Colorectal cancer is the second leading cause of cancer-related death in the Western world. Physicians today have an abundance of drug therapies available to improve survival length for more advanced cancer patients. Now the discovery of genetic biomarkers relevant to CRC means that targeted personalised medication is increasingly common.

Colorectal cancer affects approximately 150,000 patients and leads to over 52,000 deaths every year in the US alone. In the early stages, colorectal carcinoma can often be cured by surgery. It is in the more advanced, palliative cases that the abundance of drug therapies comes into play.

Oncologists now integrate conventional cytotoxic agents Oxaliplatin and Irinotecan ( which directly fight tumour cells ) with treatments such as Bevacizumab ( Avastin ) and epidermal growth factor receptor ( EGFR ) antibodies, Cetuximab ( Erbitux ) and Panitumumab ( Vectibix ), as novel targeted agents into standard medical therapy. The result is that median overall survival in metastatic colon and rectal cancer now exceeds two years for the first time.

For decades, standard first-line therapy consisted of the drugs Fluorouracil ( 5-FU ) plus Leucovorin, which helped just a fifth of patients to survive a median of one year. In the late 1990s and early 2000s, the addition of Oxaliplatin and Irinotecan to the backbone of 5-FU and Leucovorin led to dramatic improvement in median survival to nearly 24 months. Most recently, biologic agents such as Bevacizumab, Cetuximab, and Panitumumab, have yielded even better results for many patients.

One targeted agent is Bevacizumab ( a monoclonal antibody developed by Genentech ), which inhibits vascular endothelial growth factor ( VEGF ), a natural protein that the tumour uses to grow new blood vessels ( angiogenesis ). Bevacizumab was the first angiogenesis inhibitor available in the US, and has become established as a standard component of first-line chemotherapy.

To date, no researchers have identified a predictive marker for Bevacizumab's activity in metastatic colorectal tumor. Key questions surrounding Bevacizumab's use in the palliative setting are whether it provides clinical benefit beyond the stage of tumour progression, and which patient group is at higher risk for Bevacizumab-related toxicities. Data from a large observational, non-randomised cohort study by Grothey and colleagues in 2008 suggests that patients may benefit from continued use of Bevacizumab beyond tumour progression . Randomised phase III clinical trials are currently underway in Europe and the US to determine whether this should become standard practice.

Anti-epidermal growth factor receptor antibodies Cetuximab and Panitumumab are both targeted monoclonal antibody treatments that have demonstrated efficacy both in combination with chemotherapy or, in contrast to Bevacizumab, used alone. Trials on unselected patient groups show limited results. But clinical trials and translational studies now indicate that those patients with advanced colorectal cancer must have a tumour with specific genetic mutations ( wild type KRAS and wild-type BRAF ) for EGFR antibodies to be effective. Testing for BRAF and KRAS mutations now excludes about half of patients with colorectal tumor from an ineffective, but potentially harmful ( and expensive ) therapy with Cetuximab and Panitumumab.

Clinical decisions regarding whether the goal is to rapidly shrink a tumour, whether to attempt curative surgery or to rapidly boost short-term quality of life or survival, or instead aiming for a longer-term quality of life with minimum side effects will determine the physician's choice of approach.

Targeted agents have become an integral part of medical therapy for advanced colon and rectal carcinoma. The next challenge for oncologists is to develop a rationale and biomarker-based treatment algorithm to use all potentially active agents as individualized therapy.
< br> Source: Therapeutic Advances in Medical Oncology, 2009

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