Experimental drugs and drug combinations in pancreatic cancer

The current role of chemotherapy in pancreatic cancer is limited. Chemotherapy usually consists of 5-fluorouracil (5FU) and gemcitabine either as a single agent or in combinations. However, response rates are below 15% with minor effects on overall survival. Due to the aggressive behavior of the disease, current emphasis of new experimental chemotherapy is also focusing on clinical benefit: improvement of pain, performance status or weight. The results with gemcitabine indicated that evaluation of new chemotherapeutic agents in pancreatic cancer should not be limited to the evaluation of response rates; single agent gemcitabine not only showed higher response rates than 5FU, but also resulted in clinical benefit for the patients. Several new agents have been introduced into the clinic for treatment of various gastro-intestinal malignancies, whereas novel agents with different types of targets, such as marimastat deserve further attention. Several oral formulations of 5FU, such as capecitabine, UFT, and eniluracil with 5FU, aim to simulate long-term continuous infusion. Response rates of these formulations are comparable to those of 5FU continuous infusion and 5FU bolus injections. However, the convenience of oral administration with reliable plasma drug concentrations makes these agents very attractive as a replacement of traditional 5FU administration. Since 5FU acts by inhibition of thymidylate synthase (TS), resulting in inhibition of DNA synthesis, several new antifolates, directed towards TS, have been developed. However, these agents, such as ZD1694 (Tomudex, Raltitrexed) and LY231514 (MTA, multitargetted antifolate) showed only limited efficacy. Other new agents active in colorectal cancer, e.g. the topoisomerase I inhibitors topotecan and CPT-11, showed only minor activity. The same was observed for the taxanes. Combinations of gemcitabine (cisplatin, 5FU, epirubicin, marimastat) show promising activities, not only regarding response but also with respect to clinical benefit. The effects were better than that for each agent separately. Thus, despite limited activity of single agents, novel combinations especially with gemcitabine are promising, with emphasis on improvement of the clinical benefit of patients.