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Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

Key Clinical Message We describe a case of atrial fibrillation in which an intracardiac thrombus that could not be prevented with “low‐dose” dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using direct oral anticoagulants (DOACs) could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.

Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

S-1 is an oral fluoropyrimidine derivative, including three pharmacological compounds: tegafur, gimeracil and oteracil, in a molar ratio of 1: 0.4: 1.This review addresses the clinical evidence of S-1 in NSCLC in various clinical settings. Currently, S-1 for NSCLC is approved only in Japan. Prospective studies of S-1 as front-line and second-line chemotherapy with or without other agents and concurrent chemoradiotherapy are mainly reviewed. Only two Phase III clinical trials were published or presented for advanced NSCLC. S-1 and cisplatin is an active first-line chemotherapy regimen for advanced NSCLC and S-1 and carboplatin is noninferior to a carboplatin and paclitaexel regimen. The combination of S-1 and a platinum agent is active against NSCLC, regardless of tumor histology.It is becoming possible to design effective regimens with S-1 against NSCLC in various clinical settings considering the ethnic differences in pharmacokinetics and a greater understanding of the underlying molecular pathways or biomarkers of NSCLC. Further Phase III studies with S-1 for both early and advanced NSCLC are warranted worldwide.

Background A previous study showed a survival benefit with maintenance therapy with pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether continuation maintenance therapy with pemetrexed is beneficial in Japanese patients. Here, we present our phase II study that assessed the efficacy and safety of cisplatin plus pemetrexed as induction chemotherapy, followed by maintenance therapy with pemetrexed in advanced NSCLC patients in Japan. Methods Chemotherapy-naive patients received 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin on day one every three weeks for four cycles. In patients who responded to therapy or achieved stable disease, pemetrexed was continued until disease progression. The primary endpoint of this study was the progression-free survival rate at six months (PFS-6). Results Of the 35 patients initially enrolled in the study, 18 (51%) received maintenance chemotherapy with pemetrexed. The median PFS was 6.7 months, and the PFS-6 was 60% (95% confidence interval [CI], 42–76%). Median overall survival (OS) was 15.5 months (95% CI, 8.3–22.7 months). The median PFS and OS in patients who received maintenance chemotherapy with pemetrexed were 9.5 months and 25.3 months, respectively. The most frequently noted severe toxicity during induction chemotherapy was neutropenia, which occurred in seven patients. Two patients discontinued maintenance therapy owing to prolonged grade 2 edema in one patient and grade 3 neutropenia in another. Conclusion Continuation maintenance chemotherapy with pemetrexed is associated with a survival benefit in patients who have completed induction chemotherapy for non-squamous NSCLC.

Summary Background Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. Methods We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20–70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m 2 on days 1–3; intravenous cisplatin 80 mg/m 2 on day 1) plus AHTRT (1·5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m 2 on days 1, 8, 15; intravenous cisplatin 60 mg/m 2 on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. Findings 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3·2 years (95% CI 2·4–4·1). In the irinotecan and cisplatin group, median overall survival was 2·8 years (95% CI 2·4–3·6); overall survival did not differ between the two groups (hazard ratio 1·09 [95% CI 0·80–1·46], one-sided stratified log-rank p=0·70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Interpretation Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. Funding National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.

PURPOSE We evaluated the ability of diffusion-weighted imaging (DWI) at 3 tesla for diagnosing T stage and detecting stalks in bladder cancer. METHODS In total, 39 consecutive patients with bladder tumors underwent magnetic resonance (MR) imaging that included T2-weighted imaging (T2WI) and DWI using a 3T MR scanner. Two radiologists interpreted T2WI plus DWI and T2WI for diagnosis of T stage and for detection of stalks. We used McNemar's test to examine differences in diagnostic performance and Fisher's exact test to evaluate differences in stalk detection frequency. RESULTS Specificity and accuracy in differentiating T1 tumors from T2 to T4 tumors were significantly better with T2WI plus DWI (83% [20/24] and 85% [33/39]) than T2WI (50% [12/24] and 67% [26/39]; P = 0.02), and accuracy for diagnosing tumor stage was significantly better with T2WI plus DWI (82% [32/39]) than T2WI alone (59% [23/39]; P = 0.03). The observers identified stalks in 11 tumors by T2WI (48% [11/23]) and 17 by DWI (74% [17/23]) (P < 0.03). CONCLUSION DWI at 3T was superior to T2WI for evaluating the T stage of bladder cancer, particularly in differentiating T1 tumors from those T2 or higher, and in detecting stalks of papillary bladder tumors.

