Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. METHODS: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. FINDINGS: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. INTERPRETATION: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. FUNDING: National Cancer Institute.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Treatment planning and outcomes effects of reducing the preferred mean esophagus dose for conventionally fractionated non-small cell lung cancer radiotherapy.

Based on an analysis of published literature, our department recently lowered the preferred mean esophagus dose (MED) constraint for conventionally fractionated (2 Gy/fraction in approximately 30 fractions) treatment of locally advanced non-small cell lung cancer (LA-NSCLC) with the goal of reducing the incidence of symptomatic acute esophagitis (AE). The goal of the change was to encourage treatment planners to achieve a MED close to 21 Gy while still permitting MED to go up to the previous guideline of 34 Gy in difficult cases. We compared all our suitable LA-NSCLC patients treated with plans from one year before through one year after the constraint change. The primary endpoint for this study was achievability of the new constraint by the planners; the secondary endpoint was reduction in symptomatic AE. Planners were able to achieve the new constraint in statistically significantly more cases during the year following its explicit implementation than in the year before (P = 0.0025). Furthermore, 38% of patients treated after the new constraint developed symptomatic AE during their treatment as opposed to 48% of the patients treated before. This is a clinically desirable endpoint although the observed difference was not statistically significant. A subsequent power calculation suggests that this is due to the relatively small number of patients in the study.

The 3 Bs of cancer care amid the COVID-19 pandemic crisis: "Be safe, be smart, be kind"-A multidisciplinary approach increasing the use of radiation and embracing telemedicine for head and neck cancer.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis.

Hypofractionated vs. conventional radiation therapy for stage III non-small cell lung cancer treated without chemotherapy.

Background: Patients with unresectable locally advanced NSCLC who refuse or are not candidates for chemotherapy often receive radiation therapy (RT) alone. Hypofractionated RT (HFRT) regimens are becoming increasingly common. An analysis of the National Cancer Database (NCDB) was performed to evaluate the practice patterns and outcomes of HFRT vs. conventionally fractionated RT (CFRT) in patients with stage III NSCLC undergoing definitive RT alone.Material and methods: The NCDB was queried for all patients with stage III NSCLC diagnosed between 2004 and 2014 who received RT alone. CFRT was defined as patients treated to a total dose of 60-80 Gy in 1.8-2 Gy daily fractions. HFRT was defined as patients treated to a total dose of 50-80 Gy in 2.25-4 Gy fractions. Logistic regression, univariable and multivariable analyses (MVAs) for overall survival (OS) and propensity score matched analyses (PSMAs) were performed.Results: A total of 6490 patients were evaluated: 5378 received CFRT and 1112 received HFRT. Median CFRT dose was 66 Gy in 2 Gy fractions vs. 58.5 Gy in 2.5 Gy fractions for HFRT. HFRT was associated with older age, lower biological effective dose (BED10), academic facility type, higher T-stage and lower N-stage. On initial analysis, HFRT was associated with inferior OS (median 9.9 vs. 11.1 months, p<.001), but after adjusting for the imbalance in covariates such as age, BED10, T-stage and N-stage using PSMA, the difference in survival was no longer significant (p=.1).Conclusions: In the appropriate clinical context, HFRT can be an option for patients with locally advanced NSCLC who are not candidates for chemotherapy or surgical resection. HFRT needs to be further studied in prospective trials to evaluate toxicity and tumor control.

Stereotactic body radiation therapy (SBRT) improves local control and overall survival compared to conventionally fractionated radiation for stage I non-small cell lung cancer (NSCLC).

