From chemotherapy to targeted therapy in adjuvant treatment for stage III colon cancer.
ABSTRACT Colorectal cancer represents a major public health problem due to its frequency and mortality rate. Adjuvant chemotherapy has improved the prognosis of colon cancer. Six months of oxaliplatin and fluoropyrimidine in combination is the standard adjuvant treatment in stage III patients. Ongoing trials are evaluating the optimal duration of chemotherapy. A critical issue, which needs to be specifically addressed, is the role of adjuvant therapy in elderly patients. Preliminary results of trials evaluating targeted therapies in combination with chemotherapy have shown disappointing results. The monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF) and cetuximab, targeting epidermal growth factor receptor (EGFR)/HER1, which improved survival in patients with metastatic colorectal cancer, could even induce chemotherapy resistance in a significant number of patients in the adjuvant setting. A major challenge is emerging to understand the mechanism leading to this effect and to multi-target the tumor cell proliferation and survival network. Clarity regarding the clinical signal needed before launching a phase III study and optimized designs adapted to multiple agents are urgently needed for new trials.
Article: Progressive increase of matrix metalloprotease-9 and interleukin-8 serum levels during carcinogenic process in human colorectal tract.[show abstract] [hide abstract]
ABSTRACT: Inflammatory reactions, known to promote tumor growth and invasion, have been found associated with colorectal carcinoma (CRC). Macrophages are the chief component of the inflammatory infiltration that occurs early in the progression from non-invasive to malignant tumor, with a switch from the pro-inflammatory phenotype to the tumor-promoting phenotype. Tumor and stroma are additional sources of inflammation-related molecules. The study aimed to evaluate, during colorectal carcinogenesis from benign to malignant phases: i) the trend of serum levels of IL-8, IL-6, TGFβ1, VEGF and MMPs; ii) the parallel trend of CRP serum levels; iii) derangement of the principal TGFβ1 receptors (TGFβ1RI/RII) in tumor tissues. 96 patients with colon adenomas or CRC at different stages of progression, and 17 controls, were recruited. Serum IL-8, IL-6, TGFβ1, VEGF, MMPs and CRP levels were analyzed before endoscopy or surgery. TGFβ1 receptors were evaluated in adenoma biopsies and surgically-removed colorectal adenocarcinomas. Serum levels of IL-8 in adenocarcinoma patients were increased from stage II, when also the enzymatic activity of MMP-9 increased. Of note, the increasing trend of the two serum markers was found significantly correlated. Trend of serum CRP was also very similar to that of IL-8 and MMP-9, but just below statistical significance. TGFβ1 levels were lower at stage III CRC, while IL-6 and VEGF levels had no significant variations. In tissue specimens, TGFβ1 receptors were already absent in about 50% of adenomas, and this percentage of missing receptors markedly increased in CRC stages III and IV. Combined quantification of serum IL-8, MMP-9 and CRP, appears a reliable and advanced index of inflammation-related processes during malignant phase of colorectal carcinogenesis, since these molecules remain within normal range in colorectal adenoma bearing patients, while consistently increase in the blood of CRC patients, even if from stage II only.PLoS ONE 01/2012; 7(7):e41839. · 4.09 Impact Factor