Large Cell Neuroendocrine Tumor Size >3 cm Negatively Impacts Long-Term Outcomes After R0 Resection.

BACKGROUND: Minimal knowledge exists regarding the outcome, prognosis and optimal treatment strategy for patients with pulmonary large cell neuroendocrine carcinomas (LCNEC) due to their rarity. We aimed to identify factors affecting survival and recurrence after resection to inform current treatment strategies. METHODS: We retrospectively reviewed 72 patients who had undergone a curative resection for LCNEC in 8 centers between 2000 and 2015. Univariable and multivariable analyses were performed to identify the factors influencing recurrence, disease-specific survival and overall survival. These included age, gender, previous malignancy, ECOG performance status, symptoms at diagnosis, extent of resection, extent of lymphadenectomy, additional chemo- and/or radiotherapy, tumor location, tumor size, pT, pleural invasion, pN and pStage. RESULTS: Median follow-up was 47 (95%CI 41-79) months; 5-year disease-specific and overall survival rates were 57.6% (95%CI 41.3-70.9) and 47.4% (95%CI 32.3-61.1). There were 22 systemic recurrences and 12 loco-regional recurrences. Tumor size was an independent prognostic factor for systemic recurrence [HR: 1.20 (95%CI 1.01-1.41); p = 0.03] with a threshold value of 3 cm (AUC = 0.71). For tumors ≤3 cm and >3 cm, 5-year freedom from systemic recurrence was 79.2% (95%CI 43.6-93.6) and 38.2% (95%CI 20.6-55.6) (p < 0.001) and 5-year disease-specific survival was 60.7% (95%CI 35.1-78.8) and 54.2% (95%CI 32.6-71.6) (p = 0.31), respectively. CONCLUSIONS: A large proportion of patients with surgically resected LCNEC will develop systemic recurrence after resection. Patients with tumors >3 cm have a significantly higher rate of systemic recurrence suggesting that adjuvant chemotherapy should be considered after complete resection of LCNEC >3 cm, even in the absence of nodal involvement.

Safety of adjuvant atezolizumab after pneumonectomy/bilobectomy in stage II-IIIA non-small cell lung cancer in the randomized phase III IMpower010 trial.

OBJECTIVE: Adjuvant atezolizumab is a standard of care after chemotherapy in completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or greater non-small cell lung cancer based on results from the phase III IMpower010 study. We explored the safety and tolerability of adjuvant atezolizumab by surgery type in IMpower010. METHODS: Patients had completely resected stage IB-IIIA non-small cell lung cancer (Union Internationale Contre le Cancer/American Joint Committee on Cancer, 7th Ed), received up to four 21-day cycles of cisplatin-based chemotherapy, and were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤16 cycles or 1 year) or best supportive care. Adverse events and clinical characteristics were investigated by surgery type (pneumonectomy/bilobectomy or lobectomy/sleeve lobectomy) in the randomized stage II-IIIA population who received 1 or more atezolizumab dose or with 1 or more postbaseline assessment (safety evaluable) for best supportive care. RESULTS: Overall, 871 patients comprised the safety-evaluable randomized stage II-IIIA population. In the atezolizumab arm, 23% (100/433) received pneumonectomy/bilobectomy and 77% (332/433) received lobectomy/sleeve lobectomy. Atezolizumab discontinuation occurred in 32% (n = 32) and 35% (n = 115) of the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. Grade 3/4 adverse events were reported in 21% (n = 21) and 23% (n = 76) of patients in the atezolizumab arms in the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. In the atezolizumab arms of the surgery groups, 13% (n = 13) and 17% (n = 55) had an adverse event leading to hospitalization. Atezolizumab-related adverse events leading to hospitalization occurred in 5% (n = 5) and 7% (n = 23) of the surgery groups. CONCLUSIONS: These exploratory findings support use of adjuvant atezolizumab after platinum-based chemotherapy in patients with completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or more non-small cell lung cancer, regardless of surgery type.

Electronic Medical Record Inaccuracies: Multicenter Analysis of Challenges with Modified Lung Cancer Screening Criteria.

