Nejmoa

The new england journal of medicine
original article
Oxaliplatin, Fluorouracil, and Leucovorin

as Adjuvant Treatment for Colon Cancer
Thierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D.,
Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D.,
Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D.,
John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D.,
and Aimery de Gramont, M.D., for the Multicenter International Study
of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment
of Colon Cancer (MOSAIC) Investigators
abstract
background
The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). From Hôpital Tenon, Paris (T.A.);
Oxaliplatin improves the efficacy of this combination in patients with metastatic colo- GERCOR Oncology Multidisciplinary
Group, Paris (T.A., A.G.); Arcispedale San-
rectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the ta Maria Nuova, Reggio Emilia, Italy
postoperative adjuvant setting. (C.B.); Sanofi-Synthelabo, Paris (L.M.-B.,
I.T.-F.); Hospital Duran i Reynals, l’Hospi-
talet de Llobregat, Llobregat, Spain (M.N.);
methods Vall d’Hebron University Hospital, Barcelo-
We randomly assigned 2246 patients who had undergone curative resection for stage II na, Spain (J.T.); Dorset Cancer Centre,
or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary Royal Bournemouth and Poole Hospitals,
Bournemouth, United Kingdom (T.H.); Roy-
end point was disease-free survival. al Surrey County Hospital, Guildford, Sur-
rey, United Kingdom (C.T.); Ospedale Bor-
results gotrento, Verona, Italy (M.Z.); Southern
Medical Day Care Centre, Wollongong, Aus-
A total of 1123 patients were randomly assigned to each group. After a median follow- tralia (P.C.); North Middlesex Hospital,
up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a can- London (J.B.); and Hôpital Saint-Antoine,
cer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 Paris (A.G.). Address reprint requests to
Dr. de Gramont at Hôpital Saint Antoine,
percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at 184 rue du Faubourg Saint Antoine, Paris
three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group 75012, France, or at aimery.de-gramont@
given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) sat.ap-hop-paris.fr.
in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus ox- N Engl J Med 2004;350:2343-51.
aliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastro- Copyright © 2004 Massachusetts Medical Society.
intestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was
12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six
patients in each group died during treatment (death rate, 0.5 percent).
conclusions
Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant
treatment of colon cancer.
n engl j med 350;23 www.nejm.org june 3, 2004 2343
The New England Journal of Medicine

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Copyright © 2004 Massachusetts Medical Society. All rights reserved.
c olorectal cancer is the second

