Daniel J. Boffa

The New Lung Cancer Staging System

The International Association for the Study of Lung Cancer (IASLC) has conducted an extensive initiative to inform the revision of the lung cancer staging system. This involved development of an international database along with extensive analysis of a large population of patients and their prognoses. This article reviews the recommendations of the IASLC International Staging Committee for the definitions for the TNM descriptors and the stage grouping in the new non-small cell lung cancer staging system.

Using the National Cancer Database for Outcomes Research: A Review

Importance The National Cancer Database (NCDB), a joint quality improvement initiative of the American College of Surgeons Commission on Cancer and the American Cancer Society, has created a shared research file that has changed the study of cancer care in the United States. A thorough understanding of the nuances, strengths, and limitations of the database by both readers and investigators is of critical importance. This review describes the use of the NCDB to study cancer care, with a focus on the advantages of using the database and important considerations that affect the interpretation of NCDB studies. Observations The NCDB is one of the largest cancer registries in the world and has rapidly become one of the most commonly used data resources to study the care of cancer in the United States. The NCDB paints a comprehensive picture of cancer care, including a number of less commonly available details that enable subtle nuances of treatment to be studied. On the other hand, several potentially important patient and treatment attributes are not collected in the NCDB, which may affect the extent to which comparisons can be adjusted. Finally, the NCDB has undergone several significant changes during the past decade that may affect its completeness and the types of available data. Conclusions and Relevance The NCDB offers a critically important perspective on cancer care in the United States. To capitalize on its strengths and adjust for its limitations, investigators and their audiences should familiarize themselves with the advantages and shortcomings of the NCDB, as well as its evolution over time.

Stereotactic Body Radiotherapy for Central Lung Tumors

Introduction: Patients with centrally located lung tumors have been reported to have a higher risk of toxicity when treated with stereotactic body radiotherapy (SBRT) compared with patients with peripheral tumors. The optimal SBRT fractionation schedule for treatment of central tumors is unknown. The primary purpose of this study was to assess toxicity in patients with central lesions treated with SBRT at our institution, the majority of whom were treated with four fractions. Methods: Forty-seven patients with 51 central lesions, either primary lung cancer or lung metastases, were treated with SBRT at the Department of Therapeutic Radiology, Yale University School of Medicine/Yale Cancer Center from 2007 to 2011. The patients were treated with three to five fractions with the majority of patients receiving 50 Gy in four fractions of 12.5 Gy. Forty of the lesions were located within 2 cm of the proximal tracheobronchial tree whereas 11 were located within 2 cm of other mediastinal structures. Toxicity data were collected and analyzed according to pretreatment and tumor characteristics and dosimetric parameters. Lobar control data were compiled. Results: With a median follow-up of 11.3 months (range, 4.8–40.8), four patients experienced grade 3 dyspnea and one patient developed hemoptysis that contributed to respiratory failure and subsequent death. Grade 2 toxicity included fatigue (n = 3), dyspnea (n = 3), chest-wall pain (n = 1), and cough (n = 1). Patients with grade 3+ toxicity had larger maximum tumor diameters compared with those patients without grade 3+ toxicity (median diameter 4.3 cm versus 2.9 cm, p = 0.02). There were no detectable significant differences between the two groups with respect to baseline pulmonary function tests, distance to tracheobronchial tree, maximum point dose to the tracheobronchial tree, maximum dose to 5 cc of the tracheobronchial tree, mean lung dose, and volume of lung receiving 5 Gy, 10 Gy, and 20 Gy. There were two patients who experienced local recurrences. The median biological equivalent dose (linear quadratic formula, &agr;/&bgr; = 10) for patients with local recurrence was 76 Gy compared with 112.5 Gy for patients without local recurrence (2-tailed t test, p = 0.04). The 2-year actuarial lobar local control for the entire cohort was 94%. The 2-year lobar local-control rate for patients receiving a biological equivalent dose of 100 Gy or more was 100% and for those receiving less than 100 Gy was 80% (log rank, p = 0.02). Conclusion: SBRT for central lung tumors seems to be safe, although treatment of larger tumors does carry an increased risk of high-grade toxicity. Efforts to decrease the toxicity risk by decreasing the biologically equivalent dose resulted in increased local failure.

Impact of Hospital Volume of Thoracoscopic Lobectomy on Primary Lung Cancer Outcomes

BACKGROUND This study evaluated hospital operative volume of video-assisted thoracoscopic surgery (VATS) lobectomy in primary lung cancer as a predictor of short-term outcomes after pulmonary lobectomy on a national scale. Some previous analyses comparing VATS vs open lobectomy outcomes have been limited by inaccuracies in patient cohort identification. METHODS The 2008 Healthcare Utilization Project-Nationwide Inpatient Sample database was culled using the International Classification of Diseases (9th Clinical Modification) procedure codes specifically distinguishing VATS vs open lobectomies (32.41 and 32.49, respectively) available only after October 2007. High hospital VATS volume was defined as 95th percentile or higher (>20 VATS/year). Univariable and multivariable analyses were used to identify independent predictors of the following outcome measures: 30-day in-hospital morbidity and mortality, hospital length of stay (LOS), and hospital costs. RESULTS We identified 6,292 primary lung cancer patients undergoing pulmonary lobectomy, including 1,523 undergoing VATS (24%). Compared with open, VATS patients had fewer complications (38% vs 44%, p<0.001) and median LOS (5 vs 7 days; p<0.001). In multivariable analysis, VATS was an independent predictor of fewer total complications (odds ratio, 0.83; p=0.004) and shorter LOS (2.3±0.3-day difference, p<0.001). Patients undergoing VATS at high-volume VATS hospitals had shorter median LOS (4 vs 6 days, p=0.001) compared with low-volume VATS hospitals. Multivariable analysis showed high hospital VATS volume independently predicted shorter LOS (0.9±0.4-day difference, p=0.001). CONCLUSIONS In a national database, VATS lobectomy was associated with fewer complications and shorter LOS than open lobectomy in primary lung cancer patients. Among patients undergoing VATS, high hospital volume was also associated with shorter LOS.

The Eighth Edition Lung Cancer Stage Classification

&NA; Stage classification provides a nomenclature about the anatomic extent of a cancer; a consistent language provides the ability to communicate about a specific patient and about cohorts of patients in clinical studies. This paper summarizes the eighth edition of lung cancer stage classification, which is the worldwide standard as of January 1, 2017. This revision is based on a large global database, a sophisticated analysis, extensive internal validation as well as multiple assessments confirming generalizability. Practicing clinicians must be familiar with the stage classification system when managing contemporary patients with lung cancer.

An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non–small cell lung cancer

OBJECTIVE Pneumonectomy after neoadjuvant therapy remains controversial. METHODS A systematic PubMed search was performed for original articles from 1990 through 2010 describing pneumonectomy after neoadjuvant therapy. Specific data on 30-day and 90-day perioperative mortalities were abstracted from these articles. Meta-analysis compared 30-day mortality between right and left pneumonectomy with a fixed-effects model. Comparison between 30-day and 90-day mortalities was also performed. RESULTS The search strategy yielded 27 studies. Overall, 30-day and 90-day perioperative mortalities were 7% and 12%, respectively. Among 15 studies providing side-specific 30-day mortality, cumulative mortalities were 11% and 5% for right and left pneumonectomies, respectively. In the meta-analysis that included 10 studies, 30-day mortality for right pneumonectomy remained greater than for left pneumonectomy (odds ratio, 1.97; 95% confidence interval, 1.11-3.49; P = .02). Among 6 studies providing side-specific 90-day mortality, cumulative mortalities were 20% and 9% for right and left pneumonectomies, respectively. In the meta-analysis that included 4 studies, 90-day mortality for right pneumonectomy was greater than for left pneumonectomy (odds ratio, 2.01; 95% confidence interval, 1.09-3.72; P = .03). Among 11 studies providing both 30-day and 90-day mortalities, mortality difference was 5% (95% confidence interval, 4%-7%, P < .0001). Pulmonary complications were the most common cause of 30-day and 90-day deaths. CONCLUSIONS Right pneumonectomy is associated with significantly higher 30-day and 90-day mortalities after neoadjuvant therapy than left pneumonectomy. Also, 90-day mortality for all pneumonectomies appears to be greater than expected, suggesting that the 30-day mortality figure may inadequately assess the perioperative mortality.

Details and difficulties regarding the new lung cancer staging system.

The new lung cancer stage classification system is the culmination of 10 years of work and an unprecedented analysis and validation process. This article reviews details of the rules governing how to implement the system and discusses areas in which ambiguities and difficulties exist.

High expression of mammalian target of rapamycin is associated with better outcome for patients with early stage lung adenocarcinoma.

