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A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m−2 and dose escalation was done in 15 mg m−2 increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m−2). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m−2. Three of the five patients given 60 mg m−2 developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m−2 in the phase II study. The objective response rate was 76.9% (95% CI, 53.0–88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m−2 wk−1, respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity. © 1999 Cancer Research Campaign

Objective: This study aimed to evaluate the efficacy of Saiboku-to, a Japanese traditional herbal medicine (Kampo), on the production of interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-γ (IFN-γ) and interleukin-2 (IL-2) by peripheral blood mononuclear cells in bronchial asthma patients following antigenic stimulus by the house dust mite. Design: Twelve bronchial asthma patients with IgE RAST (radio-allergosorbent test) scores to mites of 3 and over were enrolled in the study. Separated mononuclear cells from the patients’ blood were suspended in a 24-hole plate with 10% fetal calf serum (FCS) and RPMI-1640 medium. Mite antigen was added to the above cell-suspension (final concentration 10 mg/ml) and cultured for 72 hours at 37°C in 5% CO2. Saiboku-to (TJ-96, Tsumura & Co.) was added to the above sample system at the same time as mite antigen and cultured for 72 hours under the same conditions. After 72 hours of incubation, the amount of various cytokines (IL-2, IL-3, IL-4, IL-5, INF-γ) was measured using enzyme-linked immunoabsorbent assay kits. Results: Saiboku-to 500 mg/L significantly inhibited the production of IL-3 and IL-4 from peripheral blood mononuclear cells. Moreover, it significantly increased the production of INF-γ from peripheral blood mononuclear cells. Conclusion: These preliminary findings suggest that Saiboku-to could be considered as one of a new class of anti-asthmatic drugs because of its influence on cytokine production.

We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC.

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3-4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.

1. To clarify part of the bronchodilating effects of theophylline, lymphocyte cyclic AMP (cAMP) and phosphodiesterase (PDE) activity in asthmatic patients and healthy adults were measured. 2. No clear differences in lymphocyte PDE activity were found regarding sexes, ages or the types of asthma. 3. Lymphocyte PDE activity in the asthma group was significantly higher than that in the control group. 4. Lymphocyte cAMP significantly increased at 30 and 60 min after intravenous injection of aminophylline in the asthma group. 5. Lymphocyte PDE activity significantly decreased 60 min after intravenous injection of aminophylline in the asthma group.

A phase I trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients. This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase II study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m(-2) intravenously (i.v.) on days 1, 8 and 15, and cisplatin 80 mg m(-2) (i.v.) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response. Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%). The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively. A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

PURPOSE Irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC) as monotherapy. Cisplatin is also a key drug against SCLC. We conducted a phase II study of CPT-11 combined with cisplatin to evaluate the efficacy and toxicity of this regimen in patients with previously untreated SCLC. PATIENTS AND METHODS Seventy-five patients with previously untreated SCLC were enrolled onto the study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1 every 28 days. Four courses of chemotherapy followed by thoracic irradiation were given to patients with limited disease (LD) and six courses to patients with extensive disease (ED). RESULTS The overall response rate was 84%, with a complete response (CR) rate of 29%. Forty patients with LD achieved an overall response rate of 83% and a CR rate of 30% and 35 patients with ED achieved an overall response rate of 86% and a CR rate of 29%. The median response duration was 8.0 months for LD patients and 6.6 months for ED patients. The median survival was 14.3 months for LD patients and 13.0 months for ED patients. The major grade 3 or 4 toxicities were neutropenia (77%), leukopenia (45%), diarrhea (19%), and anemia (39%). Two patients died with concomitant neutropenia and diarrhea. CONCLUSION This is a new active regimen for SCLC, especially ED-SCLC, with acceptable toxicity. A phase III study that compares CPT-11/cisplatin with etoposide/cisplatin for ED-SCLC is now being conducted.

