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Objective A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. Methods Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30–60 minutes) in routine clinical settings (observation period: 96 weeks). Results Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4–8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P, In this Japanese post-marketing surveillance study, the safety and effectiveness profile of temsirolimus was similar to that in the multinational phase 3 study. No new safety signals were identified.

Objective Patients’ actual age and performance status do not always accurately identify the ‘fit elderly’ for chemotherapy. This study aimed to determine whether four geriatric assessment tools could predict prognosis. Methods This study were analyzed using the data of two randomized phase III trials (JCOG0207 and JCOG0803/WJOG4307L) for elderly patients with advanced non-small cell lung cancer and included all eligible patients who were assessed before treatment with four geriatric assessment tools: the Barthel activities of daily living index, Lawton instrumental activities of daily living scale, Mini-Mental State Examination, and Geriatric Depression Scale-15. Univariable and multivariable analyses for overall survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as strata. Results This analysis included 330 patients aged 70–74, 75–79 or 80 or more (n = 95/181/54), with a performance status of 0 or 1 (n = 119/211). Patients were divided into three groups based on Mini-Mental State Examination and two groups based on Geriatric Depression Scale, but over 80% of patients had perfect scores for both activities of daily living and instrumental activities of daily living. In overall survival subgroup analyses by GA tool, only Mini-Mental State Examination scores were associated with substantial outcome differences (median survival times: 21.2, 13.5 and 12.2 months for scores 30, 29–24 and ≤23). After adjusting for baseline factors, the Mini-Mental State Examination, sex and performance status were tended to be worse overall survival. Conclusion MMSE scores, performance status and sex, but not chronological age, effectively predicted the prognosis of elderly patients. Further studies should confirm that the Mini-Mental State Examination is useful for determining the indication of chemotherapy in elderly patients with advanced non-small cell lung cancer.

OBJECTIVE Prospective trials specifically designed for elderly patients with advanced non-small-cell lung cancer demonstrating the benefit of platinum-based therapies are still lacking. This trial was designed to clarify whether the addition of cisplatin to monotherapy could improve survival for elderly patients. METHODS Elderly patients (age ≥70 years, ECOG performance Status 0-1) with advanced non-small-cell lung cancer were randomized to receive docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on Day 1, 8 and 15 (docetaxel plus cisplatin) or docetaxel 25 mg/m(2) on the same schedule (docetaxel). Both regimens were repeated every 4 weeks until disease progression. RESULTS One hundred and twenty-six patients were enrolled. Sixty-three were randomly assigned docetaxel plus cisplatin and 63 docetaxel monotherapy. Median age was 76 years (range 70-88). The second planned interim analysis was performed on 112 assessable patients (docetaxel/docetaxel plus cisplatin: 56/56). Although the formal criterion for stopping the trial was not met, the Data and Safety Monitoring Committee recommended study termination on ethical grounds based on the interaction (two-sided P = 0.077, hazard ratios for ≤74/≥75: 0.23/0.72) between age and subgroup and treatment arm, which suggested that docetaxel may not represent an adequate control arm regimen for the age subgroup of 70-74 years. CONCLUSIONS The interpretation of study results is limited due to early stopping. Further study is needed to confirm survival benefit of platinum-based chemotherapy for elderly non-small-cell lung cancer [UMIN-CTR (www.umin.ac.jp/ctr/) ID: C000000146].

Objective It is important to find optimal regimens of cisplatin (CDDP)-based third-generation chemotherapy and radiotherapy for patients with unresectable Stage III non-small cell lung cancer (NSCLC). Methods This Phase II study was designed to determine the toxicity and efficacy of two courses of chemotherapy (CDDP 80 mg/m(2) on day 1 and irinotecan 60 mg/m(2) on days 1 and 8) followed by accelerated hyperfractionated thoracic radiotherapy (60 Gy/40 fractions in 4 weeks) combined with daily carboplatin (CBDCA) administration. CBDCA was administered at a target area under the plasma level-time curve of 0.4 x (24 h creatinine clearance + 25), according to Calvert's formula. Results Twenty-six patients were enrolled in the study. The patients' median age was 63 years (range 40-74 years) and included 22 males and 4 females. Seven patients were Stage IIIA and 19 were Stage IIIB. Twenty had a performance status (PS) of 1 versus six with a PS of 0. There was one treatment-related death due to sepsis and pneumonia associated with Grade 4 neutropenia and diarrhea during chemotherapy. Grade 3 or 4 neutropenia and diarrhea were observed in 14 and 5 patients, respectively. Toxicity of the radiotherapy was mild. There were 0 complete response and 13 partial responses, giving a response rate of 50.0%. Median survival time and 2-year survival were 16.4 months and 21.5%, respectively. This study was designed with Simon's two-stage design, and the response rate did not meet the criteria to proceed to the second stage and the study was terminated early. Conclusions This regimen might be inactive for patients with unresectable Stage III NSCLC.

Objective: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of combination chemotherapy with gemcitabine (GEM) and carboplatin (CBDCA) in non-small cell lung cancer (NSCLC) patients with a performance status (PS) of 2. Methods: Chemotherapy-naive NSCLC patients with PS 2 were enrolled. Chemotherapy consisted of an escalated dose of GEM on days 1 and 8 and CBDCA on day 1 every 3 weeks. Patients were scheduled to receive GEM (mg/m 2 )/CBDCA (area under the curve: AUC) at four dose levels: 800/4 (level 1), 1000/4 (level 2), 1000/4.5 (level 3) and 1000/5 (level 4), respect- ively. Results: Between February 2004 and August 2006, 13 patients were enrolled in this study. Dose-limiting toxicities (DLTs) were thrombocytopenia, febrile neutropenia and hyponatremia. DLTs were observed in two of six patients at dose level 1 and in three of six patients at dose level 2. Dose level 2 was thus determined to be the MTD. Among 12 evaluable patients, 7 patients had stable diseases and 5 patients had progressive diseases, and the median survival time was 3.8 months. Conclusions: The MTD and the recommended dose for Phase II studies of this regimen were determined to be GEM 1000 mg/m 2 and CBDCA AUC of 4. Additional objective measures are needed to evaluate patients' risk and benefit in future clinical trials for PS 2 patients.

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts ,0.5 � 10 9 cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 mg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration‐time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.

Objective: The efficacy and safety of weekly administration of epoetin beta (EPO) for chemotherapy-induced anemia (CIA) patients was evaluated. Methods: One hundred and twenty-two patients with lung cancer or malignant lymphoma undergoing chemotherapy were randomized to the EPO 36 000 IU group or the placebo group. Hematological response and red blood cell (RBC) transfusion requirement were assessed. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire. Results: Mean change in hemoglobin level with EPO increased significantly over placebo (1.4+1.9 g/dl versus 20.8+1.5 g/dl; P , 0.001). The proportion of patients with change in hemoglobin level 2.0 g/dl was higher for EPO than those for placebo (P , 0.001). After 4 weeks of administration, the proportion of RBC transfusion or hemoglobin level ,8.0 g/dl was significantly lower for EPO than those for placebo (P ¼ 0.046). The changes in the FACT-An total Fatigue Subscale Score (FSS) were less deteriorated with EPO than those with placebo. Progressive disease (PD) did not influence the change in hemoglobin level but there was less decrease in FSS in non-PD patients. No significant differences in adverse events were observed. Thrombovascular events and pure red cell aplasia related to EPO were not observed. Retrospective analysis of survival showing the hazard ratio of EPO to placebo was 0.94. Conclusion: Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period.

Background To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. Methods Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. Results Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. Conclusions Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

Objective Pretreatment computerized tomography (CT) films of the chest was studied to clarify the influence of interstitial shadow on developing interstitial lung disease (ILD). Methods Eligible patients were those lung cancer patients who started to receive first-line chemotherapy between October 2001 and March 2004. Patients who received thoracic radiotherapy to the primary lesion, mediastinum, spinal or rib metastases were excluded. We reviewed pretreatment conventional CT and plain X-ray films of the chest. Ground-glass opacity, consolidation or reticular shadow without segmental distribution was defined as interstitial shadow, with this event being graded as mild, moderate or severe. If interstitial shadow was detected on CT films of the chest, but not via plain chest X-ray, it was graded as mild. Patients developing ILD were identified from medial records. Results A total of 502 patients were eligible. Mild, moderate and severe interstitial shadow was identified in 7, 8 and 5% of patients, respectively. A total of 188 patients (37%) received tyrosine kinase inhibitor (TKI) treatment, namely gefitinib or erlotinib. Twenty-six patients (5.2%) developed ILD either during or after chemotherapy. Multivariate analyses revealed that interstitial shadow on CT films of the chest and treatment history with TKI were associated with the onset of ILD. Conclusions It is recommended that patients with interstitial shadow on chest CT are excluded from future clinical trials until this issue is further clarified, as it is anticipated that use of chemotherapeutic agents frequently mediate onset of ILD in this context.

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

We conducted a dose-finding and feasibility study in which we administered a fixed dose 3-h infusion of paclitaxel and an escalating dose of cisplatin in Japanese patients with advanced non-small cell lung cancer.Chemotherapy consisted of fixed dose (210 mg/m(2)) paclitaxel given over 3 h on day 1 and an escalating dose of cisplatin on day 2, every 3-4 weeks. The dose of cisplatin was 40 mg/m(2) at level 1, 60 mg/m(2) at level 2 and 80 mg/m(2) at level 3.Between October 1999 and February 2001, 24 patients were enrolled and 58 cycles were administered. The major hematological toxicities were leukopenia and neutropenia. Grade 4 neutropenia developed in 83.3%, 66.7% and 83.3% of patients at the dose levels of 1, 2 and 3, respectively. The major non-hematological toxicities consisted of alanine aminotransferase (ALT) elevation and peripheral neuropathy. Grade 3 ALT elevation was observed in two of the 12 patients at level 3, but both recovered within 3 days. The peripheral neuropathy was sensory-dominant and frequent, and it was almost tolerable. The maximum tolerated dose was not identified even at the highest dose of paclitaxel (210 mg/m(2)) and cisplatin (80 mg/m(2)) administered in the study. The recommended dose was determined to be paclitaxel 210 mg/m(2) on day 1 and cisplatin 80 mg/m(2) on day 2, every 3-4 weeks. Seven partial responses were observed in the 24 patients.The combination of paclitaxel 210 mg/m(2) and cisplatin 80 mg/m(2) was found to be a well-tolerated active regimen in Japanese patients with advanced non-small cell lung cancer.

Background: A combination of cisplatin and vinorelbine chemotherapy is effective in cases of advanced non-small cell lung cancer, but the optimum administration schedule for both drugs has not yet been defined. The aim ofthis study was to determine the maximum dose of vinorelbine that can be tolerated while receiving a fixed dose of cisplatin every 3 weeks and to observe the response in Japanese patients with advanced non-small cell lung cancer who had not previously received chemotherapy. Methods: Cisplatin was given at a dose of 80 mg/m 2 on day 1. Vinorelbine was administered on days 1 and 8 at a starting dose of 25 mg/m 2 that was then increased by 5 mg/m 2 increments. This treatment was repeated every 3 weeks. Results: Twenty-one patients received a total of 54 chemotherapy cycles consisting of three different vinorelbine dosages. Toxicity and efficacy were evaluated in all of the patients. The main dose-limiting toxicity was neutropenia. Grades 3-4 leukopenia and neutropenia were observed in 57% and 86% of all cycles, respectively. These conditions were reversible and did not result in death from toxicity. The most severe non-hematological toxicity symptom was a grade 3 infection and reaction at the site of injection. The maximum tolerated dose of vinorelbine was 35 mg/m 2 . The objective response was noted in one of six patients at dose level 1, in four of 12 patients at dose level 2 and in two of three patients at dose level 3. Conclusion: The recommended doses were 80 mg/m 2 for cisplatin and 30 mg/m 2 for vinorelbine. The combination of cisplatin and vinorelbine repeated every 3 weeks is well tolerated and has shown promising anti-tumor activity against non-small cell lung cancer.

Background: The combination of paclitaxel (225 mg/m 2 , 3-h infusion) and carboplatin (area under the curve 6) is widely used for non-small cell lung cancer in the USA. In Japan, however, the recommended dose for single-use paclitaxel in 3-h infusion is 210 mg/m 2 and the optimal dose of this agent in combination with carboplatin has not been established. This dose escalation study was designed to determine the maximum tolerated dose of paclitaxel in 3-h infusion plus carboplatin at a fixed dose of area under the curve 6 for Japanese patients with advanced, untreated non-small cell lung cancer. Methods: Between October 1999 and May 2000, 19 patients were enrolled and 18 of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin area under the curve 6 and an escalated dose of paclitaxel on day 1 every 3-4 weeks. The initial dose of paclitaxel was 175 mg/m 2 and was increased by 25 mg/m 2 at each dose level. Results: Neutropenia was the major toxicity observed, but was not dose related. Febrile neutropenia was not observed. No grade 3 or more peripheral neuropathy, myalgia or arthralgia was reported. The maximum tolerated dose was not determined even at the highest paclitaxel dose level (225 mg/m 2 ) in this study. Partial responses were observed in six of the 19 patients (31.6%). Conclusion: We conclude that paclitaxel at 225 mg/m 2 in 3-h infusion and carboplatin area under the curve 6 can safely be given to Japanese patients with non-small cell lung cancer.

