Ann Surg Oncol
DOI 10.1245/s10434-014-3504-1

ORIGINAL ARTICLE – COLORECTAL CANCER

Discrepancy Between Recurrence-Free Survival and Overall
Survival in Patients with Resectable Colorectal Liver Metastases:
A Potential Surrogate Endpoint for Time to Surgical Failure
Masaru Oba, MD, PhD1, Kiyoshi Hasegawa, MD, PhD1, Yutaka Matsuyama, PhD2, Junichi Shindoh, MD, PhD1,
Yoshihiro Mise, MD, PhD1, Taku Aoki, MD, PhD1, Yoshihiro Sakamoto, MD, PhD1, Yasuhiko Sugawara, MD,
PhD1, Masatoshi Makuuchi, MD, PhD3, and Norihiro Kokudo, MD, PhD1
1

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University ofTokyo, Tokyo, Japan; 2Department of Biostatistics, School of Public Health, The University of Tokyo, Tokyo, Japan;
3
Department of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan

ABSTRACT
Background. Recurrence-free survival (RFS) may not bea surrogate for overall survival (OS) in patients withresectable colorectal liver metastases (CLM). We investigated whether a new composite tool—time to surgical
failure (TSF)—is a suitable endpoint.
Methods. The medical records of consecutive patients
who underwent curative resection for CLM at our center
over a 17-year period were reviewed. Patients with liverlimited tumors (n = 371) who had not received previous
treatment for metastasis were eligible for analysis. TSF was
defined as the time until unresectable relapse or death. The
correlations between TSF and OS, and between RFS andOS, were assessed for all the eligible patients.
Results. The median OS, TSF, and RFS were 5.7, 2.7, and
0.7 years, respectively, and the 5-year OS, TSF, and RFS
rates were 52.6, 39.8, and 23.7 %, respectively, for all
patients. The rates of first, second, and third relapse were
75.5, 77.6, and 70.8 %, respectively, and repeat resections
were performed in 54.3 % (first relapses), 40.7 % (second
relapses), and 47.1 % (third relapses) of patients. The
concordance proportions of TSF and RFS for OS eventswere 0.83 and 0.65, respectively. The correlation between
TSF and OS was stronger than that between RFS and OS in
terms of the predicted probabilities.

Ó Society of Surgical Oncology 2014
First Received: 15 May 2013
N. Kokudo, MD, PhD
e-mail: kokudo-2su@h.u-tokyo.ac.jp

Conclusions. The correlation between TSF and OS wasstronger than that between RFS and OS after curative
hepatic resection. TSF could be a suitable endpoint for
CLM overall management.

Although colorectal liver metastases (CLM) are regarded
as a distant metastatic status, surgical resection of R0 has
been accepted as a potentially curative treatment since it canenable long-term survival, with a 5-year overall survival(OS) rate ranging between 33 and 56 % in relatively large
and recent observational series.1–3 However, an incidence ofrecurrence as high as 75 % even after curative surgicalresection, with more than 50 % of recurrences occurring in
the remnant liver only, remains an unsettled and severe
problem.3–5 To reduce this high relapse rate, hepatic
resection combined with some form of adjuvant treatment
has been proposed by several investigators.6 Unfortunately,
sufficient evidence for a standard adjuvant treatment has notbeen obtained.7–9 In patients with stage III colorectal cancer,
a short-term endpoint assessed after a 3-year median followup period, known as the disease-free survival (DFS) period,has been shown to be a valid surrogate marker for the
standard 5-year OS endpoint.10 This new paradigm has
contributed to the development of adjuvant strategies,
allowing faster completion of clinical trials, and has been
accepted as a valid endpoint on which to base new standardsof care in clinical practice.11,12 On the other hand, in theabsence of any evaluation of the use of earlier endpoints as
optimal surrogates for OS in stage IV patients with resectable CLM, either the DFS period or the progression-freesurvival (PFS) period has usually been accepted as a primary
endpoint in adjuvant setting trials. However, the negativeM. Oba et al.

