Benefit-risk assessment of irinotecan in advanced colorectal cancer.
Irinotecan exerts its cytotoxic activity through inhibition of the nuclear enzyme topoisomerase I. It has been approved in most countries worldwide for treatment of patients with advanced colorectal cancer (CRC). Activity is seen in previously untreated patients and in patients refractory to fluorouracil treatment, whether it is given alone or in combination with other cytotoxic drugs. Irinotecan was first developed in patients refractory to fluorouracil. Activity in terms of tumour responses and patient benefit was seen in several phase II trials that used either a weekly or a three-weekly schedule. In two randomised trials (irinotecan vs best supportive care, and irinotecan vs an infused fluorouracil-based regimen), irinotecan prolonged median survival by approximately 2.5 months without any deterioration in quality-of-life. It was later studied in previously untreated patients with advanced CRC in combination with fluorouracil/folinic acid (leucovorin). In three large randomised trials, median time to tumour progression was prolonged by approximately 2.5 months and overall survival by about 2.5 months compared with fluorouracil/folinic acid alone. Tumour responses were also seen more frequently in the irinotecan arm (35-40% vs 20%). Again, quality-of-life scores were not deteriorated by the addition of irinotecan. Irinotecan has many acute adverse effects. The most prominent and dose limiting being diarrhoea and neutropenia. With irinotecan monotherapy, diarrhoea was seen in 80% of patients and severe grade 3 to 4 diarrhoea occurred in 30-40% of the patients. The severity of diarrhoea can be diminished by preventive actions. Less risk of diarrhoea is generally seen when irinotecan is combined with fluorouracil. Neutropenia is generally short-lived, but may be severe if diarrhoea is also present. This has been noticed particularly when irinotecan has been given in combination with a bolus fluorouracil/folinic acid regimen. Other toxicities include acute cholinergic-like symptoms, nausea and vomiting, and alopecia. In spite of these adverse effects, irinotecan has been accepted as an important first-line treatment for patients with advanced CRC, in combination with, preferably, an infused fluorouracil-based regimen, and has been approved for use as monotherapy in the second-line indication.
Glimelius
Bengt
B
Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden. bengt.glimelius@onkologi.uu.se
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000401:mortality; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012720:Severity of Illness Index
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin