VOLUME 24 䡠 NUMBER 3 䡠 JANUARY 20 2006

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

OPTIMOX1: A Randomized Study of FOLFOX4 or

From the Hôpital Saint-Antoine; Hôpital
Tenon; Sanofi-Aventis, Paris; Clinique
Saint Jean, Lyon; Hôpital Devron, Dijon;
Clinique Sainte Catherine, Avignon;
Hôpital de Senlis, Senlis; Clinique
Radiologique Armoricaine, Saint Brieuc,
France; Hospital Clínico Universitario,
Valencia; Hospital Universitario
Marques de Valdecilla, Santander,
Spain; Tel Aviv Sourasky Medical
Center, Tel Aviv, Israel; and Interna-
tional Drug Development Institute,
Brussels, Belgium.
Submitted June 8, 2005; accepted
October 24, 2005.
Supported by the GERCOR, Paris,
France.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to A. de
Gramont, MD, Hôpital Saint-Antoine,
184, rue du Faubourg Saint-Antoine,
75571 Paris Cedex 12, France; e-mail:
aimery.de-gramont@sat.ap-hop-paris.fr.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2403-394/$20.00
DOI: 10.1200/JCO.2005.03.0106
FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in
Advanced Colorectal Cancer—A GERCOR Study
Christophe Tournigand, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Marc Buyse,
Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella,
Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, and Aimery de Gramont
A B S T R A C T
Purpose
In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with
oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin
often requires therapy to be stopped in patients who are still responding. This study evaluates a
new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified
leucovorin and fluorouracil regimen with high-dose oxaliplatin.
Patients and Methods
Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2
weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12
cycles, and reintroduction of FOLFOX7 (arm B).
Results
Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor
prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months,
respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in
patients allocated to arm B (P ⫽ not significant). Response rates were 58.5% with arm A and
59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was
observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer
patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in
17.9% of the patients in arm A v 13.3% of patients in arm B (P ⫽ .12). In arm B, oxaliplatin was
reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of
these patients.
Conclusion
Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed
to fully evaluate oxaliplatin reintroduction.
J Clin Oncol 24:394-400. © 2006 by American Society of Clinical Oncology

ities of FOLFOX4 in these studies were neutrope-

INTRODUCTION
Colorectal cancer is the second leading cause of can-
cer death in Western countries.1 First-line therapy of
advanced colorectal cancer is now based on oxalipla-
tin and irinotecan administered in combination
with leucovorin (LV) and fluorouracil (FU),2-4
alongside the introduction of biologic therapies.
A combination of LV and FU with oxaliplatin
(FOLFOX), the FOLFOX4 regimen, has become
established as a standard first-line therapy for ad-
vanced disease after the European C95 and the US
N9741 studies, which demonstrated superiority
of FOLFOX4 over LV/FU and LV/FU bolus plus
irinotecan, respectively.3,5 The two limiting toxic-
nia and the specific reversible sensory neuropathy
of oxaliplatin. The occurrence of sensory neurop-
athy is significant because it may cause patients
who are continuing to respond to treatment to
discontinue treatment. The issue of oxaliplatin
neurotoxicity also arose in the C97 study, which
compared irinotecan and oxaliplatin, both in
combination with a simplified LV/FU bolus plus
infusion regimen,6 and also the FOLFOX7 regi-
men (Fig 1), in which oxaliplatin is administered at
a greater dose-intensity.7 In FOLFOX7, FU bolus
was not used to reduce the incidence of neutropenia.
One potential approach to avoiding the prob-
lem of oxaliplatin neurotoxicity is to administer the

