Masaaki Kawahara

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.

Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Cisplatin and Etoposide for Limited-Stage Small-Cell Lung Cancer: Results of the Japan Clinical Oncology Group Study 9104

PURPOSE To evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC), the Lung Cancer Study Group of the Japan Clinical Oncology Group conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT. PATIENTS AND METHODS We treated 231 patients with LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily), and the patients were randomly assigned to receive either sequential or concurrent TRT. All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. RESULTS Concurrent radiotherapy yielded better survival than sequential radiotherapy (P =.097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5-year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%, and 18.3%, respectively, as opposed to 54.4%, 29.8% and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm. However, severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm. CONCLUSION This study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective for the treatment of LS-SCLC than cisplatin plus etoposide and sequential radiotherapy.

Phase III Randomized Trial of Docetaxel Plus Cisplatin Versus Vindesine Plus Cisplatin in Patients With Stage IV Non-Small-Cell Lung Cancer: The Japanese Taxotere Lung Cancer Study Group

PURPOSE Few randomized trials have demonstrated survival benefit of combination chemotherapy involving new agents plus cisplatin compared with classic combination chemotherapy in advanced non-small-cell lung cancer (NSCLC). The primary aim of this study was to test whether docetaxel plus cisplatin (DC) improves survival compared with vindesine plus cisplatin (VdsC) in patients with previously untreated stage IV NSCLC. PATIENTS AND METHODS Eligible, stage IV, chemotherapy-naive patients (n = 311) were randomly assigned to receive docetaxel 60 mg/m(2) intravenously on day 1 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 3- or 4-week cycle, or vindesine 3 mg/m(2) intravenously on days 1, 8, and 15 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 4-week cycle. Cross-over administration of docetaxel and vindesine was prohibited for both treatment groups. RESULTS Overall, 302 patients were eligible for evaluation. The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% v 21%, respectively; P <.01) and median survival times (11.3 v 9.6 months, respectively; P =.014). Two-year survival rates were 24% for the DC arm compared with 12% for the VdsC arm. The physical domain of the Quality of Life for Cancer Patients Treated with Anticancer Drugs measure was significantly better in the DC arm than in the VdsC arm (P =.020). Toxicity was predominantly hematologic and was more severe in the VdsC arm. CONCLUSION As first-line treatment for stage IV NSCLC, DC resulted in greater clinical benefit in terms of response rate (with marked improvements in overall and 2-year survival rates) and quality of life than did treatment with VdsC.

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 clinical study of photodynamic therapy using mono-l-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung

Photofrin is the most commonly used photosensitizer for photodynamic therapy (PDT). The major side effect of Photofrin is cutaneous photosensitivity. A second generation photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) has shown anti-tumor efficacy and rapid clearance from skin. Therefore, we conducted a phase II clinical study to investigate the anti-tumor effects and safety of NPe6 in patients with early superficial squamous cell carcinoma of the lung. Enrollment criteria consisted of endoscopically evaluated early stage lung cancer with normal chest X-ray and CT images, no lymph node or distant metastasis. Tumors were located no more peripherally than subsegmental bronchi, the peripheral margin had to visible, and the tumor size had to not more than 2 cm in diameter. The histologic type of the tumor had to squamous cell carcinoma. Laser irradiation (100 J/cm2) using a diode laser was performed at 4 h after administration of NPe6 (40 mg/m2). Among 41 patients with 46 lesions, 40 with 45 lesions were eligible for safety evaluation, and 35 patients with 39 lesions were judged as eligible for efficacy evaluation. No serious adverse drug reactions were observed. Disappearance of skin photosensitivity was recognized within 2 weeks in 28 of 33 patients (84.8%) and in all the other seven patients first tested at 15-18 days. Complete response (CR) was seen in 84.6% of lesions (82.9% of patients). This study demonstrated excellent anti-tumor effects and safety, especially low skin photosensitivity in patients with early stage lung cancer. PDT using the second generation photosensitizer NPe6 and a diode laser will likely become a standard modality of PDT for central type early superficial squamous cell carcinoma of the lung.

