Research Article
Unresectable Liver Metastases from Colorectal Cancer: Any Limits for Radical Hepatectomy?
Amroun KL1*, Piardi T1, Chetboun M1, Sommacale D1, Kianmanesh R1, Djerada Z2 and Bouché O3
1Department of Digestive and Endocrine Surgery, Robert Debré University hospital, France
2Department of Pharmacology, Maison-Blanche University Hospital, France
3Department of Hepatogastroenterology and Medical Oncology, Robert Debré University Hospital, France
*Corresponding author: Koceila Lamine Amroun, Department of General, Digestive and Endocrine Surgery, Robert Debré University Hospital (CHU de Reims), Ave du général Koenig, 51100 Reims, France
Published: 26 Sep, 2016
Cite this article as: Amroun KL, Piardi T, Chetboun M,
Sommacale D, Kianmanesh R, Djerada
Z, et al. Unresectable Liver Metastases
from Colorectal Cancer: Any Limits
for Radical Hepatectomy?. Clin Surg.
2016; 1: 1141.
Abstract
Introduction: Complex therapeutic strategies were developed to allow surgical resection of initially unresectable or hardly resectable colorectal liver metastases. That consists on downsizing chemotherapy, one- or two-stage hepatectomy. However, some patients could not complete all therapeutic steps. The aim of this study is to assess associated factors of failure and occurrence of postoperative complications.
Methods: Univariate and multivariate analysis were performed to highlight associated factors that may compromise the success of the therapeutic strategy. Actuarial survival was assessed comparing patients who completed all therapeutic strategy to those who failed and those treated by palliative chemotherapy.
Results: Among 63 patients with initially hardly resectable or unresectable LM, 45 were selected to intend surgical resection. Non-response to down-sizing chemotherapy was associated to a body mass index (BMI) ≥25 kg/m2 (OR=0.073). In two-stage hepatectomy, size of LM ≥5 cm (OR = 0.093) was the associated factors of failure to reach the second step surgery. Especially when pooled with a number of LM ≥5 (0.012). Occurrence of postoperative morbidity was associated to the necessity of perioperative transfusion (OR=12). Postoperative mortality was associated to the need of perioperative transfusion (OR=23.25). Especially when pooled to size of LM ≥5 cm (OR=5.47). Three-year overall survival rate was 64.9% when patients completed therapeutic strategy.
Conclusion: Despite the limits of our study, we identified associated factors of poor response to chemotherapy, of failure of two-step surgery and occurrence of postoperative complications.
Abbreviations
BMI: Body Mass Index; CRC: Colorectal Cancer; LM: Liver Metastases; FLR: Future Liver Remnant; ALPPS: Associated Liver Partition and Portal vein ligation for Staged hepatectomy; HIPEC: Hyperthermic Intraperitoneal Chemotherapy; FOLFOX: Folinic Acid + Fluorouracil + Oxaliplatin; FOLFIRI: Folinic Acid + Fluorouracil + Irinotecan; Fol Fox Iri: Folinic acid + Fluorouracil + Oxaliplatin + Irinotecan.
Introduction
Colorectal cancer (CRC) is the third cause of death in the world. Near 50-60% of patients will
develop liver metastases (LM) and near 50% will die from their liver disease [1]. Despite significant
medical and oncological progresses, surgical resection remains the best therapeutic option [2]. After
macroscopically complete liver resection (R0/R1) and bio-chemotherapy, the 5-year survival rate
can reach 58% in selected patients [2,3]. However, less than 10-15% of patients are considered as
initially “easily” resectable, and this is more comprehensive when multiple bilobar LM are present,
mainly because of tumor location, number and size of LM [4,5]. For them, resection is proposed
when R0/R1 hepatectomy leaving behind two adjacent liver segments with appropriate outflow and
inflow can be assured. Furthermore, to avoid postoperative liver failure, the future liver remnant
(FLR) should represents at least 25-30% of the total liver volume or > 0.5-0, 6% of body weight
in patients with healthy liver, 30-40% in patients with underlying “injured” liver parenchyma (i.e.
sinusoidal obstruction syndrome, steatosis, or steatohepatitis), and more than 40% in the presence
of sever fibrosis or cirrhosis [6-9].
