Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial.
Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer.



We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants.



Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5-13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2-16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96-1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group.



In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up.



The Ministry of Health, Labour and Welfare of Japan.
Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Toshiaki
T
Takahashi
Department of Biostatistics, Yokohama City University, Yokohama, Japan.
Takeharu
T
Yamanaka
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
Takashi
T
Seto
Division of Radiation Therapy, Shizuoka Cancer Center, Shizuoka, Japan.
Hideyuki
H
Harada
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Hiroshi
H
Nokihara
Department of Respiratory Medicine and Medical Oncology, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Hideo
H
Saka
Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Makoto
M
Nishio
Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
Hiroyasu
H
Kaneda
Research Institute for Diseases of the Chest, Kyushu University, Fukuoka, Japan.
Koichi
K
Takayama
Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan.
Osamu
O
Ishimoto
Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.
Koji
K
Takeda
Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan.
Hiroshige
H
Yoshioka
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Motoko
M
Tachihara
Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.
Hiroshi
H
Sakai
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Koichi
K
Goto
Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan. Electronic address: nbyamamo@wakayama-med.ac.jp.
Nobuyuki
N
Yamamoto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000517:prevention & control* / Q000556:secondary; D016371:Cranial Irradiation / Q000009:adverse effects; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018447:Medical Futility; D008875:Middle Aged; D017671:Platinum Compounds / Q000008:administration & dosage; D055752:Small Cell Lung Carcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary; D015996:Survival Rate; D057832:Watchful Waiting
D017671:Platinum Compounds