Adhering to guideline concordant care improves survival among the different subtypes of T3 N2 non-small cell lung cancer.

Objectives: T3 disease comprises heterogeneous morphologic characteristics, a variation only further complicated when in the context of N2-confirmed involvement. This study aims to examine whether or not specific features of T3 N2 non-small cell lung cancer are associated with improved 5-year overall survival when using a multimodal therapeutic approach consistent with guideline recommendations compared with definitive surgery alone. Methods: Patients with pathologic T3 N2 non-small cell lung cancer were identified in the National Cancer Database. Therapy modality, as defined by surgery alone versus surgery with adjuvant therapy, and T3 disease descriptors were compared for differences in 5-year overall survival using Kaplan-Meier analysis and log-rank tests. Multivariable Cox regression was used to determine prognostic factors for survival. Results: A total of 1924 patients met the inclusion criteria. Of these, 80.0% (n = 1539) received adjuvant chemotherapy with or without radiation therapy following surgery and 20.0% (n = 385) underwent definitive surgery alone. Patients in the 2 cohorts differed significantly in age, race, insurance status, and Charlson-Deyo score (P < .05). The overall survival for patients who underwent surgery followed by chemotherapy with or without radiation therapy compared with those who underwent surgery alone was 31.7% and 11.1%, respectively (P < .0001). Multivariable analysis demonstrated a lower risk of death with multimodal therapeutic intervention compared with surgery alone for patients with disease marked by chest wall invasion, additional ipsilateral pulmonary nodules, tumor size, and the presence of multiple T3 features. Conclusions: The utilization of a multimodal approach to treating pathologic T3 N2 NSCLC, compared with surgery alone, is associated with superior overall survival and lower risk of death for many subtypes of T3 disease.

Adjuvant chemotherapy for visceral pleural invasion in 3-4-cm non-small-cell lung cancer improves survival.

OBJECTIVES: Visceral pleural invasion (VPI) guidelines, for tumours ≤4 cm are ambiguous. Non-small-cell lung cancers (NSCLCs) 3 to ≤4 cm are assigned the T2a designation. Similarly, any tumours with VPI, smaller than 3 cm, are upstaged and also assigned the same T2a designation. We hypothesized that adjuvant chemotherapy would significantly improve 5-year survival for NSCLC ≤4 cm with VPI. METHODS: The National Cancer Database was queried from 2010 to 2016 for cases of NSCLC with clinical stage I disease, ≤4 cm, who subsequently underwent surgical resection. These stage I NSCLCs were stratified according to clinical tumour sizes (0 to ≤1, 1 to ≤2, 2 to ≤3 and 3 to ≤4 cm). This cohort was then divided into groups with and without VPI and further split based on the administration of adjuvant chemotherapy. Kaplan-Meier analysis was used to calculate 5-year overall survival (OS) for patients categorized by tumour size, VPI status, and receipt of adjuvant chemotherapy. Multivariable Cox regression adjusting for tumour size and VPI status was used to determine associations between use of adjuvant chemotherapy and OS. RESULTS: A total of 61 454 patients with NSCLC and clinical tumour sizes <4 cm were identified and grouped based on size along with VPI and adjuvant chemotherapy. The 5-year OS for combined tumour sizes without VPI was higher than for patients with VPI (66.2% vs 59.5%, P < 0.001). The OS for tumour size (0 to ≤1, 1 to ≤2, 2 to ≤3 and 3 to ≤4 cm) was lower for patients with VPI regardless of size (all P ≤ 0.010). When all tumour sizes were combined, patients with VPI who received adjuvant chemotherapy had an improved 5-year OS compared to patients without adjuvant chemotherapy (65.5% vs 58.8%, P < 0.001). When cohorts were created by tumour size, only VPI tumours 3 to ≤4 cm had a statistically significant increase in 5-year OS for patients receiving adjuvant chemotherapy (68.8% vs 49.9%, P < 0.001). On multivariable Cox regression for OS, adjuvant chemotherapy was associated with significantly longer 5-year OS in tumour size 3 to ≤4 (hazard ratio = 0.62, 95% confidence interval 0.46-0.83, P = 0.001). CONCLUSIONS: VPI remains a poor prognostic factor in clinically node-negative, T2a or less, NSCLC patients. Guidelines recommend considering chemotherapy for high-risk T2aN0, margin-negative patients-including those patients with VPI. Based on the analysis, adjuvant chemotherapy should be considered specifically for 3 to ≤4 cm with VPI due to an observed 5-year OS advantage.

