Cyclotron and linear accelerator generated scanning proton beams for lung cancer SBRT: Interplay effects and mitigations.

BACKGROUND: Pencil beam scanning (PBS) proton therapy for moving targets is known to be impacted by interplay effects between the scanning beam and organ motion. While respiratory motion in the thoracic region is the major cause for organ motion, interplay effects depend on the delivery characteristics of proton accelerators. PURPOSE: To evaluate the impact of different types of PBS proton accelerators and spot sizes on interplay effects, mitigations, and plan quality for Stereotactic Body Radiation Therapy (SBRT) treatment of non-small cell lung cancer (NSCLC). METHODS: Twenty NSCLC patients treated with photon SBRT were selected to represent varying tumor volumes and respiratory motion amplitudes (median: 0.6 cm with abdominal compression) for this retrospective study. For each patient, plans were created using: (1) cyclotron-generated proton beams (CPB) with spot sizes of σ = 2.7-7.0 mm; (2) linear accelerator proton beams (LPB) (σ = 2.9-5.5 mm); and (3) linear accelerator proton minibeams (LPMB) (σ = 0.9-3.9 mm). The energy switching time is one second for CPB, and 0.005 s for LPMB and LPB. Plans were robustly optimized on the gross tumor volume (GTV) using each individual phase of four-dimensional computed tomography (4DCT) scans. Initially, single-field optimization (SFO) plans were evaluated; if the plan quality did not meet the dosimetric requirement, multi-field optimization (MFO) was used. MFO plans were created for all patients for comparisons. For each patient, all plans were normalized to have the same dose received by 99% of the GTV. Interplay effects were evaluated by computing the dose on 10 breathing phases, based on the spot distribution. Volumetric repainting (VR) was performed 2-6 times for each plan. We compared volume receiving 100% of the prescribed dose (V100%RX) of the GTV, and normal lung V20Gy. RESULTS: Twelve of 20 plans can be optimized sufficiently with SFO. SFO plans were less sensitive to the interplay effect compared to MFO plans in terms of target coverage for both LPB and LPMB. The following comparisons showed results utilizing the MFO technique. In the interplay evaluation without repainting, the mean V100%RX of the GTV were 99.42 ± 0.6%, 97.52 ± 3.9%, and 94.49 ± 7.3% for CPB, LPB, and LPMB plans, respectively. Following VR (2 × for CPB; 3 × for LPB; 5 × for LPMB), V100%RX of the GTV were improved (on average) by 0.13%, 1.84%, and 4.63%, respectively, achieving the acceptance criteria of V100%RX > 95%. Because of fast energy switch in linear accelerator proton machines, the delivery time for VR plans was the lowest for LPB plans, while delivery time for LPMB was on average 1 min longer than CPB plans. The advantage of small spot machines was better sparing in normal lung V20Gy, even when VR was applied. CONCLUSION: In the absence of repainting, proton machines with large spot sizes generated more robust plans against interplay effects. The number of VR increased with decreasing spot sizes to achieve the acceptance criteria. VR improved the plan robustness against interplay effects for modalities with small spot sizes and fast energy changes, preserving the low dose sparing aspect of the LPMB, even when motion is included.

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.

ASTRO Radiation Therapy Summary of the ASCO Guideline on Management of Stage III Non-Small Cell Lung Cancer.

PURPOSE: To develop a radiation therapy summary of recommendations on the management of locally advanced non-small cell lung cancer (NSCLC) based on the Management of Stage III Non-Small Cell Lung Cancer: American Society of Clinical Oncology Guideline, which was endorsed by the American Society for Radiation Oncology (ASTRO). METHODS: The American Society of Clinical Oncology, ASTRO, and the American College of Chest Physicians convened a multidisciplinary panel to develop a guideline based on a systematic review of the literature and a formal consensus process, that has been separately published. A new panel consisting of radiation oncologists from the original guideline as well as additional ASTRO members was formed to provide further guidance to the radiation oncology community. A total of 127 articles met the eligibility criteria to answer 5 clinical questions. This summary focuses on the 3 radiation therapy questions (neoadjuvant, adjuvant, and unresectable settings). RESULTS: Radiation-specific recommendations are summarized with additional relevant commentary on specific questions regarding the management of preoperative radiation, postoperative radiation, and combined chemoradiation. CONCLUSIONS: Patients with stage III NSCLC who are planned for surgical resection, should receive either neoadjuvant chemotherapy or chemoradiation. The addition of neoadjuvant treatment is particularly important in patients planned for surgery in the N2 or superior sulcus settings. Postoperatively, patients who did not receive neoadjuvant chemotherapy should be offered adjuvant chemotherapy. The use of postoperative radiation for completely resected N2 disease is not routinely recommended. Unresectable patients with stage III NSCLC should ideally be managed with combined concurrent chemoradiation using a platinum-based doublet with a standard radiation dose of 60 Gy followed by consolidation durvalumab in patients without progression after initial therapy. Patients who cannot tolerate a concurrent chemoradiation approach can be managed either by sequential chemotherapy followed by radiation or by dose-escalated or hypofractionated radiation alone.