Background: To determine the maximum tolerated dose and recommended dose of cisplatin and docetaxel administered by three consecutive weekly infusions in both non-elderly (74 years) and elderly (75 years) patients, we conducted two independent phase I studies for nonelderly and elderly patients with non-small cell lung cancer. Methods: Between April 1998 and September 1999, 26 non-elderly (median, 54 years; range, 44‐73 years) and 12 elderly (median, 76 years; range, 75‐80 years) patients with non-small cell lung cancer were entered in these studies. The eligibility criteria of both cohorts were identical except for age. Chemotherapy consisted of cisplatin 25 mg/m 2 and an escalated dose of docetaxel on days 1, 8 and 15 every 4 weeks. The initial dose of docetaxel was 20 mg/m 2 and it was increased by 5 mg/m 2 at each dose level. Results: In the non-elderly and elderly cohorts, up to 45 or 25 mg/m 2 of docetaxel, respectively, were administered. Dose-limiting toxicities were neutropenia, liver damage, pneumonia and omission of treatment on day 15 by leukopenia and refusal in the non-elderly cohort; pneumonia and omission of treatment on day 15 by refusal due to fatigue/asthenia or fever in the elderly cohort. We considered the recommended doses for phase II studies were cisplatin 25 mg/m 2 and docetaxel 35 mg/m 2 on days 1, 8 and 15 for non-elderly patients and cisplatin 25 mg/m 2 and docetaxel 20 mg/m 2 on days 1, 8 and 15 for elderly patients. Seven of 26 (27%) and seven of 12 (58%) patients achieved a partial response, median survival times were 8.7 and 7.2 months and 1 year survival rates were 27 and 27% in the non-elderly and elderly cohorts, respectively. Conclusions: Further evaluation of this combination chemotherapy is warranted for both nonelderly and elderly patients with non-small cell lung cancer but the dose of docetaxel should be lower for elderly than non-elderly patients.

BACKGROUND Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) is the first orally given platinum complex that shows in vitro cytotoxicity comparable to that of cisplatin and in vivo cytotoxicity superior to those of cisplatin and carboplatin. METHODS We conducted an escalating-dose (50, 75, 100, 120 mg/m2) phase I study of JM216 administered orally once a day for five consecutive days in patients with solid tumors to establish the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetic profile. Twenty-three patients were enrolled and all were assessable for toxicity. RESULTS The MTD was 120 mg/m2/day and the dose-limiting toxicities were leukopenia, thrombocytopenia, anemia and diarrhea. Because of the delayed hematological toxicities, it was difficult to repeat cycles every 26 days in some patients. Tumor shrinkage was observed in two patients with breast cancer, both of whom were resistant to doxorubicin. A pharmacokinetic study showed that the areas under the concentration-time curve (AUC) and peak plasma concentrations (Cmax) for total platinum (Pt) on days 1 and 5 and ultrafiltered Pt (UF-Pt) on day 1 increased in proportion to the dose of JM216. The AUCs for both total and UF-Pt on day 5 were higher than the AUCs on day 1. The AUC for UF-Pt on day 5 showed the best correlation with percentage reduction in leukocyte count and in absolute neutrophil count. CONCLUSION The recommended dose for phase II studies is 100 mg/m2/day every 4-6 weeks. The observation of tumor shrinkage in previously heavily treated breast cancer patients supports a phase II investigation.

Background: Etoposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC). Methods: Fifty-seven patients withSCLCwithextensive disease (ED)or limited disease(LD)with pleural effusion registered in the 21 institutions of the JapanClinical Oncology Groupweretreated with oral etoposide 40 mg/m 2/d for 21 days and cisplatin 80 mg/m 2 on day 1 of every28-period day. The entry period was between February 1992 and August 1995.The actualpercentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively. Results: Nine patients(15.8%) achieved a complete response resulting in an overall response rateof 82.5%(95%confidence interval, 70.1-91.3%). Leukopenia andthrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1 %) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia.The mean survival time was 47.0 weeks. Conclusions: Thisdoseandschedule of administration of etoposide in combination withcisplatin areconsidered to beclinically active. However, prolonged gastrointestinal toxicityof oraletoposide was a problem in comparison withthe standard etoposide platinum regimen givenby intravenous administration.

As the geriatric population is growing, it is increasingly important to be familiar with chemotherapy for the elderly. Age-related changes in pharmacokinetics are documented for doxorubicin, etoposide, ifosfamide, daunorubicin, mitomycin, cisplatin and methotrexate. The hematological toxicity of most standard-dose chemotherapy is not affected by age in patients with normal organic functions and good performance status, although increased toxicity with aging is suggested in the use of actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin, and in dose-intensive chemotherapy. Among non-hematological toxicities, only doxorubicin-induced cardiomyopathy and bleomycin-induced pulmonary toxicity are demonstrated to be accelerated in the elderly. There is no evidence that advanced age decreases the efficacy of chemotherapy for tumors, except for Hodgkin's disease and acute leukemia. These results suggest that advanced chronological age alone is not always associated with severe toxicity and poor prognosis, and that many elderly patients with cancer will benefit from chemotherapy. To answer questions regarding the optimal chemotherapy regimen, dose and intensity in this population, the influence of age should be analyzed in a multivariate approach in future studies.

BACKGROUND It is important to minimize the incidence of ineligible cases to improve the quality of clinical trials. To determine factors which may influence the incidence of ineligible cases, the incidence of and reasons for ineligibility in clinical trials were retrospectively analyzed. METHODS We retrospectively examined the incidence of and reasons for ineligibility for inclusion in eight clinical trials conducted by the Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group and four trials financed by trust funds from a pharmaceutical company. RESULTS In these 12 clinical studies, the incidence of ineligibility was 4.2% (32/762) (range 0-10.6%). Specific factors that might influence the incidence of ineligible cases were then analyzed. There was a significant difference in the incidence of ineligibility between the methods of registration (P 0.05). CONCLUSIONS We conclude that the incidence of ineligible cases in our studies is similar to that in clinical trials published in the Journal of Clinical Oncology. Central registration systems are useful for checking for ineligibility, and to increase the quality of clinical trials.

