Synchronous Liver Resection with Cytoreductive Surgery for the Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre

Abstract

Background: Treatment of peritoneal metastases (PM) and liver metastases (LM) from colon cancer remains controversial. LM has been viewed as exclusion criterion for cytoreductive surgery (CRS) on the basis that such spread represents systemic disease. CRS and intra-peritoneal chemotherapy (IPC) has gained increasing recognition as a treatment modality for selected patients with colon cancer and PM. This study analyses results of CRS and IPC for colon cancer and synchronous resection for treatment of LM and PM.

Full text

Synchronous Liver Resection with Cytoreductive Surgery for the Treatment of
Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian
Centre
Alzahrani N1*, Ung L1, Valle SJ1,2, Ferguson J1, Liauw W1,2 and Morris DL1
1Department of Surgery and St George Hospital Department of Surgical Oncology, University of New South Wales, Level 3, Pitney Clinical Sciences Building, Kogarah
NSW 2217, Australia
2Cancer Care Centre, St George Hospital, 1 Short Street, Kogarah NSW 2217, Australia
3College Of Medicine, Imam Muhammed Ibn Saud Islamic University, Saudi Arabia
*Corresponding author: Dr. Nayef Alzahrani, St George Hospital Department of Surgical Oncology, Level 3, Pitney Clinical Sciences Building, Kogarah, NSW 2217,
Australia, Tel: 61 432 639 166; Fax: 61 2 9113 3997; E-mail: nayefalhariri@hotmail.com
Rec date: Feb 23, 2015, Acc date: Mar 14, 2015, Pub date: Mar 22, 2015
Copyright: © 2015 Alzahrani N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Treatment of peritoneal metastases (PM) and liver metastases (LM) from colon cancer remains
controversial. LM has been viewed as exclusion criterion for cytoreductive surgery (CRS) on the basis that such
spread represents systemic disease. CRS and intra-peritoneal chemotherapy (IPC) has gained increasing
recognition as a treatment modality for selected patients with colon cancer and PM. This study analyses results of
CRS and IPC for colon cancer and synchronous resection for treatment of LM and PM.
Methods: Seventy-eight patients with PM/LM colon cancer were analysed. Forty-two patients with PM were
treated for disease limited to the peritoneum (A), and 36 patients received treatment for both PM and LM (B). Overall
survival (OS), disease-free survival (DFS), morbidity, mortality, and recurrence were compared.
Results: Median overall (OS) and disease-free survival (DFS) was 32.8 and 13.5 months. The median OS for A
and B were 45.5 and 24.4 months respectively. Within B patients, 18 had a PCI>7 and >3 LM and median survival of
21.8 months compared to 18 patients with PCI ≤ 7 and LM ≤ 3 with median survival of 38.4 months. Median DFS for
A and B were 17.7 and 8.5 months respectively. Twenty-seven in total experienced major complications following
surgery. Sixty-one patients recurred. Of A, 71.4% recurred compared to B at 86.1%.
Conclusion: While our study is limited, it has demonstrated encouraging evidence that long-term survival
outcomes can be achieved in this small but significant number of patients treated by CRS/IPC and additional
synchronous liver resection with no significant increase in morbidity when compared to CRS/IPC alone.
Keywords: Cytoreductive surgery; Peritoneal metastases; Colon
cancer; Liver metastases; PCI; Heated intraperitoneal chemotherapy
Introduction
Annually, colorectal cancer (CRC) accounts for approximately 1.2
million diagnoses of cancer and 600 000 deaths worldwide [1]. Studies
of its natural history have demonstrated that the development of liver
(LM) and peritoneal metastases (PM) are the most common causes of
death in patients with advanced disease, thought to occur in 50% [2]
and 25% [3] of all patients afflicted with this often fatal condition. The
progression from local to regional and widely disseminated disease is a
feared complication of colorectal cancer, one which has been shown to
result in death often within a year of diagnosis when treated with
supportive therapy alone, [2,4] and modest survival even with
contemporary chemotherapy.
Cytoreductive surgery (CRS) coupled with intra-peritoneal
chemotherapy has gained increasing recognition as a potential
treatment modality for carefully selected patients with CRC peritoneal
metastases. A significant survival advantage using this strategy was
demonstrated by a Dutch randomised controlled trial by Verwaal and
colleagues published in 2003, who found a median survival of 22.3
months in patients receiving CRS and heated intra-peritoneal
chemotherapy with or without systemic chemotherapy, compared to
12.6 months in patients treated with systemic chemotherapy with or
without palliative surgery [5]. Perhaps even more important than
median survival is the chance of long-term survival, which can occur
in approximately 50% of patients with low volume peritoneal disease.