Stereotactic Body Radiation Therapy for Sarcoma Pulmonary Metastases.

BACKGROUND: Lung metastases are the most common form of distant failure for patients diagnosed with sarcoma with metastasectomy considered for some patients with limited metastatic disease and good performance status. Alternatives to surgery such as stereotactic body radiation therapy (SBRT) can be considered, though data are limited. We present outcomes after SBRT for sarcoma lung metastases. METHODS: Fifty sarcoma patients with 109 lung metastases were treated with SBRT between 2005 and 2021. Outcomes evaluated included local control (LC), overall survival (OS), and toxicity including lung pneumonitis/fibrosis, chest wall toxicity, dermatitis, brachial plexus, and esophageal toxicity. Systemic therapy receipt before and after SBRT was recorded. RESULTS: SBRT schedules were divided into 3 cohorts: 30 to 34 Gy/1fx (n=10 [20%]), 48 to 50 Gy/4 to 5fx (n=24[48%]), and 60 Gy/5fx (n=16[32%]). With a median follow-up of 19.5 months, 1/3-year LC rates were 96%/88% and 1/3-year OS 77%/50%, respectively. There was no differences between the 3 regimens in terms of LC, OS, or toxicity. Size >4 cm was a predictor of worse LC ( P =0.031) and worse OS ( P = 0.039) on univariate analysis. The primary pattern of failure was new metastases (64%) of which the majority were in the contralateral lung (52%). One-year chemotherapy-free survival was 85%. Overall, 76% of patients did not require chemotherapy initiation or change of chemotherapy regimen after lung SBRT. Toxicity was reported in 16% of patients overall, including 25%, 20%, and 14% in the 30 to 34 Gy/1fx, 48 to 50 Gy/4 to 5fx, and 60 Gy/5fx cohorts, respectively. CONCLUSIONS: SBRT outcomes for lung metastases from sarcoma demonstrate high rates of LC and are similar with different dose/fractionation regimens. Lung SBRT is associated with prolonged chemotherapy-free survival. Prospective validation of these results is warranted.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience.

PURPOSE: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. METHODS AND MATERIALS: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. RESULTS: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. CONCLUSIONS: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC.

Introduction: Evidence supports the addition of immunotherapy to definitive chemoradiation for unresectable stage IIIA NSCLC. Adding pembrolizumab to neoadjuvant chemoradiation in patients with resectable stage IIIA NSCLC requires study for safety and feasibility. Methods: Patients with resectable stage IIIA NSCLC received neoadjuvant cisplatin, etoposide, and pembrolizumab concurrently with thoracic radiotherapy of 45 Gy in 25 fractions. Patients without progression underwent resection followed by 6 months of consolidation pembrolizumab. Safety and feasibility were defined as less than or equal to 30% grade 3 or higher pulmonary toxicity or any grade 4 or 5 nonhematologic toxicity. A total of 10 patients were to be enrolled initially. If less than or equal to two patients had events, another 10 were to be enrolled. Results: The study closed after enrolling nine patients. The median age was 66 (range: 49-76) years. A total of 67% were female. Median follow-up was 38.3 months. Serious adverse events occurred in seven patients, including two grade 5 events: one sudden cardiac arrest in the neoadjuvant phase and one fatal pneumocystis pneumonia after resection. Eight patients were assessable for response. The overall response rate was 67%. Six underwent complete resection. Four achieved pathologic complete response, whereas one additional patient had complete nodal clearance. Median progression-free survival has not been reached. The 3-year overall survival was 64%. Conclusions: Adding pembrolizumab to neoadjuvant concurrent cisplatin, etoposide, and radiotherapy in resectable stage IIIA NSCLC resulted in an encouraging pathologic complete response rate. Higher-than-expected toxicities necessitated trial closure after meeting the rule for infeasibility. The relationship of grade 5 events to the addition of pembrolizumab is unclear.

