Michael R. Johnston

Probability of Cancer in Pulmonary Nodules Detected on First Screening CT

BACKGROUND Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up. METHODS We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer. RESULTS In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set. CONCLUSIONS Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660.).

Three-gene prognostic classifier for early-stage non small-cell lung cancer.

PURPOSE Several microarray studies have reported gene expression signatures that classify non-small-cell lung carcinoma (NSCLC) patients into different prognostic groups. However, the prognostic gene lists reported to date overlap poorly across studies, and few have been validated independently using more quantitative assay methods. PATIENTS AND METHODS The expression of 158 putative prognostic genes identified in previous microarray studies was analyzed by reverse transcription quantitative polymerase chain reaction in the tumors of 147 NSCLC patients. Concordance indices and risk scores were used to identify a stage-independent set of genes that could classify patients with significantly different prognoses. RESULTS We have identified a three-gene classifier (STX1A, HIF1A, and CCR7) for overall survival (hazard ratio = 3.8; 95% CI, 1.7 to 8.2; P < .001). The classifier was also able to stratify stage I and II patients and further improved the predictive ability of clinical factors such as histology and tumor stage. The predictive value of this three-gene classifier was validated in two large independent microarray data sets from Harvard and Duke Universities. CONCLUSION We have identified a new three-gene classifier that is independent of and improves on stage to stratify early-stage NSCLC patients with significantly different prognoses. This classifier may be tested further for its potential value to improve the selection of resected NSCLC patients in adjuvant therapy.

Trimodality Therapy With Induction Chemotherapy Followed by Extrapleural Pneumonectomy and Adjuvant High-Dose Hemithoracic Radiation for Malignant Pleural Mesothelioma

PURPOSE Malignant pleural mesothelioma (MPM) remains associated with poor outcome. We examined the results of trimodality therapy with cisplatin-based chemotherapy followed by extrapleural pneumonectomy (EPP) and adjuvant high-dose (50 to 60 Gy) hemithoracic radiation therapy for MPM. PATIENTS AND METHODS We conducted a retrospective review of all patients prospectively evaluated for trimodality therapy protocol between January 2001 and December 2007 in our institution. RESULTS A total of 60 patients were suitable candidates. Histology was epithelioid (n = 44) or biphasic (n = 16). Chemotherapy regimens included cisplatin/vinorelbine (n = 26), cisplatin/pemetrexed (n = 24), cisplatin/raltitrexed (n = 6), or cisplatin/gemcitabine (n = 4). EPP was performed in 45 patients, and hemithoracic radiation therapy to at least 50 Gy was administered postoperatively to 30 patients. Completion of the trimodality therapy in the absence of mediastinal node involvement was associated with the best survival (median survival of 59 months v <or= 14 months in the remaining patients, P = .0003). The type of induction chemotherapy had no significant impact on survival. Pathologic nodal status remained a significant predictor of poor survival despite completion of the trimodality therapy. After completion of the protocol, the 5-year disease-free survival was 53% for patients with N0 disease, reaching 75% in patients with ypT1-2N0 and 45% in patients with ypT3-4N0. CONCLUSION This large, single-center experience with induction chemotherapy followed by EPP and adjuvant high-dose hemithoracic radiation for MPM shows that half of the patients are able to complete this protocol. The results are encouraging for patients with N0 disease. However, N2 disease remains a major factor impacting on survival, despite completion of the entire trimodality regimen.

Randomized, Placebo-Controlled, Phase II Study of Sequential Erlotinib and Chemotherapy As First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

