American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer.

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.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

"Cancer's a demon": a qualitative study of fear and multilevel factors contributing to cancer treatment delays.

PURPOSE: Delays initiating cancer therapy are increasingly common, impact outcomes, and have implications for health equity. However, it remains unclear (1) whether patients' beliefs regarding acceptable diagnostic to treatment intervals align with current guidelines, and (2) to what degree psychological factors contribute to longer intervals. We conducted a qualitative study with patients and cancer care team members ("providers"). METHODS: We interviewed patients with several common solid tumors as well as providers. Interviews were analyzed using an interpretive approach, guided by modified grounded theory. RESULTS: Twenty-two patients and 12 providers participated. Half of patients had breast cancer; 27% waited >60 days between diagnosis and treatment. Several themes emerged. (1) Patients felt treatment should begin immediately following diagnosis, while providers' opinion on the goal timeframe to start treatment varied. (2) Patients experienced psychological distress while waiting for treatment. (3) Participants identified logistical, social, and psychological sources of delay. Fear related to multiple aspects of cancer care was common. Emotion-driven barriers could manifest as not taking steps to move ahead, or as actions that delayed care. (4) Besides addressing logistical challenges, patients believed that education and anticipatory guidance, from their care team and from peers, may help overcome psychological barriers to treatment and facilitate the start of therapy. CONCLUSIONS: Patients feel an urgency to start cancer therapy, desiring time frames shorter than those included in guidelines. Psychological distress is frequently both a contributor to, and a consequence of, treatment delays. Addressing multilevel barriers, including psychological ones, may facilitate timely treatment and reduce distress.

Validation of a Molecular Diagnostic Test for Circulating Tumor DNA by Next-Gen Sequencing.

A modified version of the PGDx elioTM Plasma Resolve assay was validated as a laboratory-developed test (LDT) for clinical use in the Molecular Diagnostics Laboratory at Fox Chase Cancer Center. The test detects single nucleotide variants (SNVs) and small insertions and deletions (indels) in 33 target genes using fragmented genomic DNA extracted from plasma. The analytical performance of this assay was assessed with reference standard DNA and 29 samples from cancer patients and detected 66 SNVs and 23 indels. Using 50 ng of input DNA, the sensitivity was 95.5% to detect SNVs at 0.5% allele frequency, and the specificity was 92.3%. The sensitivity to detect indels at 1% allele frequency was 70.4%. A cutoff of 0.25% variant allele frequency (VAF) was set up for diagnostic reporting. An inter-laboratory study of concordance with an orthologous test resulted in a positive percent agreement (PPA) of 91.7%.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Development of a Multilevel Model to Identify Patients at Risk for Delay in Starting Cancer Treatment.

Importance: Delays in starting cancer treatment disproportionately affect vulnerable populations and can influence patients' experience and outcomes. Machine learning algorithms incorporating electronic health record (EHR) data and neighborhood-level social determinants of health (SDOH) measures may identify at-risk patients. Objective: To develop and validate a machine learning model for estimating the probability of a treatment delay using multilevel data sources. Design, Setting, and Participants: This cohort study evaluated 4 different machine learning approaches for estimating the likelihood of a treatment delay greater than 60 days (group least absolute shrinkage and selection operator [LASSO], bayesian additive regression tree, gradient boosting, and random forest). Criteria for selecting between approaches were discrimination, calibration, and interpretability/simplicity. The multilevel data set included clinical, demographic, and neighborhood-level census data derived from the EHR, cancer registry, and American Community Survey. Patients with invasive breast, lung, colorectal, bladder, or kidney cancer diagnosed from 2013 to 2019 and treated at a comprehensive cancer center were included. Data analysis was performed from January 2022 to June 2023. Exposures: Variables included demographics, cancer characteristics, comorbidities, laboratory values, imaging orders, and neighborhood variables. Main Outcomes and Measures: The outcome estimated by machine learning models was likelihood of a delay greater than 60 days between cancer diagnosis and treatment initiation. The primary metric used to evaluate model performance was area under the receiver operating characteristic curve (AUC-ROC). Results: A total of 6409 patients were included (mean [SD] age, 62.8 [12.5] years; 4321 [67.4%] female; 2576 [40.2%] with breast cancer, 1738 [27.1%] with lung cancer, and 1059 [16.5%] with kidney cancer). A total of 1621 (25.3%) experienced a delay greater than 60 days. The selected group LASSO model had an AUC-ROC of 0.713 (95% CI, 0.679-0.745). Lower likelihood of delay was seen with diagnosis at the treating institution; first malignant neoplasm; Asian or Pacific Islander or White race; private insurance; and lacking comorbidities. Greater likelihood of delay was seen at the extremes of neighborhood deprivation. Model performance (AUC-ROC) was lower in Black patients, patients with race and ethnicity other than non-Hispanic White, and those living in the most disadvantaged neighborhoods. Though the model selected neighborhood SDOH variables as contributing variables, performance was similar when fit with and without these variables. Conclusions and Relevance: In this cohort study, a machine learning model incorporating EHR and SDOH data was able to estimate the likelihood of delays in starting cancer therapy. Future work should focus on additional ways to incorporate SDOH data to improve model performance, particularly in vulnerable populations.

