The treatment of metastatic colorectal cancer in 2008 and beyond

Dr Mark Saunders, Christie Hospital, Manchester, UK

Around half of the 35,000 patients diagnosed with colo-rectal cancer each year in the UK will go on to develop metastases and will die of their disease. Without treatment, the median survival of these patients with advanced colo-rectal cancer (ACRC) is around 6 months, with few surviving beyond one year. Until relatively recently, treatment options were limited. 5-Fluorouracil (5FU) has been the mainstay of treatment for 40 years; its use increases median survival to around 12 months.

The development of new agents active in the treatment of ACRC has greatly altered the management of this disease. Combinations of irinotecan and oxaliplatin with 5FU have brought new opportunities to prolong survival and improve quality of life. New oral fluoropyrimidines such as capecitabine and UFT offer convenient oral alternatives to intravenous treatments and the development of surgical resection of hepatic and pulmonary metastases offers the hope of cure to patients with ACRC.

There are now a series of randomised controlled trials with irinotecan that show a survival benefit over 5FU/FA combinations. There have also been a number of randomised studies with oxaliplatin that have shown similar efficacy. “Triple therapy” with all three drugs being used at some point, has lead to even greater benefits with overall survival times approximating 18-21 months. These significant advances lead to Dr Leonard Saltz (Memorial Sloan-Kettering) to state that, “we need all three drugs. We have conflicting data about how to best use them, but, clearly, we need to have them all available for our patients” (ASCO, May 2002).

The oral fluoropyrimidines such as capecitabine and UFT are more convenient and acceptable forms of chemotherapy compared to the intravenous fluoropyrimidine, 5FU. Both are prodrugs of 5FU. Two randomised studies with capecitabine and two with UFT have shown equivalence to bolus iv 5FU/FA with acceptable toxicity profiles. Although both drugs cost more than 5FU/FA, there will be many savings in terms of central venous catheters, infusion pumps, hospital visits and staff time. Combinations of irinotecan and oxaliplatin with one of these oral fluoropyrimidines are rapidly emerging aiming to combine both efficacy and convenience of treatment without central catheters. At last, after 40 years of only being able to administer 5FU in numerous different ways, its days may be finally numbered!

As our knowledge of tumour biology and genetics matures, agents that interact with novel disease-associated targets will be developed. Two such existing agents are the monoclonal antibodies: bevacizumab; which binds vascular endothelial growth factor (VEGF) thereby interfering with signalling through the VEGF receptor and inhibiting angiogenesis, and cetuximab; which binds to and inhibits activation of the epidermal growth factor receptor (EGFR). Most of the current data relating to the efficacy of targeted agents has been derived using irinotecan combinations. Bevacizumab has been shown to provide a significant survival advantage when added to conventional irinotecan and 5FU chemotherapy in chemo-naive patients, whilst, cetuximab has shown benefits when added to irinotecan after resistance to this drug has developed.

The treatment of metastatic colorectal cancer has advanced considerably over the last five years with a corresponding increase in response rates and patient survival. There is now considerable hope for patients suffering from this awful illness.

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