394
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 Oxaliplatin and LVFU2 in Colorectal Cancer
Fig 1. Chemotherapy regimens: (A) FOLFOX4; (B) FOLFOX7; and (C) simplified
LV5FU2. FU, fluorouracil; LV, leucovorin; FOLFOX, leucovorin, fluorouracil,
and oxaliplatin.
dose-intense FOLFOX7 regimen for a defined period of time, stop
therapy before severe neurotoxicity develops, and later reintroduce
the regimen. This approach is supported by the observations that
oxaliplatin administered at a high dose-intensity in second-line ther-
apy achieved a better response rate and progression-free survival
(PFS) than a standard oxaliplatin dose,8 whereas oxaliplatin rein-
troduction was recently found to be clinically effective in a series of
patients who stopped oxaliplatin for neurotoxicity.9
Therefore, the present study investigated the use of oxaliplatin
discontinuation and reintroduction in a novel stop-and-go strategy,
OPTIMOX1. This consisted of the FOLFOX7 regimen administered
for six cycles (one cycle ⫽ 2 weeks) followed by 12 cycles of mainte-
nance and subsequent reintroduction of FOLFOX7 for another six
cycles. This regimen was compared with the FOLFOX4 regimen ad-
ministered until progression or occurrence of unacceptable toxicity.
PATIENTS AND METHODS
Patient Selection
The eligibility criteria for inclusion in the study were adenocarcinoma of
the colon or rectum; unresectable metastases; at least one bidimensionally
measurable lesion of ⱖ 1 cm or a nonmeasurable assessable lesion; adequate
bone marrow, liver (alkaline phosphatase [ALP] ⬍ 5⫻ the upper limit of the
normal [ULN] value), and renal function (creatinine ⱕ 3⫻ ULN); WHO
performance status (PS) of 0 to 2; age 18 to 80 years; and no previous chemo-
therapy for metastatic disease. Previous adjuvant chemotherapy was required
to have been completed at least 6 months before inclusion. Patients with CNS
metastases, second malignancies, bowel obstruction, peripheral neuropathy
more than grade 1, symptomatic angina pectoris, or disease confined to pre-
vious radiation fields were excluded. Written informed consent was required,
and the ethical committee approved the study. The population included an
exploratory cohort of elderly patients (age ⬎ 75 years) and/or poor prognosis
patients (ALP ⬎ 3⫻ ULN).
Chemotherapy
In the control arm (arm A), patients received FOLFOX4, which con-
sisted of a 2-hour infusion of leucovorin isomers l-LV (100 mg/m2) or dl-LV
(200 mg/m2) followed by an FU bolus (400 mg/m2) and 22-hour infusion (600
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mg/m2) for 2 consecutive days every 2 weeks, with oxaliplatin (85 mg/m2) as a
2-hour infusion on day 1. In the investigational OPTIMOX1 arm (arm B),
patients received FOLFOX7 for six cycles (consisting of a 2-hour infusion of
l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by an FU 46-hour infusion of
2,400 mg/m2 every 2 weeks, with oxaliplatin 130 mg/m2 as a 2-hour infusion
on day 1), they then received 12 cycles of the simplified (s) LV5FU2 regimen
(consisting of a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2
followed by an FU 400 mg/m2 bolus and 46-hour 3,000 mg/m2 infusion every
2 weeks), and finally, FOLFOX7 was resumed for six additional cycles.
Figure 1 illustrates the chemotherapy regimens. Treatment was contin-
ued until progression, unacceptable toxicity, or patient choice. In case of
progression during LV5FU2 alone and sensory neuropathy less than grade 2,
reintroduction of oxaliplatin was scheduled in arm B and allowed in arm A.
National Cancer Institute Common Toxicity Criteria (NCI-CTC) ver-