Inflammatory reactions in the airway in which various inflammatory cells are involved play an important role in the pathogenesis of bronchial asthma. In particular, the activation of T cells and the accompanying role of cytokines have attracted attention. We employed peripheral mononuclear blood cells and lymphocytes from mite-antigen positive patients with bronchial asthma to investigate the production of various cytokines following stimulation with mite-antigen and the relationship between IgE-the most important factor in the pathogenesis of bronchial asthma- and cytokines.The production of IL-1β, IL-2, sIL-2R, IL-3, IL-4, IL-5 and IL-6 from peripheral blood mononuclear cells (PBMC) following the addition of mite-antigen was determined by the sandwich ELISA method. The production of IL-1β, IL-2, sIL-2R, IL-3, IL-4, IL-5 and IL-6 in PBMCs was increased by stimulation with mite-antigen. When CD4+ and CD8+-enriched cell fractions were separated, the production of the cytokines IL-2, sIL-2R and IL-4 was elevated in the CD4+ T cells. IL-1β production from PBMCs increased in the presence of the CD4+-enriched cell fractions. Consequently, the effect of CD4+-enriched cell fractions in the production of IL-1β in mononuclear cells was considered.The results of a determination of IgE production from PBMCs, using a highly-sensitive method, showed that IgE production increased following the addition of IL-4 to a level similar to that induced by stimulation with mite-antigen. The addition of either IFN-γ or anti-IL-4 reduced the amount of IgE increased by the addition of IL-4 or stimulation with mite-antigen. The addition of IL-2 further increased the amount of IgE production, which had been increased by stimulation with mite-antigen or the addition of IL-4, suggesting the importance of IL-2 in IgE production in B cells.The results of our study indicate that mononuclear cells and lymphocytes, especially CD4+ T cells, are important for the onset of bronchial asthma as a Type I allergy.In patients with bronchial asthma, CD4-positive T-lymphocytes are activated, and various cytokines are produced, following stimulation of PBMC with specific antigens. It is suggested that IL-4 and IL-2, which promote the production of IgE-the most important factor in I-type allergic reactions, might produce serious allergic reactions.It is also concluded that the production of IL-3 and IL-5, which are considered to be cytokines activating eosinophils, is increased by stimulation with specific antigens which are potent inducers of further airway inflammation.The above results suggest that various cytokines play an important role in the pathogenesis of bronchial asthma in their interactions with each other.

The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m(2) ) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5-3.5 months) for the DZ group and 2.6 months (95% CI, 1.5-3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0-15.8 months) for the DZ group and 9.7 months (95% CI, 6.1-12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).

Purpose: This phase II study was conducted to determine the response and toxicity of gemcitabine (2′,2′-difluorodeoxycytidine) in chemotherapy-naive patients with non-small-cell lung cancer (NSCLC). Methods: A group of 73 patients were entered into the study. The patients had received no previous chemotherapy and all had measurable disease. The initial starting dose of gemcitabine was 1000 mg/m2 per week × 3 followed by a week of rest, and was escalated for the next cycle to 1250 mg/m2, provided there were no signs of hematologic toxicity (WBC

The importance of the dose intensity of chemotherapy in achieving maximal therapeutic effect has recently been reported for several chemosensitive malignant diseases, with Murray et al. reporting that intensive weekly chemotherapy using the cisplatin, vincristine, doxorubicin, and etoposide (CODE) regimen in small-cell lung cancer (SCLC) is very effective. However, leukopenia is the major obstacle to delivering the planned dose in intensive regimens. Therefore, we investigated whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) could allow full drug doses to be given as scheduled, thereby improving the final outcome. Extensive-stage (ES) SCLC patients were randomized to receive either CODE alone or CODE with rhG-CSF, with the CODE regimen consisting of cisplatin given i.v. at 25 mg/m2 weekly for 9 weeks; vincristine given i.v. at 1 mg/m2 during weeks 1, 2, 4, 6, and 8; and doxorubicin given i.v. at 40 mg/m2 and etoposide given i.v. at 80 mg/m2 for 3 days during weeks 1, 3, 5, 7, and 9, rhG-CSF at 50 micrograms/m2 was given s.c. on the days on which cytotoxic drugs were not given. From May 1989 to September 1991; 64 patients were enrolled in the study, of whom 63 were analyzable (31 for CODE alone and 32 for CODE with rhG-CSF). No difference in any of the patients' characteristics except gender was found between the two groups. The complete response (CR) rate was 34% in the CODE with rhG-CSF group and 23% in the CODE alone group; the median survival was 59 and 32 weeks, respectively, in these groups (P = 0.004). Therefore CODE with rhG-CSF improved the survival of ES SCLC patients. On the basis of these results a phase III study to determine whether CODE with rhG-CSF would increase survival as compared to the standard regimen in ES SCLC was designed by the Japan Clinical Oncology Group.