leading cause of death from cancer in
Western countries1; 40 to 50 percent of pa-
tients who undergo potentially curative surgery
alone ultimately relapse and die of metastatic dis-
treatment
Eligible patients were randomly assigned to receive
FL alone or with oxaliplatin. In the FL group, each
cycle comprised a 2-hour infusion of 200 mg of leu-
covorin per square meter of body-surface area fol-
ease.2 The most important prognostic indicator of lowed by a bolus of 400 mg of fluorouracil per
survival in early colon cancer is the stage of the tu- square meter and then a 22-hour infusion of 600
mor (T, according to the tumor–node–metastasis mg of fluorouracil per square meter given on 2 con-
[TNM] classification), determined by the depth of secutive days every 14 days, for 12 cycles. In the
penetration through the bowel wall, and the num- group given FL plus oxaliplatin, the same FL regi-
ber of involved lymph nodes.3 men was used, plus a two-hour infusion of 85 mg
The demonstration that postoperative adjuvant of oxaliplatin (Eloxatin, Sanofi-Synthelabo) per
treatment with fluorouracil and levamisole reduced square meter on day 1, given simultaneously with
the mortality rate by 33 percent among patients leucovorin, with the use of a Y infusion device. The
with stage III colon cancer 4 prompted several trials, use of disposable pumps (LV5 infusors, Baxter
which established six months of treatment with Healthcare) allowed outpatients to receive a contin-
fluorouracil plus leucovorin (FL) as the standard ad- uous infusion of fluorouracil.
juvant chemotherapy for stage III colon cancer.5-11 Adverse effects were graded according to the
Oxaliplatin is a third-generation platinum deriva- Common Toxicity Criteria of the National Cancer
tive, which, when combined with fluorouracil and Institute, version 1. According to these criteria, a
leucovorin, is among the most effective chemo- score of 1 indicates mild adverse effects, a score of
therapies for metastatic colorectal cancer.12-15 To 2 moderate adverse effects, a score of 3 severe ad-
determine whether oxaliplatin can also benefit pa- verse effects, and a score of 4 life-threatening ad-
tients with disease in an earlier stage, we conduct- verse effects. Dose reductions were based on the
ed an international phase 3 clinical trial in patients worst adverse effects observed during the previous
with stage II or III colon cancer — the Multicenter cycle. The dose of oxaliplatin was to be reduced to
International Study of Oxaliplatin/5-Fluorouracil/ 75 mg per square meter in the event of persistent
Leucovorin in the Adjuvant Treatment of Colon (at least 14 days) paresthesias, temporary painful
Cancer (MOSAIC). paresthesias, or functional impairment. Oxalipla-
tin was discontinued in cases of persistent painful
methods paresthesias or functional impairment. Together
with reductions in the dose of oxaliplatin, the bolus
patients dose of fluorouracil was reduced to 300 mg per
Patients were eligible if they had undergone com- square meter and the infusion to 500 mg per
plete resection of histologically proven stage II (T3 square meter in the event of grade 3 or 4 neutrope-
or T4,N0,M0) or stage III (any T,N1 or N2,M0) co- nia or thrombocytopenia (or both), diarrhea, sto-
lon cancer, as defined by the presence of the inferi- matitis, or other drug-related adverse effects of
or pole of the tumor above the peritoneal reflection grade 3. Only the dose of fluorouracil was sched-
— that is, at least 15 cm from the anal margin. uled to be reduced in the event of skin-related ad-
Treatment had to be started within seven weeks af- verse effects of grade 3 or 4. Treatment was delayed
ter surgery. Other eligibility criteria included an age by up to three weeks until the patient recovered
of 18 to 75 years; a Karnofsky performance-status from various adverse effects, the neutrophil count
score of at least 60; a carcinoembryonic antigen exceeded 1500 per cubic millimeter, and the plate-
level of less than 10 ng per milliliter; the absence of let count exceeded 100,000 per cubic millimeter.
prior chemotherapy, immunotherapy, or radio- Chemotherapy was stopped in the event of cardiac
therapy; and adequate blood counts and liver and or neurocerebellar adverse effects or grade 3 or 4 al-
kidney function. Written informed consent was re- lergic reactions.
quired from all patients, and the study was ap-
proved by the ethics committees of the participat- follow-up
ing centers. Patients were assessed before randomization, ev-
ery two weeks during treatment, and then every six
2344 n engl j med 350;23 www.nejm.org june 3 , 2004

