VOLUME 22 䡠 NUMBER 7 䡠 APRIL 1 2004

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

Survival of Patients With Advanced Colorectal Cancer

From the Divisions of Medical Oncol-
ogy and Biostatistics, Mayo Clinic,
Rochester, MN; Division of Oncology,
University of North Carolina, Chapel
Hill, NC; and Department of Hematolo-
gy/Oncology, University of Halle, Halle,
Germany.
Submitted November 8, 2002; accepted
January 23, 2004.
Supported in part by Public Health
Services grant No. CA-25224 from the
National Cancer Institute to the Mayo
Clinic in support of the North Central
Cancer Treatment Group.
Authors’ disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to Axel Gro-
they, MD, Division of Medical Oncol-
ogy, Mayo Clinic, 200 First St SW,
Rochester, MN 55905; e-mail:
grothey.axel@mayo.edu.
© 2004 by American Society of Clinical
Oncology
Improves With the Availability of Fluorouracil-
Leucovorin, Irinotecan, and Oxaliplatin in the Course
of Treatment
Axel Grothey, Daniel Sargent, Richard M. Goldberg, and Hans-Joachim Schmoll
A B S T R A C T
Purpose
Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have
proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using
FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this
disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV,
irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated.
Materials and Methods
We analyzed data from seven recently published phase III trials in advanced CRC to correlate the
percentage of patients receiving second-line therapy and the percentage of patients receiving all three
agents with the reported median OS, using a weighted analysis.
Results
The reported median OS is significantly correlated with the percentage of patients who received all three
drugs in the course of their disease (P ⫽ .0008) but not with the percentage of patients who received
any second-line therapy (P ⫽ .19). In addition, the use of combination protocols as first-line therapy was
associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73
months; P ⫽ .0083).
Conclusion
Our results support the strategy of making these three active drugs available to all patients with
advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest
that, with the availability of effective salvage options, OS should no longer be regarded as the most
appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

0732-183X/04/2207-1209/$20.00 J Clin Oncol 22:1209-1214. © 2004 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2004.11.037

studied in phase II and III trials, both as

INTRODUCTION
Colorectal cancer (CRC) is the third most
common cause of cancer deaths for both
men and women in the United States and
Europe and is the second most common
lethal cancer overall. In the last 10 years,
several new cytotoxic agents with activity
as single agents have widened the spec-
trum of therapeutic options in advanced
CRC.1 In particular, chemotherapy proto-
cols including irinotecan and oxaliplatin
alone or coupled with fluorouracil (FU)-
leucovorin (LV) have been extensively
first- and second-line therapies.
The median survival for patients with
advanced disease treated with FU-LV with-
out effective salvage therapy has been con-
sistently reported as 11 to 13 months by a
variety of investigators.2,3 This was con-
firmed recently in several large trials using
FU-LV (or capecitabine) without effective
salvage therapy, which again reported a con-
sistent median overall survival (OS) of 12 to
13 months.4,5 The positive impact of irino-
tecan as a second-line therapy on OS was
demonstrated in two pivotal multicenter