To bring to surgery, unresectable LM from CRC, tools are used
including preoperative downsizing bio-chemotherapy or less often
hepatic arterial infusion, followed by one- or two-step hepatectomies
after portal vein occlusion (i.e. ligation or embolization) [10-12]. Adjunction of targeted biotherapies such as cetuximab and
bevacizumab or tri-regimen chemotherapies enhance the response
rate and can help to increase the number of patients who can benefit
from radical surgery [10,11].
The principal aim of this study was to analyze, among selected
patients with initially not easily resectable (hardly or non-resectable)
LM from CRC, factors associated to chemotherapy response, to
occurrence of postoperative morbi-mortality, and actuarial overall
survival.
Table 1
Table 2
Table 2
Results upon morphologic responses after downsizing bio-chemotherapy comparing responder (partial/complete) vs not responder (stable/progressive) patients (RESICT and/or Choi criteria).
Table 3
Table 3
Results comparing patient who failed to complete two-stage hepatectomy to those who completed all stapes strategy.
Materials and Methods
Between November 2004 and June 2013, 63 patients presenting
with initially hardly resectable or unresectable LM from CRC
were selected for liver surgery after multidisciplinary discussions
including hepatobiliary surgeons, oncologists, gastroenterologists
and radiologists. The study was conducted in two French universityhospitals
having the same politics for the treatment of LM from
CRC according to current recommendations. All studied patients
underwent a downsizing preoperative systemic bio-chemotherapy.
RECIST, and when available, Choi’s criteria were used to evaluate the
morphological responses to preoperative bio-chemotherapy [13,14].
One or two-step hepatectomies were planned according to
tumor size, localization, relation to hepatic vessels and FLR volumes.
Different group of patients were compared upon following patients
characteristics and/or variables: (i) presence or absence of significant
morphological responses to down-sizing bio-chemotherapy (RESICT
and/or Choi), (ii) completion or not of the two-step hepatectomy, (iii)
presence or absence of postoperative ≥ grade II Dindo-Clavien scale
complications [1,15], (iv) presence or absence of mortality up to 90
postoperative days. Finally, actuarial overall survivals were assessed
according to Kaplan-Meier analyze in patients who underwent
complete surgical treatment, incomplete surgery (failure of two-step
surgery) and those who underwent no surgery and treated exclusively
by bio-chemotherapy.
Statistical analyzes
Statistical analyzes were performed using IBM SPSS statistics
software version 20.0. Univariate analyzes were done for continuous
variables using non-parametric Mann-Whitney test and for
qualitative variables using chi-square or two-tailed Fisher's exact tests
when necessary. Multivariate analyzes were done using the logistic
regression modeling. The most covariate factors were chosen by
fitting a logistic regression model using a backward stepwise selection
procedure (p< 0.05 for entry, p< 0.10 for removal) with adjusted
Odds Ratio (OR).
Omnibus test of model coefficients is associated with p value that
was used to assess significant effect for the combined predictors on
the outcome variables. The Goodness of fit and appropriateness of
the logistic regression model were evaluated using the Nagelkerke R
squared values and Hosmer-Lemeshow value and finally by the overall
correct percentage of prediction. Multicollinearity was checked for all
analyzes and the Wald test was used for hypothesis testing. To assess
discriminatory performance of a Binary Logistic Model, a receiver
operating curve (ROC) and calculated areas under the ROC curves
(AUCs) were performed.
