Immunology
Survival benefit of repeat resection of
successive recurrences after the initialhepatic resection for colorectal liver
metastases
Masaru Oba, MD, PhD,a Kiyoshi Hasegawa, MD, PhD,a Junichi Shindoh, MD, PhD,a
Suguru Yamashita, MD, PhD,a Yoshihiro Sakamoto, MD, PhD,a Masatoshi Makuuchi, MD, PhD,b and
Norihiro Kokudo, MD, PhD,a Tokyo, Japan

Background. Relapse is common after the resection of colorectal liver metastases (CLM); however, theoptimal treatment for such recurrent disease remains uncertain. We investigated whether repeat
resections for successive recurrences of CLM provide survival benefit on the postrecurrence survival.
Methods. We reviewed patients who underwent upfront, curative resection for CLM at our center during
a 15-year period. Of these, 263 patients who had not received any other perioperative treatment for themetastases were eligible for our analysis. The recurrence-free survival (RFS0) after the initial hepatic
resection and after the first (n = 108), second (n = 43), and third (n = 15) repeat resections for recurrent
disease were assessed (RFS1–3). The overall survival after the initial hepatic resection and the postrecurrence survival (n = 198) also was assessed.
Results. The median RFS0 was 0.8 years, and RFS1, RFS2, and RFS3 were 1.3, 1.1, and 2.0 years,
respectively. The hazard ratio for RFS for the first, second, and third resections versus the initial hepatic
resection was 0.9 (95% confidence interval [95% CI] 0.7–1.1; P = .34), 1.00 (95% CI 0.7–1.4; P = .97),
and 0.7 (95% CI 0.4–1.3; P = .29). The 5-year and 10-year OS rates were 54.6% and 42.2%, and the 5year and 10-year postrecurrence survival was 34.3% and 28.6%, respectively.
Conclusion. Repeat resection in patients with recurrent disease after CLM resection is beneficial, offering
the potential for cure in a small proportion of patients with recurrent disease. (Surgery 2016;159:632-40.)
From the Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery,a Graduate School of Medicine,
The University of Tokyo; and Department of Hepato-Biliary-Pancreatic Surgery,b Japanese Red Cross Medical
Center, Tokyo, JapanHEPATIC RESECTION is the only treatment that offers
the possibility of cure or long-term survival benefit;
5-year survival rates of more than 40% have been reported in patients with resectable colorectal liver metastases (CLMs), as demonstrated by recent larger
series.1-6 Nonetheless, more than 70% of patientswith CLM who undergo curative resection develop
recurrent disease, and the majority of these recurrences occur during the early postoperative phase,
Accepted for publication September 2, 2015.
Reprint requests: Norihiro Kokudo, MD, PhD, Hepato-BiliaryPancreatic Surgery Division, Department of Surgery, Graduate
School of Medicine, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kokudo-2su@h.utokyo.ac.jp.
0039-6060/$ - see front matterÓ 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.surg.2015.09.003

632 SURGERY

ie, within the first 2 years after the initial hepatic
resection.3,5-7 In the era of modern chemotherapy,
the necessity of developing adjuvant therapies has
been emphasized to improve the outcomes of patients with resectable CLM; however, lack of a significant impact on the overall survival (OS)8-12 has
made it difficult to select definitive strategies.
The long-term outcomes of patients with CLM
seem to be composite, because the postrecurrence
survival (PRS) is influenced strongly by the treatment modality adopted for the further recurrences
involving operative or nonoperative therapy withchemotherapy, ablation therapy, hepatic arterial
infusion therapy, etc.
With regard to operative management afterrecurrence relapse, for selected patients, repeatedhepatic resections for successive hepatic recurrences after the initial liver resection for CLM

