VOLUME 25 䡠 NUMBER
JOURNAL OF CLINICAL ONCOLOGY
From the U.O. Oncologia Medica, Isti-
tuto Toscano Tumori, Livorno; S.C. di
Oncologia Medica, Ospedale S. Maria
della Misericordia, Perugia; U.O. Onco-
logia Medica, Ospedale di Macerata,
Macerata; Centro Oncologico ed
Ematologico Subalpino, ASO Ospedale
S. Giovanni Battista Le Molinette,
Torino; Dipartimento di Medicina Speri-
mentale e Patologia, Oncologia Medica,
Università la Sapienza, Roma; U.O.
Oncologia Medica, Ospedale S. Elia,
Caltanissetta; Istituto Nazionale per la
Ricerca sul Cancro, Genova; S.C. di
Oncologia, Azienda Ospedaliera S.
Croce e Carle, Cuneo; Oncologia
Medica, P.O. S. Lazzaro, Alba; Oncolo-
gia Medica, Ospedale S. Maria Annun-
ziata, Istituto Toscano Tumori, Firenze,
Italy; U.O. Oncologia Medica, Azienda
Ospedaliero-Universitaria, Istituto
Toscano Tumori; and Dipartimento di
Oncologia, dei Trapianti e Nuove
Tecnologie in Medicina, Università degli
Studi, Pisa, Italy.
Submitted September 17, 2006;
accepted January 30, 2007.
Supported in part by a research grant of
the Associazione Italiana Ricerca
Cancro (A.I.R.C.) and by the Fondazione
A.R.C.O.
Presented at the 42nd Annual Meeting
of the American Society of Clinical
Oncology, Atlanta, GA, June 2-6, 2006,
and at the American Society of Clinical
Oncology 2006 Gastrointestinal Cancers
Symposium, San Francisco, CA,
January 24-27, 2006.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to Alfredo
Falcone, MD, Cattedra di Oncologia
Medica, University of Pisa, Department
of Oncology, Azienda USL-6 of Livorno,
Viale Alfieri, 36, 57124 Livorno, Italy;
e-mail: a.falcone@med.unipi.it.
© 2007 by American Society of Clinical
Oncology
0732-183X/07/2513-1670/$20.00
DOI: 10.1200/JCO.2006.09.0928
1670
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13 䡠 MAY 1 2007
O R I G I N A L R E P O R T
Phase III Trial of Infusional Fluorouracil, Leucovorin,
Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With
Infusional Fluorouracil, Leucovorin, and Irinotecan
(FOLFIRI) As First-Line Treatment for Metastatic
Colorectal Cancer: The Gruppo Oncologico Nord Ovest
Alfredo Falcone, Sergio Ricci, Isa Brunetti, Elisabetta Pfanner, Giacomo Allegrini, Cecilia Barbara, Lucio Crinò,
Giovanni Benedetti, Walter Evangelista, Laura Fanchini, Enrico Cortesi, Vincenzo Picone, Stefano Vitello,
Silvana Chiara, Cristina Granetto, Gianfranco Porcile, Luisa Fioretto, Cinzia Orlandini, Michele Andreuccetti,
and Gianluca Masi
A B S T R A C T
Purpose
The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil,
leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2
day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on
day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI).
Methods
Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no
prior chemotherapy for advanced disease. The primary end point was response rate (RR).
Results
A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral
neurotoxicity (0% v 19%; P ⬍ .001), and grade 3 to 4 neutropenia (28% v 50%; P ⬍ .001) were
observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to
4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators,
were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and
58%, (RR, 41% v 66%; P ⫽ .0002). RR confirmed by an external panel was 34% versus 60%
(P ⬍ .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm
(6% v 15%; P ⫽ .033, among all 244 patients; and 12% v 36%; P ⫽ .017 among patients with liver
metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly
improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P ⫽ .0006;
median OS, 16.7 v 22.6 months; HR, 0.70; P ⫽ .032).
Conclusion
The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased,
but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic
characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the
neoadjuvant setting are warranted.
J Clin Oncol 25:1670-1676. © 2007 by American Society of Clinical Oncology
line treatment can be also more effective in terms
INTRODUCTION
of improved progression-free survival (PFS) and
Colorectal carcinoma (CRC) is the second cause overall survival (OS).7
of cancer-related death in developed countries.1 A study by the Groupe Coopérateur Multidis-
The combinations of irinotecan (CPT-11) ⫹ flu- ciplinaire en Oncologie (GERCOR)8 suggested that
orouracil (FU)/leucovorin (LV) and oxaliplatin the exposure of metastatic colorectal cancer patients
(LOHP) ⫹ FU/LV have demonstrated increased to all the three most active agents, irrespective of
efficacy compared with FU/LV alone in random- their sequence, is associated with promising sur-
ized studies.2-6 These data have established that in vival. Moreover, a pooled analysis of seven phase III
metastatic colorectal cancer, a more active first- trials demonstrated that survival is correlated with
 FOLFOXIRI v FOLFIRI in Metastatic CRC