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been adopted as the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC), with local control rates consistently >90%. However, data directly comparing the outcomes of SBRT with those of conventionally fractionated radiotherapy (CONV) is lacking. MATERIAL AND METHODS: Between 1990 and 2013, 497 patients (525 lesions) with early-stage NSCLC (T1-T2N0M0) were treated with CONV (n = 127) or SBRT (n = 398). In this retrospective analysis, five endpoints were compared, with and without adjusting for clinical and dosimetric factors. Competing risks analysis was performed to estimate and compare the cumulative incidence of local failure (LF), nodal failure (NF), distant failure (DF) and disease progression. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by the Cox regression model. Propensity score (PS) matched analysis was performed based on seven patient and clinical variables: age, gender, Karnofsky performance status (KPS), histology, T stage, biologically equivalent dose (BED), and history of smoking. RESULTS: The median dose delivered for CONV was 75.6 Gy in 1.8-2.0 Gy fractions (range 60-90 Gy; median BED = 89.20 Gy) and for SBRT 48 Gy in four fractions (45-60 Gy in three to five fractions; median BED = 105.60 Gy). Median follow-up was 24.4 months, and 3-year LF rates were 34.1% with CONV and 13.6% with SBRT (p < .001). Three-year OS rates were 38.9 and 53.1%, respectively (p = .018). PS matching showed a significant improvement of OS (p = .0497) for SBRT. T stage was the only variable correlating with all five endpoints. CONCLUSION: SBRT compared to CONV is associated with improved LF rates and OS. Our data supports the continued use and expansion of SBRT as the standard of care treatment for inoperable early-stage NSCLC.

Evaluating a Physician Audit and Feedback Intervention to Increase Clinical Trial Enrollment in Radiation Oncology in a Multisite Tertiary Cancer Center: A Randomized Study.

PURPOSE: Clinical trial participation continues to be low, slowing new cancer therapy development. Few strategies have been prospectively tested to address barriers to enrollment. We investigated the effectiveness of a physician audit and feedback report to improve clinical trial enrollment. METHODS AND MATERIALS: We conducted a randomized quality improvement study among radiation oncologists at a multisite tertiary cancer network. Physicians in the intervention group received quarterly audit and feedback reports comparing the physician's trial enrollments with those of their peers. The primary outcome was trial enrollments. RESULTS: Among physicians randomized to receive the feedback report (n = 30), the median proportion of patients enrolled during the study period increased to 6.1% (IQR, 2.6%-9.3%) from 3.2% (IQR, 1.1%-10%) at baseline. Among those not receiving the feedback report (n = 29), the median proportion of patients enrolled increased to 4.1% (IQR, 1.3%-7.6%) from 1.6% (IQR, 0%-4.1%) at baseline. There was a nonsignificant change in the proportion of enrollments associated with receiving the feedback report (-0.6%; 95% CI, -3.0% to 1.8%; P = .6). Notably, there was an interaction between baseline trial accrual and receipt of feedback reports (P = .005), with enrollment declining among high accruers. There was an increase in enrollment throughout the study, regardless of study group (P = .001). CONCLUSIONS: In this study, a positive effect of physician audit and feedback on clinical trial enrollment was not observed. Future efforts should avoid disincentivizing high accruers and might consider pairing feedback with other patient- or physician-level strategies. The increase in trial enrollment in both groups over time highlights the importance of including a comparison group in quality improvement studies to reduce confounding from secular trends.

Impact of Surveillance Imaging in Patients With HPV-Associated Oropharyngeal Carcinoma Treated With Definitive Radiation and Chemotherapy.

OBJECTIVES: Surveillance imaging for HPV-associated oropharyngeal carcinomas (OPCs) differs among physicians and institutions. Surveillance imaging can detect disease progression earlier, but can also contribute to anxiety and cost, without proven survival benefits. We sought to determine practice patterns of surveillance imaging and the number of surveillance scans needed to detect one recurrence in patients with HPV-associated OPCs. METHODS: We performed a retrospective cohort study between 2017 and 2019 (median follow-up: 39.9 mo) of consecutive patients with locally advanced HPV-associated OPC who received definitive concurrent chemoradiotherapy (CRT) with 70 Gy at a single institution. Patients were followed post-CRT and their surveillance scans were recorded. Recurrences were classified as detected by first post-treatment scans, surveillance scans, clinical exams, or incidental findings. The number of surveillance scans needed to detect 1 recurrence was determined by dividing the number of surveillance scans by the number of recurrences detected by surveillance scans. RESULTS: Among 276 patients with a median follow-up of 39.9 months, there were 28 recurrences. Of all recurrences, 11 (39.3%) were detected by the first post-treatment scan, 11 (39.3%) by surveillance scan, 5 (17.9%) by clinical exam, and 1 (3.6%) was incidentally found. A total of 694 surveillance scans were taken. The number of surveillance scans needed to detect 1 recurrence was 64 overall, 45 within 2 years, and 248 beyond 2 years from treatment. CONCLUSIONS: First post-treatment scans and surveillance scans detected more recurrences than clinical exams. A high burden of surveillance scans is needed to detect 1 recurrence, especially beyond 2 years from treatment.