sion 2.0 was used to assess toxicity.10 In both arms, treatment could be delayed
for up to 2 weeks until recovery from stomatitis and diarrhea ⱕ grade 2, skin
toxicity ⱕ grade 2, and other toxicity ⱕ grade 2.
In arm A, the FU dose was decreased to 300 mg/m2 bolus and 500 mg/m2
continuous infusion in case of grade 3 or 4 stomatitis, diarrhea, neutropenia,
thrombocytopenia, or skin toxicity or other grade 3 major organ drug-related
toxicity. The oxaliplatin dose was decreased to 75 mg/m2/cycle in case of grade
3 or 4 neutropenia or thrombocytopenia, grade 3 diarrhea or stomatitis, any
other grade 3 major organ drug-related toxicity, or paresthesia associated with
pain. Oxaliplatin was stopped until symptom improvement in case of persis-
tent paresthesia associated with pain or functional impairment persisting
between cycles.
In arm B, during FOLFOX7 therapy, the FU dose was decreased to 2,000
mg/m2 continuous infusion and the oxaliplatin dose was decreased to 100
mg/m2/cycle in case of the toxicities listed in the previous paragraph. Oxalipla-
tin was stopped until symptom improvement in case of persistent paresthesia
associated with pain or functional impairment persisting between cycles.
When toxicity occurred during the sLV5FU2 phase of treatment in arm B, FU
bolus was stopped, and FU infusion was dose decreased to 2,400 mg/m2 in case
of the toxicities listed in the previous paragraph.
In both arms, in case of NCI-CTC ⱕ grade 2 suspected allergy or in case
of pharyngolaryngeal dysesthesias syndrome, oxaliplatin infusion time was
increased from 2 to 6 hours. In case of heart toxicity ⱖ grade 2, FU and LV were
permanently interrupted, and patients were withdrawn from the study. In
both arms, it was not permitted to re-escalate doses that had been reduced
because of toxicity. Prevention of alopecia with cold cap or stomatitis with iced
mouth rinses was not permitted. The use of implantable ports and disposable
or electronic pumps allowed chemotherapy to be administered on an outpa-
tient basis.
Evaluation Criteria
Computed tomography scans of measurable lesions were assessed at
baseline, repeated after four and six cycles, and then repeated every six cycles.
Complete response was defined as the complete disappearance of all clinically
assessable disease for at least 4 weeks. Partial response was defined as a decrease
of at least 50% of the sum of the products of the diameters of measurable
lesions for at least 4 weeks. Stable disease was defined as a decrease of less than
50% or an increase of less than 25% of measurable lesions, and progressive
disease was defined as an increase of at least 25% of measurable lesions or the
appearance of new malignant lesion(s). There was a new baseline measure-
ment in case of FOLFOX reintroduction. External review of computed tomog-
raphy scans was not performed.
The primary end point was duration of disease control (DDC;
Fig 2).11 The DDC was defined as the PFS, or, if FOLFOX was reintro-
duced, DDC was defined as the addition of the initial PFS and the PFS of the
reintroduction in case of no progression at the first evaluation on FOLFOX
reintroduction. Further assessment criteria were PFS, overall survival, re-
sponse rate, and tolerance.
Surgery of metastases was allowed in patients with tumor response and
recommended after the sixth cycle of chemotherapy. After surgery, the patient
was scheduled to receive at least 12 cycles (6 months) of their randomly
allocated treatment. The protocol required that therapy should not be inter-
rupted for more than 12 weeks for surgery. In case of relapse after complete
395
 Tournigand et al

