Yushi Nakai

S-1 Plus Cisplatin Combination Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer A Multi-Institutional Phase II Trial

Purpose: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non–small-cell lung cancer (NSCLC) patients. Experimental Design: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m2 twice a day for 21 consecutive days while cisplatin (60 mg/m2) was administered intravenously on day 8. This schedule was repeated every 5 weeks. Results: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1–12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34–61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%). Conclusions: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.

High Level of Vascular Endothelial Growth Factor in Hemorrhagic Pleural Effusion of Cancer

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.

A phase II trial of oral UFT plus cisplatin (CDDP) in patients with non-small cell lung cancer (NSCLC)

Based on the results of our previous pilot study, we conducted a multi-institutional phase II study of combination chemotherapy consisting of oral UFT (Taiho Pharmaceutical Co. Ltd, Tokyo) plus cisplatin (CDDP) in patients with advanced non-small cell lung cancer (NSCLC). UFT capsule containing 100 mg tegafur and 224 mg uracil was orally administered in two divided doses on days 1 through 21 making the total tegafur dose 400 mg/m(2)/day (maximum 600 mg/body). CDDP was administered by drip infusion at a dose of 20 mg/m(2) on a 5-day schedule from day 8 to 12. Treatment was repeated every 4 weeks as long as the criteria for initiation of therapy were still met. Between April 1995 and March 1997, 51 patients were entered into the study. The mean age of all 50 eligible patients was 64 years(range: 40-78). There were 21 patients with clinical stage IIIB disease and 29 patients with IV disease. Thirty-two patients had adenocarcinoma, 14 had epidermoid carcinoma, and four had large cell carcinoma. Of the 47 assessable patients, 18 achieved a partial response with an overall response rate of 38.3% (95% confidence interval: 24.4-52.2%). The median response duration was 113 days. The median survival time of the eligible patients was 12.8 months, and the 1-year survival rate was 54%. Among the 51 patients enrolled, grade 3 or 4 leukopenia developed in one patient (2%), neutropenia in six patients (11. 8%), thrombocytopenia in six patients (11. 8%), and anemia in three patients (5. 9%). Non-hematological grade 3 or 4 toxicities included anorexia in 10 patients (19.6%), nausea in ten (19.6%), vomiting in two (3.9%), and diarrhea in two (3. 9%). Grade 3 abnormal laboratory data included bilirubinemia in four (7. 8%), GPT elevation in one (2.0%), and hematuria in one (2.0%). In conclusion, combination of CDDP plus oral UFT is efficacious, with low toxicity, in the treatment of advanced NSCLC. In particular, the low hematological toxicity may warrant application of this regimen to the treatment of elderly patients and in trials of concurrent chemoradiotherapy in patients with locally advanced NSCLC.

Uracil/Tegafur Plus Cisplatin with Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer: A Multi-institutional Phase II Trial

Purpose: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT, which is comprised of uracil and tegafur, in locally advanced non-small cell lung cancer (NSCLC) patients. Experimental Design: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400 mg/m2/d tegafur) on days 1–14 and days 29–42 whereas 80 mg/m2 cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions from day 1. Results: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients, and the overall response rate was 81% (95% confidence interval; 70–89%). The median survival, the 1- and 2-year survival rates were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed. Conclusions: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.

Pilot study of UFT combined with 5 consecutive days cisplatin in non-small cell lung cancer

Combined use of 5-fluorouracil (5-FU) and cisplatin has proven to have synergistic effects in many experimental systems and clinical studies. UFT, an oral preparation of uracil and tegafur in a 4:1 molar ratio, was reported to have enhanced activity as compared with 5-FU or tegafur alone against various human tumors. Based on those results, we conducted a pilot study to confirm the feasibility and antitumor effect of UFT in combination with cisplatin in patients with advanced non-small cell lung cancer (NSCLC). UFT was orally administered at a dose of 400 mg/m2 according to a protocol for step-wise prolongation of the administration period, such as days 1-14 in step I, days 1-21 in step II, days 1-28 in step III. During to course, cisplatin was administered at a fixed dose of 20 mg/m2/day on days 8 through 12. The course was repeated every 4 weeks. Numbers of patients enrolled in steps I, II, III were six, ten and six (a total of 22), respectively. There were three females and 19 males, PS scored 0/1/2 = 7/14/1, stage IIIA/IIIB/IV = 3/8/11. Adenocarcinoma/squamous cell carcinoma/large cell carcinoma = 11/7/4, and median age 68 (range 52-79). All 22 patients were evaluable for toxicity, and 21 for efficacy. Compliance of UFT declined as the administration period of UFT was prolonged. In step I, one patient had grade 3 toxicity of each neutropenia, thrombocytopenia, nausea/vomiting and diarrhea. In step II, grade 3, 4 neutropenia was seen in four patients, grade 3 thrombocytopenia and anorexia in one patient, and grade 3 nausea/vomiting in four patients. In step III, there was grade 3 neutropenia in two patients and grade 3 anorexia in one patient. All other toxicities were mild. The overall response rate was 38% (one CR and 7 PR, 95% C.I.: 21-59%). Combination therapy with oral UFT and 5-day infusion of cisplatin is feasible with substantial antitumor effect against advanced NSCLC. Since UFT compliance decreased in step III (no patient in step III received > 2 courses of treatment), we considered the step II schedule to be worth for further evaluation in a combination phase II study.

Changes in Serum Erythropoietin Levels during Chemotherapy for Lung Cancer

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.

PRELIMINARY PHASE I STUDY OF BESTATIN IN LUNG CANCER CASES

Publisher Summary This chapter describes the preliminary phase I study of bestatin in lung cancer cases. A pilot study was carried out in 13 cases of lung cancer including one malignant lymphoma. The daily administration of bestatin at a 30-mg dose caused no appreciable side effect in any one of these cases, including a 22- and a 23-week-period of medication. Peak values of T-lymphocyte population were observable around 1 to 3 days post-bestatin, while in a case, a gradual increase up to day 8 was observed. Bestatin in one case exceptionally decreased an originally higher T-cell level of Case IV. The B-lymphocyte level increased instead in Case IV and decreased in Case II, while it also increased in Case I and stayed unchanged in Case III. On the other hand, however, total lymphocyte counts showed no substantial change because of bestatin. The results suggest that bestatin stimulates the surface event involved in E-rosette formation of the T-lymphocyte subpopulation.