New Drugs for Advanced Stage Pancreatic Cancer in the Pipeline

CHICAGO--After many years of frustration, there may finally be a reasonfor guarded optimism about the development of effective therapy for patientswith advanced stage pancreatic cancer, Mace Rothenberg, MD, said at the9th annual meeting of the Network for Oncology Communication and Research,based in Atlanta.

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

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

Use of gemcitabine in a phase III trial of patients who had receivedno prior treatment for pancreatic cancer also produced relatively low responserates, but 18% were still alive after one year.

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

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

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

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

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

Long-Acting Form of Octreotide

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

Octreotide has been uniformly successful in killing pancreatic cancercells 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 increaseplasma 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 ofthe two drugs seen against pancreatic cells in vitro can be duplicatedin phase II clinical trials.

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