A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.

BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER: UMIN000000608.

Increased CCL18 expression in patients with cutaneous T-cell lymphoma: association with disease severity and prognosis.

BACKGROUND: CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up-regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. OBJECTIVE: To investigate roles of CCL18 in cutaneous T-cell lymphoma (CTCL). METHODS: The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT-PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme-linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. RESULTS: The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity-weighted assessment scores, serum sIL-2R, LDH, IL-4, IL-10, IL-31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. CONCLUSION: CCL18 mRNA is up-regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.

Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis, cutaneous T-cell lymphoma and psoriasis in combination with serum thymus and activation-regulated chemokine levels.

BACKGROUND: CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T-cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. OBJECTIVE: To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation-regulated chemokine (TARC). METHODS: Serum sCD26 levels were measured using enzyme-linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. RESULTS: Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2-73.7%, 81.4-97.6%, 65.2-94.4%, and 81.4-88.9% respectively. CONCLUSION: Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.

BAFF levels are increased in lesional skin and sera in patients with cutaneous T-cell lymphoma.

BACKGROUND: B-cell-activating factor belonging to the tumour necrosis factor family (BAFF) is known for its role in the survival and maturation of B cells. It has been recently suggested that BAFF also plays important roles in T-cell activation in T-cell mediated diseases such as psoriasis. OBJECTIVES: To investigate the role of BAFF in cutaneous T-cell lymphoma (CTCL). METHODS: BAFF messenger RNA (mRNA) expression in skin samples (24 CTCL cases and seven healthy controls) and in skin-derived fibroblasts (five CTCL cases and five healthy controls) was examined by quantitative reverse transcription-polymerase chain reaction. We also performed immunohistochemical staining for BAFF and its receptors. Serum BAFF levels were measured in patients with CTCL (n=46), atopic dermatitis (n=36) or psoriasis (n=27) and 27 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Lesional skin of CTCL contained higher levels of BAFF mRNA than normal skin and the expression levels correlated with disease activity. BAFF mRNA expression levels were elevated in fibroblasts from CTCL skin. Tumour cells in the lesional skin of CTCL expressed BAFF and its receptors, while fibroblasts expressed only BAFF. Serum BAFF levels of CTCL patients were significantly higher than those of healthy controls and correlated with types of skin lesions and clinical stages. They also significantly correlated with serum soluble interleukin-2 receptor and lactate dehydrogenase levels. CONCLUSIONS: BAFF expression in CTCL skin and serum BAFF levels are significantly increased and correlate with the severity of CTCL. These results suggest that BAFF may have important roles in the development of CTCL.

Phase II study of nedaplatin and docetaxel in patients with advanced squamous cell carcinoma of the lung.

BACKGROUND: The treatment of squamous cell carcinoma of the lung has not advanced sufficiently. Nedaplatin is a second-generation platinum compound that is active against squamous cell carcinoma of the lung, with a response rate of ~40%. PATIENTS AND METHODS: Eligible patients with advanced squamous cell carcinoma of the lung were treated with docetaxel (60 mg/m(2)) and nedaplatin (100 mg/m(2)) administered i.v. on day 1; these doses were determined in an earlier phase I study. The treatment cycles were repeated every 3 weeks. The primary end point was the response rate, and the secondary end points were overall survival, progression-free survival, and toxicity. RESULTS: Twenty-one patients were enrolled. Eighteen of the patients were male, and the median age was 67 years. The objective response rate was 62%. The median progression-free survival time was 7.4 months. The median survival time was 16.1 months, and the 1-year survival rate was 66.7% (95% confidence interval 46.5% to 86.8%). The most common adverse event was neutropenia (grade 3/4, 86%). Non-hematological toxic effects were relatively mild. One patient died of sepsis. CONCLUSIONS: Combination chemotherapy with nedaplatin and docetaxel is highly active and has an acceptable toxicity. Further investigation of nedaplatin and docetaxel is warranted.

Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer.

PURPOSE: This study was undertaken to determine the activity and toxicity of dose-intensive weekly chemotherapy (cisplatin, vincristine, doxorubicin, and etoposide [CODE] regimen) for previous treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS: The 17 patients with relapsed SCLC entered onto the study were to receive intensive weekly chemotherapy with the CODE regimen. All 17 patients had been heavily pretreated with some form of cisplatin-based combination chemotherapy. Six patients had received previous chemotherapy with CODE and one patient with cisplatin and etoposide (PE) as induction therapy. Nine patients had been treated with concurrent or sequential PE plus thoracic irradiation (TRT). The median time off chemotherapy was 6.7 months (range, 3.3 to 72). Patients were treated with 9 weeks of the CODE regimen. Response, survival, and toxicity data were noted. RESULTS: All 17 patients were assessable for response, survival, and toxicity. Fifteen of 17 patients (88.2%) had an objective response, with five complete responses (CRs; 29%) and 10 partial responses (PRs; 58.8%). The median durations of response and survival were 156 days and 245 days, respectively. Myelosuppression was significant, with 76% of patients developing grade 4 leukopenia. No treatment-related death was observed. CONCLUSION: The CODE regimen is highly active in the treatment of relapsed SCLC with an encouraging survival outcome.

