Kiyoyuki Furuse

Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Mitomycin, Vindesine, and Cisplatin in Unresectable Stage III Non–Small-Cell Lung Cancer

PURPOSE A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29, and 36), and mitomycin (8 mg/m(2) on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84. 0%) than that of the sequential arm (66%) (P =.0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P =.03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P =.0001). CONCLUSION In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.

Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. METHODS Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. RESULTS Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. CONCLUSION Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group

PURPOSE A phase II study was conducted between June 1989 and February 1992 to evaluate the activity and toxicity of photodynamic therapy (PDT) with photofrin II in centrally located early-stage lung cancer and to determine the complete response (CR) rate as the primary end point. PATIENTS AND METHODS Patients had histologically proven lung cancer and endoscopically superficial thickening or small protrusions. All lesions were located in subsegmental or larger bronchi. All patients had a performance status (PS) of 0 to 2 and arterial oxygen pressure tension (PaO2) > or = 60 mm Hg. No lymph node or distant metastases were present. All patients received photofrin II (2 mg/kg) intravenously 48 hours before PDT. Tumor lesions were superficially photoradiated by an argon dye laser or an excimer dye laser. RESULTS Of 54 patients with 64 carcinomas, 51 with 61 carcinomas were eligible for toxicity evaluation and 49 with 59 carcinomas were assessable for response. Of the 59 assessable carcinomas, 50 (84.8%; 95% confidence interval, 73.0% to 92.8%) showed a CR after initial PDT. The median duration of CR was 14.0+ months (range, 2.0+ to 32.4+). The multiple regression model indicates that estimated length of longitudinal tumor extent was the only independent prognostic factor for CR (P = .002). Five carcinomas that had a CR had a local recurrence at 6, 10, 12, 16, and 18 months after initial PDT, respectively. Toxicity assessment (World Health Organization [WHO] grade 2) showed transient elevation of ALT (1.9%), pulmonary toxicity (7.7%), and allergic reaction (7.7%), as well as sunburn (1.9%). CONCLUSION PDT with photofrin II has an excellent effect on patients with centrally located early-stage lung cancer who have limited tumor invasion extending over a small area (< or = 1 cm).

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naïve patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P=0.0008) and progression-free survival (P=0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm(-3) (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (4500 mm(-3), n=204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (4500 mm(-3), n=184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.

Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m–2day–1: BSA < 1.25 m2, 40 mg b.i.d.; BSA≥1.25 but <1.5 m2; 50 mg b.i.d., and BSA≥1.5 m2: 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3–34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1–13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7–14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted.

Non-Hodgkin's lymphoma of the pleural cavity developing from long-standing pyothorax

Malignant lymphomas developing in tissue affected by a long‐standing severe inflammatory process of nonautoimmune nature are presented. Two men and a woman aged 50, 58, and 73 years, were admitted after 22 to 30 year histories of pyothorax resulting from artificial pneumothorax for the treatment of pulmonary tuberculosis or tuberculous pleuritis. The diagnoses at admission were chronic pyothorax associated with a lung mass. Microscopically, tumors diffusely or locally proliferated with thickened pleura were present. A histologic examination showed that all the tumors were diffuse non‐Hodgkins lymphomas (NHL) of immunoblastic type with (one case) or without (two cases) plasmacytoid differentiation. Immunohistochemistry on paraffin sections revealed restricted expression of immunoglobulin light chains in one case showing plasmacytoid differentiation. A review of the literature showed that malignant lymphomas of this type have been reported exclusively from Japan but never from Western countries.

Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group.

PURPOSE Irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC) as monotherapy. Cisplatin is also a key drug against SCLC. We conducted a phase II study of CPT-11 combined with cisplatin to evaluate the efficacy and toxicity of this regimen in patients with previously untreated SCLC. PATIENTS AND METHODS Seventy-five patients with previously untreated SCLC were enrolled onto the study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1 every 28 days. Four courses of chemotherapy followed by thoracic irradiation were given to patients with limited disease (LD) and six courses to patients with extensive disease (ED). RESULTS The overall response rate was 84%, with a complete response (CR) rate of 29%. Forty patients with LD achieved an overall response rate of 83% and a CR rate of 30% and 35 patients with ED achieved an overall response rate of 86% and a CR rate of 29%. The median response duration was 8.0 months for LD patients and 6.6 months for ED patients. The median survival was 14.3 months for LD patients and 13.0 months for ED patients. The major grade 3 or 4 toxicities were neutropenia (77%), leukopenia (45%), diarrhea (19%), and anemia (39%). Two patients died with concomitant neutropenia and diarrhea. CONCLUSION This is a new active regimen for SCLC, especially ED-SCLC, with acceptable toxicity. A phase III study that compares CPT-11/cisplatin with etoposide/cisplatin for ED-SCLC is now being conducted.

Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics

PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.

Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer.

PURPOSE For patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC), radiotherapy (RT) has been used conventionally for many years. Few prospective trials have determined the role of RT. Recently, chemotherapy (CT) has been shown to produce excellent responses in regionally advanced disease. We therefore conducted a randomized trial using cisplatin (P)-based CT regimens with or without thoracic irradiation. PATIENTS AND METHODS We randomly assigned 92 patients with locally advanced NSCLC to receive one of three arms of P-based combination chemotherapy: vindesine (V) plus P, mitomycin (M) plus V plus P, or etoposide (E) plus P alternating with V plus M. After two cycles of CT, patients were reevaluated and those with stage III were again randomized to receive RT or not. RT consisted of 50 to 60 Gy in 5 to 6 weeks; 2 Gy was delivered once daily in conventional fractions. RESULTS Sixty-three patients were included in the second randomization. The patients in the CT/RT group (n = 32) and CT-alone group (n = 31) were comparable in terms of age, sex, performance status, histologic features, stage of disease, and induction CT regimen. The median durations of survival were similar for the two groups (461 days in CT/RT group and 447 days in CT-alone group). The survival rate in the CT/RT group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, as compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the CT-alone group. One patient in the CT/RT group died of pneumonitis, but there were no CT-related deaths. CONCLUSION In locally advanced NSCLC, P-based combination CT followed by chest irradiation significantly increases the number of long-term survivors as compared with CT alone. RT to bulky disease in the thorax is thus an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.

A Phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer

Abstract To evaluate the effectiveness of vinorelbine (NVB) in patients with non-small cell lung cancer (NSCLC), a late Phase II study was conducted. A total of 80 patients with Stage III or IV NSCLC who had no previous therapy were entered into the study. Seventy-nine patients were eligible for response and toxicity. NVB was administered weekly by intravenous injection at a dose of 25 mg/m 2 in 20 ml of saline and was generally administered in four cycles or more, unless patients had disease progression. Of the 79 eligible patients, 23 (29.1%) showed a partial response (95% confidence interval, 19.1–40.4%). The median duration of partial responses was 14.7+ weeks. The median survival time for all patients was 40.1+ weeks. The major toxicity was leukopenia. Grade 3 and 4 leukopenia occurred in 48 patients (60.8%). Other toxicities of grade 3 or more included anemia (6.3%), local cutaneous reaction (3.8%), pneumonitis (1.3%), nausea and vomiting (1.3%), mucositis (1.3%) and constipation (1.3%). The absolute dose-intensity of NVB was 22.33 mg/m 2 /week. A weekly schedule of intravenous administration of 25 mg/m 2 /week of NVB was reasonable for maintenance of activity, and acceptable for toxicity in the chemotherapy of advanced NSCLC.