Haruyuki Kawai

Comparison of the Incidence and Pattern of Interstitial Lung Disease During Erlotinib and Gefitinib Treatment in Japanese Patients with Non-small Cell Lung Cancer: The Okayama Lung Cancer Study Group Experience

Background: Data comparing the incidence and pattern of interstitial lung disease (ILD) in non-small cell lung cancer patients receiving treatment with gefitinib versus erlotinib, both of which are epidermal growth factor receptor tyrosine kinase inhibitors, are scarce. We investigated the incidence of ILD in Japanese patients treated with gefitinib or erlotinib. Methods: We reviewed the clinical records of 209 patients treated with erlotinib in 2008 (cohort A) and 330 treated with gefitinib between 2000 and 2003 (cohort B). Toxicity within the first month of treatment was investigated. Results: The patients in cohort A had fewer known risk factors for ILD (e.g., poor performance status and prior pulmonary fibrosis). ILD was detected in two patients (1.0%) from cohort A and eight patients (2.4%) from cohort B during the first month of treatment. The events were graded as follows: one patient each in grades 1 and 2 (cohort A), and one, one, and six patients in grades 3, 4, and 5, respectively (cohort B). Multivariate analysis revealed that poor performance status and prior pulmonary fibrosis were significantly correlated with the occurrence of ILD, but the type of epidermal growth factor receptor tyrosine kinase inhibitor administered was not. Conclusion: There was a somewhat lower incidence of ILD with erlotinib therapy than with gefitinib therapy, despite no statistically significant difference. Patient selection based on awareness by Japanese physicians of the risk factors for ILD, rather than the type of agent, may explain the difference in ILD incidence between the two treatments.

Characterization of non-small-cell lung cancer cell lines established before and after chemotherapy

We established several in vitro drug-resistant cell lines after continuous, long-term exposure of each drug to elucidate mechanisms of drug resistance. Whether drug resistance in these in vitro resistant cell lines reflects clinical drug resistance still remains unanswered. In this study, a pair of lung cancer cell lines was established from one patient with squamous cell carcinoma of the lung, with one line being established before and one line after combination chemotherapy (cisplatin/ifosfamide/vindesine). Combination chemotherapy selected resistant EBC-2/R cells, which showed cross-resistance to 4-hydroxyifosfamide (3.2-fold), cisplatin (2.3-fold), and methotrexate (3.7-fold) and collateral sensitivity to vindesine (0.77-fold) compared with parent EBC-2 cells. EBC-2/R cells showed decrease in intracellular accumulation of cisplatin, increase in intracellular concentration of glutathione (GSH), and overexpression of multidrug resistance-associated protein (MRP) 3 when compared with EBC-2 cells. A single cycle of chemotherapy was not sufficient to select other mechanisms of drug resistance, such as multidrug resistance-1/P-glycoprotein, MRPs 1, 2, 4, and 5, lung resistance-related protein, metallothionein IIa, glutathione S-transferase pi, gamma-glutamylcysteine synthetase (light and heavy chain), and excision repair cross complementing 1. Sequentially we established two cell lines, which cell lines showed the differences of the cisplatin resistance, expression level of MRP3, intracellular GSH level and intracellular accumulation of cisplatin. A pair of cell lines will be useful to elucidate resistant mechanisms of cisplatin in heterogeneous lung cancer cells.

A Randomized Phase II Study of a Combination of Docetaxel and S-1 versus Docetaxel Monotherapy in Patients with Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy: Results of Okayama Lung Cancer Study Group (OLCSG) Trial 0503

Background: The survival impact of single-agent treatment with docetaxel, the standard regimen for relapsed patients with non-small cell lung cancer (NSCLC), remains modest. We conducted a randomized phase II study to evaluate the efficacy and safety of the combination of docetaxel and S-1 in the second-line setting. Methods: Patients with relapse of NSCLC after first-line platinum-based chemotherapy were randomly assigned to docetaxel alone (60 mg/m2, day 1, q3 weeks; arm A) or a combination of docetaxel (40 mg/m2, day 1, q3 weeks) and S-1 (80 mg/m2, days 1-15; arm B). The primary end point was response rate, whereas secondary endpoints included overall survival, progression-free survival, and toxicity. Results: Between 2005 and 2008, a total of 60 patients were enrolled in the study. The objective response rates were 20.7% and 16.1% in arms A and B, respectively (p = 0.81). Progression-free survival was comparable in the two arms (median: 3.7 versus 3.4 months, p = 0.27), whereas overall survival time was longer in arm A (22.9 versus 8.7 months, p = 0.02). The major toxicity was myelosuppression with grade ≥3 neutropenia in 89.7% of patients versus 64.5% in arms A and B, respectively. Conclusions: This study suggests that docetaxel monotherapy should continue to be considered the standard for second-line chemotherapy against NSCLC.

Long-term effects of beta-blocker use on lung function in Japanese patients with chronic obstructive pulmonary disease

Background Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated. Patients and methods We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for >1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1) was assessed. Results At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0±8.2 years); 32 current smokers; and Global Initiative for Chronic Obstructive Lung disease (GOLD) stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC), FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8±1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (−7.6±93.5 mL/year vs −4.7±118.9 mL/year, P=0.671). After controlling for relevant confounders in multivariate analyses, it was found that beta-blocker use was not significantly associated with the annual decline in FEV1 (β=−0.019; 95% confidence interval: −0.073 to 0.036; P=0.503). Conclusion Long-term beta-blocker use in Japanese COPD patients might not affect the FEV1, one of the most important parameters of lung function in COPD patients.

Tumor-induced Hypercalcemia and Leukocytosis in Lung Cancer.

高カルシウム血症と白血球増多症は原発性肺癌において, どちらも比較的よく遭遇する腫瘍随伴症候群であり, 時に両者は併発する.今回我々は, 高カルシウム血症と白血球増多症の頻度, 予後との相関を検討するために, 1980年から1996年までに岡山大学第2内科に入院した原発性肺癌623例について検討した.初診時高カルシウム血症発現例は51例 (8.2%), 悪性腫瘍に伴う白血球増多症の発現例は6例 (1.0%) であった.また, 高カルシウム血症発現例の生存期間中央値 (MST) は4.4ヵ月, 白血球増多症発現例では2.9ヵ月であり, いずれも全肺癌症例 (MST;9.5ヵ月) また, 臨床病期IV期の肺癌症例 (MST;8.9ヵ月) に比べて, 有意に予後不良であった (p<0.01).高カルシウム血症と白血球増多症を併発していた2例の生存期間は, 1.0ヵ月, 1.5ヵ月と極めて短かった.これらの結果より, 肺癌における高カルシウム血症あるいは白血球増多症は予後不良因子である可能性が示唆された.

Treatment of Refractory Metastatic Choriocarcinoma with Tandem High-Dose Chemotherapy Supported by Peripheral Blood Stem Cell Transplantation: A Case Report

Currently, 70% to 80% of patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy, followed by surgical resection of the residual tumor. The prognosis, however, is uniformly poor for patients who fail to respond to induction chemotherapy. In this report, we describe a patient with retroperitoneal choriocarcinoma and multiple lung metastases, who was refractory to cisplatin-based chemotherapy, but who achieved a durable marker-negative partial response after 2 cycles of high-dose chemotherapy, supported by autologous, peripheral blood stem cell transplantation. The patient is now alive and well, without recurrence, more than 24 months after this therapy.