Dynamic contrast-enhanced MRI to predict response to vinorelbine-cisplatin alone or with rh-endostatin in patients with non-small cell lung cancer and bone metastases: a randomised, double-blind, placebo-controlled trial.

ABSTRACT

BACKGROUND: Metastatic bone disease is a frequent complication of advanced non-small-cell lung cancer and causes skeletal-related events which result in a poor prognosis. A standard method to assess the therapeutic response of bone metastases does not currently exist. We used dynamic contrast-enhanced MRI to obtain quantitative measures to assess the suitability of this technique to gauge therapeutic response to vinorelbine-cisplatin plus rh-endostatinfor previously untreated non-small cell lung cancer with bone metastases. METHODS: We did a phase 4, randomised, prospective, double-blind, placebo-controlled clinical trial in Shanghai Sixth People's Hospital, Shanghai, China. Inclusion criteria were non-small-cell lung cancer patients with bone metastases confirmed by pathology or cytology; available imaging data of pelvic metastatic lesions; aged 18 to 75 years old; expected survival at least 3 months; not receiving taxane, bevacizumab, thalidomide, rh-endostatin, or bisphosphonate; not having radiation therapy within 3 months of enrollment into study; normal results of routine blood tests, liver and kidney function, and electrocardiogram; absence of cardiovascular disease, autoimmune disease, vasculitis, severe infection, diabetes, and other concomitant disease; and signed informed consent. Exclusion criteria were receiving granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor during chemotherapy, intolerance to adverse reaction, and allergy to contrast agents. Patients were randomly assigned to treatment group and control group at a ratio of 21 by random code generation by an independent biostatistician in a double-blind fashion. Participants received either vinorelbine-cisplatin plus rh-endostatin or vinorelbine-cisplatin plus placebo. Vinorelbine (25 mg/m2) and cisplatin (75 mg/m2) were administered intravenously on the first day of a 21 day cycle. Patients received rh-endostatin (7·5 mg/m2) or placebo on days 1-14 of a cycle. The primary end points were objective response rate (complete remission+partial remission)/total × 100) and disease control rate (complete remission+partial remission+stable disease)/total × 100). Measurements including Ktrans, Kep, and Ve were evaluated by dynamic contrast-enhanced MRI before treatment and after completion of 2 treatment cycles. Blood concentrations of bone metabolites, tumour markers, and tumour vascular growth related factors were measured before and after treatment. Comparisons were made using paired t-test. Kaplan-Meier survival analysis was used to indicate the correlation between some measurements and progression-free survival or overall survival. The difference in Ktrans between patients who had partial remission or stable disease group and those who had disease progression was tested using the Chi-square test. All statistical analyses were performed with SPSS version 21.0. This trial was approved by the State Food and Drug Administration (No S20050088) and China State Food and Drug Administration. The trial is registered with China Clinical Trials Registry, number chictr-ctr-09000569. Written informed consent and ethical approval was obtained. FINDINGS: We enrolled 33 patients (aged 52-70, 15 men and 18 women) of whom 28 were evaluable (20 in treatment group and 8 in control group). Five patients were excluded 2 patients in treatment group and 1 patient in control group used granulocyte-macrophage colony stimulating factor, and 2 patients in the control group refused treatment. Objective response rate was higher (30% vs 0%; p<0·00001), mean overall survival was longer (21·44 [SD 17·28] vs 7·71 [4·68] months, p=0·008), and reduction in capillary permeability (measured by Ktrans) was greater (60·0% vs 4·4%; p=0·026) in the group given rh-endostatin than in the control group. Disease control rate was 80% in the treatment group and 75% in the control group (p=0·07). Overall survival was longer in patients with a greater than 50% reduction in Ktrans than in patients with a decrease of up to 50% (13·2 [1·8] vs 9·8 [0·2] months, p=0·026). INTERPRETATION: Addition of rh-endostatin to treatment with vinorelbine-cisplatin increased the treatment response in patients with non-small cell lung cancer and bone metastases. Quantitative analysis using dynamic contrast-enhanced MRI can be used to evaluate therapeutic response and to predict survival of bone metastases after anti-angiogenesis therapy. Limitations of this study include the small number of patients and the single-centre design. FUNDING: National Natural Science Foundation of China [grant number 81201628].