Pilot study of celecoxib and infusional 5‐fluorouracil as second‐line treatment for advanced pancreatic carcinoma

Abstract

BACKGROUND Cyclooxygenase‐2 (COX‐2) is up‐regulated frequently and may constitute a promising therapeutic target in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS Patients with advanced PDAC who had progressive disease after gemcitabine‐based chemotherapy were eligible for this pilot study. Treatment was comprised of oral celecoxib (400 mg twice daily) and protracted intravenous (i.v.) infusion 5‐fluorouracil (5‐FU) (200 mg/m2 per day), both given continuously for a maximum of 9 treatment months, in the absence of disease progression or unacceptable toxicity. Patients were examined weekly for toxicity and were restaged every 6–8 weeks for tumor assessment. RESULTS Seventeen patients entered the study. Asymptomatic transaminase elevation was the most common toxicity and reached NCI‐CTC (version 3.0) Grade 3–4 in 4 of 133 treatment weeks. No other hematologic or nonhematologic toxicity > Grade 2 was observed. Four patients discontinued celecoxib due to upper gastrointestinal tract toxicity. Two confirmed partial responses (durations of 23 weeks and 68 weeks, respectively) and 2 patients with stable disease (durations of 10 weeks and 13 weeks, respectively) were observed for an overall response rate of 12% (95% confidence interval, 0–27%) in the intent‐to‐treat population. A significant decrease (≥ 50%) in serum CA 19.9 levels was observed in 3 of 9 evaluable patients. The median time to disease progression was 8 weeks, and the median overall survival was 15 weeks. CONCLUSIONS The combination of oral celecoxib and 5‐FU by protracted i.v. infusion was found to be feasible and well tolerated, and was capable of inducing durable objective responses, even in patients with far advanced, gemcitabine‐resistant/refractory PDAC. Further exploration of COX‐2 inhibitor/fluropyrimidine combinations is warranted. Cancer 2004. © 2004 American Cancer Society.

Pancreatic cancer: Pathogenesis, prevention and treatment

“…In a clinical trial, the patients with advanced pancreatic adenocarcinoma were given celecoxib in combination with 5-fluorouracil. The results showed that celecoxib with 5-fluorouracil was capable of inducing durable and objective responses, even in gemcitabine-resistant pancreatic cancer (Milella et al, 2004). These results collectively suggest that COX-2 inhibition with other novel agents could be useful in future clinical trials for pancreatic cancer.…”

Cyclooxygenase-2 Expression

“…Finally, evidence from several experimental and clinical studies has shown that selective Cox-2 inhibitors possess significant antitumor activity on their own with favorable safety profile (1,8,21,22,48) and can also enhance tumor response to radiation or cytotoxic agents (49,50). However, recent clinical studies (51,52) with rofecoxib in the treatment of metastatic colorectal cancer pointed out an increased toxicity and lack of efficacy.…”

Cyclooxygenase-independent down-regulation of multidrug resistance–associated protein-1 expression by celecoxib in human lung cancer cells

“…Recently, COX-2 inhibitors have also gained attention, either alone or in combination with other chemotherapeutic agents and/or radiation therapy, in the treatment of cancer (1). For example, a COX-2-selective inhibitor celecoxib exerted synergistic antitumor effects when combined with gemcitaine or 5-fluorouracil in patients with advanced pancreatic cancer (2), and it enhanced the response to paclitaxel and carboplatin in early-stage non -small cell lung cancer (3). The mechanism underlying the antitumor activity of COX-2 inhibitors is thought to involve inhibition of COX-2 enzyme activity and induction of apoptosis, but it is unclear whether COX-2 inhibition is required to induce apoptosis (4).…”