Sixty patients with previously untreated non-small cell lung cancer of stages III and IV were treated with a 210 mg/m2 dose of paclitaxel by means of a 3-hour infusion. The objective respon

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

A 55-year-old male who had a remote history of occupational asbestos exposure consulted us because of chest pain. Chest X-ray revealed diffuse pleural thickening and pleural effusion on the right. A diagnosis of malignant mesothelioma, biphasic type was made by needle pleural biopsy. Fourteen months later, the patient died of brain metastasis. At autopsy, malignant mesothelioma of the pleura with metastasis to the brain and bilateral adrenal glands was observed. Brain metastases proven by autopsy are rare in cases of malignant mesothelioma. The ferruginous body count in the lung tissue was 16 per gram of wet weight.

We evaluated eight cases of pulmonary mycosis in immuno compromised hosts. The underlying diseases were lung cancer with chemotherapy in one case, post bone marrow transplantation (post BMT) in two cases, acquired immunodeficiency syndrome (AIDS) in one case and bronchial asthma with massive steroid therapy in four cases. The causative fungi were Candida sp. in three cases, Aspergillus sp. in four cases, Tricosporon sp. in one case. Prognosis was guarded despite antifungal treatment. Five cases deteriorated and died of fungal infection. In five cases, who died of deterioration, 31.6 days was required from appearance of abnormal infiltration in the chest X-ray to determination of the causative fungi (including two cases who were diagnosed by autopsy) on the average. In three successfully treated cases, the average duration from the appearance of abnormal infiltration in the chest X-ray for the determination of the causative fungi was 8.3 days. On the contrary, the average duration between the appearance of abnormal infiltration in the chest X-ray and the initiation of antifungal treatment was 2.6 days who died of deterioration and 8.3 days who survived. We conclude that early identification of causative fungi and not quick institution of antifungal treatment was mandatory in the treatment of opportunistic fungal pneumonia.

We studied respiratory mucosa immune responses in bronchial asthma using guinea pigs and human respiratory epithelial cells. In asthma models (guinea pigs), CD4+ T cells enhanced LAR, and CD8+ T cells inhibited LAR after antigen inhalation. Regulatory effects of IL-5 and ICAM-1 on LAR were detected. PAF enhanced the adhesion of human respiratory epithelial cells and eosinophils. TNF-α stimulated the production of GM-CSF in human respiratory epithelial cells, while TGF-β1 depressed human eosinophil survival.

Background Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. Patients and Methods Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m2) twice a day on days 1–21, and intravenous CDDP (60 mg/m2) on day 8. This schedule was repeated every 5 weeks. Results A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3 % and 80.4 %, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3 %, 13.0 %, and 2.2 % of the patients, respectively. Conclusion CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.

Background: Early palliative intervention in advanced cancer patients with metastatic nonsmall-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. Objective: We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. Methods: Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for ,7 days (late referral group, 64 patients) and those who experienced outpatient services for � 7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. Results: Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P , 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P ¼ 0.010) and 16.5 and 20.9 months (P ¼ 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P ¼ 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P ¼ 0.018) in non-small-cell lung cancer. Conclusions: The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted.

