Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy

Abstract

Aim of the study: The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. Methods: In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400 mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. Results: VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR) = 0.64 [confidence interval (CI) 0.43-0.95], p = 0.028). Conclusion: Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.European Journal of Cancer (2012) xxx, xxx-xxx A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c

Clinical Profile of Cyclooxygenase-2 Inhibitors in Treating Non-Small Cell Lung Cancer: A Meta-Analysis of Nine Randomized Clinical Trials

“…When the index of expression of COX-2 was more than 4, the patients with celecoxib had better OS and PFS than those without celecoxib [ 14 ]. If pretreatment plasma levels of vascular endothelial growth factor (VEGF) were restricted to lower than 200 pg/ml, celecoxib had a protective effect on survival compared with placebo [ 30 ].…”

COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer

“…Preclinical findings indicate that vascular endothelial growth factor (VEGF) may rescue cancer cells from celecoxibinduced apoptosis, and that anti-metastatic effects of COX-2 inhibitors may improve during simultaneous VEGF blockade [20]. In a previous subset analysis of 107 patients from the original randomized trial, we found that low pretreatment plasma levels of VEGF were predictive of a positive effect of celecoxib on survival [21]. Interestingly, a similar finding was obtained in a smaller phase II study for breast cancer patients treated with cyclophosphamide and celecoxib [22].…”

The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

“…Thus, selective COX-2 inhibitors may have beneficial effects on not only quality of life but survival in infants with NB. Clinical studies also reported that the selective COX-2 inhibitor celecoxib prevented the occurrence of colorectal adenomas [33] and showed some therapeutic effects in patients with breast [34] , head and neck [35] , cervical [36] , non-small cell lung [37] , colorectal [38] and ovarian cancer [39] . Of note, a recent clinical study described that oral celecoxib prevented the progression of neuroblastoma [40] .…”