This multi-center, open-label, dose-finding study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research issued by the Japanese Ministry of Health, Labour and Welfare. The protocol was approved by the Clinical Trial Review Committee of the Thoracic Oncology Research Group and the Institutional Review Board or Ethics Committee of each participating center. All patients provided written informed consent. The clinical trial registry number was UMIN000004240.
Study participants
Eligible patients were aged ≥70 years and had stage IIIB/IV or recurrent non-squamous NSCLC. No patient had received prior cytotoxic chemotherapy; however, prior treatment with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) was allowed. Uracil-tegafur therapy as adjuvant chemotherapy for Stage I NSCLC was also allowed. Additional inclusion criteria were ECOG performance status (PS) of 0 or 1, at least one measurable focus of disease, neutrophil count ≥2,000 cells/μL, hemoglobin ≥9.5 g/dL, platelet count ≥100,000 cells/μL, aspartate aminotransferase and alanine aminotransferase (ALT) levels ≤2.5× the upper limit of normal, total bilirubin level ≤1.5× the upper limit of normal, serum creatinine level ≤1.2 mg/dL, oxygen saturation by pulse oximetry ≥93 %, proteinuria ≤1+, and life expectancy longer than 12 weeks.
Patients were excluded if they had undergone any surgery within the past 8 weeks, exploratory thoracotomy within the last 4 weeks, or radiotherapy or minor procedures (for example, fluid drainage with a chest tube) within the last 2 weeks before enrollment. Other major exclusion criteria were a history of hemoptysis, a history of peptic ulcer within the past year, severe or uncontrollable comorbidities, brain metastases, massive pleural/pericardial effusion or ascites, regular use of anticoagulants (≤325 mg per day of aspirin was permitted), or concomitant malignancy.
Procedures
Eligible patients were given docetaxel and bevacizumab intravenously and the treatment was repeated every 3 weeks. Patients in the Level 0 cohort received docetaxel 60 mg/m2 (the recommended dose for monotherapy in Japan) and bevacizumab 15 mg/kg, and those in the Level -1 cohort received docetaxel 50 mg/m2 and bevacizumab 15 mg/kg. In each cohort, if less than four of the first six patients had experienced dose-limiting toxicity (DLT), an additional six patients were to be enrolled in the same cohort. If four or more of the first six patients in the Level 0 cohort had experienced DLT, the study was to proceed to Level -1. If four or more of the first six patients in the Level-1 cohort had experienced DLT, the study was to be terminated. Overall toxicity was evaluated after the treatment of 12 patients in a given cohort. If six or more of the 12 patients in the Level 0 cohort had experienced DLT, the study was to proceed to Level-1.
DLT was defined as the following toxicities occurring in the first cycle: Grade 4 neutropenia lasting 4 days or more, febrile neutropenia, Grade 4 thrombocytopenia, non-hematological toxicities ≥ Grade 3 (except for nausea, hyponatremia, weight loss, anorexia, infusion reaction, and hypertension), or Grade 4 hypertension. The recommended dose for future study was determined by the overall toxicities, including all of the adverse events occurring during treatment. Primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) was not allowed. G-CSF administration was recommended for patients with Grade 4 neutropenia or Grade 4 leukopenia, this being determined by the availability of coverage by Japanese public health insurance. Although this trial defined study treatment as six cycles of docetaxel plus bevacizumab, any subsequent therapies, including continuation of docetaxel and/or bevacizumab, were allowed.
Assessments
Toxicities were evaluated according to the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Complete blood counts and serum chemistries were obtained at the beginning of each cycle, and weekly during the first cycle.
Tumor response to the chemotherapy was assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1. After baseline evaluation, tumor status was assessed every 6 weeks (two cycles). Two consecutive evaluations were required to confirm complete response or partial response to the chemotherapy.
Statistical methods
The primary objectives were to evaluate the toxicity profile and to determine the recommended dose of docetaxel-bevacizumab therapy in patients aged 70 years or older with non-squamous NSCLC. The secondary endpoints were the response rate to chemotherapy, progression-free survival (PFS), OS, and the proportion of patients who underwent three or more cycles of chemotherapy. PFS was defined as the number of months between enrollment and date of disease progression or death. Patients who remained alive without disease progression at the end of follow-up, and patients who had started subsequent chemotherapy without disease progression, were censored. OS was defined as the number of months between study enrollment and date of death. Patients alive at the end of follow-up were censored. Differences in proportions between the cohorts were evaluated using the χ2 test. Differences in age were compared using the Student’s t-test. PFS and OS were estimated using the Kaplan–Meier method, and the log-rank test was used for inter-group comparisons. All tests were two-sided with a significance level of 0.05.