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Purpose: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer., Methods: EXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures., Results: From September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34-2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration., Conclusion: Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms., Competing Interests: Declaration of competing interest Mr Fellman reported receiving grants from the National Institutes of Health (NIH) to The University of Texas MD Anderson Cancer Center during the conduct of the study. Dr Haymaker reported receiving grants from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, and TriSalus Life Sciences; receiving personal fees from Nanobiotix; receiving speaker honoraria from the Southwest Oncology Group and the Society for Immunotherapy of Cancer; and receiving stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Dr Smith reported receiving salary support from Varian Medical Systems for a strategic alliance between MD Anderson Cancer Center and Varian Medical Systems outside the submitted work and royalty and equity interest in Oncora Medical. Dr Shaitelman reported funding from the Emerson Collective Foundation and contracted research agreements with Alpha Tau, Exact Sciences, TAE Life Sciences, and Artios Pharmaceuticals, outside the submitted work. Dr. Chun declares in the past 36 months support from grants or contracts from NIH R50 CA275822 and MD Anderson; consulting fees from Curio Science, Norton Healthcare, and AstraZeneca; honoraria from Binaytara Foundation, Curio Science, Henry Ford Health Systems, Japanese Society for Radiation Oncology and Hong Kong Precision Oncology society; and support for attending meetings and/or travel from ViewRay, American Board of Radiology, Binaytara Foundation, Japanese Society for Radiation Oncology, and AstraZeneca outside the submitted work. Dr Reuben reported receiving consulting fees and honoraria from Adaptive Biotechnologies outside the submitted work. Dr Ghia reported receiving consulting fees and honoraria from Brainlab outside the submitted work. Dr. Woodward reported personal fees from Exact Sciences and Epic Sciences, outside the submitted work. Dr Gomez reported receiving grants from AstraZeneca, Merck, Varian, and Bristol Myers Squibb and receiving consulting fees and honoraria from Grail, AstraZeneca, Olympus, Johnson & Johnson, Varian, Medtronic, and Med Learning Group outside the submitted work. Dr Tang reported receiving grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar during the conduct of the study and receiving royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series outside the submitted work. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Inc.)

Background/objectives: This retrospective study evaluates outcomes of 66 patients who underwent reirradiation (re-RT) with proton beam therapy (PBT) for recurrent non-small cell lung cancer., Methods: Toxicity was scored via the CTCAE v5.0, and outcomes estimated using the Kaplan-Meier method, with associations evaluated via Cox proportional hazards and logistic regression analyses., Results: Patients were treated to a median re-RT prescription of 66 Gy/33 fxs (BED10 = 79 Gy; IQR: 71-84 Gy) at an interval of 1.4 years from prior RT. Half (50%) received concurrent chemotherapy. At 14 months follow-up, the median OS and PFS were 5 months (95%CI: 13-17) and 12.5 months (95%CI: 10-15), respectively. On multivariable analysis, a higher RT dose (BED10 > 70 Gy) [HR0.37; 95%CI: 0.20-0.68, p = 0.001] and concurrent chemotherapy (HR0.48; 95%CI: 0.28-0.81, p = 0.007) were associated with improved PFS, while treatment site overlap was adversely associated (HR1.78; 95%CI: 1.05-3.02, p = 0.031). The median PFS for definitive RT with concurrent chemotherapy ( n = 28), definitive RT alone (BED10 > 70 Gy) [ n = 22], and lower prescription RT (BED10 < 70 Gy) [ n = 16] was 15.5 months (95%CI: 7.3-23.7), 14.1 months (95%CI: 10.9-17.3), and 3.3 months (95%CI: 0-12.3), respectively (log-rank, p = 0.006), with corresponding 2-year estimates of 37% (±9), 18% (±8), and 12.5% (±8), respectively. The incidence of Grade 3+ toxicity was 10.5% (6% pulmonary; 3% esophageal; and 1.5% skin), including one Grade 4 bronchopulmonary hemorrhage but no Grade 5 events. Cases with central site overlap had higher composite Dmax to the esophagus (median 87 Gy [IQR:77-90]), great vessels (median 120 Gy [IQR:110-138]), and proximal bronchial tree (median 120 Gy [IQR:110-138]) as compared to other cases ( p ≤ 0.001 for all). However, no significant associations were identified with Grade 3+ events., Conclusions: Thoracic re-RT with PBT is an option for recurrent NSCLC with acceptable outcomes and toxicity for select patients. When feasible, higher prescription doses (BED10 > 70 Gy) should be delivered for definitive intent, and concurrent chemotherapy may benefit individual cases.