the proportion of patients who received all the three active drugs in the Stratification, Random Assignment, and Treatment
course of their disease, but not with the proportion of patients who Patients were stratified according to center, ECOG performance status
received any second-line therapy.9 This analysis also shows that, in a (0 v 1 to 2) and history of adjuvant therapy (yes v no) and then were randomly
assigned to FOLFIRI (arm A) or FOLFOXIRI (arm B; Fig 1). Treatment was
sequential strategy, not all patients who progress after first-line chem-
administered every 2 weeks until evidence of progression, unacceptable toxic-
otherapy are able to receive second-line treatment (50% to 80%) and, ity, patient refusal, or for a maximum of 12 cycles. Adverse events were
therefore, can be exposed to the three active agents. evaluated according to National Cancer Institute Common Toxicity Criteria
A way to further improve the outcome of metastatic colorectal version 2.0. No prophylactic treatment for neutropenia was recommended.
cancer patients could be to administer a first-line regimen contain- Evaluation Criteria
ing the three active agents (LOHP, CPT-11 and FU/LV). This Responses were evaluated every 8 weeks according to WHO criteria. The
regimen, if feasible, could expose all patients to these drugs. If this determination of responses and progression was initially based on
regimen will be more active than a standard two-drug combina- investigator-reported measurements; computed tomography scans of all re-
tion, it could also increase the postchemotherapy resection rate of sponding patients and of patients with stable disease were subsequently sub-
metastases and, therefore, the long-term control of disease. In fact, jected to external review by an independent panel. Quality of life was assessed
at the beginning of each treatment cycle using the Quality of Life Question-
studies conducted with LOHP- and FU-based regimens10,11 and,
naire of the European Organisation for Research and Treatment of Cancer
more recently, also with different combinations,12 indicate that an (version 2.0).
active first-line chemotherapy in initially unresectable patients can
Statistical Analysis
allow a radical resection of metastatic disease and 20% to 40% of
The primary study end point was the externally reviewed response rate
these resected patients are long-term survivors. In particular, an (RR). Secondary end points were PFS, OS, postchemotherapy R0 surgical
analysis conducted by Folpercht et al13 demonstrates a correlation resections, safety, and quality of life. We selected RR as the primary end point
between the response rate to chemotherapy and the postchem- because three meta-analyses of randomized studies in metastatic colorectal
otherapy radical resection rate of metastases.
Therefore, we studied the feasibility and the activity of a triplet
combination containing FU/LV, LOHP, and CPT-11. In an initial
phase I-II study14 a chronomodulated infusion of FU was used, and in A FOLFIRI
a subsequent phase II study, a simplified FU/LV, LOHP, and CPT-11
(FOLFOXIRI) regimen was developed.15 Treatment was well toler- CPT-11 180
ated, response rate was 72%, with a median PFS of 10.8 months and mg/m2 1-hour IV
median OS of 28.4 months. The combined analysis of the two above-
mentioned studies demonstrated that in 26% of initially unresectable l-LV 100 100
patients, a radical resection of residual metastatic disease could be mg/m2 2-hours IV 2-hours IV
performed. The 4-year survival of these patients was 37%.16 FU 400 400
On the basis of these results, the Gruppo Oncologico Nord Ovest mg/m2 bolus bolus
(GONO) launched a phase III randomized trial to compare the sim-
plified FOLFOXIRI regimen to a standard combination of FU/LV and FU 600 600
CPT-11 (FOLFIRI) that had demonstrated improved efficacy in com- mg/m2 22-hours CI IV 22-hours CI IV
parison to FU/LV.3
Day 1 Day 2 Day 3

