Accepted Manuscript

Tumor Progression during Preoperative Chemotherapy Predicts Failure to CompleteTwo-Stage Hepatectomy for Colorectal Liver Metastases: Results of an ItalianMulticenter Analysis Of 130 Patients

Felice Giuliante, MD Francesco Ardito, MD Alessandro Ferrero, MD Luca Aldrighetti,MD Giorgio Ercolani, MD Gennaro Grande, MD Francesca Ratti, MD Ivo Giovannini,MD Bruno Federico, MSc Antonio D. Pinna, MD Lorenzo Capussotti, MD GennaroNuzzo, MD

PII: S1072-7515(14)00307-X

DOI: 10.1016/j.jamcollsurg.2014.01.063

Reference: ACS 7365

To appear in: Journal of the American College of Surgeons

Received Date: 17 October 2013

Revised Date: 9 December 2013

Accepted Date: 9 January 2014

Please cite this article as: Giuliante F, Ardito F, Ferrero A, Aldrighetti L, Ercolani G, Grande G, Ratti F,Giovannini I, Federico B, Pinna AD, Capussotti L, Nuzzo G, Tumor Progression during PreoperativeChemotherapy Predicts Failure to Complete Two-Stage Hepatectomy for Colorectal Liver Metastases:Results of an Italian Multicenter Analysis Of 130 Patients, Journal of the American College of Surgeons(2014), doi: 10.1016/j.jamcollsurg.2014.01.063.

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Tumor Progression during Preoperative Chemotherapy Predicts Failure to Complete Two-

Stage Hepatectomy for Colorectal Liver Metastases: Results of an Italian Multicenter

Analysis Of 130 Patients

Felice Giuliante, MD1; Francesco Ardito, MD1; Alessandro Ferrero, MD2; Luca Aldrighetti,

MD3; Giorgio Ercolani, MD4; Gennaro Grande, MD1; Francesca Ratti, MD3; Ivo Giovannini,

MD1; Bruno Federico, MSc5; Antonio D. Pinna, MD4; Lorenzo Capussotti, MD2; Gennaro

Nuzzo, MD1

1. Hepatobiliary Surgery Unit, A. Gemelli Hospital, Università Cattolica del Sacro Cuore,

Rome.

2. Department of Digestive and Hepatobiliary Surgery, Mauriziano Umberto I Hospital,

Turin.

3. Liver Unit, San Raffaele Hospital, Milan.

4. Department of Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University

of Bologna.

5. Faculty of Health and Sport Sciences, University of Cassino, Italy. (Consultant

statistician).

Disclosure Information: Nothing to disclose.

Short title: Two-Stage Hepatectomy for Colorectal Metastases

Correspondence address: Francesco Ardito, MD

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Catholic University of the Sacred Heart, School of Medicine Dept. of Surgery, Hepatobiliary Surgery Unit L.go A. Gemelli, 8 I-00168, Rome – Italy Tel.: +39–06–30154967 E-mail: francesco.ardito@rm.unicatt.it

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ABSTRACT

Background: To evaluate the feasibility and long-term results of two-stage hepatectomy (TSH)

in patients with bilobar colorectal liver metastases (CRLM).

Study Design: Retrospective multicenter study including 4 Italian hepatobiliary surgery units.

One hundred-thirty patients were selected for TSH between 2002 and 2011. Primary endpoint

was feasibility of TSH and the analysis of factors associated with failure to complete the

procedure. Secondary endpoint was the long-term survival analysis.

Results: Patients presented with synchronous CRLM in 80.8% of cases, with a mean number of

8.3 CRLM and with concomitant extrahepatic disease in 20.0% of cases. The rate of failure to

complete TSH was 21.5% and tumor progression was the most frequent reason of failure (18.5%

of cases). Primary tumor characteristics, type, number and distribution of CRLM were not

associated with significantly different risk of disease progression. The multivariable logistic

regression analysis showed that tumor progression during pre-hepatectomy chemotherapy was

the only independent risk factor for failure to complete TSH. The 5- and 10-year overall survival

rates for patients who completed TSH were 32.1% and 24.1% with a median survival of 43

months. Duration of pre-hepatectomy chemotherapy ≥6 cycles was found to be the only

independent predictor of overall and disease-free survival.