The association between factors that could be predictors such
as sex, age, Body Mass Index (BMI) ≥25 kg/m², American Society
Anaesthesiology ASA ≥3, performance statute ≥3 (world health
organization), number of supra centimeter LM ≥5, LM size ≥5 cm
(diameter of the largest tumor), number of chemotherapy cycles,
use of associated biotherapy to chemotherapy, RECIST and/or Choi
morphological tumor response rates, presence of invaded hepatic
lymph nodes and binary outcomes as completion of two-step
hepatectomy strategy were used as well as the performance or not of
a major hepatectomy (≥3 segments), necessity of per-operative blood
transfusion and binary outcomes as morbidity (Dindo-Clavien scale
≥II) or mortality (during 90 postoperative days) were used.
Overall survival analyzes included all patients (including those
who died during ninety postoperative days). Kaplan-Meier analyzes
with log-rank test were used. In case of multiple testing, Bonferroni
correction was applied. All p values were two-tailed, with statistical
significance indicated by a value of p< 0.05.
Table 4
Table 4
Results comparing factors upon occurrence or not of postoperative morbidity for patients who underwent complete surgical procedures (one- or two-stage).
Results
Among 63 patients with initially hardly resectable or unresectable
LM, 18 (28.5%) were not illegible for a curative intent surgery after
bio-chemotherapy for following reasons: presence of unresectable
extrahepatic metastases (n=11), other medical contraindications to
major surgery (n=7). Forty-five patients were finally illegible and
enrolled a curative intent surgical strategy. Patient’s characteristics
and details of procedures are summarized in Table 1.
Primaries were removed previously to liver surgery in 40/45
(88.8%) of patients. The liver resection defined the principal type
of surgery for patients who had associated procedures. Seventy
liver procedures were realized (1.55 hepatectomy per patient).
Extra-hepatic resectable metastases were present in 11% of patients
and removed at the same operative time (right inferior pulmonary
metastases n=1, complete cytoreduction surgery with HIPEC of
peritoneal carcinomatosis n=4). Sixty per cent of patients underwent
preoperatively more than 6 cycle’s bio-chemotherapy (Table 1).
Four patients died postoperatively (up to 90 days), with a per
patient mortality rate of 9% and per procedure mortality rate of 5.7%.
The causes of deaths were major portal thrombosis (n=2), uncontrolled
septic shock (n=1) and diffuse arterial mesenteric infarction (n=1).
Overall postoperative morbidity rate (≥Dindo-Clavien II) was 35.5%
per patient and 24.3% per procedure. More than 3 days intensive-care
unit stay was needed for 20% of patients (n=9). Detail of postoperative
complications included grade IV peritonitis (n=1); grade III biliary
fistulae (n=1), biliary stenosis (n=1), intra-abdominal collection
(n=1), evisceration (n=1), myocardial infarction (n=1) and pleural
effusion (n=1); grade II pulmonary emboli (n=1), bowel fistulae
(n=1), gastric ulcer (n=1) and pulmonary effusion (n=2). The overall
mean hospital stay for all procedures was 12.9 ± 9 days.
Table 2 reports the results of uni- and multivariate analyzes
after comparison between sub-group of patients who presented or
not significant morphological responses following downsizing biochemotherapy.
Univariate analyzes found two associated factors:
(i) body mass index ≥25 kg/m2 concerned 86% of patients in not
responder sub-group vs. 48% of patients in responder sub-group (p=
0.023, OR= 6.400, 95%CI = 1.223 to 33.49) and (ii) targeted biotherapy
was associated to chemotherapy in 81% of patients in responder subgroup
vs. 50% of patient in not responder sub-group (p=0.036, OR=
4.167, 95%CI= 1.053 to 16.49). Multivariate analyzes found the body
mass index ≥25 kg/m² as being the associated factor of non-response
to bio-chemotherapy (p= 0.025, OR= 0.073, 95%CI= 0.007 to 0.712).