Traditionally however, the presence of additional liver metastases
has been viewed as an exclusion criterion for CRS on the basis that
such spread represents systemic, rather than isolated loco-regional
disease. However, as long-term survival has been observed in patients
who undergo liver resection for metastatic CRC [6], a relatively recent
development in the management of patients who present with limited
liver and peritoneal metastases has been to offer synchronous liver
resection with CRS. In this study, we critically evaluate the survival of
patients offered this treatment from a high volume Australian centre,
to determine whether this surgical strategy may be used to achieve
long-term survival in these patients.
Journal of Gastrointestinal &
Digestive System Alzahrani et al., J Gastrointest Dig Syst 2015, 5:2
http://dx.doi.org/10.4172/2161-069X.1000264
Research Article Open Access
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

Methods
Patient selection
A total of 78 patients with metastatic colon cancer, managed at St.
George Hospital Australia from April 2003 to June 2014, were drawn
from a prospective on-site database of almost 800 patients, with 178
colorectal patients; and analysed. In this time, 36 and 42 patients with
colon cancer were treated with CRS, with and without synchronous
liver resection respectively. A multidisciplinary diagnostic work-up by
participating surgeons, medical oncologists, radiologists and clinical
nurse consultants assessed the eligibility of all patients based on a
histopathological and image-based diagnosis of PM ± LM and the
presence of resectable disease. Criteria for selection and consideration
of CRS/HIPEC in colon cancer patients includes a PCI<15 ( PCI<10 in
patients with LM, no evidence of N3 lymph node involvement, no
progressive disease after pre-operative chemotherapy, no severe co-
morbidities, ECOG<2, LM<4, no extra-abdominal disease). Patients
with disease of appendiceal or rectal origin, or with benign liver
lesions, were excluded from analysis.
Patients from the PM group with additional LM treated by CRS
were compared with patients treated by CRS for isolated PM. Patients
were analysed manually using the on-site database of a group of
almost 800 cases, and the decision to include patients with isolated PM
was based on: period of surgery (2003 onwards), gender, age, PCI<10
in patients with LM, completeness of cytoreduction score, tumour
grade, lymph node status and use of pre- and post-operative
chemotherapy, in an attempt to homogenise baseline characteristics.
Treatment
All patients underwent CRS according to a standardised protocol
based on the Sugarbaker technique. Following a midline laparotomy,
the amount of disease located within the peritoneal cavity was
quantified using the Peritoneal Cancer Index (PCI) which provides a
numerical indication of abdominal tumour burden according to the
distribution and size of metastatic deposits [7]. Within thirteen
specified regions (nine abdominopelvic and four quadrants of the
small bowel mesentery), a score out of 3 was given to indicate the
presence and size of disease in that particular area. A lesion score of 0
indicated absence of disease; 1 indicated deposits <0.5 mm in
diameter; 2 indicated nodules between 0.5 mm and 5 cm and 3
indicated nodules >5 cm or tumour confluence. A maximum score of
39 was therefore possible. CRS as described by Sugarbaker consists of
the macroscopic removal of all tumour and can be achieved by a
combination of six peritonectomy procedures and associated multi-
visceral resection, including: anterior parietal, right and left sub-
phrenic, pelvic, greater omentectomy with or without splenectomy
and lesser omentectomy with or without cholecystectomy [8,9].
Intra-operative ultrasound was performed in all patients to detect
possible liver metastases. Our criteria for CRS intra-operatively PCI
upper limit of 15 for PM or PCI<10 and a maximum of four liver
lesions for combined PM and LM. Liver resection was performed
using ultrasonic dissection (Sumisonic ME2210, Simitomo Bakelite Co
or Selector Spembly). Following completion of CRS, patients received
a combination of either intra-operative heated intra-peritoneal
chemotherapy (HIPEC); consisting of an infusion of mitomycin-C
(12.5 mg/m2) in 3 L of 1.5% dextrose peritoneal dialysis fluid heated to
42°C and/or early post-operative intra-peritoneal chemotherapy
(EPIC) consisting of up to 5 days of 5-fluorouracil (650-800 mg/m2) in
1 L of 1.5% dextrose peritoneal dialysis fluid, however, EPIC was
withheld in patients with post-operative complications. The French
Bidirectional Protocol was adopted in February 2010 and consisted of
folinic acid 50 mg intravenously 1-hour prior to procedure and 5 FU
400 mg/m2 intravenously in addition to the intra-operative heated
intra-peritoneal chemotherapy (HIPEC) of an infusion of oxaliplatin
350 mg/m2 in 500 mL of 5% dextrose heated to 42°C; for 30 minutes.