This paper proposes an interference detection method in MIMO transmission, which utilizes periodical preamble signals in a frequency domain. In the propose method, second antenna receives the signals while first antenna transmits the preamble signals. Hence, the interference can be detected by observing the subcarriers which are not mapped short preamble signal using the received signal after the FFT processing. Moreover, we utilize the orthogonal polarized antennas to reduce the mutual coupling between the transmitter and receiver. By a computer simulation and measurement with the use of orthogonal polarized antenna, it is shown that the proposed method can successfully detect interference from the other system when the interfering power is greater than the noise power.

Background We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. Patients and methods Patients receiving chemotherapy including cisplatin (≥70 mg/m2) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 mg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1–3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0–120 h). Results The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0–24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24–120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). Conclusions Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Purpose To investigate the diagnostic accuracy of 3.0-T diffusion-weighted imaging (DWI) for detection of prostate cancer by using different b -values. Methods Seventy-three patients underwent magnetic resonance imaging (MRI) at 3.0 T. Three MRI sets were reviewed by two radiologists: MRI and DWI ( b =500s/mm 2 ) (protocol A), MRI and DWI ( b =1000s/mm 2 ) (protocol B), and MRI and DWI ( b =2000s/mm 2 ) (protocol C). Areas under the receiver operating characteristic curve (AUCs) were calculated. Results The mean of the AUCs in protocol C was larger than those in protocol A and in protocol B ( P Conclusion DWI ( b =2000s/mm 2 ) at 3.0 T can improve the diagnostic accuracy for detection of prostate cancer.

Purpose This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods Chemonaive patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone ( p =0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p =0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p =0.9526). No new safety signals were detected. Conclusion Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Objective: We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease smallcell lung cancer. Methods: Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m 2 )w ere administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if .45 responses were observed in the 55 patients. Results: Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6‐87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8‐18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9‐7.4). Conclusions: This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure for the pathological evaluation of the mediastinal nodal (N2) status of lung cancer; however, its feasibility in potentially operable patients with suspicion of minimal N2 disease remains unestablished. Patients and Methods: A prospective multicenter study was conducted to assess the feasibility of EBUS-TBNA in this setting. Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) and mediastinal nodal enlargement on computed tomography (CT) were eligible; patients were ineligible when CT revealed bulky (> 3 cm in the long-axis diameter) N2 or multiple (≥ 3) station N2. If EBUS-TBNA revealed negative results, surgical staging procedures were mandatory. Results: Among 20 eligible patients, EBUS-TBNA provided pathological confirmation of N2 disease (true-positive) in 12 patients. Among 8 patients with negative results with EBUS-TBNA, 4 patients were pathologically diagnosed as having N2 disease with surgical staging procedures (false-negative), and 4 were finally diagnosed as having non-N2 disease with nodal dissection by thoracotomy (true-negative). As a result, the sensitivity of EBUS-TBNA for N2 evaluation (primary endpoint) was 75.0% (95% confidence interval 47.6-92.7%). No grade 3-5 adverse event were documented. Conclusion: EBUS-TBNA is potentially safe and useful in the pathological evaluation of N2 status even in potentially operable NSCLC patients with suspicion of minimal N2 disease on preoperative CT.