PURPOSE This study investigated whether sequential administration of erlotinib and chemotherapy improves clinical outcomes versus chemotherapy alone in unselected, chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Previously untreated patients (n = 154) with stage IIIB or IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned to receive erlotinib (150 mg/d) or placebo on days 15 to 28 of a 4-week cycle that included gemcitabine (1,250 mg/m(2) days 1 and 8) and either cisplatin (75 mg/m(2) day 1) or carboplatin (5 x area under the serum concentration-time curve, day 1). The primary end point was nonprogression rate (NPR) at 8 weeks. Secondary end points included tumor response rate, NPR at 16 weeks, duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS The NPR at 8 weeks was 80.3% in the gemcitabine plus cisplatin or carboplatin (GC)-erlotinib arm (n = 76) and 76.9% in the GC-placebo arm (n = 78). At 16 weeks, the NPR was 64.5% for GC-erlotinib versus 53.8% for GC-placebo. The response rate was 35.5% for GC-erlotinib versus 24.4% for GC-placebo. PFS was significantly longer with GC-erlotinib than with GC-placebo (adjusted hazard ratio, 0.47; log-rank P = .0002; median, 29.4 v 23.4 weeks); this benefit was consistent across all clinical subgroups. There was no significant difference in OS. The addition of erlotinib to chemotherapy was well tolerated, with no increase in hematologic toxicity, and no treatment-related interstitial lung disease. CONCLUSION Sequential administration of erlotinib following gemcitabine/platinum chemotherapy led to a significant improvement in PFS. This treatment approach warrants further investigation in a phase III study.

Survival Following Aggressive Resection of Pulmonary Metastases from Osteogenic Sarcoma: Analysis of Prognostic Factors

Between 1975 and 1982, 80 patients with osteogenic sarcoma were entered into prospective trials in the Surgery Branch of the National Cancer Institute. In 43 of these patients, pulmonary metastases developed as the initial site of recurrence, and 39 underwent one or more thoracotomies for resection of the disease. The actuarial five-year survival for the group of 43 patients with pulmonary metastases was 40%. Various prognostic factors were analyzed for their influence on survival after thoracotomy. Age, sex, location of primary tumor, tumor doubling time, and involvement of one or both lungs (bilaterality) were not significant in predicting survival. Prognostic factors that influenced survival, calculated by regression analysis, included the number of nodules on preoperative lung tomograms (negative correlation, p = 0.0004), disease-free interval (positive correlation, p = 0.0136), resectability (positive correlation, p = 0.002), and the number of metastases resected at thoracotomy (negative correlation, p = 0.0032). The presence of 3 nodules or less on preoperative full-lung linear tomography was found to be the single most useful preoperative prognostic factor. The application of these prognostic factors preoperatively may identify patients who will benefit optimally from thoracotomy.

Lung perfusion with chemotherapy in patients with unresectable metastatic sarcoma to the lung or diffuse bronchioloalveolar carcinoma

Eight patients with metastatic sarcoma to the lung (n = 4) or diffuse bronchioloalveolar carcinoma of the lung (n = 4) underwent isolated lung perfusion with chemotherapy in a pilot study. Ages ranged from 18 to 60 years and half were female. The left lung was perfused in three patients (single lung perfusion) and both lungs in five patients (total lung perfusion). Perfusions ranged from 45 to 60 minutes at ambient or normothermic temperatures. One patient received perfusion at moderate hyperthermia (40 degrees C). Escalating doses of doxorubicin (1 to 10 micrograms/ml perfusate) was used in six patients, whereas two received cisplatin (14 and 20 micrograms/ml perfusate). There were two major complications and no objective responses. The isolated perfusion systems gave excellent separation between systemic and pulmonary circulations with zero to 15% of the measured peak drug concentration of the pulmonary perfusate detected in the systemic circulation. Drug concentrations in normal lung and tumor generally increased with higher drug dosages and drug was detectable in mediastinal lymph nodes of three out of four patients in whom sampling was done. Isolated lung perfusion with chemotherapy can be done safely in patients with lung malignancies and evidence suggests that higher drug dosages should be well tolerated.

