Despite advances in screening procedures and the use of adjuvant
therapy, approximately 50% of patients with
colorectal cancer eventually will develop metastatic disease. Long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung
metastases. For all other patients, treatment is palliative. For decades,
5-fluorouracil was the only available
drug for
colorectal cancer; hence, numerous trials were performed that used various administration schedules and modulating agents to improve therapeutic efficacy. The addition of
leucovorin to
5-FU improves response but not survival. Infusion schedules alter the toxicity profile but have a negligible impact on survival.
Irinotecan was the first new
drug to demonstrate activity in
colorectal cancer. It was used initially in the second-line setting, where it was shown to improve quality of life and survival over best supportive care or infusional
5-FU. Recently,
irinotecan has been incorporated into the front-line treatment of metastatic
colorectal cancer in combination with
5-FU and
leucovorin; this combination improves survival by approximately 3 months. Careful patient selection and adherence to strict dose adjustments are essential to prevent significant toxicity when patients are treated on this regimen. The oral fluoropyrimidine
capecitabine recently has been approved for the front-line treatment of patients with
colorectal cancer who are not appropriate candidates for combination
therapy.
Oxaliplatin, a novel
DACH (diaminocyclohexane)
platinum with definite activity in
colorectal cancer, is approved for this disease in Europe and is undergoing phase III clinical trials in the United States. Other drugs with potential activity in
colorectal cancer include
raltitrexed,
pemetrexed disodium, and the
epothilone analog
BMS-247550 (Bristol-Myers Squibb, New York, NY). Novel
cytostatics with promising activity in
colorectal cancer are being evaluated in clinical trials, including
epidermal growth factor receptor inhibitors, such as
IMC-C225 (Imclone Systems, New York, NY) and
ZD1839 (AstraZeneca, London, UK),
angiogenesis inhibitors such as
bevacizumab and
SU5416 (Sugen, San Francisco, CA), and
vaccines such as CEAVac (Titan
Pharmaceuticals, San Francisco, CA). For those patients whose disease is localized to the liver, there also is an emerging role for local
therapies, including
cryosurgery,
radiofrequency ablation, and hepatic artery infusional
chemotherapy, and resection. The emergence of these new drugs and new interventional modalities has allowed physicians who treat
colorectal cancer to move beyond
5-FU.