EPIC was not longer performed for colon cancer under this protocol.
A completeness of cytoreduction (CC) score was given to each patient
to reflect the amount of residual disease: CC-0 indicates all
macroscopic tumours have been removed; CC-1 indicates that no
deposit >2.5 mm remained and CC-2 indicates residual tumour
between 2.5 mm and 2.5 cm [10].
Data collection and statistical analysis
All cases included for retrospective analysis were retrieved from a
prospective database containing relevant clinicopathologic variables as
documented in Table 1. Post-operative mortality was defined as death
within 30 days of surgery, and morbidity was graded using the
National Cancer Institute’s Common Toxicity Criteria. A score of 3 or
4 was considered major morbidity and defined as complications that
necessitated return to theatre or radiological intervention [11].
Group A: Isolated Colonic Peritoneal
Metastases
Group B: Colonic Peritoneal and Liver
Metastases
P value
Total 42 36 —
Follow-up (median) 21.5 21.9 —
Age (years)
Mean (s.d.) 59.4 (14.3) 60.3 (12.6) 0.54
Sex
Male 19 (44.2) 15 (41.6) 0.75
Female 23 (54.8) 21 (58.4)
PCI
Mean (s.d.) 12.7 (9.9) 7.0 (5.1) <0.001
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 2 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

Completeness of cytoreduction
CC0 39 (92.8) 35 (97.2) 0.58
CC1 2 (4.8) 1 (2.8)
CC2 1 (2.4) 0
HIPEC
Yes 36 (85.7) 18 (50) 0.001
No 6 (14.3) 18 (50)
Tumour Grade
Well 0 2 (5.5) 0.11
Moderate 27 (64.3) 27 (75)
Poor 15 (35.7) 7 (19.5)
Mucinous Histology
Yes 19 (45.2) 8 (22.2) 0.03
No 23 (54.8) 28 (77.8)
Lymph Node Status
Positive 29 (69) 16 (44.4) 0.76
Negative 13 (31) 20 (55.6)
Pre-Operative Chemotherapy
Yes 17 (40.9) 33 (91.7) <0.001
No 25 (59.1) 3 (8.3)
Post-Operative Chemotherapy
Yes 34 (81) 33 (91.7) 0.18
No 8 (19) 3 (8.3)
Duration of Procedure (hours)
Mean (s.d.) 8.0 (3.1) 6.1 (2.3) 0.23
Duration of ICU Stay (days)
Mean (s.d.) 3.0 (3.1) 2.4 (2.7) 0.28
Duration of Hospital Stay (days)
Mean 23.7 (13.9) 21.8 (11.6) 0.66
Blood Transfusion (units)
Mean (s.d.) 4.0 (4.4) 2.4 (2.5) 0.09
Major Complications
Yes 13 (31) 14 (38.9) 0.46
No 29 (69) 22 (61.1)
Survival
Overall, median (months) 45.5 24.4 0.03
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 3 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

Disease-free, median (months) 17.7 8.5 0.002
1-year overall (%) 95 74 —
3-year overall (%) 62 33 —
5-year overall (%) 31 18 —
Recurrence
Yes 30 (71.4) 31 (86.1) 0.12
No 12 (28.6) 5 (13.9)
Table 1: Baseline comparison of characteristics between group A and B.
All statistical analysis was completed using SPSS® (Windows
Version 18). In the comparison of patient characteristics, means were
obtained using either independent samples t-test for normally
distributed data or Mann-Whitney U test for skewed data. For
categorical data, Pearson’s chi-squared test was used. Follow-up was
determined by the time between surgery and date of death or censor
date (August 2014). The end-points of this study included overall
survival (OS), the time between operation and death (or censor date if
still alive), disease-free survival (DFS), the time between operation and
relapse, and patterns of recurrence. To compare survival between
patients treated for isolated PM and PM with LM, Kaplan-Meier
curves were constructed and differences between strata computed by
the log-rank test. Univariate analyses using Kaplan-Meier curves and
the log-rank test were also conducted on patients with PM and LM to
elucidate prognostic factors associated with survival. Patients in this
group were separated into two groups: extensive disease (PCI>7 and
LM>3) and minimal to moderate disease (PCI ≤ 7 and LM ≤ 3) for this
purpose. No patient was lost from follow-up. P ≤ 0.05 was considered
statistically significant.