METHODS Repeated every 2 weeks

B FOLFOXIRI
Patient Selection
From November 2001 to April 2005, we enrolled patients who met the
following eligibility criteria: adenocarcinoma of the colon or rectum, unresect- CPT-11 165
able metastatic disease, age 18 to 75 years, Eastern Cooperative Oncology mg/m2 1-hour IV
Group (ECOG) performance status of 2 or lower if age 70 years or younger or
ECOG performance status of 0 if age 71 to 75 years, measurable disease LOHP 85
according to WHO criteria, leukocyte count of at least 3,500/mm3, neutrophils mg/m2 2-hours IV
count of at least 1,500/mm3, platelet count of at least 100,000/mm3, serum
creatinine of 1.3 mg/dL or less, serum bilirubin less than 1.5 mg/dL and AST,
l-LV 200
ALT, and alkaline phosphatase 2.5 ⫻ normal values or less (ⱕ 5 if liver mg/m2 2-hours IV
metastases). Previous fluoropyrimidine-based adjuvant chemotherapy was FU
allowed if ended more than 6 months before random assignment. Exclusion 3,200 48-hours flat continuous infusion IV
mg/m2
criteria were previous palliative chemotherapy for metastatic disease; previous
chemotherapy including irinotecan or oxaliplatin, symptomatic cardiac dis-
ease, myocardial infarction in the last 24 months or uncontrolled arrhythmia, Day 1 Day 2 Day 3
active infections, inflammatory bowel disease; and total colectomy. The study Repeated every 2 weeks
was conducted in accordance to Helsinki declaration and to Good Clinical
Practice guidelines, and patients were informed of the investigational nature of
Fig 1. Treatment schedule for (A) FOLFIRI and (B) FOLFOXIRI. IV, intravenous;
the study and provided their written informed consent before registration CI, continuous infusion; CPT-11, irinotecan; FU, fluorouracil; LV, leucovorin;
onto the study. The protocol was approved by the ethics committee of all LOHP, oxaliplatin; FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan;
participating institutions. FOLFIRI, fluorouracil, leucovorin, and irinotecan.