Practical considerations of single-fraction stereotactic ablative radiotherapy to the lung.

Stereotactic ablative radiotherapy (SABR) is a well-established treatment for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC) and pulmonary oligometastases. The use of single-fraction SABR in this setting is supported by excellent local control and safety profiles which appear equivalent to multi-fraction SABR based on the available data. The resource efficiency and reduction in hospital outpatient visits associated with single-fraction SABR have been particularly advantageous during the COVID-19 pandemic. Despite the increased interest, single-fraction SABR in subgroups of patients remains controversial, including those with centrally located tumours, synchronous targets, proximity to dose-limiting organs at risk, and concomitant severe respiratory illness. This review provides an overview of the published randomised evidence evaluating single-fraction SABR in primary lung cancer and pulmonary oligometastases, the common clinical challenges faced, immunogenic effect of SABR, as well as technical and cost-utility considerations.

Local Control With Single-Fraction Lung Stereotactic Body Radiotherapy is not influenced by Non-Small Cell Lung Cancer Histologic Subtype.

INTRODUCTION/BACKGROUND: For early stage medically inoperable lung cancer treated with fractionated stereotactic body radiotherapy (SBRT), higher local failure is associated with squamous carcinoma (SqC) compared to adenocarcinoma (AC). This study explored whether histology influences single-fraction SBRT local control. MATERIALS AND METHODS: We surveyed our prospective data registry from 12/2009 to 12/2019 for SF-SBRT cases with biopsy-proven AC or SqC only. Outcomes of interest included local (LF), nodal (NF), distant (DF) failure rates and overall survival (OS), as well as treatment-related toxicity. RESULTS: For the 10-year interval surveyed, 113 patients met study criteria. There was no association between histology and dose received (34 Gy or 30 Gy). Median follow up was 22.9 months. Patient characteristics were balanced between histologic cohorts. Median tumor size was 1.9 cm. Comparing total AC vs. SqC cohorts, 2-year LF rates (%) were 7.3 vs. 9.6, respectively (P = .9805). In %, 2-year LF, NF, DF and OS rates for AC for 30 Gy and 34 Gy, respectively, were 10.8 vs. 6.4; 10.5 vs. 16.2; 15.8 vs. 13.0; 77.9 vs.71.2 (all P = non-significant). In %, 2-year LF, NF, DF, and OS rates for SqC for 30 Gy and 34 Gy, respectively, were 11.8 vs. 8.1; 5.9 vs. 18.0; 23.5 vs. 9.7; 70.6 vs. 77.1 (all P = non-significant). When considering toxicities, there were no grade 4/5 toxicities and no significant differences in any other toxicity rate by histology or dose. CONCLUSION: SF-SBRT local control was not associated with histology, unlike fractionated schedules. This novel finding adds to the evolving understanding of this treatment schedule.

Is adaptive planning necessary for patients with large tumor position displacements observed on daily image guidance during lung SBRT?

For patients undergoing stereotactic body radiation therapy for lung cancer, their tumor positions may vary due to anatomical changes. This study is to investigate whether adaptive re-planning is necessary for patients with large tumor position displacements observed from daily kV-cone-beam computed tomography (kV-CBCT). We selected 16 fractions from 16 patients with recorded treatment couch shifts greater than 1.5 cm under kV-CBCT guidance. The treatment positions for these patients were manually restored in kV-CBCTs via bone-to-bone alignments (B2B) and tumor-to-tumor alignments (T2T) with corresponding planning CTs. The tumor volumes, including PTVs, ITVs, and GTVs, were transferred from the planning CTs to these kV-CBCTs. With the planned beam configurations and treatment isocenters, kV-CBCTs were imported into the treatment planning system for dose recalculations. To minimize uncertainties of the Hounsfield Unit (HU) in kV-CBCTs, uniformed HU values were assigned to the externals, ITVs, and lungs. The percentage volumes of GTVs, ITVs, and PTVs receiving the prescription dose (VRx) and the dose to the normal structures were analyzed. Seven out of the 16 patients were identified with >5mm tumor position displacements after subtracting the recorded couch shifts from the shifts of B2B alignment. For T2T alignments, 9 out of 16 (56.3%) patients had VRx of PTV <95% (the planning goal) with 91.4% as the lowest, while VRx of the GTV and ITV remained 100% for all 16 patients. For B2B alignments, 14 out of 16 (87.5%) patients have VRx of PTV <95%; 5 patients (31.3%) had VRx of ITV <95%; and 4 patients (25.0%) had VRx of GTV <99%. T2T alignment with 5 mm PTV margin was found superior to B2B alignment, resulting in adequate dose coverage to the ITVs, even for tumors with large positional changes. Adaptive re-planning may not be necessary under these scenarios.

