PALM BEACH, FloridaWhat is the best method for administering fluorouracil
(5-FU)? Should it be given as a continuous intravenous infusion, as often done
in Europe? Or should 5-FU be administered as an intravenous bolus, as typically
done by American physicians, at least partly to avoid the need for central
venous access and pump devices.
In a debate over the best approach, Joseph R. Bertino, MD, argued in favor
of bolus 5-FU in some situations on the ground that different effects can be
expected depending on route of administration. He is associate director, Cancer
Institute of New Jersey and professor of medicine and pharmacology, University
of Medicine and Dentistry of New Jersey in New Brunswick. Robert B. Diasio, MD,
argued that continuous infusion 5-FU is overall more effective and associated
with less severe drug-related toxicity than bolus dosing. Dr. Diasio is
chairman of pharmacology/toxicology, and associate director of the University
of Alabama Comprehensive Cancer Center in Birmingham.
Two Different Drugs
"It is a little embarrassing that 40 years after the introduction of 5-FU we
are still talking about how best to give this drug," Dr. Bertino admitted. "I
want to suggest that some of the confusion is because 5-FU is actually two
different drugs, depending on the dose schedule used. I’m not pushing for bolus
vs infusional. I’m pushing for both."
Dr. Bertino said that 5-FU is activated by several pathways. Bolus 5-FU,
which is active over 15 minutes to 24 hours, acts mainly by incorporation into
RNA. Continuous infusion 5-FU, which is active for over 24 hours to 3 weeks,
apparently acts mainly by inhibiting thymidylate synthase.
In vitro data using HCT-8 colorectal carcinoma cells showed that at the same
dose, more 5-FU was incorporated into RNA following a bolus 4-hour exposure
than following 7-day continuous exposure. "One mechanism of resistance to
repeat bolus 5-FU is decreased incorporation into RNA, due to a decrease in UMP
kinase activity," Dr. Bertino said. "A mechanism of resistance to 7-day
continuous exposure to 5-FU is decreased thymidylate synthase inhibition."
Cytotoxicity caused by bolus 5-FU is not prevented by thymidine, but
cytotoxicity produced by continuous infusion 5-FU is. Clinically, 5-FU-related
toxicities also vary depending on dose schedule, Dr Bertino said. Bolus 5-FU
causes leukopenia, mucositis, and diarrhea. Continuous infusion 5-FU causes
more hand-foot syndrome and mucositis.