Efficacy of first-line gefitinib for elderly epidermal growth factor receptor mutated patients with lung adenocarcinoma is uncertain. This study was aimed to investigate efficacy of gefitinib for such population. The primary endpoint was response rate (RR) and at least 12 cases were needed. Overall RR was 59% (95% confidence interval, 33%-81%) and first-line gefitinib was effective for elderly patients.Feasibility of gefitinib therapy in elderly patients with non-small-cell lung cancer is uncertain. This phase II study aimed to investigate the efficacy and usefulness of gefitinib therapy as a first-line treatment for elderly patients who have advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations.We enrolled chemotherapy-naïve advanced lung adenocarcinoma patients aged 75 years or older. Patients were administered gefitinib (250 mg) once daily until progression or unacceptable toxicity. The primary endpoint was response rate (RR), and secondary endpoints were disease control rate (DCR; defined as complete response [CR] plus partial response [PR] plus stable disease [SD]), progression-free survival (PFS), overall survival (OS), and toxicity profile.Between April 2008 and November 2009, 17 lung adenocarcinoma patients were enrolled. Overall RR was 59% (95% confidence interval [CI]: 33% to 81%), with 2 patients achieving CR and 8 PR. SD was noted in 5 patients, and DCR was 88% (95% CI: 62% to 98%). Median PFS was 12.9 months (95% CI: 2.2 to 23.6 months), and median OS had not yet been reached. Major grade 3 toxicities were skin rash (12%) and increased levels of aspartate aminotransferase or alanine aminotransferase (18%).First-line treatment with gefitinib was effective and well-tolerated in elderly patients with EGFR mutations.

Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non–small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m2 on day 1)/vindesine (3 mg/m2 on days 1, 8)/cisplatin (80 mg/m2 on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m2)/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. Conclusion Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

BackgroundWe previously reported that Asian ethnicity was a favorable prognostic factor for overall survival (OS) in non-small cell lung cancer (NSCLC). In this study, we performed a combined data analysis from a Japanese Cancer Registry and a regional California Cancer Registry to further validate this observation.MethodsRetrospective population-based analysis of Japanese and Caucasian patients with NSCLC with known smoking status from the Japanese National Hospital Organization Study Group for Lung Cancer and a Southern California Regional Cancer Registry between 1991 and 2001.ResultsA total of 15,185 Japanese and 13,332 US Caucasian patients were analyzed. Median age of Japanese patients was 68 years compared with 69 years for Caucasian patients (p < 0.0001). A total of 29.3% of Japanese compared with 7.3% Caucasian patients were never-smokers. Never-smoking status conferred significant improved OS for Japanese (p < 0.0001) and a trend for improved OS for Caucasian patients (p = 0.1282). Univariate analysis revealed Japanese patients with stage III (versus Caucasian; hazard ratio [HR] = 0.830, 95% confidence interval [CI]: 0.789-0.873, p < 0.0001) and IV disease (versus Caucasian; HR = 0.955, 95% CI: 0.915-0.997, p = 0.0369) had improved OS compared with Caucasian patients. Multivariate analysis revealed Japanese ethnicity (versus Caucasian; HR = 0.937, 95% CI: 0.898-0.978, p = 0.0028) and never-smoker status (versus ever-smoker; HR = 0.947, 95% CI: 0.909-0.987, p = 0.0104) to be independent favorable factors for OS in addition to younger age, female gender, early stage, and treatment received (surgery, radiation, and chemotherapy).ConclusionsJapanese ethnicity when compared with Caucasian ethnicity and never-smoker status are independent favorable prognostic factors for OS in NSCLC.

Background: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). Methods: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. Results: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36–0.97) and 0.71 (95% CI, 0.49–1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). Conclusion: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

Background The Japan-Multinational Trial Organization (JMTO) lung cancer (LC) 0003 was a prospective randomized phase III trial investigating advanced non-small cell lung cancer comparing paclitaxel (P) plus carboplatin (C) versus vinorelbine (V), gemcitabine (G) followed by docetaxel (D). This trial was conducted with Southwest Oncology Group (SWOG) 0003 using a common arm of PC. An analysis of SWOG 0003 samples showed that low osteopontin (OPN) plasma levels were highly prognostic for a better outcome. We performed an independent investigation to validate these results using samples from Japanese patients enrolled in the JMTO LC 0004, a correlative study associated with JMTO LC 0003. Methods A total of 20 ml of blood was collected before treatment from patients enrolled in JMTO LC 0003. Serum concentrations of OPN and basic fibroblast growth factor (bFGF) were measured by enzyme-linked immunosorbent assay. Effects of OPN and bFGF levels on tumor response, progression-free survival (PFS), and overall survival (OS) were examined. Results Seventy-one samples were obtained, including 32 specimens from the PC arm and 39 from the VGD arm. There were no significant relationships between either OPN or bFGF levels with patient characteristics. In an analysis of clinical outcome, low OPN levels correlated with better OS and progression-free survival (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.33–0.97; p = 0.037, HR=0.42; 95% CI, 0.25–0.70; p = 0.001, respectively) and high bFGF levels correlated with better OS (HR = 0.53; 95% CI, 0.31–0.90; p = 0.018). Conclusion Consistent with the findings from SWOG 0003, low OPN serum levels were significantly associated with a favorable prognosis in the JMTO LC 0004. Additionally, high bFGF levels were associated with improved survival.

TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ≤2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks.

IntroductionThe aim of this study was to evaluate the efficacy and safety of Erlotinib in Japanese patients with previously treated non-small cell lung cancer (NSCLC). Available tumor biopsy samples were analyzed to examine relationships between biomarkers and clinical outcome.MethodsThis open-label phase II trial enrolled stage III/IV NSCLC patients who had progressive disease after at least one prior platinum-based chemotherapy regimen. Erlotinib was administered at a dose of 150 mg/d orally until disease progression or intolerable toxicity. Analysis of epidermal growth factor receptor gene mutations in exon 18–21 by direct sequencing was performed in tumor tissue specimens obtained at the first diagnosis.ResultsSixty-two patients were enrolled and 60 patients were evaluable for efficacy. Objective response rate and disease control rate were 28.3% and 50.0%; median time to progression and overall survival were 77 days and 14.7 months, respectively. In logistic regression analysis, only smoking history was proved to be a statistically significant predictive factor for response (odds ratio: 0.06, p < 0.001). Only 7 patients had samples available for mutation analysis. Three patients who had deletion mutations on exon 19 (del E746-A750 or del S752-I759) exhibited objective response. Common toxicities were rash (98%), dry skin (81%), and diarrhea (74%). Discontinuation due to adverse events occurred in 11 patients (18%). Four patients (6%) experienced interstitial lung disease-like events, one of whom died.ConclusionErlotinib is efficacious in Japanese patients with previously treated NSCLC. The toxicity profile was similar to that in Western patients, except for a somewhat higher incidence of skin disorders and interstitial lung disease. Further studies are needed to determine the relationship between epidermal growth factor receptor mutations and outcomes with Erlotinib in Japanese patients.

Introduction The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. Methods In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m 2 ) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m 2 on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Results The recommended dose of docetaxel was 40 mg/m 2 in combination with S-1 80 mg/m 2 /d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. Conclusions This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

It has been reported that the R497K polymorphism of the epidermal growth factor receptor (EGFR) gene has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. On other hand, EGFR gene mutations at kinase domain in non-small cell lung cancer (NSCLC) have been examined for their ability to predict sensitivity to gefitinib or erlotinib.We investigated the EGFR mutations and/or R497K polymorphism statuses in 225 surgically treated NSCLC cases. 192 adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of exon 13 was analyzed by PCR-RFLP method.EGFR mutations at kinase domain were found from 95 of 225 lung cancer patients. In 86.2% of patients, homo- or heterozygous Lys497 allele was present. No correlation existed between R497K EGFR genotype and clinico-pathological features, such as gender, smoking status, and pathological subtypes.EGFR mutation status was not correlated with R497KEGFR genotype of lung cancers. In node-negative patients, R497KEGFR genotype was not correlated with disease outcome. In node-positive patients, however, R497K EGFR was significantly associated with better overall survival. This association was attributable to neo-adjuvant or adjuvant chemotherapy. In 46 total gefitinib treated NSCLC patients, the prognosis was not different between the EGFR wild type (GG) patients and AG+AA patients. R497KEGFR polymorphism might be associated with favorable prognosis of advanced lung cancers and correlated with chemosensitivity.