Objective KRAS gene mutations are a useful predictive factor for the efficacy of anti-epidermal growth factor receptor therapeutics. Since there were no large-scale studies among Asian populations, we designed an observational nationwide study in Japan. Methods Formalin-fixed paraffin-embedded tissue blocks or sections from primary or metastatic lesions were obtained from patients registered between 2009 and 2010 for genomic DNA extraction. KRAS gene was analyzed by direct sequencing or Luminex assay. The primary endpoint was the frequency of KRAS gene mutations and the secondary endpoints were differences in KRAS mutation rates by various stratification factors. Univariate and multivariate analyses were performed to investigate relationships between KRAS mutation rates and patient background factors. Results We analyzed 5790 eligible samples out of 5887 registered. The overall KRAS mutation rate was 37.6%, with 29.9% in codon 12 and 7.7% in codon 13, and wild type was 62.4%. A significant relationship with the KRAS mutation rate was found for gender, age, the year that the sample was prepared and the site of the primary lesion. Conclusion The KRAS mutation rate of Japanese colorectal cancer patients was 37.6%. Gender, age, the site of the primary lesion and the year that the sample was prepared were independent risk factors for KRAS mutations.

To assess the feasibility of treatments for patients with small cell lung cancer (SCLC) showing a poor performance status (PS, Eastern Cooperative Oncology Group; ECOG 3 or 4), we retrospectively reviewed the outcome for 13 SCLC patients showing poor PS treated at the National Cancer Center Hospital between January 1984 and May 1994. The main factors which contributed to poor prognosis were superior vena cava (SVC) syndrome, massive pleural effusion, tracheal stenosis due to lymph node swelling, pericardial effusion and pulmonary fibrosis (causing dyspnea in combination), brain metastasis resulting in neurological disturbance, cachexia, Eaton-Lambert syndrome causing muscle weakness, retroperitoneal lymph node metastasis causing abdominal pain, peritoneal effusion due to abdominal lymph node swelling, vertebral metastasis causing paraplegia, and dermatomyositis/polymyositis (DM/PM) causing muscle weakness. All of the patients received chemotherapy with or without radiotherapy. The PS of 8 patients improved with treatment, but no improvement was seen in 5. We analyzed these 13 patients and considered the treatments for those with poor PS. Chemo-radiotherapy was tolerable in SCLC patients showing PS 3, and improved their PS if severe conditions or combined disease did not arise concurrently. It was further suggested that PS 4 patients with severe conditions or combined disease should not be given the treatments.

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.

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.

Numerous molecular-targeted drugs have been developed based on the progress in the study of molecular biology. Among them, some of the antibodies and small molecule tyrosine kinase inhibitors have been approved for clinical use. Standard therapies against common cancers have completely been changed. Individualized treatments have been possible in pharmacogenomically specific populations. Unbelievably improved progression-free and/or overall survivals have been achieved and cure rate has also improved in surgically resected patients by using molecular-targeted therapy. Prognostic and/or predictive factors have been identified and biomarker testing has become mandatory for human epidermal growth factor receptor 2 expression/amplification in breast cancer and gastric cancer, Kras mutation in colon cancer and epidermal growth factor receptor mutation in lung cancer. The development of active molecular-targeted therapy and more validated markers could enable the increment of curative populations even in advanced malignancies.

This is the first clinical trial for Japanese to evaluate the dose-response and determine the clinically effective dose of darbepoetin alpha by weekly subcutaneously administration in anemic patients with lung cancer or ovarian cancer receiving chemotherapy.Eligible patients were required to have anemia (hemoglobin level ofor=11.0 g/dl). Patients were randomized in a 1:1:1 ratio to receive darbepoetin alpha (1.0, 2.25 or 4.5 microg/kg) subcutaneously once a week for up to 12 weeks. The study drug was withheld from patients who had a hemoglobin level15.0 g/dl (for men) or 14.0 g/dl (for women), and reinstated at 50% of the previous weekly dose when the hemoglobin level decreased toor=13.0 g/dl. Quality-of-life assessments were conducted using the Japanese version of the Functional Assessment of Cancer Therapy-anemia (FACT-an) questionnaire.Hemoglobin response rate was 31.6%, 55.6% and 70.3% in 1.0, 2.25 and 4.5 microg/kg groups, respectively. The dosages of 2.25 and 4.5 microg/kg thus met the clinically effective dose criterion of at least 50% of patients achieving a hemoglobin response. The FACT-fatigue subscale had a high internal consistency with Cronbach's alpha score. Although no improvement in FACT-fatigue subscale score from baseline to the end of the treatment phase was confirmed for any dose group, there was a correlation between FACT-fatigue subscale score and hemoglobin concentration. Darbepoetin alpha appears to be well tolerated in this setting and no dose-dependent adverse events were observed.Darbepoetin alpha alleviated anemia caused by platinum-based chemotherapy, and the dosage of 2.25 microg/kg was the lowest dose that met the clinically effective dose criteria when administered once weekly.

Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0‐1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 (Level 1), were studied in the dose-escalation Phase I( Step 1). The RD determined in Step 1w as carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18‐38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level 21 (pemetrexed 500 mg/m 2 , cisplatin 60 mg/m 2 ). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3‐ 61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.

An autopsy case of an 18-year-old boy with adenocarcinoma of the lung is reported. He experienced dyspnea and hemosputum in July 1988. Chest radiographs showed a diffuse bilateral streaky shadow, bilateral pleural effusion and cardiac enlargement. The diagnosis of adenocarcinoma was made by transbronchial biopsy at another hospital. He visited the National Cancer Center Hospital on October 7, 1988. The diagnosis of lung cancer was strongly suggested by positive immunohistochemical staining for pulmonary surfactant apoprotein in biopsy specimens from supraclavicular lymph nodes. Intensive systemic survey demonstrated no other primary site than the lung. The patient was treated with cisplatin, adriamycin and etoposide and his subjective symptoms such as cough and dyspnea significantly improved over the next three months. Tumor shadows in the lung increased steadily, however after February, 1989. A significant lymphangitic spread of the carcinoma and marked obsteoblastic bone metastases were revealed at autopsy.

In order to review gene alterations associated with drug responses in vitro to identify candidate genes for predictive chemosensitivity testing, we selected from literature genes fulfilling at least one of the following criteria for the definition of 'in vitro chemosensitivity associated gene': (i) alterations of the gene can be identified in human solid tumor cell lines exhibiting drug-induced resistance; (ii) transfection of the gene induces drug resistance; (iii) down-regulation of the gene increases the drug sensitivity. We then performed Medline searches for papers on the association between gene alterations of the selected genes and chemosensitivity of cancer cell lines, using the name of the gene as a keyword. A total of 80 genes were identified, which were categorized according to the protein encoded by them as follows: transporters (n = 15), drug targets (n = 8), target-associated proteins (n = 7), intracellular detoxifiers (n = 7), DNA repair proteins (n = 10), DNA damage recognition proteins (n = 2), cell cycle regulators (n = 6), mitogenic and survival signal regulators (n = 7), transcription factors (n = 4), cell adhesion-mediated drug resistance protein (n = 1), and apoptosis regulators (n = 13). The association between the gene alterations and chemosensitivity of cancer cell lines was evaluated in 50 studies for 35 genes. The genes for which the association above was shown in two or more studies were those encoding the major vault protein, thymidylate synthetase, glutathione S-transferase pi, metallothionein, tumor suppressor p53, and bcl-2. We conclude that a total of 80 in vitro chemosensitivity associated genes identified in the literature are potential candidates for clinical predictive chemosensitivity testing.