American Radium Society Appropriate Use Criteria for Radiation Therapy in the Multidisciplinary Management of Thymic Carcinoma.

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.

Monitoring PD-L1 Expression on Circulating Tumor-Associated Cells in Recurrent Metastatic Non-Small-Cell Lung Carcinoma Predicts Response to Immunotherapy With Radiation Therapy.

PURPOSE: Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non-small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown. MATERIALS AND METHODS: We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized blood was filtered to isolate TACs, which were then quantified for high/low PD-L1 expression. Progression-free survival (PFS) or overall survival (OS) hazard ratios (HRs) were evaluated at 18 and 24 months by censored univariate analysis. RESULTS: Increased TAC PD-L1 expression between T0 and T1 in patients who were not treated with ICI had no relationship with PFS or OS. However, increased TAC PD-L1 expression between T0 and T1 in patients treated with ICI had significantly better PFS (HR, 3.49; 95% CI, 1.5 to 8.3; P = .0091) and OS (HR, 3.058; 95% CI, 1.2 to 7.9; P = .0410). CONCLUSION: Blood-based monitoring of dynamic changes in PD-L1 in TACs appears to identify patients with rmNSCLC who may benefit from ICI.

Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.

INTRODUCTION: Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC. MATERIALS AND METHODS: Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m2 intravenous (IV)/irinotecan 350 mg/m2 IV (day 1), irinotecan 350 mg/m2 IV (day 1), or topotecan 1.5 mg/m2 IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed. RESULTS: A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia. CONCLUSIONS: Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days. CLINICALTRIALS: gov Identifier. NCT03098030.

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.

Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10+ advanced non-small cell lung cancer.

BACKGROUND: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577). METHODS: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×109 (dose group 1), 0.5-1.2×109 (dose group 2), and 1.2-15×109 (dose group 3/expansion) transduced cells. RESULTS: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days -5 to -2 and cyclophosphamide 1800 mg/m2 on days -5 to -4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10. CONCLUSIONS: ADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

American Radium Society Appropriate Use Criteria for Radiation Therapy in Oligometastatic or Oligoprogressive Non-Small Cell Lung Cancer.

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.

