Possibly the increased expression of these epidermal growth factor (EGF) ligands is responsible for driving the growth of these tumours. Recent reviews (146) and a pooled analysis (147) showed that both on univariate and multivariate analysis, there is a significantly lower tumour regression grade and a non significant trend towards a lower pCR rate (9% vs. 16%) when Cetuximab was added to a combination of 5-FU/ Capecitabine and Oxaliplatin. Recent work on the same data set has evaluated functional germline polymorphisms of EGF and TS (148), and biomarkers such as Kras status in combination with TS, VEGFR1 and VEGFR2d expression

Inhibitors,research,lifescience,medical (149) which appear to predict for histopathological response. Other potential markers Inhibitors,research,lifescience,medical of response include the TP53 mutation

(150). In an Italian study the EGFR gene copy number was found to correlate significantly with tumour regression and response to cetuximab (108) but is not prognostic in standard chemoradiotherapy (114). Even though in rectal cancer there will be no concern that expression in the primary tumour and metastatic Inhibitors,research,lifescience,medical sites will be different, rectal and colon cancers do have different gene expression profiles, different cytokeratin profiles, different levels of MSI-H, and different levels of mutations in Kras and BRAF (151-154). Thus PI3K inhibitor extrapolating results from colon cancer trials to the treatment in rectal cancer might not demonstrate the same outcome. Pre-clinical data suggests that the sequencing of chemotherapy, EGFR inhibition and radiation may be clinically significant and that the sequence of oxaliplatin followed by cetuximab may be more effective than cetuximab

prior to Inhibitors,research,lifescience,medical oxaliplatin [Morelli 2005 (155)]. Better efficacy might Inhibitors,research,lifescience,medical be achieved by integrating cetuximab in the latter portion of the radiotherapy, or following chemoradiation. This strategy has already been proposed when integrating anti-metabolites such as gemcitabine with EGFR inhibitors and radiation [Shewach 2007 (156)]. Finally, better selection for the potential efficacy of EGFR inhibition by molecular markers could be appropriate in the future (140). A recent study in rectal cancer examining a combined analysis of VEGF and EGFR identified a subgroup of EGFR-negative and VEGF-positive patients who appeared resistant to radiotherapy, of whom only 2/34 (6%) achieved a pCR (95). Early endpoints in terms of efficacy only at the level of the primary tumor (e.g., pCR), may not in themselves be coupled to longer-term endpoints such as DFS and OS. Phase III randomised studies are the best way to define the advantages of a novel treatment. It should be borne in mind that 50% of patients are in their 70s and more than 70% of patients with colorectal cancer are over 65. Many of these patients have extensive other co-morbidity including cardiac problems.