Seiji Nagashima

Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer.

Introduction: We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC). Methods: Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status ≤3, age ≤ 80 years, and stages IIIB–IV cancer. Epidermal growth factor receptor mutations in 23 patients were analyzed retrospectively. Results: The median plasma gefitinib values were 662 ng/ml on D3 and 1064 ng/ml on D8, and the D8/D3 ratio was 1.587. The median progression-free survival (PFS) was 71 days, and the median overall survival was 224 days. Adenocarcinoma, never smoking, and high D8/D3 ratio were associated with better PFS. Multivariate analysis showed that PFS was associated with never smoking and high D8/D3 ratio. Never-smokers with a high D8/D3 ratio showed the best PFS. Overall survival was not associated with the D8/D3 ratio. Epidermal growth factor receptor mutation analysis of 23 patients showed that 15 patients had exon 19 deletion and/or exon 21 point mutation. Median PFS was similar between mutation-positive and mutation-negative individuals in the high D8/D3 group, whereas mutation-negative individuals in the low D8/D3 group showed the worst median PFS. Conclusions: A high D8/D3 ratio was independently associated with better PFS in patients with NSCLC treated with gefitinib. Our findings suggest that the pharmacokinetics of gefitinib may be involved in its antitumor activity.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer.

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer (LD-SCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Four chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated every 28 days. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle with 20 Gy administered from the first to the third cycles (a total of 60 Gy). 17 patients were enrolled at three dose levels (CPT-11/cisplatin: 40/60, 50/60 and 60/60 mg/m(2)), and 16 were evaluable for toxicity and outcome. 2 of 4 patients at 60/60 mg/m(2) refused continuation of therapy because of general fatigue, and the relative dose intensity of CPT-11 at 50/60 mg/m(2) was approximately 50%. These levels were considered as the MTD. Tumour responses included four complete responses (CR), 11 partial responses (PR) and one no change (NC), and the overall response rate was 93.8% (95% confidence interval: (CI) 71.7-98.9%). This combined modality is tolerable, and CPT-11/cisplatin of 40/60 mg/m(2) in this modality is recommended for phase II study.

Catheter Drainage Followed by the Instillation of Bleomycin to Manage Malignant Pericardial Effusion in Non-small Cell Lung Cancer: A Multi-Institutional Phase II Trial

Introduction: Malignant pericardial effusion (MPE) causes cardiac tamponade and an extremely poor outcome unless it is well controlled. The effect of pericardial drainage and the intra-pericardial instillation of bleomycin on the control of MPE was examined in this prospective multi-institutional phase II trial. Methods: In eligible patients with cytologically defined MPE resulting from non-small cell lung cancer, the pericardial effusion of such cases was continuously drained. After complete drainage, 10 mg of bleomycin was then locally instilled via a catheter. The catheter was then removed if the total amount of drainage was less than 30 ml/day. If the catheter could not be removed within 5 days after treatment, bleomycin was administered one more time. Results: Among the 22 patients who entered this trial, the tube drainage catheter was successfully removed from 17 patients with one instillation, whereas four required such instillation twice and one required such instillation three times. No severe adverse events were observed, except for constrictive pericarditis, which resulted in the treatment-related death of one patient. The control rate of pericardial effusion was 95% ± 0.09 (95% confidence interval). No restoration of pericardial effusion was observed during the follow-up period or until death from any cause. Median survival time from the beginning of the protocol was 17.9 weeks. Conclusions: Pericardial drainage followed by the instillation of bleomycin was found to be a safe and effective method for the management of MPE associated with non-small cell lung cancer.

Randomized Phase II Trial of Irinotecan with Paclitaxel or Gemcitabine for Non-small Cell Lung Cancer Association of UGT1A1*6 and UGT1A1*27 with Severe Neutropenia

Hypothesis: Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC. Patients and Methods: Previously untreated patients with adequate organ function who gave written informed consent were randomly assigned to receive irinotecan (50 mg/m2 on days 1, 8, and 15) plus paclitaxel (180 mg/m2 on day 1) every 4 weeks (IP group) or irinotecan (100 mg/m2 on days 1 and 8) plus gemcitabine (1000 mg/m2 on days 1 and 8) every 3 weeks (IG group). The primary endpoint was the response rate. We also evaluated the relationship of response and toxicity to polymorphisms of the uridine diphosphate glucuronosyltransferase (UGT) gene. Results: Eighty patients were enrolled, and 78 patients were eligible (38 in the IP group and 40 in the IG group). The response rate was 31.6% (95% confidence interval: 17.5–48.7%) in the IP group and 20.0% (9.1–35.6%) in the IG group. The median progression-free survival time was 86 days and 145 days, respectively. Both regimens were well tolerated. The most common severe adverse event was grade 4 neutropenia (36.8% and 10.0%, respectively), which was associated with UGT1A1*6 and UGT1A1*27. UGT polymorphisms did not correlate with response. Conclusions: Irinotecan plus paclitaxel may be more active against NSCLC than irinotecan plus gemcitabine. The UGT1A1*6 and UGT1A1*27 genotypes might be useful predictors of grade 4 neutropenia in patients who receive irinotecan-based chemotherapy.

