PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction.

Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8+ T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8+ T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on programmed cell death 1 (PD-1) expression on CD8+ T cells. In the absence of PD-1 expression, CD8+ T cells form prolonged interactions with graft-infiltrating CD11c+ cells; their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ.

Gastric conduit revision postesophagectomy: Management for a rare complication.

OBJECTIVE: Severe postesophagectomy gastric conduit dysfunction refractory to standard endoscopic intervention is rare, with few published reports discussing timing, technique, or results of reoperation. This case series examines assessment and management of severe conduit dysfunction and details techniques for conduit revision. METHODS: We retrospectively reviewed patients who underwent esophagectomy between September 2008 and October 2015 and studied patients who underwent conduit revision. RESULTS: More than 400 patients underwent Ivor Lewis or transhiatal esophagectomies during this 7-year period. Eight patients underwent reoperation for conduit revision. The strategy for initial anastomosis and management of the pylorus were variable. Symptoms included dysphagia, delayed emptying, aspiration, and weight loss. Evaluation and management included esophagram, computed tomography, repeated esophagoscopy with pyloric intervention, and selective anastomotic dilation. Two patients also had associated paraconduit hiatal hernias. Average time to reoperation was 3.8 years (range 2 weeks to 6.5 years). All revisions were performed through a thoracotomy with either laparoscopy or laparotomy. Revisions were completed in 7 patients. Average length of stay was 9.9 days (range 4-21). Average follow up was 10.1 months (range 1-36). The completed revisions led to restoration of a regular diet with improved patient satisfaction. CONCLUSIONS: Severe gastric conduit dysfunction after esophagectomy is rare. Symptoms, esophagram findings, and response to interventional esophagoscopy guide the decision to revise the conduit. Principles of conduit revision include reducing paraconduit hernias, reducing redundant conduit, tubularizing a dilated conduit, and ensuring adequate gastric drainage. Selective revision was performed with minimal morbidity and durable improvement in subjective symptoms of dysphagia and reflux.

Adjuvant Chemotherapy Is Associated With Improved Survival in Locally Invasive Node Negative Non-Small Cell Lung Cancer.

BACKGROUND: The objectives of this study are to explore factors that are associated with use of adjuvant chemotherapy and to evaluate its impact on overall survival in node-negative patients who undergo lung and chest wall resection for non-small cell lung cancer (NSCLC). METHODS: Patients who underwent concomitant lung and chest wall resection for NSCLC were abstracted from the National Cancer Database. Clinical, pathologic, treatment, and follow-up data were obtained. Patients with pathologic nodal metastases or patients who received any radiation treatment were excluded, and the cohort was dichotomized based on administration of adjuvant postoperative chemotherapy. RESULTS: Between 1998 and 2010, 824 patients met the inclusion criteria. This cohort exclusively consisted of pT3 N0 patients who did not receive any induction treatment or adjuvant radiation treatment. Adjuvant chemotherapy was administered to 255 patients (31%). Patients in the chemotherapy group were younger and had shorter inpatient length of stay. Both groups had similar comorbidities, tumor size, unplanned readmission rate, and incomplete resection rate. In multivariable analysis, younger age and shorter length of stay were associated with a greater likelihood of receiving adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved survival (hazard ratio 0.74, 95% CI: 0.6 to 0.9), whereas increasing age, white race, length of inpatient stay, tumor size, and residual tumor were independently associated with greater risk of death. CONCLUSIONS: Patients who undergo lobectomy with chest wall resection for locally advanced NSCLC should be strongly considered for postoperative adjuvant chemotherapy even in the absence of nodal disease. Actual selection of patients for adjuvant chemotherapy is affected by perioperative factors.

Defining the Ideal Time Interval Between Planned Induction Therapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND: Induction therapy leads to significant improvement in survival for selected patients with stage IIIA non-small cell lung cancer. The ideal time interval between induction therapy and surgery remains unknown. METHODS: Clinical stage IIIA non-small cell lung cancer patients receiving induction therapy and surgery were identified in the National Cancer Database. Delayed surgery was defined as greater than or equal to 3 months after starting induction therapy. A logistic regression model identified variables associated with delayed surgery. Cox proportional hazards modeling and Kaplan-Meier analysis were performed to evaluate variables independently associated with overall survival. RESULTS: From 2006 to 2010, 1,529 of 2,380 (64.2%) received delayed surgery. Delayed surgery patients were older (61.2 ± 10.0 years versus 60.3 ± 9.2; p = 0.03), more likely to be non-white (12.4% versus 9.7%; p = 0.046), and less likely to have private insurance (50% versus 58.2%; p = 0.002). Delayed surgery patients were also more likely to have a sublobar resection (6.3% versus 2.9%). On multivariate analysis, age greater than 68 years (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.1 to 1.7) was associated with delayed surgery, whereas white race (OR, 0.75; 95% CI, 0.57 to 0.99) and private insurance status (OR, 0.82; 95% CI, 0.68 to 0.99) were associated with early surgery. Delayed surgery was associated with higher risk of long-term mortality (hazard ratio, 1.25; 95% CI, 1.07 to 1.47). CONCLUSIONS: Delayed surgery after induction therapy for stage IIIA lung cancer is associated with shorter survival, and is influenced by both social and physiologic factors. Prospective work is needed to further characterize the relationship between patient comorbidities and functional status with receipt of timely surgery.

Quality Measures in Clinical Stage I Non-Small Cell Lung Cancer: Improved Performance Is Associated With Improved Survival.

BACKGROUND: National organizations have recommended quality measures for operations in early-stage non-small cell lung cancer (NSCLC). The outcomes of adherence to these guidelines are unknown. METHODS: Information about patients who underwent an operation for clinical stage I NSCLC was abstracted from the National Cancer Database. After reviewing current guidelines, the following quality measures were selected: anatomic resection, operation within 8 weeks of diagnosis, achievement of negative surgical margins, and sampling of 10 or more lymph nodes. Multivariate models identified variables independently associated with receiving quality measures and a Cox model created to evaluate overall survival. RESULTS: Between 2004 and 2013, 133,026 of 133,366 (99.7%), 126,598 of 133,366 (94.9%), 91,472 of 133,366 (68.6%), and 30,041 of 133,366 (22.5%) patients met one, two, three, or four measures. Income of at least $38,000/year (odds ratio [OR] 1.20, 95% CI: 1.15 to 1.24), insurance type (private insurance: OR 1.22, 95% CI: 1.09 to 1.36; Medicare: OR 1.16, 95% CI:1.04 to 1.30), centers with at least 38 cases/year (OR 1.18, 95% CI: 1.14 to 1.22), academic institutions (OR 1.31, 95% CI: 1.27 to 1.35), and clinical stage IB patients (OR 1.50, 95% CI: 1.40 to 1.60) were more likely to meet all four measures; whereas increasing age (OR 0.99, 95% CI: 0.99 to 0.99), women (OR 0.93, 95% CI: 0.91 to 0.96), non-Caucasian race (OR 0.83, 95% CI: 0.79 to 0.87), and increasing Charlson/Deyo comorbidity score (1: OR 0.90, 95% CI: 0.87 to 0.93; ≥2: OR 0.82, 95% CI: 0.79 to 0.86) were associated with lower likelihood. Pathologic upstaging (hazard ratio [HR] 1.84, 95% CI: 1.78 to 1.89) and meeting all four measures (HR 0.39, 95% CI: 0.31 to 0.48) were most powerfully associated with overall survival. CONCLUSIONS: National adherence to quality measures in stage I NSCLC resection is suboptimal. Guideline compliance is strongly associated with survival, and vigorous efforts should be instituted by national societies to improve adherence.

Neoadjuvant Chemotherapy versus Chemoradiation Prior to Esophagectomy: Impact on Rate of Complete Pathologic Response and Survival in Esophageal Cancer Patients.

OBJECTIVES: The aim of this study was to evaluate differences in pathologic complete response (pCR) rates and overall survival among patients receiving either neoadjuvant chemotherapy or chemoradiation before esophagectomy for locally advanced esophageal cancer. METHODS: Patients with esophageal cancer receiving either neoadjuvant chemotherapy or chemoradiation before esophagectomy were identified using the National Cancer Database. Univariate analysis compared patient, tumor, and postoperative outcome characteristics. Logistic regression was performed to identify variables associated with achieving pCR. Kaplan-Meier analysis was performed to compare overall median survival by neoadjuvant therapy type and pCR status. Finally, a Cox proportional hazards model was fitted to identify variables associated with increased mortality hazard. RESULTS: From 2006 to 2012, a total of 916 of 7338 of patients (12.5%) received neoadjuvant chemotherapy whereas 6422 (87.5%) received neoadjuvant chemoradiation. Patients who received neoadjuvant chemoradiation were more likely to achieve a pCR (17.2% versus 6.4%, p < 0.001) and less likely to have positive margins (5.6% versus 11.5%, p < 0.001) than were patients who received neoadjuvant chemotherapy, with no difference in 30- or 90-day mortality. Achieving a pCR was associated with improved overall median survival (59.5 ± 4.0 months versus 30.1 ± 0.76 months for those with persistent disease, p < 0.001). On logistic regression, neoadjuvant chemoradiation therapy was independently associated with achieving a pCR (OR = 2.75, 95% confidence interval: 2.01-3.77, p < 0.001). Despite improvement in the pCR rate with neoadjuvant chemoradiation, neoadjuvant therapy type was not independently associated with long-term survival (hazard ratio = 1.12; 95% confidence interval: 0.97-1.30, p = 0.12). CONCLUSIONS: Although neoadjuvant chemoradiation is more successful in downstaging esophageal cancer before esophagectomy, it was not independently prognostic for improved long-term survival. Other factors affecting long-term survival among pathologic complete responders and among patients with persistent disease should be investigated to clarify this association.

Noninvasive Imaging of CCR2+ Cells in Ischemia-Reperfusion Injury After Lung Transplantation.

Ischemia-reperfusion injury-mediated primary graft dysfunction substantially hampers short- and long-term outcomes after lung transplantation. This condition continues to be diagnosed based on oxygen exchange parameters as well as radiological appearance, and therapeutic strategies are mostly supportive in nature. Identifying patients who may benefit from targeted therapy would therefore be highly desirable. Here, we show that C-C chemokine receptor type 2 (CCR2) expression in murine lung transplant recipients promotes monocyte infiltration into pulmonary grafts and mediates graft dysfunction. We have developed new positron emission tomography imaging agents using a CCR2 binding peptide, ECLi1, that can be used to monitor inflammatory responses after organ transplantation. Both 64 Cu-radiolabeled ECL1i peptide radiotracer (64 Cu-DOTA-ECL1i) and ECL1i-conjugated gold nanoclusters doped with 64 Cu (64 CuAuNCs-ECL1i) showed specific detection of CCR2, which is upregulated during ischemia-reperfusion injury after lung transplantation. Due to its fast pharmacokinetics, 64 Cu-DOTA-ECL1i functioned efficiently for rapid and serial imaging of CCR2. The multivalent 64 CuAuNCs-ECL1i with extended pharmacokinetics is favored for long-term CCR2 detection and potential targeted theranostics. This imaging may be applicable for diagnostic and therapeutic purposes for many immune-mediated diseases.

Patterns of care in hilar node-positive (N1) non-small cell lung cancer: A missed treatment opportunity?

BACKGROUND: For patients with non-small cell lung cancer (NSCLC) metastatic to hilar lymph nodes (N1), guidelines recommend surgery and adjuvant chemotherapy in operable patients and chemoradiation (CRT) for those deemed inoperable. It is unclear how these recommendations are applied nationally, however. METHODS: The National Cancer Database was queried to identify patients with a tumor <7 cm (T1/T2) with clinically positive N1 nodes. Patients undergoing CRT (comprising chemotherapy and radiation >45 Gy) or surgical resection were considered adequately treated. Remaining patients were classified as receiving inadequate or no treatment. RESULTS: Of the 20,366 patients who met the study criteria, 63% underwent adequate treatment (48% surgical resection, 15% CRT). The remainder received inadequate treatment (23%) or no treatment (14%). In univariate analysis, the patients receiving inadequate or no treatment were older, tended to be non-Caucasian, had a lower income, and had a higher comorbidity score. Patients undergoing adequate treatment had improved overall survival (OS) compared with those receiving inadequate or no treatment (median OS, 34.0 months vs 11.7 months; P < .001). Of those receiving adequate treatment, logistic regression identified several variables associated with surgical resection, including treatment at an academic facility, Caucasian race, and annual income >$35,000. Increasing age and T2 stage were associated with nonoperative management. Following propensity score matching of 2308 patient pairs undergoing surgery or CRT, resection was associated with longer median OS (34.1 months vs 22.0 months; P < .001). CONCLUSIONS: Despite the established guidelines, many patients with T1-2N1 NSCLC do not receive adequate treatment. Surgery is associated with prolonged survival in selected patients. Surgical input in the multidisciplinary evaluation of these patients should be mandatory.

Clinical T2N0 Esophageal Cancer: Identifying Pretreatment Characteristics Associated With Pathologic Upstaging and the Potential Role for Induction Therapy.

BACKGROUND: Although studies have suggested standard therapy for clinical T2N0 esophageal cancer should be primary surgery, we hypothesize there is a subgroup for whom induction therapy may result in improved overall survival. METHODS: Patients with cT2N0 esophageal cancer receiving induction therapy or upfront esophagectomy (UE) were identified in the National Cancer Data Base. The UE patients were dichotomized as (1) pathologically upstaged, or (2) same-staged or downstaged. Logistic regression models identified variables associated with upstaging, and Kaplan-Meier analysis compared median overall survival. RESULTS: From 2006 to 2012, 932 cT2N0 patients (52.2%) received UE, and 853 (47.8%) received induction therapy first. In all, 326 of 713 UE patients (45.7%) were upstaged: 87 of 326 (26.7%) had T upstaging; 98 of 326 (30.1%) had N upstaging; and 141 of 326 (43.3%) had both. Patients upstaged after UE had a higher tumor grade (35.1% versus 57.1% grade 3), and a higher rate of lymphovascular invasion (57.1% versus 17.7%; both p < 0.001). Variables associated with upstaging included lymphovascular invasion (odds ratio 6.0, 95% confidence interval: 2.9 to 12.5, p < 0.001) and tumor grade 3 (odds ratio 9.4, 95% confidence interval: 1.8 to 48.4, p = 0.007). Of upstaged UE patients, only 144 (44.2%) received adjuvant therapy. The median overall survival for cT2N0 patients upstaged after UE was 27.5 ± 2.5 months versus 43.9 ± 2.9 months for induction therapy patients (any resultant pathologic stage, p < 0.001). CONCLUSIONS: Half of all cT2N0 patients were pathologically upstaged after UE, with worse survival compared with patients receiving induction therapy. Refining an upstaging model would help select patients for induction therapy and increase the rate of chemotherapy in patients at risk for systemic disease.

The Role of Lymphoid Neogenesis in Allografts.

De novo induction of organized lymphoid aggregates at nonlymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, autoantigens or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3(+) cells are present in long-term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of "tolerogenic" TLOs may prove advantageous. In this review, we discuss our current understanding of how TLOs are induced and how they regulate immune responses with a particular focus on alloimmunity.

Adjuvant Therapy for Positive Nodes After Induction Therapy and Resection of Esophageal Cancer.

BACKGROUND: The value of adjuvant chemotherapy for patients with positive lymph nodes (+LNs) after induction therapy and resection of esophageal cancer is controversial. This study assesses survival benefit of adjuvant chemotherapy in this cohort. METHODS: We analyzed our single-institution database for patients with +LNs after induction therapy and resection of primary esophageal cancer between 2000 and 2013. Factors associated with survival were analyzed using a Cox proportional hazards model. RESULTS: A total of 101 of 764 esophagectomy patients received induction and had +LNs on final pathologic examination. Forty-five also received adjuvant therapy: 37 of 45 (82%) received chemotherapy alone, 1 of 45 (2%) received radiation alone, and 7 of 45 (16%) received both. Pathologic stage was IIB in 21 (47%), IIIA in 19 (42%), and IIIB in 5 (11%). In 56 node-positive patients with induction but not adjuvant therapy, pathologic stage was IIB in 28 (50%), IIIA in 18 (32%), IIIB in 7 (13%), and IIIC in 3 (5%). Neither age nor comorbidity score differed between cohorts. Adjuvant patients experienced a shorter hospital length of stay (mean, 10 days [range, 6 to 33 days] versus 11 days [range, 7 to 67 days]; p = 0.03]. Median survival favored the adjuvant group: 24.0 months (95% confidence interval, 16.6 to 32.2 months) versus 18.0 months (95% confidence interval, 11.1 to 25.0 months); p = 0.033). Multivariate Cox regression identified adjuvant therapy, length of stay, and number of +LNs as influential for survival. CONCLUSIONS: Optimal management of node-positive patients after induction therapy and esophagectomy remains unclear, but in this series, adjuvant therapy, length of stay, and number of +LNs impacted survival. A prospective trial may reduce potential bias and guide the evaluation of adjuvant therapy in this patient population.