Summary Purpose We compared the activity and toxicity of vinorelbine (VRB) and vindesine (VDS) in a randomized crossover study in patients with previously untreated stages IIIB or IV non-small-cell lung cancer (NSCLC). Patients and methods Two hundred four patients were assessable for response and toxicity. VRB was administered at a dose of 25 mg/m2 weekly and VDS at a dose of 3 mg/m2 weekly. Patients who failed to respond after 4 cycles of initial monotherapy were switched to a combination chemotherapy (VRB → VDS + cisplatin (P) or VDS ← VRB + P). Results Objective response was observed in 31.1% of patients in the VRB arm versus 8.9% of those in the VDS arm (P = 0.0002). The median duration of response to VRB was 18.5+ weeks (range, 7.9 to 107.5+ weeks) compared with 11.7+ weeks (range, 6.0 to 35.0+ weeks) for VDS. Of the 69 patients who failed to respond to initial monotherapy, 33 in the VRB group who subsequently received VDS + P did not respond and 13 (26.5%) of 49 initially on VDS who received subsequent VRB + P responded. The rates of grades 3 and 4 leukopenia were similar in the two monotherapy arms (VRB, 55.3% vs. VDS, 48.5%). However, grade 3 anemia was more frequent in the patients on VRB than in those on VDS. The incidence of peripheral neurotoxicity was significantly higher with VDS than with VRB (P = 0.002), but VRB induced a slightly higher rate of local cutaneous reaction than VDS (P = 0.012). With the combination of cisplatin and these vinca alkaloids, peripheral neurotoxicity was less frequent in the VRB group than in the VDS group. Conclusion Our results demonstrate that VRB yields a higher response rate than VDS in stage IIIB or IV NSCLC, with the same extent of toxicity in terms of leukocytopenia. The peripheral neurotoxic effects were also milder with VRB than with VDS. In second-line chemotherapy, there was a notable difference in response between the VRB + P and VDS + P regimens.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (ageor = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Background Autophagy is critical in the maintenance of cellular protein quality control, the final step of which involves the fusion of autophagosomes with lysosomes. Cathepsin‐L ( CTSL ) is a key member of the lysosomal protease family that is expressed in the murine and human heart, and it may play an important role in protein turnover. We hypothesized that CTSL is important in regulating protein processing in the heart, particularly under pathological stress. Methods and Results Phenylephrine‐induced cardiac hypertrophy in vitro was more pronounced in CTSL ‐deficient neonatal cardiomyocytes than in in controls. This was accompanied by a significant accumulation of autophagosomes, increased levels of ubiquitin‐conjugated protein, as well as impaired protein degradation and decreased cell viability. These effects were partially rescued with CTSL 1 replacement via adeno‐associated virus–mediated gene transfer. In the in vivo murine model of aortic banding ( AB ), a deficiency in CTSL markedly exacerbated cardiac hypertrophy, worsened cardiac function, and increased mortality. Ctsl −/− AB mice demonstrated significantly decreased lysosomal activity and increased sarcomere‐associated protein aggregation. Homeostasis of the endoplasmic reticulum was also altered by CTSL deficiency, with increases in Bip and GRP 94 proteins, accompanied by increased ubiquitin–proteasome system activity and higher levels of ubiquitinated proteins in response to AB . These changes ultimately led to a decrease in cellular ATP production, enhanced oxidative stress, and increased cellular apoptosis. Conclusions Lysosomal CTSL attenuates cardiac hypertrophy and preserves cardiac function through facilitation of autophagy and proteasomal protein processing.

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

未治療の非小細胞肺癌56例に対してシスプラチンとカルボプラチンの併用療法の有効性および安全性を検討するための, 臨床第II相試験を行った. 先立って行われた第I相試験により, 投与量はシスプラチン80mg/m2+カルボプラチン350mg/m2と決定された. 56例中適格完全例が55例で, 内訳は腺癌30例, 扁平上皮癌20例, 大細胞癌5例であり, 投与コースは, 1コース8例, 2コース33例, 3コースが14例であった. 抗腫瘍効果は, CR 1例, PR 15例, NC 31例, PD 5例, NE 3例で, 奏効率は30.8%であった. また, MSTはIII A期が81週, III B, IV期が37週であり全体では42週であった. 副作用は, Grade3以上の白血球減少が20.0%, 血小板減少が63.6%, 貧血が50.0%にみられ, 消化器毒性も高度であったが, 治療関連死は無く, tolerableと考えた. シスプラチンとカルボプラチンの併用療法は非小細胞肺癌に対して有効なregimenの一つであると考えた.

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).

大阪肺癌集検研究班が, 1981-1990年の10年間に行った肺癌検診において, 高危険群所属者22,753人 (受診者の24.5%) に喀痰容器が配布されたが, 回収率は87.3%, 有効検体率は98.7%であった. 精検は76人 (0.4%) で, 精検受診率は98.7%, 精検完了率は96.0%であった.高危険群所属者で, 喀痰細胞診により発見された肺癌は29人 (中心型扁平上皮癌は21人) で, このうち喀痰細胞診のみによる発見は15人 (中心型扁平上皮癌は13人) であった. 中心型扁平上皮癌の, 経年受診7人中6人, その他の受診14人中9人が臨床病期1期であった.喀痰細胞診により発見された肺癌の切除率は48.3%, 絶対的治癒切除率は27.6%であった. 1981-1983年, 1984-1986年, 1987-1990年の3時期にわけて男性中心型扁平上皮癌の標準化発見比を算出した結果, それぞれ1.595, 1.189および0.680となった.

Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907,ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS(HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.03), and patients with body weight loss ≤5% versus5% (P=0.04). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension,haemorrhagic events, neutropenia, and febrile neutropenia [corrected].Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.

Background A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (≥70 years of age) patients with locally advanced non-small cell lung cancer. Methods S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m−2 day−1. TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n = 6) or 80 (n = 6) mg m−2 day−1. Results All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n = 2), infection (n = 1), and stomatitis (n = 1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m−2 day−1. No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. Conclusions Administration of S-1 at 80 mg m−2 day−1 on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.

We evaluated the diagnostic usefulness of measurement of the soluble cytokeratin 19 fragment, a new tumor marker, in 391 patients with lung cancer and in 424 patients with benign lung diseases. Serum concentrations of cytokeratin 19 fragment were measured by a sandwich ELISA (CYFRA). The cut‐off value was defined as 3.5 ng/ml, which is associated with a specificity of 85% for benign lung diseases. CYFRA had a high sensitivity (57.5%) in all subjects with lung carcinoma, and had a higher sensitivity for squamous cell carcinoma (73.1%, n = 141) than squamous cell carcinoma‐related antigen (61.0%). CYFRA was associated with a relatively high sensitivity (42.1%) in early‐stage squamous cell carcinoma (stage I, based on the classification of the Japan Lung Cancer Society), but the CYFRA titer was higher in advanced squamous cell carcinoma than in early‐stage squamous cell carcinoma. Our findings suggest that CYFRA is potentially useful for diagnosis and monitoring of lung carcinoma, especially for squamous cell carcinoma.

Background and Methods. Thirty-nine roentgenologically occult lung cancers in 29 patients were treated using photodynamic therapy (PDT) and/or thoracic radiotherapy (TRT) from January 1986 to March 1992. With the exception of one mixed-tumor case, all were squamous cell carcinomas. Results. Initial PDT achieved complete responses in 25 of 39 (64%) of the cancers. Of the remaining 14 cancers that showed less than complete response (CR), 10 of the 14 (71.4%) showed a CR when subsequently treated with TRT, yielding an overall CR rate of 89.7% for cancers treated. Although nine patients experienced recurrences, six of these had CR when treated with PDT and/or TRT. To date, 22 patients are alive. Causes of death in the patients enrolled in this study are as follows: pyothorax (2); heart failure due to pulmonary hypertension (1); chronic respiratory insufficiency (1); subsequent primary brain cancer (1); and subsequent primary lung cancer (1). Only one died of primary lung cancer. Conclusions. These findings suggest that PDT and/or TRT may be used as an alternative to surgery in the treatment of selected patients with roentgenologically occult lung cancer.

In order to clarify the relation between cigarette smoking and lung cancer, a case-control study was conducted. The case series consisted of 1,376 lung cancer patients (1,082 males and 294 females) who were newly diagnosed and admitted to eight hospitals in Osaka during 1986-88. Smoking histories were compared with those of 2,230 controls (1,141 males and 1,089 females) admitted to the same hospitals during the same period without established smoking-related diseases. Odds ratios of current smoker versus nonsmoker were 18.1, 1.9, 21.4, and 3.8 for squamous, adeno, small, and large cell carcinoma, respectively, for males, and 9.7, 1.3, 12.1, 3.7, respectively, for females. Compared to the results from previous studies in Japan, the magnitude of the odds ratios for squamous and small cell carcinoma is approaching the level of Western Europe in the late 1970s. Population attributable risk of exsmokers has also been increasing to the level of Western Europe. Among male current smokers, smoking intensity, such as number of cigarettes per day or fraction smoked per cigarette, seemed to have a slightly greater influence on squamous cell carcinoma than adenocarcinoma, while factors associated with the spread of cigarette smoke, such as inhalation, seemed to have greater influence on adenocarcinoma. The difference in the distribution of these smoking characteristics between Japan and Western Europe could not fully explain the difference in lung cancer incidence and distribution of histologic types between the two areas.