Length and Lead Time Biases in Radiologic Screening for Lung Cancer

Objective: Our goal was to investigate whether the length and lead-time biases of radiologic screening for lung cancers vary according to the histologic type of the tumor. Methods: We analyzed the survival rates and radiographs of 119 cases of adenocarcinomas-large-cell carcinomas (ALC) and 50 peripheral squamous cell carcinomas (PSQ) detected in 205,401 screened individuals. Results: The sensitivity of screening and 5-year survival rates were 84.0% and 48.2% for ALC, and 52.0% and 18.5% for PSQ, respectively. The corrected length bias was 4.3% for ALC and 4.6% for PSQ. Stage III-IV ALC was often identified on 1-year-old films, but stage III-IV PSQ was not. Half of stage I ALC presented 2 or more years before detection, while half of stage I PSQ appeared within 1 year before detection. The survival rate of nonresected cases with stage I ALC was decreased 4 years after detection, while that of nonresected cases with stage I PSQ was decreased just after detection. The period of stage I ALC and PSQ was at least 6 years and 1 year, respectively. Conclusions: Slowly growing ALC had high sensitivity in radiologic screening and a high rate in 5-year survival, but had long lead time and delay in detection. PSQ grew rapidly resulting in low sensitivity in radiologic screening, and short lead time and survival. In both types, the magnitude of corrected length bias was not remarkable. The survival of ALC should be carefully evaluated because of the long lead time.

Irinotecan and cisplatin with concurrent split-course radiotherapy in locally advanced nonsmall-cell lung cancer : A multiinstitutional phase 2 study

The purpose was to determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split‐course thoracic radiotherapy (TRT) in locally advanced nonsmall‐cell lung cancer.

Interstitial pneumonia probably associated with sorafenib treatment: An alert of an adverse event

There has been no literature which reports a case of interstitial lung disease associated with sorafenib. However, a recent post-marketing survey in Japan revealed that interstitial pneumonia occurred in 4 among approximately 2 000 Japanese patients treated with sorafenib. In this article, we describe a Japanese patient with severe interstitial pneumonia probably caused by sorafenib treatment for metastatic renal cell carcinoma. Oncologists supervising future clinical trials for lung cancer should be alert to the fact that sorafenib can potentially induce serious interstitial lung disease, although this might depend on racial differences.

Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer.

We conducted a phase I study of paclitaxel and irinotecan (CPT-11) in advanced non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated doses (MTD). The pharmacokinetics of CPT-11 and its major active metabolite, SN-38, were also analysed. Patients received paclitaxel (day 1) followed by CPT-11 (days 1, 8 and 15), in a 4-week cycle, and paclitaxel and CPT-11 were escalated from 120 and 40 mg/m(2), respectively. 28 patients were enrolled, who were evaluated for toxicity. 2 of 6 patients at 210 mg/m(2) paclitaxel and 50 mg/m(2) CPT-11, and 2 of 4 at 180 and 60 mg/m(2) developed dose-limiting toxicity (DLT) (neutropenia, fever, neurotoxicity and diarrhoea). The area under the plasma concentration-time curve (AUC) of CPT-11 on day 1 was significantly higher than that on days 8 or 15 at each dose level (P=0.002). The AUC of SN-38 on day 1 was significantly increased using paclitaxel doses >or=150 mg/m(2). A preceding paclitaxel administration changed the pharmacokinetics of CPT-11 and SN-38. However, the toxicity was tolerable. Paclitaxel 180 mg/m(2) and CPT-11 50 mg/m(2) were the recommended doses for further phase II study of this combination.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in unresectable and locally advanced non-small cell lung cancer

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in locally advanced stage III non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Two chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated with a 28-day interval. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 24 Gy and 36 Gy administered for the first and second cycle, respectively. 24 eligible patients were enrolled at five dose levels (CPT-11/cisplatin: 40/60, 50/60, 60/60, 60/70 and 60/80 mg/m(2)), and 23 patients were evaluated for toxicity and clinical outcome. Only 1 patient experienced a DLT with neutropenia and diarrhoea at 60/60 mg/m(2). Dose escalation was limited to 60/80 mg/m(2) which was the recommended dose for CPT-11/cisplatin alone in NSCLC. Tumour responses included one complete response (CR), 15 partial response (PR), and 7 no change (NC), and the overall response rate was 69.6% (95% confidence interval (CI) 47.1-86.8%). This combined modality is tolerable, and CPT-11/cisplatin of 60/80 mg/m(2) in this modality is recommended for phase II study.

A Phase I Study of Amrubicin and Carboplatin for Previously Untreated Patients with Extensive-Disease Small Cell Lung Cancer

Background: Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established. Purpose: To determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC. Patients and methods: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0–1, age ≤75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m2, and the dose was escalated to 35 and 40 mg/m2. Results: Sixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m2 and AUC 5. A dose of 35 mg/m2 amrubicin and carboplatin AUC 5 was recommended in this regimen. Conclusions: This regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting.