Meta-Analysis of Rates and Risk Factors for Local Recurrence in Surgically Resected Patients With NSCLC and Differences Between Asian and Non-Asian Populations.

Introduction: Postoperative radiotherapy (PORT) reduces local failure in patients with NSCLC, without a clear overall survival benefit. It is unknown whether the subsets of patients benefit. Two recent large randomized controlled trials, PORT-C (People's Republic of China) and Lung ART (Europe), reported widely different locoregional recurrence (LR) rates in the control arms, at 18.3% and 28.1% (46% of which were mediastinal recurrences), respectively. We performed a meta-analysis of patients with pathologic (p) N0 to N2 disease to evaluate the risk factors for LR and to explore possible differences in recurrence risk between Asian population (AP) and non-Asian population (NAP). Methods: We identified all original studies of curative NSCLC surgical resection which reported risk of LR between January 1, 2000, and January 10, 2021, excluding studies with less than 10 LR, patients with metastatic disease, or any neoadjuvant therapy. A total of 87 studies were identified with pN0 to N2 disease; of these, 56 were of high quality (HQ) on the basis of the Newcastle-Ottawa Scale. For each risk factor, we derived pooled relative risk (RR) and 5-year rate estimates using random-effects models. Results: Overall, the three significant highest pooled RRs (95% confidence intervals) for LR were pN2 versus pN0 (3.01, 1.39-6.55), lymphovascular invasion (1.92, 1.58-2.33), and advanced pT3-4 stage versus pT1 (1.86, 1.53-2.25). For HQ studies, the highest RRs for LR were lymphovascular invasion (1.94, 1.57-2.40), sublobar versus lobar resection (1.86, 1.46-2.36), and pN1 versus pN0 (1.84, 1.37-2.47), but pN2 versus pN0 was no longer significant (3.0, 0.57-15.61), on the basis of only two eligible studies. The RRs for LR were consistent for most factors in AP and NAP, although the RR for male versus female sex was higher in AP (1.44, 1.21-1.72) than in NAP (1.09, 0.99-1.19). Where reported, the pooled rate of LR at 5 years was lower in AP (12.0%) than in NAP (22.7%), despite similar overall 5-year recurrence rates (both LR and distal) in both populations: 38.0% in AP and 37.3% in NAP. Nevertheless, a lower 5-year mortality rate was noted in AP (24.3%) than in NAP (45.9%). Conclusions: There is little high-quality evidence to support the hypothesis that pN2 disease is a risk factor for LR, but LR seems to be lower in Asians. Prospective evaluation of LR factors and rates may be necessary before further prospective evaluation of PORT, because it may not depend on nodal status alone. Recurrence rates may differ in Asians. The impact of mutational status and modern treatment including targeted therapies and immune checkpoint inhibitors is inadequately studied.

Bevacizumab's Association With a Decreased Risk of Brain Metastases in ECOG-ACRIN E1505, a Phase 3 Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab in Surgically Resected NSCLC.

Introduction: ECOG-ACRIN E1505 was a phase 3 randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with stages IB (>4 cm) to IIIA NSCLC. We sought to estimate the incidence and risk factors for brain recurrence as compared with extracranial recurrences (ECRs). Methods: ECOG-ACRIN E1505 noted that bevacizumab failed to improve overall survival (OS) (OS hazard ratio [HR] = 0.99 [0·82-1·19], p = 0.90) or recurrence-free survival when added to chemotherapy in the adjuvant setting. The cumulative incidence of brain/ECR was estimated after adjusting for recurrence at other sites and death as competing events. A multivariable regression model was fitted using competing risk analysis to evaluate the effect of covariates on brain recurrence incidence. Results: Median follow-up was 50.4 months. Among the 1501 patients enrolled, 472 developed ECR. There were 122 patients who had recurrence in the brain with or without simultaneous ECR as the first recurrence site (all-brain recurrences [ABRs]), and 84 of those with ABRs had recurrence in the brain only (isolated-brain recurrence [IBR]). The incidence of ABR, IBR, and ECR at 6 years was 9.9%, 5.9%, and 38.8%, respectively. Chemotherapy plus bevacizumab was associated with a decreased incidence of ABR (HR = 0.64, p = 0.02) and IBR (HR = 0.62, p = 0.032), but there was no significant trend for an OS decrement in the bevacizumab arm versus the control arm for both ABR and IBR. Median survivals associated with IBR, ABR, and ECR were 9.5, 9.5, and 14.1 months, respectively. Nonsquamous histology (HR = 1.87, p = 0.003) was also associated with ABR. ECR was associated with nonsquamous NSCLC histology (HR = 1.79, p < 0.01) and stage/N2 involvement (HR = 1.13/1.37, both p < 0.01). Conclusions: The addition of bevacizumab to chemotherapy was associated with reduction in brain recurrences, but not ECR. Brain metastases whether isolated or not are associated with a lower median survival than ECR and unlike ECR are not associated with traditional staging variables.

A Review of Immunotherapy for Stage III and Metastatic Non-Small Cell Lung Cancer and the Rationale for the ECOG-ACRIN EA5181 Study.

ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA-NSCLC) to concomitant durvalumab or no additional therapy, with both arms receiving 1 year of consolidative durvalumab. Radiation dose escalation failed to improve overall survival in RTOG 0617. However, conventionally fractionated radiation to 60 Gy with concomitant chemotherapy is associated with a high risk of local failure (38%-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we review conventional chemo/radiation therapy for LA-NSCLC, as well as the quickly evolving world of immunotherapy in the treatment of non-small cell lung cancer and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: This article provides an up-to-date assessment of how immunotherapy is reshaping the landscape of metastatic non-small cell lung cancer (NSCLC) and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. This article reviews the recent publications of chemo/radiation as well as those combining immunotherapy with chemotherapy and chemo/radiation, and provides a strategy for improving overall survival of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.

The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management.

Purpose: To identify the incidence, preoperative risk factors, and prognosis associated with pathologically positive lymph node (pN+) in patients undergoing a sub-lobar resection (SLR). Methods: This is a retrospective study using the National Cancer Database (NCDB) from 2004 to 2014 analyzing SLR excluding those with any preoperative chemotherapy and/or radiation, follow-up <3 months, stage IV disease, or >1 tumor nodule. Multivariable modeling (MVA) was used to determine factors associated with overall survival (OS). Propensity score matching (PSM) was used to determine preoperative risk factors for pN+ in patients having at least one node examined to assess radiation's effect on OS in those patients with pN+ and to determine whether SLR was associated with inferior OS as compared to lobectomy for each nodal stage. Results: A total of 40,202 patients underwent SLR, but only 58.3% had one lymph node examined. Then, 2,615 individuals had pN+ which decreased progressively from 15.1% in 2004 to 8.9% in 2014 (N1, from 6.3 to 3.0%, and N2, from 8.4 to 5.9%). A lower risk of pN+ was noted for squamous cell carcinomas, bronchioloalveolar adenocarcinoma (BAC), adenocarcinomas, and right upper lobe locations. In the pN+ group, OS was worse without chemotherapy or radiation. Radiation was associated with a strong trend for OS in the entire pN+ group (p = 0.0647) which was largely due to the effects on those having N2 disease (p = 0.009) or R1 resections (p = 0.03), but not N1 involvement (p = 0.87). PSM noted that SLR was associated with an inferior OS as compared to lobectomy by nodal stage in the overall patient population and even for those with tumors <2 cm. Conclusion: pN+ incidence in SLRs has decreased over time. SLR was associated with inferior OS as compared to lobectomy by nodal stage. Radiation appears to improve the OS in patients undergoing SLR with pN+, especially in those with N2 nodal involvement and/or positive margins.

Diabetes mellitus type 2 is associated with increased tumor expression of programmed death-ligand 1 (PD-L1) in surgically resected non-small cell lung cancer-A matched case-control study.

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics. METHODS: A matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID: 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0: no staining; TPS1: <1%; TPS2: 1-49%; TPS3: ≥50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model. RESULTS: Diabetics (n=40) and nondiabetics (n=39) showed no differences in age, gender, cancer stage, and follow-up. NSCLCs were more likely PD-L1 positive in diabetics but with tumor positivity <50% (TPS0: 7.5 vs. 20.5%, TPS1: 35 vs. 25.6%, TPS2: 45 vs.23.1%, TPS3: 12.5 vs. 30.8%, respectively; P<0.05). In diabetics, squamous cell carcinomas (SCC) and adenocarcinomas were mainly TPS2 (65% vs. 20%) and TPS1 (50% vs. 26%), respectively. Peritumoral inflammation correlated with TPS (r=0.228), a relationship accentuated in diabetics (r=0.377, P<0.05) but diminished and non-significant in nondiabetics (r=0.136, P≥0.05). This association was stronger in SCC (r=0.424). Diabetes was associated with increased tumor recurrence (HR: 3.08; 95%CI: 1.027-9.23). CONCLUSION: Diabetes is associated with an increase in peritumoral inflammation, PD-L1 positivity, and recurrence in NSCLC, more pronounced in SCC, suggesting the possibility of metabolic reprogramming and upregulation of PD-L1 by inducible pathways.

The Role of Race and Economic Characteristics in the Presentation and Survival of Patients With Surgically Resected Non-Small Cell Lung Cancer.

BACKGROUND: Little is understood regarding the inter-relation between economic, marital, and racial/ethnic differences in presentation and survival of surgically resected lung cancer patients. Our investigation will assess these differences in addition to known therapeutic, patient, and histopathologic factors. METHODS: A retrospective review of the Surveillance Epidemiology and End Reporting database was conducted through the years 2007-2012. The population was split into nine different ethnic groups. Population differences were assessed via chi-square testing. Multivariable analysis (MVA) were used to detect overall survival (OS) differences in the total surgical population (TS, N = 35,689) in an ear (T1-T2 < 4 cm N0) surgical population [early-stage resectable (ESR), N = 17,931]. Lung cancer-specific survival (LCSS) was assessed in the ESR. RESULTS: In the TS population, as compared to Whites, Blacks, and Hispanics presented with younger age, more adenocarcinomas, lower rates of marriage, lower rates of insurance, less stage I tumors, and had less nodes examined, but their type of surgical procedures and OS/LCSS were the same. MVA demonstrated that lower OS and LCSS were associated with males, single/divorced/widowed partnership, lower income (TS only), and Medicaid insurance. MVA also found that Blacks and Hispanics had a similar OS/LCSS to Whites and that all ethnic groups were associated with a similar or better outcomes. The 90-day mortality and positive nodes were correlated with not having insurance and not being married, but they were not associated with ethnicity. CONCLUSION: In TS and ESR groups, OS was not different in the two largest ethnic groups (Black and Hispanic) as compared to Whites, but was related to single/widowed/divorced status, Medicaid insurance, and income (TS group only). Nodal positivity was associated with patients who did not have a married partner or insurance suggesting that these factors may impact disease biology. Economic and psychosocial variables may play a role in survival of ear lung cancer in addition to standard histopathologic and treatment variables.

Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer.

A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-ß), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-ß, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.

Optimal Frequency of Psychosocial Distress Screening in Radiation Oncology.

PURPOSE: To accurately hypothesize the optimal frequency of psychosocial distress screening in patients undergoing radiation therapy using exploratory modeling of prospective data. MATERIALS AND METHODS: Between October 2010 and May 2011, 71 RT patients underwent daily screening with the Distress Thermometer. Prevalences of Distress Thermometer scores ≥ 4 were recorded. Optimal screening frequency was evaluated by planned post hoc comparison of prevalence rates and required screening events estimated by numerical modeling, consisting of data point omission to mimic weekly, every-other-week, monthly, and one-time screening intervals. Dependence on clinical variables and chronologic trends were assessed as secondary end points. RESULTS: A total of 2,028 daily screening events identified that 37% of patients reported distress at least once during the course of treatment. Weekly, every-other-week, monthly, and one-time screening models estimated distress prevalences of 32%, 31%, 23%, and 17%, respectively, but required only 21%, 12%, 7%, and 4% of the assessments required for daily screening. No clinical parameter significantly predicted distress in univariable analysis, but "alone" living situation trended toward significance (P = .06). Physician-reported grade 3 toxicity predicted distress with 98% specificity, but only 19% sensitivity. CONCLUSION: Thirty-seven percent of radiation oncology patients reported distress at least once during treatment. Screening at every-other-week intervals optimized efficiency and frequency, identifying nearly 90% of distressed patients with 12% of the screening events compared with daily screening.

Current role of radiation therapy for multiple myeloma.

BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. CONCLUSION: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.

Nodal stage of surgically resected non-small cell lung cancer and its effect on recurrence patterns and overall survival.

PURPOSE: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy (PORT) for patients with resected non-small cell lung cancer (NSCLC) with N2 involvement. We investigated the relationship between nodal stage and local-regional recurrence (LR), distant recurrence (DR) and overall survival (OS) for patients having an R0 resection. METHODS AND MATERIALS: A multi-institutional database of consecutive patients undergoing R0 resection for stage I-IIIA NSCLC from 1995 to 2008 was used. Patients receiving any radiation therapy before relapse were excluded. A total of 1241, 202, and 125 patients were identified with N0, N1, and N2 involvement, respectively; 161 patients received chemotherapy. Cumulative incidence rates were calculated for LR and DR as first sites of failure, and Kaplan-Meier estimates were made for OS. Competing risk analysis and proportional hazards models were used to examine LR, DR, and OS. Independent variables included age, sex, surgical procedure, extent of lymph node sampling, histology, lymphatic or vascular invasion, tumor size, tumor grade, chemotherapy, nodal stage, and visceral pleural invasion. RESULTS: The median follow-up time was 28.7 months. Patients with N1 or N2 nodal stage had rates of LR similar to those of patients with N0 disease, but were at significantly increased risk for both DR (N1, hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.30-2.59; P=.001; N2, HR = 2.32, 95% CI: 1.55-3.48; P<.001) and death (N1, HR = 1.46, 95% CI: 1.18-1.81; P<.001; N2, HR = 2.33, 95% CI: 1.78-3.04; P<.001). LR was associated with squamous histology, visceral pleural involvement, tumor size, age, wedge resection, and segmentectomy. The most frequent site of LR was the mediastinum. CONCLUSIONS: Our investigation demonstrated that nodal stage is directly associated with DR and OS but not with LR. Thus, even some patients with, N0-N1 disease are at relatively high risk of local recurrence. Prospective identification of risk factors for local recurrence may aid in selecting an appropriate population for further study of postoperative radiation therapy.

Would screening for lung cancer benefit 75- to 84-year-old residents of the United States?

BACKGROUND: The National Lung Screening Trial demonstrated that screening for lung cancer improved overall survival (OS) and reduced lung cancer mortality in the 55- to 74-year-old age group by increasing the proportion of cancers detected at an early stage. Because of the increasing life expectancy of the American population, we investigated whether screening for lung cancer might benefit men and women aged 75-84 years. MATERIALS/METHODS: Rates of non-small cell lung cancer (NSCLC) from 2000 to 2009 were calculated in both younger and older age groups using the surveillance epidemiology and end reporting database. OS and lung cancer-specific survival (LCSS) in patients with Stage I NSCLC diagnosed from 2004 to 2009 were analyzed to determine the effects of age and treatment. RESULTS: The per capita incidence of NSCLC decreased in the 55-74 cohort, but increased in the 75-84 cohort over the study period. Crude lung cancer death rates in the two age groups who had no specific treatment were 39.5 and 44.9%, respectively. These rates fell in both age groups when increasingly aggressive treatment was used. Rates of OS and LCSS improved significantly with increasingly aggressive treatment in the 75-84 age group. The survival benefits of increasingly aggressive treatment in 75- to 84-year-old females did not differ from their counterparts in the younger cohort. CONCLUSION: Screening for lung cancer might be of benefit to individuals at increased risk of lung cancer in the 75-84 age group. The survival benefits of aggressive therapy are similar in females between 55-74 and 75-84 years old.

Local recurrence after surgery for non-small cell lung cancer: a recursive partitioning analysis of multi-institutional data.

OBJECTIVE: To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA). METHODS: This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method. RESULTS: The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69). CONCLUSIONS: The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups.

Identification of stage I non-small cell lung cancer patients at high risk for local recurrence following sublobar resection.

OBJECTIVE: An increasing proportion of patients with stage I non-small cell lung cancer (NSCLC) is undergoing sublobar resection (L-). However, there is little information about the risks and correlates of local recurrence (LR) after such surgery, especially compared with patients undergoing lobectomy (L+). METHODS: Ninety-three and 318 consecutive patients with stage I NSCLC underwent L- and L+, respectively, from 2000 to 2006. Median follow-up was 34 months. RESULTS: In the L- group, the LR rates at 2, 3, and 5 years were 13%, 24%, and 40%, respectively. The risk of LR was significantly associated with tumor grade, tumor size, and T stage. The crude risk of LR was 33.8% (21 of 62) for patients whose tumors were grade ≥ 2. In the L+ group, the LR rates at 2, 3, and 5 years were 14%, 19%, and 24%, respectively. The risk of LR significantly increased with increasing tumor size, length of hospital stay, and the presence of diabetes. The L- group experienced a significant increase in failure in the bronchial stump/staple line compared with the L+ group (10% vs 3%; P = .04) and nonsignificant trends toward increased ipsilateral hilar and subcarinal failure rates. CONCLUSIONS: Patients with stage I NSCLC who undergo L- have an increased risk of LR compared with patients undergoing L+, particularly when they have tumors grade ≥ 2 or tumor size > 2 cm. If L- is considered, additional local therapy should be considered to reduce this risk of LR, especially with tumors grade ≥ 2 or size > 2 cm.

Lobectomy leads to optimal survival in early-stage small cell lung cancer: a retrospective analysis.

OBJECTIVE: Stage I or II small cell lung cancer is rare. We evaluated the contemporary incidence of early-stage small cell lung cancer and defined its optimal local therapy. METHODS: We analyzed the incidence, treatment patterns, and outcomes of 2214 patients with early-stage small cell lung cancer (1690 with stage I and 524 with stage II) identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2005. RESULTS: Early-stage small cell lung cancer constituted a stable proportion of all small cell lung cancers (3%-5%), lung cancers (0.10%-0.17%), and stage I lung cancers (1%-1.5%) until 2003 but, by 2005, increased significantly to 7%, 0.29%, and 2.2%, respectively (P < .0001). Surgery for early-stage small cell lung cancer peaked at 47% in 1990 but declined to 16% by 2005. Patients treated with lobectomy or greater resections (lobe) without radiotherapy had longer median survival (50 months) than those treated with sublobar resections (sublobe) without radiotherapy (30 months, P = .006) or those treated with radiotherapy alone (20 months, P < .0001). Patients undergoing sublobe without radiotherapy also demonstrated superior survival than patients receiving radiotherapy alone (P = .002). The use or omission of radiotherapy made no difference after limited resection (30 vs 28 months, P = .6). Multivariable analysis found survival independently related to age, year of diagnosis, tumor size, stage, and treatment (lobe vs sublobe vs radiotherapy alone). CONCLUSIONS: Surgery is an underused modality in the management of early-stage small cell lung cancer. Lobectomy provides optimal local control and leads to superior survival. Although sublobar resection proved inferior to lobectomy, it conferred a survival advantage superior to radiotherapy alone. The addition of radiotherapy to resection provided no additional benefit.

Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas?

BACKGROUND: To compare the presenting and prognostic characteristics of patients with large cell neuroendocrine lung cancer (LCNELC) with those of patients with small cell lung cancer (SCLC) or other large cell carcinomas (OLCs) and to compare overall survival (OS) and lung cancer-specific survival (LCSS) rates for patients undergoing definitive resection without radiotherapy (S-NoRT). METHODS: The Surveillance Epidemiology and End Results Database-17 from 2001 to 2007 was used. Differences between population characteristics were compared using χ(2) and Wilcoxon tests. The log-rank test and Cox models were used to compare differences in OS and LCSS. RESULTS: There were 1211 patients with LCNELC (324 in the S-NoRT group), 8295 patients with OLC (1120 S-NoRT), and 35,304 patients with SCLC (355 S-NoRT). The proportion of all large cell carcinomas constituted by LCNELC increased from 8 to 21% during the study period; and the proportion of patients with large cell carcinoma undergoing S-NoRT increased from 16 to 26%. Presenting and histopathologic characteristics and treatment factors of patients undergoing S-NoRT for patients with LCNELC were more similar to those of patients with OLC than to those with SCLC. OS and LCSS rates for patients with LCNELC undergoing resection without radiation were similar to those of patients with OLC and better than those for patients with SCLC, but the differences were not statistically significant on multivariate analysis. CONCLUSIONS: The clinical, histopathologic, and biologic features of LCNELC are more similar to OLC than to SCLC. Therefore, LCNELC should continue to be classified and treated as a large cell carcinoma.

Failure rates and patterns of recurrence in patients with resected N1 non-small-cell lung cancer.

PURPOSE: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non-small-cell lung cancer. METHODS AND MATERIALS: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. RESULTS: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site of local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. CONCLUSIONS: Patients with resected non-small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy.

Varying recurrence rates and risk factors associated with different definitions of local recurrence in patients with surgically resected, stage I nonsmall cell lung cancer.