SurgeryVolume 159, Number 2

Oba et al 633

are accepted as a feasible strategy that can prolong
survival.13-16 In the patients with relapse after the
initial hepatic resection, the recurrences were
distributed relatively equally among the liver,lung, and liver and lung concurrently,3 and patients with pulmonary or pulmonary with hepatic
recurrence had poorer prognoses than those withisolated intrahepatic recurrence, as reported previously by our colleagues.7 It remains unclear
whether sequential operative management for successive recurrences provides survival benefit after
relapse. Furthermore, the actual benefit ofrepeated resections alone without chemotherapy
for successive recurrences in colorectal cancer patients is still to be confirmed.
Therefore, we hypothesized that repeat resections
for successive recurrences might be an optimal
therapeutic strategy that could have positive prognostic impact on the PRS after an initial CLM
resection. To minimize any selection bias, we
compared the survival results in consecutive patients
undergoing the first, second, and third repeat resections with those in patients undergoing optimal
nonoperative treatment for unresectable recurrences in the same treatment-line, based on data
accumulated through strict long-term follow-up
during a 15-year period at a single specialized centerof patients treated by resection for the initial CLM.
MATERIALS AND METHODSPatients and treatment. The data collectedduring a 15-year period (January 1996–December2010) of 336 patients who underwent upfront
curative hepatic resection for CLM at the
Hepato-Biliary-Pancreatic Surgery Division of theTokyo University Hospital, Japan were reviewed. Of
these, 33 patients who received postoperative
adjuvant chemotherapy (which was not administered routinely during this study period, but rather
selectively, at the doctors’ discretion or the patient’s request) and 40 patients who were enrolled
in an ongoing, phase 3 trial to evaluate the efficacy
of oral adjuvant chemotherapy with uracil-tegafur
plus leucovorin after resection of CLM (UMIN
Clinical Trials Registry: C000000013) were
excluded from the current study.17 The remaining
263 patients were eligible for the analysis (Fig 1).
Because sufficient evidence for the efficacy ofstandard adjuvant treatment during the study
period was lacking at the time in Japan, adjuvant
chemotherapy was not administered routinely between 1996 and 2010 until recruitment for theuracil-tegafur plus leucovorin trial was completed.
The following data of these 263 patients wereanalyzed: sex, age, performance status, primaryFig 1. Study profile. Yes, recurrence, resectable; No,
recurrence, unresectable.

tumor site, histologic differentiation (grade), pathologic T and N stages according to the current
TNM (ie, tumor, nodes, metastases) classification,
characteristics of the initial liver metastases, type of
hepatic resection, operative margin, date of development of recurrence, dates of the repeat resections, and the date of death or of the last visit.
Table I shows the profiles of the current study
patients at the baseline. The resected liver metastases were diagnosed synchronously with the primarytumor in 142 patients (54%). Major hepatic resection was defined as the resection of 3 or more segments, as described by Couinaud. Of the 263
patients enrolled, 69 (26%) underwent major hepatic resection, and 194 (73%) underwent minor
hepatic resection. All the patients were assessed
preoperatively by contrast-enhanced computed tomography (CT), and the selection criteria for reoperation were as follows: (1) primary lesion
resectable or curatively resected; (2) all the liver
metastases were amenable to complete resection
with a clear margin, allowing an acceptableremnant liver volume of at least 40% without634 Oba et al

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February 2016

Table I. Patient and tumor characteristics at baseline
VariableSex, n (%)
Age
ECOG PS, n (%)
Primary tumor, n (%)
Location
Grade of differentiation
pT stagepN stage
Initial liver metastases, n (%)
Timing of diagnosis
Tumor distribution
Tumor number
Size of the largest tumor, cm
Preoperative serum CEA, mg/L
Type of hepatic resection, n (%)
Resectability, n (%)

Characteristic

Study patients (n = 263)

Male/female
Median (range)
0/1

172 (65)/91 (35)62 (29–81)
253 (96)/10 (4)Colon/rectum
Grade 1/Grade 2/Grade 3–4
T1–2/T3/T4
N0/N1/N2

147 (56)/116 (44)135 (51)/124 (47)/4 (2)23 (9)/189 (72)/51 (19)98 (37)/90 (34)/75 (29)Synchronous/metachronous
Unilobar/bilobar
1–4/5–8/$9<2/2–5/$5<50/50–200/$200
Major/minor
Preoperative PVE
R0/R1

