Use of irinotecan in secondline treatment of metastatic colorectal carcinoma

Question: What is the role of irinotecan (Camptosar(TM), CPT-11) in the second-line treatment of metastatic colorectal carcinoma? Perspective: Evidence was collected and reviewed by one member of the Gastro-intestinal Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The Gastro-intestinal Cancer DSG comprises of medical and radiation oncologists, surgeons, and epidemiologists. Community representatives did not participate in the development of this report, but will in future reports. Final approval of the guideline by the Co-ordinating Committee involved review by community representatives. Outcomes: Outcomes of interest were survival, time to disease progression, response rate, response duration, adverse effects, symptom improvement, and quality of life. Results: Quality of Evidence. Two randomised trials, six phase II trials, and one monograph were reviewed. Two randomised controlled trials compared irinotecan with best supportive care or 5-fluorouracil (5-FU) infusional chemotherapy in patients for whom first-line 5-FU bolus therapy failed. Benefits: One randomised controlled trial, involving 279 patients with a World Health Organization (WHO) performance status of 0-2, compared irinotecan given once every 3 weeks to best supportive care. Results demonstrated statistically significant improvement in 1-year survival (36% vs. 14%; p = 0.0001) and all domains of quality-of-life measures (except diarrhoea) favouring irinotecan. Another randomised controlled trial, with participation by 256 patients with a WHO performance status of 0-2, compared irinotecan with 5-FU infusional chemotherapy. Results demonstrated statistically significant improvement in 1-year survival (45% vs. 32%; p = 0.035) and time to disease progression (4.2 vs. 2.9 months; p = 0.030) favouring irinotecan. Quality-of-life scores were not different from those of patients treated with 5-FU infusional chemotherapy. Among 617 patients assessed in phase II trials, 26% had complete or partial tumour response to irinotecan. The pooled median time to disease progression in 497 patients with previous 5-FU failure was 4 months and the pooled median survival time was 10 months. Harms: During treatment with irinotecan, most patients experienced adverse effects, consisting of an early cholinergic syndrome, delayed diarrhoea, nausea and vomiting, neutropenia, asthenia, and/or alopecia. The randomised controlled trials used a 3-week schedule of irinotecan and detected grade 3-4 severe toxicity as follows: neutropenia in 19%, vomiting in 14%, and diarrhoea in 22% of patients. Pooled results from phase II studies revealed that grade 3-4 severe toxicity included diarrhoea in 33%, vomiting in 17%, and neutropenia in 38% of patients. A monograph reproting pooled data from three American phase II studies found cholinergic syndrome in 17% and asthenia in 12% of patients. Febrile neutropenia occurred in approximately 3% of patients and together with severe diarrhoea accounted for a less than 2% treatment-related fatality rate. About 5% of patients discontinued treatment because of toxicity. Studies that are more recent have documented lower grades of cholinergic syndrome, which can be well controlled with the early use of intravenous atropine. Delayed diarrhoea can be adequately controlled with the use of an intense schedule of oral loperamide. Nausea and vomiting are improved by prophylactic dexamethasone and ordansetron. Practice guideline: This practice guideline applies to patients with metastatic colorectal cancer in whom treatment with 5-fluorouracil has failed. Irinotecan can induce objective tumour responses in approximately 15% of patients with metastatic colorectal cancer after failure of 5-fluorouracil plus leucovorin (5-FU + LV) chemotherapy. Two randomised trials used a 3-week schedule of irinotecan for patients in whom treatment with 5-FU failed. Results demonstrated a significant increase in 1-year survival for patients treated with irinotecan compared to patients treated with best supportive care (36% vs. 14%) or patients who were retreated with 5-FU infusion regimens (45% vs. 32%). The quality of life of patients on irinotecan was better than that of patients on best supportive care, but no different from that of patients on 5-FU chemotherapy. Irinotecan is associated with serious side effects that require significant supervision and immediate treatment for severe drug-induced diarrhoea and neutropenia, which occur in 22% and 19% of patients, respectively. After full consideration of expected benefits and harms, it is appropriate to offer treatment with irinotecan for selected patients in whom 5-FU-based chemotherapy has failed. The patients in whom 5-FU-based chemotherapy failed were those that progressed during palliative chemotherapy or within 6 months of completing adjuvant therapy. Patients should also have a good performance status (2 or better) and should be able to have close medical supervision of treatment.