oxaliplatin, fluorouracil, and leucovorin for colon cancer
months for five years. The baseline assessment ment on disease-free survival across prognostic
involved a medical history taking, physical exami- subgroups, we calculated hazard ratios and 95 per-
nation, biologic tests, measurement of the carcino- cent confidence limits for subgroups defined ac-
embryonic antigen level, chest radiography, and cording to the following variables: sex, age, disease
abdominal ultrasonography or computed tomog- stage (II vs. III), baseline serum carcinoembryon-
raphy. Patients were monitored for adverse effects ic antigen level, number of involved lymph nodes
throughout the treatment period and until 28 days (≤4 vs. >4), T classification (T4 vs. T1, T2, or T3),
after the last cycle of chemotherapy, unless treat- degree of cellular differentiation (well vs. poorly
ment-related adverse effects required additional differentiated), and the presence or absence of per-
follow-up. foration, obstruction, and venous invasion.
The diagnosis of recurrence was made on the The cutoff date of the analysis was April 22,
basis of imaging and, if necessary, cytologic analysis 2003. The duration of follow-up was defined as the
or biopsy. An elevated carcinoembryonic antigen number of months from randomization to the cut-
level as a solitary finding was not accepted as evi- off date.
dence of relapse. Neurologic adverse effects were to Secondary end points were safety, including
be reported at each visit during follow-up and were long-term adverse effects, and overall survival, mea-
assessed with the use of the neurosensory section sured from the time of randomization to death from
of the Common Toxicity Criteria of the National any cause. With a median follow-up of three years,
Cancer Institute, version 1. it is too early to compare the two treatment groups
statistically in terms of survival, and only descrip-
statistical analysis tive analyses of overall survival are presented. Safe-
Randomization was performed centrally, and the ty analyses included patients who had received at
minimization method was used to balance treat- least one cycle of treatment.
ment allocation according to the TNM stage (T2 or
T3 vs. T4 and N0, N1, or N2), the presence or ab- organization of the trial
sence of bowel obstruction or tumor perforation, The concept underlying this study was developed
and the medical center. The sample size of 2200 by Dr. de Gramont, and the investigation was de-
patients was calculated under the assumptions of a signed by the investigators and Sanofi-Synthelabo.
three-year disease-free survival rate of 73 percent in Data were collected, managed, and analyzed by the
the control group and 79 percent in the group giv- sponsor. The article was written by the investiga-
en FL plus oxaliplatin, with a ratio of stage II dis- tors, on the basis of data and statistical analyses
ease to stage III disease of 0.4:0.6, an enrollment provided by Sanofi-Synthelabo.
period and a follow-up period of three years, a de- A data and safety monitoring board of indepen-
crease in the risk of relapse after three years, a sta- dent experts reviewed safety data every six months
tistical power of 90 percent, and an alpha value of during the treatment period to provide the sponsor
0.05 and two-sided P values derived with the use of with independent advice on the progress of the
the log-rank test. The primary efficacy variable was study and on safety. No interim analysis was
disease-free survival, defined as the time from ran- planned or performed.
domization to relapse or death, whichever occurred
first. Second colorectal cancers were considered results
relapses, whereas noncolorectal tumors were dis-
regarded in the analyses. study population
The primary statistical analysis of efficacy was Between October 1998 and January 2001, 2246 pa-
the comparison, after three years of follow-up, of tients were enrolled at 146 centers in 20 countries:
disease-free survival between groups according to 1123 patients were randomly assigned to receive
the intention-to-treat principle, with the use of a FL plus oxaliplatin and 1123 to receive FL without
two-sided log-rank test stratified according to base- oxaliplatin. Of these patients, 1108 received at least
line disease stage. Hazard ratios and 95 percent con- one cycle of FL plus oxaliplatin and 1111 received
fidence intervals were calculated with the use of the at least one cycle of FL. The patients’ characteristics
Cox proportional-hazards model. Survival curves were well matched in the two groups (Table 1). In
were drawn according to Kaplan–Meier methods. both groups, 60 percent of the patients had stage
To assess the consistency of the effect of treat- III disease and 40 percent had stage II disease. The

Table 1. Baseline Characteristics of the Patients in the Group Given overall median time between surgery and the start
Fluorouracil and Leucovorin (FL) plus Oxaliplatin and the FL Group. of chemotherapy was 5.7 weeks (range, 1.1 to 17.0).
A total of 41 patients (1.8 percent) did not
FL plus Oxaliplatin FL
Characteristic (N=1123) (N=1123) strictly meet eligibility criteria related to baseline
disease. In one patient in each group, the resection
All patients
of primary tumor was incomplete. Four patients in
Age — yr the group given FL plus oxaliplatin and six in the FL
Median 61 60 group had a history of cancer, including colorectal
Range 19–75 20–75 cancer. Thirteen patients (four in the group given
Age <65 yr — no. (%) 723 (64.4) 743 (66.2) FL plus oxaliplatin and nine in the FL group) had
Sex — no. (%) stage IV cancer, and three patients (two in the group
Male 630 (56.1) 588 (52.4) given FL plus oxaliplatin and one in the FL group)
Female 493 (43.9) 535 (47.6)
had cancer of the middle or lower rectum. Four pa-
tients in the group given FL plus oxaliplatin and
Karnofsky performance-status score — no. (%)
nine in the FL group had various other eligibility-
<60 5 (0.4) 5 (0.4)
criteria violations.
60–70 150 (13.4) 134 (11.9)
80–100 968 (86.2) 984 (87.6) chemotherapy
Disease stage — no. (%) The median number of cycles of chemotherapy re-
II 451 (40.2) 448 (39.9) ceived was 12 in both groups; 74.7 percent of pa-
III 672 (59.8) 675 (60.1) tients in the group given FL plus oxaliplatin and
Depth of invasion — no. (%) 86.5 percent in the FL group received the planned
T2 51 (4.5) 54 (4.8) 12 cycles. In the group that received FL plus oxali-
platin, the median dosage of oxaliplatin was 34.2
T3 853 (76.0) 852 (75.9)
mg per square meter per week across all cycles re-
T4 213 (19.0) 208 (18.5)
ceived and 36.5 mg per square meter per week
Unknown 6 (0.5) 9 (0.8)
across cycles including oxaliplatin. In both cases,
Bowel obstruction — no. (%) 201 (17.9) 217 (19.3) more than 80 percent of the planned dose was ac-
Perforation — no. (%) 78 (6.9) 78 (6.9) tually given (80.5 percent and 85.9 percent, respec-
Histologic appearance — no. (%) tively). The dose of fluorouracil received was 84.4
Well differentiated 934 (83.2) 914 (81.4) percent of the planned dose in the group given FL
Poorly differentiated 142 (12.6) 148 (13.2) plus oxaliplatin and 97.7 percent of the planned
Unknown 47 (4.2) 61 (5.4) dose in the FL group.
Patients with stage III disease — no. (%)
safety
No. of nodes involved
Neutropenia, diarrhea, and vomiting were the most
1–4 499 (44.4) 513 (45.7)
frequent grade 3 or 4 adverse effects in the group
>4 170 (15.1) 160 (14.2) given FL plus oxaliplatin (Table 2). Grade 3 or 4
Unknown 2 (0.2) 2 (0.2) neutropenia was much commoner with FL plus ox-
Patients with stage II disease — no. (%) aliplatin than with FL (41.1 percent vs. 4.7 percent,
T4 84 (18.6) 87 (19.4) P<0.001) but was complicated by fever or infection
No. of lymph nodes examined in only 1.8 percent of cases (20 patients) in the
<10 152 (33.7) 149 (33.3) group given FL plus oxaliplatin and in 0.2 percent of
≥10 295 (65.4) 294 (65.6) cases (2 patients) in the FL group (P<0.001). The
Bowel obstruction 71 (15.7) 87 (19.4)
incidence of thromboembolic events among pa-
tients who received at least one cycle of the as-
Perforation 38 (8.4) 43 (9.6)
signed regimen was similar in the two groups (63
Histologic appearance
of 1108 patients [5.7 percent] and 72 of 1111 pa-
Well differentiated 385 (85.4) 378 (84.4) tients [6.5 percent], respectively).
Poorly differentiated 47 (10.4) 42 (9.4) Although 92.1 percent of patients treated with FL
Unknown 19 (4.2) 28 (6.3) plus oxaliplatin had peripheral neuropathy during
treatment, half of these episodes were of grade 1

Table 2. Adverse Events in the Group Given Fluorouracil and Leucovorin (FL) plus Oxaliplatin and the FL Group.*
Adverse Event FL plus Oxaliplatin (N=1108) FL (N=1111) P Value

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 All Grades Grades 3 and 4
percent
Paresthesia† 92.0 12.4 NA 15.6 0.2 NA <0.001 0.001
Neutropenia 78.9 28.8 12.3 39.9 3.7 1.0 <0.001 <0.001
Thrombocytopenia 77.4 1.5 0.2 19.0 0.2 0.2 <0.001 0.001
Anemia 75.6 0.7 0.1 66.9 0.3 0.0 <0.001 0.09
Nausea 73.7 4.8 0.3 61.1 1.5 0.3 <0.001 <0.001
Diarrhea 56.3 8.3 2.5 48.4 5.1 1.5 <0.001 <0.001
Vomiting 47.2 5.3 0.5 24.0 0.9 0.5 <0.001 <0.001
Stomatitis 41.6 2.7 0.0 39.6 2.0 0.2 0.34 0.41
Skin‡ 31.5 1.4 0.6 35.5 1.7 0.7 0.05 0.67
Alopecia§ 30.2 NA NA 28.1 NA NA 0.28 NA
Allergic reaction 10.3 2.3 0.6 1.9 0.1 0.1 <0.001 <0.001
Thrombosis 5.7 1.0 0.2 6.5 1.7 0.1 0.48 0.29
or phlebitis
Neutropenia with 1.8 1.4 0.4 0.2 0.1 0.1 <0.001 <0.001
fever or infection
* Fisher’s exact test was used to calculate P values. NA denotes not applicable.
† There are only three grades of paresthesia in version 1 of the Common Toxicity Criteria of the National Cancer Institute.
‡ This category included the hand–foot syndrome.
§ There are only two grades of alopecia in version 1 of the Common Toxicity Criteria of the National Cancer Institute. The
incidence of grade 2 alopecia was 5.0 percent in each group.
(Table 3). Of the 137 patients (12.4 percent) who follow-up

