Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
BACKGROUND
Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer.


METHODS
We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828.


RESULTS
Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0-35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7-20·6) than in the topotecan group (12·5 months, 10·8-14·9; hazard ratio 0·67, 90% CI 0·51-0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group.


CONCLUSIONS
Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.


BACKGROUND
National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.
Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. Electronic address: kgoto@east.ncc.go.jp.
Koichi
K
Goto
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Yuichiro
Y
Ohe
JCOG Data Center, National Cancer Center, Tokyo, Japan.
Taro
T
Shibata
Department of Thoracic Oncology National Kyushu Cancer Center, Fukuoka, Japan.
Takashi
T
Seto
Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Toshiaki
T
Takahashi
Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
Kazuhiko
K
Nakagawa
Department of Thoracic Oncology, Niigata Cancer Center Hospital, Niigata, Japan.
Hiroshi
H
Tanaka
Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.
Koji
K
Takeda
Thoracic Oncology Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Makoto
M
Nishio
Department of Medical Oncology, Division of Thoracic Oncology, Tochigi Cancer Center, Tochigi, Japan.
Kiyoshi
K
Mori
Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan.
Miyako
M
Satouchi
Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan.
Toyoaki
T
Hida
Department of Clinical Oncology, Graduate School of Medicine, Osaka City University Hospital, Osaka, Japan.
Naruo
N
Yoshimura
Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Ehime, Japan.
Toshiyuki
T
Kozuki
Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Fumio
F
Imamura
Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
Katsuyuki
K
Kiura
Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.
Hiroaki
H
Okamoto
Division of Respiratory Medicine and Oncology, Gifu Municipal Hospital, Gifu, Japan.
Toshiyuki
T
Sawa
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Tomohide
T
Tamura
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016879:Salvage Therapy; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage
D005047:Etoposide; D000077146:Irinotecan; D019772:Topotecan; D002945:Cisplatin; D002166:Camptothecin