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 Falcone et al

cancer had demonstrated a clear correlation between RR and OS and between

the RR and the rate of radical secondary surgery on metastases, supporting the Table 1. Patient Characteristics (N ⫽ 122)
use of RR as a surrogate end point. PFS was defined as the length of time from FOLFIRI FOLFOXIRI
random assignment to disease progression or to death resulting from any Characteristic No. % No. %
cause, whichever occurred first, or to last contact. The evaluation of PFS was
based on investigators’ assessment. OS was defined as the length of time from Sex
random assignment to death or to last contact. Male 69 57 75 61
Assuming an RR of 40% in the FOLFIRI arm, to demonstrate an im- Female 53 43 47 39
provement of 20% in with FOLFOXIRI (60%), using a two-sided ␹2 test with ECOG performance status
a power of 0.80 and an alpha-error of 0.05, and considering approximately 0 74 61 74 61
10% of patients nonassessable, we planned to randomly assign a total of 240 1 41 34 45 37
patients. With this sample size, and assuming that we would observe the same 2 7 6 3 2
results reported by Douillard3 with FOLFIRI in terms of PFS, the study was Age, years
also able to demonstrate, after 218 events had occurred, by two-tailed log-rank Median 64 62
test (alpha-error ⫽ 0.05, power 0.80), a prolongation in PFS of 3.1 months Range 21-75 27-75
(from 6.7 to 9.8 months). For primary and secondary objectives we analyzed Primary tumor
the intention-to-treat population, using ␹2 tests (or Fisher’s exact test, if Colon 95 78 81 66
indicated) to compare categoric variables between treatment groups. We esti- Rectum 27 22 41 34
mated survival curves by the Kaplan-Meier method, and compared the groups Previous adjuvant chemotherapy
by the log-rank test. We tested the 14 following variables as possible predictive Yes 29 24 29 24
factors for objective response or surgical R0 resection and as possible prognos- No 93 76 93 76
tic factors: treatment, sex, age (⬍ or ⱖ 65 years), WHO performance status Time from diagnosis to random
assignment, months
(0 or 1 to 2), primary tumor site (colon or rectum), number of organs involved
⬍3 79 65 79 65
(single or multiple), sites of disease (liver only or other sites), liver involvement
ⱖ3 43 35 43 35
(⬍ or ⱖ 25%), time from first diagnosis to first metastasis (0 to 3, 3 to 12, or
No. of involved organs
⬎ 12 months), previous adjuvant therapy (yes or no), baseline lactate dehy-
1 67 55 65 53
drogenase (normal or ⱖ upper limit of normal), baseline carcinoembryonic
⬎1 55 45 57 47
antigen (⬍ or ⱖ 100 ng/mL), baseline leukocytes (⬍ or ⱖ 8,000/mL), and
Liver-only metastases
baseline hemoglobin (⬍ or ⱖ 10 g/dL). All multivariate analyses used a
Yes 42 34 39 32
step-down procedure based on the likelihood ratio test. Multivariate analyses
No 80 66 83 68
were done on the intention-to-treat population. A logistic-regression model
Liver involvement
was used to identify the predictive factors for objective response and surgical
No 28 23 31 25
R0 resection. For time to progression and OS, Cox’s proportional hazards
⬍ 25% 40 33 43 35
modeling was used. The QLQ-C30 questionnaire was analyzed with the global
ⱖ 25% 54 44 48 40
health status/quality-of-life scale as the primary end point and the other 10
LDH
scales as secondary end points. Statistical analysis was performed using SPSS/
ⱕ ULN 56 46 64 52
PC⫹11.5 statistical software (SPSS Inc, Chicago, IL).
⬎ ULN 31 25 28 23
NA 35 29 30 25
CEA
RESULTS
⬍100 70 57 72 59
ⱖ100 38 31 36 30
Patients NA 14 11 14 11
A total of 244 patients from 15 Italian centers were enrolled Abbreviations: FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOXIRI,
onto the study and randomly assigned to FOLFIRI (n ⫽ 122) or fluorouracil, leucovorin, oxaliplatin, and irinotecan; ECOG, Eastern Cooperative
Oncology Group; LDH, lactate dehydrogenase; ULN, upper limit of normal;
FOLFOXIRI (n ⫽ 122). Table 1 presents the characteristics of the NA, not applicable; CEA, carcinoembryonic antigen.
patients, which were balanced among the treatment groups. Overall,
the study population was relatively selected to exclude elderly and frail
patients with an expected increased risk of toxicity by using combina- ripheral neurotoxicity, alopecia, and thrombocytopenia (Table 3).
tion chemotherapy. Grade 3 to 4 toxicities, however, were uncommon except for neutro-
penia. In particular, the adverse events that occurred significantly
Treatment Administration and Safety
more often in patients who received FOLFOXIRI were grade 2 to 3
All randomly assigned patients received at least one cycle of study
peripheral neurotoxicity (0% v 19%; P ⬍ .0001) and grade 3 to 4
treatment and were evaluated for safety. Both treatments were rela-
neutropenia (28% v 50%; P ⫽ .0006). Nevertheless, the incidence
tively well tolerated and associated with manageable toxicities. As
of febrile neutropenia was comparable between FOLFIRI and
presented in Table 2, the median number of administered cycles was
FOLFOXIRI (3% v 5% of patients; P ⫽ .75), and there were no
10 in the FOLFIRI arm and 11 in the FOLFOXIRI arm. The relative
episodes of documented infections; granulocyte colony-stimulating
dose-intensity of administered FU, CPT-11, and LOHP ranged be-
factor was used in 2% of FOLFIRI cycles and in 6% of FOLFOXIRI
tween 82% and 87% of planned for all agents in both arms. Treatment
cycles. In four patients, LOHP was interrupted because of grade 3
interruptions because of toxicity were 4% for FOLFIRI and 9% for
neurotoxicity (n ⫽ 3) or allergic reaction (n ⫽ 1).
FOLFOXIRI (P ⫽ .19). No toxic deaths occurred, and two patients
(1.6%) in each arm died within 60 days from the treatment start, all Objective Tumor Response
because of rapidly progressive disease. Most commonly observed tox- According to an intention-to-treat analysis, all patients were
icities were neutropenia, diarrhea, nausea/vomiting, stomatitis, pe- considered assessable for response (Table 4). The RR assessed by

