New TS Inhibitor for Advanced Colon Cancer

MONTREAL, Canada--Tomudex (ZD1694), a new direct and specificthymidylate synthase (TS) inhibitor, has been shown to be especiallypromising for the treatment of patients with advanced colorectalcancer, David Cunningham, MD, said at the 19th International Congressof Chemotherapy.

The new TS inhibitor has antitumor activity at least as effectiveas the best standard therapy with the prototypic TS inhibitorfluorouracil in combination with leucovorin, while having significantlyfewer life-threatening side effects and producing better palliativeresults, said Dr. Cunningham, consultant oncologist, Institutefor Cancer Research and the Royal Marsden Hospital, Sutton, UK.

These conclusions were reached from a comparative phase III clinicaltrial in which 439 patients with previously untreated colorectalcancer were randomized to Tomudex, 3.0 mg/m² IV as a singledose once every 3 weeks (222 patients), or fluorouracil, 425 mg/m²,and leuco-vorin, 20 mg/m², as an IV bolus daily for 5 daysevery 4 or 5 weeks.

Five randomized patients did not receive therapy, but all individualswho received trial treatments, whether or not they were eligibleor evaluable, were included in the analysis.

With a median follow-up of 5.3 months, the overall response ratewas 20% in the Tomudex-treated patients (2% complete responseand 18% partial response) vs 13% for patients receiving fluorouraciland leucovorin (2% complete response and 11% partial response),Dr. Cunningham noted.

In addition, 21 patients in the Tomu-dex group and six on fluorouraciland leucovorin had 40% to 50% reductions in measurable lesionsize, strongly suggesting that with a longer follow-up, the resultswould be even more favorable with regard to Tomudex treatment,he said.

Different Toxicity Profiles

There were no statistically significant differences between thetwo treatment arms in terms of time to disease progression orsurvival, with 25% of all patients dead at 5.3 months of follow-up.There were, on the other hand, considerable differences betweenthe two treatment groups with regard to tolerability, performancestatus, and toxicity profile, Dr. Cunningham said.

Patients who received Tomudex were more likely to have an increasedperformance status, to gain weight, to spend less time in thehospital for treatment dosing (0.7 days per cycle vs 3 days percycle for fluorouracil/leucovorin), and to receive more of theplanned dose than persons in the standard therapy group.

Of particular importance, Dr. Cunningham said, Tomudex-treatedindividuals had markedly lower rates of potentially life-threateningtoxicities than did those who received fluorouracil and leucovorin.These included such adverse events as leukopenia (10% vs 26%)and mucositis (2% vs 22%). Furthermore, patients on Tomudex hada significantly lower incidence of alopecia.