Background Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC), and some common somatic mutations in EGFR have been examined for their ability to predict sensitivity to gefitinib or erlotinib. However, EGFR mutations at exon 20 have been reported to predict resistance to gefitinib therapy. Materials and methods We investigated the EGFR mutations and/or polymorphism statuses at kinase domain in 303 surgically treated non-small cell lung cancer (NSCLC) cases. One hundred ninety-four adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of kinase domains was analyzed by direct sequences. We have also investigated EGFR polymorphism status at exon 20 for 23 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. Results EGFR mutations at kinase domain were found in 75 of 303 lung cancer patients. During sequencing of EGFR tyrosine kinase domain in tumors, 86 EGFR polymorphism (G2607A) cases were identified at exon 20. G2067A polymorphism was significantly higher in nonadenocarcinomas (37.4%) than in adenocarcinoma (25.3%, P = 0.0415). The polymorphism status did not correlate with gender, smoking (never smoker versus smoker), and EGFR mutations. In 46 total gefitinib treated NSCLC patients, there was a tendency toward better prognosis in EGFR wild type (GG) patients than AG + AA patients. EGFR polymorphism in Japanese lung cancers seemed to be less frequent than Caucasian lung cancers. Conclusions EGFR-tyrosine kinase polymorphism might be associated with clinicopathological background of lung cancers.

Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC). However, EGFR mutations status at C-terminal domain has not been reported in detail.We investigated the EGFR mutation and polymorphism statuses at C-terminal domain in 398 surgically treated NSCLC cases. Two hundred and sixty-eight adenocarcinoma cases were included. The presence or absence of EGFR mutation and polymorphism was analyzed by direct sequences.A novel EGFR somatic mutation at exon 25 (G3034, D1012H) was found from 1 of 398 lung cancer patients. During sequencing of EGFR C-terminal domain in NSCLC, 194 EGFR polymorphism (C2982T) cases were identified at exon 25. The polymorphism statuses were not correlated with gender, smoking status (never smoker vs. smoker), pathological subtypes and EGFR mutations. The EGFR polymorphism ratio was significantly higher in younger NSCLC (or =60, 56.8%) than in older NSCLC (60, 45.6%, P = 0.0467). The EGFR polymorphism ratio was significantly higher in lymph node positive NSCLC (57.4%) than in lymph node negative NSCLC (44%, P = 0.0168). In 46 total gefitinib treated NSCLC patients, exon 25 polymorphism was not correlated with prognosis.EGFR mutation at C-terminal in lung cancers seemed to be extremely rare, however, this D1012H mutation might be a role in EGFR function. EGFR polymorphism at exon 25 might be correlated with progression of NSCLC.

To evaluate the epidermal growth factor receptor (EGFR) protein expression, gene mutations and amplification as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib, we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR amplification and EGFR protein expression statuses in 27 surgically treated non-small-cell lung cancer (NSCLC) cases. These patients experienced relapse after surgery and received gefitinib 250 mg/day. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR mutations were found from 15/27 lung cancer patients. EGFR mutation status was significantly correlated with better prognosis (log-rank test P=0.0023). Smoking status (never smoker vs. smoker, P=0.0032), and pathological subtypes (adenocarcinoma vs. non-adenocarcinoma, P=0.0011), but not EGFR amplification (P=0.1278), were correlated with survival of lung cancers. EGFR IHC results were correlated with FISH results (P=0.0125), but not correlated with prognosis (P=0.7921). Thus, the EGFR gene amplification or protein expression is not a predictor of gefitinib efficacy in Japanese patients with NSCLC. We have also evaluated the EGFR mutation status and clinico-pathological features for 27 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. The EGFR mutation status, especially exon19 mutation was correlated with good response to gefitinib than exon 21 point mutation.

A water soluble derivative of camptothecin, irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC), as well as non-SCLC and gastrointestinal cancers. This extended review of recently concluded and ongoing studies focuses on irinotecan in the treatment of limited (LD) and extensive (ED) SCLC specifically considering the safety of patients. Irinotecan-induced diarrhoea is pervasive, and can be severe and life-threatening especially in combination with neutropenia. It can have a significant impact on patient quality of life, negatively influencing compliance with therapy and dose-intensity. For LD SCLC, irinotecan can be administered with radiotherapy concurrently or sequentially. In a Phase III study for ED SCLC comparing etoposide and cisplatin (EP) and irinotecan and cisplatin (IP) regimens, severe myelosuppression was more frequent in the EP arm than in the IP arm, and conversely severe or life-threatening diarrhoea was more frequent in the IP arm than in the EP arm. IP resulted in significantly higher response rates and overall survival in Japan, and confirmatory Phase III studies are ongoing. Irinotecan should not be administered to patients with any degree of ongoing diarrhoea above their baseline. Irinotecan can be administered with relative safety for patients with SCLC only through careful patient monitoring, especially regarding diarrhoea and myelosuppression.

