Takehito Shukuya1, Takeharu Yamanaka2, Takashi Seto3, Haruko Daga4, Koichi Goto5, Hideo Saka6, Shunichi Sugawara7, Toshiaki Takahashi8, Soichiro Yokota9, Hiroyasu Kaneda10, Tomoya Kawaguchi11, Seisuke Nagase12, Tetsuya Oguri13, Yasuo Iwamoto14, Takashi Nishimura15, Yoshihiro Hattori16, Kazuhiko Nakagawa10, Yoichi Nakanishi17, Nobuyuki Yamamoto18. 1. Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. 2. Department of Biostatistics, Yokohama City University, Kanagawa, Japan. 3. Department of Thoracic Oncology, National Kyushu Cancer Centre, Fukuoka, Japan. 4. Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan. 5. Department of Thoracic Oncology, National Cancer Centre Hospital East, Chiba, Japan. 6. Department of Respiratory Medicine and Medical Oncology, National Hospital Organisation Nagoya Medical Centre, Aichi, Japan. 7. Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan. 8. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 9. Department of Respiratory Medicine, National Hospital Organisation Toneyama National Hospital, Osaka, Japan. 10. Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan. 11. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan. 12. Department of Thoracic Surgery, Tokyo Medical University, Tokyo, Japan. 13. Department of Respiratory Medicine, Allergy, and Clinical Immunology, Graduate School of Medical Sciences, Nagoya City University, Aichi, Japan. 14. Department of Medical Oncology, Hiroshima City Hospital, Hiroshima, Japan. 15. Department of Respiratory Medicine, Kyoto-Katsura Hospital, Kyoto, Japan. 16. Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan. 17. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 18. Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan. Electronic address: nbyamamo@wakayama-med.ac.jp.
Abstract
BACKGROUND: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. METHODS: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. FINDINGS:Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. INTERPRETATION:Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. FUNDING: West Japan Oncology Group and Sanofi.
RCT Entities:
BACKGROUND: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. METHODS: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. FINDINGS: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. INTERPRETATION: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. FUNDING: West Japan Oncology Group and Sanofi.
Authors: Vanda Téglási; Lilla Reiniger; Katalin Fábián; Orsolya Pipek; Irén Csala; Attila G Bagó; Péter Várallyai; Laura Vízkeleti; Lívia Rojkó; József Tímár; Balázs Döme; Zoltán Szállási; Charles Swanton; Judit Moldvay Journal: Neuro Oncol Date: 2017-08-01 Impact factor: 12.300