However, only one European trial of chemoradiation published in the last decade impacted on disease free survival (DFS) (4) and none on

overall survival (OS). Driving down the risk of local recurrence has in turn highlighted the risk of metastatic disease in 30-40% of cases, which appears now the predominant problem (5). Chemoradiation has an important role for more locally advanced cases where surgery for complete tumour clearance is regarded as borderline, or in unresectable cases, where Inhibitors,research,lifescience,medical the mesorectal fascia (MRF) is breached or the PD-0332991 datasheet pathological circumferential resection margin (CRM) potentially threatened according to the magnetic resonance imaging (MRI). In this advanced group selected by MRI, current chemoradiation schedules are only partially effective, since some patients still fail to achieve sufficient downstaging for surgery to be considered. Of those operated

upon many do Inhibitors,research,lifescience,medical not achieve an R0 resection (6). Even with chemoradiation at least half the patients fail to achieve T-stage downstaging (4,6). Response is therefore important Inhibitors,research,lifescience,medical not only for unresectable cancers. When downstaging is observed after radiochemotherapy, there are fewer recurrences and a better prognosis. Both combination chemotherapy and the use of targeted therapies in addition to chemotherapy have made a significant impact on the ability to resect initially unresectable liver metastases (7-9). Yet attempts to increase response rates by integrating 2 cytotoxic drugs into CRT regimens have often been accompanied by excess toxicity and only minimal increases in efficacy. The integration of biological agents into chemoradiation is an attractive strategy both to improve local control and to reduce the high risk Inhibitors,research,lifescience,medical of metastases (in combination with

or without chemotherapy) because of the targetted agents specificity and perceived lower levels of associated toxicity. However, it should be noted that Bevacizumab as a single agent was associated with a 36% overall incidence of grade 3 or 4 toxicity in the E3200 trial (10), and Cetuximab as a single agent Inhibitors,research,lifescience,medical was associated with a 43% overall incidence of grade 3 or 4 else toxicity in the BOND trial (11). It should be borne in mind that cytotoxic agents such as irinotecan and biologically targeted monoclonal antibodies such as bevacizumab and cetuximab despite their acknowledged efficacy in the metastatic setting, have consistently failed to show a benefit in DFS or OS when used as adjuvant chemotherapy in the postoperative setting in colon cancer (12-15). This observation underlines the principle that the use of combinations cannot simply be based on presumptions, but must be tested in prospective trials. Novel biologically targetted agents may interact with cell signalling pathways involved in DNA repair, cellular proliferation apoptosis and angiogenesis which are differentially expresssed in tumour and normal tissues.