Introduction: Accelerated hypofractionated radiotherapy has gained increasing interest for locally advanced NSCLC, as it can potentially increase radiobiologically effective dose and reduce health care resource utilization. Nevertheless, there is sparse prospective evidence supporting routine use of accelerated hypofractionation with or without concurrent chemotherapy. For this reason, the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally advanced NSCLC., Methods: A systematic search was conducted on Ovid MEDLINE, Ovid EMBASE, Wiley Cochrane Library, and ClinicalTrials.gov for English publications from 2010 to 2024 for prospective clinical trials and registries investigating accelerated hypofractionated radiotherapy defined as more than 2 Gy delivered in 10 to 25 fractions for nonmetastatic locally advanced (stage III) NSCLC., Results: There were 33 prospective studies identified that met the criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were six prospective registries, seven phase 1 to 2 trials, and one phase 3 randomized clinical trial, with a median dose of 60 Gy delivered in a median of 16 fractions, median progression-free survival of 6.4 to 25 months, median survival of 6 to 34 months, and 0% to 8% severe grade ≥3 esophagitis. There were 19 studies evaluating accelerated hypofractionated chemoradiation with platinum doublet-based chemotherapy as the most common concurrent regimen. Of these accelerated hypofractionated chemoradiation studies, there were 18 phase 1 to 2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median progression-free survival of 10 to 25 months, median survival of 13 to 38 months, grade ≥3 esophagitis of 0% to 23.5%, and grade ≥3 pneumonitis of 0% to 11.8%., Conclusions: Despite the increasing use of accelerated hypofractionation for locally advanced NSCLC, the supporting randomized evidence remains sparse. Only one randomized clinical trial comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not reveal the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy should be approached with caution, using advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should be carefully considered alongside other multidisciplinary options and be further investigated through prospective clinical trials., Competing Interests: Disclosure Dr. Chun is supported by grant R50CA275822 from the National Institutes of Health (content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health) and reports having financial relationships with AstraZeneca, Curio Science, Nektar Therapeutics, Elsevier, and the Binaytara Foundation. Dr. Bang reports receiving grant support from BC Cancer Foundation and having financial relationships with AstraZeneca and the International Association for the Study of Lung Cancer. Dr. Przybysz reports receiving grant funding from AstraZeneca and Astellas and having financial relationships with AstraZeneca, Astellas, UpToDate, and Guidepoint. Dr. Faivre-Finn reports receiving grant support from AstraZeneca, Merck, and Elekta. Dr. Badiyan reports receiving grant funding from AstraZeneca and having financial relationships with the RTOG Foundation, Elekta, and Reflexion. Dr. Bezjak reports having financial relationships with AstraZeneca and the Canadian Radiation Oncology Foundation. Dr. McDonald reports having financial relationships with AstraZeneca. Dr. Chua reports receiving grant support from the National Medical Research Council of Singapore and having financial relationships with Varian Medical Systems, AstraZeneca, Regeneron, Roche, Seagen, Merck Sharp & Dohme, and Takeda. Dr. Kong reports receiving grant support from Varian Medical and the Shenzhen Science and Technology Program and having financial relationships with AstraZeneca and Merck. Dr. Putora reports receiving grants from AstraZeneca, Takeda, and Bayer. Dr. Siva reports receiving grant support from the Cancer Council Victoria, Varian, Bayer, and Merck and having financial relationships with AstraZeneca, Roche, and Telix. Dr. Welliver reports receiving grant support from the United States Department of Defense and having financial relationships with Onclive and Eli Lilly. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The multidisciplinary American Radium Society Thoracic Committee was assigned to create appropriate use criteria on cardiac toxicity prevention and management for patients undergoing radiotherapy., Methods: A systematic review of the current literature was conducted. Case variants of patients with thoracic malignancies undergoing radiation were created based on presence or absence of cardiovascular risk factors and treatment-related risks assessed by dose exposure to the heart and cardiac substructures. Modified Delphi methodology was used to evaluate the variants and procedures, with less than or equal to three rating points from median defining agreement/consensus., Results: A total of six variants were evaluated. The panel felt that patients with cardiac comorbidities at high risk for radiation-related cardiac toxicity should undergo a prescreening cardiac-focused history and physical (H&P) examination, electrocardiogram, cardiac imaging including an echocardiogram, and referral to a cardiologist/cardio-oncologist. Recommendations for those without cardiac comorbidities at low risk for cardiac toxicity were to undergo a baseline H&P examination only. Conversely, those without cardiac comorbidities but at high risk for radiation-related cardiac toxicity were recommended to undergo a prescreening electrocardiogram, in addition to a H&P examination. For patients with cardiac comorbidities at low risk for cardiac toxicity, the panel felt that prescreening and postscreening tests may be appropriate., Conclusions: The American Radium Society Thoracic appropriate use criteria panel has developed multidisciplinary consensus guidelines for cardiac toxicity prevention, surveillance, and management after thoracic radiotherapy based on cardiac comorbidities at presentation and risk of radiation-related cardiac toxicity., Competing Interests: Disclosure All panelists were required to declare all conflicts of interest for the previous 36 months before initiating work on this document. These complete disclosure forms are retained by the American Radium Society in perpetuity. The American Radium Society Appropriate Use Criteria Steering Committee reviewed these disclosures with the chair and co-chair of this document and approved participation of the panelists before starting development of this work., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Definitive radiation therapy is considered standard therapy for medically inoperable early-stage NSCLC. Nevertheless, for patients with tumors located near structures such as the proximal tracheobronchial tree, esophagus, heart, spinal cord, and brachial plexus, the optimal management regimen is controversial. The objective was to develop expert multidisciplinary consensus guidelines on managing medically inoperable NSCLC located in a central or ultracentral location relative to critical organs at risk., Methods: Case variants regarding centrally and ultracentrally located lung tumors were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel. A comprehensive review of the English medical literature was performed from January 1 1946 to December 31 2023 to inform consensus guidelines. Modified Delphi methods were used by the panel to evaluate the variants and procedures, with at least three rating points from median defining agreement/consensus. The guideline was then approved by the ARS Executive Committee and released for public comment per established ARS procedures., Results: The Thoracic ARS AUC Panel identified 90 relevant references and obtained consensus in all variants. Radiotherapy alone was considered appropriate, with additional immunotherapy to be considered primarily in the clinical trial setting. Hypofractionated radiotherapy in eight to 18 fractions was considered appropriate for ultracentral lesions near the proximal tracheobronchial tree, upper trachea, and esophagus. For other ultracentral lesions near the heart, great vessels, brachial plexus, and spine, or for non-ultracentral but still central lesions, five-fraction stereotactic body radiation therapy was also considered an appropriate option. Intensity-modulated radiotherapy was considered appropriate and three-dimensional-conformal radiotherapy inappropriate for all variants. Other treatment planning techniques to decrease the risk of overdosing critical organs at risk were also considered., Conclusions: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of stage I NSCLC in a central or ultracentral location., Competing Interests: Disclosure Dr. Park reported personal fees AstraZeneca, Bristol-Myers Squibb, Daichii Sankyo, G1 Therapeutics, Galera Medical, RefleXion Medical, Regeneron, and research funding from Merck Sharp & Dohme. Dr. Rimner reported grants from Varian Medical Systems, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, and National Institutes of Health and personal fees from AstraZeneca, Merck, and MoreHealth. Dr. Chang reported grants from Bristol Myers Squibb and personal fees from Varian Medical Systems and IBA. Dr. Chun reported personal fees from AstraZeneca, Norton Healthcare, Binaytara Foundation, ViewRay, Japanese Society for Radiation Oncology, Hong Kong Precision Oncology Society, and Curio Science. Dr. Donington reported personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, and Roche/Genentech. Dr. Edelman reported personal fees from AstraZeneca, Takeda, Glaxo Smith Kline, Omega Therapeutics, Novocure, InterVenn, WindMil, Seattle Genetics, Regeneron/Sanofi, Flame Consulting, Proventus Consulting, GE Healthcare Consulting, BioAlta Consulting, Replimmune Consulting, Coherus Consulting, and AnHeart. Dr. Gubens reported personal fees from AnHeart, AstraZeneca, Atreca, Bristol-Myers Squibb, Cardinal Health, Genzyme, Genentech/Roche, Gilead, Guardant, Invitae, iTeos, Merus, Sanofi, Summit, and Surface and grants from Amgen, JNJ, Merck, OncoMed, and Trizell. Dr. Higgins reported grants from Jazz Pharmaceuticals and other support from AstraZeneca, Janssen Pharmaceuticals, and RefleXion Medical. Dr. Iyengar reported other support from Incyte and AstraZeneca. Dr. Movsas reported grants from Varian Research, Philips Research, and ViewRay Research. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important., Objective: To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC., Design, Setting, and Participants: A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification., Main Outcomes and Measures: Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose)., Results: Of 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up., Conclusions and Relevance: These findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy., Trial Registration: ClinicalTrials.gov Identifier: NCT00533949.

