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1.
Jpn J Clin Oncol ; 41(1): 148-52, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21087977

ABSTRACT

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Benzazepines/therapeutic use , Inappropriate ADH Syndrome/drug therapy , Inappropriate ADH Syndrome/etiology , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Benzamides/adverse effects , Benzamides/pharmacology , Benzazepines/adverse effects , Benzazepines/pharmacology , Biomarkers/blood , Carcinoma, Small Cell/complications , Female , Humans , Inappropriate ADH Syndrome/blood , Lung Neoplasms/complications , Male , Middle Aged , Palliative Care/methods , Quality of Life , Sodium/blood , Thymus Neoplasms/complications , Time Factors , Treatment Outcome , Uterine Cervical Neoplasms/complications
2.
Clin Orthop Relat Res ; 466(3): 729-36, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18196360

ABSTRACT

The prognosis of patients with bone metastasis from lung cancer has not been well documented. We assessed the survival rates after bone metastasis and prognostic factors in 118 patients with bone metastases from lung cancer. The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1-74.5 months). A favorable prognosis was more likely in women and patients with adenocarcinoma, solitary bone metastasis, no metastases to the appendicular bone, no pathologic fractures, performance status 1 or less, use of systemic chemotherapy, and use of an epithelial growth factor receptor inhibitor. Analyses of single and multiple variables indicated better prognoses for patients with adenocarcinoma, no evidence of appendicular bone metastases, and treatment with an epithelial growth factor receptor inhibitor. The mean survival period was longer in a small group treated with an epithelial growth factor receptor inhibitor than in the larger untreated group. The data preliminarily suggest treatment with an epithelial growth factor receptor inhibitor may improve survival after bone metastasis.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Female , Gefitinib , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Retrospective Studies , Sex Factors , Time Factors , Treatment Outcome
3.
Lung Cancer ; 58(3): 362-8, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17716779

ABSTRACT

To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3-4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK-432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Pleural Effusion, Malignant/drug therapy , Pleural Effusion, Malignant/pathology , Adult , Aged , Bleomycin/adverse effects , Bleomycin/therapeutic use , Cisplatin , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Picibanil/adverse effects , Picibanil/therapeutic use , Survival Rate
4.
Kekkaku ; 82(5): 481-5, 2007 May.
Article in Japanese | MEDLINE | ID: mdl-17564128

ABSTRACT

A 30-year-old man suffered from a chest-pain on his left side and was also having a low-grade fever though he actually neglected these symptoms for a while. Later, he was referred to our hospital due to the detection of chest abnormal shadows through the mass examination of chest X-ray taken on 18th October, 2005. His chest X-ray showed bilateral pleural effusion and it was confirmed that the right pleural effusion was encapsulated by his chest CT. The patient's hematological examination performed during his initial visit, showed an increased level of WBC with blood eosinophilia. He also had a puncture of pleural effusion at the time of admission to the center. Moreover, pleural effusion on both sides was exudative and elevations of ADA and eosinophil count as well were traced. In the patient's right pleural effusion, mycobacterium tuberculosis direct (MTD) test was positive. As there were no findings suggesting collagen disease, malignancy, parasite infection, and other complications, he was diagnosed as tuberculous pleurisy with eosinophilic pleural effusion and blood eosinophilia. He was treated with four antitubercular agents, namely, INH, RFP, EB and PZA. As the result, his pleural effusion and blood eosinophil counts were decreased along with an improvement in inflammatory reaction. The most common conditions associated with eosinophilic pleural effusion are described as malignancy, collagen disease, paragonimiasis, drug induced pleurisy, asbestosis, pneumothorax, and trauma, while there are only a few reports about such eosinophilic pleural effusion caused by tuberculous pleurisy. In this case, he also showed blood eosinophilia. Based on these findings, we finally came to the conclusion that the case is a very rare and significantly unique case of eosinophilic pleurisy with blood eosinophilia.


Subject(s)
Eosinophilia/etiology , Pleural Effusion/etiology , Tuberculosis, Pleural/complications , Adult , Antitubercular Agents/therapeutic use , Eosinophilia/drug therapy , Humans , Male , Pleural Effusion/drug therapy , Treatment Outcome , Tuberculosis, Pleural/drug therapy
5.
Invest New Drugs ; 25(3): 253-8, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17039404

ABSTRACT

PURPOSE: To evaluate the efficacy and safety of amrubicin, (+)-(7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-beta-D-erythro-pentopyranosyl )oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride, in previously untreated patients with extensive-disease small cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 35 previously untreated patients with extensive-disease SCLC were entered into the study. Amrubicin was given by daily intravenous infusion at 45 mg/m(2)/day for 3 consecutive days, every 3 weeks. Unless there was tumor regression of 25% or greater after the first cycle, or 50% or greater after the second cycle, treatment was switched to salvage chemotherapy in combination with etoposide (100 mg/m(2), days 1, 2, and 3) and cisplatin (80 mg/m(2), day 1). RESULTS: Of the 35 patients entered, 33 were eligible and assessable for efficacy and toxicity. Of the 33 patients, 3 (9.1%) had a complete response (95% confidence interval [CI], 1.9-24.3%) and 22 had a partial response, for an overall response rate of 75.8% (95% CI, 57.7-88.9%). Median survival time was 11.7 months (95% CI, 9.9-15.3 months), and 1-year and 2-year survival rates were 48.5% and 20.2%, respectively. The most common toxicity was hematologic. Non-hematologic toxicity of grade 3 or 4 was only seen in 3 patients with anorexia (9.1%) and 1 patient with alopecia (3.0%). Salvage chemotherapy was administered to only 6 patients. CONCLUSION: Amrubicin was active for extensive-disease SCLC with acceptable toxicity. Further studies in combination with other agents for SCLC are warranted.


Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Small Cell/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Anthracyclines/administration & dosage , Anthracyclines/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Small Cell/mortality , Carcinoma, Small Cell/pathology , Cisplatin/administration & dosage , Drug Administration Schedule , Etoposide/administration & dosage , Female , Humans , Infusions, Intravenous , Japan/epidemiology , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Salvage Therapy , Time Factors , Treatment Outcome
6.
Cancer ; 107(3): 599-605, 2006 Aug 01.
Article in English | MEDLINE | ID: mdl-16804877

ABSTRACT

BACKGROUND: Combined gemcitabine and carboplatin (GC) and combined gemcitabine and vinorelbine (GV) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer (NSCLC). The authors conducted a randomized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity. METHODS: One hundred twenty-eight patients with Stage IIIB or IV NSCLC were randomized to receive either carboplatin at an area under the curve of 5 on Day 1 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) or vinorelbine 25 mg/m2 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) every 3 weeks. RESULTS: Response rates were 20.3% for the GC patients and 21.0% for the GV patients. In the GC arm, the median survival was 432 days, and the a 1-year survival rate was 57.6%; in the GV arm, the median survival was 385 days, and the 1-year survival rate was 53.3% in the GV arm. The median progression-free survival was 165 days in the GC arm and 137 days in the GV arm. Severe hematologic toxicity (Grade 4) was significantly more frequent in the GC arm (45.3% vs. 25.8% in the GV arm; P = .022). Most notably, the incidence of Grade 3 or 4 thrombocytopenia was significantly higher in the GC arm (81.3% vs. 6.5% in the GV arm; P < .001). Conversely, severe nonhematologic toxicity (Grade 3 or 4) was more common in the GV arm (7.8% vs. 19.4% in the GC arm; P = .057). CONCLUSIONS: Although the GV and GC regimens had different toxicity profiles, there was no significant difference in survival among patients with NSCLC in the current study.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Adult , Aged , Carboplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Japan , Male , Middle Aged , Neoplasm Staging , Patient Selection , Survival , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinorelbine , Gemcitabine
7.
Invest New Drugs ; 24(2): 151-8, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16502350

