Mansoura Randomized Trial: Irinotecan/de Gramont Regimen Versus de Gramont Regimen Alone in Chemotherapy-Naive Metastatic Colorectal Carcinoma

Background: The mainstay of treatment for metastatic colorectal carcinoma is chemotherapy. The de Gramont regimen [high-dose leucovorin (LV) and fluorouracil (5-FU) bolus plus continuous infusion every 2 weeks] had been proved to be superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5 day bolus 5-FU/LV regimen in the metastatic state.Irinotecan (C PT-11), a semi-synthetic derivative of camptothecin, has been shown to exert a cytotoxic action in colorectal carcinoma via the potent and specific inhibition of the nuclear enzyme DNA topoisomerase 1.Purpose: Investigating the difference in response, toxicity, progression-free and overall survival between the de Gramont regimen alone and the irinotecan plus the de Gramont regimen in the management of cases of metastatic colorectal carcinoma in our locality.Patients and Methods: 160 patients with metastatic colorectal carcinoma were referred mainly from the Gastro Enterology Center (GEC) to both the Clinical Oncology and Nuclear Medicine Department and the Oncology Center of Mansoura University and randomized to receive a 2-hour infusion of LV (200mg/m^2/d) followed by a 5-FU bolus (400mg/m^2/d) and 22-hour infusion (600mg/m^2/d) for 2 consecutive days every 2 weeks, either alone (group A) or together with irinotecan (180mg/m^2, 30 min intravenous infusion) on day 1 (group B).Results: Median follow up period was 15 months. Patients allocated to the irinotecan/deGramont regimen had statistically better response rate and symptom amelioration (p=0.04). Moreover, improvement of patients weight and performance status were statistically better in group B (p=0.03 and 0.02 respectively). Concerning survival figures, group B had statistically better median progression free survival (8 versus 5 months respectively) and better median overall survival (17 versus 14 months respectively) (p=0.00 and 0.01 respectively). As regard toxicity, both diarrhea and neutropenia of grade 3 and 4 were more encountered in group B (p=0.004 and 0.003 respectively).Considering prognostic factors, independent favorable prognostic factors affecting both response and progression- free survival were receiving irinotecan, good performance status and normal levels of both hemoglobin and white blood cell count at presentation. On the other hand, independent favorable prognostic factors affecting overall survival were good performance status receiving irinotecan, limited number of metastatic foci and normal levels of hemoglobin, white blood cell count and alkaline phosphatase at presentation.Conclusion and Recommendation: The benefit of adding irinotecan to the de Gramont regimen was reflected positively on all the end points as response, progression-free and overall survival. In addition, the toxicity is generally tolerable and manageable.It is clear that performance status, the number of metastatic foci, and the level of each of hemoglobin, white blood cell count and alkaline phosphatase at time of presentation had their prognostic effect on the course of metastatic colorectal carcinoma.