Table 1. Patient Characteristics

Arm A: Arm B:
FOLFOX4 FOLFOX7/sLV5FU2
Characteristic No. % No. %

No. of patients 311 100 309 100

Sex
Male 182 59 187 61
Female 129 41 122 39
Age, years
Median 65 64
Range 29-80 32-80
WHO performance status
0 162 52 163 53
1-2 148 48 144 47
Unknown 1 0 2 1
Fig 2. Definition of duration of disease control (DDC). (A) Patient with progres- Primary site
sion before leucovorin, fluorouracil, and oxaliplatin (FOLFOX) reintroduction. Colon 201 65 191 62
FOLFOX reintroduction achieved partial response (PR) or stabilization (DDC ⫽
Rectum 101 32 110 36
progression-free survival [PFS] ⫹ PFS of FOLFOX reintroduction). (B) Patient
with progression before FOLFOX reintroduction. FOLFOX reintroduction Multiple/unknown 9 3 8 2
achieved progressive disease (PD) at first evaluation (DDC ⫽ PFS). (C) Metastases
Patients without progression before FOLFOX reintroduction (DDC ⫽ PFS). Metachronous 219 70 213 69
Synchronous 90 29 95 31
Unknown 2 1 1 0
Metastatic site(s)
surgical resection and completion of adjuvant chemotherapy, chemotherapy Liver 222 71 212 69
was resumed in both arms. Lung 80 26 75 24
Peritoneum/lymph nodes 30 10 28 9
Statistical Considerations No. of sites
Random assignment was performed using a minimization technique,12 1 185 59 182 59
stratifying patients by center, PS (0 to 1 v 2), number of metastatic sites ⱖ2 125 40 126 41
involved (one v ⬎ one site), age (18 to 50 v 51 to 75 v 76 to 80 years), and Unknown 1 0 1 0
baseline ALP (ⱕ 3⫻ ULN v ⬎ 3 to 5⫻ ULN). The primary analysis of the trial CEA
had to be performed on all randomly assigned patients, but the results also had Normal 75 24 66 21
to be presented excluding the patients with age more than 75 years and baseline 1-10 ⫻ ULN 89 29 99 32
ALP more than 3⫻ ULN for ease of reference to historical figures. Sample size ⬎ 10 ⫻ ULN 134 43 125 40
was calculated to fulfill the primary objective of this trial, which was to dem- Unknown 13 4 19 6
onstrate in advanced colorectal cancer that the test treatment extends the DDC Alkaline phosphatase
compared with the reference treatment (8 v 11 months, respectively). The Normal 170 55 160 52
final sample size was 627 patients; 560 patients were needed to provide 80% 1-3 ⫻ ULN 106 34 113 37
power for standard patients, but the sample size was inflated by 12% to ⬎ 3 ⫻ ULN 33 11 30 10
account for the exploratory cohort and for the ineligible patients and Unknown 2 1 6 2
deviations of protocol. Adjuvant chemotherapy
The Kaplan-Meier method was used to estimate survival and PFS, and Yes 67 22 63 20
the log-rank test was used to compare the curves.13 The Mantel-Haenszel test No 244 78 246 80
was used to compare proportions.14 The Cox regression model was used for
Abbreviations: FOLFOX, oxaliplatin, fluorouracil, and leucovorin; sLV5FU2,
multivariate analysis of prognostic factors for survival, using a backward selec-
simplified leucovorin and fluorouracil; CEA, carcinoembryonic antigen; ULN,
tion approach.15 The cutoff date for the final analysis was October 1, 2004. upper limit of normal.

RESULTS
Patient Characteristics
From January 2000 to June 2002, 623 patients were randomly
assigned at 56 institutions in five countries. Three patients were not
analyzed because they were not eligible and not treated. The charac-
teristics of the 620 eligible patients (311 in arm A and 309 in arm B) are
listed in Table 1. A total of 261 patients in arm A and 264 patients in
arm B had an ALP ⱕ 3⫻ ULN and age less than 76 years. There were
a further 95 patients in the exploratory cohort of elderly and/or poor
prognosis patients, and their data will be presented in detail elsewhere.
Overall, the characteristics of the patients were well balanced
between the two arms. The median follow-up time for surviving
patients was 31 months.
Second-Line and Subsequent Therapy
In arm A, 224 patients (77.5%) received a second-line chemo-
therapy, 134 (46.4%) received a third-line therapy, and 53 (18.3%)
received a fourth-line therapy. In arm B, 209 patients (72.8%) received
a second-line chemotherapy (independently from scheduled oxalipla-
tin reintroduction), 112 (39%) received a third-line therapy, and
56 (19.5%) received a fourth-line therapy. During the course of
second-line and subsequent therapies, 27% of patients in arm A had
oxaliplatin reintroduction, 70% received irinotecan-based chemo-
therapy, and 32% received other chemotherapy regimens. In arm B,
55% of patients had oxaliplatin reintroduction per protocol or later,
61% received irinotecan-based chemotherapy, and 33% received
other chemotherapy regimens.