Two-step hepatectomy was used to achieve macroscopic (R0/
R1) clearance of LM in 31/45 (68.8%) patients. Six patients failed to
reach the second-step for one or multiple following reasons: disease
progression (n=2), tumor recurrence inside FLR (n=4), insufficient
increase of FLR volume (n=2) and severe morbidity following the
first-step (n=1). Table 3 reports the results of comparison between
the two sub-groups of patients who completed (or not) the two-step
hepatectomy. Univariate analyzes reported the occurrence of major
complications after the first hepatectomy as a negative associated
factor for completion of the second-step hepatectomy (failure of
second step 50% vs. 8% in the absence of major complication, p=
0.037, OR= 11.50, 95% CI = 1.33 to 99.38). Multivariate analyze found
the size of LM ≥5 cm (p= 0.046, OR = 0.093, 95%CI = 0.009 to 0.956)
as the only independent associated factor of failure of the two-step
hepatectomy. However, the failure of the second-step surgery was
significantly higher after multivariate analyzes when both the largest
tumor size ≥5 cm and the number of supra centimeter LM ≥5 were
pooled (p= 0.012).
Postoperative morbi-mortality rates were analyzed for 39/45
(86.7%) of patients who completed radical resection. Table 4 reports
the results of comparison between the sub-groups of patients
presenting or not one or more Dindo-Clavien ≥II postoperative
complication(s). The mean number of preoperative chemotherapy
cycles was significantly higher in patients who presented Dindo-
Clavien ≥II postoperative complications (p< 0.037). Univariate
analyzes showed that patients with ≥8 cycles of bio-chemotherapy
had significant more complications vs. those who received less than 8
cycles, 85.7% vs. 48%, respectively (p=0.03, OR=4.25, 95%CI= 1.10 to
16.42, one tailed analyze). Multivariate analyze showed the necessity
of perioperative transfusion as the sole associated factor of occurrence
of postoperative complications (14.2% vs. 4%, p=0.04, OR=12,
95%CI=1.07 to 134.11). Furthermore, postoperative complications
occurred more often in patients who underwent major hepatectomy
after ≥8 chemotherapy cycles (p=0.05). Table 5, shows the results of
comparison between post-surgery dead and alive patients. Univariate
analyzes showed significant differences concerning the mean number
of bio-chemotherapy cycles 16.5 ± 5.5 for dead patients vs. 8.6 ± 1.0
for alive patients (p= 0.037), a major vs. minor hepatectomy (75% vs.
26% respectively, p= 0.045, OR=12, 95%CI=1.07 to 133.70) and the
need of perioperative transfusion (75% vs. 6% respectively, p=0.004,
OR=49.50, 95%CI= 3.41 to 719.30). Multivariate analyze showed the
perioperative transfusion as the sole associated factor of postoperative
mortality (p=0.013, OR=23.25, 95% CI=1.925 to 280.77). In addition,
when pooled, the need of perioperative transfusion and the largest
LM size ≥5 cm were statistically associated to higher occurrence of
postoperative mortality (p= 0.10, OR = 5.47, 95%CI = 0.39 to 76.39).
The mean number of liver metastases was significantly different
between patients who underwent one- vs. two-step surgery (4.0 ± 0.44
vs. 6.0 ± 0.54 respectively, p=0.043). Univariate analyzes showed less
postoperative morbidity after one- vs. two-step complete surgery (7%
vs. 48% respectively, p=0.013).
Overall survival analyzes were performed for patients (i) who
finalized the therapeutic macroscopic complete strategy (n=39), (ii)
those who failed the second-step surgery (n=6) and (iii) those who
were exclusively treated by bio-chemotherapy (n=18). For them, the
3-year overall survival rates were 65%, 0% and 0%, respectively. The
median survival of patients who completed macroscopic surgery
was 77 months vs. 24 and 17 for patients with incomplete surgery
and patients who received exclusive bio-chemotherapy, respectively
(p=0.0015, between first and second groups and p=0.001 between
first and third groups).
Table 5
Table 5
Results comparing factors upon occurrence or not of postoperative mortality for patients who underwent complete surgical procedures (one- or two-stage).
Discussion
In this series curative intent surgery is possible in highly selected
patients with initially hardly or unresectable LM from CRC with 9%
mortality, 35.5% morbidity rates and an acceptable 3-year overall
survival rate.