Importance: The treatment of locally advanced non-small cell lung cancer (LA-NSCLC) has been informed by more than 5 decades of clinical trials and other relevant literature. However, controversies remain regarding the application of various radiation and systemic therapies in commonly encountered clinical scenarios., Objective: To develop case-referenced consensus and evidence-based guidelines to inform clinical practice in unresectable LA-NSCLC., Evidence Review: The American Radium Society (ARS) Appropriate Use Criteria (AUC) Thoracic Committee guideline is an evidence-based consensus document assessing various clinical scenarios associated with LA-NSCLC. A systematic review of the literature with evidence ratings was conducted to inform the appropriateness of treatment recommendations by the ARS AUC Thoracic Committee for the management of unresectable LA-NSCLC., Findings: Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement. Committee recommendations were vetted by the ARS AUC Executive Committee and a 2-week public comment period before official approval and adoption. Standard of care management of good prognosis LA-NSCLC consists of combined concurrent radical (60-70 Gy) platinum-based chemoradiation followed by consolidation durvalumab immunotherapy (for patients without progression). Planning and delivery of locally advanced lung cancer radiotherapy usually should be performed using intensity-modulated radiotherapy techniques. A variety of palliative and radical fractionation schedules are available to treat patients with poor performance and/or pulmonary status. The salvage therapy for a local recurrence after successful primary management is complex and likely requires both multidisciplinary input and shared decision-making with the patient., Conclusions and Relevance: Evidence-based guidance on the management of various unresectable LA-NSCLC scenarios is provided by the ARS AUC to optimize multidisciplinary patient care for this challenging patient population.

Background/aim: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC., Patients and Methods: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure (LF), progression-free survival (PFS), overall survival (OS), and Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicities., Results: There were 14 patients randomized to the metformin arm and one to the placebo. Median follow-up was four years. In the metformin group, the median PFS was 4.65 years [95% confidence interval (CI)=0.31-5.93] and median survival was 4.97 years (95%CI=3.05-4.61). Five year PFS was 27.8% (95%CI=5.3-57.3%) and OS was 46.0% (95%CI=16.0-71.9%). The one patient randomized to placebo was alive and without progression at five years. There were no LFs in the primary SBRT treatment volumes and no CTCAE version 4 Grade ≥3 adverse events., Conclusion: Outcomes of SBRT and metformin for early-stage NSCLC were similar to historic controls. These findings along with the results of the NRG-LU001 and OCOG randomized trials do not support the therapeutic use of metformin for NSCLC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Stereotactic radiation therapy yields high rates of local control for brain metastases, but patients in rural or suburban areas face geographic and socioeconomic barriers to its access. We conducted a phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases in an integrated academic satellite network for patients 18 years of age or older with 4 or fewer brain metastases. Dose was based on gross tumor volume: less than 3.0 cm, 27 Gy in 3 fractions and 3.0 to 3.9 cm, 30 Gy in 5 fractions. Median follow-up was 10 months for 73 evaluable patients, with a median age of 68 years. Median intracranial progression-free survival was 7.1 months (95% confidence interval = 5.3 to not reached), and median survival was 7.2 months (95% confidence interval = 5.4 to not reached); there were no serious adverse events. Outcomes of this trial compare favorably with contemporary trials, and this treatment strategy provides opportunities to expand stereotactic radiation therapy access to underserved populations., (© The Author(s) 2023. Published by Oxford University Press.)

Macadamia felted coccid (MFC), Acanthococcus ironsidei (Williams) (Hemiptera: Eriococcidae), was first discovered in 2005 on the Island of Hawaii. Host plants are restricted to Macadamia species, with Macadamia integrifolia Maiden & Betche (Proteaceae) being grown in Hawaii for nut production. Approximately 6839 hectares macadamia nuts are harvested in Hawaii with an estimated farm value of USD 48.8 million (2019-2020 records). Exploration in Australia started in November 2013 for the evaluation of potential parasitoids being host specific for introduction into Hawaii. A dominant solitary endoparasitoid of MFC from New South Wales was discovered and described as Metaphycus macadamiae Polaszek & Noyes sp. n (Hymenoptera: Encyrtidae: Encyrtinae). Biology and host specificity testing were conducted at the Hawaii Department of Agriculture, Insect Containment Facility, on nine hemipteran and three lepidopteran eggs. Results indicated that M. macadamiae is host specific to MFC. There has been no evidence of parasitism or host feeding on any of the non-target insect hosts that were tested. Parasitoid emergence from the control (MFC) averaged 30.2% compared to 0% on non-target hosts. A low rate of parasitoid emergence in the laboratory (average 30.2%) and an increased rate of MFC nymphal mortality was due to adult feeding. Field parasitism reached up to 32.7% emergence in Alstonville, New South Wales, Australia. We report on the parasitoid performance in native Australia, rearing biology, host specificity testing, and the extant natural enemies associated with MFC in Hawaii. A petition to release this parasitoid for the biocontrol of MFC in Hawaii is pending. Once permitted for release, the colony will be shared with South African Mac Nut Association for their biocontrol program of this invasive pest. They will conduct their own testing before approval for release.

Background: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC., Methods: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (T any N any M0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment., Findings: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity., Interpretation: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required., Funding: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center., Competing Interests: Declaration of interests ABC reports grants from Blue Halo, Proteus Consortium/Pfizer, and Novocure. YYE reports consulting fees from Takeda, Bristol-Myers Squibb, AstraZeneca, Spectrum, and Sanofi. AT reports consulting fees from Ariad, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Seattle Genetics, Gilead Sciences, and Summit Therapeutics. PAB reports grants from Raysearch and Varian; and is a member of the advisory board for Raysearch/Raycare. CMG reports grants from AstraZeneca; royalties from UpToDate; honoraria from AstraZeneca, BeiGene, MJH Healthcare, and Targeted Oncology; patents pending related to small cell lung cancer; and advisory board payments from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, G1 Therapeutics, Jazz Pharmaceuticals, and MonteRosa Therapeutics. TC reports funding from Bristol-Myers Squibb; grants from Bristol-Myers Squibb, MedImmune/AstraZeneca, and EMD Serono; consulting fees from MedImmune/AstraZeneca, Bristol-Myers Squibb, Regeneron, EMD Serono, Merck, Genentech, Arrowhead Pharmaceuticals, and Mark Foundation for Cancer Research; honoraria from Bristol-Myers Squibb and IDEOlogy Health; travel grants from IDEOlogy Health, Bristol-Myers Squibb, and Dava Oncology; and advisory fees from MedImmune/AstraZeneca, Bristol-Myers Squibb, Regeneron, EMD Serono, Merck, Genentech, and Arrowhead Pharmaceuticals. SGC reports grant funding from the National Institutes for Health (R50CA275822); consulting fees from AstraZeneca, CurioScience, and Norton Healthcare; honoraria from Binaytara Foundation; and travel grants from ViewRay and AstraZeneca. GB reports grant funding from Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myer Squib, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem. CytomX Therapeutics, Duality Biologics, Mythic Therapeutics, Takeda, and Aulos Bioscience; consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, Rgeneron, Cytomx Therapeutics, Intervenn Biosciences, Onconova Therapeutics, Seagen, and Scorpion Therapeutics; advisory fees from Maverick Therapeutics and Virogin Biotech; stock or stock options in Virogin Biotech; and has an immediate family member employed by Johnson & Johnson (Janssen). XL reports grants from Eli Lilly, EMD Serono, Boehringer Ingelheim, and Regeneron; and consulting fees from EMD Serono, AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics AstraZeneca, Janssen, Blueprint Medicines, Sensei Biotherapeutics, Daiichi Sankyo, Regeneron, AbbVie, and AMVent. SJG reports grants from Bristol-Myers Squibb, Nanobiotix, and Bristol-Myers Squibb Foundation; and travel grants from AstraZeneca. JZ reports funding from the National Cancer Institute of the National Institutes for Health Research Project Grant (R01CA234629), the AACR-Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-ZHAN), the MD Anderson Physician Scientist Programme, and the MD Anderson Lung Cancer Moon Shot Programme; consulting fees from Johnson and Johnson, AstraZeneca, and Novartis; honoraria from Novartis, Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, and Hengrui; advisory fees from Novartis, AstraZeneca, GenePlus, and Catalyst; and receipt of other services from Novartis, Johnson and Johnson, and Merck. JJL reports grant funding from the National Cancer Institute (P30CA016672). SHL reports grants from Nektar Therapeutics, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals; consulting fees from XRAD Therapeutics; travel grants from AstraZeneca; advisory fees from AstraZeneca and Merck; and stock or stock options from SEEK Diagnostics. MA reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead; consulting fees from GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, and AstraZeneca; honoraria from AstraZeneca, Nektar Therapeutics, and the Society for Immunotherapy of Cancer; and advisory fees from Nanobiotix-MDA Alliance, and Hengenix. JWW reports grant funding from Alkermes, Nanobiotix, Merck, GlaxoSmithKline, Checkmate Pharmaceuticals, Varian, Bristol Myers Squibb, Reflexion, Artidis, Takeda, Gilead, HotSpot Therapeutics, and Kiromic; travel grants from Ventana, Aileron, Nanobiotix, Varian, and Reflexion; advisory fees from Alpine Immune Sciences, Reflexion, Aileron, Molecular Match, OncoResponse, Checkmate Pharmaceuticals, and Marvu Pharmaceuticals; a consultant role for Alpine Immune Sciences, Reflexion, Merck, Molecular Match, OncoResponse, Checkmate Pharmaceuticals, Marvu Pharmaceuticals, Incyte, Nanobiotix, Aileron, GI Innovation, Legion Healthcare, Roche, and Ventana Medical Systems; and stock options in Alpine Immune Sciences, Reflexion, Legion Healthcare, Molecular Match, OncoResponse, and Nanorobotix. IIW reports research funding from 4D Molecular Therapeutics, Adaptimmune, Adaptive Biotechnologies, Akoya Biosciences, Amgen, Bayer, EMD Serono, Genentech, Guardant Health, HTG Molecular Diagnostics, Lovance Biotherapeutics, Johnson & Johnson, Karus Therapeutics, MedImmune, Merck, Novartis, OncoPlex Diagnostics, Pfizer, and Takeda; personal fees from Asuragen, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca/MedImmune, HTG Molecular, Merck, Guardant Health, Oncocyte, Daiichi-Sankyo, Pfizer, and Bayer; and consulting fees from Asuragen, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca/MedImmune, Bayer, GlaxoSmithKline, Guardant Health, HTG Molecular Diagnostics, Merck, MSD Oncology, OncoCyte, Novartis, Flame, Pfizer, Regeneron, Merus, G1 Therapeutics, and AbbVie. ZL reports grant funding from the National Institutes for Health and National Cancer Institute (5 R01 HL157273-03 and P01 CA261669). JVH reports research funding from Bristol-Myers Squibb; and advisory fees from Bristol-Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Thymic carcinoma is rare, and its oncologic management is controversial due to a paucity of prospective data. For this reason, multidisciplinary consensus guidelines are crucial to guide oncologic management., Objective: To develop expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma., Evidence Review: Case variants spanning the spectrum of stage I to IV thymic carcinoma were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel to address management controversies. A comprehensive review of the English-language medical literature from 1980 to 2021 was performed to inform consensus guidelines. Variants and procedures were evaluated by the panel using modified Delphi methodology. Agreement/consensus was defined as less than or equal to 3 rating points from median. Consensus recommendations were then approved by the ARS Executive Committee and subject to public comment per established ARS procedures., Findings: The ARS Thoracic AUC panel identified 89 relevant references and obtained consensus for all procedures evaluated for thymic carcinoma. Minimally invasive thymectomy was rated as usually inappropriate (regardless of stage) due to the infiltrative nature of thymic carcinomas. There was consensus that conventionally fractionated radiation (1.8-2 Gy daily) to a dose of 45 to 60 Gy adjuvantly and 60 to 66 Gy in the definitive setting is appropriate and that elective nodal irradiation is inappropriate. For radiation technique, the panel recommended use of intensity-modulated radiation therapy or proton therapy (rather than 3-dimensional conformal radiotherapy) to reduce radiation exposure to the heart and lungs., Conclusions and Relevance: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of thymic carcinoma, perhaps the most well referenced on the topic.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial., Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone., Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022., Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression., Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing., Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm., Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals., Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Purpose: Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled., Methods and Materials: We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost., Results: All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P = .004), breast pain (P = .004), and physician-reported cosmesis (P < .001)., Conclusions: Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase., Methods and Materials: Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0., Results: From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects., Conclusions: The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate the effects of dietary supplementation of Schizosaccharomyces pombe (S. pombe) -expressed phytase on growth performance, apparent ileal digestibility, organ indexes, meat quality, toe ash, and footpad lesions score in broiler chicks., Methods: A total of 390 one-day-old broiler chicks were randomly assigned to 5 groups based on the initial body weight (42.15±0.17 g), there were 6 replicate cages per treatment and 13 birds (mixed sex) per cage. The experimental period was 45 days, including 4 periods (starter, days 1 to 10; grower, days 11 to 24; finisher 1, days 25 to 38; finisher 2, days 39 to 45). Dietary treatments were based on a corn-soybean meal-basal diet and supplemented with 500, 750, 1,000, and 1,500 FTU/kg S. pombe-expressed phytase. One phytase unit (FTU) was defined as the amount of enzyme that catalyzes the release of one micromole phosphate from phytate per minute at 37°C and pH 5.5., Results: The inclusion of increasing levels of phytase in the diet linearly increased the body weight gain during days 1 to 10 (p = 0.001), 25 to 38 (p = 0.016), 39 to 45 (p = 0.018), and 1 to 45 (p = 0.004), feed intake during days 25 to 38 (p = 0.032), feed conversion ratio during days 1 to 10 (p = 0.001), 39 to 45 (p = 0.038), and 1 to 45 (p = 0.012), carcass weight (p = 0.035), toe ash (p<0.001), and apparent ileal phosphorus digestibility (p = 0.049). However, the footpad lesions score (p = 0.040) decreased linearly with the increase in phytase levels in the diet., Conclusion: Dietary supplementation of S. pombe-expressed phytase was beneficial to the growth performance, toe ash, apparent ileal phosphorus digestibility, and footpad lesions of broiler chicks in a dose-dependent manner.