results for long-term outcome in the pivotal EORTC 40983
phase III trial indicate that an improvement in PFS does notnecessarily reflect the survival benefit.13 In recent larger
series, a survival discrepancy has seemed to exist between
DFS and OS after resection for CLM.1,3 Although OS can be
regarded as an ultimate and robust endpoint in adjuvant
setting clinical trials, it requires a long follow-up period anda large sample size, and can be affected by the use of second and further treatments for relapse. Thus, a clinicallyuseful and reliable endpoint for validating the role of adjuvant treatments in patients with resectable CLM does notpresently exist.
Why has a survival discrepancy existed between first
relapse-related events (DFS or PFS) and OS in previous
studies? One possible reason is that survival beyond relapse
is prolonged by advanced chemotherapy for metastatic
colorectal cancer, if a surgical approach cannot be selected.
On the other hand, re-resections for recurrences in theremnant liver and/or lung have been accepted as providing
a survival benefit.4,14–16 As shown by the high repeat
resection rate (more than 40 %) in patients with relapse in
the EORTC 40983 trial, the first relapse-related event does
not reflect long-term survival,13 since a second or third reresection can have curative potential in some patients withrelapse. Therefore, we hypothesized that the possibility of
repeat resection itself might have a prognostic impact on
the overall management for resectable CLM. The time until
development of an unresectable relapse, for which a repeat
resection is impossible and which would be followed by apalliative therapeutic course, was investigated as a new
endpoint. In the current study, we retrospectively investigated this hypothesis using data accumulated over a 17year period at a single specialized center.

METHODS
Patients and Treatment
Data collected prospectively over a 17-year period(January 1994–December 2010) for 422 patients who
underwent upfront hepatic resections for CLM at our center
were reviewed. Fifty-one patients who were enrolled in an
ongoing phase III trial to evaluate the efficacy of oral
adjuvant chemotherapy using tegafur/uracil and leucovorin(UFT/LV) after surgery for CLM (UMIN-CTR:
C000000013) were excluded from the present study.17 The
following data were available for curatively resectedpatients: sex, age, performance status, primary tumor site,
histologic type, pathologic T and N stage according to thecurrent TNM classification, characteristics of liver metastases, type of hepatic resection, surgical margin, date ofresectable recurrence, date of re-resection, date ofunresectable recurrence, and date of death or last visit.
Table 1 shows the profiles for the study patients at baseline. All the resected liver metastases were diagnosed
synchronously with the primary tumor in 188 patients(50.7 %). A major hepatic resection was defined as theresection of two or more segments, as described by Couinaud. Of the 371 liver resections that were performed, 83
patients (22.4 %) underwent a major hepatic resection withor without the combination of a partial resection, and 262
patients (70.6 %) underwent a partial resection only, withno surgery-related mortalities. All patients were assessed
preoperatively using enhanced computed tomography (CT)with the following selection criteria applied for surgery:(1) the primary lesion must be resectable or must have been
curatively resected; (2) all the liver metastases were amenable to resection with a negative surgical margin, leaving
a remnant liver volume of at least 40 % without potentially
ischemic or congested areas; and (3) no unresectable
extrahepatic sites of disease. During the period of ourinvestigation, our medical center’s staff had the same
policy toward hepatic resection for CLM: namely, a surgery-upfront approach was used regardless of themetastatic number, anatomic location, or extent of the liver
metastases. Furthermore, all patients were assessed preoperatively using enhanced CT and magnetic resonanceimaging (MRI) and the resectability criteria describedabove. Intraoperative ultrasonography was routinely performed to confirm the preoperative imaging and diagnosis.
Patient follow-up included the serial measurement of tumor
markers (carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA19-9]) and a CT examination of thechest and abdomen performed every 3–6 months. Sufficient evidence regarding the efficacy of standard adjuvant
treatment is lacking during the study period; therefore, thedefinitive efficacy of postoperative fluorouracil (FU)-based
chemotherapy for 6 months remains unclear.7,8 Hence,
postoperative adjuvant chemotherapy was not routinely
administered during the study period. The therapeutic
regimens were as follows: bolus-based FU/LV (n = 16);
UFT/LV (n = 30); capecitabine (n = 12); and oxaliplatin
plus infusional and bolus FU/LV (FOLFOX) (n = 22).
Preoperative chemotherapy was not performed for either
the initial liver metastases or the recurrent diseases during
this study period. The criterion for performing repeat
resections for recurrent diseases was the likelihood ofachieving a complete resection of all evident tumors. In
cases with a recurrence in the remnant liver, a repeat
hepatic resection was considered if an R0 resection andsufficient liver volume were feasible. In cases with recurrent pulmonary metastases, resectability was determined by
an experienced thoracic surgeon based on whether a metastasectomy for three or fewer tumors, in principle, could
be safely performed, regardless of their distribution. The

