Effect of a Cyclooxygenase-2 Inhibitor in Combination with (-)-Epigallocatechin Gallate or Polyphenon E on Cisplatin-Induced Lung Tumorigenesis in A/J Mice.

We investigated the effects of celecoxib combined with (-)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.

Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is characterized by severe worsening dyspnea of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B (PMX)-immobilized fiber cartridge (PMX-DHP) has been reported to improve pulmonary oxygenation and survival in patients with AE-IPF although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-IPF through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-IPF patients. In addition, the sera of these AE-IPF patients collected immediately before and after PMX-DHP, 9 stable IPF patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP (P<0.02), and VEGF and IL-12 were most prominently reduced. In addition to PDGF and VEGF, IL-1ß, IL-1ra, IL-8, IL-23, FGF basic, GM-CSF, IP-10, RANTES and TGF-ß were eluted from used PMX-fibers. Interestingly, improved pulmonary oxygenation after PMX-DHP was correlated well with the quantities of eluted VEGF. These results suggest that adsorption of proinflammatory, profibrotic and proangiogenic cytokines onto PMX-fibers is one of the mechanisms of action of PMX-DHP in AE-IPF. Notably, removal of VEGF by PMX-DHP may contribute to the rapid improvement in oxygenation by suppressing vascular permeability in the lung.

Selective cyclooxygenase-2 inhibitor prevents cisplatin-induced tumorigenesis in A/J mice.

Cisplatin is used to treat lung cancer; however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2) inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups: group 1, no treatment; group 2, low-dose celecoxib (150 mg/kg); group 3, high-dose celecoxib (1,500 mg/kg); group 4, cisplatin alone; group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62 mg/kg, i.p.) once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p < 0.05, group 4 vs. group 6). Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p < 0.01, group 4 vs. group 6).

Is adenosine deaminase in pleural fluid a useful marker for differentiating tuberculosis from lung cancer or mesothelioma in Japan, a country with intermediate incidence of tuberculosis?

The objective of this study was to evaluate the utility of the determination of adenosine deaminase (ADA) level in pleural fluid for the differential diagnosis between tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) in Japan, a country with intermediate incidence of tuberculosis (TB). We retrospectively reviewed the clinical records of 435 patients with pleural effusion and investigated their pleural ADA levels as determined by an auto analyzer. ROC analysis was also performed. The study included patients with MPE (n＝188), TPE (n＝124), benign nontuberculous pleural effusion (n＝94), and pleural effusion of unknown etiology (n＝29). The median ADA level in the TPE group was 70.8U/L, which was significantly higher than that in any other groups (p＜0.05). The area under the curve (AUC) in ROC analysis was 0.895. With a cut-off level for ADA of 36U/L, the sensitivity, specificity, positive predictive value, and negative predictive value were 85.5%, 86.5%, 69.7%, and 93.6%, respectively. As many as 9% of patients with lung cancer and 15% of those with mesothelioma were false-positive with this ADA cutoff setting. Although the ADA activity in pleural fluid can help in the diagnosis of TPE, it should be noted that some cases of lung cancer or mesothelioma show high ADA activity in geographical regions with intermediate incidence of TB, in contrast to high prevalence areas.

Triplet chemotherapy with cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer.

We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty-five patients (21 men and 4 women) with NSCLC and good performance status who were < or = 70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2; the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval: 18.7-59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy; of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%); no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice.

[A DRG/PPS simulation in the medical care of tuberculosis].

