Annals of Oncology Advance Access originally published online on August 20, 2008
Annals of Oncology 2009 20(2):251-257; doi:10.1093/annonc/mdn557
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Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study
1 Medical Oncology Service, Hospital Universitario Reina Sofía, Córdoba
2 Department of Medical Oncology, Complejo Hospitalario Juan Canalejo Marítimo de Oza, La Coruña
3 Department of Medical Oncology, Instituto Catalán de Oncología, Hospital Duran i Reinals, Barcelona
4 Department of Medical Oncology, Hospital Regional Universitario Carlos Haya, Málaga
5 Department of Medical Oncology, Hospital General Universitario de Alicante, Alicante
6 Department of Medical Oncology, Hospital Santa Creu i Sant Pau, Barcelona
7 Department of Medical Oncology, Complejo Hospitalario de Pontevedra, Pontevedra
8 Department of Medical Oncology, Fundación Hospital Alcorcón, Madrid
9 Department of Medical Oncology, Hospital General Universitario de Elche, Alicante
10 Department of Medical Oncology, Hospital Ciudad de Jaén, Jaén
11 Medical Oncology Service, Hospital Universitario Clínico San Carlos, Madrid, Spain
* Correspondence to: Dr E. Aranda, Medical Oncology Service, Hospital Universitario Reina Sofía, Avda Menéndez Pidal s.n., 14004 Córdoba, Spain. Tel: +34-957-011-582; Fax: +34-957-011-626; E-mail: earandaa{at}seom.org
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abstract |
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Background: Irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI) is accepted as a reference treatment for the first-line treatment of patients with metastatic colorectal cancer (MCRC). The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate).
Patients and methods: Chemotherapy-naive patients with MCRC were randomized to receive either irinotecan (180 mg/m2 on day 1) + 5-fluorouracil (5-FU) (400 mg/m2 bolus and 600 mg/m2 22-h infusion) + LV (200 mg/m2 on days 1–2) (FOLFIRI) every 2 weeks or irinotecan (80 mg/m2) + 5-FU (2.250 mg/m2 48-h infusion) (FUIRI) weekly.
Results: In all, 346 patients were included, 173 in each arm. In the intention-to-treat analysis, the response rates for FOLFIRI and FUIRI were 57% [95% confidence interval (CI) 49% to 64%] and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statistically significant differences were observed between FOLFIRI and FUIRI regarding median progression-free survival (8.3 versus 8.4 months; P = 0.4339) nor median overall survival (21.6 versus 19.2 months; log-rank test P = 0.2941). Grade 3/4 neutropenia was significantly more frequent on FOLFIRI arm (27% versus 9%), while the proportion of diarrhea was higher on FUIRI arm (21% versus 42%).
Conclusion: FUIRI represents a valid alternative without LV to the FOLFIRI regimen as MCRC first-line treatment.
Key words: colorectal cancer, 5-fluorouracil, irinotecan
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introduction |
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Until recently, the standard treatment for metastatic colorectal cancer (MCRC) has been 5-fluorouracil (5-FU)-based chemotherapy [1]. Furthermore, the efficacy of continuous infusion 5-FU relative to that of bolus 5-FU was a subject of ongoing debate. Most studies comparing continuous infusion with bolus administration are in favor of continuous infusion in relation to response rate and, probably, time to progression, although overall survival (OS) is not clearly better. The meta-analysis of six randomized trials in a total of 1219 patients with CRC showed higher response rates and slightly longer survival with continuous infusion 5-FU than with bolus 5-FU [2, 3]. In addition, the incidence of grades 3 and 4 hematotoxicity was lower with continuous infusion 5-FU. There is, however, no consensus on the optimal schedule of continuous infusion 5-FU. The most popular continuous infusion schedules in Europe are the de Gramont regimen (France) [4], AIO (Germany) [5] and Treatment of Digestive Tumors (TTD) (Spain) [6]. However, the response rates and median survival times achieved with infusional 5-FU alone are not optimal and more efficacious therapies are needed.
Currently, after the publication of several phase III studies of combination of 5-FU, leucovorin (LV), and irinotecan or oxaliplatin, these regimens are considered as a reference first-line treatment for MCRC [7, 8]. Irinotecan in combination with infusional 5-FU/LV, in particular, is accepted as a standard regimen for the first-line treatment of patients with advanced or MCRC [9–11]. In addition to having improved therapeutic efficacy, infusional 5-FU/LV in combination with irinotecan has the advantage of a favorable toxicity profile compared with bolus 5-FU/LV combination therapy [12, 13].
In a previous phase I/II clinical trial conducted by our group in patients with advanced colorectal cancer, the combination of irinotecan 80 mg/m2 plus TTD regimen (5-FU 2.25 g/m2 given as 48-h i.v. infusion) in a weekly schedule was shown as an active and safe regimen for the first-line treatment of advanced colorectal cancer [14]. Therefore, the TTD regimen may constitute an alternative to other 5-FU/LV-modulated regimens for combining with irinotecan as first-line colorectal cancer treatment.
To date, no randomized clinical trials have compared the different 5-FU/irinotecan schedules. In order to confirm the value of the TTD/irinotecan (FUIRI) schedule in the treatment of previously untreated MCRC, a randomized study was designed to demonstrate that the efficacy of our regimen without LV is not inferior to the standard 5FULV2/CPT-11 (FOLFIRI).
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patients and methods |
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This multicenter, prospective study was carried out by the Cooperative Group for the TTD group.
Local ethics committee approval was obtained before enrollment of any patient into the study, which was carried out in accordance with the Declaration of Helsinki and its subsequent amendments as well as Good Clinical Practice guidelines. Signed informed consent was obtained from all patients before study entry.
eligibility criteria
Patients with histological confirmed MCRC with at least one measurable lesion, chemotherapy naive or having finished prior adjuvant chemotherapy 
6 months before were included. An interval of 4 weeks must have elapsed since the end of surgery and/or radiotherapy. Other eligibility criteria included the following: age 18–75 years; World Health Organization performance status of two or less and life expectancy of >3 months; adequate hematological parameters (hemoglobin 10 g/dl, absolute neutrophil count 2 x 109/l, and platelets 150 x 109/l); total bilirubin 
1.25 x the upper limits of normal (ULN) and serum transaminase levels 3 x ULN (total bilirubin 1.5 x ULN, serum transaminase levels 5 x ULN, in presence of liver metastases); creatinine 1.25 ULN and; absence of a second primary tumor other than nonmelanoma skin cancer or in situ cervical carcinoma. Patients with central nervous system metastasis, unresolved bowel obstruction or subobstruction, Crohn's disease, ulcerative colitis, history of chronic diarrhea or known contraindications to fluorouracil (severe cardiac disease, including myocardial infarction within the 12 months before entry onto the trial, uncontrolled hypertension or angina pectoris) were excluded.
treatment schedule
Patients on the FOLFIRI arm received irinotecan 180 mg/m2 as a 90-min i.v. infusion on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22-h infusion, plus LV 200 mg/m2 on days 1 and 2, every 2 weeks. FUIRI consisted of weekly irinotecan 80 mg/m2 as a 30-min i.v. infusion followed immediately by 5-FU 2250 mg/m2 given as a 48-h i.v. infusion: treatment was administered weekly without any rest period between cycles. For both arms, a treatment cycle lasted 6 weeks, and therapy was continued until disease progression, severe toxicity, treatment refusal (unrelated to toxicity), investigator decision or death or until patient was lost to follow-up.