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Copyright © 2004 by the American Society of Clinical Oncology. All rights reserved.
 Grothey et al
randomized phase III studies conducted in FU-LV–
refractory patients with advanced CRC.6,7 Several phase III
trials investigating combination regimens with FU-LV plus
irinotecan or oxaliplatin as first-line therapy have achieved
OS of 14.8 to 21.5 months, suggesting that combining these
agents is advantageous.1 On the basis of the finding of
improved OS demonstrated in two phase III trials,8,9
FU-LV-irinotecan (IFL) was approved as first-line therapy
of advanced CRC by the United States Food and Drug
Administration in 2000, replacing FU-LV as the standard of
care. The IFL (Saltz) regimen, in which FU is delivered as a
bolus, emerged as standard therapy in the United States,
whereas in Europe, clinicians have tended to favor regimens in
which FU is delivered as a 1- to 2-day infusion in conjunction
with irinotecan. Recent results of the Intergroup trial N9741
demonstrated the superiority of an oxaliplatin-based first-line
therapy over the IFL protocol in terms of efficacy (response
rate, progression-free survival, and OS) and safety.10
It is intriguing and of great clinical interest that the
recently published phase III trials using combination pro-
tocols as first-line therapy of advanced CRC have shown
substantial variations in the reported median OS, with a
range of 14.8 to 21.5 months.3,8-13 It is unlikely that differ-
ences in patient selection or factors unrelated to the actual
treatment strategy caused this variation because of the large
number of patients enrolled onto each of these trials and the
fact that all trials were conducted within a relatively short
time frame. However, although it is conceivable and even
likely that effective salvage therapies have an impact on
patient OS and, thus, contributed to the differences in OS
observed, the impact of serial therapies has yet not been
systematically assessed in clinical trials. Therefore, our anal-
ysis was undertaken to investigate the influence of active
salvage therapies on the reported median OS in CRC in
recent clinical trials and, in particular, the impact of the
availability of all three active cytotoxic agents, FU-LV, iri-
notecan, and oxaliplatin, in the course of the treatment.
MATERIALS AND METHODS
We reviewed the data from seven recently published or presented
phase III trials in CRC. For each trial, the percentage of patients
receiving any second-line therapy and the percentage of patients
treated with all three active drugs (FU-LV, irinotecan, and oxali-
platin) in the course of their disease were recorded. The order in
which the drugs were administered was not specified, so individ-
uals could be exposed to any agent as either first- or second-line
therapy. The data were taken from published articles or, if a full
report had not yet been published, from presentations at Ameri-
can Society of Clinical Oncology meetings with updates and reval-
idation of the number of patients receiving second-line therapies
made by the authors of the trial12 that was conducted under their
supervision. In addition, we abstracted information on patient
median OS from each trial. A test for heterogeneity between regi-
mens with monotherapy versus combination initial therapy was
performed. Subsequently, only those treatment arms containing
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Copyright © 2004 by the American Society of Clinical Oncology. All rights reserved.
an irinotecan- or oxaliplatin-based combination as a first-line
therapy were included for the following reasons: (1) the test for
heterogeneity indicated a survival advantage for combination ini-
tial therapy, (2) combination initial therapy has become standard
of care, and (3) reliable and comparable data on patients receiving
all three agents in the course of their treatment were available only
on those arms. This resulted in the inclusion of 10 treatment arms
from the seven trials. We did not include secondary surgery as a
treatment modality in our analysis because this was not an end
point in any of the studies and, thus, was not consistently recorded
and analyzed. Table 1 summarizes the design of the trials used in
our analysis. The goal of the analysis was to correlate both the
percentage of patients receiving second-line therapy and the percent-
age of patients receiving all three agents with the reported median OS.
For analysis, the Spearman rank correlation test was supplemented by
simple linear regression. As a sensitivity analysis, a weighted regres-
sion was used, with weights proportional to the trial’s sample size.
P values reported are based on the weighted regression models, with
P ⬍ .05 used to denote statistical significance.
RESULTS
A test for heterogeneity between regimens that used combi-
nation versus monotherapy as the initial treatment indi-
cated significant heterogeneity between these two ap-
proaches (P ⫽ .01). Specifically, patients treated with a
combination therapy as first-line treatment had a predicted
3.5 months improvement in median survival (95% CI, 1.27
to 5.73 months). We subsequently focused on the 10 first-
line combination therapy regimens. As illustrated in Table 2
and Figure 1, the percentage of patients who were treated
with FU-LV and irinotecan and oxaliplatin at some point in
their disease showed a strong correlation with the reported
median OS. This correlation was statistically significant
(P ⫽ .0008). Thus, studies in which a high percentage of
patients had access to all three active cytotoxic drugs in the
course of their treatment showed the longest OS. The re-
ported median OS did not show a significant correlation
with the percentage of patients receiving any, that is, not
necessarily irinotecan- or oxaliplatin-based, second-line
treatment (P ⫽ .19).
DISCUSSION
The positive correlation between treatment with FU-LV,
irinotecan, and oxaliplatin and improvement in patient OS
is striking. This finding suggests that it is important to make
all drugs that have well-demonstrated clinical activity in
CRC (in particular, FU-LV, irinotecan, and oxaliplatin)
available to all patients with advanced CRC to guarantee
maximal benefit of systemic therapy for OS. The results
indicate that the percentage of patients receiving all three
active drugs (FU-LV, irinotecan, and oxaliplatin) is more
important than the overall percentage of patients receiving
any second-line therapy in influencing patient OS. This
suggests that the specific second-line therapy patients re-
JOURNAL OF CLINICAL ONCOLOGY
 Survival in CRC Improves With Use of All Active Drugs

Table 1. Basic Characteristics and Design of the Studies Used in the Analysis
Study and Treatment Arms No. of Patients per Arm Primary End Point of Study

Single agents v combination therapy

Saltz et al9
Bolus FU-LV (Mayo) 226 PFS, 40% improvement
Weekly bolus IFL 231
Irinotecan monotherapy 226
Douillard et al8
Infusional (⫹ bolus) FU-LV (biweekly LV5FU2 or weekly AIO protocol) 188 TTP, 3 months prolongation
Infusional (⫹ bolus) FU-LV plus irinotecan (FOLFIRI, biweekly or weekly, 199
two different schedules)
Koehne et al3
Weekly infusional FU-LV (AIO protocol) 216 PFS, 35% increase from 7 to 9.5 months
Weekly infusional FU-LV (AIO protocol) plus irinotecan 214
de Gramont et al11
Bolus ⫹ infusional FU-LV (LV5FU2) 210 PFS, 3 months prolongation
Bolus ⫹ infusional FU-LV plus oxaliplatin (FOLFOX 4) 210
Grothey et al12
Bolus FU-LV (Mayo) 129 PFS, 60% prolongation
Weekly 24-hour infusional FU-LV plus oxaliplatin (FUFOX) 123
Combination v combination therapy
Tournigand et al13
FOLFOX 6 followed by FOLFIRI 111 TTP, difference of 20% after second-line
therapy
FOLFIRI followed by FOLFOX 6 109
Goldberg et al10
IFL 264 TTP, hazard ratio of 0.75
FOLFOX 4 267
Irinotecan plus oxaliplatin (IROX) 264

Abbreviations: FU, fluorouracil; LV, leucovorin; IFL, weekly bolus FU-LV ⫹ irinotecan; PFS, progression-free survival; LV5FU2, biweekly bolus plus infusional
FU-LV; AIO, German Association of Medical Oncology; FOLFIRI, biweekly infusional plus bolus FU-LV ⫹ irinotecan; TTP, time to progression; FOLFOX,
biweekly infusional plus bolus FU-LV ⫹ oxaliplatin.

ceive does impact median survival; for maximum benefit in
terms of OS, patients with oxaliplatin-based first-line che-
motherapy need irinotecan-based second-line therapy and
vice versa. Thus, effective salvage therapies might indeed
compensate for a less-active first-line therapy.
We recognize that the nature of the analysis conducted
raises a question of inherent bias. Specifically, one could
argue that patients who live longer have greater opportunity
to be treated with all three active drugs. Patients with poorer
performance status and, thus, shorter life expectancy might
have been excluded from irinotecan- or oxaliplatin-based
second-line therapy. In addition, our analysis did not spe-
cifically distinguish between whether the one missing active
drug was given as second- or third-line therapy. However,
at the time the studies were conducted, not all drugs, in
particular, oxaliplatin, were available for all patients en-
rolled onto the trials. It is of interest in this context that
more recent trials, in which patients were more likely to
have access to all three active drugs, in particular, oxalipla-
tin, were associated with a longer median OS. It seems
unlikely that reasons unrelated to the use of oxaliplatin,
such as changes in general oncologic practice, could have
accounted for this effect. It is also unlikely that the percent-
age of patients in poor performance status after first-line
therapy differed greatly between the phase III trials. Fur-
thermore, the fact that not any kind but only specific
second-line therapies were significantly correlated with me-
dian OS in our analysis argues against this point because a
high percentage of patients in all trials (52% to 81.3%) lived
long enough to have the chance to receive second-line treat-
ment of any kind.
Our findings further indicate a significant advantage in
OS if combination chemotherapy is used first-line. Regi-
mens that used combination versus monotherapy as the
initial treatment were associated with a predicted 3.5-
month improvement in median survival (P ⫽ .0083; 95%
CI, 1.27 to 5.73 months). This finding of our informal
pooled analysis could be useful to further support the use of
combination protocols as first-line therapy as the optimal
treatment strategy for patients with advanced CRC. In ad-
dition and in accordance with our general hypothesis, the
percentage of patients receiving all three drugs in the course
of their treatment is higher if irinotecan- or oxaliplatin-
based combination protocols are used as first-line options
because, as is clear from Table 2, only 50% to 80% of

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 Grothey et al

Table 2. Correlation Between Percentage of Patients Receiving FU-LV and Irinotecan and Oxaliplatin in the Course of Their Disease or Any Second-Line
Therapy and the Reported Median OS
No. of % of Patients % of Patients With Any Median OS
Study and First-Line Regimen Patients With Three Drugs Second-Line Therapy (months)