Results
Patient characteristics
From 2003 to 2014, seventy-eight (78) patients at St. George
Hospital, Australia; were treated for peritoneal metastases, including a
group with liver involvement, of colonic origin. Their baseline
characteristics are shown in Table 1. In total, 42 (53.8%) patients with
isolated peritoneal disease were treated for disease limited to the
peritoneum (Group A), while 36 (46.2%) received treatment for both
peritoneal and liver metastases (Group B).
Overall, there were no significant differences observed in the
following baseline characteristics: age (mean 59.4 versus 60.3 years,
p=0.54), sex (p=0.75), completeness of cytoreduction (p=0.58),
tumour grade (p=0.11), lymph node metastases (p=0.76), post-
operative chemotherapy (p=0.18). There were statistically significant
differences in the PCI (mean 12.7 versus 7.0, p<0.001), use of HIPEC
(p=0.001), mucinous histology (p=0.03) and the use of pre-operative
chemotherapy (p<0.001). The difference in the number of patients
receiving both HIPEC and EPIC between both groups was of
borderline significance (p=0.06).
Peri-operative outcomes
One (1.3%) patient died within thirty days of the procedure. This
patient died from acute respiratory distress syndrome. Operative data
showed that there were no differences observed in the duration of the
procedure (mean 8.0 hours versus 6.1, p=0.23), duration of ICU stay
(mean 3.0 days vs. 2.4, p=0.28), total hospital stay (mean 23.7 days
versus 21.8 days, p=0.66) and amount of blood transfusion units
required (mean 4.0 units versus 2.4, p=0.09). A total of 27 (n=27,
34.6%) experienced major complications following surgery, but there
was no difference between both groups (p=0.46).
Complications included infection (n=22, 28.2%), post-operative
haemorrhage (n=4, 5.1%), cardiotoxicity (n=3, 3.8%), pneumonia
(n=3, 3.8%), pleural effusion (n=19, 24.4%), pneumothoraces (n=7,
9.0%), pulmonary embolism (n=4, 5.1%), fistula formation (n=6,
7.7%), ileus (n=4, 5.1%), pancreatic leakage (n=4, 5.1%), small bowel
obstruction (n=1, 1.3%) and leak of intra-peritoneal chemotherapy
(n=4, 5.1%). A total of 7 patients (9%) were returned to the operating
theatre for surgical resolution of their post-operative complication.
Survival and recurrence
The overall median follow-up was 21.8 months (range, 1-86). For
patients with isolated peritoneal metastases (A), follow-up was 21.5
months compared to 21.9 months for patients with both peritoneal
and liver metastases (B). The median overall survival (OS) and disease-
free survival (DFS) were 32.8 months (95% CI 19.0-46.5) and 13.5
months (95% CI 10.3-16.7). The median OS for groups A and B were
45.5 months and 24.4 months respectively (p=0.03, Figure 1).
The median DFS were 17.7 months and 8.5 months respectively
(p=0.002, Figure 2). The 1-year, 3-year and 5-year survival was 95%,
62% and 31% for group A, compared to 74%, 33% and 18% for group
B. Within group B patients, 18 patients had a PCI>7 and greater than 3
LM, and had a median survival of 21.8 (95% CI 6.2-37.3) compared to
the remaining 18 patients with PCI ≤ 7 and LM ≤ 3 who achieved
survival of 38.4 months (95% CI 23.2-53.5, p=0.03, Figure 1).
It is important to note that the proportion of mucinous patients is
higher in the LM group (group B) and this, especially in a larger series,
may have translated in an overall survival difference. On univariate
analysis, post-operative chemotherapy (p<0.001) and lower PCI
(p=0.01) were factors associated with an improved survival (Table 2).