OBJECTIVE To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial. METHODS A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18,000 or 36,000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements. RESULTS Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36,000 IU group was significantly greater than that in the 9000 IU group (1.75 +/- 2.15 versus 0.04 +/- 1.98 g/dl; P = 0.009), and a significant dose-response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups. CONCLUSIONS Once-weekly epoetin-beta 36,000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.

The combination of cisplatin and gemcitabine is one of the most active chemotherapy regimens against non-small cell lung cancer. However, the optimum schedule for this combination has not been determined. This study was performed to determine the maximum tolerated dose of gemcitabine combined with cisplatin in a 3-week cycle regimen and to observe safety and efficacy for Japanese patients with advanced non-small cell lung cancer.80 mg/m(2) of cisplatin on day 1 and escalated doses of gemcitabine on days 1 and 8 were administered every 3 weeks to patients with previously untreated, advanced non-small cell lung cancer. The initial dose of gemcitabine was 1000 mg/m(2) and was escalated in 250 mg/m(2) increments.Twenty-four patients were enrolled between March and December 2000. In total, 64 courses were given. The main toxicities were neutropenia, thrombocytopenia and hepatotoxicity. The maximum tolerated dose was determined to be 1500 mg/m(2) of gemcitabine combined with 80 mg/m(2 )of cisplatin. Nine of 24 patients (37.5%) achieved a partial response.This study demonstrates that the combination of cisplatin and gemcitabine repeated every three weeks is tolerable for Japanese patients with advanced non-small cell lung cancer. We determined 1250 mg/m(2) of gemcitabine combined with 80 mg/m(2 )of cisplatin to be the recommended dose.

Background We attempted dose escalation of standard-fractionated and accelerated-hyperfractionated radiotherapy combined with concurrent cisplatin and vindesine to improve local control and survival in unresectable non-small cell lung cancer. Methods Twenty-one patients were enrolled between June 1996 and August 1997. There were 19 males and two females and their median age was 65 years (range 45-74 years). Performance status was 0 in 10 cases and 1 in 11 cases. Disease stage was IIIA in three cases and IIIB in 18 cases. The cases were randomized to a standard-fractionated arm (n = 10) or an accelerated-hyperfractionated radiotherapy arm (n = 11) with two or three cycles of concomitant cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8 every 4 weeks in both arms. Dose escalation from 60 Gy/30 fractions/6 weeks to 70 Gy/35 fractions/7 weeks was planned in the standard-fractionated radiotherapy group and from 54 Gy/36 fractions/3.6 weeks to 60 Gy/40 fractions/4 weeks and then 66 Gy/44 fractions/4.4 weeks in the accelerated-hyperfractionated radiotherapy group. Results Grade 3 or 4 hematological toxicities were observed as follows: in the standard-fractionated/accelerated-hyperfractionated radiotherapy group, leukocytopenia 9/10, anemia 2/3 and thrombocytopenia 0/2. Grade 3 non-hematological toxicity consisted of esophagitis 0/3, increased serum total bilirubin 2/0 and hypoxia 0/1. Two patients died of radiation pneumonitis in the standard-fractionated radiotherapy group. Dose-limiting toxicity was observed in four of the 10 and seven of the 11 patients at initial dose level of standard-fractionated radiotherapy, 60 Gy/30 fractions/6 weeks, and of accelerated-hyperfractionated radiotherapy, 54 Gy/36 fractions/3.6 weeks, respectively. Thus, we failed to escalate the dose of radiotherapy in both arms. The overall response rate in the standard-fractionated group and the accelerated-hyperfractionated radiotherapy group was 70 and 73% and the 1-year survival rate was 70 and 64%, respectively. Conclusions We concluded that these schedules of radiotherapy with concurrent cisplatin and vindesine were unacceptable for use in patients with unresectable non-small cell lung cancer. Further modifications of the schedule for radiotherapy and evaluation of combination with new chemotherapy are warranted.

Chemotherapeutic regimens containing new anticancer agents in combination with cisplatin and carboplatin have been demonstrated to be equivalently active against advanced non-small cell lung cancer. The choice of a chemotherapeutic regimen depends on differences in time to progression, response rate, toxicity profile, cost and symptom relief. Several other strategies, such as three-drug combinations, sequential use of a third drug, weekly administration, etc., have been evaluated to improve the chemotherapeutic effect. The sequencing of the human genome may permit targeting of specific abnormalities related to each lung cancer with target-based drugs. This should increase the possibility of application of individualized therapy and, we would hope, improve survival.

Background: To establish the toxicities and maximum tolerated dose of paclitaxel given over 3 h in combination with cisplatin, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity, we conducted a combination phase I study in non-small cell lung cancer. Methods: Patients received paclitaxel doses of 150‐210 mg/m 2 given over 3 h and cisplatin doses of 60‐80 mg/m 2 as a1hi nfusion 2ha fter the end of the paclitaxel infusion. Results: A total of 25 patients with previously untreated non-small cell lung cancer were enrolled. Granulocytopenia was the most frequent hematological toxicity and the most prominent non-hematological toxicity was sensory dominant neuropathy. Two of six patients experienced dose limiting toxicities (leukopenia, infection and neuropathy) at a dose of paclitaxel 210 mg/m 2 and cisplatin 60 mg/m 2 , which was considered the maximum tolerated dose. There were seven partial responses among 24 evaluable patients, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. As the paclitaxel pharmacokinetic parameters in this study were consistent with those of our previous single agent study, we found no significant drug‐drug interaction between the 3 h infusion paclitaxel and cisplatin. Conclusion: The recommended doses for further study are determined to be paclitaxel 180 mg/m 2 and cisplatin 80 mg/m 2 . This is a well-tolerated and active regimen for non-small cell lung cancer. In view of the promising survival outcome, further evaluation in prospective randomized trials versus other regimens is warranted.