Regional Variation in Treatment for Highest-Risk Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer patients with multiple high-risk socioeconomic factors experience treatment and survival disparities. We aim to assess whether disparities in treatment and survival vary by region for patients with 3 or more high-risk socioeconomic factors. METHODS: The National Cancer Database was queried for patients with clinical stage I-IIA non-small cell lung cancer diagnosed between 2010 and 2015. Patients were categorized into 3 groups: standard treatment, nonstandard treatment, and no curative treatment. Multivariable logistic regression was used to evaluate regional differences in treatment. Cox proportional hazards regression and the Kaplan-Meier method were used for survival analysis. All statistical tests were 2-sided. RESULTS: A total of 93,211 patients met inclusion criteria. For patients with 3 or more high-risk socioeconomic factors, the odds of nonstandard treatment were significantly greater in 6 regions compared with New England, greatest in West North Central (odds ratio 2.09, P < .001). The odds of no curative treatment were significantly greater in 7 regions compared with New England, greatest in West South Central (odds ratio 3.56, P < .001). West North Central was associated with the highest risk of all-cause mortality compared with New England (hazard ratio 1.10, P < .001), and Middle Atlantic was associated with the lowest (hazard ratio 0.86, P < .001). The 5-year overall survival was longest in Middle Atlantic (60.8%) and shortest in Mountain (36.8%). CONCLUSIONS: Patients with 3 or more high-risk socioeconomic factors experience treatment and survival disparities across the United States, though disparities are more pronounced in certain regions. Regional interventions may help mitigate disparities among highest risk non-small cell lung cancer patients.

Differential outcomes of residual disease in surgically-resected non-small cell lung cancer and the importance of guideline-concordant adjuvant therapy.

BACKGROUND: Positive mediastinal lymph nodes, a marker for systemic disease, and positive margins, a marker for local disease, following resection of non-small cell lung cancer (NSCLC) are forms of residual disease. The objective of this study is to compare survival of patients with residual disease and to study the effect of receipt of guideline vs. non-guideline concordant care. METHODS: The National Cancer Database (NCDB) was used to identify patients who underwent treatment naïve surgical resection with clinical stage T1-3N0-1M0 NSCLC between 2006-2016 and had pN2 disease, positive surgical margins, or both. Concordant care was determined based on form of chemotherapy and radiation, dosage, volume, modality, and duration. Kaplan-Meier survival curves and log-rank tests were used to compare five-year survival. Multivariable analysis using Cox proportional hazards modeling identified factors that contributed to worse overall survival. RESULTS: There were 8,189 patients included: pN2 (5,416), positive margins (2,386), and both (387). Five-year survival rates for all patients were pN2 (35.8%), positive margins (33.9%), and both (22.9%) (P<0.0001). On multivariable analysis, positive margins were an independent predictor of better survival relative to pN2 disease (HR =0.729, CI: 0.676, 0.787, P<0.0001). Receipt of non-guideline concordant treatment was an independent predictor of worse survival compared to receipt of guideline-concordant treatment (HR =1.61, CI: 1.504, 1.725, P<0.0001). CONCLUSIONS: In upfront surgical patients, guideline-concordant treatment in the setting of residual disease is associated with better overall survival compared with non-guideline concordant treatment. Pathologic N2 disease is associated with a lower survival rate than positive resection margins, possibly reflecting the systemic nature of pN2 disease.

Adjuvant Chemotherapy Improves Survival in pN-positive Clinical Stage IIIA Non-Small Cell Lung Cancer After Neoadjuvant Therapy and Resection.

