2 Clinical need and practice
2.1 Colorectal cancer is one of the most common malignancies in the UK, with an annual incidence of about 47 cases per 100,000 individuals. In 1999, 31,000 new cases of colorectal cancer were reported in England and Wales, and in 1998 almost 15,000 deaths were reported.
2.2 Colorectal cancer is rare in people under the age of 40 years. Approximately 41% of individuals with colorectal cancer are aged over 75 years, and 52% of deaths from colorectal cancer occur in this age group.
2.3 Colorectal cancer is defined as advanced if, at presentation or recurrence, it is either metastatic or so locally invasive that surgical resection is unlikely to be carried out with curative intent. Approximately 30% of individuals diagnosed with colorectal cancer present with advanced disease. Approximately 50% of those individuals who do not have advanced disease at presentation will subsequently develop this condition. Individuals with advanced colorectal cancer may experience a wide range of physical and psychological symptoms resulting in decreased quality of life. The 5-year survival rate is, on average, less than 5%.
2.4 The management of advanced colorectal cancer is mainly palliative, and involves a combination of specialist treatments (palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual's remaining life, while also controlling symptoms. Early chemotherapy before onset of symptoms has been shown to prolong survival and improve overall quality of life.
2.5 Individuals with advanced disease who are sufficiently fit (those with a World Health Organization [WHO] performance status of 2 or better) are usually treated with systemic chemotherapy as first- or second-line therapy. In individuals with a WHO performance status of 3 or 4 the adverse effects of chemotherapy may often be judged to outweigh the potential benefits, although the decision depends on the individual's clinical circumstances.
2.6 The standard chemotherapy regimen is typically a combination of 5-fluorouracil (5-FU) and folinic acid (calcium folinate, leucovorin). Thymidylate synthase (TS) – a key enzyme in pyrimidine biosynthesis – is inhibited by 5-FU, and folinic acid (FA) enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5-FU–TS complex. However, an increasing number of alternative chemotherapeutic options are under evaluation.
2.7 There are different 5-FU regimens, in which the drug is given either by intravenous infusion or bolus injection. There is considerable variability in current UK practice because of a lack of consensus over the optimum regimen. Although the rates obtained in individual trials have shown variation, there is some evidence to suggest that infusional regimens, for example the Lockich and de Gramont, may be more effective in terms of progression-free survival, tumour response, safety, toxicity and quality of life than bolus regimens, for example the Mayo. However, infusional regimens are more complex to administer and the use of central venous lines increases the rate of complications, such as infection and thrombosis.
2.8 Approximately 60% of individuals experience a response or a period of stable disease following first-line 5-FU/FA therapy. There is evidence from five RCTs that early chemotherapy for advanced disease improves survival by 3–6 months compared with a policy of deferring chemotherapy until required for symptom relief. In the five studies, median survival was increased from a range of 5–9 months to a range of 7.5–14 months. However, the benefits of therapy must be considered against the side effects of treatment, the potential need for multiple hospital visits and, in many cases, the problems and anxieties of having a central venous line.