Systematic Review of Single-Fraction Stereotactic Body Radiation Therapy for Early Stage Non-Small-Cell Lung Cancer and Lung Oligometastases: How to Stop Worrying and Love One and Done.

Adoption of single-fraction lung stereotactic body radiation therapy (SBRT) for patients with medically inoperable early stage non-small-cell lung cancer (NSCLC) or oligometastatic lung disease, even during the coronavirus disease 2019 (COVID-19) pandemic, was limited despite encouraging phase II trial results. Barriers to using single-fraction SBRT may include lack of familiarity with the regimen and lack of clarity about the expected toxicity. To address these concerns, we performed a systematic review of prospective literature on single-fraction SBRT for definitive treatment of early stage and oligometastatic lung cancer. A PubMed search of prospective studies in English on single-fraction lung SBRT was conducted. A systematic review was performed of the studies that reported clinical outcomes of single-fraction SBRT in the treatment of early stage non-small-cell lung cancer and lung oligometastases. The current prospective literature including nine trials supports the use of single-fraction SBRT in the definitive treatment of early stage peripheral NSCLC and lung oligometastases. Most studies cite local control rates of >90%, mild toxicity profiles, and favorable survival outcomes. Most toxicities reported were grade 1-2, with grade ≥3 toxicity in 0-17% of patients. Prospective trial results suggest potential consideration of utilizing single-fraction SBRT beyond the COVID-19 pandemic.

Evaluation of Automated Treatment Planning and Organ Dose Prediction for Lung Stereotactic Body Radiotherapy.

PURPOSES: To evaluate whether the auto-planning (AP) module can achieve clinically acceptable treatment plans for lung stereotactic body radiotherapy (SBRT) and to evaluate the effectiveness of a dose prediction model. METHODS: Twenty lung SBRT cases planned manually with 50 Gy in five fractions were replanned using the Pinnacle (Philips Radiation Oncology Systems, Fitchburg, WI) AP module according to the dose constraint tables from the Radiation Therapy Oncology Group (RTOG) 0813 protocol. Doses to the organs at risk (OAR) were compared between the manual and AP plans. Using a dose prediction model from a commercial product, PlanIQ (Sun Nuclear Corporation, Melbourne, FL), we also compared OAR doses from AP plans with predicted doses. RESULTS: All manual and AP plans achieved clinically required dose coverage to the target volumes. The AP plans achieved equal or better OAR sparing when compared to the manual plans, most noticeable in the maximum doses of the spinal cord, ipsilateral brachial plexus, esophagus, and trachea. Predicted doses to the heart, esophagus, and trachea were highly correlated with the doses of these OARs from the AP plans with the highest correlation coefficient of 0.911, 0.823, and 0.803, respectively. CONCLUSION: Auto-planning for lung SBRT improved OAR sparing while keeping the same dose coverage to the tumor. The dose prediction model can provide useful planning dose guidance.

A Principal Component of Quality-of-Life Measures Is Associated with Survival: Validation in a Prospective Cohort of Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy.

The association between HRQOL metrics and survival has not been studied in early stage non-small-cell lung cancer (NSCLC) patients undergoing SBRT. The cohort was derived via a post-hoc analysis of a prospective randomized clinical trial examining definitive SBRT for peripheral, early-stage NSCLC with a single or multi-fraction regimen. Patients completed HRQOL questionnaires prior to and 3 months after treatment. Using principal component analysis (PCA), changes in each HRQOL scale following treatment were reduced to two eigenvectors, PC1 and PC2. Cox regression was employed to analyze associations with survival-based endpoints. A total of 70 patients (median age 75.6 years; median follow-up 41.1 months) were studied. HRQOL and symptom comparisons at baseline and 3 months were vastly unchanged except for improved coughing (p = 0.02) and pain in the chest at 3 months (p = 0.033). PC1 and PC2 explained 21% and 9% of variance, respectively. When adjusting for covariates, PC1 was significantly correlated with progression-free (PFS) (HR = 0.78, 95% CI 0.67-0.92, p = 0.003) and overall survival (OS) (HR = 0.76, 95% CI 0.46, p = 0.041). Changes in global health status, functional HRQOL performance, and/or symptom burden as described by PC1 values are significantly associated with PFS and OS. The PC1 quartile may facilitate the identification of at-risk patients for additional interventions.