Optimal Endpoint for CLM Overall Management
TABLE 1 Patient and tumor characteristics at baseline

TABLE 1 continued

VariableStudy patients (n = 371)

Variable

Male

67.4

Postoperative adjuvant CT (%)

Female

32.6

FU/LV

4.3

62.5 (29–83)

UFT/LV

7.8

Sex (%)

Age [years; median (range)]

R1

ECOG PS (%)
0

97.0

1

3.0

Primary tumor (%)
Location
Colon
RectumHistological differentiation

57.1
42.9

Well

51.2

Moderate

46.9

Poor

1.9

pT stage
T1

2.7

T2

5.1

T3

72.8

T4

19.4

pN stage
N0

37.2

N1

34.2

N2

28.6

Initial liver metastases (%)
Timing of diagnosis
Synchronous
Metachronous

50.7
49.3

Study patients (n = 371)
10.8

Cape

3.2

FOLFOX

5.9

ECOG PS Eastern Cooperative Oncology Group performance status,well well-differentiated adenocarcinoma, moderate moderately differentiated adenocarcinoma, poor poorly differentiated adenocarcinoma,pT and pN pathologic primary tumor (T) and regional lymph nodes(N) stage, CEA carcinoembryonic antigen, CT chemotherapy, FU/LV
fluorouracil plus leucovorin, UFT/LV tegafur/uracil and leucovorin,
Cape capecitabine, FOLFOX oxaliplatin plus infusional and bolus
FU/LV

surgical policy of our institution is to always attempt toretain as much of the liver or pulmonary reserve as possible, since future repeat resections might be necessary.
However, relapses to distant lymph nodes other than the
primary (colorectal) local site or solitary and limited
lesions were regarded as contraindications for a repeat
resection. During the current study period, we regarded
ablation therapy as a non-curative procedure and did not
use this technique as a substitute for re-resection in patientswith resectable recurrent disease since its efficacy for CLM
is inferior to resection in terms of the rates of local
recurrence and the 5-year OS.4,18
Definitions of Survival

Tumor distribution
Unilobar

61.2

Bilobar

38.8

Tumor number
Single40.7

Multiple

59.3

1–4

73.6

5–8

14.6

C9

11.8

Size of largest tumor (cm)
\2

19.1

2–5

49.0

C5

31.9

Preoperative CEA (lg/L)
[50

47.7

Type of hepatic resection (%)
Major

22.4

Minor

77.6

Surgical margin (%)
R0

89.2

OS was defined as the time interval from the initialsurgery until death by any cause, while recurrence-freesurvival (RFS) was defined as the time interval from theinitial surgery until the first recurrence of colorectal cancer
or death as a result of any cause. In this study, the significance of repeat resection was evaluated using a composite
endpoint, the time to surgical failure (TSF). This endpoint
was defined as the time interval from the initial surgery
until the first unresectable recurrence or death as a result of
any cause (Fig. 1). While including the possibility of arepeat resection, the overall outcome in CLM patients was
represented as the sum of each resectable RFS for
sequential repeat resections plus palliative survival after
the unresectable relapse event. Standard criteria for repeat
resectability are difficult to specify as they depend on
technical aspects that are related to the experience of thesurgeon and the oncological question of whether thecomplete resection of the recurrences is likely to result in a
potential cure. The current study was undertaken at a single
institute where the selected staff had the same policy

M. Oba et al.

S

r RS

RFS

r RS

2nd RFS

Event-free probability
1.0

uR

3rd RFS
Chemotherapy &palliative care

TSF

OS
TSF
RFS

0.8

0.6

OS

FIG. 1 Associations between each time-to-event (RFS, TSF, and OS) in
the overall management of patients with resectable CLM. TSF was
defined as the sum of the resectable RFS until the time of an unresectable
relapse (surgical failure event). RFS recurrence-free survival, TSF time tosurgical failure, OS overall survival, CLM colorectal liver metastasis, rR
resectable relapse, uR unresectable relapse

toward the potential window for a cure, considering thepossibility of repeat resections whenever possible fromtechnical or oncological aspects; if a repeat resection was
not feasible, the selection of optimal chemotherapy or otherpalliative therapy for unresectable relapse was considered.

0.4

0.2

0

4

8
Time (year)

1216

Number at risk
371
371
371

142
115
53

52
42
21

19
14
9

3
2
0

RFS

OS

Event
CensoredConcordance proportion

Event
154
131

Censored
0
86

0.65

TSF
Event
154
63

Censored
0
154

0.83

Statistical Analysis
The follow-up and survival periods were estimatedusing the Kaplan–Meier method, and were described using
the median and 95 % confidence interval (CI). Significant
differences were determined using the log-rank test, andp \ 0.05 was considered significant. Surviving patientswere censored at the time of the last follow-up. The correlations between RFS events and OS events, and between
TSF events and OS events, were each evaluated using theconcordance proportion. The Spearman rank correlation
coefficient was used to estimate the correlations between
the probabilities of RFS and OS, and between the probabilities of TSF and OS, as predicted using the Cox
proportional hazards model in all the resected patients. To
identify prognostic factors for TSF, a multivariate regression analysis was performed using the proportional hazard
model with backward elimination for variables with
p \ 0.1 in the univariate analysis. All the statistical analyses were conducted using SAS, version 9.2 (SAS Institute,Cary, NC, USA). Statistical significance was set at
p \ 0.05.
RESULTS
Survival, Relapse, and Repeat Resections
The median OS, TSF, and RFS were 5.72 years (95 % CI
4.33–8.06 years), 2.68 years (95 % CI 1.98–3.66 years),
and 0.66 years (95 % CI 0.54–0.78 years), respectively, for

FIG. 2 Kaplan-Meier plots of OS, TSF, and RFS in all study patients(n = 371). The concordance proportions between RFS and OS, andbetween TSF and OS, are shown. OS overall survival, TSF time tosurgical failure, RFS recurrence-free survival

all resected patients (n = 371; Fig. 2). The 5-year OS rate, 5year TSF rate, and 5-year RFS rate was 54.3, 39.8, and19.8 %, respectively. The 10-year OS rate, 10-year TSF rate,and 10-year RFS rate was 41.1, 32.4, and 17.1 %, respectively. As shown in Table 2, relapses occurred in 280
patients (75.5 %) after the initial hepatic resection, andrepeat resections were performed in 152 patients (54.3 %).
Of the 152 first repeat resections that were performed, second
relapses occurred in 118 patients (77.6 %), and additional
second repeat resections were performed in 48 patients(40.7 %). Of the 48 second repeat resections that were performed, third relapses occurred in 34 patients (70.8 %), andadditional third repeat resections were performed in 16
patients (47.1 %). Of the 112 patients with a first recurrence
to the liver only, 89 (79.5 %) underwent a repeat hepatic
resection. The remaining 23 patients (20.5 %) did notundergo surgical treatment but did receive palliative chemotherapy. Among the 83 patients with a first recurrence tothe lung only, 40 (48.2 %) underwent pulmonary resection,
whereas the remaining 43 (51.8 %) received palliative chemotherapy. For first recurrence to the liver plus lung, 18 of 64
patients (28.1 %) underwent simultaneous or staged resections. As for the second and third recurrences, surgicalresection was performed, if possible (Table 2).

Optimal Endpoint for CLM Overall Management
TABLE 2 Entire history of relapse and repeat resection after initialhepatic resection
Variable

TABLE 2 continued
VariableStudy patients(n = 371)

Actual 5-year survivors (1994–2008)

n = 124

Study patients(n = 371)

First relapses (% of initial hepatic resection) 280 (75.5)

Relapse episode (%)

75 (60.5)

First relapse sites (% of first relapses)

Re-resections episode (%)

66 (53.2)

Liver only
Lung only

112 (40.0)
83 (29.6)

Once

32

Liver plus lung64 (22.9)

Twice

21

Others21 (7.5)

Thrice or moreFirst repeat resections (% of first relapses)

152 (54.3)

First repeat resections to site (% resection rates)
Liver only

89 (79.5)

Lung only

40 (48.2)

Liver plus lung18 (28.1)