A Phase II Study Evaluating the Effect of Intensity Modulated Postmastectomy Radiation Therapy on Implant Failure Rates in Breast Cancer Patients With Immediate, 2-Stage Implant Reconstruction With an MRI Imaging Correlative Substudy.

PURPOSE: Postmastectomy radiation therapy is a mainstay in the adjuvant treatment of node-positive breast cancer, but it poses risks for women with breast reconstruction. Multibeam intensity-modulated radiation therapy improves dose conformality and homogeneity, potentially reducing complications in breast cancer patients with implant-based reconstruction. To investigate this hypothesis, we conducted a single-arm phase 2 clinical trial of breast cancer patients who underwent mastectomy/axillary dissection and prosthesis-based reconstruction. METHODS AND MATERIALS: The primary endpoint was the rate of implant failure (IF) within 24 months of permanent implant placement, which would be considered an improvement over historical controls if below 16%. IF was defined as removal leading to a flat chest wall or replacement with another reconstruction. Patients were analyzed in 2 cohorts. Cohort 1 (RT-PI) received radiation therapy to the permanent implant. Cohort 2 (RT-TE) received radiation therapy to the TE. IF rates, adverse events, and quality of life were analyzed. Follow-up/postradiation therapy assessments were compared with the baseline/preradiation therapy assessments at 3 to 10 weeks after exchange surgery. A subgroup underwent serial magnetic resonance imaging (MRI) sessions to explore the association between MRI-detected changes and capsular contracture, a known adverse effect of radiation therapy. RESULTS: Between June 2014 and March 2017, 119 women were enrolled. Cohort 1 included 45 patients, and cohort 2 had 74 patients. Among 100 evaluable participants, 25 experienced IF during the study period. IF occurred in 8/42 (19%) and 17/58 (29%) in cohorts 1 and 2, respectively. Among the IFs, the majority were due to capsular contracture (13), infection (7), exposure (3), and other reasons (2). Morphologic shape features observed in longitudinal MRI images were associated with the development of Baker grade 3 to 4 contractures. CONCLUSIONS: The rate of IF in reconstructed breast cancer patients treated with intensity-modulated radiation therapy was similar to, but not improved over, that observed with conventional, 3-dimensional-conformal methods. MRI features show promise for predicting capsular contracture but require validation in larger studies.

Clinical Experience With an Offline Adaptive Radiation Therapy Head and Neck Program: Dosimetric Benefits and Opportunities for Patient Selection.

PURPOSE: The objective of this study was to develop a linear accelerator (LINAC)-based adaptive radiation therapy (ART) workflow for the head and neck that is informed by automated image tracking to identify major anatomic changes warranting adaptation. In this study, we report our initial clinical experience with the program and an investigation into potential trigger signals for ART. METHODS AND MATERIALS: Offline ART was systematically performed on patients receiving radiation therapy for head and neck cancer on C-arm LINACs. Adaptations were performed at a single time point during treatment with resimulation approximately 3 weeks into treatment. Throughout treatment, all patients were tracked using an automated image tracking system called the Automated Watchdog for Adaptive Radiotherapy Environment (AWARE). AWARE measures volumetric changes in gross tumor volumes (GTVs) and selected normal tissues via cone beam computed tomography scans and deformable registration. The benefit of ART was determined by comparing adaptive plan dosimetry and normal tissue complication probabilities against the initial plans recalculated on resimulation computed tomography scans. Dosimetric differences were then correlated with AWARE-measured volume changes to identify patient-specific triggers for ART. Candidate trigger variables were evaluated using receiver operator characteristic analysis. RESULTS: In total, 46 patients received ART in this study. Among these patients, we observed a significant decrease in dose to the submandibular glands (mean ± standard deviation: -219.2 ± 291.2 cGy, P < 10-5), parotids (-68.2 ± 197.7 cGy, P = .001), and oral cavity (-238.7 ± 206.7 cGy, P < 10-5) with the adaptive plan. Normal tissue complication probabilities for xerostomia computed from mean parotid doses also decreased significantly with the adaptive plans (P = .008). We also observed systematic intratreatment volume reductions (ΔV) for GTVs and normal tissues. Candidate triggers were identified that predicted significant improvement with ART, including parotid ΔV = 7%, neck ΔV = 2%, and nodal GTV ΔV = 29%. CONCLUSIONS: Systematic offline head and neck ART was successfully deployed on conventional LINACs and reduced doses to critical salivary structures and the oral cavity. Automated cone beam computed tomography tracking provided information regarding anatomic changes that may aid patient-specific triggering for ART.