Down-sizing bio-chemotherapy is mostly proposed as the first
line treatment to bring initially hardly or unresectable LM from CRC
to surgery. This sequence provides the best long-term survival rates
[5,8,16]. All of the patients in the present series had preoperative
down-sizing chemotherapy either with bi-regimen (FolFox or
FolFiri) or tri-regimen (Fol-Fox-Iri) drugs. For 71% of them, targeted
biotherapies (21 bevacizumab and 11 cetuximab) were associated to
chemotherapy regimens. The mean number of cycles was 8, that by
necessity to observe significant morphological responses or at least
to do not propose surgery in progressive patients. We observed that
the adjunction of targeted biotherapie intensify the down-sizing
action of chemotherapy. This was reported by other series in which
patients with CRC LM were treated by bi-regimen chemotherapy
with adjunction of either, cetuximab, bevacizumab or panitumumab
[11,17-21]. However, tri-regimen chemotherapy without target
therapies is associated to similar high response rates [16,22]. In
the present series, patients with a BMI ≥25 were both in uni- and
multivariate analyzes associated to a negative impact in terms of
morphological responses after bio-chemotherapy.
More than ¾ of patients in the present series had a two-step
hepatectomy. For these patients, we considered that all in one-step
extended liver surgery would be too risky. Patients who failed to reach
the second-step procedure presented intrahepatic recurrence inside
the FLR and absence of significant liver hypertrophy of the FLR.
We observed two factors as being associated to failure of the twostep
procedure. Firstly, the size-number of LM (≥5 in number and/
or ≥5 cm). Secondly, the occurrence of significant morbidity after the
first-step liver surgery. We did not opted to perform Associated Liver
Partition and Portal vein ligation for Staged hepatectomy (ALPPS)
technique because we believe that this procedure needs “maturation”
in terms of technical and medical aspects and could not be proposed
routinely as a standard care in such patients [5,23-25].
When radical surgery (in one- or two-step) was planned, there
was a negative impact in term of morbidity, after major hepatectomy
in patients who received more than 8 cycles of bio-chemotherapy.
Karoui et al. [26] reported a cut-off of 6 cycles of chemotherapy
(without biotherapies) as increasing significantly the postoperative
morbidity rates. Lehmann et al. [27] reported more contradictory
results, especially when metastases were accessible for surgery.
However, we observed that the performance of major hepatectomy
with perioperative need of transfusion, especially in patients who
received a long history of chemotherapy were significant associated
factors of occurrence of higher rate postoperative complications.
In the present series, the rate of histological liver injuries was not
directly associated to the occurrence of major complications. For
patients with more than 5 cm in size and 5 LM, for whom more than
6-8 cycles’ chemotherapy are required with the need of major liver
resection, we suggest to propose a two-step procedure.
Among the advantages of the two-step procedure is the selection
of appropriate candidates to radical extensive surgery after the
first-step. Indeed, left surgical or ablative clearance of the LM with
performance of right portal vein occlusion are reversible steps that will
not compromise further therapeutics. The first step surgery will allow,
liver parenchyma histological analyzes, a better estimation of number
and location of LM by intraoperative ultrasound, there contact to the
venous inflow outflow system and presence of intrahepatic collateral
vein, also detection of peritoneal carcinomatosis [28]. We also believe
that serious postoperative morbidity may delay or avoid postoperative
interval chemotherapy and may represent a “loss of chance” [29-33].
Interestingly, Muratore et al. [34] in a small series of patients with
bilobar LM, reported that routine use of chemotherapy between the
first and second-step hepatectomy (interval chemotherapy) did not
guarantee lower progression disease or drop-out rates.
The negative impact of transfusions on perioperative and
long-term outcome after liver resection reported by Kooby et al.
[35] is in concordance with our results. Indeed, they reported that
non-transfused patients had significantly fewer postoperative
complications than those who received blood products (33% vs. 46%,
p< 0.0001). Also, transfused patients had decreased survival compared
to non-transfused patients with a median survival of 37 months vs.
