Most patients with colorectal cancer (CRC) who have failed initial 5-fluorouracil (5-FU) chemotherapy have worsening of disease-related symptoms (DRS) and quality of life (QOL). Irinotecan has a reported response rate of 10%-20% in such patients. The aim of this phase II trial was to prospectively determine the palliative benefit of irinotecan utilizing DRS as primary endpoints of response. Patients had advanced CRC refractory to 5-FU with at least 1 DRS defined as (1) Karnofsky performance status (KPS) 60%-80%, (2) baseline analgesic use > or = 10 mg morphine/day (or equivalent), or (3) disease-related pain score > 1 cm on a 10-cm linear analogue self-assessment (LASA) scale. Patients received irinotecan 125 mg/m2 weekly for 4 weeks on an every-6-weeks schedule. The primary endpoint was palliative response defined as > or = 50% decrease in pain score or analgesic usage, or 10% increase in KPS, from baseline for 4 weeks. QOL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) version 2 instrument. A total of 65 patients were entered onto the study. Median baseline parameters were KPS 70%, analgesic score 11 mg/day, and pain score 2.4 cm. A palliative response was achieved in 27 patients (42%), improvement in pain score predominated. LASA and EORTC QLQ-C30 instruments showed parallel changes in DRS. The radiological response rate was 11% (complete responses and partial responses, n = 46); 23 patients achieved stable disease. Median overall survival was 7.2 months. Irinotecan provides a rate of palliative benefit higher than the radiological response rate. Patients-oriented palliative endpoints can be useful in assessing the benefit of agents in early-phase clinical trials.