A Phase II Study of Celecoxib with Weekly Paclitaxel as a Safe and Active Therapy for Non-Small Cell Lung Cancer (with Biological Correlates)
A recent article published in the Cancer Journal investigated the efficacy and safety of utilising a combination of Celecoxib and weekly Paclitaxel for the second-line treatment of non-small cell lung cancers. The study employed correlation of the biomarkers, interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) for objective responses as a secondary endpoint in study design. Study participants had diagnoses of platinum-refractory non-small cell lung cancer and an Eastern Cooperative Group performance status within the range of 0-2. Weekly doses of Paclitaxel were administered to 58 patients along with twice daily doses of Celecoxib for 8-week cycles. The results exhibited a median overall survival of 11 months and one-year survival in 42.5% of participants. Levels of VEGF were significantly reduced in those patients who received objective responses from therapy, implicating a relationship between the regulation of signal transduction pathways of angiogenesis and suppression of tumour growth. Hence, this study concluded that the combination of Celecoxib and Paclitaxel is a safe and effective second-line therapy for non-small cell lung cancer.
The effectiveness of salvage chemotherapy in progressive disease following platinum-based chemotherapy for Non-Small Cell Lung Cancer (NSCLC) is somewhat lacking based on prior research. A number of agents have been trialled for the second line therapy of such non-responsive patients, and of these Docetaxel and Gefitinib have acquired recommendation status in the American Society of Clinical Oncology Guidelines. Further phase I/II studies have demonstrated similar therapeutic efficacy between Docetaxel and Paclitaxel, and an enhanced tolerability with Paclitaxel at a dose of 80mg/m2/week. Nonetheless, lung cancer has acquired the status of being the leading cause of death related to cancer, and there is a resultant demand for more efficacious and tolerable treatment schedules. More recent research has determined a relationship between tumour progression and various signal transduction pathways, regulating cell proliferation and angiogenesis. In particular, there is compelling evidence that inhibition of the cyclo-oxygenase enzyme, COX-2, and resultant inhibition of prostaglandin synthesis could provide a promising pharmacological target for tumour suppression. This theory relates to the frequent over-expression of this COX enzyme in early disease, and there are obvious advantages in its clinical availability. Several pre-clinical and investigational studies have documented anti-tumour efficacy of selective COX inhibitors, and Celecoxib has been seen to reduce the discovery of colorectal polyps in patients with familial adenomatous polyposis. Celecoxib has already been trialled with other chemotherapeutic agents, and its efficacy and tolerability has certainly been confirmed in NSCLC patients, which has been reinforced in this study. Fifty eight patients were enrolled into the study and administered twice daily doses of Celecoxib 400mg PO for the full length of each 8 week cycle or until their disease progressed or unacceptable toxicity occurred. Patients were also given weekly doses of Paclitaxel 80mg/m2 IV for a period of 6 weeks, followed by a two week rest, where only the Celecoxib would follow on. Neuropathy was the chief toxicity, and this was observed in 15.2% of patients with severe disease. The use of the biomarkers, interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as secondary endpoints allowed for correlation of results in a subset of patients. This analysis was undertaken at baseline and every 2 cycles subsequently, and VEGF levels were found to be significantly lower in patients who experienced objective responses, reinforcing a link between tumour suppression via down regulation of signal transduction pathways. Tumour response was assessed based on the World Health Organisation and toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria. Results displayed median progression-free survival of 5 months, median overall survival of 11 months, and one-year survival in 42.5% of cases. Overall, the study found this combination of Celecoxib and weekly Paclitaxel to be a safe and efficacious option in the treatment of NSCLC; however, further refined trials encompassing larger sample sizes are certainly warranted. Reference:Gasparini G, Meo S, Comella G, et al. The combination of the selective cyclooxygenase-2 inhibitor Celecoxib with weekly Paclitaxel is a safe and active second-line therapy for non-small cell lung cancer: A phase II study with biological correlates. The Cancer Journal 2005; 11(3); 209-16.