Purpose: Mammalian target of rapamycin (mTOR) is a key kinase downstream of phosphoinositide 3-kinase (PI3K)/AKT predominantly involved in translational control in the presence of nutrients and energy. Despite the well known role of mTOR in carcinogenesis, its prognostic potential in lung cancer has not been investigated. Here, we quantitatively assessed mTOR protein expression in two large data sets to investigate the impact of mTOR expression on patient survival. Experimental Design: Automated quantitative analysis (AQUA), a fluorescent-based method for analysis of in situ protein expression, was used to assess mTOR expression in a training cohort of 167 lung cancer patients. An independent cohort of 235 lung cancer patients (from a second institution) was used for validation. Results: Tumors expressed mTOR in the cytoplasm in 56% and 50% of the cases in training and validation cohorts, respectively; mTOR expression was not associated with standard clinical or pathologic characteristics. Patients with high mTOR expression had a longer median overall survival compared with the low expressers (52.7 versus 38.5 months; log rank P = 0.06), which was more prominent in the adenocarcinoma group (55.7 versus 38.88 months; log rank P = 0.018). Multivariate analysis revealed an independent lower risk of death for adenocarcinoma and adenocarcinoma stage IA patients with mTOR-expressing tumors (hazard ratio, 0.48; 95% confidence interval, 0.24-0.98; P = 0.04, and hazard ratio, 0.12; 95% confidence interval, 0.03-0.72; P = 0.019, respectively). Conclusions: mTOR expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of lung adenocarcinoma patients as well as incorporation of mTOR into clinical decisions.

Bolstering the case for lobectomy in stages I, II, and IIIA small-cell lung cancer using the National Cancer Data Base.

Introduction: Current therapy for small-cell lung cancer (SCLC) relies on chemoradiation therapy, and the role of primary surgical resection in these patients remains controversial. A minority of SCLC patients present without metastatic disease and are candidates for surgery. This study investigates the role of surgical resection in select patients with SCLC, using a national cohort of approximately 2500 resected patients. Methods: A retrospective study of SCLC patients in the National Cancer Data Base (NCDB) was performed where patients were grouped for comparison by stage and treatment regimen. Survival was estimated by Kaplan–Meier methods and multivariate comparisons using Cox regression. Results: Of 28,621 cases of potentially resectable SCLC, 2476 patients (9%) underwent surgery of the primary site with curative intent. Five-year overall survival for patients after resection was 51%, 25%, and 18% for clinical stages I, II, and IIIA, respectively. Addition of surgery to chemotherapy was associated with decreased likelihood of death (hazard ratio: 0.57, 95% confidence interval: 0.47–0.68), independent of age, stage, and comorbidity score. Lobectomy was associated with a 5-year overall survival of 40% compared with 21% and 22% for sublobar resection and pneumonectomy, respectively. Hazard ratio for death after sublobar resections compared with lobectomy was 1.38 (95% confidence interval: 1.12–1.71). Conclusions: Patients with stages I, II, and III SCLC, who underwent surgical resection as part of initial treatment with chemotherapy had respectable OS. These data may warrant prospective studies of including surgery in the multimodality treatment of SCLC in specific circumstances.

High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology

BackgroundBcl-2 promotes cell survival by inhibiting adapters needed for the activation and cleavage of caspases thus blocking the proteolytic cascade that ultimately dismantles the cell. Bcl-2 has been investigated as a prognostic factor in non small cell lung cancer (NSCLC) patients with conflicting results.MethodsHere, we quantitatively assessed Bcl-2 expression in two large and independent cohorts to investigate the impact of Bcl-2 on survival. AQUA®, a fluorescent-based method for analysis of in situ protein expression, was used to measure Bcl-2 protein levels and classify tumors by Bcl-2 expression in a cohort of 180 NSCLC patients. An independent cohort of 354 NSCLC patients was used to validate Bcl-2 classification and evaluate outcome.ResultsFifty % and 52% of the cases were classified as high expressers in training and validation cohorts respectively. Squamous cell carcinomas were more likely to be high expressers compared to adenocarcinomas (63% vs. 45%, p = 0.002); Bcl-2 was not associated with other clinical or pathological characteristics. Survival analysis showed that patients with high BCL-2 expression had a longer median survival compared to low expressers (22 vs. 17.5 months, log rank p = 0.014) especially in the subset of non-squamous tumors (25 vs. 13.8 months, log rank p = 0.04). Multivariate analysis revealed an independent lower risk for all patients with Bcl-2 expressing tumors (HR = 0.53, 95% CI 0.37-0.75, p = 0.0003) and for patients with non-squamous tumors (HR = 0.5, 95% CI 0.31-0.81, p = 0.005).ConclusionsBcl-2 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of NSCLC patients.