The eligibility criteria included histologically or cytologically proven, unresectable, advanced CRC. The patients had to be previously untreated for advanced disease, except for those patients in whom this therapy had been performed in the adjuvant setting at least 6 months before enrollment. Recurrent disease was defined as evident tumor progression after curative surgical resection or adjuvant treatment. The patients in this study were required to be 18 to 75 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 and a life expectancy of at least 3 months, and the presence of at least one uni-dimensionally measurable lesion was mandatory. Additional eligibility criteria included adequate bone marrow reserves (a white blood cell count ≥3×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥100 g/L and a hematocrit ≥30%), and also adequate liver function (a total bilirubin ≤3 times the upper limit of normal; an AST and/or ALT ≤5 times the upper limit of normal) and adequate renal function (creatinine ≤1.4 ml/min).

Patients were excluded if they had any active infection, any uncontrolled central nervous system metastasis requiring emergency radiotherapy and/or corticosteroids, any serious concomitant systemic disorders, a second primary malignancy (except in situ carcinoma of the cervix or non-melanomatous skin cancers) or any severe cardiovascular disease. Any patients who were pregnant or breast-feeding were excluded from the study.

The patients were non-randomly assigned to receive either FOLFIRI or a simplified FOLFIRI regimen. The FOLFIRI regimen consisted of irinotecan 180 mg/m² in 500 ml of 5% dextrose only on day 1, and this was concurrent with LV 200 mg/m² that was administered as a 2-hour infusion via a Y-connector before FU 400 mg/m² was administered as an intravenous bolus injection, and then FU 600 mg/m² was administered as a 22-hour infusion. The LV and FU were repeated on days 1 and 2. The simplified FOLFIRI regimen consisted of the same dosage of irinotecan with the simplified administration of LV 400 mg/m² as a 2-hour infusion before the FU 400 mg/m² was administered as an intravenous bolus injection, and then FU 2,400 mg/m² was administered as a 46-hour infusion (Fig. 1). Both regimens were administered at 2-week intervals until disease progression, unacceptable toxicity or stoppage by patient choice. Antiemetic prophylaxis with 5-HT3-receptor antagonist was routinely administered. Prophylactic use of granulocyte colony-stimulating factor or antibiotics was not permitted. Diarrhea or abdominal cramping or any other important symptoms of cholinergic syndrome that occurred during or within 1 hour after receiving irinotecan were treated with subcutaneous atropine 0.25 mg. For treating the symptoms of diarrhea and/or abdominal cramping that occurred more than 12 hours after receiving treatment, the patients were instructed to begin taking high-dose loperamide as soon as the first liquid stool occurred (2 mg orally every 2 hours for at least 12 hours and up to 12 hours after the last liquid stool, without exceeding a total treatment duration of 48 hours). Oral hydration with large volumes of water and electrolytes was prescribed during the whole diarrhea episode. If diarrhea persisted for more than 24 hours despite the recommended loperamide treatment, then 7-day, prophylactic, oral, broad spectrum antibiotic therapy with fluoroquinolone was initiated.

The dose adjustment schedule was evaluated at the beginning of a new course and during the previous course. It was based on laboratory analyses that were done on the scheduled day of treatment and on the day that the maximum toxicity was encountered. Chemotherapy was delayed until recovery if the neutrophils were ≥1.5×10⁹/L, the platelets were ≥100×10⁹/L, or for any significant persisting nonhematologic toxicity. The dose of Irinotecan was reduced to 150 mg/m² for grades 2 to 4 neutropenia, thrombocytopenia and diarrhea. The FU bolus and infusion dose was reduced to 80% if related ≥grade 3 toxicity occurred, whereas the LV dose remained fixed.

The clinical response evaluation procedure included all the laboratory or imaging studies that had shown abnormal findings prior to treatment. Objective tumor responses were assessed after three cycles according to the Response Evaluation Criteria In Solid Tumor (RECIST) (12). Briefly, a complete response (CR) was defined as the absence of disease at all previously known tumor sites for at least four weeks. A partial response (PR) was defined as a 30% reduction in the sum of the longitudinal diameters of all the target lesions, and this response lasted at least four weeks. Progressive disease (PD) was defined as either a 20% increase in the area of any one lesion over the prior measurement, or the development of one or more new lesions. Stable disease (SD) was defined as any change in the previous lesion that did not fit into either the PR or PD categories. All of the patients were evaluated for adverse reactions after the first dose of therapy according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0.