PURPOSE Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

Oral BOF-A2 (Emitefur), a new derivative of 5-fluorouracil (5-FU) containing both 1-ethoxymethyl-5-FU (EMFU), a masked form of 5-FU, and 3-cyano-2,6-dihydroxypyridine (CNDP), an inhibitor of 5-FU degradation, was administered to 71 non-small cell lung cancer (NSCLC) patients in a multi-center phase II study. The patients were scheduled to receive at least 2 courses of treatment, each consisting of 200 mg twice daily for 2 weeks followed by a 2-week rest period. Out of 62 evaluable patients, 11 (18%) responded (8 of 44 adeno- and 3 of 15 squamous cell carcinomas). Thirty-four patients showed no change and 17 progressive disease. The incidences of gradeor = 2 hematologic toxicity were 5-8% for leukopenia, thrombocytopenia, and anemia. The incidences of non-hematologic toxicity of gradeor = 2, such as anorexia, nausea/vomiting, and diarrhea, were close to 20% or lower.

Evaluation of health-related quality-of-life (HRQoL) and symptom improvement were preplanned secondary objectives for the overall population and posthoc analyses for epidermal growth factor receptor (EGFR) mutation-positive/negative subgroups in IPASS.HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI); symptom improvement by the Lung Cancer Subscale (LCS). Improvements defined as: 6 or more (FACT-L; TOI), 2 or more (LCS) points increase maintained for 21 or more days.Overall (n = 1151/1217 evaluable), HRQoL improvement rates were significantly greater with gefitinib versus carboplatin/paclitaxel; symptom improvement rates were similar for both treatments. Significantly more patients recorded improvements in HRQoL and symptoms with gefitinib in the EGFR mutation-positive subgroup (n = 259; FACT-L 70.2% versus 44.5%; odds ratio, 3.01 [95% confidence interval, 1.79-5.07]; p0.001; TOI 70.2% versus 38.3%; 3.96 [2.33-6.71]; p0.001; LCS 75.6% versus 53.9%; 2.70 [1.58-4.62]; p0.001), and with carboplatin/paclitaxel in the EGFR mutation-negative subgroup (n = 169; FACT-L 14.6% versus 36.3%; odds ratio, 0.31 [0.15-0.65]; p = 0.002; TOI 12.4% versus 28.8%; 0.35 [0.16-0.79]; p = 0.011; LCS 20.2% versus 47.5%; 0.28 [0.14-0.55]; p0.001). Median time-to-worsening (months) FACT-L score was longer with gefitinib versus carboplatin/paclitaxel for the overall population (8.3 versus 2.5) and EGFR mutation-positive subgroup (15.6 versus 3.0), and similar for both treatments in the EGFR mutation-negative subgroup (1.4 versus 1.4). Median time-to-improvement with gefitinib was 8 days in patients with EGFR mutation-positive tumors who improved.HRQoL and symptom endpoints were consistent with efficacy outcomes in IPASS and favored gefitinib in patients with EGFR mutation-positive tumors and carboplatin/paclitaxel in patients with EGFR mutation-negative tumors.

IntroductionIn IPASS (IRESSA Pan-Asia Study), clinically selected patients with pulmonary adenocarcinoma received first-line gefitinib or carboplatin/paclitaxel. This preplanned, exploratory analysis was conducted to increase understanding of the use of surrogate samples, such as serum, versus tumor biopsy samples for determining EGFR mutation status in the Japanese cohort (n = 233).MethodsEGFR mutations were assessed using tumor tissue-derived DNA (n = 91) and circulating free (cf) DNA from pretreatment serum samples (n = 194).ResultsFewer patients were EGFR mutation positive when assessed using pretreatment cfDNA (23.7%) versus tumor tissue-derived DNA (61.5%). cfDNA results identified no false positives but a high rate of false negatives (56.9%). There was a significant interaction between cfDNA EGFR mutation status and treatment for progression-free survival (PFS) (p = 0.045). PFS was significantly longer and objective response rate (ORR) higher with gefitinib than carboplatin/paclitaxel in the cfDNA EGFR mutation-positive subgroup (PFS: hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.14–0.60; p < 0.001; ORR: odds ratio [OR], 1.71; 95% CI, 0.48–6.09; 75.0% versus 63.6%; p = 0.40). There was a slight numerical advantage in PFS and ORR for gefitinib over carboplatin/paclitaxel in the cfDNA EGFR mutation-negative subgroup, likely due to the high rate of false negatives within this subgroup.ConclusionsThese results merit further investigation to determine whether alternative sources of tumor DNA, such as cfDNA in serum, could be used for determining EGFR mutation status in future; currently, where a sample is available, analysis of tumor material is recommended.