Single agent v combination therapy

Saltz et al,9 2000
Irinotecan monotherapy 226 — 79 12.0
Bolus FU-LV 226 — 70 12.6
IFL 231 5 52 14.8
Douillard et al,8 2000
FU-LV 188 — 58.3 14.1
FOLFIRI 198 15.7 39.4 17.4
Koehne et al,3 2003
FU-LV 216 — 65 16.9
FUFIRI 214 54 56 20.1
de Gramont et al,11 2000
LV5FU2 210 — 60.5 14.7
FOLFOX 210 29.5 58.1 16.2
Grothey et al,12 2002
Bolus FU-LV 129 31.0 76.7 16.1
FUFOX 123 67.5 81.3 19.7
Combination v combination therapy
Tournigand et al,13 2001
FOLFOX 111 62 73.9 20.6
FOLFIRI 109 74 80.7 21.5
Goldberg et al,10 2003
IROX 264 50 70 17.4
IFL 264 24 67 14.8
FOLFOX 267 60 75 19.5

Abbreviations: FU, fluorouracil; LV, leucovorin; OS, overall survival; IFL, weekly bolus FU-LV ⫹ irinotecan; FOLFIRI, biweekly-infusional plus bolus FU-LV ⫹
irinotecan; FUFIRI, weekly infusional FU-LV ⫹ irinotecan; LV5FU2, biweekly infusional FU-LV; FOLFOX, biweekly infusional plus bolus FU-LV ⫹ oxaliplatin;
FUFOX, weekly infusional FU-LV ⫹ oxaliplatin; IROX, irinotecan ⫹ oxaliplatin.

patients can receive effective salvage therapies after failure
of first-line treatments.
The importance of effective second-line therapies for
OS in advanced CRC was first highlighted by the pivotal
phase III trials using irinotecan as a salvage option in pa-
tients who had experienced failure on or progressed after
first-line FU-LV treatment. In both trials, a significant pro-
longation of OS was achieved with second-line irinotecan
versus best supportive care7 or infusional FU-LV.6 The
value of active salvage therapies for the prognosis of patients
with CRC is further supported by the results of the study
recently presented by Tournigand et al,13 which tried to
assess the optimal sequence of treatment protocols
(biweekly infusional plus bolus FU-LV plus oxaliplatin
[FOLFOX] followed by biweekly infusional plus bolus
FU-LV plus irinotecan [FOLFIRI] v FOLFIRI followed by
FOLFOX). The obligatory cross over within the study led to
a high rate of patients who received FU-LV and oxaliplatin
and irinotecan. This study has reported the longest median
OS in a phase III study on advanced CRC so far. Interest-
ingly, median OS did not differ significantly between the
two sequences studied, although the sample size for this
trial was relatively small by modern standards. However,
the importance of the high percentage of cross over for
patient survival in the Tournigand et al13 study is illustrated
by the results of Intergroup trial N974110 in which a smaller
proportion of patients receiving IFL as first-line therapy had
second-line access to oxaliplatin, which, at the time of the
study, was not approved in the United States. In contrast,
patients receiving FOLFOX upfront had a much greater
opportunity to receive irinotecan-based therapy. The effi-
cacy of oxaliplatin-based therapy as second-line treatment
in patients with CRC who had progressed on or relapsed
within 6 months of first-line therapy with the IFL protocol has
recently been demonstrated in a phase III trial of 463 patients.
The combination protocol of oxaliplatin plus infusional (⫹
bolus) FU-LV was superior to oxaliplatin monotherapy and to
infusional FU-LV alone in terms of response rate (9.9% v 1.3%
v 0%, respectively) and progression-free survival (4.6 v 1.6 v 2.7
months, respectively).14 The data led to the registration of
oxaliplatin in combination with infusional FU-LV as second-
line therapy in advanced CRC in the United States.
A possible alternative explanation for these findings is
that, as time has progressed and trials have included multi-
ple agents, the advances that have been observed in median
survival are the result of better patient selection, improve-