Conclusions: This study showed that selection of patients by response to pre-hepatectomy

chemotherapy may be extremely important before planning TSH, because tumor progression

while receiving pre-hepatectomy chemotherapy was associated with significantly higher risk of

failure to complete the second stage. For patients who completed the TSH strategy, long-term

outcome can be achieved with results similar to those observed following a single-stage

hepatectomy.

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INTRODUCTION

Liver resection for colorectal liver metastases (CRLM) provides the only chance of long-term

survival, with 5-year survival rates of 40% (1-3), and exceeding 50% in selected patients (4-5).

More recently, improvements in surgical technique and in response rates to chemotherapy have

expanded the criteria for resectability of CRLM (6-8), to include any patient in whom all disease

can be removed with negative margins and who has adequate liver remnant (1, 9, 10). However,

only about 25%-30% of patients with CRLM are resectable at diagnosis according to the

currently used criteria (1, 9, 10).

The two-stage hepatectomy (TSH) procedure has been advocated in patients with multiple and

bilateral CRLM who were considered unresectable because of the inability to remove all CRLM

by a single hepatectomy while leaving an adequate functional liver volume (11, 12).

TSH consists in combining two sequential liver resections, with or without perioperative portal

vein embolization, with the aim of allowing the liver to regenerate during the interval between

the two procedures, without the risk of postoperative liver failure (11, 12).

In the literature TSH has been shown to provide long-term overall survival in patients with

multiple bilobar CRLM (13, 14). However the strength of data on TSH is limited because the

available studies have included few patients from single centers.

The aim of this Italian multicenter study was to evaluate the feasibility and long-term results of

TSH procedure in a large cohort of patients presenting with multiple and bilobar CRLM.

METHODS

Data were collected from 4 hepatobiliary Italian centers, members of the Italian Chapter of the

International Hepato-Pancreato-Biliary Association (IHPBA): Agostino Gemelli Hospital

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(Rome); Mauriziano Umberto I Hospital (Turin); San Raffaele Hospital (Milan) and Sant'Orsola-

Malpighi Hospital (Bologna).

The study included patients who underwent two-stage hepatectomy (TSH) between January 2002

and December 2011 for CRLM.

Indications for TSH included patients with multiple and bilateral CRLM in whom a complete

removal of all metastases was not feasible by a single hepatectomy because of insufficient future

remnant liver (FRL) volume: <25% in healthy liver; <30% in liver injured by chemotherapy, and

<40% in case of intensive preoperative chemotherapy. In most cases, at the first stage, minor

liver resections on the left hemiliver were performed, leaving the right or right extended

hepatectomy for the second stage.

Portal vein embolization (PVE) or portal vein ligation (PVL) were often used to enhance the

increase of FRL volume. In such cases liver volumetry by CT was performed 4 weeks after PVE

to assess FRL growth and surgical resectability. Interval chemotherapy was administered

between the two stages at the discretion of the treating surgeon and oncologist. When

chemotherapy was administered between the first and the second stage hepatectomy, time

interval after PVE exceeded 4 weeks.

Administration of post-hepatectomy chemotherapy was scheduled regularly for all patients. All

the resected patients were treated postoperatively by the same line of chemotherapeutic agents

used during the pre-hepatectomy setting, for at least 6 months.

Liver resections were defined according to the International Hepato-Pancreato-Biliary

Association terminology (15).

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Before surgery routine blood tests were assessed. Preoperative radiological investigations

included abdominal ultrasonography, abdominal computed tomography (CT) or magnetic

resonance (MR), and CT scan of the chest.

The following data were collected for each patient: demographics; site of primary tumor;

primary tumor nodal involvement; size, number and distribution of CRLM; type of CRLM

(synchronous or metachronous); presence of extrahepatic disease; use of perioperative

chemotherapy and use of PVE or PVL. Chemotherapy given before the first stage hepatectomy

was defined as pre-hepatectomy chemotherapy. Chemotherapy given between the first and the

second stage hepatectomy was defined as interval chemotherapy. Response to pre-hepatectomy

chemotherapy was classified according to World Health Organization criteria, by using the

Response Evaluation Criteria in Solid Tumors (16). Responses were classified as follows:

complete response (disappearance of all known disease); partial response (≥50 % decrease in

total tumor size of the lesions); stable disease (<50 % decrease or <25 % increase in total tumor

size); and progression of disease (≥25 % increase in total tumor size and/or the appearance of

new lesions at any site) (16).

