propose a class solution for these lesions using proton radiotherapy (PrT). MATERIALS AND METHODS: The records of the Indiana University Health Proton Therapy Center were reviewed for patients presenting between January 1, 2005 and October 1, 2013 with midline central nervous system (CNS) lesions. Twenty-four patients were identified. After Institutional Review Board approval was granted, their dosimetry was reviewed for target volume doses and OAR dose avoidance. RESULTS: For these cases, meningiomas were the most common histology (8 cases), and next most prevalent were craniopharyngiomas (6 cases). The others were various different deep midline brain tumors (10 cases). In all cases, fields formed by vertex and/or anterior/posterior superior oblique PrT beams along the midsagittal plane were used to provide coverage with minimal dose to the brain stem or to the cerebral hemispheres. The median prescribed dose to the planning target volume for treating these patients was 54.0 Gy RBE (range 48.6-62.5) with a mean dose of 53.5 Gy RBE. The average of the mean doses to the brain stems using these fields in the 24 plans was 18.4 Gy RBE (range 0.0-44.7). Similarly, the average of the mean doses to the hippocampi was 15.8 Gy RBE (range 0.0-52.6). CONCLUSIONS: We consider these patients to be optimally treated with PrT. The use of modified midsagittal PrT schemas allows for the treatment of midline CNS lesions with sparing of most of the uninvolved brain.

Proton therapy for atypical meningiomas.

We report clinical outcomes of proton therapy in patients with World Health Organization grade 2 (atypical) meningiomas. Between 2005 and 2013, 22 patients with atypical meningiomas were treated to a median dose of 63 Gy (RBE) using proton therapy, as an adjuvant therapy after surgery (n = 12) or for recurrence or progression of residual tumor (n = 10). Six patients had presumed radiation-induced meningiomas, but none had received prior radiotherapy for their meningioma. The median follow-up time after radiation was 39 months (range 7-104) and all patients remain alive at last follow-up. The 5-year estimate of local control was 71.1% (95% CI 49.3-92.9%). The 5-year estimate of local control was 87.5% following a radiation dose >60 Gy (RBE), compared to 50.0% for ≤ 60 Gy (RBE) (p = 0.038). The 5-year estimate of neuraxis dissemination was 5% (95% CI 0-14.6%) and 6.2% (95% CI 0-18.2%) for metastases outside of the central nervous system. Radiation necrosis was observed in one patient with a history of prior cranial irradiation. Fractionated proton therapy was associated with favorable tumor control rates for grade 2 meningiomas. Prospective studies are needed to define the optimal radiation dose for high-grade meningiomas.

Dose perturbation effect of metallic spinal implants in proton beam therapy.

The purpose of this study was to investigate the effect of dose perturbations for two metallic spinal screw implants in proton beam therapy in the perpendicular and parallel beam geometry. A 5.5 mm (diameter) by 45 mm (length) stainless steel (SS) screw and a 5.5 mm by 35 mm titanium (Ti) screw commonly used for spinal fixation were CT-scanned in a hybrid phantom of water and solid water. The CT data were processed with an orthopedic metal artifact reduction (O-MAR) algorithm. Treatment plans were generated for each metal screw with a proton beam oriented, first parallel and then perpendicular, to the longitudinal axis of the screw. The calculated dose profiles were compared with measured results from a plane-parallel ion chamber and Gafchromic EBT2 films. For the perpendicular setup, the measured dose immediately downstream from the screw exhibited dose enhancement up to 12% for SS and 8% for Ti, respectively, but such dose perturbation was not observed outside the lateral edges of the screws. The TPS showed 5% and 2% dose reductions immediately at the interface for the SS nd Ti screws, respectively, and up to 9% dose enhancements within 1 cm outside of the lateral edges of the screws. The measured dose enhancement was only observed within 5 mm from the interface along the beam path. At deeper depths, the lateral dose profiles appeared to be similar between the measurement and TPS, with dose reduction in the screw shadow region and dose enhancement within 1-2 cm outside of the lateral edges of the metals. For the parallel setup, no significant dose perturbation was detected at lateral distance beyond 3 mm away from both screws. Significant dose discrepancies exist between TPS calculations and ion chamber and film measurements in close proximity of high-Z inhomogeneities. The observed dose enhancement effect with proton therapy is not correctly modeled by TPS. An extra measure of caution should be taken when evaluating dosimetry with spinal metallic implants.

Institution-level Patterns of Care for Early-stage Oropharynx Cancers in the United States.

OBJECTIVES: The adoption of transoral robotic surgery and shifting epidemiology in oropharyngeal squamous cell cancer have stimulated debate over upfront and adjuvant treatment. Institutional variation in practice patterns can be obscured in patient-level analyses. We aimed to characterize institutional patterns of care as well as identify potential associations between patterns of care and survival. METHODS: This was a retrospective cohort study of patients identified from 2004-2015 in the National Cancer Database. We analyzed 42,803 cases of oropharyngeal squamous cell cancer Stage cT1-2N0-2bM0 (AJCC 7th edition) treated with curative intent surgery and/or radiotherapy. We defined facility-4-year periods to account for changing institutional practice patterns. The 42,803 patients were treated within 2578 facility-4-year periods. We assessed institutional practice patterns, including the ratio of upfront surgery to definitive radiotherapy, case volumes, use of adjuvant therapies (radiotherapy or chemoradiotherapy), and margin positivity rates. Survival associations with institutional practice patterns were estimated with Cox regression. RESULTS: The ratio of upfront surgery to definitive radiotherapy ranged from 80-to-1 to 1-to-23. The institution-level median rate of adjuvant radiotherapy was 69% (IQR 50%-100%), adjuvant chemoradiotherapy was 44% (IQR 0%-67%), and margin-positive resection was 33% (IQR 0%-50%). On patient-level MVA, worse overall survival was not significantly associated with institutional case volume, adjuvant radiotherapy, or adjuvant chemoradiotherapy utilization. CONCLUSIONS: High rates of multimodal therapy and positive margins underscore the importance of multidisciplinary care and highlight variable patterns of care across institutions. Further work is warranted to explore indicators of high-quality care and to optimize adjuvant therapy in the HPV era.

Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.

Purpose: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution. Materials and Methods: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans. Results: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03). Conclusion: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.

Assessing survival outcomes of patients with oral tongue squamous cell carcinoma: Focus on age, sex, and stage.

BACKGROUND: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma. METHODS: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi-square tests and overall survival rates were estimated using Kaplan-Meier method. RESULTS: A total of 17 642 patients were included in the study. The 5-year overall survival rates were 82.0% (95% CI: 79.8%-84.0%) in younger patients versus 67.5% (95% CI: 66.7%-68.3%, p-value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2-NA) versus 129.8 (95% CI: 125.4-138.7, p-value <0.0001) in males. CONCLUSIONS: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: implications for patterns of disease recurrence and overall survival.

BACKGROUND: The use of radiation therapy (RT) "cone-down" boost to reduce high-dose treatment volumes according to tumor response to induction chemotherapy in patients with pediatric rhabdomyosarcoma (RMS) may reduce treatment morbidity, yet the impact on tumor control is unknown. METHODS: Fifty-five children, including 18 (33%) with parameningeal (PM) RMS and 37 (67%) with non-PM RMS, who received definitive treatment with chemotherapy and RT from April 2000 through January 2010 were retrospectively reviewed. RESULTS: In total, 28 patients (51%) received a cone-down boost. The high-dose boost volume was reduced by a median of 56% of the initial target volume (range, 5%-91%). The median time to initiating RT was 3 weeks for patients with PM RMS and 16 weeks for patients with non-PM RMS (P < .001). After a median follow-up of 41 months, local failure occurred in 5 patients (9%), including 2 patients who received a cone-down boost, and there were no marginal failures. Twelve patients (67%) with PM RMS had intracranial tumor extension. In this subgroup, 4 patients (30%) who received a cone-down boost and had ≥ 3 weeks between chemotherapy and RT initiation experienced leptomeningeal failure as their first site of disease progression, and a delayed time to RT initiation was associated with decreased survival (P = .055) CONCLUSIONS: A cone-down boost allowed for significant reductions in high-dose RT treatment volume while maintaining excellent tumor control in most patients. However, in the subset of patients with PM RMS and intracranial tumor extension, early RT initiation and wider margin RT to cover adjacent areas at high risk for meningeal extension may be more important for adequate disease control.

