I. Shchepotin

PURPOSE: The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. RESULTS: The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. CONCLUSION: The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

4000 Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m 2 initial dose then 250 mg/m 2 /week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m 2 , FA 400 mg/m 2 , 5-FU bolus 400 mg/m 2 , 5-FU infusion 2,400 mg/m 2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone. [Table: see text]

To date, none of the potential biological markers in colorectal cancer attempts to link the epidemiological data with the molecular biology of the disease. In an attempt to link dietary and epidemiological factors and to obtain a better understanding of the molecular biology of colorectal cancer, we measured vitamin D receptor (VDR) expression in 75 human colorectal cancers as a potential predictive marker of the biological behavior of the disease. Our results showed that a high level of VDR expression was associated with a favorable prognosis. The results of the studies reinforce the potential role that VDR may play in the development of the pathogenesis of colorectal cancer. Larger studies looking exclusively at stage I and stage II disease will hopefully lead to the development of a sensitive hormonal marker that can be used to predict the biological behavior of colorectal cancer, identifying at-risk patients in need of adjuvant treatment.

BACKGROUND: Some physicians still consider invasion of adjacent organs by the carcinoma of stomach as a sign of incurable disease. METHODS: This retrospective study has been done with particular reference to 353 T4 gastric cancer patients who underwent combined gastrectomies with adjacent organs. RESULTS: Subtotal gastrectomy was performed in 237 (67.1%) patients and total gastrectomy was performed in 116 (32.9%) patients. Organs most commonly resected with the stomach were the transverse colon in 159 (45%) cases, the tail of pancreas and spleen in 150 (42.5%), the left lobe of liver in 101 (28.5%), and the head of pancreas in 37 (10.5%) patients. A total of 110 postoperative complications occurred in this subset of patients corresponding to a complication rate of 31.2%. A total of 48 postoperative deaths occurred in this subset of patients corresponding to a mortality rate of 13.6%. The 5-year survival rate for all patients who underwent combined gastrectomy with adjacent organs was 25%. Of the node-negative T4 gastric cancer resections, 37% survived 5 years whereas the T4 node-positive resections have only a 15% 5-year survival. CONCLUSIONS: Patients who present with T4 gastric cancer (about 20% of the patient population) will benefit from aggressive en bloc surgical resection and should not be considered unresectable.