Operative details included: type of liver resection; rate of intraoperative blood transfusions;

radicality of liver resection. When the surgical free-margin was zero mm, or there was exposed

tumor along the transection plane, liver resection was classified as R1-resection.

Early results included: postoperative morbidity and 60-day mortality. Complications were scored

according to the Clavien grading system (17).

Late results included 5-year overall and disease-free survival rates; recurrence rate and site of

recurrence.

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Statistical analysis

The chi-square test was used to compare categorical variables and the Student t-test was used for

numerical variables. Significance was defined as p <0.05.

Multivariable logistic regression analysis was used to assess the risk factors for failure to

complete TSH. The Kaplan-Meier method was used to analyze actuarial overall and disease-free

survival. Overall survival was calculated from the time of liver resection to the last follow-up.

Disease-free survival was calculated from the time of liver resection to the time of first untreated

recurrence (18). Patients who died during the postoperative course were included in the survival

analysis, according to the “intention-to-treat” criteria, but were excluded from the disease-free

survival analysis. Differences between subgroups in overall survival and disease-free survival

were tested with the log-rank test. Factors found to be significant at the 0.2 level at the univariate

analyses were used to build multivariable Cox proportional hazards models and these were

retained if significant at the 0.05 level at the multivariable analysis. Results of these models were

expressed as Hazard Ratios (HR) with 95% Confidence Intervals (95% CI).

Statistical analysis was performed using the SPSS software for Windows version 13.0 (SPSS,

Chicago, Illinois, USA).

RESULTS

Between January 2002 and December 2011, 130 patients with bilobar CRLM were selected for

TSH at the four hepatobiliary Italian centers and they are the object of this study.

The characteristics of the 130 patients are summarized in Table 1. There were 80 men (61.5%)

and 50 women (38.5%). The mean age of the patients was 58.6 years (range, 36-81). One

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hundred and five patients (80.8%) had synchronous CRLM and 26 patients (20.0%) presented

with extrahepatic disease (Table 1). The mean number of CRLM was 8.3 (range, 2-27).

Pre-hepatectomy chemotherapy

Pre-hepatectomy chemotherapy was administered to 113 patients (86.9%), with a median

number of 9 cycles (range, 3-22) (Table 1). Systemic chemotherapy was performed in 106

patients (93.8%), hepatic arterial chemotherapy in 1 patient (0.9%) and both systemic and

hepatic arterial in 6 patients (5.3%). All these patients were treated with modern systemic

chemotherapy consisting of oxaliplatin or irinotecan-based regimens (Table 1). Partial response

was observed in 67 patients (61.5%) (Table 1).

First stage hepatectomy

Operative data regarding the first stage hepatectomy are shown in Table 2. Minor resections

were performed in most patients (96.9%). Additional radiofrequency ablation was performed in 5

patients (3.8%). Pedicle clamping was used in 30 patients (23.1%) with a mean duration of 28

minutes (range, 5-55). Fifty-eight (55.2%) of the 105 patients with synchronous CRLM

underwent simultaneous resection of the primary tumor (Table 2). The other 47 patients with

synchronous CRLM were referred after being operated on for their primary tumor at other

institutions.

Postoperative mortality rate was nil. Postoperative morbidity rate was 16.9% and the rate of

major complications (Grade III-IV) was 8.5% (Table 2). Out of the 105 patients with

synchronous CRLM, the overall morbidity rate was significantly higher in patients who

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underwent simultaneous resection of the primary tumor than in patients who underwent delayed

first stage hepatectomy (14/58, 24.1% vs. 4/47, 8.5%, respectively; p=0.030).

Portal vein occlusion

One hundred and fourteen patients (87.7%) underwent right portal vein occlusion in order to

increase the volume of the remnant liver (Table 2). PVL with or without alcohol injection was

performed in 59 patients (51.8%) at the time of the first stage hepatectomy (Table 2). PVE was

used in 55 patients (48.2%) after the first hepatectomy (Table 2).