142 (54)/121 (46)156 (59)/107 (41)194 (74)/40 (15)/29 (11)50 (19)/129 (49)/84 (32)160 (61)/47 (18)/56 (21)69 (26)/194 (74)16 (6)
231 (88)/32 (12)

CEA, Carcinoembryonic antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; Grade 1, well differentiated adenocarcinoma;
Grade 2, moderately differentiated adenocarcinoma; Grade 3–4, poorly differentiated adenocarcinoma; pT and pN, pathologic stage of the primary tumor(T) and regional lymph nodes (N) according to the current TNM classification (UICC 2010); PVE, portal vein embolization.

potentially ischemic or congested areas; and (3)no unresectable extrahepatic sites of disease.
During the period of this investigation, ourmedical center maintained the same policy toward
hepatic resection for CLM, ie, upfront resection
was performed, regardless of the number, distribution, or extent of the liver metastases. Intraoperative ultrasonography (US) was performed
routinely to confirm the preoperative findings on
imaging and diagnosis. Moreover, contrastenhanced intraoperative US was introduced in
200718 and performed consecutively to obtain
more accurate intraoperative diagnosis. The patients were followed by serial assays of carcinoembryonic antigen (CEA) and carbohydrate antigen
19-9, abdominal US, and by chest and abdominal
CT every 3 months during the first 2 years. Thereafter, patients were followed by measurements of
CEA and carbohydrate antigen 19-9 and abdominal US every 3 months, and by CT every 6 months.
We performed repeat hepatic resection immediately on detecting resectable recurrent disease
without delaying the resection to select appropriate patients for repeat resection. In cases withrecurrence in the remnant liver, repeat hepatic
resection was performed according to the aforementioned criteria. In cases with recurrent pulmonary metastases, the following criteria were applied
for resection of the recurrent pulmonary metastases, taking into account the volume of the lungparenchyma remaining after the resection: (1)number of metastatic tumors #3 regardless ofwhether unilateral or bilateral; and (2) no involvement of thoracic lymph node, as assessed bypreoperative imaging.
Resectability was determined by an experienced
thoracic surgeon who determined whether a metastasectomy could be performed safely. In cases withsimultaneous intrahepatic plus pulmonary recurrence, the indication for operation was decided
according to the aforementioned criteria for therespective metastases, and simultaneous or staged
resection was performed. The presence of
extrahepatic and nonpulmonary metastases, inprinciple, was treated as a contraindication for
re-resection, except in cases with a solitary metastasis or metastasis limited to an organ such as theprimary (colorectal) local site, local lymph node,celiac lymph node, para-aortic lymph node, adrenal gland, or peritoneum, with or without intrahepatic and/or pulmonary recurrence.
During the current study period, ablation therapy was not performed as a substitute for resection
in patients with resectable recurrent disease,because its efficacy for CLM is inferior to resection,
both in terms of the rates of local recurrence andthe 5-year OS.3,19 After repeat resection, all patients were followed in the same way as after the
initial hepatic resection. Our historic strategy in
our center for the treatment of recurrent disease
from colorectal cancer has been to perform
repeated resections alone for the management of
intrahepatic and/or extrahepatic disease if resectable and to withhold chemotherapy until theSurgeryVolume 159, Number 2

recurrent disease became unresectable during thestudy period.
Data and outcomes. OS was defined as the timefrom the date of initial hepatic resection to allcause death or the date of the last follow-up used
for censoring, and PRS was defined as the timefrom the date of the first relapse after the initialhepatic resection to all-cause death or the date of
the last follow-up used for censoring. RFS0 was
defined as the time from the date of initial hepatic
resection to recurrence from colorectal cancer or
all-cause death, whichever occurred first. RFS1,
RFS2, and RFS3 were defined as the time from thedate of the first, second, and third repeat surgery,respectively, to relapse from colorectal cancer or
all-cause death, whichever occurred first. The median follow-up period was 7.4 years. Detailed information on the type of relapse was always available.
Standard criteria for the resectability of recurrent disease are difficult to specify, because they
depend on technical aspects related to the skill
level of the operating surgeon. The current study
was undertaken at a single, specialized institute,
where the staff adopted the same policy towards
the potential window for cure, considering thepossibility of repeat resections whenever possible
as part of a multidisciplinary approach, and if
repeat resection was not feasible or impossible,
optimal nonoperative therapy for unresectable
relapse was selected, eg, systemic chemotherapy
or other palliative therapy.
Statistical methods. Continuous variables werecompared with the Mann–Whitney U test, and categorical variables were compared using the v2 test
or Fisher exact test where appropriate. Survival
curves were generated by the Kaplan–Meiermethod, and the differences between curves were
evaluated by the log-rank test. With regard to comparison of the RFS, patients who underwent initialhepatic resection, and first, second, and third
repeat resections were defined as independentgroups eligible for the analysis. To identify the
prognostic factors for PRS, a multivariate regression analysis was performed using the Cox proportional hazards model with backward eliminationfor variables identified as significant with P < .1
in the univariate analysis. All statistical analyses
were performed using JMP 11 (SAS Institute Inc,
Cary, NC).
RESULTSOS after the initial hepatic resection and the
PRS. The median OS was 5 years (95% confidence
interval [CI], 4.1–6.3 years) in the patients who had
undergone the initial resection for CLM (n = 263).

Oba et al 635

The 5-year and 10-year OS rates were 54% and 42%,
respectively. Relapses occurred in 198 patients(75%) after the initial hepatic resection, and repeat
resection(s) was performed in 108 patients (54%)(Table II). In regard to the results classified according to subgroups, the 5-year OS in the recurrencefree (n = 63) subgroup and subgroups with resectable recurrence (n = 108) and unresectable recurrence (n = 90) were 96%, 63%, and 13% and the
10-year OS rates were 84%, 51% and 0%, respectively (Fig 2). The median PRS was 2.8 years (95%CI, 2.5–3.3 years), and the 5-year and 10-year PRS
rates were 34% and 28%, respectively (Fig 3). The
sequential outcomes of the study patients are shownin Fig 1. Of the 108 patients undergoing the first
repeat resection, 74 (68%) developed a second
relapse; of these 74 patients, 43 (58%) underwent
a second repeat resection. Of the 43 patients who
underwent a second repeat resection, 32 (74%)
developed a third relapse, of which 15 (47%) underwent a third repeat resection. Of the 15 patients
who underwent a third repeat resection, 11 (73%)
developed a fourth recurrence, of which 4 (36%)
underwent a fourth repeat resection (Table II).
Efficacy and safety of the first, second, andthird repeat resections. The median RFS0 was
0.82 years (95% CI, 0.63–1.12), and the median
RFS1, RFS2 and RFS3 were 1.3 years (95% CI,
0.76–1.71), 1 years (95% CI; 0.61–1.69), and 2 years(95% CI, 0.27–NR), respectively. The 3-year RFS0
rate was 27%, and the 3-year RFS1, RFS2, andRFS3 rates were 35%, 29%, and 38%, respectively.
The hazard ratio (HR) for the recurrence-free survival for the first repeat surgery was 0.88 (95% CI,
0.68–1.14; P = .34), that for the second repeat surgery vs the initial hepatic resection was 0.99 (95%CI, 0.67–1.42; P = .97), and that for the third
repeat surgery vs the initial hepatic resection was
0.72 (95% CI, 0.36–1.29; P = .29) (Fig 4).
In regard to the postoperative complicationsclassified according to the Clavien-Dindo classification,20 severe complications (Grade III)occurred in 15 of 108 patients (14%) after the first
repeat resection, 8 of 43 patients (19%) after thesecond repeat surgery, and 3 of 15 patients(20%) after the third repeat resection. There
were no cases of life-threatening complications(Grade IV) or death (Grade V) at any repeat surgery (Table II).
Multivariate analysis. A multivariate analysis
revealed that the nonresectability was the only
independent prognostic factor
for PRS(P < .0001; HR, 4.29; 95% CI, 2.47–7.84), andthat a recurrence-free interval of <6 months, preoperative CEA values of >50 mg/L, presence of636 Oba et al