Introduction: Treatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(-) NSCLC when added to systemic therapy including immunotherapy., Materials and Methods: Alliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(-) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy vs. systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy., Conclusions: This phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(-) NSCLC. It is now open in the National Clinical Trials Network (NCTN)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aim: The condition of footpad is an important aspect of poultry welfare. This is a problem that plagues the poultry industry because it occurs whether birds are reared in the cage or on the floor. It is reported that feeding phytase to floor-reared broiler chicks could ameliorate footpad lesions, which is related to the reduction of litter moisture. However, some studies reported that phytase supplementation could ameliorate footpad lesions, but did not affect litter quality. Therefore, phytase supplementation may have other potential mechanisms to improve the footpad lesions. Cage-reared broiler chicks were used in this study because they had no access to litter., Material and Methods: A total of 234 1-day-old broiler chicks were randomly assigned to three groups based on the initial body weight (42.22 ± 0.18 g) with six replicate cages and 13 birds (mixed sex) per cage. The experimental period was 45 days. Dietary treatments were based on a corn-soybean meal-basal diet and supplemented with 500 and 750 FTU/kg Saccharomyces pombe expressed phytase. The unit of phytase (FTU) was defined as the amount of enzyme that catalyzes the release of one micromole phosphate from phytate per minute at 37°C and pH 5.5., Result and Conclusion: We found that dietary supplementation of S. pombe expressed phytase could improve calcium and phosphorus digestibility and subsequent improvement in toe ash, thus ameliorating footpad lesions in broiler chicks with no access to litter., (© 2022 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Purpose: Recent randomized studies have suggested improvements in progression-free and overall survival with the addition of stereotactic body radiation therapy (SBRT, also known as SABR) in patients with oligometastatic non-small cell lung cancer. Given the novelty and complexity of incorporating SBRT in the oligometastatic setting, the multidisciplinary American Radium Society Lung Cancer Panel was assigned to create appropriate use criteria on SBRT as part of consolidative local therapy for patients with oligometastatic and oligoprogressive non-small cell lung cancer., Methods and Materials: A review of the current literature was conducted from January 1, 2008, to December 25, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to systematically search the PubMed database to retrieve a comprehensive set of relevant articles., Results: Based on representation in existing randomized trials, the panel defined the term "oligometastasis" as ≤3 metastatic deposits (not including the primary tumor) in the previously untreated setting or after first-line systemic therapy after the initial diagnosis. "Oligoprogression" also referred to ≤3 discrete areas of progression in the setting of prior or ongoing receipt of systemic therapy. In all appropriate patients, the panel strongly recommends enrollment in a clinical trial whenever available. For oligometastatic disease, administering first-line systemic therapy followed by consolidative radiation therapy (to all sites plus the primary/nodal disease) is preferred over up-front radiation therapy. Owing to a dearth of data, the panel recommended that consolidative radiation therapy be considered on a case-by-case basis for 4 to 5 sites of oligometastatic disease, driver mutation-positive oligometastatic disease without progression on up-front targeted therapy, and oligoprogressive cases., Conclusions: Although SBRT/SABR appears to be both safe and effective in treating patients with limited metastatic sites of disease, many clinical circumstances require individualized management and strong multidisciplinary discussion on account of the limited existing data., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The first high-quality clinical trial to support ultrahypofractionated whole-breast irradiation (ultra-HF-WBI) for invasive early-stage breast cancer (ESBC) was published in April 2020, coinciding with the beginning of the COVID-19 pandemic. We analyzed adoption of ultra-HF-WBI for ductal carcinoma in situ (DCIS) and ESBC at our institution after primary trial publication., Methods and Materials: We evaluated radiation fractionation prescriptions for all patients with DCIS or ESBC treated with WBI from March 2020 to May 2021 at our main campus and regional campuses. Demographic and clinical characteristics were extracted from the electronic medical record. Treating physician characteristics were collected from licensure data. Hierarchical logistic regression models identified factors correlated with adoption of ultra-HF-WBI (26 Gy in 5 daily factions [UK-FAST-FORWARD] or 28.5 Gy in 5 weekly fractions [UK-FAST])., Results: Of 665 included patients, the median age was 61.5 years, and 478 patients (71.9%) had invasive, hormone-receptor-positive breast cancer. Twenty-one physicians treated the included patients. In total, 249 patients (37.4%) received ultra-HF-WBI, increasing from 4.3% (2 of 46) in March-April 2020 to a high of 45.5% (45 of 99) in July-August 2020 ( P < .001). Patient factors associated with increased use of ultra-HF-WBI included older age (≥50 years old), low-grade WBI without inclusion of the low axilla, no radiation boost, and farther travel distance ( P < .03). Physician variation accounted for 21.7% of variance in the outcome, with rate of use of ultra-HF-WBI by the treating physicians ranging from 0% to 75.6%. No measured physician characteristics were associated with use of ultra-HF-WBI., Conclusions: Adoption of ultra-HF-WBI at our institution increased substantially after the publication of randomized evidence supporting its use. Ultra-HF-WBI was preferentially used in patients with lower risk disease, suggesting careful selection for this new approach while long-term data are maturing. Substantial physician-level variation may reflect a lack of consensus on the evidentiary standards required to change practice., (© 2021 The Authors.)

Aim: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer., Methods: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response., Results: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT., Conclusions: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC)., Patients and Methods: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale., Results: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events., Conclusions: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank is a scientific advisory board member of Breakthrough Chronic Care; he has received research grants from C4 Imaging, Eli Lilly, Elekta, and Hitachi, and he has reported personal fees from Varian Medical Systems, Inc (consultant/advisory board), C4 Imaging (founder and director), Hitachi (honoraria/advisory board), Augmenix (honoraria), and National Comprehensive Cancer Center (board member). Stephen G. Chun, MD, is a consultant for AstraZeneca, PLC. The authors report no other conflicts of interest., (©Copyright 2021 The Author(s).)

