[in Japanese]

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We presented typical and atypical CT findings of small lung cancers and benign lesions. Endobronchial lung cancers and located centrally may be missed on CT, as well as small lung cancers near the threshold for the detectability. A potential contributor to overlooked lung cancer is a satisfaction-of-search error. Well-defined and smooth edges are typical of benign lesions. Although some malignant nodules such as endobronchial tumors show welldefined and slightly lobulated edges, benign patterns of calcification, presence of fat, absence of significant lung nodule enhancement and no connection between vessels and the nodule at CT are strongly predictive of a benign nature. Most nodules with irregular or spiculated edges are malignant. However, some benign nodules such as organizing pneumonia show these edges, and the presence of satellite lesions, thickening of bronchovascular bundles and a concave contour are suggestive of a benign nature. Well-defined margins and notches are suggestive of a malignant lesion in nodules with only ground-glass attenuation. Note that some lung cancers in emphysema patients show findings similar to focal organizing pneumonia, i.e. a spindle-shaped or trapezoidal lesion adjacent to the pleura or along the bronchovascular bundle and evidence of satellite lesions. The CT findings around the nodules and in the whole lung field and the clinical information of present illness or past history are sometimes important in the differentiation of small pulmonary nodules.

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Objective. Multidetecter-row CT (MDCT) made the multiplanar reconstruction (MPR) images, coronal image or sagittal image, high resolution as same as axial image. We evaluated the branching pattern of pulmonary artery, A² and A³, in the right upper lobe from the MPR images. Methods. We studied the patients with known or suspected disease of the lung parenchyma and the volunteers using MDCT. We evaluated the arterial variations of A²ai, A²aii, A²bi, A²bii, A³ai, A³aii, A³bi and A³bii, arising from either the superior trunk or the ascending artery, which arises from inferior trunk. Results. Usually, the artery in the right upper lobe originates from the superior trunk and runs superior to the bronchi. Sometimes, the pulmonary segmental or sub segmental order artery in A² and A³ originates from the ascending artery runs inferior to the bronchi, which arises from inferior trunk. A few cases showed the relations between the bronchi and the artery paradoxical position. Conclusion. The MPR images can provide the detail information for the assessment of the bronchovascular trees. This technique can also provide the developing faculties reading film for young doctors or residents.

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Objective. To evaluate the useful CT finding for differentiating benign from malignant pulmonary nodule and for CT-bronchoscopic correlation, and to evaluate the usefulness of artificial neural networks (ANN). Methods. Sixty-six patients of solitary pulmonary nodule smaller than 3cm were evaluated for differential diagnosis and CTbronchoscopic correlation. One hundred fifty-five patients of solitary pulmonary nodule smaller than 3 cm were evalu-ated for ANN analysis. Results. In lung cancers, air bronchogram/bronchiologram, grossly irregular margin, and the involvement of pulmonary vein were common, while straight or inward concave margin and satellite lesions were pre-dominantly seen in benign nodules. The positive bronchus sign on CT was useful in predicting the success of transbronchial biopsy. The average Az value for all radiologists increased with the use of the ANN output.

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Newly developed multidetector-row CT can acquire whole lung data during a single breath hold. With multi-slice data, high resolution 3 D reconstruction images can be easily obtained in daily practice. Threedimensional reconstruction images such as multiplanar reconstruction (MPR) and maximum intensity projection (MIP) are useful to evaluate the association between pulmonary metastases and surrounding pulmonary structures. It is well known that typical radiologic findings of a pulmonary metastasis are of a round nodule or mass with a smooth margin. However, metastases with atypical radiologic features are often encountered, and are often difficult to distinguish from non-malignant pulmonary diseases or primary lung cancer. Detailed knowledge of the atypical radiologic features of pulmonary metastases is essential for correct diagnosis.

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Objective. To help in appreciating the significance of bronchoscopy in the diagnosis of lung cancer, basic knowledge essential to the procedure of bronchoscopy as well as endoscopic findings of lung cancer are described. Methods and Results. We outlined essential knowledge concerning bronchial anatomy and bronchoscopic technique, as well as the endoscopic findings of lung cancer. The lesion of non-early stage and early stage lung cancer of the hilar type is divided into three types (1. mucosal invasion type:(a) thickened type, (b) nodular type and (c) polypoid type, 2. submucosal invasion type, 3. extramural type) and four types (1. occult type, 2. thickened type, 3. nodular type, 4. polypoid type), respectively by the Japan Lung Cancer Society. Typical cases of each type were presented. A few unusual benign or with low-malignant tumors were also presented. It is important to identify the endoscopic type of lung cancer to suspect or confirm the histologic type and degree of the extent of carcinoma. Conclusion. Bronchoscopy is essential for establishing the histopathologic diagnosis and extent of lung cancer.