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 FOLFOXIRI v FOLFIRI in Metastatic CRC

Table 2. Number of Cycles and Relative Dose Intensities Table 3. Maximum Toxicity per Patient
Variable FOLFIRI FOLFOXIRI FOLFIRI FOLFOXIRI
(n ⫽ 122) (n ⫽ 122)
No. of cycles Toxicity (NCI-CTC
Total 1,056 1,083 grade) No. % No. % P (grade 3/4)
Median 10 11 Nausea NS
Range 1-16 1-16 Grade 1 48 39 49 40
Relative dose intensity with respect Grade 2 20 16 34 28
to planned, % Grade 3 1 1 7 6
Oxaliplatin — 83 Grade 4 0 0 0 0
Irinotecan 87 82 Vomiting NS
Fluorouracil 86 82 Grade 1 28 23 24 20
Abbreviations: FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOXIRI, Grade 2 22 18 31 25
fluorouracil, leucovorin, oxaliplatin, and irinotecan. Grade 3 1 1 8 7
Grade 4 1 1 0 0
Diarrhea NS
Grade 1 30 25 40 33
Grade 2 27 22 30 25
investigators was 66% for FOLFOXIRI and 41% for FOLFIRI
Grade 3 13 11 21 17
(P ⫽ .0002). The externally reviewed RR was also significantly Grade 4 1 1 4 3
higher for FOLFOXIRI compared with FOLFIRI (60% v 34%; Stomatitis NS
P ⬍ .0001). Moreover, the rate of progression was significantly Grade 1 28 23 32 26
lower for patients treated with FOLFOXIRI (11% v 24%; P ⫽ .02). Grade 2 7 6 17 14
In the multivariate analysis, only treatment with FOLFOXIRI was Grade 3 4 3 5 4
Grade 4 0 0 1 1
an independent predictive factor for response (hazard ratio [HR],
Neurotoxicity ⬍ .0001ⴱ
2.8; 95% CI, 1.7 to 4.8; P ⬍ .001). Grade 1 0 0 45 37
Secondary Surgery on Metastases Grade 2 0 0 21 17
The superior tumor shrinkage achieved with FOLFOXIRI al- Grade 3 0 0 3 2
Grade 4 0 0 0 0
lowed an increased rate of postchemotherapy radical surgery of me-
Astenia NS
tastases. In particular, 18 patients (15%) underwent to radical (R0) Grade 1 29 24 27 22
surgery of metastases in the FOLFOXIRI arm compared with seven Grade 2 12 10 19 16
patients (6%) in the FOLFIRI arm (P ⫽ .033). Considering only Grade 3 4 3 7 6
patients with metastases confined to the liver, the rate of secondary R0 Grade 4 0 0 0 0
surgery of metastases was 36% for FOLFOXIRI compared with 12% Thrombocytopenia NS
for FOLFIRI (P ⫽ .017). In the multivariate analysis, only treatment Grade 1 5 4 22 18
Grade 2 3 2 7 6
with FOLFOXIRI was an independent predictive factor for achieving Grade 3 1 1 2 2
an R0 resection (HR, 3.1; 95% CI, 1.2 to 7.9; P ⫽ .018). Grade 4 0 0 0 0
PFS and Second-Line Treatment Anemia NS
Grade 1 50 41 53 43
The improved activity of FOLFOXIRI resulted in an increased
Grade 2 11 9 23 19
PFS; in particular, 104 patients in the experimental arm (FOLFOXIRI) Grade 3 1 1 4 3
versus 112 patients in the reference arm (FOLFIRI) have progressed, Grade 4 0 0 0 0
and the median PFS is 9.8 months versus 6.9 months (P ⫽ .0006) with Neutropenia .0006
an HR for progression of 0.63 (95% CI, 0.47 to 0.81; Fig 2). In addition, Grade 1 22 18 16 13
the rate of early progression (patients who progressed within 6 months Grade 2 16 13 24 20
Grade 3 21 17 40 33
from the treatment onset) was significantly lower in the FOLFOXIRI
Grade 4 13 11 21 17
arm (18% v 45%; P ⬍ .0001). The Cox’s multivariate analysis demon- Febrile neutropenia 4 3 6 5 NS
strates that independent prognostic factors for reduction of the pro-
gression risk were: treatment arm (HR, 0.60; 95% CI, 0.46 to 0.79; P ⬍ Abbreviations: FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOXIRI,
fluorouracil, leucovorin, oxaliplatin, and irinotecan; NCI-CTC, National Cancer
.001), male sex (HR, 0.68; 95% CI, 0.51 to 0.91; P ⫽ .01), and leukocyte Institute Common Toxicity Criteria; NS, not significant.
ⴱ
count less than 8,000/mm3 (HR, 0.60; 95% CI, 0.45 to 0.81; P ⫽ .003). Grade 2-3.

