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New Drugs for Advanced Stage Pancreatic Cancer in the Pipeline

New Drugs for Advanced Stage Pancreatic Cancer in the Pipeline

CHICAGO--After many years of frustration, there may finally be a reason for guarded optimism about the development of effective therapy for patients with advanced stage pancreatic cancer, Mace Rothenberg, MD, said at the 9th annual meeting of the Network for Oncology Communication and Research, based in Atlanta.

One drug, gemcitabine (Gemzar), is now available that reduces the severity of symptoms and another on the horizon may strengthen the effectiveness of standard 5-fluorouracil (5-FU) treatment. Other drugs just entering clinical trials may even prove to have a significant cytolytic effect on pancreatic tumor cells.

In the first phase II trial of gemcitabine in 44 patients, the agent had an objective response rate of only 11% but a 23% survival rate at one year, which was higher than expected and considerably higher than the 2% one-year survival seen with 5-FU, Dr. Rothenberg said. The agent alleviated symptoms in 30% of patients.

Use of gemcitabine in a phase III trial of patients who had received no prior treatment for pancreatic cancer also produced relatively low response rates, but 18% were still alive after one year.

Furthermore, 24% of the patients had symptom relief, "which is well out of proportion to the objective response activity," said Dr. Rothenberg, associate professor of medicine, University of Texas Health Sciences Center, San Antonio.

A third clinical trial in the United Kingdom had similar results--only a 6% partial response rate but a 29% rate of symptom relief. "It's a very convincing picture that, while this compound does not have much impact in terms of radiographic appearance of pancreatic cancer, it is having an impact on symptoms," he said.

The experimental drug 776C85, also known as 5-ethynyluracil, is particularly exciting, he said, because it transforms "a clinically significant problem associated with the use of 5-FU into a potential treatment weapon." He explained that approximately 1% to 2% of cancer patients lack the enzyme dihydropyrimidine dehydrogenase, which is the first enzyme in the degradation pathway of 5-FU. Standard doses of 5-FU therefore are excessively toxic to these patients.

By inhibiting the action of the dihy-dropyrimidine dehydrogenase enzyme, 776C85 enhances the activity of 5-FU. "The drug prolongs the half-life of 5-FU from 15 minutes to 4½ hours, and may improve the antitumor spectrum of 5-FU because it prevents the production of certain metabolites," he said.

While 776C85 alone had no direct antitumor effect on pancreatic cancer in an experimental animal study, in combination with one-tenth the usual dose of 5-FU, the drug was able to increase both the spectrum and bioactivity of 5-FU.

Long-Acting Form of Octreotide

Just underway is a clinical trial of two agents that have shown a cytolytic effect on pancreatic tumor cells in vitro--octreotide pamoate and gamcitabine.

Octreotide has been uniformly successful in killing pancreatic cancer cells in lab studies but has been disappointing in clinical investigations, probably due to an inability to achieve adequate plasma concentrations. Octreotide pamoate is a long-acting form of the drug that may increase plasma concentrations by as much as two to three logs.

The agent is being studied at the University of Texas, San Antonio, in combination with gemcitabine to determine if the additive effects of the two drugs seen against pancreatic cells in vitro can be duplicated in phase II clinical trials.

Finally, he said, onconase, a chemical derived from frog eggs and embryos that has been active against pancreatic cancer cells in the test tube, is being evaluated in phase III trials as a possible front-line therapy and as a second-line drug in patients who have received gemcitabine.

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