An 18F-FDG PET/CT and Mean Lung Dose Model to Predict Early Radiation Pneumonitis in Stage III Non-Small Cell Lung Cancer Patients Treated with Chemoradiation and Immunotherapy.

Radiation pneumonitis (RP) that develops early (i.e., within 3 mo) (RPEarly) after completion of concurrent chemoradiation (cCRT) leads to treatment discontinuation and poorer survival for patients with stage III non-small cell lung cancer. Since no RPEarly risk model exists, we explored whether published RP models and pretreatment 18F-FDG PET/CT-derived features predict RPEarly Methods: One hundred sixty patients with stage III non-small cell lung cancer treated with cCRT and consolidative immunotherapy were analyzed for RPEarly Three published RP models that included the mean lung dose (MLD) and patient characteristics were examined. Pretreatment 18F-FDG PET/CT normal-lung SUV featured included the following: 10th percentile of SUV (SUVP10), 90th percentile of SUV (SUVP90), SUVmax, SUVmean, minimum SUV, and SD. Associations between models/features and RPEarly were assessed using area under the receiver-operating characteristic curve (AUC), P values, and the Hosmer-Lemeshow test (pHL). The cohort was randomly split, with similar RPEarly rates, into a 70%/30% derivation/internal validation subset. Results: Twenty (13%) patients developed RPEarly Predictors for RPEarly were MLD alone (AUC, 0.72; P = 0.02; pHL, 0.87), SUVP10, SUVP90, and SUVmean (AUC, 0.70-0.74; P = 0.003-0.006; pHL, 0.67-0.70). The combined MLD and SUVP90 model generalized in the validation subset and was deemed the final RPEarly model (RPEarly risk = 1/[1+e(- x )]; x = -6.08 + [0.17 × MLD] + [1.63 × SUVP90]). The final model refitted in the 160 patients indicated improvement over the published MLD-alone model (AUC, 0.77 vs. 0.72; P = 0.0001 vs. 0.02; pHL, 0.65 vs. 0.87). Conclusion: Patients at risk for RPEarly can be detected with high certainty by combining the normal lung's MLD and pretreatment 18F-FDG PET/CT SUVP90 This refined model can be used to identify patients at an elevated risk for premature immunotherapy discontinuation due to RPEarly and could allow for interventions to improve treatment outcomes.

Clinical and Dosimetric Risk Factors Associated With Radiation-Induced Lung Toxicities After Multiple Courses of Lung Stereotactic Body Radiation Therapy.