Aim: To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib. Materials & methods: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case–control study component (‘CCS’; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher’s exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests. Results: The CCS data provided some false discovery rate evidence that the significance of top-ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene–gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses. Conclusion: Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research. Presented, in part, at the 26th ICPE: International Conference on Pharmacoepidemiology & Therapeutic Risk Management, Brighton, UK, 19–22 August 2010. Original submitted 1 December 2010; Revision submitted 22 February 2011

To investigate the role of p53 abnormalities in predicting the survival of patients with non-small cell lung cancer (NSCLC), polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses were performed on 74 and 67 tumor samples, respectively, from patients with pathological stage I-IIIa NSCLC. An abnormally migrating SSCP band was observed in 21 of 74 (28%) tumor specimens. DNA sequence analysis revealed 23 intragenic mutations including 3 small deletions and 20 point mutations. Immunohistochemical analysis using the DO-7 monoclonal antibody showed abnormal expression of p53 in 27 of 67 (40%) patients. The concordance rate between immunohistochemical and PCRSSCP analyses was 73% (49/67) in this study. Univariate and multivariate analyses demonstrated that abnormal expression of p53 may be associated with prolonged survival (p=0.0997 and 0.0099, respectively). In contrast, no relationship was observed between p53 mutation and overall survival (0.6968). These results suggest that p53 status and the survival outcome changes between immunohistochemical and mutational analyses in stage I-IIIa NSCLC.

This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC).Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m(2) and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible.Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021).The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC.

Introduction Monotherapy with a third generation anticancer agent has been regarded as the standard therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether elderly patients with a good performance status can tolerate platinum-doublet chemotherapy like younger patients. Methods A combination phase I/II study was conducted in chemo-naive elderly patients with NSCLC to establish the toxicity and maximum tolerated dose (MTD) and to investigate the antitumor activity of carboplatin (CBDCA) plus gemcitabine (GEM). GEM was infused on days 1 and 8, and CBDCA on day 1 every 3weeks. Results Seventy-five patients were enrolled. The most frequent toxicities were hematological, especially thrombocytopenia. Three of three patients experienced a dose-limiting toxicity at dose level 3: 1000mg/m 2 GEM with AUC 5 CBDCA (MTD), and one of seven patients at level 2a: 1000mg/m 2 GEM with AUC 4 CBDCA (recommended dose). In the phase II study, the overall response rate was 22.2% and the median overall survival time was 14.2months. Conclusions Although the recommended dosage is restricted to a lower level compared to younger patients, combination therapy using CBDCA with GEM is tolerable and promising for elderly patients with advanced NSCLC.

Objectives The aim of the present study was to evaluate the efficacy and safety of carboplatin plus paclitaxel versus gemcitabine plus vinorelbine in patients with advanced nonsmall cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group performance status (PS) of 2. Methods Chemotherapy-naive patients with NSCLC of stage IIIB or IV and a PS of 2 were eligible. The patients received 3-week cycles of carboplatin (area under the curve of 6) plus paclitaxel (200 mg/m(2)) on day 1 (CP) or gemcitabine (1000 mg/m(2)) plus vinorelbine (25 mg/m(2)) on days 1 and 8 (GV). The primary end point was 1-year survival rate for selection of the better treatment arm for further study. Results Of the 89 patients enrolled, 84 were assessable (41 in the CP arm, 43 in the GV arm). The overall response rate, median survival time, and 1-year survival rate were 29.3%, 5.9 months, and 22.0%, respectively, for the CP arm and 20.9%, 6.0 months, and 27.9% for the GV arm. Common toxicities of grade 3 or 4 included neutropenia (67.5% for the CP arm vs. 65.1% for the GV arm), febrile neutropenia (20% vs. 14%), and infection (25.0% vs. 23.2%). The frequency of nausea of grade 3 was greater for the CP arm (17.5% vs. 2.3%), whereas that of anemia of grade 3 or 4 (30.2% vs. 12.5%) or treatment-related death (7.0% vs. 2.4%) was greater for the GV arm. Conclusions The 1-year survival rate did not exceed 30% for either doublet chemotherapy. Furthermore, each treatment was associated with a substantial degree of toxicity.

Purpose A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non–small-cell lung cancer was conducted. Methods and Materials Patients with unresectable Stage III non–small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m 2 ) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m 2 ). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade ≥4 esophagitis and neutropenic fever and Grade ≥3 other nonhematologic toxicities, was monitored for 90 days. Results Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.

Purpose The primary goal of this open-label, multicenter, randomized phase III trial was to determine whether treatment with carboplatin plus the oral fluoropyrimidine derivative S-1 was noninferior versus that with carboplatin plus paclitaxel with regard to overall survival (OS) in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods A total of 564 patients were randomly assigned to receive either carboplatin (area under the curve, 5) on day 1 plus oral S-1 (40 mg/m2 twice per day) on days 1 to 14 or carboplatin (area under the curve, 6) plus paclitaxel (200 mg/m2) on day 1 every 21 days. Results At the planned interim analysis, with a total of 268 death events available, the study passed the O'Brien-Fleming boundary of 0.0080 for a positive result and noninferiority of carboplatin and S-1 compared with carboplatin and paclitaxel was confirmed for OS (hazard ratio, 0.928; 99.2% CI, 0.671 to 1.283). Median OS was 15.2 months in the carboplatin and S-1 arm and 13.3 months in the carboplatin and paclitaxel arm, with 1-year survival rates of 57.3% and 55.5%, respectively. Rates of leukopenia or neutropenia of grade 3/4, febrile neutropenia, alopecia, and neuropathy were more frequent in the carboplatin and paclitaxel arm, whereas thrombocytopenia, nausea, vomiting, and diarrhea were more common in the carboplatin and S-1 arm. The carboplatin and S-1 arm had significantly more dose delays than the carboplatin and paclitaxel arm. Conclusion Oral S-1 with carboplatin was noninferior in terms of OS compared with carboplatin and paclitaxel in patients with advanced NSCLC, and is thus a valid treatment option.

Asia needs a guideline for non-small-cell lung cancer because of differences in medical care, medical care insurance, ethnic variation and drug approval lag within Asian countries and compared with Western countries. Due to ethnic differences, drug dosages are often higher in the USA than in Japan. EGFR mutation in non-small-cell lung cancer was detected in 32% of Asians but only 6% of non-Asians, while differences in irinotecan metabolism cause higher frequencies of toxicity (leukopenia, diarrhea) in Asians. Pharmacodynamic ethnic differences in relation to paclitaxel/carboplatin resulted in longer median survival and a higher 1-year survival rate for Japanese-advanced non-small-cell lung cancer patients compared with Americans. To solve the problem of drug lag, pharmaceutical companies must perform multinational Asian clinical trials with quick accrual of patients, while regulatory authorities must establish high-quality, efficient approval processes, and achieve regulatory harmonization. The National Comprehensive Cancer Network promotes creation of national clinical practice guidelines, and Korea, China and Thailand adapted the National Comprehensive Cancer Network guidelines. Many Asian countries still lack such guidelines, and there are no pan-Asian guidelines for non-small-cell lung cancer. Japan developed its own non-small-cell lung cancer guidelines and also a gefitinib guidance. The study group members concluded that immediate establishment of an Asian non-small-cell lung cancer guideline will be difficult because of the differences among the countries. Asian collaborative trials on treatment of non-small-cell lung cancer need to be started at an early date to generate Asian data.

Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.

Objective: It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. Methods: Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m 2 on days 1 and 29, with irinotecan 60 mg/m 2 on days 1, 8, 15, 29, 36, and 43 and 30 mg/m 2 on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). Results: From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2‐75.9%). The median survival time was 16.5 (95% confidence interval, 12.6‐19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4‐77.1%) and 32.9% (95% confidence interval, 21.6‐44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. Conclusions: Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.

The antimetabolic agent S-1 inhibits thymidylate synthase similar to pemetrexed, but through a different mechanism of action. Whether the antitumour activity of S-1 depends on histological type remains unclear. We analysed pooled data from 2 phase II clinical studies of cisplatin and S-1 in patients with previously untreated advanced non-small cell lung cancer.We comprised 110 patients with stage IIIB or IV non-small cell lung cancer. Univariate and multivariate analyses were performed to determine the effects of histological type on progression-free survival and response rates.On pooled analysis of the data, according to histological type, median progression-free survival was 3.8 months in patients with squamous cell carcinoma and 4.4 months in those with non-squamous cell carcinoma. Both analyses showed that progression-free survival and response rate did not differ significantly.Unlike molecular targeted agents and pemetrexed, a combination of cisplatin and S-1 may be no difference in response according to histological type.

Most non–small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)–targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647–56. ©2010 AACR.