Ryutaro Kakinuma

Screening for Lung Cancer With Low-Dose Helical Computed Tomography: Anti-Lung Cancer Association Project

PURPOSE Because efficacy of lung cancer screening using chest x-ray is controversial and insufficient, other screening modalities need to be developed. To provide data on screening performance of low-dose helical computed tomography (CT) scanning and its efficacy in terms of survival, a one-arm longitudinal screening project was conducted. PATIENTS AND METHODS A total of 1,611 asymptomatic patients aged 40 to 79 years, 86% with smoking history, were screened by low-dose helical CT scan, chest x-ray, and 3-day pooled sputum cytology with a 6-month interval. RESULTS At initial screening, the proportions of positive tests were 11.5%, 3.4%, and 0.8% with low-dose helical CT scan, chest x-ray, and sputum cytology, respectively. In 1,611 participants, 14 (0.87%) cases of lung cancer were detected, with 71% being stage IA disease and a mean tumor diameter of 19.8 mm. At repeated screening, the proportions of positive tests were 9.1%, 2.6%, and 0.7% with low-dose helical CT, chest x-ray, and sputum cytology, respectively. In 7,891 examinations, 22 (0.28%) cases of lung cancer were detected, with 82% being stage IA disease and a mean tumor diameter of 14.6 mm. The 5-year survival rate for screen-detected lung cancer was 76.2% and 64.9% for initial and repeated screening, respectively. CONCLUSION Screening with low-dose helical CT has potential to improve screening efficacy in terms of reducing lung cancer mortality. An evaluation of efficacy using appropriate methods is urgently required.

Computer-aided diagnosis for pulmonary nodules based on helical CT images

We present a computer assisted automatic diagnostic system for lung cancer that detects nodule candidates at an early stage from helical CT images of the thorax. Our diagnostic system consists of analytic and diagnostic procedures. In the analysis procedure, we extract the lung and the blood vessel regions using a fuzzy clustering algorithm, then we analyze the features of these regions. In the diagnosis procedure, we define diagnostic rules utilizing the extracted features which support the determination of the candidate nodule locations.

First-Line Single Agent Treatment With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer: A Phase II Study

PURPOSE We conducted a phase II study of single agent treatment with gefitinib in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC) to assess its efficacy and toxicity. PATIENTS AND METHODS Patients received 250 mg doses of gefitinib daily. Administration of gefitinib was terminated if partial response (PR) was not achieved within 8 weeks or if tumor reduction was not observed within 4 weeks. In these cases, platinum-based doublet chemotherapy was given as a salvage treatment. We evaluated mutation status of the epidermal growth factor receptor (EGFR) gene in cases with available tumor samples. RESULTS Forty-two patients were enrolled between March and November 2003, with 40 of these patients being eligible. The response rate was 30% (95% CI, 17% to 47%). The most common toxicity included grade 1 or 2 acne-like rash (50%) and grade 1 diarrhea (18%). Grade 2 or 3 hepatic toxicity was observed in 8% of patients. Four patients developed grade 5 interstitial lung disease (ILD). Thirty patients received second-line chemotherapy. Median survival time was 13.9 months (95% CI, 9.1 to 18.7 months), and the 1-year survival rate was 55%. Tumor samples were available in 13 patients, including four cases of PR, six cases of stable disease, and three cases of progressive disease. EGFR mutations (deletions in exon 19 or point mutations [L858R or E746V]) were detected in four tumor tissues. All four patients with EGFR mutation achieved PR with gefitinib treatment. CONCLUSION Single agent treatment with gefitinib is active in chemotherapy-naïve patients with advanced NSCLC, but produces unacceptably frequent ILD in the Japanese population.

Progression of focal pure ground-glass opacity detected by low-dose helical computed tomography screening for lung cancer.

Objective: To clarify the progression of focal pure ground-glass opacity (pGGO) detected by low-dose helical computed tomography (CT) screening for lung cancer. Methods: A total of 15,938 low-dose helical CT examinations were performed in 2052 participants in the screening project, and 1566 of them were judged to have yielded abnormal findings requiring further examination. Patients with peripheral nodules exhibiting pGGO at the time of the first thin-section CT examination and confirmed histologically by thin-section CT after follow-up of more than 6 months were enrolled in the current study. Progression was classified based on the follow-up thin-section CT findings. Results: The progression of the 8 cases was classified into 3 types: increasing size (n = 5: bronchioloalveolar carcinoma [BAC]), decreasing size and the appearance of a solid component (n = 2: BAC, n = 1; adenocarcinoma with mixed subtype [Ad], n = 1), and stable size and increasing density (n = 1: BAC). In addition, the decreasing size group was further divided into 2 subtypes: a rapid-decreasing type (Ad: n = 1) and a slow-decreasing type (BAC: n = 1). The mean period between the first thin-section CT and surgery was 18 months (range: 7–38 months). All but one of the follow-up cases of lung cancer were noninvasive whereas the remaining GGO with a solid component was minimally invasive. Conclusions: The pGGOs of lung cancer nodules do not only increase in size or density, but may also decrease rapidly or slowly with the appearance of solid components. Close follow-up until the appearance of a solid component may be a valid option for the management of pGGO.

Localized pure ground-glass opacity on high-resolution CT: histologic characteristics.