Failure to complete TSH

Among 130 patients who underwent the first stage hepatectomy, 28 (21.5%) did not complete

TSH (Table 3). The flow chart in Figure 1 shows the progress of the 130 patients scheduled to

undergo TSH. Tumor progression in the liver was the most frequent reason of failure of TSH

(9.2%) (Table 3). Overall only-hepatic tumor progression occurred in 20 patients (15.4%). Eight

of these patients could complete the TSH because they underwent associated contralateral minor

liver resection during the second stage hepatectomy; in the other twelve patients the extent of

tumor progression in the liver did not allow the completion of TSH (Table 3).

The median interval between the first and the second stage of TSH was 39 days (range, 20-180).

Interval chemotherapy was administered to 39 patients (30.0%) with a median number of 4

cycles (range, 2-23). The median time between the first and the second stage of TSH in such

patients was significantly longer than that in patients without interval chemotherapy; 80 days

(range, 30-180) vs. 36 days (range, 20-80) (p<0.001). Rate of interval chemotherapy

administration was significantly higher in patients who did not undergo right portal vein

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occlusion than in patients who underwent PVE or PVL (10/16, 62.5% vs. 29/114, 25.4%,

respectively; p=0.004).

The 102 patients who completed TSH were compared with the 24 patients who did not complete

TSH because of tumor progression (Table 4). No statistically significant differences were found

between the two groups in terms of primary tumor characteristics or type, number and

distribution of CRLM (Table 4). Administration of interval chemotherapy between the two

stages was not associated with a significantly lower risk of disease progression. The

multivariable logistic regression analysis showed that tumor progression during pre-hepatectomy

chemotherapy was the only independent risk factor for failure to complete TSH (Table 4).

Second stage hepatectomy

One hundred and two patients (78.5%) underwent the second stage hepatectomy which was

major resection in most cases (97.1%) (Table 3). Operative data regarding the second stage

hepatectomy are shown in Table 3. Pedicle clamping was used in 45 patients (44.1%) with a

median duration of 38 minutes (range 8-132). Postoperative mortality was 3.9% (4 patients) and

all cases were related to liver failure following right hepatectomy. All these four patients had

undergone prolonged pre-hepatectomy chemotherapy (≥6 cycles).

Survival analysis

The median follow-up for the total group of patients was 19 months (range 2-145) (mean follow-

up, 25.5 months) and for the surviving patients it was 21 months (range 2-145) (mean follow-up,

29.4 months).

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On an intention-to-treat basis, the 5- and 10-year overall survival rates for all 130 patients

scheduled for TSH were 24.7% and 18.5%, respectively. The 5- and 10-year overall survival

rates for patients who completed TSH were significantly higher than that for patients who failed

TSH (32.1% and 24.1% vs. 0, respectively; p<0.001) (Figure 2). Median survival of patients who

completed TSH was significantly higher than that of patients who failed TSH (43 vs. 12 months,

respectively; p<0.001). Of those patients unable to complete TSH, none survived beyond 27

months.

Recurrence occurred in 73.5% of patients who completed TSH (72/98 patients, excluding the 4

postoperative deaths). Median time to recurrence was 11.5 months (mean: 15.4; range 1-45).

Seventeen patients developed only hepatic recurrence, 33 patients only extrahepatic recurrence

and 22 patients both intra- and extrahepatic recurrence. Hepatic recurrence with or without

extrahepatic recurrence occurred in 39 patients (54.2%). Out of the 72 patients with recurrence,

15 (20.8%) underwent re-resection: 7 patients underwent repeat hepatectomy, 5 patients

underwent extrahepatic resection and 3 patients underwent both repeat liver resection and

extrahepatic resection. Their 5- and 10-year disease-free survival rates leveled to 20.4% from the

first liver resection.

Several clinical factors were analyzed to predict the overall and disease-free survival (Table 5).

On univariate analysis, the duration of pre-hepatectomy chemotherapy ≥6 cycles was associated

with significantly lower overall survival and disease-free survival (p=0.046 and p=0.026,

respectively) (Table 5).

