An Overview of Clinical Trials of Targeted Therapies in Pancreatic Cancer

Abstract

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States ( 1 ). Over 75% of patients with pancreatic cancer have locally advanced or metastatic disease at diagnosis ( 2 ). The median survival of patients with metastatic and locally advanced pancreatic cancer is 3–6 months and 8–10 months, respectively. The only potentially curative treatment is surgical resection. Patients who undergo a potentially curative resection have a median survival of 14–20 months and <20% are long-term survivors because of the development of metastatic disease. Therefore, improvement in the outcome of patients with pancreatic cancer is dependent on the development of more effective systemic therapies. Gemcitabine is considered the standard chemotherapy in advanced pancreatic cancer. The response rate, median survival and 1-year survival in patients with advanced pancreatic cancer treated with gemcitabine in the pivotal trial were 5.4%, 5.6 months, and 18%, respectively ( 3 ). Combination chemotherapy did not demonstrate any significant survival advantage in randomized trials as compared with single-agent gemcitabine ( 4 , 5). In the adjuvant setting, gemcitabine has been shown to be superior to observation ( 6) or 5-fluorouracil ( 7 ). Therefore, the impact of cytotoxic chemotherapy in pancreatic cancer has been at best modest. Nevertheless, most of the new drug development using targeted agents has been based on a gemcitabine platform. Fundamental processes associated with carcinogenesis include molecular aberrations involving cell cycle control, signal transduction, apoptosis, angiogenesis, and invasion. The identification of agents that target these abnormalities offers an opportunity for the development of effective and selective systemic treatments for pancreatic cancer. Unfortunately, recently conducted clinical trials evaluating the role of novel targeted therapies in pancreatic cancer have demonstrated somewhat disappointing results (Table 33.1 ). This chapter reviews the clinical studies that have been undertaken in patients with pancreatic cancer using targeted agents.