The National Comprehensive Cancer Network expanded their lung cancer screening (LCS) criteria to comprise one additional clinical risk factor, including chronic obstructive pulmonary disease (COPD). The electronic medical record (EMR) is a source of clinical information that could identify high-risk populations for LCS, including a diagnosis of COPD; however, an unsubstantiated COPD diagnosis in the EMR may lead to inappropriate LCS referrals. We aimed to detect the prevalence of unsubstantiated COPD diagnosis in the EMR for LCS referrals, to determine the efficacy of utilizing the EMR as an accurate population-based eligibility screening "trigger" using modified clinical criteria. We performed a multicenter review of all individuals referred to three LCS programs from 2012 to 2015. Each individual's EMR was searched for COPD diagnostic terms and the presence of a diagnostic pulmonary functionality test (PFT). An unsubstantiated COPD diagnosis was defined by an individual's EMR containing a COPD term with no PFTs present, or the presence of PFTs without evidence of obstruction. A total of 2834 referred individuals were identified, of which 30% (840/2834) had a COPD term present in their EMR. Of these, 68% (571/840) were considered unsubstantiated diagnoses: 86% (489/571) due to absent PFTs and 14% (82/571) due to PFTs demonstrating no evidence of postbronchodilation obstruction. A large proportion of individuals referred for LCS may have an unsubstantiated COPD diagnosis within their EMR. Thus, utilizing the EMR as a population-based eligibility screening tool, employing expanded criteria, may lead to individuals being referred, potentially, inappropriately for LCS.

Sublobar Resection in the Treatment of Peripheral Typical Carcinoid Tumors of the Lung.

BACKGROUND: The role of sublobar resection in the treatment of pulmonary typical carcinoids is controversial. This study aims to compare long-term outcomes between sublobar and lobar resections in patients with peripheral typical carcinoid. METHODS: We retrospectively compared consecutive patients who underwent curative sublobar resection with patients who underwent lobectomy for cT1-3 N0 M0 peripheral pulmonary typical carcinoid in eight centers between 2000 and 2015. Primary outcomes were rates and patterns of recurrence and overall survival. Cox regression modeling was performed to identify factors influencing overall survival and recurrence. Propensity score analysis was done, and overall survival was compared between the two groups. RESULTS: In all, 177 patients were analyzed, consisting of 74 sublobar resections and 103 lobectomies, with a total of 857 person-years of follow-up. The R1 resection rates were 7% and 1% after sublobar resection and lobectomy, respectively (P = .08). One of 5 patients with sublobar R1 resection had recurrence. Recurrence rate was 0.02 (95% confidence interval [CI]: 0.009 to 0.044) per person-year of follow-up after sublobar resection and 0.008 (95% CI: 0.003 to 0.02) after lobectomy (P = .15). Five-year survival rates were 91.7% (95% CI: 78.5% to 96.9%) and 97.4% (95% CI: 90.1% to 99.4%) after sublobar and lobar resection, respectively (P = .08). Extent of resection was not a predictor of recurrence or survival. Propensity score analysis confirmed a similar survival and freedom from recurrence between the two groups. CONCLUSIONS: Sublobar resection of peripheral cT1-3 N0 M0 pulmonary typical carcinoid was not associated with worse short- or long-term outcomes compared with lobectomy. In select patients, sublobar resection may be considered for treatment of peripheral typical carcinoids if an R0 resection is obtained.

Variability in invasive mediastinal staging for lung cancer: A multicenter regional study.