1212 JOURNAL OF CLINICAL ONCOLOGY

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 Survival in CRC Improves With Use of All Active Drugs
Fig 1. Regression plot and relationship between percentage of patients
(pts) receiving fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin (3
drugs) in the course of their disease and the reported median overall survival
(OS). Mathematical equitation of regression (based on a weighted model
[solid line]): median OS (months) ⫽ 14.09 ⫹ 0.09 ⫻ (% patients with three
drugs). First-line therapies: circles, infusional FU-LV ⫹ oxaliplatin; squares,
infusional FU-LV ⫹ irinotecan; diamonds, bolus FU-LV ⫹ irinotecan; and
triangle, irinotecan ⫹ oxaliplatin. Pts, patients.
ments in supportive care, or earlier detection of advanced
disease. We find this explanation unlikely for two reasons.
First, the median survival for patients with advanced CRC
remained highly consistent at approximately 12 months for
many years before the introduction of irinotecan and oxali-
platin. This consistent median survival was also observed in
recently published phase III trials on oral fluoropyrimi-
dines4,5,15,16 and a trial comparing continuous versus inter-
mittent FU-LV or raltitrexed in advanced CRC17 with lim-
ited access to irinotecan- or oxaliplatin-based protocols as
second-line therapy. Second, the median survival times for
the FU-LV control arms that had low rates of second-line
treatment in the studies included in this analysis were again
approximately 12 to 13 months (12.6 months for the Saltz et
al9 trial and 12.9 months for the FU-LV arm of N9741,18
which, however, only included 61 patients). We recognize
that this study was not conducted as a formal meta-analysis
because individual patient data was not obtained and only
the reported median OS were used for analysis and, there-
fore, should be viewed as hypothesis generating. However,
given the recent nature of many of these studies and the delays
that are inherent in the processes of data collection, clean-up,
analysis, and eventual publication, we feel that this less formal
analysis still provides valuable information for the practitio-
ner. A detailed assessment of the influence of prognostic or
predictive factors on OS has to be reserved for future studies or
a meta-analysis of all presently available clinical trials.
Our results suggest that the use of all three active drugs
in advanced CRC produces the longest OS. Because sequen-
tial treatment with all three agents cannot be guaranteed for
100% of patients, one might consider the use of a triple-
combination protocol as first-line therapy. The safety and
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efficacy of this approach has been assessed in several phase
II trials. Triple-combination protocols using FU-LV plus
irinotecan plus oxaliplatin have consistently resulted in
high response rates of 57% to 78% in patients with previ-
ously untreated advanced CRC.19-22 Reliable data on
progression-free survival and OS are still lacking, although
an encouraging median OS of 22.5 months was reported in
one trial.21 We caution against extrapolating from our re-
gression model for a predicted median OS if 100% of pa-
tients received all three drugs because this is outside the range
of our data and because concurrent (as opposed to sequential)
administration of all three agents might yield different out-
comes. The ability of first-line triple combinations to achieve
or improve on the OS associated with dual-combination pro-
tocols as first-line therapy can only be assessed in a phase III
trial.
On the basis of these results, we would propose that OS
may no longer be the appropriate parameter and primary
end point to assess the contribution of a new agent to the
efficacy of first-line therapy in advanced CRC. Our analysis
supports previous reports that second- and presumably
third-line treatments can have a substantial impact on OS.
It is not realistic to assume that sequential steps of therapies
can be predefined in a phase III protocol because of differ-
ences in the availability of drugs, the experience of the
investigators, and reimbursement issues. Therefore, other
parameters, such as progression-free survival, time to treat-
ment failure, and 60-day mortality, should be used in addi-
tion to OS to evaluate efficacy and clinical usefulness of
first-line protocols. Our analysis could not address the
question of the best sequence of treatment options (ie,
whether an irinotecan- or oxaliplatin-based protocol
should be preferred as first-line therapy). Current data do
not definitively suggest the superiority of one sequence over
the other, at least in terms of efficacy. This question can only
be answered by future randomized trials comparing differ-
ent sequential treatment strategies.
■ ■ ■
Authors’ Disclosures of Potential
Conflicts of Interest
The following authors or their immediate family
members have 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. Acted
as a consultant within the last 2 years: Axel Grothey,
Sanofi-Synthelabo; Hans-Joachim Schmoll, Sanofi-
Synthelabo; Richard M. Goldberg, Sanofi-Synthelabo,
Pharmacia. Received more than $2,000 a year from a
company for either of the last 2 years: Axel Grothey,
Sanofi-Synthelabo, Aventis; Richard M. Goldberg,
Sanofi-Synthelabo, Pharmacia; Hans-Joachim Schmoll,
Sanofi-Synthelabo.
1213

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