ABSTRACT

PURPOSE: Amrubicin is a novel 9-aminoanthracycline. This multicenter phase II study was conducted to evaluate the efficacy and safety of amrubicin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-one previously untreated patients with stage III or IV NSCLC were entered this study. The patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Amrubicin was administered by daily intravenous injection at 45 mg/m2/day for 3 consecutive days every 3 weeks. At least 3 cycles of treatment were administered to each patient. RESULTS: All 61 patients registered in this trial were eligible and assessable for efficacy and toxicity. Of them, 17 patients achieved objective responses, consisting of one complete response and 16 partial responses, and the overall response rate was 27.9% (95% confidence interval [CI], 17.1% to 40.8%). The median survival time was 9.8 months (95% CI, 7.7 months to 14.9 months). The major toxicity was myelosuppression. The incidences of grade 3 or 4 toxicity were 72.1% for neutropenia, 52.5% for leukopenia, 23.0% for anemia, and 14.8% for thrombocytopenia. As noticeable toxic events, grade 3 hypotention and alkaline phosphatase elevation were transiently observed in one patient each. In addition, three patients who had had asymptomatic interstitial pneumonitis, identified by diagnostic imaging before treatment, aggravated after amrubicin treatment; two of them died. Other non-hematologic toxicities were relatively mild. CONCLUSION: Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.


Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Anthracyclines/administration & dosage , Anthracyclines/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Female , Humans , Japan , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis
8.
Nihon Kokyuki Gakkai Zasshi ; 44(12): 1002-5, 2006 Dec.
Article in Japanese | MEDLINE | ID: mdl-17233403

ABSTRACT

A 52-year-old asymptomatic man was referred to our hospital due to right pleural effusion detected on a chest X-ray mass screening. Chest X-ray film and chest CT showed moderate pleural effusion. The effusion was milky yellow, suggesting a high triglyceride level. There was no organic disease that would cause chylothorax so his condition was diagnosed as idiopathic chylothorax. The patient's right pleural effusion increased although he had been receiving outpatient dietary therapy for one month. He was consequently admitted to our hospital and received drainage of the pleural space and pleurodesis by intrapleural injection of OK-432. His condition was greatly improved by the therapy and he was discharged. There are few reports of idiopathic chylothorax in adults. Such a case of idiopathic chylothorax detected by chest X-ray mass screening has never been reported before. We, therefore, conclude that this case is very rare and has unique aspects.


Subject(s)
Chylothorax/diagnostic imaging , Mass Chest X-Ray , Chylothorax/surgery , Chylothorax/therapy , Drainage , Humans , Male , Middle Aged , Picibanil/administration & dosage
9.
Clin Cancer Res ; 11(15): 5534-8, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-16061870

ABSTRACT

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


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Carcinoma, Small Cell/drug therapy , Carcinoma, Small Cell/radiotherapy , Cisplatin/administration & dosage , Etoposide/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Adult , Aged , Camptothecin/administration & dosage , Carcinoma, Small Cell/mortality , Combined Modality Therapy , Dose Fractionation, Radiation , Female , Humans , Irinotecan , Lung Neoplasms/mortality , Male , Middle Aged , Pilot Projects , Time Factors , Treatment Outcome
10.
Invest New Drugs ; 23(4): 331-7, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16012792

ABSTRACT

PURPOSE: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. RESULTS: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m(2)/day) and four at dose level 2 (45 mg/m(2)/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m(2)/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m(2)/day and 45 mg/m(2)/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. CONCLUSION: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.


Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Anthracyclines/adverse effects , Antineoplastic Agents/adverse effects , Electrocardiography/drug effects , Female , Humans , Injections, Intravenous , Leukopenia/chemically induced , Male , Maximum Tolerated Dose , Middle Aged , Neutropenia/chemically induced , Survival Analysis , Topoisomerase II Inhibitors
11.
Jpn J Clin Oncol ; 35(4): 195-201, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15845568

ABSTRACT

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


Subject(s)
Antineoplastic Agents/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Combined Modality Therapy , Dose Fractionation, Radiation , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Lung Neoplasms/mortality , Male , Pulmonary Fibrosis/etiology , Radiation Pneumonitis/etiology , Radiotherapy/adverse effects , Survival Rate
12.
Clin Cancer Res ; 10(23): 7860-4, 2004 Dec 01.
Article in English | MEDLINE | ID: mdl-15585618