had grade 3 peripheral neuropathy during treat- There was good compliance with follow-up visits.
ment, grade 3 symptoms were still present in 8 pa- The mean time between visits was 5.97 months in
tients at the six-month follow-up visit and in 5 pa- the group given FL plus oxaliplatin and 5.98 months
tients at the one-year visit. In 12 patients, grade 3 in the FL group. The median interval was 6.01
peripheral neurosensory symptoms appeared after months in both groups.
the end of treatment, and 6 of these patients had
persistent grade 3 symptoms after one year. In total,
11 of 1018 patients (1.1 percent) who were assessed Table 3. Incidence of Neurosensory Symptoms during Treatment
one year after the end of treatment continued to and Follow-up in the Group Given Fluorouracil, Leucovorin, and Oxaliplatin.*
have grade 3 peripheral neurosensory symptoms. During 1 Mo 6 Mo 12 Mo 18 Mo
This number dropped to five (0.5 percent) after 18 Treatment Follow-up Follow-up Follow-up Follow-up
months (Table 3). Grade (N=1106) (N=1092) (N=1058) (N=1018) (N=967)
Twelve patients — six in each group (0.5 per- number (percent)
cent) — died within 1 month after the end of treat-
0 87 (7.9) 424 (38.8) 624 (59.0) 718 (70.5) 738 (76.3)
ment; these included three deaths in each group
during the first 60 days of treatment. In the group 1 533 (48.2) 439 (40.2) 338 (31.9) 240 (23.6) 191 (19.8)
given FL plus oxaliplatin, four patients died of in- 2 349 (31.6) 174 (15.9) 82 (7.8) 49 (4.8) 33 (3.4)
fection or sepsis (two with neutropenia) and two of 3 137 (12.4) 55 (5.0) 14 (1.3) 11 (1.1) 5 (0.5)
intracranial hemorrhage. In the FL group, one pa-
tient each died of sepsis, Stevens–Johnson syn- * Only patients who actually received treatment were included in the analysis.
drome in the context of severe diarrhea and flucon- A grade of 0 indicates no change or no symptoms, a grade of 1 mild paresthe-
azole treatment, and anoxic cerebral infarction; sia and loss of deep tendon reflexes, a grade of 2 mild or moderate objective
sensory loss and moderate paresthesia, and a grade of 3 severe objective sen-
one patient committed suicide; and two died sud- sory loss or paresthesias that interfere with function.
denly from cardiac causes.

disease-free survival The hazard ratio for recurrence in the group given
At the time of analysis (median follow-up, 37.9 FL plus oxaliplatin, as compared with the FL group,
months), 237 patients in the group given FL plus was 0.77 (P=0.002), corresponding to a 23 percent
oxaliplatin (21.1 percent) had relapsed or died, as reduction in the risk of relapse. The probability of
compared with 293 (26.1 percent) in the FL group. disease-free survival at three years was 78.2 percent
(95 percent confidence interval, 75.6 to 80.7 per-
cent) in the group given FL plus oxaliplatin and
Table 4. Analysis of Disease-free Survival According to the Intention-to-Treat
72.9 percent (95 percent confidence interval, 70.2
Principle.*
to 75.7 percent) in the FL group (P=0.002 by the
FL plus Oxaliplatin FL stratified log-rank test) (Table 4 and Fig. 1).
Variable (N=1123) (N=1123)
Among patients with stage III disease, the haz-
Follow-up — mo ard ratio for relapse was 0.76 (95 percent confi-
Median 37.9 37.8
Range 27–54 27–54
dence interval, 0.62 to 0.92) in the group given FL
plus oxaliplatin, as compared with the FL group,
Probability of disease-free survival 78.2 (75.6–80.7) 72.9 (70.2–75.7)
at 3 yr — % (95% CI)† and the three-year disease-free survival rate was
Event — no. (%) 237 (21.1) 293 (26.1) 72.2 percent and 65.3 percent, respectively (Fig. 2).
Relapse‡ 208 (18.5) 279 (24.8) Among patients with stage II disease, the hazard
Metastasis 169 (15.0) 229 (20.4) ratio for relapse was 0.80 (95 percent confidence
Second colorectal carcinoma 6 (0.5) 9 (0.8)
Local relapse 38 (3.4) 51 (4.5) interval, 0.56 to 1.15) in the group given FL plus
Death without relapse 29 (2.6) 14 (1.2)
oxaliplatin, as compared with the FL group, and
the three-year disease-free survival rates were 87.0
* FL denotes fluorouracil and leucovorin, and CI confidence interval. percent and 84.3 percent, respectively (Fig. 2).
† P=0.002 by the stratified log-rank test for the comparison between groups. A Cox-model analysis showed that the reduced
‡ The same patient could have been counted in more than one relapse category risk of recurrence with FL plus oxaliplatin was sim-
if several types of relapses were reported at the same follow-up visit.
ilar in patients with stage II and those with stage III
disease (P=0.77). Calculation of hazard ratios and
95 percent confidence intervals (Fig. 3) showed
1.0 that the reduced risk of relapse was consistent in all
0.9
subgroups defined on the basis of prognostic fac-
FL plus oxaliplatin (237 events, 21.1%)
tors at baseline.
Probability of Disease-free Survival
0.8
0.7 overall survival

FL (293 events, 26.1%)
0.6 At the time of the cutoff date of the primary analy-
0.5
sis, 133 patients had died in the group given FL
plus oxaliplatin, as compared with 146 patients in
0.4
the FL group (hazard ratio for death, 0.90; 95 per-
0.3 cent confidence interval, 0.71 to 1.13), and the prob-
0.2 ability of survival at three years was 87.7 percent
P=0.002 and 86.6 percent, respectively. Most of the patients
0.1
who died had stage III disease (104 in the group
0.0
0 6 12 18 24 30 36 42 48 given FL plus oxaliplatin and 119 in the FL group);
Months the hazard ratio for death in this subgroup was
No. at Risk 0.86 (95 percent confidence interval, 0.66 to 1.11).
FL+oxaliplatin 1123 1086 1023 959 888 663 395
FL 1123 1066 981 903 817 619 356
discussion
Figure 1. Kaplan–Meier Estimates of Disease-free Survival in the Group Giv-
en Fluorouracil and Leucovorin (FL) and the Group Given FL plus Oxaliplatin,
In previous trials, the addition of oxaliplatin to
According to the Intention to Treat. fluorouracil and leucovorin doubled the response
The hazard ratio for recurrence in the group given FL plus oxaliplatin, as com- rate and prolonged progression-free survival among
pared with the FL group, was 0.77 (95 percent confidence interval, 0.65 to patients with metastatic colorectal cancer.14 The
0.91; P=0.002). efficacy and safety of this regimen were recently
confirmed in a large, randomized, phase 3 trial,

1.0
0.9 Stage II, FL+oxaliplatin (56 events, 12.4%)
Probability of Disease-free Survival

