Surgical Science, 2011, 2, 312-317
doi:10.4236/ss.2011.26066 Published Online August 2011 (http://www.SciRP.org/journal/ss)
Copyright © 2011 SciRes. SS
Effects of Surgery and Palliative Chemotherapy in the
Treatment of Colorectal Liver Metastasis
Nigel Bird, Ruth Bird, Ali Majeed
Liver Research Group, Royal Hallamshire Hospital, Sheffield, UK
Received May 24, 2011; revised July 8, 2011; accepted July 27, 2011
Purpose: 1) to compare the survival of patients with colorectal liver metastases who underwent resection as
the primary treatment against patients who had chemotherapy as the primary treatment; 2) to compare the
survival in patients with recurrent inoperable liver metastases (after resection) treated with Oxaliplatin or
Irinotecan against those patients with inoperable recurrence who were treated with 5-FU. Patients and
Methods: 538 patients with colorectal liver metastases were referred to our unit between November 1997
and May 2005; 247 underwent liver resection and 291 had palliative chemotherapy. Results: only 7.8% of
non-operated patients survived for 5 years compared to 32.9% of the liver resection group. After surgery,
191 patients developed inoperable recurrent disease. These patients were treated with chemotherapy; Ox/Ir
patients had a 3 year survival of 55% compared to 32% of those who received 5-FU. Our data shows that in
patients who relapse after liver surgery, chemotherapy with Oxaliplatin or Irinotecan confers a significant
Keywords: Colorectal Cancer, Liver Metastasis, Surgery, Survival, Chemotherapy
There are more than one million new cases and over half
a million deaths from colorectal cancer in the world each
year . Over the course of their disease about half of all
patients will develop liver metastases, with around 25%
of patients having metastases at the time of presentation
(synchronous metastases). A further 25% - 50% of pa-
tients will develop metastases in the liver during the
course of their disease (metachronous metastases), typi-
cally during the first two years following the treatment of
the primary cancer. Liver metastases are seen as a major
cause of death in patients with colorectal cancer and,
although survival is closely related to metastatic tumour
burden, the long-term outlook for untreated patients is
universally recognised as poor with little or no observed
five-year survival [2-5].
Since the mid-1980’s resection of colorectal liver me-
tastases has become more widely performed and is now
the therapeutic option of choice, representing the only
chance of prolonged survival in those suitable for sur-
gery. The first large studies from specialist centres on
surgery for colorectal liver metastases reported resection
rates of 20% - 30% for all patients referred for surgery
[6,7] with 5-year su rvival in the range of 25% - 40% and
an operative mortality of between 0.5% and 5.5%. More
recent studies have confirmed the efficacy of this ap-
proach, with advances in surgical technique, intra- and
peri-operative care allowing the more widespread appli-
cation of surgery. Peri-operative mortality rates are now
in the range of 0.5% - 2.0% whilst 5-year survival data is
commonly reported to be between 35% and 40% [8,9].
In contrast to the results from surgery, systemic che-
motherapy alone offers little hope of long-term survival.
Response rates for 5-Fluoruracil-based (5-FU) regimes
remain static at around 20% and median survival rates
rarely exceed 2 years [10-12]. The Advanced Colorectal
Meta-Analysis project considered the efficacy of 5-FU in
the treatment of patients with measurable non-resectable
metastases who had no evidence of extrahepatic disease
. Covering 1400 patients from nine trials, the results
suggested a 23% tumour response rate and an overall
median survival of approximately 12 months for 5-FU +
There is unfortunately little published data concerning
the use of, or strategy for post-operative chemotherapy
for recurrent disease after surgical resection of liver me-
tastases . The aim of our study was to compare the
N. BIRD ET AL.313
effect of surgery and palliative chemotherapy with 5-FU
and Irinotecan/Oxaliplatin in the treatment of colorectal
liver metastases with respect to survival and recurrences.
We evaluated the survival of all patients referred for su r-
gical removal of colorectal liver metastases during the
period from November 1997 to May 2005. In those pa-
tients on whom liver surgery was performed and who
subsequently relapsed, we examined the surv iv al of those
receiving 5-fluoruracil based regimes and compared
them with those who received the newer oxaliplatin/iri-
notecan based therapies (which were approved for rou-
tine use in the UK after April 2002).
2. Patients and Methods
538 patients with colorectal liver metastases from the
North Trent Region were referred to our unit for assess-
ment for surgery in the period from November 1997 to
May 2005. Of these, 247 underwent partial-hepatectomy
and 291 received either palliative chemotherapy or best
supportive care. In the operated group there were 197
anatomical resections, of which 29 were ‘extended’ left
or right hepatectomies, and 50 metastasectomies. Metas-
tases were diagnosed intra-operatively at primary surgery
in 27.1%, by ultrasound scan in 32%, CT in 31.7%, MRI
in 6.3% and by CEA levels in 2.8% of cases.