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.

Phase III Study Comparing Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105

PURPOSE This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m(2) on days 1, 8)/carboplatin (AUC 5 on day 1); C, weekly paclitaxel (40 mg/m(2))/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m(2) on day 1)/carboplatin (AUC 5 on day 1). RESULTS The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. CONCLUSION Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

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.

EGFR and erbB2 mutation status in Japanese lung cancer patients

Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Somatic mutations of the EGFR gene were found in about 25–40% of Japanese lung cancer patients. More recently, erbB2 mutations are found in about 4% of European‐derived lung cancer patients. We have investigated EGFR and erbB2 mutation status in 95 surgically treated nonsmall cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Seventy‐five adenocarcinoma cases were included. The presence or absence of EGFR and ernB2 mutations of kinase domains were analyzed by reverse transcription polymerase chain reaction (RT‐PCR) amplifications and direct sequences. We have also investigated erbB2 mutation status in 27 surgically treated NSCLC cases followed by treatment with gefitinib from Kinki‐chuo Chest Medical Center. EGFR mutations (CTG→CGG; L858R) were found from 14 of 95 lung cancer patients. We also detected the deletion 1a‐type mutations from 9 patients and deletion 4‐type mutations from 6 patients in exon 19. In exon 20, 4 mutations including 2 novel mutations were found. Total EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p = 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p = 0.0021). On the other hand, erbB2 mutation was only found from 1 of 95 patients, at exon 20. This patient was female and a never smoker with adenocarcinoma. This 12 nucleotide insertion mutation (2324–2325 ins ATACGTGATGGC) was located in the exon 20 at kinase domain (775–776 ins YVMA). There was no erbB2 mutation in 27 gefitinib‐treated NSCLC patients. In total, we have found only 1 erbB2 mutation from 122 (0.8%) Japanese NSCLC patients. There was a significantly higher erbB2 positive (2+/3+) ratio in EGFR mutant patients (13/25, 52.0%) compared to EGFR wild‐type patients (10/62, 16.1%; p = 0.0247). The NSCLC specimen with erbB2 mutation showed 1+ immunoreactivity. The EGFR mutation status might correlate with the clinicopathologic features related to good response to gefitinib, such as gender, smoking history and pathologic subtypes of lung cancers. However, erbB2 mutation is rare from Japanese lung cancer and is of limited value for molecular target therapy.

Performance Status and Smoking Status Are Independent Favorable Prognostic Factors for Survival in Non-small Cell Lung Cancer: A Comprehensive Analysis of 26,957 Patients with NSCLC

Background: Performance status (PS) is an important factor in determining survival outcome in non-small cell lung cancer (NSCLC) but is generally confounded by stage, age, gender, and smoking status. We investigated the prognostic significance of PS taking into account these important factors. Methods: Retrospective analysis of registry database of the National Hospital Study Group for Lung Cancer (NHSGLC) between1990 and 2005. Univariate analysis was performed using Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards model to identify independent prognostic factors. Results: A total of 26,957 patients with NSCLC were analyzed of which 12,613 patients (46.8%) had World Health Organization (WHO) PS = 0, 8,137 patients were never smokers (30.2%), and most of them were females (72.7%). The majority of PS = 0 patients presented with stage I disease (56.9%). Patients with PS = 0 constituted the group with the highest proportion of never smokers (36.7%). There was a significant difference in the median overall survival (OS) between patients with PS = 0 and PS = 1 (51.5 months versus 15.4 months, respectively; p < 0.0001) and among patients with various PS within individual American Joint Committee on Cancer stage (all p values <0.0001). Never smokers had significantly improved median OS than ever smokers (30.0 months versus 19.0 months, respectively; p < 0.0001). Multivariate analysis demonstrated good PS, never smoker (versus ever smoker; hazard ratio = 0.935, 95% confidence interval: 0.884–0.990; p = 0.0205), early stage, female gender, squamous cell carcinoma histology, and treatment were all as independent favorable prognostic factors. Conclusions: PS and smoking status are independent prognostic factors for OS in NSCLC.