Purpose: Irinotecan and cisplatin (IP) significantly improved survival compared with etoposide and cisplatin (EP), in patients with extensive-stage small cell lung cancer (SCLC) in a previous Japan Clinical Oncology Group (JCOG) randomized trial. JCOG9903 was conducted to evaluate the safety of sequentially given IP following concurrent EP plus twice-daily thoracic irradiation (TRT) for the treatment of limited-stage SCLC (LSCLC). Experimental Design: Between October 1999 and July 2000, 31 patients were accrued from 10 institutions. Thirty patients were assessable for toxicity, response, and survival. Treatment consisted of etoposide 100 mg/m2 on days 1 to 3, cisplatin 80 mg/m2 on day 1, and concurrent twice-daily TRT of 45 Gy beginning on day 2. The IP regimen started on day 29 and consisted of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1, with three 28-day cycles. Results: There were no treatment-related deaths. The response rate was 97% (complete response, 37%; partial response, 60%). Median overall survival was 20.2 months; 1-, 2-, and 3-year survival rates were 76%, 41%, and 38%, respectively. Of the 24 patients who started the IP regimen, 22 received two or more cycles. Hematologic toxicities of grade 3 or 4 included neutropenia (67%), anemia (50%), and thrombocytopenia (4%). Nonhematologic toxicities of grade 3 or 4 included diarrhea (8%), vomiting (8%), and febrile neutropenia (8%). Of the 20 patients with recurrence, none had local recurrence alone and only two had both local and distant metastasis as the initial sites of disease progression. Conclusions: IP following concurrent EP plus twice-daily TRT is safe with acceptable toxicities. A randomized phase III trial comparing EP with IP following EP plus concurrent TRT for LSCLC is ongoing (JCOG0202).

The prognosis of lung cancer patients with surgically resected non-small-cell lung cancer (NSCLC) can be predicted generally from age, sex, histologic type, stage at diagnosis, and additional treatment. Nine studies have reported that a history of smoking before diagnosis influences the prognosis of the disease in lung cancer patients. In this study, a total of 3082 patients who underwent surgery and were diagnosed with primary pathological stage IA NSCLC at 36 national hospitals from 1982 to 1997 were analyzed for the effect of smoking on survival. Smoking history and other factors influencing either the overall survival or the disease-specific survival rates of patients were estimated with the Cox proportional hazards model. Multivariate analysis demonstrated significant associations between overall survival and age (P0.0001), sex (P = 0.0002), and performance status (PS) (P0.0001). Disease-specific survival was associated with age (P = 0.0063), sex (0.00161), and PS (P = 0.0029). In males, disease-specific survival was associated with age (P = 0.0120), PS (P = 0.0022), and pack-years (number of cigarette packs per day, and years of smoking) (P = 0.0463). These results indicate that smoking history (pack-years) is important clinical prognostic factor in estimating disease-specific survival, in male patients with stage IA primary NSCLC that has been surgically resected.

Background: The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly assigned to the radiotherapy alone (RT) arm, irradiation with 60 Gy; or the chemoradiotherapy (CRT) arm, the same radiotherapy and additional concurrent use of carboplatin 30 mg/m 2 per fraction up to the first 20 fractions. Results: This study was terminated early when 46 patients were registered from November 1999 to February 2001. Four patients (one in the RTarm, three in the CRTarm) were considered to have died due to treatment-related causes. The JCOG Radiotherapy Committee assessed these treatment-related deaths (TRDs) and the compliance with radiotherapy in this trial. They found that 60% of the cases corresponded to protocol deviation and 7% were protocol violation in dose constraint to the normal lung, two of whom died due to radiation pneumonitis. As to the effectiveness for the 46 patients enrolled, the median survival time was 428 days [95% confidence interval (CI) = 212–680 days] in the RTarm versus 554 days (95% CI = 331 to not estimable) in the CRT arm. Conclusions: Due to the early termination of this study, the effectiveness of concurrent use of carboplatin remains unclear. We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee.