Brian C. McCaughan

Systematic Review and Meta-Analysis of Randomized and Nonrandomized Trials on Safety and Efficacy of Video-Assisted Thoracic Surgery Lobectomy for Early-Stage Non–Small-Cell Lung Cancer

PURPOSE The current randomized trials comparing video-assisted thoracic surgery (VATS) lobectomy with open lobectomy for patients with early-stage non-small-cell lung cancer (NSCLC) have been of small size. We performed the present meta-analysis of the randomized and nonrandomized comparative studies in an attempt to assess the safety and efficacy of VATS lobectomy. METHODS Electronic searches identified 21 eligible comparative studies (two randomized and 19 nonrandomized) for inclusion. Two reviewers independently appraised each study. Meta-analysis was performed by combining the results of reported incidence of morbidity and mortality, recurrence, and 5-year mortality rates. The relative risk (RR) was used as a summary statistic. RESULTS There were no significant statistical differences between VATS and open lobectomy in terms of postoperative prolonged air leak (P = .71), arrhythmia (P = .86), pneumonia (P = .09), and mortality (P = .49). VATS did not demonstrate any significant difference in locoregional recurrence (P = .24), as compared with the open lobectomy arm, but the data suggested a reduced systemic recurrence rate (P = .03) and an improved 5-year mortality rate of VATS (P = .04). There was no evidence to suggest heterogeneity of trial results. Fourteen studies reported VATS to open lobectomy conversion rate ranging from 0% to 15.7% (median = 8.1%). CONCLUSION Both randomized and nonrandomized trials suggest that VATS lobectomy is an appropriate procedure for selected patients with early-stage NSCLC when compared with open surgery.

Randomized Controlled Trial of the Role of Positron Emission Tomography in the Management of Stage I and II Non-Small-Cell Lung Cancer

PURPOSE Positron emission tomography (PET) is a costly new technology with potential to improve preoperative evaluation for patients with non-small-cell lung cancer (NSCLC). There is increasing pressure for PET to be included in standard diagnostic work-up before decisions about surgical management of NSCLC. The resource implications of its widespread use in staging NSCLC are significant. METHODS A randomized controlled trial was conducted to investigate the impact of PET on clinical management and surgical outcomes for patients with stage I-II NSCLC. The primary hypothesis was that PET would reduce the proportion of patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through identification of patients with inoperable disease. RESULTS One hundred eighty-four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had stage I disease. Following exclusion of one ineligible patient, 92 patients were assigned to no PET and 91 to PET. Compared with conventional staging, PET upstaged 22 patients, confirmed staging in 61 and staged two patients as benign. Stage IV disease was rarely detected (two patients). PET led to further investigation or a change in clinical management in 13% of patients and provided information that could have affected management in a further 13% of patients. There was no significant difference between the trial arms in the number of thoracotomies avoided (P =.2). CONCLUSION For patients who are carefully and appropriately staged as having stage I-II disease, PET provides potential for more appropriate stage-specific therapy but may not lead to a significant reduction in the number of thoracotomies avoided.

Quality of Life and Survival in the 2 Years After Surgery for Non–Small-Cell Lung Cancer

PURPOSE Although surgery for early-stage non-small-cell lung cancer (NSCLC) is known to have a substantial impact on health-related quality of life (HRQOL), there are few published studies about HRQOL in the longer term. This article examines HRQOL and survival in the 2 years after surgery. PATIENTS AND METHODS Patients with clinical stage I or II NSCLC (n = 173) completed HRQOL questionnaires before surgery, at discharge, 1 month after surgery, and then every 4 months for 2 years. HRQOL was measured with a generic cancer questionnaire (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ] C30) and a lung cancer-specific questionnaire (EORTC QLQ-LC13). Data were analyzed to examine the impact of surgery and any subsequent therapy, and to describe the trajectories of those who remained disease free at 2 years and those with recurrent cancer diagnosed during follow-up. RESULTS Disease recurred within 2 years for 36% of patients and 2-year survival was 65%. Surgery substantially reduced HRQOL across all dimensions except emotional functioning. HRQOL improved in the 2 years after surgery for patients without disease recurrence, although approximately half continued to experience symptoms and functional limitations. For those with recurrence within 2 years, there was some early postoperative recovery in HRQOL, with subsequent deterioration across most dimensions. CONCLUSION Surgery had a substantial impact on HRQOL, and although many disease-free survivors experienced recovery, some lived with long-term HRQOL impairment. HRQOL generally worsened with disease recurrence. The study results are important for informed decision making and ongoing supportive care for patients with operable NSCLC.

Testing for ALK rearrangement in lung adenocarcinoma : a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization

Rearrangements of anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) define a molecular subgroup of tumors characterized clinically by sensitivity to ALK tyrosine kinase inhibitors such as crizotinib. Although ALK rearrangements may be detected by reverse transcriptase-PCR, immunohistochemistry or fluorescence in situ hybridization (FISH), the optimal clinical strategy for identifying ALK rearrangements in clinical samples remains to be determined. We evaluated immunohistochemistry using three different antibodies (ALK1, 5A4 and D5F3 clones) to detect ALK rearrangements and compared those with FISH. We report the frequency and clinicopathologic features of lung cancers harboring ALK translocations in 594 resected NSCLCs (470 adenocarcinomas; 83 squamous carcinomas, 26 large cell carcinomas and 15 other histological subtypes) using a tissue microarray approach. We identified an ALK gene rearrangement in 7/594 cases (1%) by FISH and all anti-ALK antibodies correctly identified the seven ALK-positive cases (100% sensitivity), although the intensity of staining was weak in some cases. These data indicate that the use of antibodies with high sensitivity and avidity to ALK may provide an effective pre-screening technique to complement the more expensive and labor-intensive approach of ALK FISH testing.

A Systematic Review of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

Introduction: The primary objective of the present systematic review was to evaluate the safety and efficacy of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma. Methods: A systematic review of relevant studies identified through five online search databases was performed. Two reviewers independently appraised each study. Results: Thirty-four of 58 relevant studies from 26 institutions containing the most updated data were evaluated for survival and perioperative outcomes after EPP. The median overall survival varied from 9.4 to 27.5 months, and 1-, 2-, and 5-year survival rates ranged from 36 to 83%, 5 to 59%, and 0 to 24%, respectively. Overall perioperative mortality rates ranged from 0 to 11.8%, and the perioperative morbidity rates ranged from 22 to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13 to 23.9 months. Discussions: The current evidence suggests that selected patients with malignant pleural mesothelioma may benefit from EPP, especially when combined with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy.

Guidelines for the diagnosis and treatment of malignant pleural mesothelioma

Malignant Pleural Mesothelioma (MPM), the asbestos-induced neoplasm originating in the mesothelial lining of the lung cavities represents significant diagnostic and therapeutic challenges for clinicians in Australia. Very seldom diagnosed prior to the advent of widespread asbestos mining in the early to midtwentieth century, it has sharply risen in incidence over the last five decades. According to the most recent Australian Institute of Health and Welfare data, there were 666 cases of malignant mesothelioma diagnosed in Australia in 2009 and around 90% of them originated in the pleura.

PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma

OBJECTIVES Immune checkpoint blockade using inhibitors of programmed death-1 have shown promise in early phase clinical trials in NSCLC and programmed death-ligand 1 (PD-L1) tumoral expression could potentially be a useful predictive marker. Data reporting the prevalence of PD-L1 expression in NSCLC and clinicopathologic associations is very limited. We sought to determine the frequency of PD-L1 expression in NSCLC and investigate associations with clinicopathologic features and patient outcome. MATERIALS AND METHODS PD-L1 expression was analyzed using immunohistochemistry (Merck; clone 22C3) in 678 stages I-III NSCLC and 52 paired nodal metastases using tissue microarrays. Tumors with ≥50% cells showing positive membrane staining were considered to have high expression of PD-L1. RESULTS PD-L1 expression of any intensity was identified in 32.8% of cases. High PD-L1 expression was found in 7.4% of NSCLC. Squamous cell carcinomas (8.1%) and large cell carcinomas (12.1%) showed high PD-L1 expression more commonly than adenocarcinomas (5.1%) but this was not statistically significant (p=0.072). High PD-L1 expression was associated with younger patient age and high tumor grade (p<0.05). There was no association with gender, tumor size, stage, nodal status, EGFR or KRAS mutation status. In multivariate analysis, patients with high PD-L1 expression had significantly longer overall survival (p<0.05). CONCLUSIONS PD-L1 is expressed at high levels in a significant proportion of NSCLC and appears to be a favorable prognostic factor in early stage disease. As there are potential sampling limitations using tissue microarrays to assess heterogeneously expressed biomarkers, and as the results may differ in advanced stage disease, further studies are recommended.

Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma

BACKGROUND Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown. MATERIALS AND METHODS MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. RESULTS Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth. CONCLUSIONS The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.

DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma

The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARβ in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARβ. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers.

The MARS feasibility trial: conclusions not supported by data

The value of extrapleural pneumonectomy (EPP) in the context of multimodality therapy for patients with malignant pleural mesothelioma is controversial. Several phase 2 studies have been reported on the role of neoadjuvant chemotherapy, EPP, and postoperative radiotherapy. These studies have included patients with T1–3 tumours, but diff ered in the inclusion of N2 status and sarcomatoid histology. Around three-quarters of patients included in these trials underwent EPP and about three-fi fths received postoperative radiotherapy. Median survival ranged from 16·8 to 25·5 months, and the operative mortality from EPP from 0% to 5% (table). Independent assessment of the distinct components of a multimodality concept is desirable, especially of radical surgery and postoperative radiotherapy, because both have a more pronounced potential to aff ect survival than does chemotherapy alone. The MARS trial attempted to assess the effi cacy of EPP, and an ongoing SAKK trial is assessing the value of postoperative radiotherapy after neoadjuvant chemotherapy and EPP (ClinicalTrials.gov identifi er NCT00334594). Because of the anticipated diffi culty in recruitment of patients to a trial comparing EPP with a non-surgical approach, the MARS researchers designed a feasibility trial with the objective of randomly assigning 50 patients within 1 year to assess the possibility of completing a larger trial to clarify the role of EPP. The study was therefore not designed to test the benefi t (or absence thereof) of EPP for patient outcome, and any conclusions are speculative. Moreover, this feasibility study failed, because it took 3 years to accrue 50 patients. According to the investigators of the MARS trial, 670 patients would be needed to identify any signifi cant diff erence in overall survival between EPP and no EPP. However, the survival results reported in The Lancet Oncology are based on only 30 deaths. Thus, no fi rm conclusion can be drawn about the eff ect of EPP on overall survival from these data.