New Drugs Show Promise in Front- and Second-Line Treatment of Colorectal Cancer

CHICAGO--With an overall response rate of only 2.8% to drugs testedon more than 1,200 colorectal cancer patients over the last 20years, new drug development has given gastrointestinal oncologistslittle to be enthusiastic about.

This picture has changed markedly in the last year, however, withFDA approval of CPT-11 or irinotecan (Camptosar), a drug activeagainst refractory colorectal cancer, and early clinical trialresults of three other drugs which could someday supplant fluorouracilin the treatment of primary colorectal cancer, said Mace Rothenberg,MD, at the 9th meeting of the Atlanta-based Network for OncologyCommunication & Research.

CPT-11 was approved based on overall response rates of 13% inthree phase II clinical trials of patients whose colorectal diseasehad progressed after one fluorouracil-based regimen. More important,Dr. Rothenberg said, the drug stabilized colorectal cancer inan additional 50% of patients.

"We were all trained to believe that stable disease indicatedno benefit. I disagree with that position. With this drug, wesee a consistently high percentage of patients whose disease stabilizedfor a median period of 6 months, a meaningful period of time beforedeveloping progression," said Dr. Rothenberg, associate professorof medicine, University of Texas Health Science Center, San Antonio.

Tomudex Results Pending

Among the drugs that have potential as front-line therapies forcolorectal cancer, tomudex (Merck & Co., Inc.) has progressedthe furthest in clinical testing, Dr. Rothenberg said. In phaseII trials in Europe and Australia, the drug achieved an overallresponse rate of 26% and stabilized disease in an additional 49%of 177 newly diagnosed patients with colorectal cancer.

The drug also appeared to be equivalent to fluorouracil plus low-doseleuco-vorin in a European phase III trial involving 439 newlydiagnosed colorectal cancer patients.

Overall response rates were 20% for tomudex and 16.4% for fluorouracil;time to progression was 4.9 months for tomudex versus 3.6 monthsfor fluorouracil; and median survival was 10.3 months for tomudexversus 10.6 months for fluorouracil. In addition, patients takingtomudex had significantly less grade 3 or 4 mucositis and leukopenia.

Findings from two follow-up phase III trials comparing tomudexwith the fluorouracil/leucovorin combination are pending. "Whenthese results mature, if they indeed show that the two drug regimensare equivalent and that tomudex is more convenient and less toxic,you may see approval of tomudex in a year's time," Dr. Rothenbergsaid.

MTA and Capecitabine

Multi-targeted antifol or MTA (LY231514, Eli Lilly and Company),which inhibits three enzymes involved in DNA synthesis, is ata pivotal stage of development awaiting final data from phaseII trials, he said.

The two-staged trials have documented objective responses to MTAin the first 25 colorectal patients studied, but full accrualof 45 patients has not yet been completed. "We did see somepromising activity in the early stages, but the final resultsare not available yet," Dr. Rothenberg noted.

Capecitabine (Hoffmann-La Roche, Inc.) is a fluorouracil pro-drugthat is activated by pyrimidine nucleoside phosphorylase, an enzymeexpressed in higher levels in tumor cells. "So there is potentialfor inducing selective cytotoxicity in tumor cells--somethingwe've all been striving for but have been very unsuccessful atachieving," Dr. Rothenberg said.

Capecitabine Activates Cytokines

In addition, he said, capecitabine appears to have a superiortherapeutic index compared to fluorouracil, and it activates cytokines,such as tumor necrosis factor and interleukin-2, which may contributeto cytotoxicity.

At least one European phase I trial has documented objective responsesto cape-citabine in colorectal cancer patients, and a trial inthe United States showed that capecitabine given on a continuousdosing schedule twice a day was rapidly taken up by the GI tract,"which is what was hoped for," Dr. Rothenberg said.