The rate of patients who received a second-line treatment was

73% for FOLFIRI and 76% for FOLFOXIRI. In particular, the
regimens administered as second-line treatment (FOLFIRI v
FOLFOXIRI) were FU/LV and LOHP (FOLFOX; 67% v 12%),
median OS is significantly longer for FOLFOXIRI (22.6 v 16.7 months;
FOLFIRI (4% v 22%), FOLFOXIRI (0% v 14%), mitomycin (0% v
P ⫽ .032), corresponding to an HR for death of 0.70 (95% CI, 0.50 to
14%), cetuximab (1% v 2%), and other chemotherapy (1% v 14%).
0.96; Fig 2). The Cox’s multivariate analysis demonstrates that the only
OS independent prognostic factors for reduction of the death risk was
After a median follow-up of 18.4 months, 65 patients in the liver involvement less than 25% (HR, 0.57; 95% CI, 0.39 to 0.84;
experimental arm and 81 in the reference arm have died, and the P ⫽ .005). Treatment with FOLFOXIRI was significantly predictive of

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 Falcone et al

Table 4. Objective Responses

A
% FOLFOXIRI (median 9.8 months)
100
FOLFIRI (median 6.9 months)
FOLFIRI FOLFOXIRI
Response (n ⫽ 122) (n ⫽ 122)

Progression Free (%)

Investigators assessment 75
Complete 6 8
Partial 35 58
Complete ⫹ partial 41ⴱ 66ⴱ 50
95% CI 0.32 to 0.50 0.56 to 0.74
Stable disease 33 21
Progression 24† 11†
25
Not assessable 2 2
Externally reviewed
Log-rank P = .0006
Complete 6 7
Partial 28 53
0 6 12 18 24 30
Complete ⫹ partial 34‡ 60‡
95% CI 0.25 to 0.43 0.51 to 0.68 Time (months)
Stable disease 34 21
Progression 24† 11† B
Not reviewed 8 8 FOLFOXIRI (median 22.6 months)
100 FOLFIRI (median 16.7 months)
Abbreviations: FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOXIRI,
fluorouracil, leucovorin, oxaliplatin, and irinotecan.
ⴱ
P ⫽ .0002. 75
†P ⫽ .002.
‡P ⬍ .0001.
Alive (%)
50