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 4 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

Factor Number (n) Median survival (months) Univariate P
Age
>60 21 (58.3) 28.7 0.13
≤ 60 15 (41.7) 21.8
Sex
Male 15 (41.7) 25.5 0.81
Female 21 (58.3) 23.5
Tumour grade
Well 2 (5.6) 10.7 0.26
Moderate 27(75) 27.8
Poor 7 (19.4) 21.8
Mucinous histology
Mucinous 8 (22.2) 23.0 0.20
Non-mucinous 28 (78.8) 27.8
Lymph node metastases
Yes 26 (72.2) 23.0 0.12
No 10 (27.8) 32.8
Pre-operative chemotherapy
Yes 33 (91.7) 23.5 0.10
No 3 (8.3) 38.4
Post-operative chemotherapy
Yes 33 (91.7) 25.5 <0.001
No 3 (8.3) 8.6
PCI
1-5 16 47.2 0.01
6-10 13 23.5
>10 7 21.8
Number of Liver Lesions
≥ 3 11 11.6 0.15
< 3 25 27.8
HIPEC
Yes 18 (50) 32.8 0.27
No 18 (50) 22.2
EPIC
Yes 20 (55.6) 23.0 0.15
No 16 (44.4) 38.4
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 5 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

HIPEC + EPIC
Yes 6 (16.7) 23.0 0.34
No 30 (83.3) 24.4
Extent of Disease
PCI>7 and LM>3 18 (50) 21.8 0.03
PCI ≤ 7 and LM ≤ 3 18 (50) 38.4
Table 2: Univariate analysis of clinicopathologic factors influencing survival for patients treated for colorectal peritoneal and liver metastases.
Figure 1: Overall Survival (p=0.03) (left) and Overall Survival
according to PCI and number of LM (p=0.03) (right).
In the 78 patients, 61 patients experienced recurrence (78.2%). Of
group A patients, 30 of 42 (71.4%) patients recurred compared to 31 of
36 of patients from group B (86.1%). There was no statistically
significant difference between groups and their association with
recurrence ( (2, n=78)=2.5, p=0.12).
Figure 2: Disease-Free Survival (p=0.002).
Discussion
In the last decade, cytoreductive surgery and intra-peritoneal
chemotherapy (CRS/IPC) has become recognised as an appropriate
management strategy for a subset of patients with metastatic colorectal
cancer with peritoneal disease. While natural history studies of
patients with disseminated peritoneal metastases of colorectal origin
have reported a median survival range of 3.1 - 7 months when treated
by palliative means [4,12], large multicentre studies have shown that
CRS/IPC may improve this range to 30 - 32.4 months [13,14]. In a
recent update of our results from this Australian tertiary referral
centre, we showed that the median survival in 109 patients treated by
CRS/IPC for colorectal peritoneal metastases was 37.1 months [15].
The surgical rationale behind CRS/IPC appears to lie in the
observation that peritoneal metastases may not represent widespread
lymphohaematogenous spread of the primary tumour, but rather a
loco-regional entity for which surgical resection may be warranted.
However, a recent development in the management of peritoneal
metastases by CRS/IPC has been the expansion of this subset of
patients to include patients with limited liver involvement, for which
additional synchronous liver resection may be performed in
conjunction with CRS/IPC. While no phase III trial has ever evaluated
liver metastasectomy for colorectal metastases against controls, this
form of surgery is nevertheless regarded as the standard of care in
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 6 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

many centres globally. The aim of this retrospective analysis was to
compare the results of CRS/IPC with and without synchronous liver
resection in this Australian centre with a view to determining whether
the selection criteria of CRS/IPC may be extended to patients with
limited liver disease.
This study demonstrated that promising survival outcomes may be
achieved in carefully selected patients who are treated by CRS/IPC
with additional synchronous liver resection. In comparing patients
with similar baseline characteristics, most notably PCI, we showed that
although there was a statistically significant difference in both overall
and disease-free survival between patients with and without liver
metastases (median OS 45.5 months versus 24.4 months, p=0.03,
Figure 1 and median DFS 17.7 months versus 8.5 months, p=0.002,
Figure 2), the five-year survival rate of patients undergoing
synchronous liver resection was 18%. While our study is limited by its
observational, retrospective nature, the selection biases inherent in
single-institution studies and our small sample size; our results
nevertheless may suggest that long-term survival is achievable in a
small but significant number of patients who undergo CRS/IPC with
additional synchronous liver resection for liver metastases. Elias et al.
prospectively studied 24 patients who had CRS for colon cancer with
liver metastases and/or moderate peritoneal carcinomatosis. The five-
year survival rate of all patients was 26.5% with a median overall
survival of 30-36 months.
Our recorded median survival of 24.4 months should be recognised
in the context of current survival outcomes in patients with liver and
peritoneal disease arising from colorectal cancer when treated by the
current standard of palliative chemotherapy and surgery to relieve
symptoms. In the last ten years, great strides have been made to this
end, with the publication of several high-profile randomised
controlled trials which have evaluated the efficacy of several modern
chemotherapy regimens in the treatment of metastatic colorectal
cancer. Currently, oxaliplatin- and irinotecan-based chemotherapies
have improved median survival to 20.8-23.1 months respectively
[16,17]. The recent addition of targeted therapies to these regimens,
including bevacizumab and cetuximab has further improved survival
up to 28 months [18,19].
However, it is questionable whether these survival outcomes may be
achieved in patients with concomitant liver and peritoneal metastases.
First, patients with isolated peritoneal metastases of colorectal origin
are unlikely to have been entered into these aforementioned trials due
to the difficulties encountered in accurately detecting and quantifying
disease according to the Response Evaluation Criteria in Solid
Tumours (RECIST) criteria [20]. Second, recent efforts to stratify
response rates according to the site of metastatic spread has shown
that patients with colorectal peritoneal metastases may achieve inferior
outcomes possibly due to the presence of a plasma-peritoneum barrier
which may inhibit exposure of tumorous nodules to the administered
chemotherapy. This was clearly shown by a pooled subgroup analysis
by Franko et al. who analysed 2095 patients enrolled in two high
profile chemotherapy trials for metastatic colorectal cancer, NCCTG-
N9741 and NCCTG-N9841 [21]. The authors demonstrated that the
median overall and progression-free survival was significantly shorter
in patients with peritoneal metastases compared to patients with non-
peritoneal metastases (12.7 versus 17.6 months, p<0.001 and 5.8 versus
7.2 months, p=0.001 respectively) [21]. Therefore in patients with both
liver and peritoneal disease, a more aggressive surgical approach may
be warranted to augment systemic chemotherapy in order to achieve
long-term survival.
While our results cannot be extrapolated to other centres given
important differences in the surgical expertise of different operating
teams, selection criteria and the type and mode of intra-peritoneal
chemotherapy administered, it is nonetheless important to note that
the results of this study are consistent with the published literature. A
systematic review of all studies identifying patients undergoing
additional liver surgery as a subset of patients undergoing CRS/IPC is
presented in Table 3, demonstrating a median overall and disease-free
survival in the order of 24.4-36 months and 8.5-24 months
respectively. The median five-year survival documented was 26.2%
(18-31%).
Authors n IPC used Mean PCI Mean No. of
Liver
Lesions
Median
follow-up
(months)
Median
overall
survival
(months)
Median
disease-free
survival
(months)
Survival
rates (%)
Morbidity
n (%)*
Mortality
n (%)*
Alzahrani et al.
(current study-
unpublished
data)
78 HIPEC:
Oxaliplatin 350
mg/m2 500
mL of 5%
dextrose,
42°C, 30
minutes.
Mitomycin
(12.5 mg/m2),
42ºC, 3 L,
30-90 minutes.
EPIC: 1 L
650-800
mg/m² 5-FU in
1 L 1-5 days
(pre 02/10).
12.7 2.7 21.8 32.8 13.5 A: 1, 3, 5
year: 95,
62 and 31
B: 1, 3, 5
year: 74,
33 and 18
27 (34.6) 1 (1.3)
Ung et al. 36 HIPEC:
Mitomycin
(12.5 mg/m2)
in 42ºC 3 L
peritoneal
7.0 2.3 21.8 24.4 8.5 1, 3, 5
year: 74,
33 and 18
14 (39) 1 (3)
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 7 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

dialysis fluid,
30-90 minutes.
EPIC: 1 L
650-800
mg/m² 5-FU in
1 L peritoneal
dialysis fluid,
1-5 days
Maggiori et al.
[22]
37 — 11 (median) 2 (median) 36 (mean) 32 9 3 and 5
year: 40
and 26
19 (51) 3 (8)
Chua et al.
[23]**
16 (55
total)
As Ung et al. 8.0 — 19 — — 2 year:
65%
17 (31)* 0
Kianmanesh et
al. [24]***
16 (43
total)
HIPEC: 6 L
mitomycin 120
mg and 6 L
200 mg/m2 for
30-90 minutes
— — — 36 — — 17 (39)* 1 (2)*
Elias et al. [25] 24 Various 8.6 4.4 27.8 (mean) 30 - 36 18-24 2, 3, 5
year: 61.3,
41.5 and
26.5
14 (58) 1 (4)
MEDIAN (RANGE) [26] 8.6 (7-12.7) 2.5 (2-4.4) 21.8 (19-36) 24.4-36 8.5 - 24 5-year:
26.25
(18-31)
35 (31-58) 1 (0-8)
Table 3: Systematic Review of Retrospective Studies of Patients Undergoing Liver Resection with CRS/IPC. *Presented as percentage of all
included patients** Of 16 patients with liver metastases, 10 patients had synchronous liver resection, 2 had cryotherapy and 4 had both. ***The
timing of liver metastectomy in this study varied – between pre-operative, intra- and post-operative. “—‘’ denotes “unstated” or not applicable.
A reasonable question to posit, however, is how survival in this
carefully selected group may be further improved to more closely
resemble patients with isolated peritoneal metastases. In our centre,
patients were generally selected on the basis of relatively low disease
burden or PCI as well as having 3 or fewer liver lesions. In this study,
we compared this group by patients with “higher” disease volume
(PCI>7 and >3 LM) and “lower” disease volume (PCI ≤ 7 and LM ≤ 3).
Patients with higher disease volume had a median overall survival of
21.8 months compared to patients with a lower burden of disease who
recorded a median survival of 38.4 months, approaching that of non-
LM patients (p=0.03). It would therefore appear that the greatest
benefit from this procedure may be experienced by patients in this
latter group and may come into consideration in the revision of our
surgical criteria.
This study provides encouraging evidence that patients with
peritoneal and liver metastases of colon origin, particularly those with
limited disease burden may achieve long term survival through a
radical surgical approach consisting of CRS/IPC and synchronous liver
resection. By refining the surgical criteria and selection process, this
strategy may be used to augment the use of systemic chemotherapy in
order to optimise patient outcomes.
Acknowledgements
Database manager, Jing Zhao, for providing statistics and data.
References
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer
statistics. CA Cancer J Clin 61: 69-90.
2. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J (1994) Factors
influencing the natural history of colorectal liver metastases. Lancet 343:
1405-1410.
3. Koppe MJ, Boerman OC, Oyen WJ, Bleichrodt RP (2006) Peritoneal
carcinomatosis of colorectal origin: incidence and current treatment
strategies. Ann Surg 243: 212-222.
4. Jayne DG, Fook S, Loi C, Seow-Choen F (2002) Peritoneal
carcinomatosis from colorectal cancer. Br J Surg 89: 1545-1550.
5. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, et
al. (2003) Randomized trial of cytoreduction and hyperthermic
intraperitoneal chemotherapy versus systemic chemotherapy and
palliative surgery in patients with peritoneal carcinomatosis of colorectal
cancer. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology 21: 3737-3743.
6. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, et al.
(2006) Surgical resection of hepatic metastases from colorectal cancer: a
systematic review of published studies. Br J Cancer 94: 982-999.
7. Sugarbaker PH (2005) Surgical management of carcinomatosis from
colorectal cancer. Clin Colon Rectal Surg 18: 190-203.
8. Sugarbaker PH (1998) Intraperitoneal chemotherapy and cytoreductive
surgery for the prevention and treatment of peritoneal carcinomatosis
and sarcomatosis. Semin Surg Oncol 14: 254-261.
9. Chua TC, Pelz JO, Morris DL (2012) Surgery for colorectal peritoneal
carcinomatosis. Scand J Gastroenterol 47: 277-285.
10. Glehen O, Gilly FN, Boutitie F, Bereder JM, Quenet F, et al. (2010)
Toward curative treatment of peritoneal carcinomatosis from nonovarian
origin by cytoreductive surgery combined with perioperative
intraperitoneal chemotherapy: a multi-institutional study of 1,290
patients. Cancer 116: 5608-5618.
11. (2014) National Cancer Institute. National Cancer Institute Common
Toxicity Criteria Version 2. 1999. Accessed.
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 8 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264

12. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, et al. (2000)
Peritoneal carcinomatosis from non-gynecologic malignancies: results of
the EVOCAPE 1 multicentric prospective study. Cancer 88: 358-363.