ABSTRACT

PURPOSE: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non-small-cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m(2) twice a day for 21 consecutive days while cisplatin (60 mg/m(2)) was administered intravenously on day 8. This schedule was repeated every 5 weeks. RESULTS: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1-12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34-61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%). CONCLUSIONS: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Administration, Oral , Adult , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Cisplatin/administration & dosage , Drug Administration Schedule , Drug Combinations , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Oxonic Acid/administration & dosage , Pyridines/administration & dosage , Survival Rate , Tegafur/administration & dosage , Treatment Outcome
13.
Cancer Chemother Pharmacol ; 54(5): 459-68, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15290094

ABSTRACT

PURPOSE: The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170. EXPERIMENTAL DESIGN: KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m2 according to a modified Fibonacci method. RESULTS: A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m2. The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m2 and in two of two patients treated at 53.0 mg/m2; therefore, the MTD was 53.0 mg/m2. Although no patients showed a complete response (CR)or partial response (PR), 15 patients were evaluated a shaving freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CLtot) and volume of distribution (Vdss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC 0-infinity). In addition, there was a good correlation between neutropenia and AUC 0- infinity. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxi-dative metabolites were observed in the patients' plasma and urine. CONCLUSIONS: The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m2.A significant linear relationship was observed between neutropenia and AUC 0- infinity. We estimate the recommended dose for phase II studies to be 41.0 mg/m2.


Subject(s)
Acridines/pharmacokinetics , Acridines/toxicity , Neoplasms/drug therapy , Pyrazoles/pharmacokinetics , Pyrazoles/toxicity , Adult , Aged , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Area Under Curve , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasms/classification , Pyrazoles/blood
14.
Gan To Kagaku Ryoho ; 31(4): 567-73, 2004 Apr.
Article in Japanese | MEDLINE | ID: mdl-15114701

ABSTRACT

The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Quinazolines/administration & dosage , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Gefitinib , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Survival Rate
15.
Carcinogenesis ; 25(8): 1395-401, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15044328

ABSTRACT

APE1 (apurinic/apyrimidinic endonuclease 1) and XRCC1 (X-ray cross-complementing group 1) are DNA repair proteins that play important roles in the base excision repair (BER) pathway. Polymorphisms in their encoding genes are associated with altered DNA repair capacity and thus may impact on cancer risk. In the present case-control study with 178 Japanese incident lung cancer cases and 449 age- and sex-matched controls, we investigated the gene-environment interaction among APE1 Asp148Glu, XRCC1 Arg399Gln and smoking habit in lung cancer risk. The results were analyzed by using conditional logistic regression models, adjusted for age, sex and smoking status. The adjusted odds ratio for the current smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotype as compared with the never smokers with the Asp/Asp genotype were 3.01 (95% CI 1.39-6.51, P = 0.005), 2.73 (95% CI 1.29-5.77, P = 0.008) and 7.33 (95% CI 2.93-18.3, P < 0.001), respectively. The gene-environment interaction between current smoking and APE1 148Glu/Glu genotype was statistically significant (OR 3.59, 95% CI 1.28-10.1, P = 0.015). When APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were evaluated together, the adjusted odds ratios for the current smokers with 0-1, 2 and 3-4 of APE1 148Glu or XRCC1 399Gln alleles as compared with never smokers with the 0 of these alleles were 2.96 (95% CI 1.57-5.58, P = 0.001), 3.86 (95% CI 1.85-8.05, P < 0.001) and 6.01 (95% CI 2.25-16.1, P < 0.001), respectively. The gene-environment interaction between current smoking and three or more APE1 148Glu or XRCC1 399Gln alleles was statistically significant (OR 2.44, 95% CI 1.00-9.22, P = 0.049). The OR for the gene-environment interaction of Glu/Glu genotype of APE1 codon 148 with heavy smoking was 1.04 (95% CI 0.38-2.90, P = 0.936) and that with light smoking was 2.67 (95% CI 1.00-7.68, P = 0.049). These results suggest that APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms might modify the risk of lung cancer attributable to cigarette smoking exposure.


Subject(s)
DNA Repair , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Genetic Predisposition to Disease , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Polymorphism, Genetic , Smoking , Adult , Aged , Alleles , Arginine/genetics , Aspartic Acid/genetics , Codon , DNA-Binding Proteins/genetics , Environment , Female , Genotype , Glutamic Acid/genetics , Glutamine/genetics , Humans , Japan , Male , Middle Aged , Odds Ratio , Risk , Risk Factors , X-ray Repair Cross Complementing Protein 1
16.
J Clin Oncol ; 22(2): 254-61, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14722033

ABSTRACT

PURPOSE: Few randomized trials have demonstrated survival benefit of combination chemotherapy involving new agents plus cisplatin compared with classic combination chemotherapy in advanced non-small-cell lung cancer (NSCLC). The primary aim of this study was to test whether docetaxel plus cisplatin (DC) improves survival compared with vindesine plus cisplatin (VdsC) in patients with previously untreated stage IV NSCLC. PATIENTS AND METHODS: Eligible, stage IV, chemotherapy-naive patients (n = 311) were randomly assigned to receive docetaxel 60 mg/m(2) intravenously on day 1 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 3- or 4-week cycle, or vindesine 3 mg/m(2) intravenously on days 1, 8, and 15 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 4-week cycle. Cross-over administration of docetaxel and vindesine was prohibited for both treatment groups. RESULTS: Overall, 302 patients were eligible for evaluation. The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% v 21%, respectively; P <.01) and median survival times (11.3 v 9.6 months, respectively; P =.014). Two-year survival rates were 24% for the DC arm compared with 12% for the VdsC arm. The physical domain of the Quality of Life for Cancer Patients Treated with Anticancer Drugs measure was significantly better in the DC arm than in the VdsC arm (P =.020). Toxicity was predominantly hematologic and was more severe in the VdsC arm. CONCLUSION: As first-line treatment for stage IV NSCLC, DC resulted in greater clinical benefit in terms of response rate (with marked improvements in overall and 2-year survival rates) and quality of life than did treatment with VdsC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Docetaxel , Female , Humans , Infusions, Intravenous , Lung Neoplasms/pathology , Male , Middle Aged , Quality of Life , Survival Analysis , Taxoids/administration & dosage , Vindesine/administration & dosage
17.
Lung Cancer ; 43(1): 93-100, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14698543

ABSTRACT

OBJECTIVES: Vinorelbine (V) and gemcitabine (G) are two active single agents used in the treatment of non-small cell lung cancer (NSCLC). A multicenter clinical trial (West Japan Thoracic Oncology Group (WJTOG) 9908) was conducted to evaluate the efficacy and toxicity of V and G in patients (pts) with advanced NSCLC. ELIGIBILITY CRITERIA: no previous chemotherapy; performance status (PS) 0 or 1; age <75 years old. V, 25mg/m2, was given as a 2-3 min IV infusion, followed by a 30 min IV infusion of G, 1000 mg/m2, on days 1 and 8 of each 21-day cycle. RESULTS: From April 2000 to September 2000, 52 pts were enrolled in the study. Two pts were ineligible. Baseline characteristics: median age 60, males 30 (60%), Eastern Cooperative Oncology Group (ECOG) PS 0/1=21/29 (58%), stage IIIB/IV=12/38 (76%), adenocarcinoma=35 (70%). The median number of cycles administered was 2. Fifty pts were evaluable for response. The response rate was 18% by the Response Evaluation Criteria in Solid Tumors (RECIST) (no complete response (CR), 9 partial response (PR), 25 stable disease, 12 progressive disease, 4 not evaluable). Grade III/IV toxicities were as follows: neutropenia grade III/IV=66%, anemia grade III/IV=16%, thrombocytopenia grade III/IV=2%, nausea grade III/IV=10%, vomiting grade III/IV=0%, documented infection grade III/IV=10%, skin rash grade III/IV=2%, and hepatic grade III/IV=8%. There were no treatment-related deaths. The median time to progression was 4.1 months. The overall median survival time (MST) was 13.9 months (range, 2.4 to >16.2 months) with a median follow-up time of 13.9 months. The MST for stage IIIB and stage IV was >14.5 and 12.7 months, respectively. The overall estimated 1-year survival rate was 55.4%. CONCLUSIONS: This regimen has modest activity and is very well tolerated, with an encouraging 1-year survival rate.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/administration & dosage , Female , Humans , Infusions, Intravenous , Japan , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Treatment Outcome , Vinblastine/administration & dosage , Vinorelbine , Gemcitabine
18.
Lung Cancer ; 42(1): 35-41, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14512185

