12) in patients with wild-type K-ras (114) In contrast, K-ras s

12) in patients with wild-type K-ras (114). In contrast, K-ras status did not significantly influence response in a Belgian study using cetuximab prior to and concurrent with capecitabine and (97). In a pooled analysis of 2 phase II studies, KRAS mutations were detected in 20 of the 82 patients (24.4%). 3-year DFS was higher i.e., 86.6% versus 75.0% Inhibitors,research,lifescience,medical but not significantly improved for patients receiving cetuximab with chemoradiation

and chemoradiation alone, The lack of difference in outcomes remained whether assessed in KRAS wild-type or mutant patients (115). Some authors have pointed out that there may be an optimal sequence of chemotherapy, biological agent and radiation if we are Inhibitors,research,lifescience,medical to avoid the potential for antagonism (58). The lack of additive effect can be explained if the addition of other agents

leads to an over targeting of one target (? the endothelial cells within the tumour); if the novel agent leads to cell-cycle arrest protecting cells from the effects of 5-FU; if drug concentrations are suboptimal because of the low weekly doses being ineffectual; if there are antagonistic drug-drug interactions which could be more prominent in the presence of radiation [we know from the PACCE and CAIRO (23,116) trials that combinations of cetuximab and chronic myelocytic leukemia bevacizumab with 5-FU and oxaliplatin are antagonistic]; if biological agents and the Inhibitors,research,lifescience,medical apoptotic response and hence secondary Inhibitors,research,lifescience,medical immune phenomena are modified—after all neither bevacizumab nor cetuximab appear effective in the adjuvant setting; finally a heightened inflammatory response may simply attract more stem cells and actually assist repair. The multifactorial nature of these potential problems is obvious and poses a significant challenge if we wish to continue this form of biological, chemotherapeutic and radiation integration. However,

some authors claim that target guided individualisation Inhibitors,research,lifescience,medical of treatment according to molecular markers can be successfully achieved (117). A large multinational randomised phase II study EXPERT-C (NCT00383695) has compared neoadjuvant therapy comprising combination chemotherapy (oxaliplatin and capecitabine), with or without cetuximab followed by chemoradiotherapy with capecitabine with or without cetuximab in 164 patients (56). In the EXPERT-C trial, retrospective molecular analysis for KRAS/BRAF Drug_discovery was successfully performed in 149 patients, of whom 90 (60%) were wild type. The pCR rate was not significantly higher with the addition of cetuximab to preoperative chemotherapy and CRT either for the group with locally advanced rectal cancer as a whole (18% versus 15% respectively), nor for KRAS wild-type – although this percentage is diluted by the fact that some samples achieving pCR were not available for Kras testing. Interestingly DFS in the selected KRAS wild-type group who received cetuximab was higher (56).

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