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 Oxaliplatin and LVFU2 in Colorectal Cancer

DDC and PFS

In terms of DDC, the results in the two arms were comparable.
The median DDC was 9.0 months in arm A and 10.6 months in arm B
(hazard ratio ⫽ 0.99; 95% CI, 0.81 to 1.15; P ⫽ .89; Fig 3). In patients
with ALP ⱕ 3⫻ ULN and age younger than 76 years, the median DDC
was 9.2 months in arm A and 10.7 months in arm B (P ⫽ .91).
The median PFS was 9.0 months in arm A compared with 8.7
months in arm B (hazard ratio ⫽ 1.06; 95% CI, 0.89 to 1.20;
P ⫽ .47; Fig 3). In patients with ALP ⱕ 3⫻ ULN and age younger than
76 years, the median PFS was 9.2 v 9.0 months, respectively (P ⫽ .58).
Independent prognostic factors for improved PFS in the multivariate
analysis were good PS (P ⫽ .001), low carcinoembryonic antigen
(CEA) level (P ⫽ .001), normal ALP level (P ⫽ .003), and only one
metastatic site (P ⫽ .034).
In arm A, oxaliplatin was reintroduced in 23 patients (7.4%), and Fig 4. Overall survival curves. FOLFOX, leucovorin, fluorouracil, and oxaliplatin.
only eight patients (2.6%) had a longer DDC than PFS. In arm B,
oxaliplatin was reintroduced per protocol in 124 patients (40.1%), of
whom 53 patients (17.2%) had a longer DDC than PFS, reflecting a
(P ⬍ .0001), normal lactate dehydrogenase level (P ⬍ .0001), only one
successful response to oxaliplatin after reintroduction.
metastatic site (P ⫽ .001), and center (P ⫽ .012). When oxaliplatin
Overall Survival reintroduction was included in the model, it too was an independent
Median survival time was 19.3 months in patients allocated to prognostic factor for improved overall survival (P ⫽ .032).
arm A compared with 21.2 months in patients allocated to arm B
Objective Tumor Responses
(hazard ratio ⫽ 0.93; 95% CI, 0.72 to 1.11; P ⫽ .49; Fig 4). The median
Tumor response rates were also similar for the two treatment
survival times in patients with ALP ⱕ 3⫻ ULN and age younger than
arms (58.5% in arm A; 95% CI, 54.5% to 62.5%; and 59.2% in arm B;
76 years were 20.0 and 21.6 months, respectively (P ⫽ .68).
95% CI, 55.2% to 63.2%; P ⫽ not significant). The response rates are
Independent prognostic factors for improved overall survival in
listed in Tables 2 and 3. A CEA decline of 50% or more in patients who
the multivariate analysis were PS of 0 (P ⬍ .0001), normal ALP level
had an increased baseline CEA level was observed in 121 patients
(54.3%) in arm A and 137 patients (61.2%) in arm B (P ⫽ .15).
Secondary Surgery
Results for the two regimens were also similar in terms of the
number of patients proceeding to surgery and their long-term out-
comes. Secondary surgery to remove metastases was performed in 55
patients (17.7%) in arm A compared with 47 patients (15.2%) in arm
B. An R0 resection was achieved in 35 patients (11.3%) in arm A and in
29 patients (9.4%) in arm B. The median overall survival time in
patients who had surgery was 38.9 months in arm A and 43.0 months
in arm B (P ⫽ .93).
Reintroduction of FOLFOX Therapy
In arm B, only 40.1% of the patients had per-protocol reintro-
duction. Patients could not have reintroduction because of death or
early progression (18.5%), chemotherapy-related toxicity (18.4%,

Table 2. Objective Tumor Response Rates

Arm A: Arm B:
FOLFOX4 FOLFOX7
(n ⫽ 311) (n ⫽ 309)
Response No. % No. %

Overall response rate 182 58.5 183 59.2

Complete response 20 6.4 25 8.1
Partial response 162 52.1 158 51.1
Stable disease 88 28.3 84 27.2
Progression 35 11.3 29 9.4
Not assessable 6 2.1 13 4.2

Fig 3. Duration of disease control and progression-free survival curves (n ⫽ 620). Abbreviation: FOLFOX, oxaliplatin, fluorouracil, and leucovorin.
FOLFOX, leucovorin, fluorouracil, and oxaliplatin.