With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices., Materials/methods: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P - Plan/D - Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S - Study)., Results: There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3., Conclusion: We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A - Act)., Competing Interests: Dr. Chun reports being a consultant for AstraZeneca, PLC., and for Norton Healthcare, Inc. Dr. Reed reports being a consultant for Varian Medical Systems, Inc. Dr. Koong reports holding stock in Aravice, Inc., (© 2021 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Objective: Although intensity-modulated radiation therapy (IMPT) is dosimetrically superior to passive scattering proton therapy (PSPT) for locally advanced NSCLC (LA-NSCLC), direct comparisons of clinical outcomes are lacking. Here, we compare toxicity profiles and clinical outcomes after IMPT versus PSPT for LA-NSCLC., Methods: This is a nonrandomized, comparative study of two independent cohorts with LA-NSCLC (stage II-IIIB, stage IV with solitary brain metastasis) treated with concurrent chemotherapy and proton beam therapy. Toxicity (Common Terminology Criteria for Adverse Events version 4.0) and outcomes were prospectively collected as part of a clinical trial (ClinicalTrials.gov identifier NCT00915005) or prospective registry (ClinicalTrials.gov identifier NCT00991094)., Results: Of 139 patients, 86 (62%) received PSPT and 53 (38%) IMPT; median follow-up times were 23.9 and 29.0 months, respectively. IMPT delivered lower mean radiation doses to the lungs (PSPT 16.0 Gy versus IMPT 13.0 Gy, p < 0.001), heart (10.7 Gy versus 6.6 Gy, p = 0.004), and esophagus (27.4 Gy versus 21.8 Gy, p = 0.005). Consequently, the IMPT cohort had lower rates of grade 3 or higher pulmonary (17% versus 2%, p = 0.005) and cardiac (11% versus 0%, p = 0.01) toxicities. Six patients (7%) with PSPT and zero patients (0%) with IMPT experienced grade 4 or 5 toxicity. Lower rates of pulmonary (28% versus 3%, p = 0.006) and cardiac (14% versus 0%, p = 0.05) toxicities were observed in the IMPT cohort even after propensity score matching for baseline imbalances. There was also a trend toward longer median overall survival in the IMPT group (23.9 mo versus 36.2 mo, p = 0.09). No difference was found in the 3-year rates of local (25% versus 20%, p = 0.44), local-regional (29% versus 36%, p = 0.56) and distant (52% versus 51%, p = 0.71) recurrences., Conclusions: IMPT is associated with lower radiation doses to the lung, heart, and esophagus, and lower rates of grade 3 or higher cardiopulmonary toxicity; additional clinical studies will be needed to assess the potential differences in survival between the two techniques., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The standard-of-care therapy for extensive-stage SCLC has recently changed with the results of two large randomized trials revealing improved survival with the addition of immunotherapy to first-line platinum or etoposide chemotherapy. This has led to a lack of clarity around the role of consolidative thoracic radiation and prophylactic cranial irradiation in the setting of chemoimmunotherapy., Methods: The American Radium Society Appropriate Use Criteria are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with the application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for extensive-stage SCLC., Results: Current evidence supports either prophylactic cranial irradiation or surveillance with magnetic resonance imaging every 3 months for patients without evidence of brain metastases. Patients with brain metastases should receive whole-brain radiation with a recommended dose of 30 Gy in 10 fractions. Consolidative thoracic radiation can be considered in selected cases with the recommended dose ranging from 30 to 54 Gy; this recommendation was driven by expert opinion owing to the limited strength of evidence, as clinical trials addressing this question remain ongoing., Conclusions: Radiation therapy remains an integral component in the treatment paradigm for ES-SCLC., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Combined modality therapy with concurrent chemotherapy and radiation has long been the standard of care for limited-stage SCLC (LS-SCLC). However, there is controversy over best combined modality practices for LS-SCLC. To address these controversies, the American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) Committee have developed updated consensus guidelines for the treatment of LS-SCLC., Methods: The ARS AUC are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for LS-SCLC. Agreement or consensus was defined as less than or equal to 3 rating points from the panel median. The consensus ratings and recommendations were then vetted by the ARS Executive Committee and subject to public comment before finalization., Results: The ARS Thoracic AUC committee developed multiple consensus recommendations for LS-SCLC. There was strong consensus that patients with unresectable LS-SCLC should receive concurrent chemotherapy with radiation delivered either once or twice daily. For medically inoperable T1-T2N0 LS-SCLC, either concurrent chemoradiation or stereotactic body radiation followed by adjuvant chemotherapy is a reasonable treatment option. The panel continues to recommend whole-brain prophylactic cranial irradiation after response to chemoradiation for LS-SCLC. There was panel agreement that prophylactic cranial irradiation with hippocampal avoidance and programmed cell death protein-1/programmed death-ligand 1-directed immune therapy should not be routinely administered outside the context of clinical trials at this time., Conclusions: The ARS Thoracic AUC Committee provide consensus recommendations for LS-SCLC that aim to provide a groundwork for multidisciplinary care and clinical trials., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Immunotherapy, targeted therapy, and adoptive T-cell therapy have been revolutionary advancements in cancer research. Some of these therapies have become the standard of care for lung cancer and replaced older treatment algorithms; some continue to be studied in clinical trials. This article discusses the current state of novel treatment options for non-small cell lung cancer patients with metastatic and locoregional disease, with focus on immunotherapy, targeted therapy, and adoptive T-cell therapy., Competing Interests: Disclosure B. Sepesi receives consultant fees from Bristol-Myers Squibb and research funding from Rexanna Foundation. T. Cascone reports speaker’s fees from the Society for Immunotherapy of Cancer and Bristol-Myers Squibb, consulting fees MedImmune/Astra Zeneca and Bristol-Myers Squibb, and advisory role fees from EMD Serono and Bristol-Myers Squibb. S.G. Chun is on the advisory board and receives consultant fees from Astra Zeneca. M. Altan receives advisory fees from GlaxoSmithKline and Shattuck Labs and research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol-Myers Squibb, Eli Lilly, and Adaptimmune. X. Le receives consultant and advisory fees from Eli Lilly, Astra Zeneca, and EMD Serono and research funds from Eli Lilly and Boehringer Ingelheim., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes., Methods: We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect., Results: Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4 + T cells and NK cells abrogated the observed antitumor effect., Conclusion: Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors., Competing Interests: Competing interests: JW serves on the science advisory boards for Alpine Immune Sciences, RefleXion Medical, Mavu Pharma, MolecularMatch and Checkmate Pharmaceuticals, and he is the founder of Healios Oncology, MolecularMatch, and OncoResponse companies. MD Anderson Cancer Center has a trademark for RadScopal (TM). JW has research support collaborations with Bristol Myers Squibb, Checkmate Pharmaceuticals, Mavu pharma, Merck, and Nanobiotix. AD is an advisory board member for Nektar Therapeutics. IG is a consultant for Bristol Myers Squibb and Array Biopharma. DSH has consulting/advisory role in Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics. DSH has research/grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda. DSH's ownership interests include MolecularMatch (Advisor), OncoResponse (founder), Presagia Inc (Advisor)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Radiation therapy interruption (RTI) worsens cancer outcomes. Our purpose was to benchmark and map RTI across a region in the United States with known cancer outcome disparities., Methods and Materials: All radiation therapy (RT) treatments at our academic center were cataloged. Major RTI was defined as ≥5 unplanned RT appointment cancellations. Univariate and multivariable logistic and linear regression analyses identified associated factors. Major RTI was mapped by patient residence. A 2-sided P value <.0001 was considered statistically significant., Results: Between 2015 and 2017, a total of 3754 patients received RT, of whom 3744 were eligible for analysis: 962 patients (25.8%) had ≥2 RT interruptions and 337 patients (9%) had major RTI. Disparities in major RTI were seen across Medicaid versus commercial/Medicare insurance (22.5% vs 7.2%; P < .0001), low versus high predicted income (13.0% vs 5.9%; P < .0001), Black versus White race (12.0% vs 6.6%; P < .0001), and urban versus suburban treatment location (12.0% vs 6.3%; P < .0001). On multivariable analysis, increased odds of major RTI were seen for Medicaid patients (odds ratio [OR], 3.35; 95% confidence interval [CI], 2.25-5.00; P < .0001) versus those with commercial/Medicare insurance and for head and neck (OR, 3.74; 95% CI, 2.56-5.46; P < .0001), gynecologic (OR, 3.28; 95% CI, 2.09-5.15; P < .0001), and lung cancers (OR, 3.12; 95% CI, 1.96-4.97; P < .0001) compared with breast cancer. Major RTI was mapped to urban, majority Black, low-income neighborhoods and to rural, majority White, low-income regions., Conclusions: Radiation treatment interruption disproportionately affects financially and socially vulnerable patient populations and maps to high-poverty neighborhoods. Geospatial mapping affords an opportunity to correlate RT access on a neighborhood level to inform potential intervention strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer., Methods: This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up)., Results: This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar., Conclusion: For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