13. Glehen O, Cotte E, Schreiber V, SayagaeBeaujard A, Vignal J, et al. (2004)
Intraperitoneal chemohyperthermia and attempted cytoreductive surgery
in patients with peritoneal carcinomatosis of colorectal origin. British
journal of surgery 91: 747-754.
14. Glehen O, Gilly FN, Arvieux C, Cotte E, Boutitie F, et al. (2004)
Peritoneal carcinomatosis from gastric cancer: a multi-institutional study
of 159 patients treated by cytoreductive surgery combined with
perioperative intraperitoneal chemotherapy. Annals of surgical oncology
17: 2370-2377.
15. Ung L, Chua T, Morris D (2013) Peritoneal metastases of lower
gastrointestinal tract origin: a comparative study of patient outcomes
following cytoreduction and intraperitoneal chemotherapy. Journal of
Cancer Research and Clinical Oncology 2013: 1-10.
16. Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, et al.
(2007) Phase III study of capecitabine plus oxaliplatin compared with
continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in
metastatic colorectal cancer: final report of the Spanish Cooperative
Group for the Treatment of Digestive Tumors Trial. Journal of clinical
oncology : official journal of the American Society of Clinical Oncology
25: 4224-4230.
17. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, et al. (2007)
Randomized, controlled trial of irinotecan plus infusional, bolus, or oral
fluoropyrimidines in first-line treatment of metastatic colorectal cancer:
results from the BICC-C Study. J Clin Oncol 25: 4779-4786.
18. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, et
al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for
metastatic colorectal cancer. N Engl J Med 350: 2335-2342.
19. Fuchs CS, Marshall J, Barrueco J (2008) Randomized, controlled trial of
irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line
treatment of metastatic colorectal cancer: updated results from the BICC-
C study. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology 26:689-690.
20. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, et al.
(2000) New guidelines to evaluate the response to treatment in solid
tumors. European Organization for Research and Treatment of Cancer,
National Cancer Institute of the United States, National Cancer Institute
of Canada. Journal of the National Cancer Institute 92: 205-216.
21. Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, et al. (2012)
Treatment of colorectal peritoneal carcinomatosis with systemic
chemotherapy: a pooled analysis of north central cancer treatment group
phase III trials N9741 and N9841. Journal of clinical oncology : official
journal of the American Society of Clinical Oncology 30: 263-267.
22. Maggiori L, Goéré D, Viana B, Tzanis D, Dumont F, et al. (2013) Should
patients with peritoneal carcinomatosis of colorectal origin with
synchronous liver metastases be treated with a curative intent? A case-
control study. Ann Surg 258: 116-121.
23. Chua T, Yan T, Zhao J, Morris D (2009) Peritoneal carcinomatosis and
liver metastases from colorectal cancer treated with cytoreductive surgery
perioperative intraperitoneal chemotherapy and liver resection.
European Journal of Surgical Oncology (EJSO) 35: 1299-1305.
24. Kianmanesh R, Scaringi S, Sabate JM, Castel B, Pons-Kerjean N, et al.
(2007) Iterative cytoreductive surgery associated with hyperthermic
intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis
of colorectal origin with or without liver metastases. Ann Surg 245:
597-603.
25. Elias D, Benizri E, Pocard M, Ducreux M, Boige V, et al. (2006)
Treatment of synchronous peritoneal carcinomatosis and liver metastases
from colorectal cancer. European Journal of Surgical Oncology (EJSO)
32: 632-636.
26. Klaver YL, Simkens LH, Lemmens VE, Koopman M, Teerenstra S, et al.
(2012) Outcomes of colorectal cancer patients with peritoneal
carcinomatosis treated with chemotherapy with and without targeted
therapy. European Journal of Surgical Oncology (EJSO) 38: 617-623.
Citation: Alzahrani N, Ung L, Valle SJ, Ferguson J, Liauw W, et al. (2015) Synchronous Liver Resection with Cytoreductive Surgery for the
Treatment of Liver and Peritoneal Metastases from Colon Cancer: Results from an Australian Centre. J Gastrointest Dig Syst 5: 264.
doi:10.4172/2161-069X.1000264
Page 9 of 9
J Gastrointest Dig Syst
ISSN:2161-069X JGDS, an open access journal Volume 5 • Issue 2 • 1000264