Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer

Colorectal cancer is a malignant neoplasm arising from the lining (mucosa) of the large intestine (colon and rectum). Colorectal cancer is the third most common cancer in the UK, with approximately 30,000 new cases registered in England and Wales in 2002. This represents 12% of all new cancer cases in women and 14% of all new cancer cases in men. The incidence of colorectal cancer increases with age. In people between the ages of 45 and 49 years, the incidence is 20 per 100,000. Amongst those over 75 years of age, the incidence is over 300 per 100,000 for men and 200 per 100,000 per year for women. The median age of patients at diagnosis is over 70 years. The overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in survival exist according to the stage of disease at diagnosis.

Metastatic colorectal cancer, where the tumour has spread beyond the confines of the lymph nodes to other parts of the body, is generally defined as stage IV of the American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system or stage D of Dukes' classification.

The population of patients with metastatic colorectal cancer includes both those who present with metastatic disease and those who develop metastatic disease after surgery. Estimates of people presenting with metastatic colorectal cancer range from 20% to 55% of new cases. Out of those who have undergone surgery for colorectal cancer with apparently complete excision, approximately 50% will eventually develop advanced disease and distant metastases (typically presenting within 2 years of initial diagnosis). The 5-year survival rate for metastatic colorectal disease is 12%.

The management of metastatic colorectal cancer is mainly palliative and involves a combination of specialist treatments (such as 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. Clinical outcomes such as overall survival, response and toxicity are important, but alternative outcomes such as progression-free survival, quality of life, convenience, acceptability and patient choice are also important.

The most frequent site of metastatic disease is the liver. In up to 50% of patients with metastatic disease, the liver may be the only site of spread. For these patients, surgery provides the only chance of longer-term survival. Approximately 10% of patients with metastatic colorectal cancer present with potentially resectable liver metastases and for approximately 14% chemotherapy may render unresectable liver metastases operable.

Individuals with metastatic disease who are sufficiently fit (normally those with World Health Organization performance status 2 or better) are usually treated with active chemotherapy as first- or second-line therapy. First-line active chemotherapy options include infusional 5-fluorouracil plus folinic acid or leucovorin (calcium folinate; 5-FU/FA, 5-FU/LV), oxaliplatin plus infusional 5-FU/FA (FOLFOX), and irinotecan plus infusional 5-FU/FA (FOLFIRI). Oral analogues of 5-FU (capecitabine and tegafur with uracil) may also be used instead of infusional 5-FU. For those patients first receiving FOLFOX, irinotecan may be a second-line treatment option, whereas for patients first receiving FOLFIRI, FOLFOX may be a second-line treatment option (in accordance with its licensed indication). Patients receiving 5-FU/FA or oral therapy as first-line treatment may receive treatment with FOLFOX and irinotecan as second-line and subsequent therapies.

Survival estimates for patients with metastatic colorectal cancer receiving best supportive care are approximately 6 months. The use of infusional 5-FU/FA can increase survival to approximately 10 to 12 months, whereas combinations of FOLFIRI followed by FOLFOX, or FOLFOX followed by irinotecan, have been reported to increase survival to 20 to 21 months.