prolonged survival in the univariate analysis (P ⫽ .032), but in the

multivariate analysis, it was borderline significant (P ⫽ .054). 25

Quality of Life Log-rank P = .032

Eighty-nine patients (36% in the FOLFIRI arm and 37% in the
FOLFOXIRI arm) were assessable for quality of life. Although the 0 6 12 18 24 30
number of patients from whom quality-of-life questionnaires were Time (months)
obtained was probably too low to make clear conclusions, there were
no significant differences between the two arms. Fig 2. Kaplan-Meier estimates of (A) progression-free survival and (B) overall
survival. FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan; FOLFIRI,
fluorouracil, leucovorin, and irinotecan.
DISCUSSION

During recent years, the treatment of metastatic colorectal cancer has
achieved considerable progress, mainly improvements in the efficacy
of chemotherapy, for increased use of surgery on metastases,17 and,
more recently, the use of targeted agents.18,19 Data have suggested that
exposure to all the three main active cytotoxic agents obtains the best
outcome in unresectable patients,9 but that only 50% to 80% of
patients can be exposed to all three drugs in a sequential strategy with
doublets. Furthermore, there is consistent evidence that by increasing
the activity of chemotherapy, a greater proportion of patients can
undergo a secondary surgery on metastases, and that this can allow
long-term survival in a fraction of them.13
On the basis of these data, several groups have developed three-
drug combinations including FU, CPT-11 and LOHP.20-25 In the
present trial, we selected the schedule we had previously developed15
because it was particularly convenient, well tolerated, and active com-
pared with other three-drug combinations. We used a biweekly sched-
ule, and we omitted the administration of FU by intravenous bolus to
deliver elevated dose intensities of CPT-11, LOHP, and infusional FU.
Results obtained in the FOLFIRI arm are in line with those
reported in most other randomized studies.2,8,26-29 With regard to
FOLFOXIRI, results demonstrate that toxicities are moderately in-
creased, mainly neurotoxicity and uncomplicated neutropenia, but
this combination remains feasible and well tolerated. FOLFOXIRI
clearly increased RR, which is among the highest ever reported in
any randomized study of metastatic colorectal cancer. This im-
proved activity allowed a significant increase in the rate of radical
secondary surgery of metastases, and the rate of R0 patients achieved
with FOLFOXIRI was particularly impressive in patients with liver
metastases only (12% v 36%; P ⫽ .017). The baseline unresectability of
metastases was a key inclusion criterion of the trial, and centers were
strongly encouraged to exclude patients with resectable metastases.
However, this is was a multicenter trial, and the evaluation of resect-
ability was not centralized, but was performed independently by the
multidisciplinary team of each center. In particular, the resection
rate observed with FOLFIRI was comparable to that reported in the
literature; hence, it is unlikely that the improvement obtained with
FOLFOXIRI resulted from different patient selection. Treatment with
FOLFOXIRI was the only significant independent predictive factor for
obtaining an objective response and an R0 resection. Furthermore,
FOLFOXIRI significantly increased PFS by approximately 3 months,

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 FOLFOXIRI v FOLFIRI in Metastatic CRC