Irinotecan was administered according to the guidelines used for irinotecan monotherapy, including recommendations for the use of concurrent antiemetics, atropine, and loperamide. Patients were assessed for toxicity before each infusion using the National Cancer Institute—Common Toxicity Criteria, version 2.0, April 1999 [15]. For any patient with severe toxicity, therapy had to be delayed until complete normalization, and the dose of 5-FU and irinotecan had to be reduced to 80% of the previous dose for all further administrations. In case of grade 4 neutropenia or febrile neutropenia concomitant with diarrhea, preventive oral antibiotic therapy was indicated. At the end of the treatment period, patients were followed up every 3 months to document death, progression, or further cancer treatment.
evaluations during the study
Physical examination and laboratory studies, including complete blood counts with differential, serum liver function tests, and actual or estimated creatinine clearance, were carried out within 7 days of enrollment; electrocardiography and carcinoembryonic antigen were determined within 21 days before treatment start; and chest radiograph or computed tomography (CT) scan and abdominal CT scan were completed within 28 days of enrollment. Women of childbearing potential had a negative serum pregnancy testing within 7 days of registration. During treatment, safety assessments and blood counts were carried out before each infusion (weekly in arm A and every 2 weeks in arm B). Serum chemical values were assessed at the beginning of each treatment cycle (every 6 weeks).
Tumor response studies were carried out using the response evaluation criteria in solid tumors criteria [16] every 12 weeks or sooner if clinically indicated, until the disease progressed or the patient died. The duration of response was measured from the first documentation of response to disease progression. Disease-free survival was defined as the time interval from randomization until progression or death. The time to treatment failure was calculated from randomization to the date of treatment failure, regardless of cause of it (disease progression, relapse, death, or any other cause of discontinuing the study treatment). Without contradictory data, patients who died or were lost to follow-up were assumed to have progressed at the time they were last documented to be progression free. OS was measured from the randomization to date of death.
statistical considerations
Randomization was centralized without patients’ stratification. We planned to include 328 patients (164 per arm) to show a significant difference in response rate (overall response rate, complete, and partial responses) between treatment groups, assuming response rates of 38% in the FOLFIRI group and 38% ± 15% in the FUIRI group, by use of two-tailed chi-square tests (
= 0.05, β = 0.2).
Chi-square tests were used to compare categorical variables between treatment groups. For continuous variables, we used Student's t-tests. The Kaplan–Meier method was used to estimate survival curves, and the log-rank test was used to compare the curves. Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs). All randomized patients were included in an intention-to-treat analysis; patients who canceled before the initiation of therapy were excluded from the toxicity analyses (Figure 1).
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From October 2001 to October 2005, a total of 346 patients from 18 Spanish centers were enrolled onto the study and randomly assigned to FOLFIRI (n = 173) or FUIRI (n = 173). Table 1 presents the characteristics of the patients, which were balanced among the treatment groups: nevertheless, the rectum was the primary tumor site in a higher proportion of patients in the FUIRI group (31%) than in the FOLFIRI group (24%). Fifty per cent of the patients had an Eastern Cooperative Oncology Group performance status of zero at baseline, and more than two-thirds of patients in each group had at least two organs involved, with the liver being the most common site of metastatic disease.
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treatment compliance
Three patients did not receive any treatment infusion, all of them in the FUIRI group, two because consent was withdrawn and another due to toxicity (sepsis and bowel obstruction) before starting treatment. As presented in Table 2, the median number of administered cycles was 4 in both arms (range 1–24). Sixty-two per cent of patients in the FOLFIRI group and 55% in the FUIRI group received more than three complete cycles (18 weeks) of chemotherapy.
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The median relative intensity of the doses of irinotecan and 5-FU (calculated as the actual dose delivered divided by the intended dose) were significantly higher in the FOLFIRI group than in the FUIRI group (89% versus 83%, P = 0.002).
toxicity
Grades 3 and 4 toxic effects occurring at a frequency of 3% or more are shown in Table 3. Diarrhea was the most frequent grade 3 or 4 non-hematological toxic effect in each of the treatment groups, being significantly more frequent in the FUIRI group (P < 0.00001): most of the cases were grade 3 (19 of 21 in the FOLFIRI arm and 36 of 42 in the FUIRI arm). Grade 3 or 4 hematological toxicity was higher in the FOLFIRI arm, reaching statistically significance for neutropenia (P < 0.00001): for leucopenia the difference was close to significance (P = 0.0672).