Background: The aim was to determine the maximum tolerated dose (MTD) and recommended dose of irinotecan hydrochloride (CPT-11) in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC). Methods: Etoposide was administered continuously at 25 mg/m 2 /day for 14 days. The initial dose of CPT-11 was 40 mg/m 2 given as a 90 min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m 2 until severe or lifethreatening toxic effects were observed. Results: Nine refractory or advanced LC patients (eight at level 1, one at level 2) were entered in this study, of whom two at level 1 were not assessable for toxicity because of patient’s refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catecholamine for more than 48 h were observed at level 1, a CPT-11 dose of 40 mg/m 2 . The MTD of CPT-11 was 40 mg/m 2 . Therapeutic efficacy could be assessed in seven patients, of whom two achieved a partial response. Conclusions: This regimen was too toxic and the recommended dose was outside the levels in this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.

Background: Thymic carcinoma is a rare mediastinal neoplasm with poor prognosis. Although the clinical benefit of chemotherapy for thymic carcinoma is controversial, cisplatin-based chemotherapy with or without radiation therapy is ordinarily adopted in advanced cases. We evaluated the clinical outcome of platinum-based chemotherapy with or without radiation therapy in unresectable thymic carcinoma patients. Methods: Ten patients with unresectable thymic carcinoma were treated with platinum-based chemotherapy with or without radiation therapy in the National Cancer Center Hospital between 1989 and 1998. We reviewed the histological type, treatment, response and survival of these patients. Results: Four of the 10 patients responded to chemotherapy and both the median progression-free survival period and the median response duration were 6.0 months. The median survival time was 11.0 months. There was no relationship between histological classification and prognosis. Conclusions: Platinum-based chemotherapy with or without thoracic radiation is, regardless of tumor histology, marginally effective in advanced thymic carcinoma patients, giving only a modest tumor response rate and short response duration and survival.

Although neutropenia increases the risk of life-threatening infections, bacterial meningitis is rarely encountered as a complication during cancer chemotherapy in adults with a solid tumor. A 66-year-old male with adenosquamous carcinoma of the lung, cT2N3M0, stage IIIB, was enrolled in a phase I trial of chemoradiotherapy and treated with cisplatin 80 mg/m 2 (122 mg/ body) on day 1, vinorelbine 20 mg/m 2 (32 mg/body) on days 1 and 8 and thoracic radiotherapy 30 Gy/15 fractions, beginning on day 2, with dexamethasone administered for antiemesis at a dose of 16 mg on day 1, 8 mg on days 2 and 3, 4 mg on day 4 and 2 mg on day 5. The patient developed headache and fever on day 6 of the second cycle of the treatment and bacterial meningitis was diagnosed based on the findings of consciousness disturbance, an elevated peripheral blood leukocyte count and numerous leukocytes in the cerebrospinal fluid. In spite of the doctor’s delay in establishing the exact diagnosis, the bacterial meningitis in this case was successfully treated with intensive antibiotic therapy. This life-threatening complication, equivalent to a grade 4 non-hematological adverse reaction, was not counted as dose-limiting toxicity in the current phase I trial, because there are only a few reports of bacterial meningitis associated with cancer chemotherapy and it developed in this case without any associated decrease in the peripheral blood leukocyte count.

This study was performed to assess the prognostic factors and the predictors of long-term (3-year) survival in patients with small cell carcinoma of the lung, accrued in one randomized trial, and to define patient subgroups showing significantly different survivals using recursive partitioning and amalgamation analysis. A total of 300 patients with small cell carcinoma of the lung were entered into a randomized study comparing cyclophos- phamide, adriamycin and vincristine (CAV), cisplatin and etoposide (PE) and alternating treatments of CAV and PE. Of these, 286 patients were analysed for the present study of prognostic factors. Multivariate analysis showed that poor performance status (2-3) (P = 0.0001), extensive disease (P = 0.0015) and abnormally elevated serum lactate dehydrogenase (P = 0.0001) and alkaline phosphatase (P = 0.0013) were independently adverse pretreatment prognostic factors. Of limited disease patients, performance status (P = 0.029) and white blood cell count (P = 0.044) had a significant influence on the probability of 3-year disease-free survival. Using recursive partitioning and amalgamation analysis, three classes of similar prognosis were identified: the most favorable class was defined by knowledge of lactate dehydrogenase (normal), performance status (0-1) and serum sodium levels (normal) with median survival time of 16.0 months, and the class with the poorest prognosis was defined by knowledge of lactate dehydrogenase (elevated) and performance status (2-3) (median survival time 6.6 months). The intermediate class had a median survival time of 9.4 months. In conclusion, this subclassification system will be used for the design, implementation and interpretation of clinical studies as well as decision-making in individual patients.

A study was conducted to evaluate the impact of cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) with granulocyte colony-stimulating factor (G-CSF) on advanced thymoma or thymic cancer. Between August 1989 and December 1994, 14 patients with invasive, metastatic or recurrent thymoma or thymic cancer were treated with cisplatin (80 mg/m2, on day 1), doxorubicin (45 mg/m2, on day 1), cyclophosphamide (800 mg/m2, on day 1) and etoposide (80 mg/m2, on day 1-3) with G-CSF (90 micrograms/m2, on day 5-18) at the National Cancer Center Hospital, Tokyo. Courses were repeated every 3 or 4 weeks for a maximum of 4 cycles. Twelve patients were treated with 2 or more courses of PACE. Two patients were treated with only one course, one refused and another required emergency thoracic radiotherapy after one course of PACE. Six patients had partial responses (3 thymomas and 3 thymic cancers) but there were no complete remissions (response rates, 42.9%; 95% confidence interval, 17.7% to 71.1%). Moderate hematological toxicities were observed: grade 3 or 4 leukopenia, neutropenia, anemia and thrombocytopenia in 10, 13, 8 and 6 patients, respectively. Six patients developed infections that required antibiotics. Surgical resection or thoracic radiotherapy after PACE treatment was performed in 2 and 7 patients, respectively. The overall median survival time was 14.7 months (range, 5.9 to 59.7 months). For 9 patients who had received no prior treatment before chemotherapy, the median survival time was 8.9 months, and one patient survived for 4 years and is still alive. In conclusion, PACE with G-CSF frequently produces objective remissions in patients with advanced thymoma or thymic cancer. A large-scale intergroup study is necessary to determine the impact of this regimen on advanced thymoma and thymic cancer.