Purpose The aim of this study is to assess the histologic characteristics in cases of localized pure ground-glass opacity (LPGGO) that do not exhibit consolidation on high-resolution CT (HRCT) images. Method Twenty surgically resected lesions from 20 consecutive cases were retrospectively investigated. Each of the 20 lesions had exhibited LPGGO on HRCT images. The HRCT images and histopathologic findings were examined for correlations. Results The areas of LPGGO had a maximum diameter of 2.0–24 mm on the HRCT images. Histopathology of the LPGGO lesions resulted in diagnosis of fibrosis (n = 3; 15%), atypical adenomatous hyperplasia (n = 5; 25%), bronchioloalveolar carcinoma (n = 10; 50%), and adenocarcinoma with stromal invasion (n = 2; 10%). Nonaerogenous components corresponding to solid components without normal alveolar septal destruction were pathologically observed in 15 of the 20 lesions. The diameter of the nonaerogenous components varied between 0.2 and 2.0 mm. Conclusion Because 10% of LPGGO lesions include invasive disease, patients with LPGGO should undergo pathologic examination for confirmation.

Comparison of Pharmacokinetics and Pharmacodynamics of Docetaxel and Cisplatin in Elderly and Non-Elderly Patients: Why Is Toxicity Increased in Elderly Patients?

PURPOSE Following phase I studies of docetaxel and cisplatin in patients with non-small-cell lung cancer, the recommended doses of docetaxel were different for elderly (> or = 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients. PATIENTS AND METHODS Twenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m(2) for elderly and non-elderly patients, respectively. All patients received 25 mg/m(2) of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients. RESULTS There were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was -11.2% (95% CI, -21.8 to -0.5%). CONCLUSION The pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.

Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen

Neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA) have been reported to be useful markers for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer (SCLC). Recently, pro-gastrin-releasing peptide (Pro-GRP) became available as a sensitive, specific, and reliable tumor marker for patients with SCLC. The aim of this study is to determine the most useful tumor marker to detect the relapse of SCLC. Furthermore, we analyzed the relationship between tumor markers at relapse and survival from relapse or response to salvage chemotherapy. Medical records were reviewed to obtain serum levels of Pro-GRP, NSE, and CEA before and after the initial chemotherapy, and at relapse. Consecutive 66 patients with SCLC, with an objective response and confirmed relapse treated at the National Cancer Center Hospital East, were analyzed in this study. The percentages of patients whose tumor marker level were elevated before treatment, decreased after the treatment, and increased again at relapse were 67% (95% CI, 55-78) for Pro-GRP, 20% (10-29) for NSE, and 38% (26-50) for CEA. Multivariate analysis indicated that poor performance status before initial treatment and elevated serum levels of lactate dehydrogenase at relapse were poor prognostic factors for patients with recurrent SCLC (P<0.005). None of the serum levels of Pro-GRP, NSE, and CEA at relapse was a significant prognostic factor and associated with an objective response to salvage chemotherapy. The present study demonstrated that serum levels of Pro-GRP reflect the disease course of patients with SCLC most accurately.

Computer-aided diagnosis system for lung cancer based on retrospective helical CT image

In this paper, we present a computer-aided diagnosis (CAD) system for lung cancer to detect nodule candidates at an early stage from the present and the early helical CT screening of the thorax. We developed an algorithm that can compare automatically the slice images of present and early CT scans for the assistance of comparative reading in retrospect. The algorithm consists of the ROI detection and shape analysis based on comparison of each slice image in the present and the early CT scans. The slice images of present and early CT scans are both displayed in parallel and analyzed quantitatively in order to detect the changes in size and intensity affection. We validated the efficiency of this algorithm by application to image data for mass screening of 50 subjects (total: 150 CT scans). The algorithm could compare the slice images correctly in most combinations with respect to physicians point of view. We validated the efficiency of the algorithm which automatically detect lung nodule candidates using CAD system. The system was applied to the helical CT images of 450 subjects. Currently, we are carrying out the clinical field test program using the CAD system. The results of our CAD system have indicated good performance when compared with physicians diagnosis. The experimental results of the algorithm indicate that our CAD system is useful to increase the efficiency of the mass screening process. CT screening of thorax will be performed by using the CAD system as a counterpart to the double reading technique actually used in herical CT screening program, not by using the film display.

Serum levels of KL-6 are useful biomarkers for severe radiation pneumonitis

The antigen KL-6, a mucin-like high-molecular-weight glycoprotein, is expressed on type-2 pneumocytes and bronchiolar epithelial cells. Serum levels of KL-6 have been shown to correlate well with the activities of several different kinds of interstitial pneumonia. The purpose of this study was to assess the usefulness of monitoring serum KL-6 levels in patients who had received thoracic radiotherapy (TRT). In particular, the usefulness of such a protocol for the early diagnosis of severe radiation pneumonitis (RP) and the evaluation of its progress and severity was examined. Serum KL-6 levels were retrospectively monitored in 16 patients with lung cancer who had received TRT with or without chemotherapy. Eight of these patients had developed severe RP and eight had developed localized (within the irradiated field) RP. Serum KL-6 levels were measured using a modified sandwich-type enzyme-linked immunosorbent assay. In patients who developed severe RP, serum KL-6 levels showed a consistent tendency to increase after the clinical diagnosis of RP. In four patients, serum KL-6 levels even began to rise before a clinical diagnosis of severe RP had been made. In the patients with localized RP, on the other hand, the serum levels did not show any tendency to increase during or after TRT. Moreover, patients whose serum KL-6 levels rose more than 1.5 times higher than their pre-treatment serum KL-6 level, had a large chance of developing severe RP that was unresponsive to steroid hormones and resulted in death. Serum KL-6 levels, therefore, should be useful indicators for the early diagnosis of severe RP and for estimating its progress and severity in patients treated with TRT.

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

Objective: To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). Methods: Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. Results: The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. Conclusions: Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.