The management of patients with “locally advanced rectal cancer” (LARC) or unresectable cancer is changing. Different strategies and techniques have developed independently in different countries – and evolved separately in the face of local historical links, local experts, regional biases and individual national trials. Radiotherapy has a well-defined role to reduce local recurrence. In more advanced borderline/unresectable cases, where the circumferential resection margin (CRM) is breached or threatened (<1mm) according to magnetic resonance imaging (MRI), many patients still fail to achieve sufficient downstaging with current fluoropyrimidine-based CRT schedules. Even if local control is achieved, distant metastases have now become the predominant cause of failure in rectal cancer.

Rectal cancer is a heterogeneous entity. The response of an individual patients’ rectal cancer to CRT is highly variable and in an era of personalised medicine much effort is being applied to identify subgroups of patients who gain most and least from this treatment. An enormous effort has focussed on imaging and molecular biomarkers to predict response and outcomes.

Expanding options for cytotoxic chemotherapy and biologically targetted treatments with high response rates in metatsatic disease have created new interest. Integrating additional agents might enhance curative resection rates and improving distant control and survival.

However, to date, we lack validated biomarkers for these biological agents apart from wild-type KRAS.For cetuximab, an acneiform rash is associated with response, but low levels of magnesium appear more controversial. There are no molecular biomarkers for bevacizumab. Markers such as circulating endothelial cells (CECS), circulating levels of VEGF and the development of hypertension, have been proposed for bevacizumab. Yet these biomarkers only emerge after a trial of the agent.  We also lack a simple method of ongoing monitoring of ‘on target’ effects of these biological agents, which could determine and pre-empt the development of resistance, prior to radiological and clinical assessessments or even molecular imaging. These shortcomings probably explain our current relative lack of success in the arena of combining these agents with chemoradiation.