In the non-operated group, follow-up data were avail-
able in all 291; 4 died before being seen, 105 had exten-
sive disease within the liver involving 5 or more lobes
and therefore not considered amenable to downsizing
pre-operative chemotherapy at that time, 126 had ex-
tra-hepatic disease, either peritoneal or pulmonary me-
tastases diagnosed by contrast-enhanced CT scans, 27
were found to have benign disease and 29 refused sur-
gery or were unfit for surgery.
Overall, 49.4% of referrals were from within the Shef-
field Teaching Hospitals Trust, which equ ates to a resec-
tion rate per capita of 3.8 patients per 100,000 population,
compared to the calculated conservative rate of 4 per
100,000 population . The resection rate for the rest of
the North Trent Region was 0.98 per 100,000.
The period of this study (between 1997 to 2005) was a
period of great change in the availability of various che-
motherapy agents and the regimens that were applied to
them. We cannot therefore directly compare the efficacy
of these regimens simply because of the heterogeneity of
the data, we therefore present a “real –life” description of
what chemotherapy was administered. The doses and
cycles of the various chemotherapeutic regimes in our
study were according to routine oncological practices
and dose reduction and toxicity assessments were ac-
cording to the Oncologists discretion and we have not
specifically assessed these parameters for our study.
Kaplan Meier estimates were performed using SPSS (v
16.0 for Mac). The Log rank test was used to determine
statistical significances between groups, using the R
language and environment for statistical computing. Dif-
ferences we re considered to be significant if p < 0.05.
The median survival for all patients who underwent
resection for colorectal liver metastases was 34.4 months
(95% CI 25.75 - 43.0) at the census date September 2010;
there were 173 deaths in this group, including 2 peri-
operative deaths. The cumulative proportion surviving
for 5 or more years was 3 2. 9 % .
In the non-operated group the median overall survival
was 12.1 months (95% CI 10.3 - 13.91); there were 209
deaths in this group overall, 36 within 3 months of refer-
ral. (Figure 1)
2) Liver Surgery + Chemotherapy (for inoperable
Oxaliplatin and Irinotecan were introduced into rou-
tine use after April 2002 and prior to this, patients with
recurrent colorectal cancer were treated with 5-FU based
regimes. In our series, there were 191 patients who un-
derwent liver surgery and subsequent chemotherapy for
inoperable relapse. Of these, 143 had chemotherapy re-
gimes based solely on 5-FU (Figure 2(a)). There were
46 deaths in this group with a median survival of 24.7
months (95% CI 18.74 - 30.61). In the remaining 48 pa-
tients, who received oxaliplatin or irinotecan for inoper-
Table 1. Demographic data of patients in the study groups.
Surgery Only Palliative Chemo/Supportive CareRecurrences treated with Oxaliplatin/Irinotecan Recurrences Treated with 5-FU
n = 247 n = 291 n = 48 n = 143
Age 63.2 years (35 - 89)
Age 66.1 years (34 - 91)
Age 58.2 years (36.6 - 80.8)
Age 65.7 years (36.2 - 89.3)
Copyright © 2011 SciRes. SS
N. BIRD ET AL.
Copyright © 2011 SciRes. SS
Figure 1. Kaplan Meier plots of cumulative survival pro-
portion for 247 patients who had surgery (solid line) and
291 non-operated patients (dashed line).
able relapse, there were 23 deaths with a median survival
for the group of 42.6 months (95% CI 28.25 - 57.04).
3) Chemotherapy alone
In the non-operated patients, 125 had chemotherapy
with a median survival of 17.61 months (95% CI 14.5 -
20.72) and 40 patients had no treatment with a median
survival of 7 months (95% CI 3.49 - 10.51). Within the
chemotherapy group, there were 83 patients who had
5-FU based treatment with a median survival of 15.3
months (95% CI 12.72 - 17.84) compared to 42 patients
who had chemotherapy, including oxaliplatin or iri-
notecan at some stage of their disease with a median sur-
vival of 21.7 m onths (95% CI 15 .6 0 - 2 7. 70 ). (Figure 3)
Statistical analysis of the survival data using the Log
rank test showed the expected highly significant differ-
ence in survival between those who underwent surgery
against those wh o di d not (p = 0.0001).
The major finding of our study is to show that surgery
(where possible) is the most effective treatment for colo-
rectal liver metastases. In patients that have a recurrence
in the liver (and/or lungs) the survival in patients given
palliative chemotherapy with Oxaliplatin and Irinotecan
is significantly better than those given 5-FU. Historically,
5-FU based chemotherapeutic regimens have been the
Figure 2. (a) Kaplan Meier plot of cumulative survival proportion of 62 post-hepatectomy patients who had recurrent, inop-
erable liver metastasis followed solely by 5FU-based chemotherapy; (b) Kaplan Meier plot of cumulative survival proportion
of 48 post-hepatectomy patients who had recurrent, inoperable liver metastasis followed chemotherapy which included ox-
aliplatin or irinotecan.
N. BIRD ET AL.315
Figure 3. Dendrogram of all patients referred for surgery for colorectal liver metastasis between November 1997 and May
2005. Figures in the boxes represent median survival in months and 95% CI.
mainstay of treatment of recurrent colorectal cancer over
many decades. Large series and meta-analyses of these
treatments confirm that the effectiveness of these drugs
is at best palliative, with very few complete or sustained
responses obtained. The survival data of 7 months for
untreated recurrent colorectal cancer and 11.7 months for
5-FU based regimens is generally accepted, with hepatic
infusional chemotherapy affording a similar benefit .
Our results for non-operated patients given 5-FU based
chemotherapy were somewhat better (median survival
15.3 months) although this could be attributed to the se-
lection bias introduced by the fact that they were referred
to the regional hepato-biliary unit for consideration of
hepatic resection and thus probably had relatively small
During the past decade or so, two major advances in
the management of recurrent colorectal cancer have had
a significant impact on survival and mortality from this
disease. These are the introduction of surgical treatment
of recurrent disease and the availability of new chemo-
The survival benefit from surgical resection of metastatic
liver disease is clearly established with most studies
showing a 25% - 39% 5-year survival [2,4,5,9]. Our re-
sults of a 32.9% 5-year cumulative proportion surviving
compare well with these studies. Many Japanese series
show a 5-year survival of around 50% [17,18] although
European publications place the survival figure closer to
25% . The benefit from lung resection for colorectal
lung metastasis is less clear and although some studies
show a clear survival benefit, surgical resection of these
metastases is not universally accepted. The benefit from
surgical treatment of loco-regional recurrence is also less
clear [18,19] as small numbers of patients have been
treated at very few specialized centres.
5.2. Surgery + Chemotherapy for Inoperable
The potential benefits of the new chemotherapeutic
agents (of which oxaliplatin and irinotecan are the com-
monest used) in the treatment of metastatic disease has
been evaluated in several randomised clinical trials but
do not show a clear survival benefit with a median sur-
vival of 13 - 16 months for oxaliplatin, 15 - 17 months
for irinotecan vs 11 - 14 months for 5-FU based regi-
mens [11,20,21]. Whether adjuvant post-hepatectomy
chemotherapy confers a survival benefit in patients who
have undergone a potentially curative resection of their
liver metastases is unclear. The value of adjuvant
5-FU/leu-covor in after hepatectomy has been assessed in
a recently published randomised study with no difference
in overall 5 year survival (41.1% for no adjuvant 5-FU vs
51.1% for adjuvant 5-FU) . The results from an
EORTC funded study to examine the benefit of pre and
post-hepatectomy chemotherapy based on oxaliplatin
show a modest progr ession free survival advantage bene-
fit in those receiving pre- and post-hepatectomy chemo-
This study showed that surgical resection (where possi-
Copyright © 2011 SciRes. SS
N. BIRD ET AL.
ble) is the most effective treatment for colorectal liver
metastases in providing long term survival. There was a
survival benefit from oxaliplatin or irinotecan based
chemotherapy in patients who recurred after liver resec-
tion and these recurrences were inoperable. They were
therefore given palliative chemotherapy. Those patients
treated with 5-FU had a significantly poorer survival
than those treated with Oxaliplatin or Irinotecan. We
propose that unless the value of adjuvant post-hepatec-
tomy chemotherapy is clarified by a randomised study,
patients with resectable liver and/or lung metastases
should undergo surgical resection and re-resection with
or without pre-operative downsizing if required. The use
of oxaliplatin and irinotecan in the palliative setting
should be reserved for inoperable recurrences only. This
approach is likely to confer the highest chance of cure as
well as a significant prolongation of survival in those that
are inoperable and as a bonus, may render a small num-
ber of patients with inoperable recurrence to be subse-
We have described a consecutive series of patients
with colorectal liver metastasis who underwent liver
surgery (if suitable) or chemotherapy/best supportive
care (if unsuitable). Our analysis suffers from the limita-
tion that these groups of patients are probably not di-
rectly comparable because those patients who did not
undergo liver surgery due to distribution of disease or
fitness had, by definition, biologically aggressiv e disease
or a weak host and their survival would therefore be ex-
pected to be worse. Patients who had liver surgery fol-
lowed by inoperable recurrence and were treated with
two different kinds of chemotherapy were more compa-
rable and showed that modern drugs offer a clear sur-
vival benefit. What is not known is whether any su rvival
benefit was conferred by surgical resection of liver me-
tastasis for patients who later relapsed. A randomized
trial comparing chemotherapy alone versus surgery alone
in patients with resectable, low-volume liver involve-
ment may show the added benefit of surgical resection,
however the potential for long-term disease free survival
offered by liver resection may make recruitment to such
a trial difficult if not impossible. Wagner (1984) showed
that patients with resectable liver disease who were not
operated upon or given chemotherapy had a median sur-
vival of 21 months. Our results show modern liver sur-
gery and modern chemotherapy for metastatic colorectal
cancer can lead to a cure in up to a third of cases and
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