Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer.

BACKGROUND: Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC. PATIENTS AND METHODS: Forty-eight patients entered the trial and received irinotecan 350 mg/m2 d.1 and raltitrexed 3 mg/m2 d.2, every three weeks. After recruitment of the first 16 patients, grade III-IV toxicity was observed in 6 patients (38%). Therefore, an amendment reduced by 15% the dose of both drugs (irinotecan 300 mg/m2, raltitrexed 2.6 mg/m2). RESULTS: A total of 290 cycles were administered (range 1-18, median number 6). According to intention-to-treat analysis, the overall response rate was 27% (95% confidence interval 16%-42%), including 3 complete responses and 10 partial responses. The median duration of response was 10 months, while median progression-free survival and overall survival were 5 and 14 months, respectively. In the first 16 patients, the main toxicities were grade III-IV diarrhea in 25% and grade III-IV neutropenia in 13%. In the subsequent 32 patients, they were grade III-IV diarrhea in 34% and grade III neutropenia in 6%. Two toxic deaths occurred. CONCLUSION: The combination irinotecan-raltitrexed is an active regimen, but the significant incidence of side-effects requires accurate patient selection and, eventually, new schedules.

Experimental assessment of chemotherapy-induced early intestinal damage in colon cancer the lactulose-mannitol permeability test.

AIMS AND BACKGROUND: Although chemotherapy plays an important role in the management and cure of cancer, it has undesiderable side effects mostly affecting the bone marrow and gastrointestinal tract, which greatly limit patient compliance and treatment efficacy. METHODS: The lactulose-mannitol test was used to assess intestinal mucosa damage 48 hours after the end of the first adjuvant chemotherapy cycle with 5-fluorouracil (5-FU) and levamisole in 12 patients with colon cancer. Fifteen age- and sex-matched subjects were studied as controls. The excreted amount of lactulose and mannitol was expressed as the percentage of the administered doses recovered in the urine as well as their ratio. RESULTS: The percent urinary recovery of lactulose was significantly (P < 0.001) higher in colon cancer patients (1.1 +/- 0.5%) than in the control group (0.3 +/- 0.03%), whereas the mannitol recovery was only slightly reduced in the former. As a result, the lactulose/mannitol excretion ratio was significantly (P < 0.001) higher in colon cancer patients (0.07 +/- 0.03) than in the control group (0.01 +/- 0.01). CONCLUSIONS: As assessed by the lactulose-mannitol test, the combined chemotherapy regimen with 5-FU and levamisole affects mainly the barrier function of the intestinal mucosa rather than its absorption capacity. The toxic effect seems to be attributable to the 5-FU molecule rather than to levamisole. The lactulose-mannitol test is a simple, safe and reliable tool to evaluate chemotherapy-induced early damage to the intestinal epithelium, in particular when new kinds of substances are being administered. Its use in clinical practice seems appropriate to establish the correct timing of drug administration, thereby enhancing treatment efficacy and improving patient compliance.