BACKGROUND: The objective of this study was to examine the effects of different definitions of local recurrence on the reported patterns of failure and associated risk factors in patients who undergo potentially curative resection for stage I nonsmall cell lung cancer (NSCLC). METHODS: The study included 306 consecutive patients who were treated from 2000 to 2005 without radiotherapy. Local recurrence was defined either as 'radiation' (r-LR) (according to previously defined postoperative radiotherapy fields), including the bronchial stump, staple line, ipsilateral hilum, and ipsilateral mediastinum; or as 'comprehensive' (c-LR), including the same sites plus the ipsilateral lung and contralateral mediastinal and hilar lymph nodes. All recurrences that were not classified as "local" were considered to be distal. RESULTS: The median follow-up was 33 months. The proportions of c-LR and r-LR at 2 years, 3 years, and 5 years were 14%, 21%, and 29%, respectively, and 7%, 12%, and 16%, respectively. Significant risk factors for c-LR on multivariate analysis were diabetes, lymphatic vascular invasion, and tumor size; and significant factors for r-LR were resection of less than a lobe and lymphatic vascular invasion. The proportions of distant (non-local) recurrence using these definitions at 2 years, 3 years, and 5 years were 10%, 12%, and 18%, respectively, and 14%, 19%, and 29%, respectively. Significant risk factors for distant failure were histology when using the c-LR definition and tumor size when using the r-LR definition. CONCLUSIONS: Local recurrence increased nearly 2-fold when a broad definition was used instead of a narrow definition. The definition also affected which factors were associated significantly with both local and distant failure on multivariate analysis. Comparable definitions must be used when analyzing different series.

Extent of lymphadenectomy and outcome for patients with stage I nonsmall cell lung cancer.

BACKGROUND: It is uncertain whether lymphadenectomy (LA) affects overall survival (OS) or disease-free survival (DFS) rates for patients with stage I nonsmall cell lung cancer (NSCLC), as is the optimal number of lymph nodes that should be recovered. METHODS: There were 24,273 patients with stage I NSCLC diagnosed from 1992 to 2002 who were included in the Surveillance, Epidemiology, and End Results database and who underwent a definitive surgical procedure. Median follow-up was 35 months. RESULTS: For the entire population, having LA was associated with an increase in the 5-year OS rate from 41.6% to 58.4% (P<.0001) and in DFS from 58.0% to 73.09%, compared with not having LA. Outcome improved with increasing number of recovered lymph nodes, with a plateau at 11 or more lymph nodes. For patients diagnosed from 1998 to 2002 undergoing only N1 or only N2 dissections, LA was also associated with statistically significant improvements in OS in both groups and a significant difference and trend for improved DFS in the 2 groups, respectively. The maximum differences in both OS and DFS between those with no LA and those with LA occurred when 11 to 16 lymph nodes were removed for the former group or 7 to 10 lymph nodes for the latter group, respectively. CONCLUSIONS: LA was associated with increased rates of OS and DFS, compared with no LA. Our results also suggest the minimum number of recovered lymph nodes needed to see the maximum staging accuracy conferred by LA.

Factors associated with local and distant recurrence and survival in patients with resected nonsmall cell lung cancer.

BACKGROUND: This study assessed the impact of surgical, histopathologic and patient-related factors on the risks of local and distant recurrence and overall survival for patients with stages I through IIIA nonsmall cell lung carcinoma (NSCLC) undergoing definitive resection with or without adjuvant chemotherapy. METHODS: This study included 373 consecutive patients treated between 2000 and 2005 who did not receive adjuvant or neoadjuvant radiotherapy, had at least 3 months of follow-up, and did not have a history of other cancers within 5 years of the diagnosis of their NSCLC. Of these, 52% had pathologic stage IA disease, 30% had stage IB, 5% had stage IIA, 8% had stage IIB and 5% had stage III disease. Forty-four patients received chemotherapy. RESULTS: The median follow-up was 33 months. Local failure rates at 2 years, 3 years, and 5 years were 16%, 22%, and 32%, respectively; distant recurrence rates were 13%, 15%, and 21%, respectively. Multivariable analysis revealed that local recurrence was significantly associated with the presence of lymphatic or vascular invasion (LVI), the use of chemotherapy, and having diabetes; distant recurrence was significantly higher in patients with nonsquamous cell histology, those undergoing pneumonectomy, and those with more advanced TNM stage. Survival was significantly associated with age, history of myocardial infarction, performance of a pneumonectomy, histology, LVI, and the number of positive N1 lymph nodes. CONCLUSIONS: Local recurrence was the predominant type of failure in this series. Patient with diabetes or LVI may benefit from close surveillance and aggressive therapy of asymptomatic local recurrences, especially when chemotherapy is given in addition to surgery.