Background: Metformin reduces glucose uptake in physiologic tissues and has been shown to affect non-small cell lung cancer (NSCLC) metabolism. We hypothesized that positron emission tomography (PET) scans could detect the impact of metformin on glucose uptake in NSCLC and we sought to test this hypothesis in a prospective clinical trial., Materials and Methods: A single-blinded phase II clinical trial was performed with subjects randomized 6:1 to 3 to 4 weeks of metformin versus placebo for inoperable early-stage NSCLC. PET scans were performed at baseline, mid-treatment (after 2 wk study medication), and 6 months postradiation. The primary endpoint of the trial was tumor metabolic response to metformin by PERCIST before definitive radiation. Stereotactic body radiotherapy to 50 Gy in 4 fractions was used for peripheral tumors and 70 Gy in 10 fractions for central tumors., Results: There were 14 subjects randomized to the metformin and 1 to placebo. Histologies were 60% adenocarcinoma, 33.3% squamous cell carcinoma, and 6.7% poorly differentiated carcinoma. At mid-treatment PET scan, 57% of subjects randomized to metformin met PERCIST criteria for metabolic response, of which 75% had progressive metabolic disease and 25% had partial metabolic response, whereas the placebo subject had stable metabolic disease. At 6 months, the metformin arm had 69% complete metabolic response, 23% partial metabolic response and 1 progressive metabolic disease, and the subject treated with placebo had a complete metabolic response. There were no CTCAE grade ≥3 toxicities., Conclusions: Despite low accrual, majority of subjects treated with metformin had metabolic responses by PERCIST criteria on PET imaging. Contrary to the effect of metformin on most physiologic tissues, most tumors had increased metabolic activity in response to metformin.

Importance: Small cell lung cancer (SCLC) is an aggressive neoplasm requiring rapid access to subspecialized multidisciplinary care. For this reason, insurance coverage such as Medicaid may be associated with oncologic outcomes in this disproportionately economically vulnerable population. With Medicaid expansion under the Affordable Care Act, it is important to understand outcomes associated with Medicaid coverage among patients with SCLC., Objective: To determine the association of Medicaid coverage with survival compared with other insurance statuses., Design, Setting, and Participants: This cohort study included adult patients with limited-stage (LS) and extensive-stage (ES) SCLC in the US National Cancer Database from 2004 to 2013. Data were analyzed in January 2019., Main Outcomes and Measures: Patients were analyzed with respect to insurance status. Associations of insurance status with survival were interrogated with univariate analyses, multivariable analyses, and propensity score matching., Results: A total of 181 784 patients with SCLC (93 131 [51.2%] female; median [interquartile range] age; 67 [60-75] years for patients with LS-SCLC and 68 [60-75] years for patients with ES-SCLC) were identified, of whom 70 247 (38.6%) had LS-SCLC and 109 479 (60.2%) had ES-SCLC. On univariate analyses of patients with LS-SCLC, Medicaid coverage was not associated with a survival advantage compared with being uninsured (hazard ratio, 1.02; 95% CI, 0.96-1.08; P = .49). Likewise, on multivariable analyses of patients with ES-SCLC, compared with being uninsured, Medicaid coverage was not associated with a survival advantage (hazard ratio, 1.00; 95% CI, 0.96-1.03; P = .78). After propensity score matching, median survival was similar between the uninsured and Medicaid groups both among patients with LS-SCLC (14.4 vs 14.1 months; hazard ratio, 1.05; 95% CI, 0.98-1.12; P = .17) and those with ES-SCLC (6.3 vs 6.4 months; hazard ratio, 1.00; 95% CI, 0.96-1.04; P = .92)., Conclusions and Relevance: Despite of billions of dollars in annual federal and state spending, Medicaid was not associated with improved survival in patients with SCLC compared with being uninsured in the US National Cancer Database. These findings suggest that there are substantial outcome inequalities for SCLC relevant to the policy debate on the Medicaid expansion under the Affordable Care Act.

Introduction: The highest concentration of military personnel in the United States is located in Hawaii where occupational exposures, such as to asbestos in the Pacific Fleet shipyards, predispose them to thoracic malignancies. For this reason, Veterans Affairs (VA) insurance outcomes for lung cancer in Hawaii are of interest., Methods: All cases of lung cancer in the Hawaii Tumor Registry from 2000 to 2015 were evaluated. The selection criterion included evidence of extensive-stage SCLC (ES-SCLC) or metastatic NSCLC. Overall survival was compared using the Kaplan-Meier log-rank method. Univariate analysis and multivariable analysis (MVA) were carried out to understand the variables associated with overall survival., Results: There were 434 cases of ES-SCLC and 2139 cases of metastatic NSCLC identified. VA insurance (median survival [MS], 2 mo), Medicaid (MS, 4 mo), and Medicare (MS, 4 mo) had worse survival (log-rank p < 0.001) than private insurance (MS, 8 mo). In ES-SCLC, VA insurance (hazard ratio [HR], 2.74; 95% confidence interval [CI]: 1.50-5.01; p  = 0.001) and Medicaid (HR, 1.46; 95% CI: 1.04-2.03; p  = 0.027) had significantly worse survival compared with private insurance on MVA. VA insurance (HR, 1.84; 95% CI: 1.34-2.53; p < 0.001) and Medicaid (HR, 1.40; 95% CI: 1.20-1.63; p < 0.001) also had worse survival compared with private insurance in metastatic NSCLC on MVA., Conclusions: VA insurance coverage was associated with dismal survival for metastatic lung cancer that was effectively similar to hospice or supportive care, compelling further investigation to identify reasons for this disparity., (© 2020 The Authors.)

Background: Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting., Methods: A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types., Results: The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004)., Conclusions: Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.

Importance: Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases., Objective: To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases., Design, Setting, and Participants: This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions., Main Outcomes and Measures: The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT., Results: In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT., Conclusions and Relevance: Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival., Trial Registration: ClinicalTrials.gov identifier: NCT02163226.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Importance: Combined-modality therapy with chemotherapy and radiation therapy plays a crucial role in the upfront treatment of patients with limited-stage small cell lung cancer (SCLC), but there may be barriers to utilization in the United States., Objective: To estimate utilization rates and factors associated with chemotherapy and radiation therapy delivery for limited-stage SCLC using the National Cancer Database., Design, Setting, and Participants: Analysis of initial management of all limited-stage SCLC cases from 2004 through 2013 in the National Cancer Database., Main Outcomes and Measures: Utilization rates of chemotherapy and radiation therapy at time of initial treatment. Multivariable analysis identified independent clinical and socioeconomic factors associated with utilization and overall survival., Results: A total of 70 247 cases met inclusion criteria (55.3% female; median age, 68 y [range, 19-90 y]). Initial treatment was 55.5% chemotherapy and radiation therapy, 20.5% chemotherapy alone, 3.5% radiation therapy alone, and 20.0% neither (0.5% not reported). Median survival was 18.2 (95% CI, 17.9-18.4), 10.5 (95% CI, 10.3-10.7), 8.3 (95% CI, 7.7-8.8), and 3.7 (95% CI, 3.5-3.8) months, respectively. Being uninsured was associated with a lower likelihood of both chemotherapy (odds ratio [OR], 0.65; 95% CI, 0.56-0.75; P < .001) and radiation therapy (OR, 0.75; 95% CI, 0.67-0.85; P < .001) administration on multivariable analysis. Medicare/Medicaid insurance had no impact on chemotherapy use, whereas Medicaid (OR, 0.79; 95% CI, 0.72-0.87; P < .001) and Medicare (OR, 0.86; 95% CI, 0.82-0.91; P < .001) were independently associated with a lower likelihood of radiation therapy delivery. Lack of health insurance (HR, 1.19; 95% CI, 1.13-1.26; P < .001), Medicaid (HR, 1.27; 95% CI, 1.21-1.32; P < .001), and Medicare (HR, 1.12; 95% CI, 1.09-1.15; P < .001) coverage were independently associated with shorter survival on adjusted analysis, while chemotherapy (HR, 0.55; 95% CI, 0.54-0.57; P < .001) and radiation therapy (HR, 0.62; 95% CI, 0.60-0.63; P < .001) were associated with a survival benefit., Conclusions and Relevance: Substantial proportions of patients documented in a major US cancer registry did not receive radiation therapy or chemotherapy as part of initial treatment for limited-stage SCLC, which, in turn, was associated with poor survival. Lack of radiation therapy delivery was uniquely associated with government insurance coverage, suggesting a need for targeted access improvement in this population. Additional work will be necessary to conclusively define exact population patterns, specific treatment deficiencies, and causative factors leading to heterogeneous care delivery.

Small-cell lung cancer (SCLC) has a high predilection for metastasizing to the brain after chemotherapy. This has been blamed on the blood-brain barrier, which prevents chemotherapy from penetrating into the brain, thus creating a sanctuary site. It has been estimated that up to three quarters of patients with SCLC will eventually develop brain metastases. This led investigators to administer prophylactic cranial irradiation (PCI) to decrease this risk. Several trials were performed in patients with SCLC after initial therapy (chemotherapy with or without thoracic radiotherapy) that compared the outcomes of PCI versus no PCI. Early trials generally found that PCI significantly decreased the risk of brain metastases but did not significantly improve survival. These trials were re-evaluated in two larger meta-analyses that included patients with either limited-stage SCLC or extensive-stage SCLC (ESCLC). Both meta-analyses reported that PCI significantly decreased brain metastases and improved survival in patients who had a complete response following initial therapy. These studies were performed before the advent of modern imaging with computed tomography or magnetic resonance imaging (MRI). There have been two modern trials of PCI versus no PCI in patients with ESCLC and both found that PCI decreases brain metastases. The first did not include brain MRI before registration and found that PCI improved survival, whereas the second study did include MRI before registration and at frequent intervals thereafter. That trial found that PCI did not confer a survival advantage. This review will examine the evidence and provide recommendations regarding the role of PCI for patients with ESCLC.

With increasing use of low-dose screening CT scans, the diagnosis of early-stage small-cell lung cancer (SCLC) without evidence of mediastinal nodal or distant metastasis is likely to become more common, but the role of adjuvant therapies such as prophylactic cranial irradiation (PCI) are not well understood in this population. We performed a review of the literature pertaining to the impact of PCI in patients who underwent surgical resection of early-stage SCLC. Four studies were identified that were pertinent including three single-institution retrospective analyses and a National Cancer Database analysis. Based upon these studies, we estimate the rate of brain metastases to be 10-15% for Stage I and 15-25% for Stage II disease without PCI. However, the impact of PCI on the development of brain metastases and its ultimate impact on overall survival were not consistent across these studies. In summary, there is sparse evidence to guide recommendations for PCI following resection of early-stage SCLC. While it may be reasonable to offer PCI to maximize likelihood of cure, alternative strategies such as observation with close imaging follow-up can also be considered for the appropriate patient given the known neurocognitive side effects of PCI.

The purpose of this study was to commission and clinically test a robotic stereotactic delivery system (CyberKnife, Sunnyvale, CA) to treat early-stage glottic laryngeal cancer. We enrolled 15 patients with cTis-T2N0M0 carcinoma of the glottic larynx onto an institutional review board (IRB)-approved clinical trial. Stereotactic body radiotherapy (SBRT) plans prescribed 45 Gy/10 fractions to the involved hemilarynx. SBRT dosimetry was compared with (1) standard carotid-sparing laryngeal intensity-modulated radiation therapy (IMRT) and (2) selective hemilaryngeal IMRT. Our results demonstrate that SBRT plans improved sparing of the contralateral arytenoid (mean 20.0 Gy reduction, p <0.001), ipsilateral carotid D max (mean 20.6 Gy reduction, p <0.001), contralateral carotid D max (mean 28.1 Gy reduction, p <0.001), and thyroid D mean (mean 15.0 Gy reduction, p <0.001) relative to carotid-sparing IMRT. SBRT also modestly improved dose sparing to the contralateral arytenoid (mean 4.8 Gy reduction, p = 0.13) and spinal cord D max (mean 4.9 Gy reduction, p = 0.015) relative to selective hemilaryngeal IMRT plans. This "phantom-to-clinic" feasibility study confirmed that hypofractionated SBRT treatment for early-stage laryngeal cancer can potentially spare dose to adjacent normal tissues relative to current IMRT standards. Clinical efficacy and toxicity correlates continue to be collected through an ongoing prospective trial., (Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)