MB ChB MRCS
Riccardo A Audisio(*†)
Consultant Surgical Oncologist
Honorary Senior Lecturer
*Department of General Surgery
**Klinik für Onkologie/Hämatologie
†University of Liverpool
5-Fluorouracil (5-FU) has been the main drug used in adjuvant chemotherapy for colorectal cancer during the past 40 years. Two other agents in common usage are irinotecan and oxaliplatin. Studies continue into their role in first- and second-line treatment, and in combination with each other and 5-FU. Other new agents under development include cyclooxygenase 2 (cox-2) inhibitors and growth factor receptor inhibitors.
For the past 40 years, 5-FU has been the mainstay of treatment for advanced colorectal cancer. Various biochemical modulations of this drug have been investigated to identify its most efficacious form of administration. It has been proven that if folinic acid (FA) is given in combination with 5-FU, response rates increase, improving both progression-free survival and overall survival.(1)
Debate is ongoing over whether to give 5-FU as an infusion or orally. Infusional 5-FU appears to be more effective and have less toxic side-effects. However, a Port-a-Cath system is required, and many physicians feel that the oral route is more acceptable for patients. Various agents are currently being studied to improve the bioavailability of oral fluoropyramidines.
Ftorafur is metabolised to 5-FU by the liver, and uracil competitively inhibits the degradation of 5-FU. Phase II trials show further improvement in efficacy when given in combination with FA.
Capacitabine is an oral prodrug of 5-FU in the liver and in tumour cells.(2,3) No improvement in efficacy has been demonstrated when given in combination with FA.(4) Response rates obtained with capecitabine are similar to those found with bolus 5-FU regimens.(5,6) Lower rates of gastrointestinal and haematological toxicity have been found with capecitabine; however, 17% of patients developed a severe hand–foot syndrome.
Irinotecan, an active cytotoxic agent for various cancers, interacts with topoisomerase I. Significant improvements in response rate, progression-free survival and overall survival rates have been observed when given in combination with 5-FU/FA as first-line treatment.(7–10) Irinotecan has also been shown to prolong survival and improve quality of life when given as second-line treatment once the cancer fails to respond to 5-FU.(11) Late-onset diarrhoea is dose- limiting and requires loperamide and antibiotics in severe cases.
Oxaliplatin is a diaminocyclohexane platinum that acts by cross-linking DNA. When given in combination with infusional 5-FU/FA, a higher response rate and progression-free survival rate but no overall survival benefit are observed compared with infusional 5-FU/FA alone. Similarly, when given as a second-line therapy, oxaliplatin has been shown to improve response rate and progression-free survival but not overall survival benefit.(12–16) Neurotoxicity limits the use of this drug at high doses. Oxaliplatin has also been shown to cause thrombocytopenia in long-term use.
There is currently no general consensus as to whether combination therapy of 5-FU/FA with either
oxaliplatin or irinotecan should be used as first-line therapy or whether these drugs should be used in a sequential fashion. High toxicity and cost currently outweigh any proven survival benefit in first-line combination therapy. However, early trials show a benefit if the aim is for hepatic metastatic disease to become amenable to resection. (17–22) Current studies are investigating the benefits of three-drug combinations (5-FU, oxaliplatin and irinotecan).(23–28)
Cox-2 is an enzyme that is upregulated in colo‑rectal cancer adenomas and carcinoma.(29–32) Preclinical trials have shown that cox-2 inhibitors such as celecoxib and rofecoxib reduce the size of adenomas and cox-2-expressing tumour xenografts. They have also been shown to reduce the number of polyps by 28% in patients with familial adenomatous polyposis.(32) Further research is ongoing into the exciting potential of this group of drugs.
Cell proliferation, angiogenesis, apoptosis inhibition and metastasis involve the epidermal growth factor receptor (EGFR) pathway and promote cancer development.(33) Approaches to inhibit this signal cascade include antibodies against the EGFR and small molecules binding to the intracellular site of the receptor and inhibiting the tyrosine kinase.
Cetuximab (c225, Erbitux) is a chimeric monoclonal antibody with a high affinity for EGFR.(34) Ongoing studies show promising results when using cetuximab in combination with irinotecan.(35–38)
Tyrosine kinase inhibitors
Tyrosine kinase inhibitors (TKIs) bind to intracellularly localised tyrosine kinases of the EGFR. Phase II trials are being conducted, but so far no significant benefit has been proven.
The use of vascular endothelial growth factor receptor (VEGFR) inhibitor bevacizumab, in combination with 5-FU/FA or 5-FU/FA and irinotecan, leads to an increase in response rate and overall and progression-free survival rates, compared with 5-FU/FA alone.(39)
5-FU/FA remains the standard therapy in the treatment of advanced colorectal cancer. However, significant advances are being made, particularly with the introduction of irinotecan and oxaliplatin, with improved response rates and reduced metastatic liver deposits (such that they are becoming potentially resectable). Combination and sequential therapies also increase overall survival compared with 5-FU/FA alone. Promising research is arising, with the development of drugs targeting EGF or VEGF receptors. Strategies will increasingly aim to become more individually targeted, depending on performance status and personal requirements.
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