PURPOSE: To study the expected usefulness of the introduction of the DRG-PPS (Diagnosis-Related Group/Prospective Payment System, in which an insurer pays a fixed medical fee per hospitalization) into the current medical care of tuberculosis (TB) in Japan. METHOD: The medical fees were reviewed for all TB inpatients at 19 hospitals under the National Hospital Organization who were discharged in either June 2007 or February 2008. The sum of the fixed fee by the DRG was assumed based on the bivariate regression analysis of each patient's hospital days and his or her total actual fees during the hospital stay under the current (fee for care) system, since it was difficult to directly calculate the daily fees for every patient that would be the basis of DRG-PPS. RESULTS: Linear regression analysis estimated that the medical fees (including fees for the medical examinations and the treatments) for a hospital stay of 60 days, which is the standard for TB treatment, was 1,192,470 yen (19,870 yen per person per day) in June 2007, and 1,167,600 yen (19,460 yen per person per day) in February 2008. DISCUSSION: If we assume an average medical fee of about Y1.1-1.2 million yen for the standard hospital care of TB, the economic balance of the hospitals is negative, with a deficit of 0.6-0.7 million yen, given the estimated expenses of 1.8 million yen (i.e., 30,000 yen per person per day x 60 days). CONCLUSION: If the DRG-PPS is to be implemented based on the current medical fee rating system, the hospital administrators could not accept its introduction to the TB medical care service as it is, because it may undermine the economic management of hospitals.

Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung: Okayama Lung Cancer Study Group experience.

BACKGROUND: Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. METHODS: We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy (250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender. RESULTS: Among the 260 patients, 157 were male (60%). Median pack-years was 40 (range 8-160) and 23 (range 1-74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [odds ratio (OR) = 0.971, 95% confidence interval (CI) = 0.947-0.995; P = 0.0159] in male patients, but not in female patients (OR = 0.999, 95%CI = 0.957-1.042). Additionally, pack-years significantly influenced the overall survival in males (hazard ratio = 1.010; 95%CI = 1.002-1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor (P = 0.7639). CONCLUSIONS: In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.

Aberrant promoter hypermethylation in serum DNA from patients with silicosis.

It is well established that patients with silicosis are at high risk for lung cancer; however, it is difficult to detect lung cancer by chest radiography during follow-up treatment of patients with silicosis because of preexisting diffuse pulmonary shadows. The purpose of this study is to evaluate the usefulness of detection of serum DNA methylation for early detection of lung cancer in silicosis. Serum samples from healthy controls (n = 20) and silicosis patients with (n = 11) and without (n = 67) lung cancer were tested for aberrant hypermethylation at the promoters of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a), ras association domain family 1A (RASSF1A), the apoptosis-related gene death-associated protein kinase (DAPK) and retinoic acid receptor beta (RARbeta) by methylation-specific polymerase chain reaction. Aberrant promoter methylation in at least one of five tumor suppressor genes was detected more frequently in the serum DNA of silicosis patients with lung cancer than in that of patients without it (P = 0.006). Furthermore, the odds ratio of having lung cancer was 9.77 (P = 0.009) for those silicosis patients with methylation of at least one gene. Extended exposure to silica (>30 years) was correlated with an increased methylation frequency (P = 0.017); however, methylation status did not correlate with age, smoking history or radiographic findings of silicosis. These results suggest that testing for aberrant promoter methylation of tumor suppressor genes using serum DNA may facilitate early detection of lung cancer in patients with silicosis.

Association of the benefit from gefitinib monotherapy with smoking status in Japanese patients with non-small-cell lung cancer.