Risk factors of treatment-related death in chemotherapy and thoracic radiotherapy for lung cancer.

We retrospectively analysed the incidence and risk factors of treatment-related death in the treatment of chemotherapy- and thoracic radiotherapy-naïve patients with lung cancer. Between July 1992 and December 1997, 1799 patients were diagnosed as having lung cancer in our hospital and 926 patients received chemotherapy and/or thoracic radiotherapy. 25 patients (2.7%) died from toxicity of the treatment, 10 from pneumonia, 7 from radiation pneumonitis, 6 from sepsis, 1 from perforation of the small intestine and 1 for an unknown reason. 18 patients (2.3%) died from chemotherapy-related toxicity. The incidence of treatment-related death (TRD) from chemotherapy was highly correlated with the performance status (PS), PS 0: 0.7%, PS 1: 2.2%, PS 2: 4.0%, PS 3: 7.7% and PS 4: 25% (P=0.004). 7 patients (1.6%) died from pneumonitis after thoracic radiotherapy. Multivariate analyses demonstrated that poor PS (relative risk (RR): 1.95, 95% confidence interval (CI): 1.05-3.65, P=0.034) and chemotherapy using the cisplatin+vindesine+mitomycin C regimen (RR: 9.36, 95% CI: 1.29-68.0, P=0.027) are associated with treatment-related death from chemotherapy. Pulmonary fibrosis identified on a plain chest X-ray film (RR: 165.7, 95% CI: 8.79-3122, P<0.001), the combination of cisplatin+irinotecan (RR: 120.5, 95% CI: 2.90-4993, P=0.012), advanced age (RR: 1.17, 95% CI: 1.002-1.37, P=0.047), and elevated lactate dehydrogenase (LDH) (RR: 10.4, 95% CI: 1.20-90.2, P=0.033) were also associated with treatment-related death from thoracic radiotherapy. The administration of mitomycin C in addition to cisplatin-based regimens for patients with lung cancer should be carefully considered.

Efficacy of droperidol in the prevention of cisplatin-induced delayed emesis: a double-blind, randomised parallel study.

We conducted a prospective, randomized, double-blind, parallel study comparing the antiemetic activity and tolerability of treatment with droperidol (2.5 mg d.i.v. twice daily for 5 days) and placebo, both combined with granisetron (3 mg d.i.v. on the first day) and dexamethasone (16 mg d.i.v. on the first day, 8 mg d.i.v. on days 2, 3, and 4 mg d.i.v. on days 4, 5). A total of 180 lung cancer patients receiving high-dose cisplatin (80 mg/m(2))-containing chemotherapy were enrolled in the study, and 171 of them were capable of being evaluated. The clinical characteristics of the patients in the two treatment arms were well balanced. Complete protection from nausea and vomiting was recorded in the acute phase in 97% of patients who treated with droperidol versus 98% of patients who given the placebo (P=0.920), and in 42% versus 38% in the delayed phase (P=0.615). The multiple logistic regression analysis showed that a history of motion sickness was a significant risk factor for cisplatin-induced delayed emesis (odds ratio [OR]=5.98; 95% CI=2.15 to 16.7, P=0.0006). Droperidol-containing treatment was well tolerated by most patients, however, the incidence of sleepiness in the droperidol group was higher than in the placebo group (69% versus 30%, P<0.0001). In conclusion, our data did not support the hypothesis that addition of droperidol to granisetron and dexamethasone reduces the delayed emesis induced by high-dose cisplatin.

Video-assisted thoracoscopic surgery for small indeterminate pulmonary nodules: indications for preoperative marking.

STUDY OBJECTIVE: To determine the indications for preoperative localization of a small indeterminate pulmonary nodule. DESIGN: In this retrospective study, univariate and multivariate analyses were performed by the logistic regression procedure. SETTING: A single National Cancer Center Hospital in Japan. PATIENTS: A series of 92 consecutive patients who underwent video-assisted thoracoscopic surgery (VATS) at our institute between 1993 and 1996. INTERVENTIONS: The frequency and reasons for conversion to thoracotomy were assessed retrospectively. All preoperative CT scans were reviewed for eight radiologic features by two of the authors. These data were entered into univariate and multivariate analyses to identify the significant risk factors for a failure to detect a pulmonary nodule. MEASUREMENTS AND RESULTS: Fifty patients (54%) needed conversion to a thoracotomy. The most common reason for the conversion was failure to localize nodules (46%). Univariate and multivariate analyses of 11 variables revealed one significant risk factor in the failure to detect nodules: distance to the nearest pleural surface (p < 0.05). Tumor size on radiograph remained marginally significant (p = 0.065) in multivariate analyses. If the distance to the pleural surface was > 5 mm in cases of nodules < or = 10 mm in size, the probability of failure to detect a nodule was 63%. CONCLUSIONS: Our results suggested the indications for preoperative localization of a peripheral pulmonary nodule. Preoperative marking for a small indeterminate pulmonary nodule should be considered when the distance to the nearest pleural surface is > 5 mm in cases of lung nodules of < or = 10 mm in size.

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.

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.

Japanese experience of telemedicine in oncology.

We started telemedicine projects from 1990 with a telepathology system within Tsukiji Campus of National Cancer Center. In 1994, we connected Tsukiji Campus and Kashiwa Campus by 6 Mbps optical fiber leased line using IP protocol for data transmission, for teleconference, telepathology, and teleradiology projects. We also started connection of regional cancer centers and are now forming a cancer center network of 14 cancer centers. We are at present organizing 130 teleconferences per year with an attendance of more than 16000 people as summary. We have also used a high-resolution image transferring system, such as SHD (2000 pixelsx2000 pixels resolution) system on one side, and an economical telemedicine system using JAVA and a WWW browser (NCC_image) on the other side. We think that providing information is another field of telemedicine. We began the experimental gopher and WWW service in 1993. We are now providing official up-to-date cancer information for patients and healthcare professionals. We are getting more than 400000 hits per month. We are also providing a teleconference video session which is held every week on the Internet using a Real Video system with synchronized slide presentation on the WWW browser. We are also organizing a Cancer Image Reference Database System including DICOM images with viewer software. This paper is a summary of the telemedicine projects performed at the National Cancer Center.

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

In this paper, 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 analytical and diagnostic procedures. In the analytical procedure, first we extract the lung and the pulmonary blood vessel regions using the fuzzy clustering algorithm, then we analyze the features of these regions using image-processing techniques. In the diagnostic procedure, we define diagnostic rules utilizing the extracted features which support the determination of the candidate nodule locations. We show the effectiveness of our system by giving the results from its application to image data for mass screening of 450 patients.

Virtual reality enhanced surgical conference system.

We present our ongoing work on an enhanced surgical conference system with a technology of virtual reality (VR). We reported on a surgical simulation support system by using a technology of virtual reality last year. In the present time, while using our VR simulation system, we realized that many surgeons and nurses needed to see both a solid real image and a virtual image of the surgical operation at the same time. According to this reason we added a solid video system to our previous VR simulation system. The new system can display both real and virtual images on 100 inch wide screen and a console monitor of Onyx computer. The doctors can see both images with shutter glasses on the screen or console. We can now simulate various cancer surgery while watching the real solid surgical picture. We expect our enhanced surgical conference system to be beneficial for surgeons and nurses with limited experience to familiarize surgical procedures. The system could be also employed in planning a surgical procedure and educating medical staffs. Here we discuss about the aim of the system, current implementation, its limitations and its future directions.

[Development of helical CT and clinical application].

We applied helical CT to examinations of the clinical image diagnosis. Scanning was performed continuously while the couchtop of the CT scanner was shifted at a constant speed. The entire lung field could be scanned during a single holding of the breath when the couchtop speed was 20 mm/s. Tumors as small as 2 mm were detected. The diagnostic detectability and accuracy of helical CT were far superior to those conventional chest radiography. During abdominal examination, the target organ could be scanned at any specified phase (preferably arterial) during the injection of contrast medium. We detected very small hepatic tumors which could not be detected by conventional CT. Helical CT produced continuous data, which was reconstructed to display three-dimensional image. Helical CT could be used in mass screening for the detection of early lung cancer and in computer-aided diagnosis.

Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography.

PURPOSE: To compare low-dose spiral computed tomography (CT) with radiography of the chest for the screening and detection of small peripheral lung cancers in a high-risk population. MATERIALS AND METHODS: Posteroanterior and lateral radiographs and low-dose spiral CT scans were obtained twice a year from September 1993 to April 1995 in 1,369 individuals (a total of 3,457 examinations) who were at high risk for lung cancer. Low-dose spiral CT parameters were 120 kvP, 50 mA, 10-mm collimation, and 2:1 pitch. RESULTS: Peripheral lung cancer was detected in 15 of 3,457 examinations (0.3%). Among the 15 cases, the results of chest radiography were negative in 11 (73%), and the tumors were detected only at low-dose spiral CT. The detection rates of low-dose spiral CT and chest radiography were 0.43% (15 of 3,457 examinations), respectively. Fourteen (93%) of the 15 (exclusion of one pulmonary lung cancer) tumors were stage I. CONCLUSION: Low-dose spiral CT was superior to chest radiography in the screening and detection of peripheral lung cancer in high-risk individuals. Further large-scale studies are warranted, however, to clarify the efficacy and cost-effectiveness of low-dose spiral CT in a randomized, controlled population.