Novel candidate tumor marker genes for lung adenocarcinoma

Using the representational difference analysis (RDA) technique on pooled mRNA of five primary lung adenocarcinomas and their corresponding non-neoplastic lung tissues, we identified six genes that were putatively overexpressed in this type of lung cancer. Five corresponded to previously isolated genes, while one (Lc19) matched with the sequence of an unannotated EST. Real-time RT–PCR analyses of expression levels in a panel of 34 paired primary non-small cell lung cancer (NSCLC) and corresponding grossly normal appearing lung tissues confirmed the common overexpression of these genes in non-small cell lung cancer. Among these genes, overexpression of Lc19, hyaluronan binding protein 2 (HABP2) and crystalline-mu appeared more specific to adenocarcinoma, whereas ceruloplasmin, integrin α-11 and collagen type XI alpha 1 were overexpressed at high frequency among both adenocarcinoma and squamous cell carcinoma. These genes represent novel candidate tumor biomarker genes for NSCLC and its histological subtypes.

Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma.

OBJECTIVE The aim of the study was to determine the impact of tumor-infiltrating lymphocytes on survival in patients with malignant pleural mesothelioma treated with induction chemotherapy followed by extrapleural pneumonectomy. METHODS We performed an immunohistochemical analysis of 32 extrapleural pneumonectomy specimens to assess the distribution of T-cell subtypes (CD3(+), CD4(+), and CD8(+)), regulatory subtypes (CD25(+) and FOXP3(+)), and memory subtype (CD45RO(+)) within the tumor. RESULTS Patients with high levels of CD8(+) tumor-infiltrating lymphocytes demonstrated better survival than those with low levels (3-year survival: 83% vs 28%; P = .06). Moreover, high levels of CD8(+) tumor-infiltrating lymphocytes were associated with a lower incidence of mediastinal node disease (P = .004) and longer progression-free survival (P = .05). Higher levels of CD8(+) tumor-infiltrating lymphocytes were observed in patients treated with cisplatin and pemetrexed than in those treated with cisplatin and vinorelbine (P = .02). Patients presenting high levels of CD4(+) or CD25(+) tumor-infiltrating lymphocytes or low levels of CD45RO(+) also demonstrated a trend toward shorter survival. However, the presence of FOXP3(+) tumor-infiltrating lymphocytes did not affect survival. After multivariate adjustment, high levels of CD8(+) tumor-infiltrating lymphocytes remained an independent prognostic factor associated with delayed recurrence (hazard ratio = 0.38; confidence interval = 0.09-0.87; P = .02) and better survival (hazard ratio = 0.39; confidence interval = 0.09-0.89; P = .02). CONCLUSION The presence of high levels of CD8(+) tumor-infiltrating lymphocytes is associated with better prognosis in patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma. The stimulation of CD8(+) lymphocytes can be a potential therapeutic strategy to improve outcome.

Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors

BackgroundWe conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers.Methods445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk.ResultsAny previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk.ConclusionsOccupational exposures and family history of cancer with young onset were important risk factors among never smokers.

Middle Lobe Syndrome

A review of the major literature dealing with the middle lobe syndrome shows that benign inflammatory disease is the most common etiological factor (62%), with bronchiectasis responsible for at least a quarter of the patients in these series. Early workers indicated that carcinoma rarely originates in the right middle lobe; however, 22% of patients reviewed had malignant tumors as a cause of the syndrome. The original view that bronchial compression was the pathophysiological abnormality leading to development of the syndrome has been rejected by more recent authors. The focus has now turned to the relative isolation of the middle lobe, especially when a complete minor fissure is present. This isolation prevents the aerating effects of collateral ventilation of the upper lobe from reaching the middle lobe and thus impairs the clearing of secretions from the middle lobe bronchus. Bronchoscopy and bronchography are vital in the rational approach to this syndrome. Severe stenosis of the bronchus or tumor can be seen endoscopically in about 40% of patients, and bronchography will demonstrate an anatomical abnormality more than 70% of the time. Both the surgical and the medical approaches to therapy have been endorsed strongly by various authors in the 30 years since the syndrome was described. It now appears that bronchoscopy and, if need be, bronchography should be undertaken to rule out an endobronchial lesion. Timing of these studies will depend on the patients age, with early examination advocated for the older patient at high risk for lung cancer. If there is reasonable evidence that the process is benign, medical management should be attempted. Lobectomy is performed if malignancy is suspected or if medical therapy fails.