BACKGROUND: The utility of adjuvant chemotherapy (AC) after neoadjuvant therapy and curative intent surgery for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) is not defined. We sought to evaluate the contribution of AC to overall survival (OS) in patients with cIIIA NSCLC who underwent neoadjuvant therapy followed by curative intent surgical resection. METHODS: The National Cancer Database was queried from 2010 to 2016 for patients with cIIIA NSCLC who underwent curative intent surgical resection after neoadjuvant therapy. Patients were grouped by receipt of AC, and OS was calculated using the Kaplan-Meier method. The association between mortality and AC was evaluated using Cox regression. Ninety-day landmark and propensity score-matched analyses were performed to address bias associated with early postoperative morbidity and mortality. RESULTS: Of 3847 patients who met the inclusion criteria, 780 received AC (20.2%). In the unadjusted cohort there was no difference in 5-year OS between the AC and no AC groups (42.8% vs 43.9%, P = .105). Cox regression demonstrated a decreased risk of mortality in pN > 0 patients receiving AC (hazard ratio, 0.79; 95% confidence interval, 0.68-0.92; P < .003), whereas no difference was seen in node-negative patients (hazard ratio, 0.95; 95% confidence interval, 0.78-1.17; P = .64). In the propensity score-matched groups OS was significantly increased in pN > 0 patients who received AC (5-year OS: 42.4% vs 37%, P < .01), whereas no survival benefit was seen in those who were pN0. CONCLUSIONS: For patients with completely resected cIIIA NSCLC after neoadjuvant therapy, AC is associated with an increase in OS for patients with residual pathologic lymph node involvement.

Trends in pneumonectomy for treatment of small-cell lung cancer.

BACKGROUND: According to practice guidelines, patients with clinical stage T1-2 node-negative small-cell lung cancer are candidates for surgical resection. However, the role of pneumonectomy in small-cell lung cancer patients is not well understood. The objective of this study was to assess the extent to which pneumonectomy is used and to evaluate the survival implications for small-cell lung cancer patients who underwent pneumonectomy. METHODS: A total of 106 small-cell lung cancer patients who underwent pneumonectomy between 2006 and 2016 and met the study criteria were identified in the National Cancer Database. Demographics and treatment regimens are described, and overall survival was assessed using Kaplan-Meier and log-rank tests. RESULTS: The most common treatment was surgery with adjuvant chemotherapy, followed by surgery only and surgery with neoadjuvant therapy. The 5-year overall survival for the entire cohort after pneumonectomy was 23%. In subgroup analysis, the 5-year overall survival was 30% for guideline-concordant clinical stage I patients and 28% for clinical stage II/III patients who underwent pneumonectomy. There was no statistical difference in survival according to pathologic N disease. Patients with a right-sided pneumonectomy had higher mortality than patients with a left-sided pneumonectomy. CONCLUSIONS: This study suggests a role for pneumonectomy in clinical stage I and potentially some clinical stage II and III small-cell lung cancer patients. Right-sided pneumonectomy is associated with higher mortality and should be approached with caution. Despite declining trends over the past decades, pneumonectomy is still an effective treatment that is able to achieve acceptable survival outcomes.

A systematic review of paraneoplastic syndromes associated with thymoma: Treatment modalities, recurrence, and outcomes in resected cases.

OBJECTIVE: Paraneoplastic syndromes associated with thymomas remain incompletely understood. The objective was to examine the association between surgically resected thymomas and paraneoplastic syndromes over the past half century. METHODS: A primary PubMed/MEDLINE search was used to identify published articles describing paraneoplastic syndromes associated with thymomas from 1960 to 2019. A secondary search identified additional articles referenced in the articles found in the primary search. Kaplan-Meier and log-rank test were used for time-to-event data analyses. RESULTS: From 407 articles describing 507 patients, 123 different paraneoplastic syndromes were associated with thymoma. The 5 most common paraneoplastic syndromes were myasthenia gravis, pure red cell aplasia, lichen planus, Good syndrome, and limbic encephalitis. Complete or partial resolution of paraneoplastic syndrome symptoms after surgery was noted in 76% of patients, of whom 21% had a relapse or new paraneoplastic syndrome onset after surgery. The most common adjunctive therapy associated with resolution of paraneoplastic syndrome was corticosteroids (30%). For all patients after surgery, thymoma recurrence was observed in 17% of cases, whereas recurrence of paraneoplastic syndrome was observed in 34% of cases, and both were observed in approximately 11% of cases. The 5- and 10-year overall survivals were 78% and 66%, respectively. Improved overall survival was associated with patients who had total resolution from paraneoplastic syndrome. CONCLUSIONS: A comprehensive assessment of publications over the past half century suggests that a multimodal treatment approach that includes surgical resection of thymomas is able to achieve paraneoplastic syndrome resolution in a majority of patients. Onset of new paraneoplastic syndromes after surgery is associated with the recurrence of the first paraneoplastic syndrome, and resolution of paraneoplastic syndrome is associated with improved overall survival.

Disparities in Guideline-Concordant Treatment for Pathologic N1 Non-Small Cell Lung Cancer.

BACKGROUND: Socioeconomic status (SES) disparities in the surgical management of patients with non-small cell lung cancer (NSCLC) are well described. Disparities in the receipt of adjuvant chemotherapy are poorly understood. We assessed the influence of SES on adjuvant chemotherapy after resection in patients with pN1 NSCLC. METHODS: The National Cancer Database was queried for cN0/N1 NSCLC patients who underwent surgical resection and had demonstrated pN1 disease. This cohort was further divided into those who received multiagent adjuvant chemotherapy (MAAC) vs surgery-only treatment. Factors associated with treatment assignment were examined, and long-term survival was compared. RESULTS: Of the 14,892 patients who underwent resection for pN1 disease, 8061 (54.1%) received MAAC. Patients were less likely to receive MAAC if they resided in rural areas (odds ratio, 1.23; 95% confidence interval [CI], 1.11-1.37; P < .001), or were uninsured or on Medicaid (odds ratio, 1.23; 95% CI, 1.07-1.41; P = .004). The propensity score-weighted 5-year survival was significantly higher for those receiving MAAC compared with surgery only (53.6% vs 39.5%, log-rank P < .001). Lower income (hazard ratio, 1.06; 95% CI, 1.00-1.12; P = .044) and uninsured or Medicaid insurance status (hazard ratio, 1.22; 95% CI, 1.13-1.31; P < .001) were independently associated with increased mortality by Cox regression in the propensity score-weighted cohort. CONCLUSIONS: pN1 NSCLC patients living in rural areas or who are uninsured or on Medicaid insurance are at increased risk of not receiving MAAC. Treatment with MAAC significantly improves long-term survival of pN1 patients. Efforts should be made to ensure these at-risk groups receive guideline-concordant care.

Trimodality vs Chemoradiation and Salvage Resection in cN2 Stage IIIA Non-Small Cell Lung Cancer.

To determine the overall survival (OS) in patients who underwent planned trimodality therapy (TMT) and those who underwent definitive concurrent chemoradiation (CRT), but later received salvage resection (SR) for stage IIIA (cN2) (AJCC 7th ed.) non-small cell lung cancer. National Cancer Database data set from 2004 to 2014 was queried. TMT was defined as multiagent CRT with dose >45 Gy, followed by lobectomy or pneumonectomy ≤90 days from end of CRT. SR was defined as multiagent CRT with dose >59 Gy and lobectomy or pneumonectomy performed >90 days from CRT completion. Propensity score weighting and propensity score matching methods were used to balance patient and tumor characteristics and to calculate hazard ratios. A total of 2025 (1899 TMT and 126 SR) patients were analyzed. TMT and SR groups shared similar characteristics. Surgery occurred at a median of 41 days (range 1-90) after CRT in the TMT group and 114 days (91-440) in the SR group. The 90-day mortality after surgery was 6.5% for TMT and 5% for SR (P = 0.43). The 3- and 5-year OS were 55.1% and 35.7% for TMT and 51.6% and 45.0% for SR (P = 0.92, 0.68), with no difference across unadjusted cohort and propensity-adjusted cohort. Patients with cN2 stage IIIA non-small cell lung cancer treated in the United States with definitive CRT followed by SR had similar OS as upfront TMT with similar postoperative mortality despite SR occurring >90 days after >59 Gy CRT. SR remains an option for medically appropriate patients after definitive dose CRT.