ABSTRACT

ZD1839 ('Iressa') is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR signaling. Emerging evidence indicates that ZD1839 has clinical potential in lung cancer, but very little is known about the molecular characteristics of lung cancers that may determine sensitivity to ZD1839. We examined a panel of 19 lung cancer cell lines to investigate possible association between ZD1839 sensitivity and histological type, expression level and constitutive phosphorylation of EGFR and K-ras gene status. Our results indicate that neither expression level nor constitutive activation status of EGFR seems to predict sensitivity to ZD1839. In addition, ZD1839 sensitivity was not associated with expression of human epidermal growth factor receptor-2 (HER-2), another member of this tyrosine kinase receptor family nor with co-expression of EGFR and HER-2. Finally, no correlation was found between the presence of activating mutations of the K-ras gene, an important downstream mediator of the EGFR-transduced signals and the relative resistance to ZD1839. These findings warrant future study to clarify how ZD1839 inhibits lung cancer cell growth and to find a useful marker for prediction of sensitivity to this novel and promising agent for the treatment of lung cancers.


Subject(s)
Enzyme Inhibitors/therapeutic use , ErbB Receptors/metabolism , Genes, ras/physiology , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Receptor, ErbB-2/metabolism , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Epidermal Growth Factor/antagonists & inhibitors , Gefitinib , Humans , Lung Neoplasms/metabolism , Phosphorylation/drug effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Tumor Cells, Cultured
19.
Clin Cancer Res ; 8(7): 2443-7, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12114451

ABSTRACT

This study reports that a selective COX-2 inhibitor JTE-522inhibits both in vitro and in vivo growth of human lung cancer cells as a single agent. Furthermore, the adjunct use of JTE-522 is shown to significantly enhance treatment efficacy of conventional anticancer drugs not only in vitro but also in vivo without causing any noticeable side effects. Indeed, IC(50)s of various anticancer agents in vitro were reduced by up to 70%, whereas the combination therapy of JTE-522 with docetaxel and vinorelbine inhibited tumor growth in vivo by 65 and 55%, respectively. Taken together, these findings suggest that the use of a selective COX-2 inhibitor in the treatment of lung cancer may be promising, especially because of its enhancement of the treatment efficacy of conventional anticancer agents without compromising quality of life.


Subject(s)
Adenocarcinoma/drug therapy , Anthracyclines , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzenesulfonates/therapeutic use , Cyclooxygenase Inhibitors/therapeutic use , Isoenzymes/antagonists & inhibitors , Lung Neoplasms/drug therapy , Oxazoles/therapeutic use , Paclitaxel/analogs & derivatives , Taxoids , Vinblastine/analogs & derivatives , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Antibiotics, Antineoplastic/pharmacology , Cell Division/drug effects , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Docetaxel , Drug Resistance, Neoplasm , Female , Humans , In Vitro Techniques , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Membrane Proteins , Mice , Mice, Nude , Neoplasm Transplantation , Paclitaxel/administration & dosage , Prostaglandin-Endoperoxide Synthases , Tumor Cells, Cultured/drug effects , Vinblastine/administration & dosage , Vinorelbine
20.
J Clin Oncol ; 20(14): 3054-60, 2002 Jul 15.
Article in English | MEDLINE | ID: mdl-12118018

ABSTRACT

PURPOSE: To evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC), the Lung Cancer Study Group of the Japan Clinical Oncology Group conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT. PATIENTS AND METHODS: We treated 231 patients with LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily), and the patients were randomly assigned to receive either sequential or concurrent TRT. All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. RESULTS: Concurrent radiotherapy yielded better survival than sequential radiotherapy (P =.097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5-year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%, and 18.3%, respectively, as opposed to 54.4%, 29.8% and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm. However, severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm. CONCLUSION: This study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective for the treatment of LS-SCLC than cisplatin plus etoposide and sequential radiotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Small Cell/drug therapy , Carcinoma, Small Cell/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant/adverse effects , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Prospective Studies , Radiotherapy Dosage , Radiotherapy, Adjuvant/adverse effects , Risk , Survival Analysis , Treatment Outcome
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