49 months respectively, p< 0.0004. Multivariate analyze showed the
perioperative transfusion as the sole predictive factor of postoperative
mortality in our series (p=0.013, OR=23.25, 95% CI=1.925 to 280.77).
In addition, when pooled, the need of perioperative transfusion
and the largest LM size ≥5 cm were statistically associated to higher
occurrence of postoperative mortality (p= 0.10, OR = 5.47, 95%CI =
0.39 to 76.39).
In the present series, patients who underwent one-step
hepatectomy presented less postoperative complications. All in onestep
strategy was not feasible for all of our patients especially those
who presented with synchronous bilobar disease and/or diffuse
peritoneal carcinomatosis [36-38]. In addition, the lowest morbidity
after one-step surgery might be due to the fact that this was not
proposed routinely to the majority of patients but to highly selected
patients. Previously, series reported a higher rate of morbi-mortality
after one-step surgery as soon as the majority of patient underwent
one-step resection of all macroscopic bilobar liver disease and
other major abdominal resections [5,39]. Yet, we believe that if the
resection is not risky and technically possible in one-step, this should
be proposed [28,40]. Furthermore, the recurrence rate following onestage
ultrasonically guided liver resection was reported to be similar
to that reported after two-stage liver resection [28]. In a particular
way, we always discuss a one-step hepatectomy with multiple
radiofrequency ablations of all lesions each time when the patient did
not received more than 6-8 cycles of chemotherapy.
Lam et al. [39] reported a systemic review of 459 patients with
initially unresectable LM from CRC. The majority of patients had
preoperative chemotherapy (88%). Postoperative morbidity and
mortality after the first-step were 17% and 0.5%, respectively. Portal
vein occlusion was used in 76% of patients. Ultimately, 352 of the
initial 459 (77%) patients underwent the second-step of hepatectomy
(major liver resection 84%). Postoperative morbidity and mortality
after the second-hepatectomy were 40% and 3%, respectively. Median
overall survival was 37 months (range: 24-44 months) in patients who
completed both stages. In patients who did not complete both stages,
median survival was 16 months (range: 10-29 months). The 3-year
disease-free survival rate was 20% (range: 6-27%).
Concerning factors related to the occurrence of 90 days
postoperative mortality, the small number of dead vs. alive patients
(n= 4 vs. 35) did not allowed appropriate statistical analyzes. Thus,
we observed more chemotherapy cycles in dead vs. alive patients
(16.5 vs. 8.6, respectively), major liver resections were more observed
in dead patients (75% vs. 26%, respectively) as well as the need of
postoperative blood transfusions (75% vs. 6%, respectively). These
3 reported factors, when pooled together could increase the rate of
mortality after major hepatectomy by 3 to 5 folds. Surprisingly, dead
patients did not present with more severe histopathological liver
parenchyma injuries related to bio-chemotherapy such as steatosis,
steatohepatitis and/or sinusoidal lesions. Yet, we do not know
whether this was due to the fact that most of the patients underwent a
two-step surgery with a relatively long period of time of interruption
of systemic chemotherapy.
Finally, a significant gain of survival rates in highly selected
patients for whom radical surgery was performed compared to
patients who had incomplete or no surgery. This is conform to several
other reported series of hepatectomies for LM from CRC reporting a
relatively high rate of 3 and 5-year survival after radical liver resection
or re-resection in highly selected patients in specialized centers
[5,30,39,41-43]. For these patients, the important point would be to
determine the impact of initial aggressive oncological management by
the most appropriate drugs that would induce the best response rate,
rendering resectable, initially unresectable patients [8,11,12,38,39].
This emphasizes the importance of including patients in appropriate
prospective trials to better determine the impact of multimodal
therapies in patients with CRC liver metastatic disease including triregimen
chemotherapies associated to biotherapies [17].
