HAMBURGThe challenge in the treatment of pancreatic cancer is to take systemic therapy one step further, whether its with new drugs or with novel approaches based on new biologic information, Margaret Tempero, MD, of the University of Nebraska Medical Center, Omaha, said at the Ninth European Cancer Conference (ECCO 9), sponsored by the Federation of European Cancer Societies.
One of the more promising options, she said, involves the use of gemcitabine (Gemzar). Recent studies have suggested that this cytidine analog may be superior to fluorouracil, producing a small but significant increase in median survival.
However, Dr. Tempero said, the full therapeutic potential of gemcitabine has yet to be exploited. Because gemcitabine is a prodrug that is metabolized intracellularly, she explained, optimal therapy would entail increasing the rate of formation of the more active triphosphate metabolite.
An ongoing randomized, multicenter trial in patients with metastatic pancreatic cancer is pitting a dose-intensified regimen, 2,200 mg/m2 administered over 30 minutes, against a prolonged-infusion regimen, 1,500 mg/m2 infused over 150 minutes.
With the prolonged-infusion regimen, Dr. Tempero said, the intracellular accumulation of the active triphosphate metabolite climbs steadily, far exceeding the level reached with the dose-intensified regimen.
We really believe that, if it is true that the triphosphate is the important moiety for cell kill, then this dosing strategy may well result in a better clinical outcome, she commented. In fact, she pointed out, in a previous study of this approach to administering gemcitabine, the 2-year survival rate was as high as 10%.
Dr. Tempero went on to describe an innovative radioconjugate immunotherapy approach, which attempts to harness the power of radiotherapy in disseminated pancreatic cancer. The idea is to use antibodies to such tumor antigens as TAG (tumor-associated glycoprotein)-72 to carry a therapeutic radionuclide payload to the tumor cell targets.
In clinical trials of high-affinity anti-TAG-72 antibodies conducted at the University of Nebraska, the only major side effect has been profound myelosuppression from the circulating radioactivity, she noted.
Current goals, Dr. Tempero said, are to decrease myelosuppression and potential liver toxicity, reduce immunogenicity by using human rather than mouse antibodies, and increase uptake of the radioisotope by the tumor tissue. A possible strategy for achieving this last objective, she said, could be to use synthetic analogs of C5a (a component of complement) to increase vascular permeability at the tumor site.
As an illustration of how current biologic therapies are capitalizing on the differences between tumor cells and normal cells, Dr. Tempero cited a vaccine developed at Johns Hopkins University. The vaccine is made from allogeneic tumor cells with a k-ras mutation that have been modified to produce GM-CSF.
Phase I Vaccine Trial
In a phase I trial being conducted by Elizabeth Jaffee, MD, patients receive the vaccine after undergoing pancreatic resection and are then monitored biologically. They next receive chemotherapy, radiotherapy, and a booster dose of the vaccine.
This trial has only been active for a few months, but I think its important for all of us to know that new biologic approaches are coming into the clinic, Dr. Tempero said.