Harmonized Outcome Measures for Use in Non-Small Cell Lung Cancer Patient Registries and Clinical Practice.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States and globally, and many questions exist about treatment options. Harmonizing data across registries and other data collection efforts would yield a robust data infrastructure to help address many research questions. The purpose of this project was to develop a minimum set of patient and clinician relevant harmonized outcome measures that can be collected in non-small cell lung cancer (NSCLC) patient registries and clinical practice. METHODS: Seventeen lung cancer registries and related efforts were identified and invited to submit outcome measures. Representatives from medical specialty societies, government agencies, health systems, health information technology groups, patient advocacy organizations, and industry formed a stakeholder panel to categorize the measures and harmonize definitions using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework (OMF). RESULTS: The panel reviewed 66 outcome measures and identified a minimum set of 8 broadly relevant measures in the OMF categories of patient survival, clinical response, events of interest, and resource utilization. The panel harmonized definitions for the 8 measures through in-person and virtual meetings. The panel did not reach consensus on 1 specific validated instrument for capturing patient-reported outcomes. The minimum set of harmonized outcome measures is broadly relevant to clinicians and patients and feasible to capture across NSCLC disease stages and treatment pathways. A pilot test of these measures would be useful to document the burden and value of the measures for research and in clinical practice. CONCLUSIONS: By collecting the harmonized measures consistently, registries and other data collection systems could contribute to the development research infrastructure and learning health systems to support new research and improve patient outcomes.

Benchmarks for Academic Oncology Faculty.

The role of clinical researchers is vital to cancer progress. The teaching, research, and leadership roles that academic oncologists hold need to be accounted for and appropriately compensated. National metrics are currently inexistent, but are necessary to move the oncology research field forward. Clinical research and routine clinical care must be harmoniously integrated without competing. This article reviews the national landscape of clinical cancer research and proposes a call for action.

American Radium Society Appropriate Use Criteria on Radiation Therapy for Extensive-Stage SCLC.

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.

American Radium Society Appropriate Use Criteria: Radiation Therapy for Limited-Stage SCLC 2020.

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.

Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non-small cell lung cancer.

OBJECTIVE: Concern exists regarding surgery after thoracic radiation. We aimed to assess early results of anatomic resection following induction therapy with platinum-based chemotherapy and full-dose thoracic radiation for resectable N2+ stage IIIA non-small cell lung cancer. METHODS: Two prospective trials were recently conducted by NRG Oncology in patients with resectable N2+ stage IIIA non-small cell lung cancer with the primary end point of mediastinal node sterilization following concurrent full-dose chemoradiotherapy (Radiation Therapy Oncology Group trials 0229 and 0839). All surgeons demonstrated postinduction resection expertise. Induction consisted of weekly carboplatin (area under the curve, 2.0) and paclitaxel (50 mg/m2) and concurrent thoracic radiation 60 Gy (0839)/61.2 Gy (0229) in 30 fractions. Patients in study 0839 were randomized 2:1 to weekly panitumumab + chemoradiotherapy or chemoradiotherapy alone during induction. Primary results were similar in all treatment arms and reported previously. Short-term surgical outcomes are reported here. RESULTS: One hundred twenty-six patients enrolled; 93 (74%) had anatomic resection, 77 underwent lobectomy, and 16 underwent extended resection. Microscopically margin-negative resections occurred in 85 (91%). Fourteen (15%) resections were attempted minimally invasively, including 2 converted without event. Grade 3 or 4 surgical adverse events were reported in 26 (28%), 30-day mortality in 4 (4%) and 90-day mortality in 5 (5%). Patients undergoing extended resection experienced similar rates of grade 3 or 4 adverse events (odds ratio, 0.95; 95% confidence interval, 0.42-3.8) but higher 30-day (1.3% vs 18.8%) (odds ratio, 17.54; 95% confidence interval, 1.75-181.8) and 90-day mortality (2.6% vs 18.8%) (odds ratio, 8.65; 95% confidence interval, 1.3-56.9). CONCLUSIONS: Lobectomy was performed safely following full-dose concurrent chemoradiotherapy in these multi-institutional prospective trials; however, increased mortality was noted with extended resections.

Prophylactic Cranial Irradiation for Small-Cell Lung Cancer: Time for a Reassessment.

Prophylactic cranial irradiation (PCI) has been an accepted part of the management of both limited and small-cell lung cancer; however, the data that support its use in limited-stage disease is based on an analysis of trials done before currently accepted approaches to staging (i.e., brain MRI and/or PET scanning) were available. For extensive disease, data are available from two randomized studies that are in direct conflict. This article explores the basic rationale for PCI and the evidence indicating that it is time to readdress the question of its routine use.