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.

Real-World Neoadjuvant Treatment Patterns and Outcomes in Resected Non-Small-Cell Lung Cancer.

BACKGROUND: Novel neoadjuvant chemoimmunotherapy treatments are being investigated for locally advanced non-small-cell lung cancer (NSCLC), but real-world outcomes for neoadjuvant treatments are poorly understood. This study examined neoadjuvant treatment patterns, real-world event-free survival (rwEFS) and overall survival (OS) in patients with resected, stage II-III NSCLC in the United States (US). METHODS: This retrospective study identified patients in the SEER-Medicare database (2007-2019) with newly diagnosed stage II, IIIA, and IIIB (N2) NSCLC (AJCC 8th edition) treated with neoadjuvant chemo/chemoradiotherapy and resection (index date: neoadjuvant therapy initiation). Neoadjuvant treatment regimens were described. rwEFS (time from index to first recurrence or death, whichever occurred first) and OS (time from index to death) were summarized by Kaplan-Meier analysis for overall population, by disease stage at diagnosis, and by neoadjuvant treatment modality. RESULTS: 221 patients (stage II, N=70; stage III, N=151) met eligibility criteria. The median follow-up from index was 32.7 months. All patients received neoadjuvant chemotherapy (51%) or chemoradiotherapy (49%) prior to surgery; 97% of patients received platinum-based regimens, among which carboplatin+paclitaxel was the most frequent (45%). In all patients, median rwEFS was 17.6 months and 5-year rwEFS was 20.9%; median OS was 48.5 months and 5-year OS was 44.9%. 71% of patients had disease recurrence during follow-up; among them, 28% developed locoregional recurrence as the first recurrence event. CONCLUSIONS: Patients with resected, stage II-III NSCLC who received neoadjuvant chemo/chemoradiotherapy have high rates of disease recurrence and poor survival outcomes, highlighting need for more effective treatments to improve survival rates.

Pack-Year Smoking History: An Inadequate and Biased Measure to Determine Lung Cancer Screening Eligibility.

PURPOSE: Pack-year smoking history is an imperfect and biased measure of cumulative tobacco exposure. The use of pack-year smoking history to determine lung cancer screening eligibility in the current US Preventive Services Task Force (USPSTF) guideline may unintentionally exclude many high-risk individuals, especially those from racial and ethnic minority groups. It is unclear whether using a smoking duration cutoff instead of a smoking pack-year cutoff would improve the selection of individuals for screening. METHODS: We analyzed 49,703 individuals with a smoking history from the Southern Community Cohort Study (SCCS) and 22,126 individuals with a smoking history from the Black Women's Health Study (BWHS) to assess eligibility for screening under the USPSTF guideline versus a proposed guideline that replaces the ≥20-pack-year criterion with a ≥20-year smoking duration criterion. RESULTS: Under the USPSTF guideline, only 57.6% of Black patients with lung cancer in the SCCS would have qualified for screening, whereas a significantly higher percentage of White patients with lung cancer (74.0%) would have qualified (P < .001). Under the proposed guideline, the percentage of Black and White patients with lung cancer who would have qualified for screening increased to 85.3% and 82.0%, respectively, eradicating the disparity in screening eligibility between the groups. In the BWHS, using a 20-year smoking duration cutoff instead of a 20-pack-year cutoff increased the percentage of Black women with lung cancer who would have qualified for screening from 42.5% to 63.8%. CONCLUSION: Use of a 20-year smoking duration cutoff instead of a 20-pack-year cutoff greatly increases the proportion of patients with lung cancer who would qualify for screening and eliminates the racial disparity in screening eligibility between Black versus White individuals; smoking duration has the added benefit of being easier to calculate and being a more precise assessment of smoking exposure compared with pack-year smoking history.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revisions of the T-Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: An international database was created by the International Association for the Study of Lung Cancer to inform on the ninth edition of the TNM classification of lung cancer. The present analyses concern its T component. METHODS: Data on 124,581 patients diagnosed with lung cancer from January 1, 2011 to December 31, 2019 were submitted to the International Association for the Study of Lung Cancer database. Of these, 33,982 met the inclusion criteria for the clinical T analysis, and 30,715 met the inclusion criteria for the pathologic postsurgical analysis. Survival was measured from the date of diagnosis or operation for clinically and pathologically staged tumors, respectively. T descriptors were evaluated in univariate analysis and multivariable Cox regression analysis adjusted for age, sex, pathologic type, and geographic region. RESULTS: Comprehensive survival analysis revealed that the existing eighth edition T component criteria performed adequately in the ninth edition data set. Although pathologic chest wall or parietal pleura involvement (PL 3) yielded a worse survival compared with the other T3 descriptors, with a similar survival as T4 tumors, this difference was not observed for clinical chest wall or PL 3 tumors. Because of these inconsistent findings, no reallocation of chest wall or PL 3 tumors is advised. CONCLUSIONS: The T subcommittee members proposed not to implement any changes and keep the current eighth-edition T descriptors for the ninth edition.

Event-free survival as a predictor of overall survival and recurrence burden of patients with non-small cell lung cancer receiving neoadjuvant therapy.

OBJECTIVES: Event-free survival has replaced overall survival as a primary end point in many recent and ongoing clinical trials. This study aims to examine the correlation between real-world event-free survival and overall survival and to assess the clinical and economic burden associated with disease recurrence among patients with resected stage II to III non-small cell lung cancer who received neoadjuvant therapy in the United States. METHODS: This retrospective study used the Surveillance, Epidemiology, and End Results Medicare database (2007-2019) to identify patients with newly diagnosed, resected, stage II to IIIB (N2) non-small cell lung cancer who received neoadjuvant therapy. The correlation between real-world event-free survival and overall survival was assessed using the normal scores rank correlation and landmark analysis. Overall survival, all-cause health care resource use and costs, and non-small cell lung cancer-related health care resource use and costs were compared between patients with and without recurrence. RESULTS: A total of 221 patients met the eligibility criteria (median follow-up time from neoadjuvant treatment initiation: 32.7 months). The mean age was 72.1 years, and 57.0% of patients were male. Real-world, event-free survival and overall survival are positively and significantly correlated (0.68; 95% CI, 0.52-0.79). Patients with recurrence had significantly shorter median overall survival (19.3 vs 116.9 months), 4.59 times increased risk of death (95% CI, 2.56-8.26), and significantly higher all-cause and non-small cell lung cancer-related health care resource use and costs (adjusted mean monthly costs per patient difference: $5758 and $3187, respectively [all P < .001]). CONCLUSIONS: These findings help validate event-free survival as a clinically meaningful end point and strong predictor for overall survival and highlight the need for additional novel therapies that may delay or prevent recurrence in resectable stage II and III non-small cell lung cancer.

What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?

Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.

Restructuring lung cancer care to accelerate diagnosis and treatment in patients vulnerable to healthcare disparities using an innovative care model.

The diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to disparities for vulnerable patients. Our model involved a multi-institutional, multidisciplinary conference to address the complexity of lung cancer care in vulnerable patient populations. The conference was conducted using a process adapted from the problem-solving method entitled FastTrack, pioneered by General Electric. Conference attendees established critical social determinants of health specific to lung cancer and designed a practical care model to accelerate diagnosis and treatment in this population. The resulting care delivery model, the Lung Cancer Strategist Program (LCSP), was led by a lung cancer trained advanced practice provider (APP) to expedite diagnosis, surgical and oncologic consultation, and treatment of a suspicious lung nodule. We compared the timeliness of care, care efficiency, and oncologic outcomes in 100 LCSP patients and 100 routine referral patients at the same thoracic surgery clinic. Patient triage through our integrated care model transitioned initial referral evaluation to a lung cancer trained APP to coordinate multidisciplinary patient-centered care that was highly individualized and significantly reduced the time to diagnosis and treatment among vulnerable patients at high-risk for treatment delay due to healthcare disparities.•To develop the Lung Cancer Strategist Program care model, we used a three-step (Design, Meeting, and Culmination), team-based, problem-solving process entitled FastTrack.•An advantage of FastTrack is its ability to overcome barriers embedded within hierarchal and institutional social systems, empowering those closest to the relevant issue to propose and enact meaningful change.•Under this framework, we engaged a diverse field of experts to assess systemic barriers in lung cancer care and design an innovative care pathway to improve the timeliness and efficiency of lung cancer care in patients at risk for healthcare disparities.

Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.

Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS. Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma. Design, Setting, and Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023. Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS. Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127. Conclusions and Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.

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.

Treatment Decisions for Resectable Non-Small-Cell Lung Cancer: Balancing Less With More?

For patients with non-small-cell lung cancer (NSCLC), the outcomes for patients with resectable disease are historically poor compared with other solid organ malignancies. In recent years, there have been significant advances in multidisciplinary care, which have resulted in improved outcomes. Innovations in surgical oncology include the use of limited resection and minimally invasive techniques. Recent data in radiation oncology have suggested refinements in pre- and postoperative radiation therapy, resulting in optimization of techniques in the curative setting. Finally, the success of immune checkpoint inhibitors and targeted therapies in the advanced setting has paved the way for inclusion in the adjuvant and neoadjuvant settings, resulting in recent regulatory approvals for four regimens (CheckMate-816, IMpower010, PEARLS, ADAURA). In this review, we will provide an overview of the seminal studies informing advancements in optimal surgical resection, radiation treatment, and systemic therapy for resectable NSCLC. We will summarize the key data on survival outcomes, biomarker analyses, and future directions for perioperative studies.

Current Management of Stage IIIA (N2) Non-Small-Cell Lung Cancer: Role of Perioperative Immunotherapy, and Tyrosine Kinase Inhibitors.

There have been numerous recent advances in the treatmetn of stage IIIA non-small cell lung cancer. The most significant involve the addition of targeted therapies adn immune checkpoint inhibitors into perioperative care. These exciting advances are improving survival in this challenging patient population, but some-decade old controveries around the definition of resectability, prognositic importance of tumor response to induction therapy, and the role of pneumonectomy persist.

STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS: This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS: Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION: In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Impact of Federal Lung Cancer Screening Policy on the Incidence of Early-stage Lung Cancer.

BACKGROUND: In December 2013 the US Preventative Services Task Force (USPSTF) recommended annual lung cancer screening for high-risk patients. The Centers for Medicare & Medicaid Services (CMS) later announced coverage in 2015. The impact of these federal decisions at the population level is unknown. METHODS: Using the Surveillance, Epidemiology, and End Results database, we studied changes in lung cancer incidence by stage and linked to US census data to obtain age-adjusted estimates standardized to the US population. Based on age at diagnosis we stratified patients as age-eligible or age-ineligible for screening. We used difference-in-differences regression to determine the effect of screening on lung cancer incidence by stage. RESULTS: For all age groups the incidence of early-stage lung cancer both before and after the USPSTF guidelines remained relatively stable at 12.8 ± 0.52 and 13.5 ± 0.92 per 100,000 patients, respectively (P = .068). However the difference-in-differences analysis estimated an absolute increase in the age-adjusted incidence by 3.4 per 100,000 persons in the age-eligible group after the announcement of the guidelines (P = .007). The effect was even larger after the CMS decision (4.3/100,000 persons, P < .001). Similarly there was a 14.2 per 100,000 persons absolute reduction in the incidence of advanced-stage lung cancer (P < .001). CONCLUSIONS: The 2013 USPSTF lung cancer screening guidelines and CMS coverage decisions were associated with an increased incidence of early-stage lung cancer and decreased incidence of advance-staged lung cancer at the population level.

Integration of New Systemic Adjuvant Therapies for Non-small Cell Lung Cancer: Role of the Surgeon.