and it halved the risk of early progression. Finally, survival, with the
limits that this was not a primary end point and that the number of
patients is relatively low, was significantly improved.
These results support the hypothesis that this three-drug up-
front exposure strategy is more active and probably more effective
than the initial use of a doublet compared with FOLFIRI. No conclu-
sion can be drawn with regard to the comparison with FOLFOX.
However, although FOLFOX has more data with regard to the capac-
ity to induce resectability in previously unresectable patients, similar
results have been reported with FOLFIRI as well.12 Furthermore,
comparisons of FOLFOX with FOLFIRI in randomized studies have
reported equivalent activity and efficacy.8,26
The Hellenic Oncology Research Group (HORG) reported the
results of a study comparing FOLFIRI to a combination of FU, CPT-
11, and LOHP. This study, although indicating some improvements
for the triplet combination in terms of RR, surgical R0 resections, PFS,
and OS, failed to demonstrate statistically significant benefits in favor
of the triplet.29 There are two substantial differences between the
HORG study and the present study. First, in the schedule used by
HORG, the FU bolus was maintained, and this required the use of a
dose of LOHP and CPT-11 significantly lower than used in our study
(65 v 85 mg/m2 for LOHP and 150 v 165 mg/m2 for CPT-11). Despite
this, diarrhea was substantial (grade 3 to 4, 27.7%) and more frequent
than with our combination. The second relevant difference is the
study population, which was older and with a poorer performance
status. In fact, in the HORG study, patients older than 75 years or
between 71 and 75 but with an ECOG performance status of 1 or
higher were not excluded; median age was also greater in the HORG
study (66 v 62 years). In addition, only 36% of patients in the HORG
study had an ECOG performance of 0 (61% in our study), and more
patients had an ECOG performance status of 2 (11% v 2%). Indeed,
Souglakos et al29 report a significantly higher incidence of toxicity in
older patients and those with a performance status of 2.
In conclusion, FOLFOXIRI represents the first studied combina-
tion demonstrated to be superior to an infusional FU-containing
doublet compared with FOLFIRI, and this improvement in effi-
cacy, coupled with a manageable toxicity profile, supports the use
of FOLFOXIRI as a first-line option of care for selected patients with
metastatic colorectal cancer. In particular, patients appropriate for
FOLFOXIRI should have characteristics similar to those included in
our study; therefore, patients aged more than 75 years or 71 to 75 years
but with an ECOG performance status of at least 1, or with expected
increased risk of toxicity (performance status of 2), should not receive
this triplet. We believe that the use of FOLFOXIRI should be of
particular interest in a neoadjuvant strategy in initially unresectable
patients and perhaps, also, in patients with few chances to achieve a
three-drug exposure in a sequential strategy. Future developments
should evaluate the integration of FOLFOXIRI with targeted agents.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author or immediate family members indicated a financial interest. No
conflict exists for drugs or devices used in a study if they are not being
evaluated as part of the investigation. For a detailed description of the
disclosure categories, or for more information about ASCO’s conflict of
interest policy, please refer to the Author Disclosure Declaration and the
Disclosures of Potential Conflicts of Interest section in Information
for Contributors.
Employment: N/A Leadership: N/A Consultant: Alfredo Falcone,
Roche, Sanofi-aventis, Pfizer, Baxter Stock: N/A Honoraria: Alfredo
Falcone, Roche, Sanofi-aventis, Pfizer Research Funds: N/A Testimony:
N/A Other: N/A
AUTHOR CONTRIBUTIONS
Conception and design: Alfredo Falcone, Giacomo Allegrini, Cinzia
Orlandini, Michele Andreuccetti, Gianluca Masi
Administrative support: Michele Andreuccetti
Provision of study materials or patients: Alfredo Falcone, Sergio Ricci,
Isa Brunetti, Elisabetta Pfanner, Giacomo Allegrini, Lucio Crinò,
Giovanni Benedetti, Walter Evangelista, Laura Fanchini, Enrico Cortesi,
Vincenzo Picone, Stefano Vitello, Silvana Chiara, Cristina Granetto,
Gianfranco Porcile, Luisa Fioretto, Gianluca Masi
Collection and assembly of data: Cecilia Barbara, Michele Andreuccetti,
Gianluca Masi
Data analysis and interpretation: Alfredo Falcone, Cecilia Barbara,
Cinzia Orlandini, Michele Andreuccetti, Gianluca Masi
Manuscript writing: Alfredo Falcone, Michele Andreuccetti,
Gianluca Masi
Final approval of manuscript: Alfredo Falcone, Gianluca Masi

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■ ■ ■

Acknowledgment
We thank Michele Malventi, MD, for coordinating the external radiological review panel and Simona Giannace for data management and
technical assistance.

Appendix
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