These results were confirmed on multivariable analysis, where duration of pre-hepatectomy

chemotherapy ≥6 cycles was found to be the only independent predictor of overall and disease-

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free survival: HR 4.11 (95% CI 0.97-17.33, p=0.050) and HR 3.39 (95% CI 1.05-10.95,

p=0.041), respectively.

DISCUSSION

This is the largest multicenter series reporting the feasibility and the long-term outcome of TSH

in patients with advanced bilateral CRLM.

Recently, the introduction of more effective systemic chemotherapy and the improvements in

surgical technique and perioperative care have contributed to increase the number of patients

with CRLM who are candidates for liver resection (6, 7). Currently, resectability of CRLM has

been defined as the ability to achieve resection with negative margins while preserving a

sufficient future remnant liver, sparing two contiguous hepatic segments, and maintaining

adequate biliary drainage and vascular inflow and outflow (9). However about 75%-85% of

patients with CRLM are not candidates for surgery at diagnosis, mainly due to the extent and

distribution of the hepatic disease which cannot be resected by a single curative hepatectomy

because of insufficient FRL (1, 9, 10).

The TSH has been developed as a strategy to allow curative resection of extensive bilateral

CRLM, and consists in sequential hepatectomies associated with PVE (19). Several studies in the

literature showed that TSH was a safe and effective strategy in selected patients (20). However

the available data on TSH have limited strength and often originate from single center

experiences including few patients (20-23).

This multicentre study collected the results of 130 patients who were selected for TSH. Among

these patients, 102 (78.5%) completed the two-stage approach and were able to undergo the

second stage hepatectomy in order to completely resect the liver disease. Five- and 10-year

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overall survival rates for patients who completed TSH were 32.1% and 24.1%, respectively. The

median overall survival was 43 months. These results are similar to those reported in the

literature and are comparable with those of liver resection in patients with resectable CRLM (20).

However it should be emphasized that these good long-term results were obtained in patients

with advanced disease at diagnosis, with synchronous CRLM in 80.8% of cases, with a mean

number of 8.3 CRLM and with concomitant extrahepatic disease in 20.0% of cases. Moreover,

although these patients had already undergone extensive and complex liver surgery, an

aggressive surgical policy was adopted in case of recurrence after TSH. Indeed 20.8% of patients

underwent re-resection in case of recurrence and their 5- and 10-year disease-free survival rates

leveled to 20.4%. Interestingly, all patients who were disease-free 5 years after completed TSH

did not recur during the subsequent follow-up, and for this reason they might be classified as

“cured” patients, as reported in previous papers (24, 25).

Moreover, long-term survival following completed TSH was comparable to that of patients

treated with a planned single-stage hepatectomy (14, 26).

However it should be emphasized that the most relevant drawback of TSH strategy is that the

second stage hepatectomy may not be feasible in about 20-25% of the patients in whom it was

initially planned (13, 14, 20, 26, 27). The reason of drop-out is mainly due to disease progression

between the two surgical steps. In our study 28 patients (21.5%) did not complete the TSH

strategy (24 for tumor progression) and their 5-year overall survival was significantly lower than

that following completed TSH (0 vs. 32.1%, respectively; p<0.001). Out of the patients who

were unable to complete the TSH, none survived beyond 27 months. For these reasons, some

authors prefer to approach such patients by a 1-stage procedure which, of course, avoids the time

interval between the two stages of the TSH, where the risk of tumor progression is high. The 1-

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stage procedure maximizes parenchymal-sparing, avoids major liver resections and is associated

with a significantly lower risk of failure than the TSH procedure (28). However its main

drawback is that it often results in resection margin of 0 mm with a high rate of R-1 resections

(28). In our study the rate of R-0 resections in completed TSH was 84.3%. It should be

emphasized that the radicality of resection with negative resection margin is one of the most

important prognostic factors following liver resection for CRLM (29, 30). Moreover R-0

resection is confirmed to be an independent prognostic factor also in patients undergoing TSH

procedure (22).

