Study participants
We carried out a multicenter feasibility study of previously untreated elderly patients with nonsquamous NSCLC from nine healthcare institutions. This study was approved by the ethics committee of all participating hospitals (Shikoku Cancer Center, Chiba University Hospital, Kanagawa Cardiovascular and Respiratory Center, Japanese Red Cross Medical Center, Fujisawa City Hospital, Nippon Medical School Chiba Hokusoh Hospital, and Okayama Rosai Hospital). Actual enrolments were performed at four hospitals (Shikoku Cancer Center, Chiba University Hospital, Kanagawa Cardiovascular and Respiratory Center, and Japanese Red Cross Medical Hospital). Written informed consent was obtained from all participating patients. This trial was registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN-CTR), issue number UMIN000004263.
Eligible patients had histologically or cytologically confirmed nonsquamous NSCLC; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; measurable lesions as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and no prior chemotherapy (except for uracil and tegafur or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor). Patients were unfit for bolus administration of cisplatin or combination chemotherapy, and had adequate bone marrow, hepatic, and renal functions (leucocyte counts ≥4000/mm3, absolute neutrophil counts ≥2000/mm3, platelet counts ≥100,000/mm3, haemoglobin ≥9.5 g/dl, serum aspartate aminotransferase (AST) ≤2.5× upper limit of normal (ULN) range, alanine aminotransferase (ALT) ≤2.5× ULN, total bilirubin ≤1.5 mg/dl, serum creatinine ≤1.5 mg/dl, and urinalysis of proteinuria by dipstick (dipstick result ≤(+)). Key exclusion criteria included the presence of brain metastasis, a history of hemoptysis (≥2.5 ml), active infectious disease, massive pleural effusion, pericardial effusion, or abdominal effusion, severe co-morbidity (heart disease, interstitial lung disease, inadequately controlled hypertension, or diabetes mellitus), a history of thoracic irradiation, concomitant malignancy within the last 5 years, coagulation disorders or therapeutic anti-coagulation, gastrointestinal perforation, minor surgery within the last 2 weeks, major surgery within the last 4 weeks, and major surgery with lobectomy or pneumonectomy within the last 8 weeks.
Study design
Patients were administered intravenously with pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) on day 1, with repeat administration given every 3 weeks thereafter—defined as level 0. The planned number of patients enrolled in this trial consisted of a minimum of 12 to a maximum of 24 patients. If dose-limiting toxicities (DLTs) were observed in ≥4 out of six patients or ≥6 out of 12 patients at level 0, we evaluated the patients as level −1 when pemetrexed dosage was reduced to 375 mg/m2. If <6 out of 12 patients experienced DLTs at each level, this dose level was considered to be feasible. Treatment was repeated for a total of 6 cycles, although if toxicity was acceptable, treatment was continued until disease progression.
DLTs were evaluated in the first cycle of chemotherapy and defined according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 4.03: grade 4 neutropenia lasting for ≥4 days; febrile neutropenia; grade 4 thrombocytopenia; and grades 3–5 nonhaematological toxicities (except for nausea, hyponatremia, weight loss, anorexia, or hypertension).
The primary endpoint of this study was safety, and the secondary endpoints were the progression-free survival (PFS), overall survival (OS), objective response ratio (ORR) according to RECIST version 1.1, and the completion ratio of three cycles or more.
Statistical analysis
Survival curves were estimated using the Kaplan–Meier method. PFS was defined as starting from the date of enrolment to the first documented date of disease progression or last contact. OS was defined as starting from the date of enrolment to the date of death from any causes, or last contact.