David O. Wilson

The Pittsburgh lung screening study (PLuSS): Outcomes within 3 years of a first computed tomography scan

RATIONALE The role of computed tomography (CT) screening for lung cancer is controversial, currently under study, and not yet fully elucidated. OBJECTIVES To report findings from initial and 1-year repeat screening low-radiation-dose CT of the chest and 3-year outcomes for 50- to 79-year-old current and ex-smokers in the Pittsburgh Lung Screening Study (PLuSS). METHODS Notified of findings on screening CT, subjects received diagnostic advice from both study and personal physicians. Tracking subjects for up to three years since initial screening, we obtained medical records to document diagnostic procedures, lung cancer diagnoses, and deaths. MEASUREMENTS AND MAIN RESULTS 3,642 and 3,423 subjects had initial and repeat screening. A total of 1,477 (40.6% of 3,624) were told about noncalcified lung nodules on the initial screening and, before repeat screening, 821 (55.6% of 1,477, 22.5% of 3,642) obtained one or more subsequent diagnostic imaging studies (CT, positron emission tomography [PET], or PET-CT). Tracking identified 80 subjects with lung cancer, including 53 subjects with tumor seen at initial screening. In all, 36 subjects (1.0% of the 3,642 screened), referred for abnormalities on either the initial or repeat screening, had a major thoracic surgical procedure (thoracotomy, video-assisted thoracoscopic surgery [VATS], median sternotomy, or mediastinoscopy) leading to a noncancer final diagnosis. Out of 82 subjects with thoracotomy or VATS to exclude malignancy in a lung nodule, 28 (34.1%) received a noncancer final diagnosis. Forty of 69 (58%) subjects with non-small cell lung cancer had stage I disease at diagnosis. CONCLUSIONS Though leading to the discovery of early stage lung cancer, CT screening also led to many diagnostic follow-up procedures, including major thoracic surgical procedures with noncancer outcomes.

Anatomic segmentectomy for stage I non-small-cell lung cancer: comparison of video-assisted thoracic surgery versus open approach.

OBJECTIVES Anatomic segmentectomy is increasingly being considered as a means of achieving an R0 resection for peripheral, small, stage I non-small-cell lung cancer. In the current study, we compare the results of video-assisted thoracic surgery (n = 104) versus open (n = 121) segmentectomy in the treatment of stage I non-small-cell lung cancer. METHODS A total of 225 consecutive anatomic segmentectomies were performed for stage IA (n = 138) or IB (n = 87) non-small-cell lung cancer from 2002 to 2007. Primary outcome variables included hospital course, complications, mortality, recurrence, and survival. Statistical comparisons were performed utilizing the t test and Fisher exact test. The probability of overall and recurrence-free survival was estimated with the Kaplan-Meier method, with significance being estimated by the log-rank test. RESULTS Mean age (69.9 years) and gender distribution were similar between the video-assisted thoracic surgery and open groups. Average tumor size was 2.3 cm (2.1 cm video-assisted thoracic surgery; 2.4 cm open). Mean follow-up was 16.2 (video-assisted thoracic surgery) and 28.2 (open) months. There were 2 perioperative deaths (2/225; 0.9%), both in the open group. Video-assisted thoracic surgery segmentectomy was associated with decreased length of stay (5 vs 7 days, P < .001) and pulmonary complications (15.4% vs 29.8%, P = .012) compared with open segmentectomy. Overall mortality, complications, local and systemic recurrence, and survival were similar between video-assisted thoracic surgery and open segmentectomy groups. CONCLUSIONS Video-assisted thoracic surgery segmentectomy can be performed with acceptable morbidity, mortality, recurrence, and survival. The video-assisted thoracic surgery approach affords a shorter length of stay and fewer postoperative pulmonary complications compared with open techniques. The potential benefits and limitations of segmentectomy will need to be further evaluated by prospective, randomized trials.

Anatomic segmentectomy for the solitary pulmonary nodule and early-stage lung cancer.

BACKGROUND Anatomic segmentectomy is a versatile sublobar resection approach that can be both diagnostic and therapeutic in the setting of the indeterminate pulmonary nodule (IPN), metastasectomy, as well as small, peripheral cancers. We analyzed the clinical indications and perioperative outcomes after anatomic segmentectomy and explored its utility in the diagnosis and treatment of IPNs and small stage IA lung cancers. METHODS This study is a retrospective review of 785 consecutive patients undergoing anatomic segmentectomy from 2002 to 2010. Primary outcome variables include perioperative course, morbidity, mortality, recurrence patterns, and survival. RESULTS Surgical indications included IPN (62.4%), known lung cancer (27.6%), suspected metastasis (4.1%), bullous disease (3.7%), or other (2.2%). Video-assisted thoracic surgery was employed in 468 (59.6%) and open thoracotomy in 317 (40.4%) patients. Median length of stay was 6 days. Overall complication rate was 34.9%. Thirty-day mortality was 1.1%. Among 490 patients with an IPN, 381 (77.7%) were found to have lung cancer, 41 (8.4%) metastatic cancer, and 68 (13.9%) benign disease. Among patients with pathologic stage IA lung cancer, there was no difference in recurrence rates (14.5% vs 13.9%) or 5-year freedom from recurrence estimates (78% in each group, p=0.738) when comparing segmentectomy and lobectomy. CONCLUSIONS Anatomic segmentectomy provides acceptable morbidity and mortality when approaching the IPN. Cancer is identified in 86% of lesions. Complete surgical resection can be achieved with generous parenchymal margins and thorough nodal staging for small, peripheral stage IA non-small cell lung cancer. The use of anatomic segmentectomy should be considered in this era of competing image-guided diagnostic and therapeutic approaches to peripheral lung pathology.

Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer. Cancer Prev Res; 4(6); 793–802. ©2011 AACR.

Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease. Development and Validation of the COPD Lung Cancer Screening Score

RATIONALE Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs. OBJECTIVES To develop a predictive score for LC risk for patients with COPD. METHODS The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP. MEASUREMENTS AND MAIN RESULTS By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category. CONCLUSIONS The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals Found to be Cancer-Free by CT Screening

Introduction: Clinical decision making in the setting of computed tomography (CT) screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules. Methods: To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP (Luminex Corporation) multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non–small-cell lung cancer and 56 age-, sex-, and smoking-matched CT-screened controls. Results: We identified a panel of 10 serum biomarkers—prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, erbb-2, cytokeratin fragment 21.1, and serum amyloid A—that distinguished lung cancer patients from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0 ± 3.8% from 20-fold internal cross-validation. We then iteratively evaluated this model in an independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using enzyme-linked immunosorbent assays in a second independent case/control population, further validating the robustness of the panel. Conclusions: The performance of this 10-biomarker panel–based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary nodules detected by CT screening.

Increased Levels of Tumor-Infiltrating Lymphocytes are Associated with Improved Recurrence-Free Survival in Stage 1A Non-Small-Cell Lung Cancer

BACKGROUND Tumor-infiltrating lymphocytes (TILs) have been found to increase survival in many forms of cancer, including, endometrial, bile ductal, colonic, esophageal, and urothelial cancers, as well as melanoma and follicular lymphoma. The relevance of TILs in the prognosis of non-small-cell lung cancer (NSCLC), however, still remains controversial. We compared the outcomes of stage 1A NSCLC with and without tumor infiltrating lymphocytes to evaluate the effects of TILs on recurrence and survival patterns. MATERIALS AND METHODS From 2000 to 2009, 273 anatomic segmentectomies and lobectomies were performed on stage 1A NSCLC. Patients were stratified into TIL- and TIL+ cohorts based on pathologic evaluation. Further investigation was conducted on the effects of TILs in patients with and without angiolymphatic invasion. Variables analyzed include overall survival, recurrence-free survival, and type of recurrence. RESULTS Overall 5-y survival was not affected by TIL status (65% versus 60%, P = 0.469). Five-year recurrence-free survival (RFS) was significantly increased in the TIL+ group versus the TIL- group (87% versus 73%, P = 0.011), most significantly in women (P = 0.016). The presence of angiolymphatic invasion (ALI) was associated with decreased 5-y RFS versus patients without ALI (61% versus 85%, P < 0.001). Interestingly, in the ALI negative group, TIL+ patients experienced a significantly increased 5-y recurrence-free survival versus TIL- patients (93% versus 80%, P = 0.036). CONCLUSIONS High levels of intratumoral TILs are associated with improved recurrence-free survival in stage 1A NSCLC patients as well as a reduced likelihood of systemic recurrence. When angiolymphatic invasion is not present, the beneficial effects of TILs become even more profound.

Doubling Times and CT Screen–Detected Lung Cancers in the Pittsburgh Lung Screening Study

RATIONALE As computed tomography (CT) screening for lung cancer becomes more widespread, volumetric analyses, including doubling times, of CT-screen detected lung nodules and lung cancers may provide useful information in the follow-up and management of CT-detected lung nodules and cancers. OBJECTIVES To analyze doubling times in CT screen detected lung cancers and compare prevalent and nonprevalent cancers and different cell types on non small cell lung cancer. METHODS We performed volumetric and doubling time analysis on 63 non–small cell lung cancers detected as part of the Pittsburgh Lung Screening Study using a commercially available VITREA 2 workstation and VITREA VITAL nodule segmentation software. MEASUREMENTS AND MAIN RESULTS Doubling times (DT) were divided into three groups: rapid (DT<183 d), typical (DT 183–365 d), and slow (DT>365 d). Adenocarcinoma/bronchioloalveolar carcinoma comprised 86.7% of the slow DT group compared with 20% of the rapid DT group. Conversely, squamous cell cancer comprised 60% of the rapid DT group compared with 3.3% of the slow DT group. Twenty-eight of 42 (67%) prevalent and 2 of 21 (10%) nonprevalent cancers were in the slow DT group (P<0.0001; Fishers exact test). Twenty-four of 32 (75%) prevalent and 1 of 11 (9%) nonprevalent adenocarcinomas were in the slow DT group (P<0.0002; Fishers exact test). CONCLUSIONS Volumetric analysis of CT-detected lung cancers is particularly useful in AC/BAC. Prevalent cancers have a significantly slower DT than nonprevalent cancers and a higher percentage of adenocarcinoma/bronchioloalveolar carcinoma. These results should affect the management of indeterminant lung nodules detected on screening CT scans.

Smoking Behavior 1 Year after Computed Tomography Screening for Lung Cancer: Effect of Physician Referral for Abnormal CT Findings

Background: Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study. Methods: Pittsburgh Lung Screening Study recruited 50- to 79-year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes 1 year after study entry in a subgroup that contained 2,094 active cigarette smokers without interval lung cancer diagnosis (50.7% women; median age, 57 years; 40-year median duration of cigarette smoking; and 65.2% ≥20 cigarettes/d). Analyses compared efforts to quit in relation to physician referral for abnormal CT. Results: Since study entry, 58.5% [95% confidence interval (95% CI), 56.3-60.6%] reported any quit attempt and 27.2% (95% CI, 25.3-29.1%) reported any quit interval >30 days. One year after study entry, 15.5% (95% CI, 14.0-17.1%) reported not smoking for >30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n = 156; 7.4%) to persons not referred for any reason (n = 1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval >30 days increased 18.8% (95% CI, 11.1-26.5%) and 17.7% (95% CI, 9.4-26.0%), respectively. The fraction quit >30 days at 1 year increased 12.2% (95% CI, 4.9-19.5%). Conclusions: Persons who experienced referral because of abnormal CT reported more smoking cessation. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3484–9)

Validation of a blood protein signature for non-small cell lung cancer

BackgroundCT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations.ResultsBlood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation.ConclusionsSelecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.