In conclusion, initially hardly or unresectable patients with LM
from CRC can be resected usually by two-step hepatectomy, after
aggressive down-sizing bio-chemotherapy with acceptable morbimortality.
Studying predictive factors of failure and complications by
including such patients in prospective randomized trials may help us
to find the best potentially curative therapies for them.
References
- Poston GJ, Figueras J, Giuliante F, Nuzzo G, Sobrero AF, Gigot JF, et al. Urgent need for a new staging system in advanced colorectal cancer. J Clin Oncol. 2008; 26: 4828-4833.
- Abdalla EK. Resection of colorectal liver metastases. J Gastrointest Surg. 2011; 15: 416-419.
- Benoist S, Nordlinger B. The role of preoperative chemotherapy in patients with resectable colorectal liver metastases. Ann Surg Oncol. 2009; 16: 2385-2390.
- Pawlik TM, Cosgrove D. The role of peri-operative chemotherapy for resectable colorectal liver metastasis: what does the evidence support? J Gastrointest Surg. 2011; 15: 410-415.
- Mentha G, Terraz S, Andres A, Toso C, Rubbia-Brandt L, Majno P. Operative management of colorectal liver metastases. Semin Liver Dis. 2013; 33: 262-272.
- Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg. 2003; 237: 208-217.
- Wicherts DA, de Haas RJ, Andreani P, Sotirov D, Salloum C, Castaing D, et al. Impact of portal vein embolization on long-term survival of patients with primarily unresectable colorectal liver metastases. Br J Surg. 2010; 97: 240-250.
- Adam R, De Gramont A, Figueras J, Guthrie A, Kokudo N, Kunstlinger F, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist. 2012; 17: 1225-1239.
- Shindoh J, Tzeng CW, Aloia TA, Curley SA, Zimmitti G, Wei SH, et al. Optimal future liver remnant in patients treated with extensive preoperative chemotherapy for colorectal liver metastases. Ann Surg Oncol. 2013; 20: 2493-2500.
- Abdalla EK, Bauer TW, Chun YS, D'Angelica M, Kooby DA, Jarnagin WR. Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements. HPB (Oxford). 2013; 15: 119-130.
- Nordlinger B, Adam R, Arnold D, Zalcberg JR, Gruenberger T. The role of biological agents in the resection of colorectal liver metastases. Clin Oncol (R Coll Radiol). 2012; 24: 432-442.
- Adam R, Wicherts DA, de Haas RJ, Ciacio O, Lévi F, Paule B, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009; 27: 1829-1835.
- Chun YS, Vauthey JN, Boonsirikamchai P, Maru DM, Kopetz S, Palavecino M, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA. 2009; 302: 2338-2344.
- Shindoh J, Loyer EM, Kopetz S, Boonsirikamchai P, Maru DM, Chun YS, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012; 30: 4566-4572.
- Dindo D, Clavien PA. What is a surgical complication? World J Surg. 2008; 32: 939-941.
- Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, et al. Longterm outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009; 249: 420-425.
- Ychou M, Rivoire M, Thezenas S, Quenet F, Delpero JR, Rebischung C, et al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann Surg Oncol. 2013; 20: 4289-4297.
- Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, Maspero F, et al. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin Colorectal Cancer. 2013; 12: 145-151.
- Stein A, Glockzin G, Wienke A, Arnold D, Edelmann T, Hildebrandt B, et al. Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature. BMC Cancer. 2012; 12: 356.
- Ciliberto D, Prati U, Roveda L, Barbieri V, Staropoli N, Abbruzzese A, et al. Role of systemic chemotherapy in the management of resected or resectable colorectal liver metastases: a systematic review and metaanalysis of randomized controlled trials. Oncol Rep. 2012; 27: 1849-1856.
- Adam R, Hoti E, Bredt LC. Evolution of neoadjuvant therapy for extended hepatic metastases--have we reached our (non-resectable) limit? J Surg Oncol. 2010; 102: 922-931.
- Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007; 25: 1670- 1676.
