A Phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer.

A Phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer

Uwagawa T et al. Ann Oncol, 2008 [epub ahead of print]

The diagnosis of an exocrine pancreatic adenocarcinoma is usually made when disease is widespread and surgery with curative intent is not feasible. In the small percentage of patients who do undergo surgery, disease will almost always recur. The mortality incidence ratio is 98%.

Gemcitabine has been the standard treatment for advanced pancreatic cancer since 1997 when comparison of gemcitabine with 5-fluorouracil (5-FU) was performed [1]. Clinical benefit and 1-year survival were significantly improved (23.8% versus 4.5% and 18% versus 2%, respectively). Gemcitabine doublets with cisplatin, oxaliplatin, irinotecan, pemetrexed, capecitabine and docetaxel have been tested. A recent Phase III trial has shown a significant advantage for overall survival (OS) with the combination of gemcitabine and erlotinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), over gemcitabine alone, with a median OS of 6.24 versus 5.91 months (hazard ratio = 0.82; P = 0.038) and a 1-year survival of 23% versus 17% (P = 0.023), respectively [2]. Two meta-analyses have demonstrated a small but significant survival benefit for doublets of gemcitabine with either platinum compounds or capecitabine. The benefit was greater in the patients with good performance status (PS) whereas those with a poor PS seemed to have no survival benefit from combination chemotherapy [3,4].

Constitutive activation of nuclear factor-[kappa]B (NF-[kappa]B) is a frequent molecular alteration in pancreatic cancer [5] and may play an important role in resistance to chemotherapy [6]. Gemcitabine also induces NF-?B activation as well as 5-FU and irinotecan [7]. The combination of gemcitabine with an NF-[kappa]B inhibitor could improve efficacy in pancreatic cancer treatment.

Nafamostat mesilate is a synthetic serine protease inhibitor of NF-[kappa]B activation, commercially approved for disseminated intravascular coagulation (DIC) in Japan, which also induces apoptosis of pancreatic cancer cells [8]. Continuous regional arterial infusion increases the concentration of nafamostat mesilate in the pancreas as compared with iv infusion, and may inhibit NF-[kappa]B activation and induce apoptosis of pancreatic cancer cells.

The primary objective of this Phase I trial was to determine the dose-limiting toxicities (DLTs), and maximum tolerated dose, of intra-arterial nafamostat mesilate in combination with full-dose gemcitabine, in patients with unresectable locally advanced or metastatic pancreatic cancer.

Previously untreated advanced pancreatic cancer patients received gemcitabine (1000 mg/[m.sup.2] iv for 30 min) on days 1, 8, and 15, with increasing doses of nafamostat mesilate (continuous regional arterial infusion for 24 hours through a port-catheter system) on days 1, 8, and 15; every 28 days. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until the dose of 4.8 mg/kg was reached, the clinically permitted level for DIC treatment in Japan. No DLTs were reported among the 12 patients recruited in this study. No complications derived from arterial procedures.

From a total of 12 patients, three (25%) achieved a partial remission with the combination, and 11 patients (92%) showed a reduction in the serum CA19-9 level. Overall survival was 7.1 months for all patients. An analgesic effect was attributed to nafamostat mesilate with subsequent symptom relief.

Genetically altered core pathways and regulatory processes can explain the major features of pancreatic tumorigenesis. Enrolling pancreatic cancer patients into carefully designed clinical trials and obtaining their biological samples to test new treatment strategies and drugs is crucial to achieve better results in this deadly disease. Genetically altered core pathways and regulatory processes can explain the major features of pancreatic tumorigenesis.

References

[1.] Burris H, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol, 1997, 15, 2403-2413.

[2.] Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007, 25, 1960-1966.

[3.] Heinemann V, Boeck S, Hinke A et al. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination therapy applied in advanced pancreatic cancer. BMC Cancer, 2008, 8, 82.

[4.] Banu E, Banu A, Fodor A et al. Meta-analysis of randomized trials comparing gemcitabine-based doublets versus gemcitabine alone in patients with advanced and metastatic pancreatic cancer. Drugs Aging, 2007, 24, 865-879.

[5.] Sebens S, Arlt A, Schafer H. NF-kappaB as a molecular target in the therapy of pancreatic carcinoma. Recent Results Cancer Res, 2008, 177, 151-164.

[6.] Arlt A, Schafer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther, 2002, 40, 336-347.

[7.] Camp ER, Li J, Minnich DJ et al. Inducible nuclear factor-kappaB activation contributes to chemotherapy resistance in gastric cancer. J Am Coll Surg, 2004, 199, 249-258.

[7.] Uwagawa T, Li Z, Chang Z et al. Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer, 2007, 109, 2142-2153.

Commentary by Alfredo Carrato and Carmen Guillen-Ponce (1)

(1) Medical Oncology Department, Elche University Hospital, Alicante, Spain