OBJECTIVE: Prior studies have reported underuse of-but not variability in-invasive mediastinal staging in the pretreatment evaluation of patients with lung cancer. We sought to compare rates of invasive mediastinal staging for lung cancer across hospitals participating in a regional quality improvement and research collaborative. METHODS: We conducted a retrospective study (2011-2013) of patients undergoing resected lung cancer from the Surgical Clinical Outcomes and Assessment Program in Washington State. Invasive mediastinal staging included mediastinoscopy and/or endobronchial/esophageal ultrasound-guided nodal aspiration. We used a mixed-effects model to mitigate the influence of small sample sizes at any 1 hospital on rates of invasive staging and to adjust for hospital-level differences in the frequency of clinical stage IA disease. RESULTS: A total of 406 patients (mean age, 68 years; 69% clinical stage IA; and 67% lobectomy) underwent resection at 5 hospitals (4 community and 1 academic). Invasive staging occurred in 66% of patients (95% confidence interval [CI], 61%-71%). CI inspection revealed that 2 hospitals performed invasive staging significantly more often than the overall average (94%, [95% CI, 89%-96%] and 84% [95% CI, 78%-88%]), whereas 2 hospitals performed invasive staging significantly less often than overall average (31% [95% CI, 21%-44%] and 17% [95% CI, 7%-36%]). CONCLUSIONS: Rates of invasive mediastinal staging varied significantly across hospitals providing surgical care for patients with lung cancer. Future studies that aim to understand the reasons underlying variability in care may inform quality improvement initiatives or lead to the development of novel staging algorithms.

Regional Thoracic Surgery Quality Collaboration Formation: Providence Thoracic Surgery Initiative.

BACKGROUND: Surgery quality initiatives improve clinical outcomes in cardiac and general surgery. No mature thoracic surgery (TS) regional effort has been described. METHODS: An intramural grant funded the Thoracic Surgery Initiative (TSI). Professional organization, site-specific administrative and clinical databases were used to identify surgeons performing TS across a large Western health system. Participants were recruited through stakeholder surveys, personal contact, and meetings. Differences in practices and outcomes were identified. Fourteen centers performing TS in 5 states formed the TSI with a mission to define, implement, and monitor TS quality. RESULTS: A TS data system based on The Society of Thoracic Surgeons General Thoracic Surgery Database was implemented. Clinical data from 2015 and 2016 revealed significant differences in outcomes. Clinical data allow quality implementation, including identification and propagation of internal best practices and monitoring. TS practice standardization was agreed to using predefined TS best practice components that were incorporated into standardized TS care documents. Standardized care document completion by providers was intended to provoke desired TS care. The standardized care documents reside on the system-wide electronic health record. Literature and substantial surgeon experience were used to develop standardized TS care pathways for important or common clinical scenarios (pneumonectomy, primary spontaneous pneumothorax, etc). The TSI internet site serves as a harbor for standardization products. CONCLUSIONS: The TSI is evolving. Surgeon engagement remains high. The TSI enabled surgeons to lead, set the agenda, and remain in control of our destiny. Indeed, health care cannot appropriately evolve without such physician vision, engagement, and leadership.

Improvement in TNM staging of pulmonary neuroendocrine tumors requires histology and regrouping of tumor size.

OBJECTIVE: Neuroendocrine tumors of the lung are currently staged with the 7th edition TNM non-small cell lung cancer staging system. This decision, based on data analysis without data on histology or disease-specific survival, makes its applicability limited. This study proposes a specific staging system for these tumors. METHODS: We retrospectively analyzed 510 consecutive patients (female/male, 313/197; median age, 61 years; interquartile range, 51-70) undergoing lung resection for a primary neuroendocrine tumor between 2000 and 2015 in 8 centers. Multivariable analysis was performed using a Cox proportional hazard model to identify factors associated with disease-specific survival. A new staging system was proposed on the basis of the results of this analysis. Kaplan-Meier disease-specific survival was analyzed by stage using the proposed and the 7th TNM staging system. RESULTS: Follow-up was completed in 490 of 510 patients at a median of 51 months (interquartile range, 18-99). Histology (G1-typical carcinoid vs G2-atypical carcinoid vs G3-large-cell neuroendocrine carcinoma) and pT were independently associated with survival, but pN was not. After regrouping histology and pT, we proposed the following staging system: IA (pT1-2G1), IB (pT3G1, pT1G2), IIA (pT4G1, pT2-3G2, pT1G3), IIB (pT4G2, pT2-3G3), and III (pT4G3). The 5-year survivals were 97.9%, 81.0%, 69.1%, 51.8%, and 0%, respectively. By using the 7th TNM, 5-year survivals were 95.0%, 92.3%, 67.7%, 70.9%, and 65.1% for stage IA, IB, IIA, IIB, and III, respectively. CONCLUSIONS: Incorporating histology and regrouping tumor stage create a unique neuroendocrine tumor staging system that seems to predict survival better than the 7th TNM classification.

External Validation of a Prognostic Model of Survival for Resected Typical Bronchial Carcinoids.

BACKGROUND: This study aimed to assess the reliability and the validity of a prognostic model of survival recently developed by the European Society of Thoracic Surgery Neuroendocrine Tumor Working Group to predict 5-year overall survival after surgical resection of pulmonary typical carcinoid. METHODS: We retrospectively collected data on 240 consecutive patients (164 men, 76 women; median age, 58 years [interquartile range, 47 to 68]) who underwent curative lung resection for pulmonary typical carcinoid in seven centers between 2000 and 2015. For each patient, we calculated the corresponding risk class (A, B, C, D) using the following variables: male, age, previous malignancy, Eastern Cooperative Oncology Group performance status, peripheral tumor, TNM stage. Kaplan-Meier method, and Cox proportional hazards model were used for the statistical analysis. RESULTS: During a median follow-up of 42 months (interquartile range, 11 to 84), the 5-year overall survival was 94.2% (95% confidence interval [CI]: 90.2% to 98.2%); 15 of 240 patients died. A significantly decreasing rate of survival was observed from class A to class D (p = 0.004) with rates of 100% (95% CI: 100% to 100%), 96.3% (95% CI: 88.6% to 98.8%), 86.7% (95% CI: 63.0% to 95.7%), and 33.3% (95% CI: 0.9% to 77.4%), respectively, for class A, B, C, and D. This difference persisted also using clinical stage as a variable in the risk class calculation (p = 0.006). No differences were observed in term of overall survival among TNM stage I, II, and III patients (p = 0.94). CONCLUSIONS: This prognostic model of survival is easily applicable, it is validated by our independent cohort, and it appears to stratify better than the traditional TNM staging. Therefore, it may be useful in counseling patients about their outcomes from surgical treatment and in tailoring treatment for high-risk patients.

Is there a role for traditional nuclear medicine imaging in the management of pulmonary carcinoid tumours?

OBJECTIVES: The clinical utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) and somatostatin receptor scintigraphy (SRS) in pulmonary carcinoids staging is unclear. This study aims to determine the role of FDG-PET and SRS in detecting hilar-mediastinal lymph node metastasis from these tumours. METHODS: We retrospectively collected the data of 380 patients who underwent lung resection for primary pulmonary carcinoid in seven centres between 2000 and 2015. Patients without nodal sampling ( n = 78) were excluded. In 302 patients [35% men, median age 58 (interquartile range 47-68) years] the results of preoperative computed tomography (CT) scan, FDG-PET and SRS were analysed and compared to the pathological findings after resection to determine the respective utility of these two nuclear tests. RESULTS: The sensitivity, specificity and negative predictive value in detecting N1 and N2 disease were respectively 33% and 46%, 93% and 90%, 88% and 95% for computed-tomography-scan, 38% and 60%, 93% and 95%, 88% and 95% for FDG-PET, 22% and 33%, 95% and 98%, 84% and 87% for SRS. The diagnostic accuracy for N1 and N2 disease of CT scan was not significantly different from that of FDG-PET ( P = 1.0 and P = 0.37 for N1 and N2 disease respectively) and of SRS ( P = 0.47 and P = 0.35 for N1 and N2 disease respectively). The sensitivity and specificity of these imaging tests were also similar when analysed by typical vs atypical histology. CONCLUSIONS: CT scan, FDG-PET and SRS showed similar performance in terms of nodal staging for pulmonary carcinoid. These findings suggest that additional nuclear imaging beyond CT scan is not required as long as a lymphadenectomy or nodal sampling is completed at resection.