The National Surgical Quality Improvement Program risk calculator does not adequately stratify risk for patients with clinical stage I non-small cell lung cancer.

OBJECTIVE: The study objective was to validate the National Surgical Quality Improvement Program (NSQIP) Risk Calculator in stratifying risk estimates for patients who received surgery or stereotactic body radiation therapy for clinical stage I non-small cell lung cancer. METHODS: A retrospective analysis of patients with clinical stage I non-small cell lung cancer undergoing surgery (N = 279) or stereotactic body radiation therapy (N = 206) from 2009 to 2012 was performed. NSQIP complication risk estimates were calculated for both surgical and stereotactic body radiation therapy cases using the NSQIP Surgical Risk Calculator. NSQIP complication risk estimates were compared as continuous variables and by quartile ranges. RESULTS: Compared with patients undergoing video-assisted thoracoscopic surgery wedge resection, patients receiving stereotactic body radiation therapy were older, had larger tumors, had lower forced expiratory volume (FEV1) in 1 second and diffusing capacity of the lungs (DLCO) for carbon monoxide values, had higher American Society of Anesthesiologists scores, had higher rates of dyspnea, and had higher NSQIP serious complication risk estimates (all P < .05). Compared with patients undergoing video-assisted thoracoscopic surgery lobectomy, patients receiving stereotactic body radiation therapy had similar disparities, along with higher Adult Comorbidity Evaluation-27 (ACE) scores comorbidity scores, higher rates of cardiac comorbidities, and worse functional status (all P < .05). Variables associated with receiving stereotactic body radiation therapy treatment, rather than wedge resection, included increasing age, higher Adult Comorbidity Evaluation (ACE)-27 comorbidity score, dyspnea status, and decreasing FEV1 in 1 second and DLCO for carbon monoxide, but NSQIP serious complication risk score. In addition, surgical patients' actual serious complication rate (16.6% vs 8.8%) and pneumonia rate (6.0% vs 3.2%) were significantly higher than the NSQIP risk calculator predicted (all P < .05). CONCLUSIONS: The National Surgical Quality Improvement Program risk calculator does not effectively classify or stratify risk in patients with stage I non-small cell lung cancer. Continued efforts are needed to assess risk in this population and develop more tailored treatment decision aids.

Pneumonectomy for Clinical Stage IIIA Non-Small Cell Lung Cancer: The Effect of Neoadjuvant Therapy.

BACKGROUND: The role of pneumonectomy after neoadjuvant therapy for stage IIIA non-small cell lung cancer (NSCLC) remains uncertain. METHODS: Patients who underwent pneumonectomy for clinical stage IIIA NSCLC were abstracted from the National Cancer Database. Individuals treated with neoadjuvant therapy, followed by resection, were compared with those who underwent resection, followed by adjuvant therapy. Logistic regression was performed to identify factors associated with 30-day mortality. A Cox proportional hazards model was fitted to identify factors associated with survival. RESULTS: Pneumonectomy for stage IIIA NSCLC with R0 resection was performed in 1,033 patients; of these, 739 (71%) received neoadjuvant therapy, and 294 (29%) underwent resection, followed by adjuvant therapy. The two groups were well matched for age, gender, race, income, Charlson comorbidity score, and tumor size. The 30-day mortality rate in the neoadjuvant group was 7.8% (57 of 739). Median survival was similar between the two groups: 25.9 months neoadjuvant vs 31.3 months adjuvant (p = 0.74). A multivariable logistic regression model for 30-day mortality demonstrated that increasing age, annual income of less than $35,000, nonacademic facility, and right-sided resection were associated with an elevated risk of 30-day mortality. A multivariable Cox model for survival demonstrated that increasing age was predictive of shorter survival and that administration of neoadjuvant therapy did not confer a survival advantage over adjuvant therapy (p = 0.59). CONCLUSIONS: Most patients who require pneumonectomy for clinical stage IIIA NSCLC receive neoadjuvant chemoradiotherapy, without an improvement in survival. In these patients, primary resection, followed by adjuvant chemoradiotherapy, may provide equivalent long-term outcomes.

Unexpected readmission after lung cancer surgery: A benign event?

