Biochemical Modulation Promising in RT-Resistant GI Cancer

PARIS, France--Biochemical modulators have brightened the prospectsfor patients with advanced gastrointestinal cancer, Scott Wadler,MD, reported at the American Radium Society annual meeting.

New evidence suggests that the use of these modulators in combinationwith radiation may require revision of traditional assumptionsregarding radiation sensitizers (see below).

The basic principle of biochemical modulation is that one drugis used to enhance the action of another, as occurs when fluorouracilis paired with leucovorin, said Dr. Wadler, of the Albert EinsteinCollege of Medicine.

The conditions necessary for a successful partnership are thatboth drugs must have access to the cellular target, one drug mustaugment the effects of the other at that target, and there mustbe no compensatory mechanism that would enable the cell to developresistance.

Although the addition of leucovorin to fluorouracil therapy inpatients with advanced colorectal cancer has increased the responserate to 24%, compared with 10% for fluorouracil alone, mediansurvival has remained static at 11 months, underscoring the needfor more effective therapies for this disease.

Encouraging results came from a phase II study conducted at AlbertEinstein, and a subsequent ECOG trial, which showed that the combinationof fluorouracil and interferon (IFN)-alpha yielded response ratesof 40% to 60%.

Fluorouracil/Interferon-Beta

Dr. Wadler went on to describe the results of a phase II trialjust completed at Albert Einstein, which coupled fluorouracilwith IFN-beta rather than IFN-alpha in patients with advancedcolorectal cancer. He said that IFN-beta may be a better radiosensitizerthan IFN-alpha, and may have more potent antiproliferative effectsand less toxicity as well.

Participants in the Einstein study were assigned to receive 45million units of IFN-beta either three times a week, daily, ordaily in combination with granulocyte-macrophage colony stimulatingfactor (GM-CSF). "Surprisingly, the use of GM-CSF did notdiminish the incidence of either diarrhea or leukopenia,"Dr. Wadler said.

He pointed out that the response rates with thrice-weekly interferonwere the same as those achieved with leucovorin (22%), but increasedto 38% with the use of daily interferon. Median survival was 15months, with confidence intervals of 12.5 to 17.5 months. "Thislower level is still above the median survival observed with fluorouracilplus leucovorin in the metaanalysis," he noted.

Dr. Wadler said that the combination of fluorouracil and interferonis also a promising approach to the treatment of esophageal carcinomasthat are beyond the scope of surgical resection or definitiveradiation therapy.

He cited reports from Einstein and Memorial Sloan-Kettering showingthat patients with disseminated disease achieved objective responserates of 25% to 27% with the combination, which were higher thanthose of historical controls treated with fluorouracil alone inan ECOG trial.

Different Patterns of DNA Breaks Seen After Chemotherapy andRadiation Therapy

Preliminary data from Dr. Scott Wadler's laboratory (see storyabove) may suggest a basis for incorporating biochemical modulationstrategies into multimodality therapy for gastrointestinal cancer.

Using the sensitive new method of pulsed field gel electrophoresisto measure double-stranded DNA breaks, the Einstein team foundthat the combination of fluorouracil and interferon-alpha significantlyincreased the number of double-stranded DNA breaks over that seenwith fluorouracil alone.

They observed, however, that while the number of double-strandedbreaks induced by certain doses of fluorouracil plus interferonwas the same as that caused by 0.74 Gy of radiation, the patternsof breaks attributable to the two modalities were different.

"This suggested to us that perhaps we're dealing with a differentmechanism and a different type of lesion, and that the assumptionswe made for the incorporation of more potent regimens such asfluorouracil and interferon into the anticancer armamentariumshould also be different," he said.

Dr. Wadler hypothesized, based on the different patterns of strandbreaks, that cells may be capable of repairing radiation-inducedDNA breaks but not breaks induced by fluorouracil and interferon.Based on these data, he further hypothesized that modulator regimensmay have potential utility against radioresistant cell populations.