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Considerable experience has been gained with MR imaging of thoracic diseases, however the clinical role of MR imaging for staging of lung cancer remains limited. It offers advantages such as the assessment of chest-wall/mediastinal invasion, superior sulcus tumor, or differentiating hilar tumor from secondary peripheral obstructive changes in patients in whom CT remains equivocal. Although the evaluations of tumor characteristics using contrastenhanced dynamic MR imaging, such as differentiating malignant from benign nodules or imaging-pathologic correlation, have been reported recently, only a limited number have been shown to have a significant clinical usefulness. In this article, the clinical usefulness of MR imaging for pulmonary nodule is illustrated and reviewed.

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Although the results of randomized controlled trials (RCTs) are usually more reliable than that of case-control studies, not all RCTs reflect the truth. RCT concerning mass screening is very difficult to conduct properly because of the large number of participants and the long study period. For example, compliance and contamination in the Mayo Lung Project were reported 75% and 73%, respectively. The results of RCTs evaluating the efficacy of lung cancer screening, mainly in the 1970s, failed to show that lung cancer mortality would decrease by screening. There were four case-control studies evaluating the efficacy of lung cancer screening in the 1980s-early 1990s. In two of them, the results did not show screening efficacy, whereas another study showed that screening significantly reduced the risk for lung cancer deaths. The remaining study suggested that screening could reduce the risk for lung cancer deaths, but not significantly. Recently four other case-control studies evaluating the efficacy of lung cancer screening in 1990s were reported from Japan. The results of three studies showed significant reduction of the risk for lung cancer deaths by screening, and the results of the remaining study indicated a similar trend. The latest four case-control studies are reliable to evaluate the efficacy of current lung cancer screening systems. Problems and future studies in lung cancer screening systems are also discussed.

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Lung cancer screening with chest x-ray is not recommended as a public health policy in most countries, since randomized controlled trials have not demonstrated a reduction in lung cancer mortality. In Japan, lung cancer screening with chest x-ray and/or sputum cytology has been introduced since 1987 under the Health and Medical Services Law for the Aged. The efficacy of the screening was evaluated mainly by case-control studies, and some beneficial effects have been suggested. It has been criticized, however, that case-control studies are vulnerable to several biases. Also, time trends for age-adjusted incidence and mortality rates of lung cancer appear almost parallel for these decades, which means no beneficial effects due to early detection at the nationwide level. Therefore, it is not justifiable to state that efficacy of lung cancer screening with chest x-ray has been proved, unless the differential trends of incidence and mortality of lung cancer are clearly observed.

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[in Japanese]

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Cancer is regarded as an “acquired multigene disease”. Hence, diagnosis and treatment of cancer based on molecular pathogenesis are potentially superior to conventional methods. There have been many reports concerning the significance of molecular markers in the diagnosis and therapy of lung cancer over the last 10 years. Those include identification of people more susceptible to lung cancer by SNP analysis, early diagnosis or molecular staging based on highly sensitive PCR technology, or molecular markers as prognosticators or predictors of chemosensitivity. However, there is no evidence, established by good quality clinical trials, of the superiority of molecular-based approaches to conventional ones for the better outcome of patients with lung cancer. Recently, owing to the Human Genome Project and the advent of DNA chip technology, it has become possible to perform comprehensive analysis of cancer by expression profiling. It is now the focus of interest of many investigators to accurately predict patient prognosis or sensitivity to treatment, although it has been difficult to do so by analysis of single or limited numbers of gene (s). Iressa is a newly introduced molecular-targeted drug for lung cancer and it specifically inhibits EGFR tyrosine kinase. Although it is not possible to predict which patients would benefit from Iressa treatment, it will soon be possible in the near future. For the future development of this field, it is important to accumulate specimens of good quality from patients who are treated under the same protocol as well as to develop more sophisticated methodology.