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 Tournigand et al

more than 50% of their patients either during the study or later was
Table 3. Response Rate at Reintroduction in Arm B
25.5 months (115 patients).
% of Patients
Toxicity
Reintroduction Before Reintroduction After
Progression Progression In arm A, patients received a median of 12 cycles of chemother-
Response (n ⫽ 33) (n ⫽ 89) apy (range, one to 43 cycles), of which a median of 11 cycles were
Overall response 24.2 6.7 FOLFOX4 (range, one to 30 cycles). Patients who had oxaliplatin
Stable disease 54.5 42.7 reintroduction received a median of five cycles (range, two to 11
Progression 3 44.9 cycles). The relative dose-intensity was 88% for oxaliplatin, 89% for
Not assessable 18.2 5.6 FU bolus, and 91% for FU infusion. In arm B, patients received a
median of 15 cycles of chemotherapy (range, one to 51 cycles), includ-
ing a median of six cycles of FOLFOX7 (range, zero to 14 cycles).
Patients who had oxaliplatin reintroduction received a median of six
with 11% of the patients having a residual neurotoxicity grade ⬎ 1), or
cycles (range, one to 14 cycles). The relative dose-intensity during the
secondary surgery (5.5%). For 17.5% of the patients, which represents
first six cycles was 79% of the scheduled dose for oxaliplatin and 84%
30.1% of the patients eligible for reintroduction, oxaliplatin was not
for FU infusion. The median oxaliplatin dose-intensity was 37%
reintroduced without specific reason. Of the patients who did proceed
higher in arm B compared with arm A.
to a second period of oxaliplatin treatment, reintroduction was fre-
During early treatment, the tolerability and toxicity profiles of the
quently delayed; although scheduled to begin after 18 cycles or 9
two regimens were similar. In arm B, fewer patients experienced
months, 73% of the patients who then had no tumor progression had
NCI-CTC grade 3 or 4 neutropenia, but more patients had thrombo-
oxaliplatin reintroduction after 10 months. Twelve percent of patients
cytopenia, nausea, mucositis, and hand-foot syndrome. Grade 3 sen-
had a complete chemotherapy stop before reintroduction.
sory neuropathy was observed in 17.9% of the patients in arm A and
Tumor response to per-protocol reintroduction was assessed in
13.3% of patients in arm B (P ⫽ .12). Febrile neutropenia occurred in
122 of 124 patients in arm B. Overall, reintroduction achieved re-
eight patients (2.6%) in arm A and two patients (0.6%) in arm B.
sponses or stabilizations in 69.4% of the patients. Responses are listed
Vascular events, phlebitis, and pulmonary embolism were reported in
in Table 3. In patients without progression at reintroduction (n ⫽ 33),
11 patients (3.5%) in arm A and in two patients (0.6%) in arm B.
the response rate was 24.2%, the stable disease rate was 54.5%, and
Overall, 54.4% and 48.2% of patients experienced a grade 3 or 4
the progressive disease rate was 3.0%, whereas 18.2% of patients were
toxicity in arm A and arm B, respectively (P ⫽ not significant). Table
nonassessable. These patients included three patients who had surgery
4 lists the toxicities. During the first 60 days, five patients (1.6%) died
and one patient who remained in complete response. PFS after reintro-
in arm A, and eight patients (2.6%) died in arm B (P ⫽ .42).
duction was not assessable in this subgroup. In patients in whom reintro-
Of note, the risk of developing a grade 3 to 4 toxicity was greatly
duction was made after progression (n ⫽ 89), the response rate was only
reduced in arm B from cycle 7 to cycle 18, when patients did not
6.7%, the stable disease rate was 42.7%, and the progressive disease rate
receive oxaliplatin (Fig 5B). Similarly, grade 3 neuropathy, which
was 44.9%, whereas 5.6% of the patients were nonassessable. The median
occurred earlier with arm B’s FOLFOX7 regimen than with arm A’s
PFS from reintroduction was 12 weeks in these patients.
FOLFOX4 regimen, was greatly reduced in arm B after the sixth cycle
In arm A, tumor response to oxaliplatin reintroduction was as-
(Fig 5C). Only two patients (2%) developed a grade 3 neurotoxicity
sessed in 24 patients, among whom 20 had oxaliplatin reintroduced
and 31 patients (28%) developed a grade 2 neurotoxicity after oxali-
after progression and four had oxaliplatin reintroduced before pro-
platin reintroduction.
gression. The response rate was 12.5%, the stable disease rate was
20.8%, and the progressive disease rate was 45.8%. A further 20.8% of Weight and PS
patients proceeded to surgery and were nonassessable. The overall A weight increase of at least 5% was recorded for 90 patients
median survival time in centers that had reintroduced oxaliplatin in (29.1%) in arm A and 115 patients (37.5%) in arm B (P ⫽ .13). In arm