Recently a new technique has been proposed in order to reduce the time interval between portal

vein occlusion and second stage hepatectomy and to decrease the possibility of tumor

progression (31). Schnitzbauer et al. (31) reported a novel concept of two-stage extended right

hepatectomy with portal vein ligation and in situ splitting to induce rapid hypertrophy of the left

lateral lobe (ALPPS procedure). This procedure led to the induction of marked and rapid

hypertrophy of the left lateral lobe in about 75% of cases within a median of 9 days. However,

the reported high overall mortality rate of 10% or even greater, has led to a debate about the

clinical safety of this procedure which still necessitates an optimal definition for the selection of

patients who might benefit from this approach (31-33). In a recent multicenter Brazilian study

which collected 39 patients who underwent ALPPS procedure (32 patients for liver metastases),

the overall mortality rate was 12.8%.

Further studies should compare the feasibility of these procedures, on an intention-to-treat basis,

including also the postoperative mortality rates. In our study, including postoperative deaths, 32

out of the 130 patients did not complete the TSH, resulting on an overall incidence of failure of

24.6%.

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Selection of patients before planning the TSH approach is fundamental, in order to spare patients

who will not benefit from this approach. In our study a multivariable logistic regression analysis

was performed on the 130 patients who were selected for TSH. Interestingly, patients who failed

TSH did not present any difference in tumor characteristics or type, number and distribution of

CRLM as compared with patients who completed TSH. Moreover the use of interval

chemotherapy between the two stages did not show any impact on the possibility to successfully

complete the TSH, because it did not decrease the risk of tumor progression during the interval

time before the second stage hepatectomy. For this reason, as a result of our study, the routine

use of interval chemotherapy during TSH may not be recommended. These results are similar to

those reported in a previous paper by Muratore et al (34). In our study the multivariable logistic

regression analysis showed that tumor progression during pre-hepatectomy chemotherapy was

the only independent risk factor for failure to complete TSH. Tumor progression while receiving

systemic chemotherapy has been shown to be a powerful poor prognostic factor, suggesting a

very aggressive tumor biology (35). In a recent paper, disease progression during chemotherapy

was confirmed as an independent negative prognostic factor of survival (36). However, in that

paper, the 5-year survival rate in patients resected with disease progression was 35%, largely

better than the survival rate expected after palliative chemotherapy (36). For this reason,

although tumor response to chemotherapy has a prognostic value, the present data do not allow

us to consider disease progression as an absolute contraindication to resection (36). Our study

showed that such patients will not benefit from the TSH approach because of the significantly

higher risk of failure to complete the second stage. At least disease stabilization should be

obtained before planning the TSH approach. However tumor progression should not preclude

potentially curative treatments, and other surgical strategies should be considered in such

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patients, such as the ALPPS procedure which may be indicated when the risk of failure of TSH is

high. Indeed this strategy may help to accelerate the hypertrophic effect on the remnant liver and

to reduce the time interval which is reported to be around 9 days.

In our study the survival analysis in patients who completed TSH, showed that the duration of

pre-hepatectomy chemotherapy ≥6 cycles was found to be the only independent predictor of

overall and disease-free survival. Again, primary tumor characteristics or type, number and size

of CRLM were not independent predictors of long-term results in such patients with advanced

disease. It is likely that administration of multiple cycles of chemotherapy reflected the difficulty

to control the aggressive tumor biology.

Finally the TSH strategy includes complex liver surgery associated with PVE or PVL and

concurrent ablation procedures. Consequently, severe postoperative complications such as liver

failure, can occur particularly after the second stage procedure (23). In our study postoperative

mortality after the first stage was 0, but it was 3.9% after the second stage and all cases were

related to liver failure following right hepatectomy. These results confirm the importance of

preoperative assessment of hypertrophy cutoffs for extended liver resection, especially in case of

prolonged pre-hepatectomy chemotherapy. However a recent paper by Clavien et al. showed that

major liver resections in the TSH strategy were not associated with a higher rate of overall or

severe postoperative complications compared to what is observed in one-stage major liver

resections (32). In our patients, morbidity rate after the first stage was generally low, being

16.7%, with 8.5% major complications. However we found that combined resection of the

primary tumor with the first stage of liver resection was associated with an increased risk of

complications. These results are similar to those reported in a recent paper by Brouquet et al

(27).