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The analyses of molecular markers are potentially useful as a prognostic factor, for sensitivity tests of anticancer drugs and for diagnosis. There are many reports that examine the relation between molecular markers and the prognosis of lung cancer. However, statistically significant prognostic factors are not always clinically useful prognostic factors. Clinically useful prognostic factor such as stage and performance status should show distinct differences in survival. A small difference in survival defined by only meta-analysis is useless as a prognostic factor even if it is statistically significant. There are many reports that the sensitivity of anticancer drugs depends on the status of molecular markers. However, a randomized clinical trial is essential to prove that individual chemotherapy depending on the status of molecular markers is superior than empirical chemotherapy. Recently, target-based drugs have been developed and molecular markers are increasingly viewed as a target of these drugs. Gefenitib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is very promising drugs for lung cancer. At present the relationship between the expression of EGFR and the antitumor response of gefenitib is not clear. The development of molecular markers to detect the antitumor response of gefenitib is not only clinically but also economically important, thus, it is expected that a marker will be developed in the near future.

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Objective. To assess the efficacy of postoperative adjuvant chemotherapy for completely resected pathologic (p-) stage IB-IIIA non-small cell lung cancer (NSCLC) and to examine the validity in clinical practice. Methods. All the reported prospective randomized studies on postoperative adjuvant chemotherapy in more than 100 patients with resected NSCLC were reviewed. Results. Most chemotherapy regimens such as cisplatin-based intravenous chemotherapy regimens failed to improve the postoperative survival of patients with completely resected NSCLC. However, some prospective studies suggested that two oral drugs, UFT and ubenimex, could be effective as postoperative adjuvant therapy for resected NSCLC, whereas these two drugs showed minimal anti-tumor effect against advanced NSCLC. These results show that drugs that can be administrated for a long time after surgery, not drugs with potent anti-tumor activity, may be used postoperatively. Conclusion. It is clinically valid to perform postoperative adjuvant therapy using drugs that can be given with good compliance, such as UFT and ubenimex, whereas the efficacy has not been established.

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The clinical significance of preoperative induction therapy for IIIA (N2) non-small cell lung cancer (NSCLC) was reviewed. In locally advanced NSCLC patients, therapeutic results have remained poor. Five-year survival rate of clinical stage IIIA and pathological one was 34% and 28%, respectively. A number of studies demonstrate that adjuvant chemotherapy may be associated with some biological effect. Nonetheless, chemotherapy and radiotherapy in adjuvant setting remains experimental and cannot be definitively recommended outside the context of a randomized trial. With regard to potentially respectable stage IIIA-N2 NSCLC, the results of randomized trials support the conclusion that induction chemotherapy follwed by surgery (with or without postoperative radiotherapy) may enhance survival compared to that achieved with surgical resection alone. And the results of phase II trials include induction chemotherapy or chemoradiotherapy have demonstrated the following: 1) patients who respond either completely or partially to this induction therapy and are down-staged have a better survival. 2) patients with N2 disease at the time of surgery have a disappointing 5-year survival. and 3) patients with incomplete resection are rarely cured of their disease. These induction therapies are tolerable without significant morbidity either during the induction or postoperative phases of treatment. In future, some clinical problems shold be solved as follow; 1) which induction therapy before surgery is most appropriate-chemotherapy alone or chemoradiotherapy?, 2) which induction chemoradiotherapy is most efficacious prior to surgery-chemoradiotherapy or chemotherapy followed by chemoradiotherapy?, 3) what is the role of surgery for persistent N2 disease after induction therapy?, and 4) what is the role of adjuvant treatments following induction therapy and surgery?

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It was described in PDQ or NCCN guideline in US that one of the standard treatment for patients with respectable IIIA N2 non-small cell lung cancer (NSCLC) is induction chemotherapy plus surgery. However, we do not think that induction chemotherapy plus surgery is established as standard therapy in Japan because clinical trials registered sufficient patients have been conducted in Japan and the only randomized controlled trial compared induction chemotherapy plus surgery with surgery alone in Japan was negative result. The recent large scale randomized trial reported Depierre showed that induction chemotherapy was effective against early stage NSCLC patient but not effective for patients with N2 NSCLC. At present, the randomized controlled trials evaluated a meaning of an additional surgery have been conducted in US or Europe and as a result, it is possible that chemoradiotherapy becomes a standard therapy of respectable IIIA N2 NSCLC. Because induction chemotherapy plus surgery becomes a standard therapy for patients with respectable IIIA N2 NSCLC in Japan, I think that there is need for at least one clinical trial that is registered sufficient patients and showed usefulness of induction chemotherapy and is conducted in Japan.