BACKGROUND: This review describes a new therapeutic landscape in the adjuvant treatment of resectable non-small cell lung cancer (NSCLC) and discusses the role of the surgeon in ensuring the best outcomes within this treatment paradigm. METHODS: We conducted a narrative literature review using the search terms "non-small cell lung cancer" and "adjuvant" to identify randomized Phase III trials of systemic adjuvant therapy for NSCLC through March 17, 2022. We also searched ClinicalTrials.gov to identify ongoing trials of adjuvant immunotherapies and targeted therapies for NSCLC. RESULTS: Three recent randomized Phase III trials reported significant improvements in disease-free survival with adjuvant immune checkpoint inhibitors or targeted therapy in patients with resectable NSCLC: IMpower010 (atezolizumab vs best supportive care; NCT02486718), KEYNOTE-091 (PEARLS) (pembrolizumab vs placebo; NCT02504372), and ADAURA (osimertinib vs placebo; NCT02511106). Numerous other Phase III trials evaluating adjuvant immune checkpoint inhibitors and targeted therapies are currently underway, many of which demonstrate an evolution of trial design and end points for adjuvant therapy trials. This rapidly changing treatment landscape requires a shift in the role of the surgeon to facilitate appropriate biomarker screening for planning of the perioperative period and molecular testing of the surgical specimen to guide adjuvant therapy. CONCLUSIONS: After decades of stagnation in the management of NSCLC, recent results with immune checkpoint inhibitors and targeted therapies are ushering in a new era of precision medicine in the adjuvant treatment of early-stage NSCLC. Surgeons have an important role in facilitating multidisciplinary care in this rapidly evolving landscape.

Racial differences in phenotypic frailty assessment among general thoracic surgery patients.

Objectives: The American Association for Thoracic Surgery recommends using frailty assessments to identify patients at higher risk of perioperative morbidity and mortality. We evaluated what patient factors are associated with frailty in a thoracic surgery patient population. Methods: New patients aged more than 50 years who were evaluated in a thoracic surgery clinic underwent routine frailty screening with a modified Fried's Frailty Phenotype. Differences in demographics and comorbid conditions among frailty status groups were assessed with chi-square and Student t tests. Logistic regressions performed with binomial distribution assessed the association of demographic and clinical characteristics with nonfrail, frail, prefrail, and any frailty (prefrail/frail) status. Results: The study population included 317 patients screened over 19 months. Of patients screened, 198 (62.5%) were frail or prefrail. Frail patients undergoing thoracic surgery were older, were more likely single or never married, had lower median income, and had lower percent predicted diffusion capacity of the lungs for carbon monoxide and forced expiratory volume during 1 second (all P < .05). More non-Hispanic Black patients were frail and prefrail compared with non-Hispanic White patients (P = .003) and were more likely to score at least 1 point on Fried's Frailty Phenotype (adjusted odds ratio, 3.77; P = .02) when controlling for age, sex, number of comorbidities, median income, diffusion capacity of the lungs for carbon monoxide, and forced expiratory volume during 1 second. Non-Hispanic Black patients were more likely than non-Hispanic White patients to score points for slow gait and low activity (both P < .05). Conclusions: Non-Hispanic Black patients undergoing thoracic surgery are more likely to score as frail or prefrail than non-Hispanic White patients. This disparity stems from differences in activity and gait speed. Frailty tools should be examined for factors contributing to this disparity, including bias.

Lung resection surgery in Jehovah's Witness patients: a 20-year single-center experience.

BACKGROUND: The paucity of literature on surgical outcomes of Jehovah's Witness (JW) patients undergoing lung resection suggests some patients with operable lung cancers may be denied resection. The aim of this study is to better understand perioperative outcomes and long-term cancer survival of JW patients undergoing lung resection. METHODS: All pulmonary resections in JW patients at one institution from 2000 through 2020 were examined. Demographics, comorbidities, operative parameters, and perioperative outcomes were reviewed. Among operations performed for primary non-small cell lung cancer (NSCLC), details regarding staging, extent of resection, additional therapies, recurrence, and survival were abstracted. RESULTS: Seventeen lung resections were performed in fourteen patients. There were nine anatomic resections and eight wedge resections. Fourteen resections (82%) were approached thoracoscopically, of which 3 of 6 anatomic resections were converted to thoracotomy as compared to 1 of 8 wedge resections. There was one (6%) perioperative death. Ten resections in 8 patients were performed for primary pulmonary malignancies, and two patients underwent procedures for recurrent disease. Median survival for resected NSCLCs (N = 7) was 65 months. Three of 6 patients who survived the immediate perioperative period underwent additional procedures: 2 pulmonary wedge resections for diagnosis and one pleural biopsy. CONCLUSIONS: This series of JW patients undergoing lung resections demonstrates that resections for cancer and inflammatory etiologies can be performed safely in the setting of both primary and re-operative procedures.

Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs). METHODS: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated. RESULTS: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9). CONCLUSIONS: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.