0.8 Stage II, FL (67 events, 15.0%)
0.7 Stage III, FL+oxaliplatin (181 events, 26.9%)

0.6 Stage III, FL (226 events, 33.5%)
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48
Months
No. at Risk
Stage II, FL+oxaliplatin 451 445 435 417 387 295 170
Stage II, FL 448 435 418 400 369 274 162
Stage III, FL+oxaliplatin 672 641 588 542 501 368 225
Stage III, FL 675 631 563 503 448 345 194
Figure 2. Kaplan–Meier Estimates of Disease-free Survival in the Group Given Fluorouracil and Leucovorin (FL)
and the Group Given FL plus Oxaliplatin, According to the Stage of Disease and the Intention to Treat.
which found that this approach was superior (with relapses after curative surgery occur within the first
respect to all efficacy variables, including overall three years, we consider our results in this respect
survival) to the combination of irinotecan, fluoro- to be complete.
uracil (given as a bolus), and leucovorin.15 Our trial Although it is agreed that patients with stage III
was designed to test the efficacy of adjuvant treat- disease benefit from adjuvant treatment, whether
ment with the regimen of FL plus oxaliplatin. We all patients with stage II disease should receive
chose disease-free survival as the primary end such treatment remains debatable. This controver-
point of the study because, like others,16 we believe sy was sustained for years by the contradictory con-
that the absence of relapse is the best indicator of clusions of two large groups of investigators. The
efficacy, since it relates directly to the effect of the National Surgical Adjuvant Breast and Bowel
treatment under investigation. By allowing early Project concluded that the relative benefits of treat-
appraisal of the results, the use of three-year dis- ment were largely the same for stage II and stage
ease-free survival as the primary end point for adju- III tumors,20 whereas the International Multicen-
vant trials of patients with colon cancer should per- tre Pooled Analysis of B2 Colon Cancer Trials
mit rapid evaluation of new treatments. Whether (IMPACT B2) failed to demonstrate a statistically
disease-free survival should be a primary end point significant benefit for stage II tumors.21
is still under discussion, but a recent analysis of A recent meta-analysis from the Mayo Clinic,22
several studies supports the appropriateness of the which evaluated individual data on 3300 patients
use of three-year disease-free survival as a good who were enrolled in five randomized trials, in-
predictor of five-year overall survival in trials of ad- cluding those analyzed in IMPACT B2, concluded
juvant treatment of colon cancer.17 that patients with stage II disease could benefit
Disease-free survival in the FL group in our from adjuvant chemotherapy, but to a lesser extent
study falls within the highest range reported in than patients with stage III tumors. Indeed, the ab-
most studies of adjuvant treatment of colon cancer solute benefit among patients with stage II disease
with FL.6-8,18,19 The improvement in disease-free is only half as great as that among patients with
survival among patients who were treated with FL stage III disease, and twice as many patients with
plus oxaliplatin corresponds to a relative reduction stage II tumors are required in such studies in or-
in the risk of recurrence of 23 percent. Since most der to detect a difference.

A test for interaction is an appropriate statistical III colorectal cancer. From a clinical standpoint,
approach to the question of whether the benefit of stage II colon cancer occurs in a heterogeneous,
adjuvant treatment differs between stage II and node-negative population in which clinical and bi-
stage III colorectal cancer.23 In our study, this test ologic prognostic factors other than the status of
showed no significant interaction between the stage lymph-node involvement need to be taken into ac-
of disease and the treatment, indicating that FL count. Tools are being developed to help physi-
plus oxaliplatin benefited both stage II and stage cians assess the risk–benefit ratio of adjuvant che-
motherapies for individual patients.22
With no clear consensus on the most effective
Prognostic Factor Hazard Ratio (95% CI) FL regimen to be used for adjuvant treatment, we
Overall chose a twice-monthly regimen because of its effi-
Sex cacy and low rates of adverse effects in patients
Male with advanced colorectal cancer, alone and in com-
Female bination with oxaliplatin.12,14,24 Supporting our
Age decision are recent results demonstrating that this
≥65 yr
approach to adjuvant therapy is less toxic than
<65 yr
monthly bolus injections of FL and is just as effec-
Tumor stage
tive.18 This approach led to a straightforward study
design, since the treatment in both groups was
T4
similar except for the addition of oxaliplatin in the
T1–T3
group given FL plus oxaliplatin. The improved dis-
Nodal stage
ease-free survival in the FL-plus-oxaliplatin group
N2
is thus directly linked to oxaliplatin.
N0 or N1
The main safety concern regarding the use of
Stage
oxaliplatin is peripheral neuropathy. Oxaliplatin in-
III duces frequent, transient, distal paresthesias dur-
II ing or shortly after the first minutes of infusion. In
Obstruction some cases these neurosensory symptoms increase
Present in intensity with cumulative doses, persist between
Absent cycles, and interfere with function (in the case of
Perforation grade 3 effects).12,14,25 We observed grade 3 periph-
Present eral neuropathy in 12.4 percent of patients who
Absent were receiving oxaliplatin. At one year, 11 patients
CEA after surgery (1.1 percent) had grade 3 neuropathy. Among them,
≥5 ng/ml two were found to have underlying disease that
<5 ng/ml could have caused these symptoms (diabetes and
Degree of differentiation hemiplegia, respectively). Although more frequent
Well differentiated
among patients receiving FL plus oxaliplatin than
Poorly differentiated
among those treated with FL alone, grade 3 or 4 neu-
Venous invasion
tropenia led to fever or infection in only 1.8 percent
of patients in the former group. Similar findings
Present
have been reported among patients with metastat-
Absent
ic colorectal cancer.14 From a safety standpoint,
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
the rate of death from any cause was similarly low
FL+Oxaliplatin FL Better during treatment in both groups and, at 0.5 per-
Better
cent, is among the lowest figures reported in trials
Figure 3. Hazard Ratios and 95 Percent Confidence Intervals for Recurrence
of adjuvant chemotherapy.5,18,26,27
in the Group Given Fluorouracil and Leucovorin (FL) plus Oxaliplatin, Figures for overall survival at this stage of the
as Compared with the FL Group, According to Baseline Prognostic Factors study are preliminary, and no conclusion can be
and the Intention to Treat. drawn about differences in survival between the
CEA denotes carcinoembryonic antigen. treatment groups. Since the median overall surviv-
al from the time of diagnosis of metastatic colorec-