The Effect of Socioeconomic Status on Treatment and Mortality in Non-Small Cell Lung Cancer Patients.

BACKGROUND: Treatment decisions for patients with non-small cell lung cancer (NSCLC) are based on patient and tumor characteristics, including socioeconomic status (SES) factors. The objective was to assess the contribution of SES factors to treatment and outcomes among patients with stage I NSCLC. METHODS: The National Cancer Database was queried for operable patients with stage I NSCLC. Patients were divided into three treatment groups: primary resection (ie, surgery only); nonstandard treatments consisting of chemotherapy with or without radiation; and no therapy. The SES of patients who made up the treatment groups was assessed, and the 5-year survival of all groups was analyzed. RESULTS: The cohort included 69,168 patients with stage I NSCLC. Each of these patients had between zero and five SES risk factors. The factors associated with no surgery were low income, nonwhite race, low high school graduation rate, Medicaid or no insurance, rural residence, and distance less than 12.5 miles from treatment facility. Patients with several SES risk factors have linearly increasing odds of undergoing nonstandard treatments and quadratically increasing odds of having no therapy (for patients with five factors, to odds ratio 4.7; 95% confidence interval, 3.44 to 6.30). Surgery alone was associated with significantly longer 5-year survival (71.8%) compared with nonstandard treatments (22.7%) and no therapy (21.8%; P < .001). CONCLUSIONS: Socioeconomic status factors increase the risk of undergoing guideline discordant therapy for stage I NSCLC. As the number of SES factors increases, the odds of no therapy rises quadratically whereas the odds of nonstandard treatments rises constantly. The surgery only group had significantly longer survival than the nonstandard treatment and no therapy groups.

Fortification of Preservation Solution With Nitroprusside Does Not Alter Lung Allograft Survival in Clinical Human Lung Transplantation.

Background: Nitric oxide improves gas exchange following primary lung allograft dysfunction. Nitroprusside, a potent nitric oxide donor, has reduced reperfusion injury and improved oxygenation in experimental lung transplantation. Methods: We sought to study the effect on lung allograft outcomes of fortifying the preservation solution with nitroprusside. We conducted a single-center clinical study of 46 consecutive lung recipients between 1998 and 2000: 24 patients received donor organs preserved in modified Euro-Collins solution with prostaglandin E1 (PGE1) (control group), and 22 patients received organs preserved in modified Euro-Collins with PGE1 and nitroprusside (NP group). The primary endpoint was overall survival. Results: Baseline characteristics were similar between the groups except for a significantly longer graft ischemic time in the NP group vs the control group (253.3 ± 52 vs 225.3 ± 41 minutes, respectively, P=0.04). No significant differences were found in partial pressure arterial oxygen to fraction inspired oxygen ratio at ≤48 hours, primary graft dysfunction, or bronchiolitis obliterans-free days. Overall survival at 1, 3, and 5 years was 89%, 73%, and 63% in the control group and 76%, 38%, and 23% in the NP group. Log-rank survival analysis showed that the NP group had a significantly increased risk of mortality (P=0.034) compared to the control group. Conclusion: The addition of nitroprusside to the lung transplant perfusate in this clinical trial did not improve survival; however, a large randomized trial would likely reduce confounding ischemia times and increase the power of the study.

Disparities in the surgical management of early stage non-small cell lung cancer: how far have we come?