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In conclusion this multicenter study showed that selection of patients by response to pre-

hepatectomy chemotherapy may be fundamental before planning TSH. Indeed patients who

presented tumor progression while receiving pre-hepatectomy chemotherapy did not benefit from

the TSH approach because of the significantly higher risk of failure to complete the second stage.

For patients who completed the TSH strategy, long-term outcome can be achieved with a 5-year

overall survival comparable with that of patients treated with a planned single-stage

hepatectomy.

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Table 1. Characteristics of the 130 Patients Selected for Two-Stage Hepatectomy

Characteristic Data

Mean age, y (range) 58.6 (36-81)

Sex, n (men:women)

Primary tumor, n (%)

Colon

Rectum

N 0

N 1

Unknown

80:50

97 (74.6)

33 (25.4)

39 (31.0)

87 (69.0)

4

Liver metastases

Synchronous, n (%)

Mean number (range)

Mean no. in right hemiliver (range)

Mean no. in left hemiliver (range)

Mean size, cm (range)

105 (80.8)

8.3 (2-27)

5.9 (1-21)

2.4 (1-13)

4.8 (1-13)

Concomitant extrahepatic disease, n (%)

Lung metastases

Localized peritoneal metastases

Adrenal gland metastases

26 (20.0)

20 (15.4)

5 (3.8)

1 (0.8)

Pre-hepatectomy chemotherapy 113 (86.9)

Oxaliplatin

Irinotecan

Both

Other

Associated bevacizumab

Associated cetuximab

61 (54.0)

34 (30.1)

14 (12.4)

4 (3.5)

56 (49.5)

8 (7.1)

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Response to chemotherapy, n (%)

Progression

Stable disease

Partial response

Unknown

7 (6.4)

35 (32.1)

67 (61.5)

4

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Table 2. Operative Results after the First Stage Hepatectomy (n=130)

n %

Minor liver resection

Primary tumor simultaneous resection (no. of synchronous

CRLM)

126

58/105

96.9

55.2

Combined radiofrequency ablation

Pedicle clamping

Intraoperative blood transfusions

Postoperative morbidity

Grade I-II17

Biliary leak

Noninfected collection

Pulmonary

Cardiovascular

Urinary infection

Prolonged ileus

Grade III-IV17

Leakage of colorectal anastomosis

Hemorrhage

Liver failure

Subphrenic collection

Ascites

Pneumothorax

Small bowel obstruction

Relaparotomy

Mortality

Portal vein occlusion

Percutaneous portal vein embolization

5

30

9

22

11

2

1

4

1

1

2

11

5

1

1

1

1

1

1

5

0

114

55

3.8

23.1

6.9

16.9

8.5

1.5

0.8

3.1

0.8

0.8

1.5

8.5

3.8

0.8.

0.8

0.8

0.8

0.8

0.8

3.8

0

87.7

48.2

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Intraoperative portal vein ligation

Portal vein ligation with alcohol

49

10

43.0

8.8

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Table 3. Second Stage Hepatectomy (n=130)

Patients who failed the second stage hepatectomy 28 (21.5%)

Reason of failure

Tumor progression

Hepatic

Extrahepatic

Both (hepatic + extrahepatic)

Insufficient hypertrophy

Other

Patients who completed two-stage hepatectomy

Major liver resection

Associated contralateral minor resection

Pedicle clamping

Intraoperative blood transfusions

Postoperative morbidity (no. of survivors)

Grade I-II17

Biliary leak

Transient liver failure

Pulmonary

Cardiovascular

Wound infection

Lymphatic fistula

Grade III-IV17

Liver failure

Ascites

Subphrenic collection

Bile duct injury

Bowel perforation

24 (18.5%)

12 (9.2%)

4 (3.1%)

8 (6.1%)

2 (1.5%)

2 (1.5%)

102 (78.5%)

99 (97.1%)

8 (7.8%)

45 (44.1%)

22 (21.6%)

34/98 (34.7%)

24 (24.5%)

9 (9.2%)

6 (6.1%)

3 (3.1%)

4 (4.1%)

1 (1.0%)

1 (1.0%)

10 (10.2%)