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February 2016

Table II. Profiles of the repeat hepatic resections and safety
Variable
Resection organ site, n (%)
Liver only
Lung only
Liver plus lung
Liver plus others
Others only
Resected tumor number (liver), n1
2–4
5 or more
Resected tumor number (lung), n1
2–3
4 or moreType of hepatic resection, n (%)
Partial resection
Segmentectomy/Sectionectomy
Hemihepatectomy
Type of pulmonary resection, n (%)
Wedge resection
Segmentectomy
Lobectomy
Resectability
R0/R1/R2
Complications (Clavien-Dindo), nGrade I/II
Grade IIIa/IIIb
Grade IVa/IVb
Grade V
Overall recurrence rates, %Median recurrence-free survival, y (95% CI)
Median overall survival, y (95% CI)

First repeat
resection (n = 108)

Second repeat
resection (n = 43)

Third repeat
resection (n = 15)

P value.25

61 (57)29 (27)13 (12)
3 (2)
2 (2)

21 (49)14 (33)5 (12)2 (4)1 (2)8 (54)
5 (33)
2 (13)
0 (0)
0 (0)

28
30
19

18
8
2

5
4
1

23
15
4

11
7
1

4
3
0

65 (85)8 (10)4 (5)

24 (86)
2 (7)
2 (7)

8 (80)
1 (10)
1 (10).99

34 (80)4 (10)
4 (10)

16 (84)1 (5)2 (11)

7 (100)
0 (0)
0 (0)

.38

<.0001.002

97/8/3

39/3/1

13/2/0

.91

26/18
12/3
0/0
0
68.5
1.28 (0.76–1.71)
11.3 (4.92–14.21)

13/9
6/2
0/0
0
74.4
1.06 (0.61–1.69)
7.86 (3.51–NR)

4/4
2/1
0/0
0
70.8
1.96 (0.27–NR)
NR (3.18–NR)

.09
.33
—
—
.91
—
—

‘‘Others’’ includes metastasis at the site of the primary tumor, or in the local lymph nodes, celiac lymph nodes, para-aortic lymph nodes, adrenal glands, orperitoneum.
CI, Confidence interval; NR, not reached.

multiple metastases, largest tumor size $5 cm,
and an intrahepatic plus extrahepatic relapse
pattern had no statistically significant influence.
DISCUSSION
The current study demonstrated the survival
benefit of repeated resections for successive
recurrences after CLM. The PRS was prolonged
by this treatment modality, as shown by strict
long-term follow-up, potentially offering the possibility of cure in some proportion of patients,
notwithstanding the development of recurrent
disease.
In this study, there were no significant differences in the RFS after the initial hepatic resection,
or after the first, second, and third repeat
resections. This observation suggests that thesurvival benefit of repeat resections of recurrent
CLM was maintained consistently, regardless ofthe number of previous resections. Although theeffectiveness of repeated resection for CLM has
been suggested with the use of the results ofsurgery for the first recurrence, the current data
including cases of resections for the second andthird recurrence is new and clinically important.
Thus, we suggest that sequential repeat resections
may offer the possibility of cure in some patients,
notwithstanding the development of recurrent
disease. At each of the repeat resections withcurative intent, approximately one-third of thepatients remained recurrence-free, and two-thirds
developed recurrence events; of the latter, onehalf were found to be suitable candidates forfurther resection.

SurgeryVolume 159, Number 2

Oba et al 637

Fig 2. OS in the recurrence-free (n = 65) subgroup, subgroup with resectable recurrence (n = 108), and subgroup withunresectable recurrence (n = 90) of the 263 patients included in the current analysis after the initial hepatic resection
for CLM. Rec., Recurrence.

Fig 3. PRS in all 198 patients with relapse of the 263 patients included in the current analysis after the initial hepatic
resection for CLM.

