Ann Surg Oncol (2009) 16:2385–2390
DOI 10.1245/s10434-009-0492-7
EDUCATIONAL REVIEW – CONTROVERSIES IN THE MANAGEMENT OF HEPATIC COLORECTAL METASTASES
The Role of Preoperative Chemotherapy in Patients
with Resectable Colorectal Liver Metastases
Stéphane Benoist, MD, PhD and Bernard Nordlinger, MD
Department of Digestive and Oncologic Surgery, AP-HP, Hôpital Ambroise Paré Boulogne, Université Versailles Saint
Quentin en Yvelines, Versailles, Cedex, France
ABSTRACT
Background. Liver metastases develop in 40–50% of
patients with colorectal cancer and represent the major
cause of death in this disease. Surgical resection remains
the only treatment procedure that can ensure long-term
survival and provide cure when liver metastases can be
totally resected with clear margins, when the primary
cancer is controlled, and when there is no nonresectable
extrahepatic disease. Five-year survival rate after surgical
resection of colorectal metastases varies from 25% to 55%,
but cancer relapse is observed in most patients.
Aim. To review the potential benefits and disadvantages of
neoadjuvant chemotherapy administered before surgery to
patients with initially resectable metastases.
Results. European Organization for Research and Treat-
ment of Cancer (EORTC) study 40983 has shown that
neoadjuvant chemotherapy could reduce the risk of relapse
by one-quarter, and allows to test the chemosensitivity of
the cancer, to help to determine the appropriateness of
further treatments, and to observe progressive disease,
which contraindicates immediate surgery. Neoadjuvant
chemotherapy can induce damage to the remnant liver.
Oxaliplatin-based combination regimen is associated with
increased risk of vascular lesions, whereas irinotecan-
containing regimens have been associated with increased
risks of steatosis and steatohepatitis. Analysis of EORTC
study 40983 showed that administration of six cycles of
neoadjuvant systemic chemotherapy with 5-fluorouracil,
leucovorin, and oxaliplatin (FOLFOX) was associated with
moderate increase of the risk of reversible complications
after surgery, but mortality rate was below 1% and not
Ó Society of Surgical Oncology 2009
First Received: 19 July 2008;
Published Online: 25 June 2009
B. Nordlinger, MD
e-mail: bernard.nordlinger@apr.aphp.fr
increased. If patients are not overtreated, chemotherapy
before surgery is well tolerated. The integration of novel
targeted agents in combination with cytotoxic drugs is a
promising way to improve outcome in patients with
advanced colorectal cancer. Preliminary trials have shown
that targeted agents combined with cytotoxic regimens can
increase tumor response rates. Another impact of preop-
erative chemotherapy is that metastases that respond to
treatment may no longer be visible on computed tomog-
raphy (CT) scan or at surgery. Patients should be carefully
monitored and receive surgery before metastases disappear.
Conclusion. Treatment of most patients with liver metas-
tases—those with resectable metastases as well as those with
initially unresectable metastases—should start with che-
motherapy. If drugs are well chosen and the duration of
treatment is monitored with care during multidisciplinary
meetings, benefits largely outweigh potential disadvantages.
Colorectal cancer is one of the most common causes of
cancer death in the Western world, ranking second in
Europe and third in the USA.1 Approximately 50% of
patients with colorectal cancer develop liver metastases at
some point during the course of their disease.1–3 Surgical
resection remains the only treatment that can, to date,
ensure long-term survival in 25–40% of the patients.4,5
Using the current indications for surgery, 15–20% of
patients with colorectal liver metastases are directly suit-
able for surgical resection.6 In the other patients,
metastases are considered unresectable and chemotherapy
is the treatment of choice, but 5-year survivors with che-
motherapy alone are very rare. After resection of liver
metastases cancer relapse is still observed in most
patients.5 Neoadjuvant chemotherapy has been evaluated in
patients with initially resectable liver metastases,
This review will summarize the current data on the
rationale, benefits, and potential disadvantages of
2386
neoadjuvant chemotherapy in patients with resectable
colorectal liver metastases.
RATIONALE FOR NEOADJUVANT
CHEMOTHERAPY IN PATIENTS WITH
RESECTABLE LIVER METASTASES
After ‘‘curative’’ liver resection of colorectal liver
metastases, 5-year survival rates are 30–50%, but cancer
relapse is observed in the majority of patients despite
progress in surgical technique and improved surgical
skills.4,5,7
In order to improve these results, adjuvant treatment
using systemic chemotherapy or hepatic arterial infusion
with 5-fluorouracil (5FU), folinic acid or floxuridine has
been tested after resection of liver metastases from colo-
rectal cancer in several randomized studies, but survival
benefit has not yet been clearly proven.8–12 Recently, a
meta-analysis showed that adjuvant CT with a 5FU-based
regimen tends to improve disease-free and overall survival
after complete resection of colorectal cancer (CRC)
metastases but the observed improvement in survival was
not statistically significant.13 A randomized phase III study
comparing systemic chemotherapy with 5FU-versus irino-
tecan-based regimen as adjuvant treatment after complete
resection of colorectal liver metastases has been presented
at American Society of Clinical Oncology (ASCO) 2008.14
This study did not demonstrate any significant advantage in
terms of disease-free survival for the addition of irinotecan
to 5FU.14
The sole administration of chemotherapy after resection
of liver metastases may not be sufficient to improve
prognosis. New approaches are needed. In this setting, the
administration of chemotherapy before liver surgery has
several potential advantages in patients with resectable
liver metastases (Table 1).
– It can serve to test the chemoresponsiveness of
metastases while they are still present in the liver,
which can be helpful to determine which treatment
should be given after resection.3
– Neoadjuvant chemotherapy can in theory eliminate
micrometastatic disease and allow eradication of dor-
mant cancer cells in the liver.
– If tumor shrinkage is observed during neoadjuvant
chemotherapy, the rate of complete resection or
complete resection with more conservative liver sur-
gery may be increased.15
– Two recent studies have shown that response to
neoadjuvant chemotherapy was an important prognos-
tic factor and could allow a better selection of
candidates for surgical resection.16,17 In one study,
the outcomes of patients referred for resection of
S. Benoist, B. Nordlinger
TABLE 1 Potential advantages and disadvantages of preoperative
chemotherapy
Advantages Disadvantages
Improved progression-free Delayed surgery
survival
Evaluation of More reversible surgical complications
chemoresponsiveness
Selection for surgery Chemotherapy-associated liver
injuries if prolonged chemotherapy
Fewer ‘‘open and close’’ Complete response making metastases
difficult to find
Low operative mortality Cost
synchronous colorectal liver metastases with or without
previous neoadjuvant chemotherapy were compared
retrospectively.16 Five-year survival was similar in both
groups. Patients with stable disease or disease respond-
ing to chemotherapy had a better survival than patients
who did not receive chemotherapy (85% versus 35%,
p = 0.03). In another study, the impact of complete
pathologic response on survival was assessed in 767
patients who underwent liver resection after systemic
preoperative chemotherapy.17 Twenty-nine of 767
patients (4%) had complete pathologic response.
Patients with complete pathologic response had a
higher 5-year survival when compared with patients
without complete pathologic response (76% versus
45%), suggesting that response to chemotherapy is an
important prognostic factor.
POTENTIAL DISADVANTAGES OF
PREOPERATIVE CHEMOTHERAPY
Neoadjuvant chemotherapy has potential disadvantages
(Table 1):
– Administration of preoperative chemotherapy can be
associated with pathologic changes in liver paren-
chyma.18–25 Two main types of chemotherapy-
associated liver injuries have been reported: vascular
changes including sinusoidal dilatation and chemother-
apy-associated steatohepatitis (CASH). Administration
of 5-fluorouracil may be associated with increased risk
of steatosis.26 Administration of oxaliplatin-based
combination regimens can increase the risk of vascular
lesions in the liver.18,22,23,25 Irinotecan-containing reg-
imens have been associated with increased risks of
steatosis and steatohepatitis.19,20,22
The main question is whether collective damages to the
liver induced by preoperative chemotherapy have any
Preoperative Chemotherapy in Resectable Colorectal Liver Metastases 2387

clinical significance and in particular if they increase the biliary fistula were more frequent after administration of
risk of liver surgery for metastases. Some retrospective chemotherapy. Thus, administration of six cycles of FOL-
studies have looked at the relation between the type of FOX before surgery is safe and feasible. Other reports have
lesions induced by chemotherapy and their potential clin- shown that administration of up to six cycles of neoadjuvant
ical consequences. Kooby et al. showed that steatosis was systemic chemotherapy was safe and did not increase mor-
associated with an increased risk of complications, in tality and morbidity after major liver resections.21,25
particular infectious complications, but had no significant Patients with more than 12 cycles of preoperative chemo-
impact on mortality.19 In the report by Vauthey et al., therapy had higher risk of reoperation and longer hospital
steatohepatitis was observed in 20% of patients who had stay.23 Preoperative chemotherapy is safe if it is well
received irinotecan-based chemotherapy and was consid- selected and monitored and if patients are not overtreated
ered responsible for death due to postoperative liver failure with chemotherapy before surgery. Only little information is
in 7% of patients with steatohepatitis.22 In the same study, available on the potential risks of liver surgery after
vascular injury increased the risk of operative bleeding but administration of combinations of cytotoxic drugs and tar-
not perioperative morbidity or mortality.22 geted agents. Anti-epidermal growth factor (EGF) agents
The EORTC intergroup phase III study 40983, compar- and in particular cetuximab have no known side-effect
ing perioperative chemotherapy with 5FU, leucovorin, and which could interfere with surgery. Recent reports suggest
oxaliplatin (six cycles before surgery and six cycles after), to that anti-vascular endothelial growth factor (VEGF) agents
surgery alone in 364 patients was recently reported.27 Safety such as bevacizumab can be administered safely before liver
results showed that the mortality rate of surgery after resection of colorectal liver metastases, provided adminis-
administration of chemotherapy was less than 1% and tration of bevacizumab is discontinued 6–8 weeks before
comparable in the two treatment arms.27 Reversible com- surgery.29,30 Ongoing prospective clinical studies should
plications occurred more often in the chemotherapy arm further precise further the feasibility of liver surgery after
than in the surgery alone arm (25% versus 16%; p = 0.04) administration of novel systemic targeted agents (EORTC
(Table 2), but remained within the range observed in study 40052, Bos study)
other reports.4,5,28 Intra-abdominal abscesses and transient
– Some liver metastases may be no more visible on
imaging after response to chemotherapy. This is the so-
TABLE 2 Postoperative complications in EORTC intergroup trial called complete response. It is important to know
40983 (modified from Lancet27) whether these metastases are really cured or if they are
Perioperative CT Surgery group just no longer visible but still present. To address this
group n = 159 n = 170 problem, patients with 66 liver metastases that had
disappeared on CT scan were reviewed.31 The study
Reversible postoperative 40 (25%) 27 (16%)
complications* showed that cancer persisted in more than 80% of cases
Cardio-pulmonary failure 3 (2%) 2 (1%) at the initial site of liver metastases that had disap-
Bleeding 3 (2%) 3 (2%) peared on imaging, suggesting that complete radiologic
Biliary fistula 13 (8%) 7 (4%) response does not mean cure of the disease.31 This also
Hepatic failure 11 (7%) 8 (5%) means that patients with resectable liver metastases
Wound infection 5 (3%) 4 (2%)
should be referred to surgeons before liver metastases
Intra-abdominal infection 11 (7%) 4 (2%)
have completely disappeared. If unfortunately they
have disappeared, resection of the initial site is
Need for reoperation 5 (3%) 3 (2%)
necessary, but it may be difficult or impossible for
Urinary infection 4 (3%) –
the surgeon to identify this precise site in the liver.
Pleural effusion 3 (2%) 1 (1%)
– Another theoretical risk is that metastases become
Pulmonary embolism/deep 2 (1%) 1 (1%)
venous thrombosis unresectable if they progress during preoperative
Pneumopathy 2 (1%) – chemotherapy. In the EORTC intergroup phase III
Neutropenia 2 (1%) – study 40983, progressive disease was observed in 12 of
Ascites 1 (1%) 1 (1%)
182 (7%) patients who received systemic chemother-
Ileus 2 (1%) 1 (1%)
apy.27 Of these 12 patients, 4 could still undergo
resection of metastases. Among the eight others,
Cardiac arrhythmia – 1 (1%)
unresectability was due to appearance of new extrahe-
Renal failure – 1 (1%)
patic lesions in four cases and it is likely that these new
Other 4 (3%) 4 (2%)
lesions would have occurred anyway after immediate
* p = 0.04 surgery. In only four cases, unresectability was due to
2388 S. Benoist, B. Nordlinger

progression of the known liver metastases. It has been
reported that progression of liver metastases while on
chemotherapy is a factor of poor prognosis after
resection. Most of these patients have early cancer
relapse. Thus progression of liver metastases while on
chemotherapy should be considered a contraindication
for surgery.32
BENEFITS OF PREOPERATIVE CHEMOTHERAPY
IN PATIENTS WITH RESECTABLE LIVER
METASTASES
The potential interests of preoperative chemotherapy
have been suggested in phase II studies using oxaliplatin,
or oxaliplatin- and irinotecan-based regimen.33,34
The EORTC intergroup phase III study 40983 is a
prospective randomized study which compared periopera-
tive chemotherapy (six cycles before surgery and six cycles
after) with 5FU, leucovorin, and oxaliplatin to surgery
alone in 364 patients with one to four potentially resectable
liver metastases.27 The primary endpoint of the study was
progression-free survival. Eleven of 182 patients in each
arm were ineligible due mostly to disease more advanced
than allowed for entry in the protocol. Preoperative che-
motherapy was well tolerated. Partial or complete response
according to response evaluation criteria in solid tumors
(RECIST) criteria was observed in 43% of patients.27 Size
of tumor was reduced by 25% after chemotherapy. Surgical
resection could actually be performed in 83% of patients in
each treatment arm. With a median follow-up of 3.9 years,
the absolute increase in rate of progression-free survival at
three years was 8.1% (range 28.1–36.2%; p = 0.041) in
eligible patients (Fig. 1). In the 303 patients in whom
resection was actually achieved, the rate of progression-
free survival at 3 years was increased by 9.2% (range 33.2–
42.4%; p = 0.025). In summary this study showed that
perioperative FOLFOX4 chemotherapy reduced the risk of
cancer relapse by a quarter, and was compatible with major
surgery. Data concerning overall 5-year survival, a sec-
ondary endpoint, are not yet available.
This study is the first one to validate the principle of
combined chemotherapy and surgery to treat colorectal
liver metastases. Perioperative chemotherapy should be
considered as the standard of care for most patients with
resectable colorectal liver metastases (Fig. 2).