Approach to Oligometastatic Cancer in the Elderly Patient.

PURPOSE OF REVIEW: Patients with advanced cancer who have "oligometastatic" disease (OMD) have a limited burden of metastatic sites such that they may benefit from definitive therapies with limited toxicities. The incidence of cancers diagnosed in the elderly is increasing and treatment choices for them are often made because of their vulnerability to side effects. The present review discusses treatment of the elderly with OMD considering cancer outcomes and treatment toxicity. RECENT FINDINGS: Stereotactic body radiation therapy (SBRT) is emerging as a standard in the management of OMD because of its excellent local control and minimal toxicity. Phase II trials suggest that SBRT added to palliative therapy may improve overall survival and may delay the initiation of systemic therapy in OMD patients. Elderly patients are well represented in OMD studies SBRT will contribute significantly to the management of OMD in the elderly patient population by optimizing cancer control and limiting side effects.

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. OBJECTIVE: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS: Chemoradiation and consolidation chemotherapy with or without metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02186847.

Ten-Year Experience in Implementing Single-Fraction Lung SBRT for Medically Inoperable Early-Stage Lung Cancer.

PURPOSE: To review 10 years of using single-fraction lung stereotactic body radiation therapy (SF-SBRT) for medically inoperable peripheral early-stage lung cancer. METHODS AND MATERIALS: An institutional review board-approved prospective lung SBRT data registry was surveyed until the end of December 2019 for all patients receiving SF-SBRT with minimum 6-month follow-up. Doses used were either 34 Gy or 30 Gy. Outcomes of interest included rates of local failure and overall survival (OS), as well as treatment-related toxicity graded per Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 229 patients met the study criteria. Patient characteristics included female sex (55%); median age, 74.6 years (range, 47-94); and median Karnofsky Performance Status 80 (range, 50-100). Tumor characteristics included median diameter, 1.6 cm (range, 0.7-4.1); median positron emission tomography standardized uptake value maximum 6.1 (range, 0.8-24.3); and 63.6% of patients biopsied. SF-SBRT dose was 34 Gy in 72.1% cases and 30 Gy in 27.9%, with patient and tumor characteristics balanced between cohorts. Overall median follow-up times for 30 Gy and 34 Gy were 36.7 and 17.2 months, respectively (P < .0001). At analysis, 55.9% patients were alive. Two (0.9%) patients developed grade 3 toxicities, and none had grade 4/5 toxicities. Grades 1 to 2 pneumonitis and chest wall toxicity were seen in 7% and 12.7% patients, respectively. Median overall survival was 44.1 months. Rates of 2-year local, nodal, and distant failure were 7.3%, 9.4%, and 12.2%, respectively. There were no significant differences in outcomes by dose. CONCLUSIONS: This is the largest institutional series to date reporting on SF-SBRT outcomes for medically inoperable peripheral early-stage lung cancer and the first to report on a decade's experience in implementing this schedule. Outcomes from this analysis are comparable to published results from 2 randomized trials and validate the use of this schedule in routine practice. In the absence of phase 3 trials, this study should encourage increased use of SF-SBRT for inoperable tumors.

An International Expert Survey on the Indications and Practice of Radical Thoracic Reirradiation for Non-Small Cell Lung Cancer.

PURPOSE: Thoracic reirradiation for non-small cell lung cancer with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating non-small cell lung cancer with radiation therapy in the setting of prior thoracic irradiation. METHODS AND MATERIALS: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined during 4 rounds on the definition of reirradiation, selection of appropriate patients, pretreatment assessments, planning of radiation therapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents' comments and re-presented in subsequent rounds. RESULTS: Fifteen radiation oncologists participated in the 4 surveys between September 2019 and March 2020. The first 3 rounds had a 100% response rate, and the final round was completed by 93% of participants. Thirty-three out of 77 statements across all rounds achieved consensus. Key recommendations are as follows: (1) appropriate patients should have a good performance status and can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude reirradiation; (2) a full diagnostic workup should be performed in patients with suspected local recurrence and; (3) any reirradiation should be delivered using optimal image guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. CONCLUSIONS: These consensus statements provide practical guidance on appropriate patient selection for reirradiation, appropriate radiation therapy techniques, and cumulative dose constraints.