Table 4. Frequency of Common Toxicities (maximal toxicity per patient)

Arm A: FOLFOX4 Arm B: FOLFOX7/sLV5FU2
(n ⫽ 309) (n ⫽ 303)
Grade Grade Grade Grade Grade Grade Grade Grade P: Grade 3/4
Toxicity 1 (%) 2 (%) 3 (%) 4 (%) 1 (%) 2 (%) 3 (%) 4 (%) (arm A v arm B)

Neutropenia 18 23 21 11 24 22 16 5 .002
Thrombocytopenia 50 16 4 0 42 25 9 0 .006
Anemia 51 22 2 0 57 22 1 0 NS
Nausea/vomiting 36 24 5 0 31 33 9 1 .040
Diarrhea 26 21 9 2 25 24 7 3 NS
Mucositis 27 11 3 0 27 13 6 0 .031
Cutaneous 13 0 0 0 21 6 3 0 .006
Alopecia 21 2 NA NA 18 5 NA NA NA
Neurologic 34 37 18 0 36 42 13 0 .12

Abbreviations: NA, not applicable; NS, not significant; FOLFOX, oxaliplatin, fluorouracil, and leucovorin; sLV5FU2, simplified leucovorin and fluorouracil.

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 Oxaliplatin and LVFU2 in Colorectal Cancer
Fig 5. Comparison of the proportion of patients who developed a grade 3 or 4
toxicity at each cycle. (A) Number of patients who received each cycle. (B)
Percentage of patients with grade 3 or 4 toxicity. (C) Percentage of patients with
neurologic grade 3 toxicity. FOLFOX, leucovorin, fluorouracil, and oxaliplatin.
A, PS improved in 92 (62%) of 148 assessable patients with a PS more
than 0 compared with 92 (64%) of 144 assessable patients in arm B
(P ⫽ not significant).
DISCUSSION
Studies achieving a median survival time of more than 20 months in
advanced colon cancer therapy remain few6,16-19 and have two main
characteristics. The first is the use of FU with oxaliplatin, irinotecan, or
irinotecan and bevacizumab. The second is that a high proportion
(50% to 80%) of patients receive a second-line therapy with active
drugs not used in first-line therapy.
In the present OPTIMOX1 study, median survival time exceeded
20 months among patients with initially inoperable metastatic colo-
rectal cancer with less stringent inclusion criteria than in preceding
studies undertaken by the same group.5,6,20 Of note, the FOLFOX4
arm reproduced the results achieved with this regimen in previous
studies.3,5 The proportion of patients who received second-line irino-
tecan (⬎ 60%) was high in both arms of the trial.
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OPTIMOX1 has shown that stopping oxaliplatin after six cycles
followed by sLV5FU2 alone achieves the same efficacy results, re-
sponse rate, PFS, and overall survival as continuing oxaliplatin until
progression or toxicity. Furthermore, avoiding oxaliplatin after the
sixth cycle greatly reduced the risk of grade 3 to 4 toxicity.
The results of this study are consistent with the proposition that,
for most patients, six cycles of FOLFOX7 are sufficient to achieve the
full clinical benefits of oxaliplatin treatment. However, it is also possi-
ble that other factors may have contributed to the equivalent disease
control achieved by the two regimens. For instance, because oxalipla-
tin dose-intensity was increased by 37% in the FOLFOX7-based arm
B, it might be supposed that this contributed to the result by offsetting
the effects of discontinuing oxaliplatin. However, response rates were
comparable between the two groups during first-line treatment, indi-
cating that this is unlikely. The LV5FU2 regimens also differed be-
tween the two arms, but although these differences impact on cost and
convenience of treatment, the present study indicates that they do not
differ in efficacy. However, it is possible that the use of the full
sLV5FU2 regimen in arm B after the six cycles of FOLFOX7 contrib-
uted to the clinical response because the median PFS of this regimen
alone was found to be unusually prolonged in a previous study.21
Oxaliplatin reintroduction, as scheduled in the protocol, was
unsuccessful in this study. This does not mean that reintroduction is
not active, but protocol violations were so frequent that it raises the
question of its feasibility. Furthermore, almost 75% of the patients had
delayed oxaliplatin reintroduction, including a significant proportion
(12%) even after a complete therapy stop. This poor compliance with
the protocol could mean that many investigators were not convinced
by the new concept of oxaliplatin reintroduction or that patients
feared to resume a regimen more toxic than sLV5FU2. Because a
significant number of patients received oxaliplatin-based therapy after
the protocol and in both arms of the study, the results do not make it
possible to draw final conclusions about oxaliplatin reintroduction.
Nevertheless, detailed consideration of the results suggests that rein-
troduction could have a significant impact on survival; reintroduction
rate among centers was an independent prognostic factor for pro-
longed survival, which suggests that a more favorable population is
not the sole explanation of the 25-month median survival time ob-
served in centers that reintroduced oxaliplatin in more than 50% of
their patients.
To further assess oxaliplatin reintroduction, we have con-
ducted a new study, OPTIMOX2, which is designed to evaluate the
feasibility of oxaliplatin reintroduction after LV5FU2 maintenance
in selected centers and to further evaluate a complete chemother-
apy stop-and-go regimen wherein reintroduction is performed in
non–FU-resistant tumors.
Given the results of the present study, we now consider that six
cycles of FOLFOX7 is the optimal duration of the combined chemo-
therapy for most patients with advanced colorectal cancer. However,
considering these results, we modified the FOLFOX7 schedule and
now use a dose of oxaliplatin of 100 mg/m2 associated with an
increased dose of FU (3,000 mg/m2). Modified FOLFOX7 and
XELOX (oxaliplatin) regimens, combined with angiogenesis and epi-
dermal growth factor receptor inhibitors, are currently being evalu-
ated in the double inhibition, reintroduction, avastin (Genentech Inc,
South San Francisco, CA), metastic colorectal cancer (DREAM)/
OPTIMOX3 study.
399
 Tournigand et al

8. Maindrault-Goebel F, de Gramont A, Louvet 16. Hurwitz H, Fehrenbacher L, Novotny W, et al:

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Appendix
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Adobe® Acrobat Reader®) version.

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Christophe Tournigand, Marc Buyse, Laurent Mineur, Christophe Louvet, Isabelle Tabah-Fisch, Aimery de Gramont
Financial support: Isabelle Tabah-Fisch
Provision of study materials or patients: Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc
Etienne, Fernando Rivera, Isabel Chirivella, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Aimery de Gramont
Collection and assembly of data: Christophe Tournigand, Andres Cervantes, Arie Figer, Gérard Lledo, Marc Buyse, Laurent Mineur, Elisabeth Carola,
Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Thierry André, Aimery de Gramont
Data analysis and interpretation: Christophe Tournigand, Marc Buyse, Nathalie Perez-Staub, Aimery de Gramont
Manuscript writing: Christophe Tournigand, Nathalie Perez-Staub, Thierry André, Aimery de Gramont
Final approval of manuscript: Christophe Tournigand, Andres Cervantes, Marc Buyse, Laurent Mineur, Pierre-Luc Etienne, Christophe Louvet,
Thierry André, Isabelle Tabah-Fisch, Aimery de Gramont

400 JOURNAL OF CLINICAL ONCOLOGY

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