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During the first 60 days, five patients died in the FOLFIRI arm and four in the FUIRI arm. There were two therapy-related deaths in the FOLFIRI arm (sepsis and febrile neutropenia: both in the first 60 days) and four in the FUIRI arm (two septic shock, one sudden death, and one diarrhea: two in the first 60 days, one septic shock, and one diarrhea).
response to treatment
Thirty-five patients (14%) who did not complete the first cycle of treatment were included in the efficacy analysis as nonevaluable, 10 on FOLFIRI arm and 25 on FUIRI arm, mainly due to toxicity, consent withdrawn or not cancer-related death. In the intent-to-treat analysis (Table 4), where all randomized patients were included (346 patients), the response rates for the FOLFIRI and the FUIRI arms were 57% (95% CI 49% to 64%) and 51% (95% CI 43 to 59%), respectively: no statistically significant differences were detected (P = 0.2809) (Table 4). The median duration of response was 7.2 (95% CI 5.9–8.5) months in the FOLFIRI group and 6.1 (95% CI 5.6–7.5) months in the FUIRI group (P = 0.3137). Secondary resection of liver metastases was possible in 10 patients in each arm of treatment.
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survival analysis
After a median follow-up of 17.2 months (95% CI 15.7% to 18.5%), 160 patients in the FOLFIRI arm and 158 in the FUIRI arm had progressed or died. The median progression-free survival in the FOLFIRI group was 8.3 months (95% CI 7.3–8.9 months) versus 8.4 months (95% CI 7.1–9.1 months) in the FUIRI group (P = 0.4339; Figure 2). The median OS was 21.6 months (95% CI 19.9–25.3 months) in patients treated with FOLFIRI compared with 19.2 months (95% CI 17.4–23.8 months) in the FUIRI group (P = 0.2941; Figure 3).
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Seventy-five per cent of patients in the FOLFIRI group and 68% in the FUIRI group (P = 0.122) received additional second-line treatment (Table 5). No significant differences were founded in the proportion of patients receiving further treatment with oxaliplatin between the two groups (72% FOLFIRI versus 62% FUIRI).
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discussion |
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This trial is the first randomized study comparing two European regimens of 5-FU ± LV in combination with irinotecan in the treatment of advanced colorectal cancer. This study provides convincing evidence that FUIRI is an active regimen for the treatment of patients with previously untreated advanced colorectal cancer, without statistically significant differences in efficacy with the FOLFIRI regimen and with a different toxicity profile. The control regimen of 5-FU/LV/irinotecan selected has been one of the most commonly and active used (and tested in phase III studies) treatments for MCRC in Europe, having showed increased response rates, time to progression, and survival in comparison with the same combination without irinotecan [9].
In the present trial, we used the schedule we had previously developed in a phase I/II study [14] in which 5-FU is not modulated by LV, in order to increase the dose intensity of continuous infusion 5-FU. As we have previously demonstrated, the addition of LV to high doses of FU does not increase activity but does increases toxicity and treatment cost [17, 18].
Although comparisons over time and studies may be problematic, the efficacy results showed in the present study for both arms are among the highest reported to date in randomized trials in patients with advanced colorectal cancer treated with an irinotecan/5-FU combination [9–11, 19–24]: Table 6 summarizes the results of the randomized studies of irinotecan (CPT-11) in combination with 5-FU continuous infusion as first-line treatment of colorectal cancer. Indeed, it is noteworthy that the median survival times achieved by patients treated in both arms are similar to the best reported in randomized multicenter trials including either irinotecan- or oxaliplatin-based combinations. This may be a consequence of the high proportion of patients who received a second-line therapy, mainly based in oxaliplatin, what strongly suggests that all patients should receive all available active drugs during the course of their disease, as have been argued previously by other authors [10, 11, 22, 23].