Compared with previous studies in which
repeated resections were carried out for selectedrecurrences in the liver or lung (Supplementary
Table I, online version only),13-16,21 our results provide the following additional clinically beneficial

information: (1) the outcomes of sequential resections for successive recurrences, namely, natural
history in the patients who underwent upfront
curative hepatic resection; (2) the actual benefitof the repeat resection itself without perioperative638 Oba et al

Surgery
February 2016

Fig 4. Comparison of the RFS after the initial hepatic resection (n = 263), and after the first (n = 108), second (n = 43),
and third (n = 15) repeat resections.

intervention (ie, systemic chemotherapy, ablation
therapy, or hepatic arterial infusion therapy) as
the second, third, and fourth lines of treatment;and (3) data from a sufficient number of patientstreated according to the same therapeutic policy
for CLM and followed for a sufficient duration oftime at a single specialized center. The recent
report by Saiura et al21 also lends support to thepotentially curative role of repeat resection, especially for a first recurrence in the liver or lungalone after the initial liver resection for CLM.
Our experience demonstrated that the frequency of severe morbidity (grade III according
to the Clavien-Dindo classification) after first, second, and third repeat resection was 14%, 19%, and20%, respectively, which we consider to be acceptable. Therefore, repeat resection should be a partof multidisciplinary management in specialized
centers, where the incidence of operative complications would be expected to be reasonable. Ourfindings suggest that the frequency (about 80%) ofparenchyma-saving resections (ie, partial hepatic
resection or pulmonary wedge resection) appears
to increase the chance of a safe subsequent repeat
resection in the event of another recurrence
developing at the same site.
It remains uncertain whether re-resection, systemic chemotherapy, or both combined are theoptimal treatment choice for recurrence after
hepatic resection of CLM. Modern chemotherapy

for unresectable metastatic colorectal diseaseevidently offers improved survival (median survival
20–30 months), even in the palliative setting,according to recent clinical trials.22-25 The PRS in
selected patients in our study, however, was still
prolonged by our strategy of repeated resections
for successive recurrences, with the possibility ofcure, which cannot be achieved by modern chemotherapy alone. Thus, we suggest that the optimaltreatment choice for recurrence is resection if
the lesion is resectable, just as for the initial
CLM. As we reported previously, the presence orabsence of recurrence after CLM resection is nota reliable endpoint for determining the clinicaloutcome, and re-resection for successive recurrences appears to result in an improvement of
the long-term survival.26 This finding suggests theimportance of reporting the characteristics ofrecurrent disease in detail and employing further
treatment modalities including those with curative
intent for CLM patients in clinical trials.
We are aware of the methodologic limitations of
our study, which was based on the data from aselected cohort from a single institution over along period, in which various kinds of chemotherapeutic regimens were available as palliative therapies. During the current study period, we had
maintained a consistent therapeutic strategy, inwhich repeat resection was considered as thetreatment of first choice for resectable recurrence,SurgeryVolume 159, Number 2

without chemotherapy administered until a recurrence proved to be unresectable. Therefore, we
believe that any potential bias on our results by thelong study period of 15 years and the changes in
the chemotherapy regimens would be minimal.
We should pay careful attention before applying
our results in clinical practice, especially in westerncountries, because perioperative chemotherapies
are generally used in these countries, quite
different from the situation in Japan. In contrast,
this study has clinical importance because our data
showed the true survival impact of repeated resections, which cannot be evaluated in westerncountries. The next step should be to investigate
how to improve prognosis of repeat resection withfull use of modern and advanced chemotherapies.
We determined the OS after CLM resection
composed in three subgroups of patients, ie, therecurrence-free subgroup, the subgroup withresectable recurrence, and the subgroup withunresectable recurrence. Currently, the ideal adjuvant strategy using systemic chemotherapy could
potentially suppress the risk of recurrence or
increase the possibility of re-resection, which could
result in improved OS.
In summary, our study showed that the efficacyof repeated resections for successive recurrences(first, second, and third recurrence) after the
initial hepatic resection was similar to that of theinitial resection for CLM. Therefore, attempts at
repeat resection should be considered as the
optimal treatment strategy for each successive
recurrence in patients with recurrent disease after
CLM resection.
SUPPLEMENTARY DATA
Supplementary data related to this article can be foundat http://dx.doi.org/10.1016/j.surg.2015.09.003
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