Proton liver stereotactic body radiation therapy: Treatment techniques and dosimetry feasibility from a single institution.

Purpose: To assess the resulting dosimetry characteristics of simulation and planning techniques for proton stereotactic body radiation therapy (SBRT) of primary and secondary liver tumors. Methods: Consecutive patients treated under volumetric daily image guidance with liver proton SBRT between September 2019 and March 2022 at Emory Proton Therapy Center were included in this study. Prescriptions ranged from 40 Gy to 60 Gy in 3- or 5-fraction regimens, and motion management techniques were used when target motion exceeded 5 mm. 4D robust optimization was used when necessary. Dosimetry evaluation was conducted for ITV V100, D99, Dmax, and liver-ITV mean dose and D700cc. Statistical analysis was performed using independent-samples Mann-Whitney U tests. Results: Thirty-six tumors from 29 patients were treated. Proton therapy for primary and secondary liver tumors using motion management techniques and robust optimization resulted in high target coverage and low doses to critical organs. The median ITV V100% was 100.0%, and the median ITV D99% was 111.3%. The median liver-ITV mean dose and D700cc were 499 cGy and 5.7 cGy, respectively. The median conformity index (CI) was 1.03, and the median R50 was 2.56. Except for ITV D99% (primary 118.1% vs. secondary 107.2%, p = 0.005), there were no significant differences in age, ITV volume, ITV V100%, ITV maximum dose, liver-ITV mean dose, or D700cc between primary and secondary tumor groups. Conclusion: The study demonstrated that proton therapy with motion management techniques and robust optimization achieves excellent target coverage with low normal liver doses for primary and secondary liver tumors. The results showed high target coverage, high conformality, and low doses to the liver.

Factors Affecting Clinical Outcomes Among Patients Infected With HIV and Anal Cancer Treated With Modern Definitive Chemotherapy and Radiation Therapy.

Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months' posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P < .001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P = .049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months' posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.

Insurance Authorization and Access to Proton Therapy for Patients With Head and Neck Cancers.

PURPOSE: We evaluated our institutional experience to assess potential racial inequities in insurance coverage for proton therapy in patients with head and neck (HN) cancer. METHODS AND MATERIALS: We examined the demographics of 1519 patients with HN cancer seen in consultation at our HN multidisciplinary clinic (HN MDC) and 805 patients for whom a proton insurance authorization was sought (PAS) from January 2020 to June 2022. The prospects for proton therapy insurance authorization were prospectively noted based on each patient's ICD-10 (International Classification of Diseases, 10th Revision) diagnosis code and their specific insurance plan. Proton-unfavorable (PU) insurance were those plans whose policy describes proton beam therapy as "experimental" or "not medically necessary" for the given diagnosis. RESULTS: For patients seen in our HN MDC, Black, Indigenous, and people of color (BIPOC) were significantly more likely to have PU insurance than non-Hispanic White (NHW) patients (24.9% vs 18.4%, P = .005). In multivariable analysis including race, average income of residence ZIP code, and Medicare eligibility age, BIPOC patients had an odds ratio of 1.25 for PU insurance (P = .041). In the PAS cohort, while there was no difference in the percentage of patients receiving insurance approval for proton therapy between NHW and BIPOC populations (88% vs 88.2%, P = .80), for patients with PU insurance, the median time to determination was significantly longer (median, 15.5 days), and the median time to start any radiation of any modality was longer (46 vs 35 days, P = .08). Compared with NHW patients, the median time from consultation to start of radiation therapy was longer for BIPOC patients (37 vs 43 days, P = .01). CONCLUSIONS: BIPOC patients were significantly more likely to have insurance plans unfavorable to proton therapy coverage. These PU insurance plans were associated with a longer median time to determination, a lower approval rate for proton therapy, and a longer time to start radiation of any modality.

Ninety-day mortality following transoral robotic surgery or radiation at Commission on Cancer-accredited facilities.

BACKGROUND: Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown. METHODS: NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson-Deyo score 0-1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities. RESULTS: 3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality. CONCLUSIONS: There is minimal difference between 90-day mortality in patients treated with TORS or radiotherapy for early-stage OPSCC. While overall rates are low, for patients with expectation of cure, work is needed to identify optimal treatment.