OBJECTIVE: The study objective was to study the incidence, predictors, and implications of unanticipated early postoperative readmission after lung resection for non-small cell lung cancer. METHODS: Patients undergoing surgery for clinical stage I to III non-small cell lung cancer were abstracted from the National Cancer Database. Regression models were fitted to identify predictors of 30-day readmission and to study the association of unplanned readmission with 30-day and long-term survival. RESULTS: Between 1998 and 2010, 129,893 patients underwent resection for stage I to III non-small cell lung cancer. Of these, 5624 (4.3%) were unexpectedly readmitted within 30 days. In a multivariate regression model, increasing age, male gender, preoperative radiation, and pneumonectomy (odds ratio, 1.77; 95% confidence interval, 1.56-2.00) were associated with unexpected readmissions. Longer index hospitalization and higher Charlson comorbidity score were also predictive of readmission. The 30-day mortality for readmitted patients was higher (3.9% vs 2.8%), as was the 90-day mortality (7.0% vs 3.3%, both P < .001). In a multivariate Cox proportional hazards model of long-term survival, increasing age, higher Charlson comorbidity score, and higher pathologic stage (hazard ratio, for stage III 1.81; 95% confidence interval, 1.42-2.29) were associated with greater risk of mortality. Unplanned readmission was independently associated with a higher risk of long-term mortality (hazard ratio, 1.40; 95% confidence interval, 1.34-1.47). The median survival for readmitted patients was significantly shorter (38.7 vs 58.5 months, P < .001). CONCLUSIONS: Unplanned readmissions are not rare after resection for non-small cell lung cancer. Such events are associated with a greater risk of short- and long-term mortality. With the renewed national focus on readmissions and potential financial disincentives, greater resource allocation is needed to identify patients at risk and develop measures to avoid the associated adverse outcomes.

Treatment Outcomes in Stage I Lung Cancer: A Comparison of Surgery and Stereotactic Body Radiation Therapy.

INTRODUCTION: The relative roles of surgery and stereotactic body radiation therapy in stage I non-small-cell lung cancer (NSCLC) are evolving particularly for marginally operable patients. Because there is limited prospective comparative data for these treatment modalities, we evaluated their relative use and outcomes at the population level using a national database. METHODS: Patient variables and treatment-related outcomes were abstracted for patients with clinical stage I NSCLC from the National Cancer Database. Patients receiving surgery were compared with those undergoing stereotactic body radiation therapy (SBRT) in exploratory unmatched and subsequent propensity matched analyses. RESULTS: Between 1998 and 2010, 117,618 patients underwent surgery or SBRT for clinical stage I NSCLC. Of these, 111,731 (95%) received surgery, whereas 5887 (5%) underwent SBRT. Patients in the surgery group were younger, more likely to be males, and had higher Charlson comorbidity scores. SBRT patients were more likely to have T1 (versus T2) tumors and receive treatment at academic centers. Thirty-day surgical mortality was 2596 of 109,485 (2.4%). Median overall survival favored the surgery group in both unmatched (68.4 versus 33.3 months, p < 0.001) and matched analysis based on patient characteristics (62.3 versus 33.1 months, p < 0.001). Disease-specific survival was unavailable from the data set. CONCLUSION: In a propensity matched comparison, patients selected for surgery have improved survival compared with SBRT. In the absence of information on cause of death and with limited variables to characterize comorbidity, it is not possible to assess the relative contribution of patient selection or better cancer control toward the improved survival. Rigorous prospective studies are needed to optimize patient selection for SBRT in the high-risk surgical population.

The Role of Surgical Resection in Stage IIIA Non-Small Cell Lung Cancer: A Decision and Cost-Effectiveness Analysis.

BACKGROUND: This study evaluated the cost-effectiveness of combination chemotherapy, radiotherapy, and surgical intervention (CRS) vs definitive chemotherapy and radiotherapy (CR) in clinical stage IIIA non-small cell lung cancer (NSCLC) patients at academic and nonacademic centers. METHODS: Patients with clinical stage IIIA NSCLC receiving CR or CRS from 1998 to 2010 were identified in the National Cancer Data Base. Propensity score matching on patient, tumor, and treatment characteristics was performed. Medicare allowable charges were used for treatment costs. The incremental cost-effectiveness ratio (ICER) was based on probabilistic 5-year survival and calculated as cost per life-year gained. RESULTS: We identified 5,265 CR and CRS matched patient pairs. Surgical resection imparted an increased effectiveness of 0.83 life-years, with an ICER of $17,618. Among nonacademic centers, 1,634 matched CR and CRS patients demonstrated a benefit with surgical resection of 0.86 life-years gained, for an ICER of $17,124. At academic centers, 3,201 matched CR and CRS patients had increased survival of 0.81 life-years with surgical resection, for an ICER of $18,144. Finally, 3,713 CRS patients were matched between academic and nonacademic centers. Academic center surgical patients had an increased effectiveness of 1.5 months gained and dominated the model with lower surgical cost estimates associated with lower 30-day mortality rates. CONCLUSIONS: In stage IIIA NSCLC, the selective addition of surgical resection to CR is cost-effective compared with definitive chemoradiation therapy at nonacademic and academic centers. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes.

