Anthony W. Kim

Physiologic Evaluation of the Patient With Lung Cancer Being Considered for Resectional Surgery: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer. METHODS The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee. RESULTS The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V˙O2 peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V˙O2 peak > 20 mL/kg/min or 75% predicted indicates a low risk. CONCLUSIONS A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.

Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

OBJECTIVES Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients. METHODS Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews. RESULTS For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival. CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.

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.

Management of Malignant Pleural Effusions Using the Pleurx Catheter

BACKGROUND A malignant pleural effusion can cause significant morbidity to terminal patients. Drainage and control of the fluid can provide great palliation. Improving the quality of life for these patients on an outpatient basis is a worthy goal. METHODS We have inserted 231 Pleur(x) (Cardinal Health Systems, McGaw Park, IL) catheters into 202 patients with symptomatic malignant pleural effusions with the goal of treating the fluid on an outpatient basis. The catheters were drained at home, using vacuum bottles, every other day after an initial week of draining daily. No sclerosing agents were instilled. The catheters were removed when drainage was less than 50 mL/day. Primary tumor sites, irradiation to the hemithorax, and incomplete re-expansion of the lung were studied for their ability to predict prolonged drainage (over 100 days). RESULTS In all cases, evacuation of the fluid with a Pleur(x) catheter palliated the patients symptoms. Overall, 134 of 231 (58.0%) catheters were removed after the drainage tapered off. Reaccumulation of the pleural effusion occurred in 5 of 132 (3.8%) patients. The incidence of infection was 5 of 231 (2.2%) and was usually limited to cellulitis at the insertion site. The incidence of blockage was 11 of 231 (4.8%) and was most common in patients with an underlying cancer at sites other than breast and gynecologic primaries. Drainage for more than 100 days was seen most often in patients who had incomplete reexpansion of the underlying lung (p < 0.001). Primary tumor site and irradiation did not have significant predictive value. CONCLUSIONS Insertion of Pleur(x) catheters is an effective way to treat patients with a malignant pleural effusion on an outpatient basis with a high degree of patient compliance and few complications. Overall, almost 60% of the catheters can be removed with a very low chance of reaccumulation, and without the need to instill a sclerosing agent. Even patients with a trapped lung can be palliated and released from hospital, although the likelihood of removing the catheter is small.

PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients.

The primary objective of this study is to identify prognostic site‐specific epigenetic changes in surgically treated Stage I and II nonsmall cell lung cancer (NSCLC) patients by quantifying methylation levels at multiple CpG sites within each gene promoter. Paraffin‐embedded tumors from stage Ib, IIa and IIb in training and validation groups of 75 and 57 surgically treated NSCLC patients, respectively, were analyzed for p16, MGMT, RASSF1, RASSF5, CDH1, LET7, DAPK and PTEN promoter hypermethylation. Hypermethylation status was quantified individually at multiple CpG sites within each promoter by pyrosequencing. Molecular and clinical characteristics with time to recurrence (TTR) and overall survival (OS) were evaluated. Overall average promoter methylation levels of MGMT and RASSF1 were significantly higher in smokers than in nonsmokers (p = 0.006 and p = 0.029, respectively). Methylation levels of the p16 promoter were significantly higher in squamous cell carcinoma than in adenocarcinoma (p = 0.020). In univariate analysis, hypermethylation of RASSF1 at CpG sites −53 and −48 and PTEN at CpG site −1310 were the significantly associated with shorter TTR (p = 0.002 and p < 0.000, respectively). Hypermethylation of PTEN at −1310 and DAPK at −1482 were most significantly associated with outcome in multivariate analysis. These results show that methylation of specific promoter CpG sites in PTEN, RASSF1 and DAPK is associated with outcome in early stage surgically treated NSCLC.

Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer

Purpose: Non–small cell lung cancer (NSCLC) has an overall 5-year survival of <15%; however, the 5-year survival for stage I disease is over 50%. Unfortunately, 75% of NSCLC is diagnosed at an advanced stage not amenable to surgery. A convenient serum assay capable of unambiguously identifying patients with NSCLC may provide an ideal diagnostic measure to complement computed tomography–based screening protocols. Experimental Design: Standard immunoproteomic method was used to assess differences in circulating autoantibodies among lung adenocarcinoma patients relative to cancer-free controls. Candidate autoantibodies identified by these discovery phase studies were translated into Luminex-based “direct-capture” immunobead assays along with 10 autoantigens with previously reported diagnostic value. These assays were then used to evaluate a second patient cohort composed of four discrete populations, including: 117 NSCLC (81 T1-2N0M0 and 36 T1-2N1-2M0), 30 chronic obstructive pulmonary disorder (COPD)/asthma, 13 nonmalignant lung nodule, and 31 “normal” controls. Multivariate statistical methods were then used to identify the optimal combination of biomarkers for classifying patient disease status and develop a convenient algorithm for this purpose. Results: Our immunoproteomic-based biomarker discovery efforts yielded 16 autoantibodies differentially expressed in NSCLC versus control serum. Thirteen of the 25 analytes tested showed statistical significance (Mann-Whitney P < 0.05 and a receiver operator characteristic “area under the curve” over 0.65) when evaluated against a second patient cohort. Multivariate statistical analyses identified a six-biomarker panel with only a 7% misclassification rate. Conclusions: We developed a six-autoantibody algorithm for detecting cases of NSCLC among several high-risk populations. Population-based validation studies are now required to assign the true value of this tool for identifying early-stage NSCLC. Clin Cancer Res; 16(13); 3452–62. ©2010 AACR.

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.

Human heparanase-1 gene expression in pancreatic adenocarcinoma

Extracellular matrix degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase-1 (HPR1) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a chief component of the extracellular matrix. HPR1 is not expressed in normal epithelial cells but can be detected in a variety of malignancies. In the present study, we examined HPR1 expression in pancreatic cancer by using in situ hybridization and tested whether HPR1 expression correlated with any clinicopathlogic parameters. HPR1 was not detected in the ductal cells of normal pancreas samples obtained from 10 patients at autopsy. However, HPR1 was detected in 77 (78%) of 99 panceatic adenocarcinomas. Among them, 69 (78%) of 89 primary pancreatic adenocarcinomas and 8 (80%) of the 10 metastases were HPR1 positive. Age, sex, tumor stage, and lymph node status were not predictive of HPR1 expression. Log-rank test of the Kaplan-Meier survival curves revealed that HPR1 expression in early-stage tumors was associated with decreased survival. HPR1 expression was frequent in pancreatic adenocarcinomas and was associated with decreased survival in early-stage tumors. This suggests that HPR1 may contribute to the highly invasive and early metastatic behavior of pancreatic cancer.

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.