The objective response rate (RR) was defined as the best overall response for the CR or PR. Disease control was defined as the best tumor response for the CR, PR or SD that was confirmed and sustained for 4 weeks or longer. The overall survival (OS) was calculated from the date of enrollment to the date of death or to the date when the patient was last known to be alive. The time to the progression (TTP) of disease was calculated from the date of enrollment to the date of progression or death.

Evaluation of the objective response was the primary end point in this trial. The objective responses were reported as relative rates. The secondary end points were TTP, OS, the disease control rate and toxicity.

The intent-to-treat (ITT) population included all the patients who were assigned and treated, and who had undergone at least one disease assessment with using the same lesion imaging procedure that was used at the study's baseline. Per protocol analysis was performed on those subjects who were eligible and assessable for response without them having incurred any major protocol deviations. The primary analysis was made on the ITT population.

The RR and disease control rate were assessed with using chi-square tests. The results were presented in terms of the estimated difference in the response rates and the p value. The OS and TTP were estimated with using the Kaplan-Meier method, and these parameters were compared with using the log-rank test (13). Multivariate analysis of the prognostic factors was performed by the Cox proportional hazard method, with the variables of age (≤60, >60 years), gender (male, female), PS (0, 1 or 2), prior adjuvant chemotherapy (relapsed, initially metastatic), the number of involved organs, liver or lung metastasis, the type of the FOLFIRI regimen that was used and the presence of salvage chemotherapy (14). Statistical significance was defined as p values ≤0.05 for the analyses. All p values were based on two-sided testing.

From May 2001 and April 2006, a total of 26 previously untreated patients were recruited for this trial; all of them received chemotherapy and so they were included in the safety analysis. Among the 26 treated patients, 2 patients were excluded from the response evaluation due to their discontinuation of chemotherapy after one cycle; this was attributable to consent withdrawal and lost to follow-up for one patient each. Twenty-four patients finally constituted the per-protocol population. All the reported data are for the ITT population (26 patients). The median follow-up period was 8.5 months (range: 0.5~52.3). The characteristics of the patients are shown Table 1. The median age was 54 years (range: 40~75). Fourteen patients had previously received curative therapy including surgery or adjuvant treatment. Moreover, 13 patients had received LV plus FU adjuvant chemotherapy. The relapse-free survival of those 13 patients was 15.2 months. Twenty patients had 2 or more multiple organ metastases. Eleven patients received FOLFIRI and 15 patients simplified FOLFIRI.

The tumor response and disease control rate in the ITT population are presented in Table 2. Five of the 26 patients (19.2%) had a PR with one CR (3.8%). The RR was 23.1% (95% CI: 6.1~40.1). Although the RR for the FOLFIRI treated patients was higher than that for the simplified FOLFIRI treated patients (9.1 vs 33.3%, respectively), the RR of the two groups did not statistically differ (p=0.098). The observed disease control rate was 69.2%, and each disease control rate was 71.7% and 66.7% for the patients who received FOLFIRI and the simplified FOLFIRI, respectively (p=0.813).

The median survival was 11.2 months (range: 0.5~52.3, 95% CI: 7.4~15) (Fig. 2). The independent prognostic factor for improved survival was a good PS (p=0.001) (Fig. 3). The survival of the ECOG PS 0 patients did not reach to the median value, and the median survival of patients with an ECOG PS of 1 and 2 were 10.1 months and 7.3 months, respectively. Survival of the patients was not affected by other factors such as gender, age, prior adjuvant chemotherapy, the number of involved organs, liver or lung metastasis, the type of FOLFIRI and the salvage chemotherapy. The median TTP was 5.3 months (range: 0.4~19.9, 95% CI: 4.5~6.1) (Fig. 4). Any independent factors with statistically significance for improving the TTP were not detected.

All patients were assessable for toxicity. A total of 194 cycles were performed, and there were no therapy-related deaths. The median number of cycles was 7 (range: 1~18). Table 3 presents the patients who experienced treatment-related toxicities of NCI-CTCAE. The frequently observed toxicities were grades 1 and 2. A higher incidence of neutropenia was recorded for the patients who received the simplified FOLFIRI than for those patients who received FOLFIRI. Grade 3~4 neutropenias were more frequent for the simplified FOLFIRI treated patients. The incidence of the other grades 1~4 non-hematological and hematological toxicities were similar in both treatment groups.