2 (2.0%)

3 (3.1%)

2 (2.0%)

1 (1.0%)

1 (1.0%)

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Pulmonary embolism

Relaparotomy

Mortality

Liver failure

R0-resection

1 (1.0%)

1/102 (1.0%)

4 (3.9%)

4 (3.9%)

86 (84.3%)

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Table 4. Comparison of Patients Who Completed and Failed the Two-Stage Hepatectomy Because of Tumor

Progression

Completed TSH

(102 patients)

Failed TSH

for tumor progression

(24 patients)*

p

Value

OR 95% CI p

Value

Age >65 y 24 (23.5%) 9 (37.5%) 0.109

Primary rectal tumor 27 (26.5%) 5 (20.8%) 0.388

Primary tumor N + 68 (66.7%) 16 (66.7%) 0.574

Liver metastases

Synchronous 79 (77.4%) 22 (91.7%) 0.094 NS

≥10 metastases 28 (27.4%) 9 (37.5%) 0.232

>1 lesion in FRL 63 (61.8%) 19 (79.2%) 0.082 NS

Extrahepatic disease 20 (19.6%) 6 (25.0%) 0.368

Pre-hepatectomy

chemotherapy

Before first stage 88 (86.3%) 21 (87.5%) 0.588

No. of cycles ≥10 38 (37.2%) 10 (41.7%) 0.482

No. of lines >1 11 (10.8%) 1 (4.2%) 0.289

Between first

and second stage

31 (30.4%)

7 (29.2%)

0.559

Progression during

chemotherapy

3 (2.9%)

4 (16.7%)

0.028

6.35

1.30-31.01

0.022

Primary tumor simultaneous

resection

44 (43.1%)

12 (50.0%)

0.350

*Four patients who failed the TSH for reasons other than tumor progression were excluded from this analysis

[Add dagger for bolded p values.]

OR, Odds Ratio; FRL, future remnant liver; NS, not significant.

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Table 5. Univariate Predictors of Overall and Disease-Free Survival in Patients Who

Completed Two-Stage Hepatectomy (n=102)

n. 5-year survival (%) p Value * 5-year disease-free (%) p Value *

Age, y

< 65

≥ 65

78

24

28.0

42.5

0.401

20.7

22.2

0.281

Primary tumor

Colon

Rectum

Node -

Node +

75

27

34

68

31.6

32.6

30.1

32.6

0.669

0.869

22.1

12.6

21.0

18.5

0.721

0.986

Type of metastases

Synchronous

Metachronous

No. of metastases

<10 lesions

≥10 lesions

79

23

74

28

31.3

38.4

33.4

25.0

0.432

0.940

16.6

33.8

18.6

31.7

0.327

0.726

<5 cm

≥5 cm

55

47

39.1

26.7

0.287 17.0

22.5

0.457

Extrahepatic disease

Yes

No

20

82

18.4

36.9

0.550

8.9

23.0

0.401

Chemotherapy before first

stage

Yes

No

No. of cycles ≥6

Yes

No

Unknown

Chemotherapy before second

stage

Yes

88

14

76

10

2

31

27.7

50.8

22.4

66.7

33.3

0.219

0.046

0.149

21.5

23.1

15.7

63.0

22.8

0.317

0.026

0.892

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No 71 34.0 19.2

Primary tumor simultaneous

resection

Yes

No

44

35

29.3

34.5

0.516

19.0

11.8

0.381

*Log-rank test.

[Add dagger for bolded p values.]

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LEGENDS FOR FIGURES

Figure 1. Flow chart for the 130 patients scheduled to undergo two-stage hepatectomy.

Figure 2. Overall survival following completed and failed two-stage hepatectomy (TSH). The 5-

and 10-year overall survival rates for patients who completed TSH were significantly higher than

those for patients who failed TSH (32.1% and 24.1% vs. 0, respectively; p<0.001).

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Precis

Two-stage hepatectomy may not be feasible in 30% of patients because of disease progression.

This study showed that response to preoperative chemotherapy may be useful to select patients

before planning two-stage hepatectomy, because tumor progression during chemotherapy was

associated with significantly higher risk of failure to complete two-stage hepatectomy.

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