A recent approach in the treatment of limited-stage small cell lung cancer (LDSCLC) has involved a combined modality of chemotherapy and chest irradiation. In using the modality, the study of scheduling methods for combining chemotherapy and radiotherapy should lead to other trials of combined modalities against LDSCLC since it is the most basic issue to be evaluated. We have thus conducted a multicenter phase II trial of concurrent cisplatin-etoposide (PVP) chemotherapy and radiotherapy for LDSCLC to determine the effects of the concurrent administration of a PVP regimen and chest irradiation on response rate, relapse, survival and treatment toxicity. The chemotherapy regimen consisted of a four-week cycle: cisplatin (80 mg/m2, given intravenously on day 1) and etoposide (100 mg/m2, given intravenously on days 1-3). This cycle was given four to six times within six months. Chest irradiation to the primary tumors at both the hili and the mediastinum was administered in standard fractions on days 2-12 in the first cycle of chemotherapy and on days 29-47 in the second cycle, with a total dose of 40-50 Gy. Prophylactic cranial irradiation was performed among complete remission (CR) or good partial remission (PR) patients after completion of the concurrent therapy. A total of 66 patients were entered into the trial and 59 were evaluated. The concurrent therapy induced an overall response rate of 94.9% in 59 patients: 24 patients, 40.7% CR, 32 patients, 54.2% PR. The median response duration was 8.7 months, and the median survival time for all eligible patients was 14.8 months. The percentage of patients with two-year survival periods was 20. A local relapse within the irradiated area was seen in only 22% of relapse patients. Brain metastases occurred in 24% of patients. Four of 32 patients treated with prophylactic cranial irradiation had brain metastases. Toxic effects, chiefly grades 3 and 4 leukopenia, as established by the World Health Organization, were detected in all treated patients. Other toxicities, including radiation-induced esophagitis and pneumonitis, were deemed almost acceptable. We concluded concurrent treatment of a PVP regimen with chest irradiation to be a feasible and beneficial therapy with an efficacy compatible to that of other published reports. The outcome of this protocol warrants further investigation to determine the optimal type of schedule for concurrent chemoradiotherapy against LDSCLC.

JCOG (Japan Clinical Oncology Group) was started in 1990 and is the only governmental clinical trial group in Japan. The ultimate purpose of JCOG is to establish gold standard therapies for each tumor type based on scientifically and ethically scheduled investigator-initiated clinical trials. JCOG is composed of various committees for auditing and management, a data center and clinical study groups. The steering committee meeting is held four times a year and decides the missions, principles and policies of JCOG, the exchange of JCOG members and the approval of practical protocols for clinical trials. JCOG has 15 study groups and about 170 member institutions and hospitals. The number of nominated institutions is limited to keep high quality of JCOG. Inactive institutions have been replaced with other institutions by the steering committee. The number of patients accrued for each clinical trial is influenced by the number of active protocols in each trial group. Some groups are very active, while others have not yet completed any trials. JCOG conducts only investigator-initiated trials and so far has not been involved in any IND (Investigational New Drug) trials. Because JCOG does not receive any funding from pharmaceutical companies, the data are not biased by conflicts of interest. Since 1978, JCOG has conducted 216 clinical trials, the majority of which were Phase III trials. The results have been presented at regional and international scientific meetings and have been reported in mainly English language journals as original articles. Some have been published in journals with high impact factors, such as the New England Journal of Medicine, the Journal of the National Cancer Institute, and the Journal of Clinical Oncology. In addition to the evaluation of new anticancer drugs, radiation therapy and new surgical procedures have also been tested in randomized controlled trials. Extremely important data have been published by surgical groups. Some clinical trials have produced positive results, but others did not achieve their primary endpoints. In addition, the accrual of patients was sometimes so poor that the clinical trial had to be interrupted. In a few studies, an independent data monitoring committee suggested that patient accrual be stopped because of the high incidence of severe toxicity arising from treatment and unexpected negative or inverse results. Recently, the publication of such data has become extremely difficult because of the rapid increase in articles that are being submitted to popular journals. The editors of such journals have suggested that the rejection rate should be as high as 80–90% and that ‘Me too-type’ articles with no significant data and single-arm Phase II studies of standard therapy should be rejected because the cost of publication is becoming too high and too many articles are waiting for publication. As a result of this situation, data concerning negative results or interrupted clinical trials are often difficult to publish. Nevertheless, such information is very important to young active investigators who are developing new protocols for clinical trials. JCOG has a policy that the outcome of a clinical trial should be published in English once it has been approved by the protocol review committee. The Japanese Journal of Clinical Oncology has agreed to publish review articles for each clinical trial group, enabling ‘hidden data’ to become available. Consequently, the chairman of each group in JCOG has been asked to write a review article on their study group. In each review, the author has included all the clinical trials within their group that have been approved by the protocol review committee of JCOG. Readers should be able to recognize the development/refinement of each study group and understand the reasons for negative results and low patient accruals as well as the unexpected early termination of studies. Readers will also be able to understand the success rate of clinical trials. To complete each clinical trial, numerous specialists must join and collaborate with one other. Therefore, clinical trials with negative results and with low accruals should be avoided as much as possible. This series will provide important information regarding the writing of proper clinical protocols for clinical trials. The first review is written by Dr Takashi Onda, Gynecologic Oncology Division of National Cancer Center, on behalf of the chairman of the gynecological group. The group has published four articles reporting the results of the JCOG9412, 0206, 0602 and 0505 trials in the Int J Gynecol Cancer, Gynecol Oncol, Jpn J Clin Oncol and Jpn J Clin Oncol, respectively. Additionally, JCOG0102 and 0503 are introduced in the review article.

We performed a phase I trial to evaluate the toxicity and the maximum tolerated dose of high dose epirubicin on a three-consecutive-day schedule on Japanese patients with advanced non-small cell lung cancer. Fourteen patients were entered in the study. At least three patients were assigned to each different dose level. Epirubicin was given intravenously daily for three day by bolus injection. The dose was started at 60 mg/m2/course and escalated by 30 mg/m2/course. Granulocytopenia was found to be the dose limiting toxicity with a maximum tolerated dose of 150 mg/m2/course. Thrombocytopenia and non-hematological toxicities were mild and well tolerated. The maximum tolerated dose was lower than that in Europe and Canada. Partial responses were observed in two out of five patients on 150 mg/m2/course. The recommended phase II dose for high dose epirubicin was demonstrated to be 120 mg/m2/course. A further dose-escalating study of epirubicin in conjunction with the administration of granulocyte colony stimulating factor is scheduled for the determination of its antitumor activity in non-small cell lung cancer.