BACKGROUND: Gefitinib has been reported to be more effective in patients with non-small-cell lung cancer (NSCLC) who had low or never-smoking history than for heavier smokers. However, this has been criticized because the better survival in such subpopulation might be attributable simply to their favorable natural history, rather than any treatment effect. METHODS: We retrospectively reviewed the clinical records of 155 Japanese patients with relapsed NSCLC who received gefitinib (gefitinib-treated patients; n=83) and those who did not receive it, but were treated with other cytotoxic agents (gefitinib-untreated patients; n=72). A light smoker was defined as one with <20 pack-years. Survival was assessed stratified by gefitinib treatment and smoking status using stepwise proportional hazard modeling. RESULTS: Among the 155 relapsed patients, 58 (37%) had low or never-smoking history. The benefit from gefitinib monotherapy was associated with smoking status (test for interaction, p=0.01). Gefitinib monotherapy, as compared to the cytotoxic agents, significantly prolonged survival among patients with low or never-smoking history (hazard ratio [HR]=0.377; 95% confidence interval [CI]=0.181-0.785; p=0.01), but not among the heavier smokers. Additionally, among gefitinib-treated patients, those with low or never-smoking history survived longer than heavier smokers (HR=0.461; 95% CI=0.244-0.871; p=0.02), while the survival benefit of cytotoxic agents was comparable between those with low or never-smoking history and with heavy smoking habits among the gefitinib-untreated group. CONCLUSIONS: Patients with relapsed NSCLC and low or never-smoking habits appeared to benefit from gefitinib monotherapy, while patients with heavy smoking habits did not.

Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung.

Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18-21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient.

Serum level of arginine-vasopressin influences the prognosis of extensive-disease small-cell lung cancer.

PURPOSE: The purpose of this study is to elucidate the influence of serum arginine-vasopressin (AVP) level on prognosis of extensive-disease small-cell lung cancer (ED-SCLC). METHODS: We retrospectively investigated the clinical records of 163 patients with ED-SCLC, who were admitted to Okayama University Hospital or National Shikoku Cancer Center Hospital. The influence of 14 pretreatment variables on survival was analyzed. RESULTS: In a multivariate analysis of 163 patients, elevation of serum LDH level (P = 0.028) and poor performance status (PS > or = 2, P = 0.002) were independent poor prognostic factors. In 34 patients whose serum AVP levels were available, high serum AVP level was related to the poor prognosis (P < 0.001). The serum-sodium level did not affect the survival. Median serum level of osmotic pressure in 34 patients was normal (284.9 mOsm/kg), although, serum osmotic pressure was low in four of six patients with high serum AVP level. In all patients with high serum AVP level, serum LDH level was elevated. CONCLUSIONS: The data from the current study suggested that serum LDH level and PS were the poor prognostic factors for ED-SCLC. But we additionally identified the prognostic significance of serum AVP level, which may be a more useful factor than serum-sodium level.

A phase II trial of cisplatin and irinotecan alternating with doxorubicin, cyclophosphamide and etoposide in previously untreated patients with extensive-disease small-cell lung cancer.

PURPOSE: The aim of this trial was to investigate the efficacy and safety of cisplatin (P) and irinotecan (I) (PI) alternating with doxorubicin (A), cyclophosphamide (C) and etoposide (E) (ACE) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients with previously untreated ED-SCLC were enrolled in this trial. In the first, third and fifth cycles, PI (P: 60 mg/m(2) on day 1; I: 60 mg/m(2)/day on days 1, 8 and 15) was administered, whereas ACE (A: 50 mg/m(2) on day 1; C: 750 mg/m(2) on day 1; E 80 mg/m(2)/day on days 1-3) was given in the second, fourth and sixth cycles. Each cycle was repeated every 4 weeks. At the end of six cycles, patients who had obtained a complete response were given prophylactic cranial irradiation. RESULTS: In total, 28 patients were enrolled, of whom 27 were assessable for efficacy and safety. Objective responses, including 4 (15%) complete responses, were observed in 25 patients (93%). Median survival time was 12.9 months. The principal toxicity was myelosuppression; grade 4 neutropenia and thrombocytopenia were observed in 89 and 4%, respectively. Febrile neutropenia occurred in 30% of patients. Diarrhea was mild (grade 3-4; 4%). All toxicities were reversible and there were no treatment-related deaths. The mean percentage of the delivered doses, relative to the projected doses, of PI and ACE were 84.6 and 91.1%, respectively. CONCLUSIONS: These results indicate the PI-ACE regimen to have promising activity against ED-SCLC with moderate toxicities.

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study.