FIG. 1 Progression-free survival a b

by treatment group in all eligible Progression-Free Progression-Free
patients (from Lancet27). a All Survival (Percent) Survival (Percent)
100 100
randomly assigned patients, b All
eligible patients, c all resected
80 80
patients
60 60

40 PeriOpCT 40 PeriOpCT
Surgery Surgery
20 HR 0.79 (95.66%CI, 0.62–1.02); p = 0.058 20 HR 0.77 (95.66%CI, 0.60–1.00); p = 0.041

0 1 2 3 4 5 6 0 1 2 3 4 5 6
Number Years Number Years
at Risk at Risk
Surgery 182 85 59 39 24 10 Surgery 171 83 57 37 22 8
PeriOpCT 182 118 76 45 23 6 PeriOpCT 171 115 74 43 21 5

c
Progression-Free
Survival (Percent)
100

80

60

40 PeriOpCT
Surgery
20 HR 0.73 (95.66%CI, 0.55–0.97); p = 0.025

0 1 2 3 4 5 6
Number Years
at Risk
Surgery 152 85 59 39 24 10
PeriOpCT 151 118 76 45 23 6
Preoperative Chemotherapy in Resectable Colorectal Liver Metastases
FIG. 2 Treatment
recommendations for liver
metastases of colorectal cancer
Resectable
Preoperative
chemotherapy
Surgery
Postoperative
chemotherapy
Although EORTC study 40983 is the first one to eval-
uate the combination of surgery and chemotherapy in this
indication with sufficient power, it does not answer to other
important questions:
– Should chemotherapy be administered before surgery
or after or both (perioperative)?
– How many cycles of chemotherapy should be
administered?
Other question for future trial can concern the role of
intensification of treatment by combination of cytotoxic
chemotherapy with targeted agents or combination of
several cytotoxic drugs in order to improve outcome.
CONCLUSIONS
Preoperative chemotherapy, as all other treatment pro-
cedures, has advantages and potential disadvantages.
Potential disadvantages are easily manageable if the choice
of drugs and the duration of treatment are decided and
monitored with care. For most patients with resectable
colorectal liver metastases, perioperative chemotherapy
should be considered the standard treatment. These patients
should not be overtreated, to avoid disadvantages of che-
motherapy, in particular chemotherapy-induced liver
damage.
In the fast-moving field of combined treatment of
patients with colorectal cancer liver metastases, multidis-
ciplinary discussion and repeated evaluations are
indispensable.
2389
Liver metastases of
colorectal cancer
Unresectable
Chemotherapy
re-evaluate 2 months
Resectable Response No response
Remains Second-line
unresectable chemotherapy
Continue
chemotherapy
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