CPT-11, a new camptothecin analogue, has been demonstrated to be a promising antineoplastic agent. Late side effects of carcinogenicity and teratogenicity have been unclear from clinical phase I and II trials. In order to elucidate the carcinogenicity and teratogenicity of CPT-11, we have examined the cytogenetic changes in human peripheral blood lymphocytes induced by CPT-11 and its active metabolite, SM-38. We have also analyzed the correlation between chromosomal damage and acute clinical side effects. When peripheral blood lymphocytes obtained from a healthy donor were exposed to CPT-11, SN-38, cisplatin and mitomycin C, a significant dose-dependent increase of sister chromatid exchange (SCE) was obtained. The SCE frequency per cell cultured with 0.244 nM SN-38 was similar to that cultured with 100 nM CPT-11, 300-500 times the concentration of SN-38. A transient increase in SCE frequency was also observed in the peripheral blood lymphocytes of 11 cancer patients receiving 100 mg/m2 of CPT-11 intravenously, compared with pretreatment values (P = 0.0001). In addition, a significant correlation was observed between the frequency of SCE on day 3 and the degree of decrease in platelet count (P = 0.012). In conclusion, SN-38 might possibly have a high risk of mutagenicity and carcinogenicity; and measurement of SCE values in peripheral blood lymphocytes appears to have a potential application in the clinical prediction of chemotherapy-induced side effects.

A 58-year-old man developed an acquired factor VIII inhibitor in association with adenocarcinoma of the lung. Laboratory examinations showed a marked prolonged activated partial thromboplastin time and a low level of factor VIII activity. Further study revealed his serum to have a factor VIII inhibitor which was characterized as an IgG. Treatment with prednisolone was successful in reducing the inhibitor so that the bleeding manifested by epistaxis and subcutaneous hemorrhages in the extremities ceased. Circulating inhibitors against factor VIII associated with malignancies appear to be very rare. Fourteen patients with factor VIII inhibitors associated with malignancies were reviewed.

The relation between degree of myelosuppression and episodes of infection was analyzed in 36 patients (92 treatment courses) with small cell lung cancer (SCLC) treated with intensive chemotherapy. The two regimens used were cisplatin (CDDP) + adriamycin (ADR) + cyclophosphamide (CPA) + etoposide (VP-16) + granulocyte-colony stimulating factor (G-CSF) and CDDP + teniposide (VM-26) + G-CSF, and they induced grade 3 or 4 leukopenia in 88% of treatment courses and febrile episodes in 60%. In the febrile courses, the mean nadirs of leukocyte and neutrophils (820 +/- 581/mm3, 101 +/- 267/mm3) were significantly longer (P less than 0.01) and the mean durations of grade 3 and 4 leukopenia and neutropenia significantly longer (P less than 0.001) than those of the non-febrile courses. It was noted, however, that febrile episodes appeared frequently in courses having the nadir of leukocytes below 1,000/mm3 (80%) or the nadir of neutrophils below 100/mm3 (74%). The administration of antibiotics was required for about 7 days to patients with febrile episodes. Sepsis was experienced in five courses, in which the neutrophils were all zero. All the patients, however, could be managed by an administration of antibiotics immediately after a febrile episode appeared, without delaying the subsequent chemotherapy except for one patient, who had had a performance status (PS) of 3 prior to chemotherapy.

Among 238 patients with advanced inoperable non-small cell lung cancer (NSCLC), we evaluated the characteristics of three-year survivors and analyzed them to determine whether or not there were any specific pretreatment prognostic factors which could make it possible to discriminate this group the rest. All patients received chemotherapy according to the protocol for phase II or III trials at the National Cancer Center, Japan, between 1980 and 1987. Eighteen (8%) patients survived for over three years. Five of the 18 responded to initial therapy, seven received thoracic irradiation and five surgical resection after chemotherapy. No patient achieved a complete response by chemotherapy. Among five disease-free survivors, two received surgery after completion of chemotherapy. Their clinical stage was IIIA. Three patients received radiation therapy, but they could not be evaluated. Although some radiologically detectable shadows remained, these patients survived for more than three years with no active lesion, indicating the difficulty in diagnosing a complete response to treatment. Thirteen patients survived for more than three years with disease. Some unknown biological factors might influence survival in this group. Pulmonary fibrosis, as treatment toxicity, was observed in six of the 18. The pretreatment prognostic factors that discriminated three-year survivors from the rest were Eastern Cooperative Oncology Group performance status (PS) (P = 0.0015), clinical T factor (P = 0.0093), and serum LDH (P = 0.0317) by means of univariate analysis, and PS (P = 0.0134) and clinical T factor (P = 0.0117) by means of multivariate analysis with a logistic regression procedure.

From 1984 to 1989, 20 of 142 patients with small cell carcinoma of the lung received surgery after intensive chemotherapy alone or chemotherapy combined with thoracic irradiation. All patients giving informed consent and having an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 were included in the present retrospective study. Ages ranged from 37-74 (median 58) years. All patients received 1-10 cycles of chemotherapy intravenously every three or four weeks (PVP: 80 mg cisplatin/m2, 100 mg etoposide/m2 x 3; CAV: 800 mg cyclophosphamide/m2, 50 mg doxorubicin/m2, 1.4 mg vincristine/m2, and other combinations) and were evaluated for surgery 1-27 months after the initial systemic chemotherapy. Clinically, two, three, eleven and for patients were diagnosed as having stages I, II, III and IV disease, respectively at the beginning of treatment. At the time of reevaluation after chemotherapy or chemotherapy plus chest radiotherapy there were one (5%) complete responder, 17 (85%) partial responders, and two (10%) with stable disease. Twenty patients underwent thoracotomy consisting of nine lobectomies and 11 pneumonectomies. Eighteen of the 20 had resectable lesions. According to postoperative pathological findings, there were six, one, seven and two patients with stages I, II, III and IV disease, respectively. In two patients no tumor was demonstrated pathologically. Small cell carcinoma was detected in 15 specimens and three had non-small cell carcinoma. Two of the 20 patients survived for more than five years. The median survival of the 20 patients was 22 months. It would appear that resection is applicable in only a selected subset of patients with small cell carcinoma of the lung.

Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater than or equal to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.

A 68-year-old man was admitted to the National Cancer Center Hospital on November 10, 1988 to undergo chemotherapy for recurrent lung cancer, which had been resected on June 22, 1988. The tumor was diagnosed histologically as large cell carcinoma with trophoblastic differentiation, and human chorionic gonadotropin (HCG) was immunohistochemically found in tumor cells. Chemotherapy was initiated on November 14, 1988. The patient received three courses of methotrexate, actinomycin D and cyclophosphamide (MAC); and two courses of cisplatin and etoposide (PVP). Following this therapy, partial response was achieved, however, the tumor soon progressed and the serum HCG level increased to 7,571 mIU/ml. The patient was consequently given four courses of cisplatin, adriamycin, cyclophosphamide and etoposide (PACE) up to September 13, 1989, and received 52 Gy irradiation to the chest from July 20 to August 24. The tumor regressed markedly and the serum HCG decreased to within normal limits. The changes in serum HCG levels in serial samples correlated well with the clinical tumor burden. The patient is now in partial remission having survived for more than 15 months after the initiation of chemotherapy.