It is currently estimated that nearly one-third of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage I-II disease on clinical evaluation. Curative-intent surgical resection has been a cornerstone of the therapeutic management of such patients, offering the best clinical and oncologic outcomes in the long-term. In 1999, Peter Bach and colleagues brought attention to racial disparities in the receipt of curative-intent surgery in the NSCLC population. In the time since this seminal study, there is accumulating evidence to suggest that disparities in the receipt of definitive surgery continue to persist for patients with early stage NSCLC. In this review, we sought to provide an up-to-date assessment of 20 years of surgical disparities literature in the NSCLC population. We summarized common and unrecognized disparities in the receipt of surgical resection for early stage NSCLC and demonstrated that demographic and socioeconomic factors such as race/ethnicity, special patient groups, income and insurance continue to impact the receipt of definitive resection. Additionally, we found that discrepancies in patient and provider perceptions of and attitudes toward surgery, access to invasive staging, distance to treatment centers and negative stigmas about lung cancer that patients experience may act to perpetuate disparities in surgical treatment of early stage lung cancer.

A Modern Reaffirmation of Surgery as the Optimal Treatment for Solitary Fibrous Tumors of the Pleura.

BACKGROUND: The objective of this study was to identify the most effective treatment for survival in patients with solitary fibrous tumors of the pleura (SFTP). METHODS: The National Cancer Database was queried for patients with malignant SFTPs. Patients were divided into two groups, those who had surgical treatment and those who did not. The primary outcome was 5-year overall survival, which was assessed by the Kaplan-Meier method and compared using the log rank test. RESULTS: There were 204 patients with SFTPs identified between 2004 and 2014. Of those, 65% of patients (133) had surgical intervention, whereas 18% (37) had no surgical intervention, and 17% (34) had unknown treatment information. Among patients who underwent resection, 42% (56) had sublobar resections, 45% (60) had lobectomies, and 13% (17) had pneumonectomies. The overall 5-year survival for SFTP patients was 56%. Patients who had surgical intervention had a relative survival of 64%, and patients with no surgical intervention had 22% (p < 0.001). There was no difference in 5-year survival among patients who had sublobar resections compared with patients who had greater anatomic resections (65% versus 64%, p = 0.823). CONCLUSIONS: Patients with SFTP who were managed with surgical intervention have better overall survival than patients who are not managed with surgery. Furthermore, similar 5-year survival for sublobar resections compared with greater anatomic resections suggested that the former, when possible, is sufficient.

A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE).

RATIONALE: This is the first multicenter randomized controlled trial to evaluate the effectiveness and safety of Zephyr Endobronchial Valve (EBV) in patients with little to no collateral ventilation out to 12 months. OBJECTIVES: To evaluate the effectiveness and safety of Zephyr EBV in heterogeneous emphysema with little to no collateral ventilation in the treated lobe. METHODS: Subjects were enrolled with a 2:1 randomization (EBV/standard of care [SoC]) at 24 sites. Primary outcome at 12 months was the ΔEBV-SoC of subjects with a post-bronchodilator FEV1 improvement from baseline of greater than or equal to 15%. Secondary endpoints included absolute changes in post-bronchodilator FEV1, 6-minute-walk distance, and St. George's Respiratory Questionnaire scores. MEASUREMENTS AND MAIN RESULTS: A total of 190 subjects (128 EBV and 62 SoC) were randomized. At 12 months, 47.7% EBV and 16.8% SoC subjects had a ΔFEV1 greater than or equal to 15% (P < 0.001). ΔEBV-SoC at 12 months was statistically and clinically significant: for FEV1, 0.106 L (P < 0.001); 6-minute-walk distance, +39.31 m (P = 0.002); and St. George's Respiratory Questionnaire, -7.05 points (P = 0.004). Significant ΔEBV-SoC were also observed in hyperinflation (residual volume, -522 ml; P < 0.001), modified Medical Research Council Dyspnea Scale (-0.8 points; P < 0.001), and the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index (-1.2 points). Pneumothorax was the most common serious adverse event in the treatment period (procedure to 45 d), in 34/128 (26.6%) of EBV subjects. Four deaths occurred in the EBV group during this phase, and one each in the EBV and SoC groups between 46 days and 12 months. CONCLUSIONS: Zephyr EBV provides clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life out to at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe. Clinical trial registered with www.clinicaltrials.gov (NCT 01796392).