Purpose: Data are limited on radiation-induced lung toxicities (RILT) after multiple courses of lung stereotactic body radiation therapy (SBRT). We herein analyze a large cohort of patients to explore the clinical and dosimetric risk factors associated with RILT in such settings. Methods and Materials: A single institutional database of patients treated with multiple courses of lung SBRT between January 2014 and December 2019 was analyzed. Grade 2 or higher (G2+) RILT after the last course of SBRT was the primary endpoint. Composite plans were generated with advanced algorithms including deformable registration and equivalent dose adjustment. Logistic regression analyses were performed to examine correlations between patient or treatment factors including dosimetry and G2+ RILT. Risk stratification of patients and lung constraints based on acceptable normal tissue complication probability were calculated based on risk factors identified. Results: Among 110 eligible patients (56 female and 54 male), there were 64 synchronous (58.2%; defined as 2 courses of SBRT delivered within 30 days) and 46 metachronous (41.8%) courses of SBRT. The composite median lung V20, lung V5, and mean lung dose were 9.9% (interquartile range [IQR], 7.3%-12.4%), 32.2% (IQR, 25.5%-40.1%), and 7.0 Gy (IQR, 5.5 Gy-8.6 Gy), respectively. With a median follow-up of 21.1 months, 30 patients (27.3%) experienced G2+ RILT. Five patients (4.5%) developed G3 RILT, and 1 patient (0.9%) developed G4 RILT, and no patients developed G5 RILT. On multivariable regression analysis, female sex (odds ratio [OR], 4.35; 95% CI, 1.49%-14.3%; P = .01), synchronous SBRT (OR, 8.78; 95% CI, 2.27%-47.8%; P = .004), prior G2+ RILT (OR, 29.8; 95% CI, 2.93%-437%; P = .007) and higher composite lung V20 (OR, 1.18; 95% CI, 1.02%-1.38%; P = .030) were associated with significantly higher likelihood of G2+ RILT. Conclusions: Our data suggest an acceptable incidence of G2+ RILT after multiple courses of lung SBRT. Female sex, synchronous SBRT, prior G2+ RILT, and higher composite lung V20 may be risk factors for G2+ RILT.

Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation.

PURPOSE: Disease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20-40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. MATERIALS/METHODS: Published CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. RESULTS: Tumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). CONCLUSIONS: A re-fitted pre-treatment model using the two most frequently published features - tumor diameter and SUVmax - successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

Clinical outcomes of stereotactic body radiation therapy for malignant pleural mesothelioma.

BACKGROUND: The objective of this study is to determine the outcomes and toxicities of patients with malignant pleural mesothelioma (MPM) treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Data were extracted from an institutional tumor registry for patients diagnosed with mesothelioma and treated with SBRT. Kaplan-Meier and Cox regression analyses were employed to determine local control (LC) and overall survival (OS). RESULTS: Forty-four patients with 59 total treated tumors from December 2006 to April 2022 were identified. Fifty-one (86.4 %) cases had oligoprogressive disease (five sites or less). The median prescription dose delivered was 3000 cGy in 5 fractions (range: 2700-6000 cGy in 3-8 fractions). Fifty-one (86.4 %) tumors were in the pleura, 4 (6.8 %) spine, 2 (3.4 %) bone, 1 (1.7 %) brain, and 1 (1.7 %) pancreas. The median follow-up from SBRT completion for those alive at last follow-up was 28 months (range: 14-52 months). The most common toxicities were fatigue (50.8 %), nausea (22.0 %), pain flare (15.3 %), esophagitis (6.8 %), dermatitis (6.8 %), and pneumonitis (5.1 %). There were no grade ≥ 3 acute or late toxicities. There were 2 (3.4 %) local failures, one of the pleura and another of the spine. One-year LC was 92.9 % (95 % CI: 74.6-98.2 %) for all lesions and 96.3 % (95 % CI: 76.5-99.5 %) for pleural tumors. One-year LC was 90.9 % (95 % CI: 68.1-97.6 %) for epithelioid tumors and 92.1 % (95 % CI: 72.1-98.0 %) for oligoprogressive tumors. One-year OS from time of SBRT completion was 36.4 % (95 % CI: 22.6-50.3 %). On multivariable analysis, KPS was the lone significant predictor for OS (p = 0.029). CONCLUSIONS: Our single-institutional experience on patients with MPM suggests that SBRT is safe with a low toxicity profile and potentially achieve good local control.

A Prospective Study on Deep Inspiration Breath Hold Thoracic Radiation Therapy Guided by Bronchoscopically Implanted Electromagnetic Transponders.

BACKGROUND: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. METHODS: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. RESULTS: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. CONCLUSIONS: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

BACKGROUND AND PURPOSE: A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. METHODS: We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. RESULTS: Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. CONCLUSION: In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial.

PURPOSE: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm. METHODS AND MATERIALS: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival. RESULTS: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004). CONCLUSIONS: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.