tal cancer is approximately 20 months,13-15,28 we and lecture fees from Sanofi-Synthelabo and Baxter. Dr. Mounedji-
Boudiaf and Dr. Tabah-Fisch are employed by Sanofi-Synthelabo.
expect that the effect of oxaliplatin on survival will We are indebted to all those who have contributed to the conduct
become apparent within the next 2 years. and analysis of the MOSAIC trial, including the 146 investigators
Supported by Sanofi-Synthelabo. from France, the United Kingdom, Spain, Italy, Belgium, Greece,
Dr. Boni reports having received consulting fees from Sanofi- Hungary, the Netherlands, Portugal, Germany, Sweden, Austria, Po-
Synthelabo and Lilly; Dr. Tabernero consulting and lecture fees from land, Denmark, Norway, Australia, Israel, Cyprus, Singapore, and
Sanofi-Synthelabo; and Dr. Hickish consulting and lecture fees from Switzerland who enrolled patients in the study; to the members of
Sanofi-Synthelabo, Aventis, and Roche. Dr. Topham reports having the data and safety monitoring board, especially Marc Buyse (statis-
equity ownership in Sanofi-Synthelabo and having received lecture tician); to the dedicated teams from Sanofi-Synthelabo, including
fees from Sanofi-Synthelabo and consulting fees from Roche and Christelle Lorenzato and Robert Bigelow (statistical department)
Baxter. Dr. Bridgewater reports having received consulting fees from and Jeanne Marceau-Suissa, Nathalie Lebail, and Noelle Muller
Novartis Consumer Health; Dr. Clingan consulting fees from Sanofi- (clinical development); and to Daniel Sargent (Mayo Clinic) for the
Synthelabo and Roche Australia; and Dr. de Gramont consulting discussion of the results.
references
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The new england journal of medicine

Oxaliplatin, Fluorouracil, and Leucovorin

n engl j med 350;23 www.nejm.org june 3, 2004 2343

The New England Journal of Medicine

c olorectal cancer is the second

2344 n engl j med 350;23 www.nejm.org june 3 , 2004

The New England Journal of Medicine

n engl j med 350;23 www.nejm.org june 3, 2004 2345

The New England Journal of Medicine

2346 n engl j med 350;23 www.nejm.org june 3 , 2004

The New England Journal of Medicine

Adverse Event FL plus Oxaliplatin (N=1108) FL (N=1111) P Value

(Table 3). Of the 137 patients (12.4 percent) who follow-up

n engl j med 350;23 www.nejm.org june 3, 2004 2347

The New England Journal of Medicine

0.7 overall survival

2348 n engl j med 350;23 www.nejm.org june 3 , 2004

The New England Journal of Medicine

0.9 Stage II, FL+oxaliplatin (56 events, 12.4%)

Probability of Disease-free Survival

0.7 Stage III, FL+oxaliplatin (181 events, 26.9%)

n engl j med 350;23 www.nejm.org june 3, 2004 2349

The New England Journal of Medicine

2350 n engl j med 350;23 www.nejm.org june 3 , 2004

The New England Journal of Medicine

n engl j med 350;23 www.nejm.org june 3, 2004 2351

The New England Journal of Medicine

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