- Oldhafer KJ, Donati M, Jenner RM, Stang A, Stavrou GA. ALPPS for Patients with Colorectal Liver Metastases: Effective Liver Hypertrophy, but Early Tumor Recurrence. World J Surg. 2014; 38: 1504-1509.
- Dokmak S, Belghiti J. Which limits to the "ALPPS" approach? Ann Surg. 2012; 256: e6.
- Aloia TA, Vauthey JN. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is gained and what is lost? Ann Surg. 2012; 256: e9.
- Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006; 243: 1-7.
- Lehmann K, Rickenbacher A, Weber A, Pestalozzi BC, Clavien PA. Chemotherapy before liver resection of colorectal metastases: friend or foe? Ann Surg. 2012; 255: 237-247.
- Torzilli G, Procopio F, Botea F, Marconi M, Del Fabbro D, Donadon M, et al. One-stage ultrasonographically guided hepatectomy for multiple bilobar colorectal metastases: a feasible and effective alternative to the 2-stage approach. Surgery. 2009; 146: 60-71.
- Sorbye H, Mauer M, Gruenberger T, Glimelius B, Poston GJ, Schlag PM, et al. Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983). Ann Surg. 2012; 255: 534-539.
- Karoui M, Vigano L, Goyer P, Ferrero A, Luciani A, Aglietta M, et al. Combined first-stage hepatectomy and colorectal resection in a two-stage hepatectomy strategy for bilobar synchronous liver metastases. Br J Surg. 2010; 97: 1354-1362.
- Homayounfar K, Liersch T, Schuetze G, M Niessner, A Goralczyk, J Meller, et al. Two-stage hepatectomy (R0) with portal vein ligation--towards curing patients with extended bilobular colorectal liver metastases. Int J Colorectal Dis. 2009; 24: 409-418.
- Adam R, Miller R, Pitombo M, Wicherts DA, de Haas RJ, Bitsakou G, et al. Two-stage hepatectomy approach for initially unresectable colorectal hepatic metastases. Surg Oncol Clin N Am. 2007; 16: 525-536.
- Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC, Bachellier P. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg. 2004; 240: 1037-1049.
- Muratore A, Zimmitti G, Ribero D, Mellano A, Viganò L, Capussotti L. Chemotherapy between the first and second stages of a two-stage hepatectomy for colorectal liver metastases: should we routinely recommend it? Ann Surg Oncol. 2012; 19: 1310-1315.
- Kooby DA, Stockman J, Ben-Porat L, Gonen M, Jarnagin WR, Dematteo RP, et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg. 2003; 237: 860-869.
- Kianmanesh R, Scaringi S, Sabate JM, Castel B, Pons-Kerjean N, Coffin B, et al. Iterative cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis of colorectal origin with or without liver metastases. Ann Surg. 2007; 245: 597-603.
- Sasanuma H, Yasuda Y, Mortensen FV, Yamashita K, Nihei Y, Houjou N, et al. Simultaneous colorectal and liver resections for synchronous colorectal metastases. Scand J Surg. 2006; 95: 176-179.
- Cauchy F, Faivre S, Belghiti J. Surgical results after downstaging of initially marginal or non-resectable liver metastases. Dig Dis. 2012; 30: 143-149.
- Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford). 2013; 15: 483-491.
- Spampinato MG, Mandala L, Quarta G, Del Medico P, Baldazzi G. Onestage, totally laparoscopic major hepatectomy and colectomy for colorectal neoplasm with synchronous liver metastasis: safety, feasibility and shortterm outcome. Surgery. 2013; 153: 861-865.
- Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver metastases. J Surg Oncol. 2013; 107: 211-216.
- Brouquet A, Abdalla EK, Kopetz S, Garrett CR, Overman MJ, Eng C, et al. High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol. 2011; 29: 1083-1090.
- Wicherts DA, Miller R, de Haas RJ, Bitsakou G, Vibert E, Veilhan LA, et al. Long-term results of two-stage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg. 2008; 248: 994-1005.