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Cisplatin based chemotherapy prolog the survival of good performance status patients with advanced non-small cell lung cancer, and improve the quality of life. Recently, Key drug for non-small cell lung cancer is shifting to carboplatin, based on the difference of toxicities. In this study cisplatin based chemotherapy were compared to carboplatin based chemotherapy in meta-analysis about tumor response and 1 year survival rate, in the randomized trials for non-small cell lung cancer. In the analysis on 8 randomized trials comparing cisplatin to carboplatin with same combination drugs, response rate was statistically significantly better in cisplatin base therapy than carboplatin. One year survival rate of Cisplatin and Carboplatin based therapy was 38.9% and 36.8% respectively. In the analysis on 6 randomized studies comparing cisplatin to carboplatin with newer agents combination therapy, response rate and one year survival rate were no significantly differences. One year survival rate of cisplatin and carboplatin based therapy were 37.7% and 36.8% respectively. In the chemotherapy for advanced non-small cell lung cancer, it is reasonable to choose the carboplatin as a key drug for combination therapy with newer agents.

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Objective. To review relative clinical activities of cisplatin and carboplatin, an analog of cisplatin, which was introduced into cancer chemotherapy to help circumvent renal, neurologic, and emetogenic effects of cisplatin, in the treatment of advanced non-small-cell lung cancer. Methods. We identified seven prospective randomized clinical trials comparing cisplatin and carboplatin combined with the same drugs, published in the English language medical literature. We compare the toxicology and clinical activity of these two platinum agents. Results. Nausea and vomiting is much more severe and frequent in cisplatin arm. There seems to be no significant difference in neurotoxicity and severe renal toxicity. Thrombo cytopenia is usually frequent in carboplatin arm than cisplatin ann. Cisplatin-based regimen produced superior response rates in all seven trials. Four of 7 trials showed a trend toward better survival in favor of cisplatin. In other 3 trials survival was equivalent. Conclusion. Carboplatin does not possess equivalent activity to cisplatin in advanced non-small-cell lung cancer. Cisplatin-based chemotherapy should still be used as platform in the context of clinical trials seeking for future better strategy. However, in general practice it is appropriate to choose between these two agents on the basis of patients, renal or heart function and convenience.

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Objective and method. A review of the literature was carried out to determine the usefulness ofprophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC). Results. In the many comparativetrials performed until the 1980s, PCI was shown to decrease the incidence of brain metastasis, however no reportsrevealed a survival advantage. Furthermore, since PCI seemed to be associated with a variety of types of neurologicalimpairment, the role of PCI had not been established. Auperin et al then conducted a meta-analysis of seven randomizedtrials and reported that PCI significantly improved both incidence of brain metastasis and survival (3-year survival rate: 20.7% vs 15.3%, P=0.01) among patients with SCLC in complete remission (CR). According to the two trials conductedby Arriagada et al and Gregor et al, the incidence of neither cognitive function impairment nor brain atrophy on CT scanwas increased by PCI. Conclusion. PCI is considered to be a standard treatment in patients with SCLC achieving CR.Further research is needed to define optimal dose, fractionation and timing, and to clarify the possibility of delayed neurologicaltoxicity.

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Patients with limited-disease small cell lung cancer (LD-SCLC) are treated with cisplatin-containingchemotherapy combined with radiotherapy and the 5-year survival is expected to be 20-25%. As the outcome of treatmentand local control have been improved, brain metastasis has become a major site of first failure and prophylacticcranial irradiation (PCI) has been investigated to prevent brain metastasis. The conditions for PCI to be clinically usefulare that brain metastasis is the only site of recurrence in most patients, that PCI is effective to eradicate microscopicmetastasis, that the toxicity of PCI is not severe, and that PCI prolongs the survival. The metaanalysis of PCI trials reportedin 1999 concluded that PCI should be considered for patients who obtain complete response (CR) after first-linetreatment. However, issues such as the diagnostic modality used in response evaluation, optimal dose and timing, andprecise evaluation of late toxicity remain unsolved. Here these issues are reviewed and future directions are indicated.

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Objective. Chest radiography films used in lung cancer screening by the Saga General Health Associationare read by 2 groups consisting of 2 examines per group and compared individually. Positive predictive valueand the number of individuals having further examinations are higher, the number of individuals requiring further examinationsis lower, and detection rate is the same as or higher than the national average. Quality was adequately controlled. To improve quality, we started case conferences for screening-detected lung cancer attended by all examines in1999. Methods. Reading is to be standardized by returning and jointly discussing information to examines. Results. The detection rate exceeded the national average and the number of individuals requiring further examination increased. Positive predictive value declined but is still much better than the average. The number of individuals seekingfurther examination is rising. Conclusion. Screening-detected lung cancer case conferences appear to be vital to ensuringquality control in reading radiography films.

