Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy

Colorectal cancer originates in the lower part of the digestive system, including the colon and rectum. In metastatic colorectal cancer, the tumour spreads beyond the local or regional lymph nodes to other parts of the body. Approximately 32,000 people were diagnosed with colorectal cancer in England and Wales in 2008. The prevalence of colorectal cancer increases with age, from 35 per 100,000 in people younger than 60 years, to 345 per 100,000 in people over 75 years. The median age of people 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 duration of survival exist according to the stage of disease at diagnosis. In 2007, over 93% of people in the UK diagnosed with Stage A on the modified Dukes' classification system (the earliest stage of the disease) survived for 5 years compared with less than 7% of people with metastatic disease.

At the time of diagnosis, an estimated 20% to 55% of people with colorectal cancer already have metastatic disease. In addition, of the people who have undergone surgery for early-stage colorectal cancer, approximately 50% to 60% will eventually develop metastatic disease, most commonly in the liver.

Advanced, or metastatic, colorectal cancer is cancer that has spread beyond the colon to other areas of the body. The management of metastatic colorectal cancer is mainly palliative, that is, to relieve symptoms, and combines specialist treatments (such as palliative surgery, chemotherapy and radiation) with control of symptoms and psychosocial support. However, approximately 8% of people with metastatic colorectal cancer have potentially resectable liver metastases and, in some, chemotherapy may make these liver metastases operable.

The aim of treatment is to improve both the length and quality of the patient's remaining life. People with metastatic disease in sufficiently good health (World Health Organization performance status 2 or better) are usually treated with first-line chemotherapy and then, if their cancer progresses, second-line chemotherapy. For other people, the harms from chemotherapy may outweigh the potential benefits. Therefore, treatment depends on the person's individual circumstances.

Characteristics of the tumour that influence outcomes of treatment in people with metastatic colorectal cancer include the presence of: epidermal growth factor receptor (EGFR) and the 'wild-type' (non-mutated) form of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. Drugs that target EGFR are more effective against tumours expressing EGFR and a normal (wild-type) KRAS gene compared with those not expressing EGFR and with a mutated KRAS gene. Around 80% of people with metastatic colorectal cancer have EGFR-expressing disease and 30% to 50% have the KRAS wild-type gene.

As first-line treatment options for advanced colorectal cancer, NICE has recommended oxaliplatin in combination with 5-fluorouracil plus folinic acid (FOLFOX) and irinotecan in combination with 5-fluorouracil plus folinic acid (FOLFIRI) in NICE's previous technology appraisal guidance on colorectal cancer (advanced) – irinotecan, oxaliplatin and raltitrexed (now replaced by NICE's guideline on colorectal cancer). Other first-line treatment options recommended for metastatic colorectal cancer are the oral analogues of 5-fluorouracil: capecitabine or tegafur with uracil (in combination with folinic acid), in NICE's technology appraisal guidance on the use of capecitabine and tegafur. If metastatic disease is confined to the liver, and the patient has KRAS wild-type disease, the aim of first-line treatment is to make the metastases resectable surgically, and cetuximab may be given with FOLFOX or FOLFIRI, as in NICE's previous technology appraisal guidance on cetuximab (now replaced by NICE's technology appraisal guidance on cetuximab and panitumumab).

For second-line therapy in people whose disease has progressed despite first-line treatment, TA93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.