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The safety profile of both regimens was consistent with that reported in previous randomized studies using the same or similar schedules [9–11, 19–24]: the FOLFIRI schedule was associated with higher frequency of grade 3 or 4 hematological toxicity while non-hematological toxic effects (mainly diarrhea) were more frequent with FUIRI. In particular, the safety profile of the FUIRI regimen was comparable to that reported by Khöne et al. [11] using a similar regimen (AIO) based on 5-FU administered as high-dose continuous infusion (plus LV). Indeed, in that study, the initial 5-FU dose of 2300 mg/m2 was reduced to 2000 mg/m2 due to an elevated percentage of grades 3–4 diarrhea (36% of patients) and three toxic deaths in the irinotecan + AIO arm. Nevertheless, the proportion of grade 4 diarrhea during treatment with FUIRI was much lower than in our prior phase I/II study [14]: this fact underlines the importance of the strict adherence to guidelines for patient surveillance and dose adjustment followed by the investigators participating in this study. The death rates within the first 60 days of treatment and the proportion of toxic deaths were comparable between both arms (no statistically significant differences were observed) in the expected range with these regimens.
In conclusion, FUIRI represents a valid alternative to the standard FOLFIRI regimen as a first-line option of care for patients with MCRC. Our regimen seems suitable to be combined with new targeted agents, such as cetuximab or bevacizumab: in fact, bevacizumab has been approved in Europe and the United States for combination with 5-FU/LV and irinotecan on the basis of the increases in OS, progression-free survival, and response rate over the same regimen without bevacizumab and the addition of bevacizumab cause an increase of neutropenia that could be less pronounced in case of combination of FUIRI with bevacizumab [25].
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Pfizer.
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acknowledgements |
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The physicians listed below cared for the patients in this study. The authors thank them for their cooperation and support: Dr Valladares Ayerbes, Complejo Hospitalario Juan Canalejo Marítimo de Oza, La Coruña, Dr Martinez Villacampa, Instituto Catalán de Oncología, Hospital Duran i Reinals, Barcelona, Dr Benavides Orgaz, Hospital Regional Universitario Carlos Haya, Málaga, Dr Aranda Aguilar, Hospital Universitario Reina Sofía, Córdoba, Dr Massutti Sureda, Hospital General Universitario de Alicante, Alicante, Dr Marcuello Gaspar, Hospital Santa Creu i Sant Pau, Barcelona, Dr Constenla Figueiras, Complejo Hospitalario de Pontevedra, Pontevedra, Dr Camara Vicario, Fundación Hospital Alcorcón, Madrid, Dr Carrato Mena, Hospital General Universitario de Elche, Alicante, Dr Sánchez Rovira, Hospital Ciudad de Jaén, Jaén, Dr Almenar Cubells, Hospital Universitario, Dr Peset, Valencia, Dr Llanos Muñoz, Hospital Universitario de Canarias, Tenerife, Dr Sastre Valera, Hospital Universitario Clínico San Carlos, Madrid, Dr Galán Brotons, Hospital de Sagunto, Valencia, Dr Etxeberria Larrea, Instituto Oncológico, Guipúzcoa, Dr García López, Hospital Ramón y Cajal, Madrid, Dr Checa Ruiz, Instituto de Oncología Corachán, Barcelona, Dr Aranda Bellido, Hospital de Mérida, Badajoz. Monitoring, Statistics and Data Management: Pivotal. TTD (Spanish Cooperative Group for the Treatment of Digestive Tumors): Ruiz de Mena, I. Author's disclosures of potential conflicts of interest: the authors indicated no potential conflicts of interest.
Received for publication May 7, 2008. Revision received July 11, 2008. Accepted for publication July 14, 2008.
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