PURPOSE: We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. RESULTS: The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. CONCLUSION: These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation.

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

Aberrant promoter methylation profile in pleural fluid DNA and clinicopathological factors in patients with non-small cell lung cancer.

The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC). In samples from 34 lung patients with malignant pleural effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor beta(RARbeta). There is no association between methylation status of five tumor suppressor genes including MGMT, p16INK4a, RASSF1A, DAPK and RARbeta in pleural fluid DNA and clinicopathological parameters including clinical outcome. Aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could not be a valuable prognostic marker of NSCLC patients with malignant pleural effusion.

Elevated pleural fluid RCAS1 is a diagnostic marker and outcome predictor in lung cancer patients.

RCAS1, a type II membrane protein also secreted in soluble form, may be important in tumor cell evasion of immune surveillance and contribute to the aggressiveness of human tumors. We examined the implications of elevated pleural fluid RCAS1 at the onset of effusion in lung cancer patients. Of 102 patients presenting with pleural effusion, 59 proved to have a malignant effusion and 43, nonmalignant. Malignant effusions exhibited higher RCAS1 concentrations than nonmalignant effusions (mean +/- SD; 36.3 +/- 114 vs. 2.7 +/- 1.8 U/ml; p=0.014). Lung cancer patients with pleural fluid RCAS1 concentrations below 15 U/ml had a longer mean survival than those with higher concentrations (4.7 vs. 1.7 months; p<0.05). By multivariate analysis, pleural fluid RCAS1 was an independent prognostic factor in lung cancer patients with effusion. In conclusion, RCAS1 determination at onset of pleural effusion is informative for both diagnosis and outcome prediction in lung cancer patients.

A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer.

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.

A phase I study of 3-day topotecan and cisplatin in elderly patients with small-cell lung cancer.

PURPOSE: The aim of this phase I study was to determine the maximum-tolerated dose (MTD) in elderly patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients aged over 75 years with previously untreated SCLC were enrolled in this study. Both topotecan and cisplatin were administered on days 1-3 and repeated every 3 weeks. The starting dose of topotecan was 0.5 mg/m2/day, while cisplatin was fixed at the dose of 20 mg/m2/day. Patients with limited disease (LD) SCLC received thoracic irradiation after the completion of chemotherapy. RESULTS: Twenty-one elderly patients were enrolled in this study and received a total of 59 cycles. The major hematological toxicity was neutropenia and non-hematological toxicities including diarrhea were generally mild and reversible. The MTD of topotecan was determined as 1.2 mg/m2/day. The recommended phase II study dose of topotecan was determined as 1.0 mg/m2/day with cisplatin 20 mg/m2/day daily for 3 days. An objective response was observed in 6 of 10 patients (60%) with LD-SCLC and 6 of 11 (55%) with extensive disease (ED) SCLC. The median survival time in patients with LD-SCLC and those with ED-SCLC were 16.0 and 11.0 months, respectively. CONCLUSION: The combination chemotherapy of 3-day topotecan and cisplatin appears to be tolerable and effective in elderly patients with SCLC.

The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells.

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Successful treatment of a patient with gastric and duodenal metastases from large cell carcinoma of the lung with carboplatin and gemcitabine.

A 62-year-old man with large cell carcinoma of the lung underwent a right upper lobectomy and four months later demonstrated a relapse in the stomach and duodenum. He received systemic chemotherapy consisting of carboplatin and gemcitabine. After the first cycle of chemotherapy, the duodenal lesion disappeared, however, the gastric lesion demonstrated no response. Considering the risk of bleeding or perforation, a partial gastroduodenal resection was therefore performed. Subsequently, he received adjuvant chemotherapy with the same regimen. He has since been doing well for 24 months after the recurrence. Although the prognosis for patients with gastrointestinal metastases from lung cancer tends to be extremely poor, treatment with chemotherapy and a metastasectomy have resulted in this patient, achieving a long survival.