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Objectives. We made a preliminary report regarding the effectiveness of population-based screening with chest radiography and sputum cytology for lung cancer in Nagasaki Prefecture, Japan. Methods. Using data of the population-based cancer registry, the effectiveness of screening was evaluated. Results. The effectiveness of screening varied according to histological type and gender. Conclusions. The heterogeneity of lung cancer should be considered when evaluating the effectiveness of screening for lung cancer.

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Objective. Prior to settling on a plan for the “A Healthy Hoshuyama Village for the 21st Century” project, our objective should be to review data collection and health care services, to have a firm grasp of the issues involving lung cancer examinations, and to put a plan based on these observations into action. Research Plan (Procedure). Information on the following three items were collected from 1994 to 2001 and the results analyzed. 1: Mortality studies that show the dynamic trends in population change in Hoshuyama Village. 2: Excluding illnesses and ailments, medical treatment statistics of Hoshuyama Village (The amount spent every year in five month periods for medical treatment). 3: The current condition of receiving medical examinations for lung cancer in Hoshuyama Village. Results-Conclusion. With regards to 35% of the elderly population of Hoshuyama Village, at the same time as prevention of cerebrovascular disorders is being actively pursued, lung cancer is increasing among the elderly. It's reasonable to think that the lifestyle of the village has become more urbanized, however, we believe the origin of this increase for persons over the age of 70 may be related to the coal mine located beside the farms and forestry workplaces. And we think that from now on surveying and analyzing hearing examinations will also be necessary. In order to increase the rate of medical examinees, we must obtain the cooperation of the respective groups, administer efficient medical examinations as well as sufficient consultations with the residents, and create a suitable environment for medical examinations.

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[in Japanese]

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Although the results of randomized controlled trials evaluating the efficacy of lung cancer screening in the 1970s-early 1980s failed to show that lung cancer mortality would decrease by screening, four case-control studies evaluating the efficacy of lung cancer screening in the 1990s were recently reported from Japan. These indicated that screening would decrease the risk for lung cancer deaths by 30-60%. However, quality control in the screening system is not enough in some parts of Japan. Prefectural govemments should evaluate the quality of screening systems in each region and report the results. Preliminary reports conceming lung cancer screening using thoracic CT revealed that not only the detection rate of lung cancer but also the survival rate of detected lung cancer patients were very high. However, overdiagnosis bias must affect the results, and a randomized controlled trial should be conducted to evaluate the true efficacy of lung cancer screening using thoracic CT.

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Objective. To evaluate retrospectively the efficacy of lung cancer screening by low-dose helicalcomputed tomography (CT). Subjects and methods. During a six-year period (April 1, 1996 to March 31, 2001), therewere 2, 013 participants who received add-on screening of helical CT and 1, 300 participants who needed to receive furtherwork-up examinations after chest roentgenogram screening and who underwent detailed screening by helical CT. The detection rate of lung cancer of their pulmonary abnormal shadows was analyzed. Results. Four lung cancers weredetected by add-on screening of helical CT with a detection rate of 0.2%. Out of 195, 123 participants in chest roentgenogramscreening (annual health examination, mass screening for lung cancer and mass screening for tuberculosis), 3, 361 patients needed to receive further work-up examinations. Of those, 1, 300 (38.7%) consulted our hospital and underwentdetailed screening by helical CT and 61 lung cancers were detected in those 1, 300 cases. Compared with 41lung cancer patients detected among 2, 061 cases who consulted other hospitals (it was not clear whether or not they received detailed screening by helical CT), the detection rate of lung cancer in patients who consulted our hospital washigher (4.7% vs 2.0%, p<0.0001). There were 373 pulmonary abnormal shadows detected by both add-on screening ofhelical CT and detailed screening of helical CT. Lung cancers were detected in 61 of 238 solitary nodules (26%), 1 of 53patchy consolidations (2%) and 3 of 11 nodular ground glass opacities (27%). Although 50 patients were diagnosedas lung cancer after initial CT screening, follow-up screening of helical CT was recommended to exclude growth of tumorsin 15 cases (23%). Conclusion. Helical CT appears suitable for mass screening because of its high sensitivity tosmall nodules, but this test entails a high risk of unnecessary biopsy of benign lesions. Because there were some problemsfor starting helical CT examination for initial annual mass screening of lung cancer, it is important to performfollow-up screening of helical CT as well as detailed screening of helical CT for patients who need to receive furtherwork-up.

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