Pathologic Upstaging in Patients Undergoing Resection for Stage I Non-Small Cell Lung Cancer: Are There Modifiable Predictors?

BACKGROUND: A substantial proportion of patients with clinical stage I non-small cell lung cancer (NSCLC) have more advanced disease on final pathologic review. We studied potentially modifiable factors that may predict pathologic upstaging. METHODS: Data of patients with clinical stage I NSCLC undergoing resection were obtained from the National Cancer Database. Univariate and multivariate analyses were performed to identify variables that predict upstaging. RESULTS: From 1998 to 2010, 55,653 patients with clinical stage I NSCLC underwent resection; of these, 9,530 (17%) had more advanced disease on final pathologic review. Of the 9,530 upstaged patients, 27% had T3 or T4 tumors, 74% had positive lymph nodes (n > 0), and 4% were found to have metastatic disease (M1). Patients with larger tumors (38 mm vs 29 mm, p < 0.001) and a delay greater than 8 weeks from diagnosis to resection were more likely to be upstaged. Upstaged patients also had more lymph nodes examined (10.9 vs 8.2, p < 0.001) and were more likely to have positive resection margins (10% vs 2%, p < 0.001). Median survival was lower in upstaged patients (39 months vs 73 months). Predictors of upstaging in multivariate regression analysis included larger tumor size, delay in resection greater 8 weeks, positive resection margins, and number of lymph nodes examined. There was a linear relationship between the number of lymph nodes examined and the odds of upstaging (1 to 3 nodes, odds ratio [OR] 2.01; >18 nodes OR 6.14). CONCLUSIONS: Pathologic upstaging is a common finding with implications for treatment and outcomes in clinical stage I NSCLC. A thorough analysis of regional lymph nodes is critical to identify patients with more advanced disease.

Multidisciplinary Treatment for Stage IIIA Non-Small Cell Lung Cancer: Does Institution Type Matter?

BACKGROUND: Improved survival of patients with early-stage non-small cell lung cancer (NSCLC) undergoing resection at high-volume centers has been reported. However, the effect of institution is unclear in stage IIIA NSCLC, where a variety of neoadjuvant and adjuvant therapies are used. METHODS: Treatment and outcomes data of clinical stage IIIA NSCLC patients undergoing resection as part of multimodality therapy was obtained from the National Cancer Database. Multivariable regression models were fitted to evaluate variables influencing 30-day mortality and overall survival. RESULTS: From 1998 to 2010, 11,492 clinical stage IIIA patients underwent resection at community centers, and 7,743 patients received resection at academic centers. Academic center patients were more likely to be younger, female, non-Caucasian, have a lower Charlson-Deyo comorbidity score, and to receive neoadjuvant chemotherapy (49.6% vs 40.6%; all p < 0.001). Higher 30-day mortality was associated with increasing age, male gender, preoperative radiotherapy, and pneumonectomy. Patients undergoing operations at academic centers experienced lower 30-day mortality (3.3% vs 4.5%; odds ratio, 0.75; 95% confidence interval [CI], 0.60 to 0.93; p < 0.001). Decreased long-term survival was associated with increasing age, male gender, higher Charlson-Deyo comorbidity score, and larger tumors. Neoadjuvant chemotherapy (hazard ratio, 0.66; 95% CI, 0.62 to 0.70), surgical intervention at an academic center (hazard ratio, 0.92; 95% CI, 0.88 to 0.97), and lobectomy (hazard ratio, 0.72; 95% CI, 0.67 to 0.77) were associated with improved overall survival. CONCLUSIONS: Stage IIIA NSCLC patients undergoing resection at academic centers had lower 30-day mortality and increased overall survival compared with patients treated at community centers, possibly due to higher patient volume and an increased rate of neoadjuvant chemotherapy.