Salvage Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Primary Surgical Resection of Non-small-cell Lung Cancer.

INTRODUCTION: We sought to evaluate the safety and efficacy of stereotactic body radiation therapy (SBRT) as salvage treatment for local recurrence after prior surgical resection for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We surveyed our prospective lung SBRT registry for patients who received salvage SBRT (sSBRT) for local recurrence after previous resection of a primary NSCLC. Following sSBRT, local control, distant metastases, overall survival, and treatment-related toxicity were evaluated. RESULTS: From 2004 to 2017, 48 patients met inclusion criteria. At initial surgery, 44 (83%) patients had stage I to II disease, and surgical approaches were 47.9% wedge resection, 4.2% segmentectomy, 43.8% lobectomy, and 4.2% bilobectomy. The median time to local recurrence after surgery was 26.4 months, and 36 (75%) recurrences were biopsy-proven. Surgical salvage was not possible owing to un-resectability or underlying comorbidities in 45 (93.8%) patients. Most (68.8%) patients received 50 Gy in 5 fractions. The median follow-up after sSBRT was 22.6 months (range, 3.8-108.8 months). Eight (16.7%) patients experienced local or lobar failure, and 9 (19.1%) patients had nodal failure at a median of 12.5 months (range, 2-66.1 months). Nineteen (39.6%) patients failed distantly at a median of 11.4 months. The median overall survival after sSBRT was 29.3 months. A total of 72.9% of patients experienced no toxicity after sSBRT. Three (6.3%) patients developed grade III toxicity (cough, atelectasis, or soft tissue necrosis) following sSBRT. CONCLUSIONS: Similar to SBRT for primary early stage NSCLC, sSBRT for local relapse following surgical resection of NSCLC offers high rates of local control with limited toxicity. Distant failure remains the primary pattern of failure.

Does Motion Management Technique for Lung SBRT Influence Local Control? A Single Institutional Experience Comparing Abdominal Compression to Breath-Hold Technique.

PURPOSE: Abdominal compression (COMP) and breath-hold with an active breathing coordinator (ABC) device are 2 different respiratory motion management techniques used in lung stereotactic body radiation therapy (SBRT) practice. We compared local failure (LF) results for COMP versus ABC. METHODS AND MATERIALS: We surveyed our institutional review board-approved prospective registry for patients who were treated with SBRT for either a primary lung cancer (PRIME) or an oligometastatic (OLIGO) diagnosis with a minimum of 6 months' follow-up to determine their rates of local failure by motion management modality. RESULTS: From October 2003 to July 2014, 873 patients with 931 lesions were treated. Patient characteristics included: 455 (52.1%) female; median age of 73 years (range, 37-97); median Karnofsky performance status (KPS) of 80 (range, 40-100); and median BMI of 26.2 (range, 12.1-56.3). Tumor characteristics included: median tumor size of 2.2 cm (range, 0.7-10.0); median maximum standardized uptake value from positron emission tomography PET SUVmax of 7.5 (range, 0.8-59); 234 (25.4%) were central lesions; 830 (89.2%) lesions were PRIME; and 101 (10.8%) were OLIGO. Median follow-up and SBRT dose were 16.4 months and 50 G in 5 fractions, respectively. Overall crude rate of LF was 9.9%. Use of ABC was not associated with increased LF compared with COMP: hazard ratio (HR) = 1.043 (95% CI 0.48-2.29; P = .92). Three-year actuarial rates of LF for ABC versus COMP were 13.8% and 16.5%, respectively. After stratifying by OLIGO/PRIME, neither ABC nor COMP was significantly associated with LF. Central location may be associated with LF with ABC (HR = 2.087, P = .066). On univariate analysis, BMI, tumor size, PET SUV max and central location were associated with failure, with size the most significant. CONCLUSIONS: LF rates after lung SBRT were not influenced by form of motion control overall or when stratified by tumor type. Further study on LF rates for central tumors where ABC is used is warranted.