Others5 (23.8)

No. of times for re-resections

13

Cancer-free status at 5 years (%)

87 (70.2)

Re-resections history (%)

49 (56.3)‘Others’ includes metastatic site of primary local site, pedicularlymph nodes, celiac lymph nodes, para-aortic lymph nodes, adrenal
gland, or peritoneum ±liver and/or lungType of first repeat resections [% of sites]
Partial liver resection

80.7

Limited pulmonary resection

80.0

Second relapses (% of first repeat resections) 118 (77.6)

Correlation Between Recurrence-Free Survival andOverall Survival (OS), and Between Time to Surgical
Failure and OS

Second relapse sites (% of second relapses)
Liver only
Lung only

39 (33.1)
33 (28.0)

Liver plus lung28 (23.7)

Others18 (15.2)

Second repeat resections (% of second
relapses)48 (40.7)

Second repeat resections to site (% resection rates)
Liver only

22 (56.4)

Lung only

15 (45.5)

Liver plus lung

8 (28.6)

Others3 (16.7)

Type of second repeat resections % of sites
Partial liver resection
Limited pulmonary resection

81.5
91.3

Third relapses (% of second repeat
resections)

34 (70.8)

Third relapse sites (% of third relapses)
Liver only

12 (35.3)

Lung only

8 (23.5)

Liver plus lung

7 (20.6)

Others7 (20.6)

Third repeat resections (% of third relapses)

16 (47.1)

Third repeat resections to site (% resection rates)
Liver only

9 (75.0)

Lung only

5 (62.5)

Liver plus lung
Others2 (28.6)
0 (0.0)Type of third repeat resections [% of sites]
Partial liver resection

81.8

Limited pulmonary resection

100.0

The concordance proportions for RFS and OS, and for
TSF and OS, were 0.65 and 0.83 for all patients, respectively (Fig. 2). The correlation between TSF and OS wasstronger than that between RFS and OS. The Spearman
rank correlation coefficients separately assessing the associations between the RFS, TSF, and OS events are shownin Fig. 3.
Multivariate Analysis
A multivariate analysis revealed that a recurrence-freeinterval \12 months was the only independent risk factor
for TSF (p = 0.04; hazard ratio 1.98; 95 % CI 1.06–3.81),
whereas a preoperative CEA value [50 lg/L, a metastatic
number C3 tumors, a largest tumor size C5 cm, an intraplus extra-hepatic relapse pattern, and no adjuvant CT were
not statistically significant.
DISCUSSION
Our study demonstrated a survival discrepancy between
RFS and OS in patients with resectable CLM. TSF, a newly
defined time-to-event, seemed to be more strongly associated with OS and to be capable of reflecting the long-term
outcome.
In this study, we proposed a new composite endpoint,
TSF, as a surrogate for OS after the resection of CLM,
taking the unique biological characteristics of colorectal
cancer (in which the development of first relapse after an
initial hepatic resection does not reflect surgical failure or
non-curability) into consideration. This characteristic

M. Oba et al.
FIG. 3 Correlations between
RFS and OS, and TSF and OS,
in all patients (a, c) and eventalone patients (b, d). RFS
recurrence-free survival, OSoverall survival, TSF time tosurgical failure

All patients

RFS

aEvent aloneb

OS probability
1.0

OS probability
1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

n = 371, r = 0.491
0.0

0.2

0.4

0.6

0.8

1.0

n = 154, r = 0.493
0.0

0.2

TSF

RFS probabilitycdOS probability
1.0

OS probability
1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

n = 371, r = 0.814
0.0

0.2

0.4

0.6

0.8

TSF probability

differs from other malignancies in which liver metastasis ora relapse event is directly associated with cancer-related
death, although modern chemotherapy can prolong patient
survival to a certain extent. Previous clinical trials in a
CLM adjuvant setting have been judged using DFS or PFS
as the primary endpoint, the improvement of which cannot
be translated into the ultimate goal of a long-term survival
benefit. The current study demonstrated that RFS, or thetime to first recurrence, was not clinically associated withOS because of the sequential surgical management forrecurrent diseases. Of the actual 5-year survivors(n = 124), 60.5 % (n = 75) developed recurrences within
5 years after their initial hepatectomy, and 53.2 %(n = 66) underwent repeat resections. Moreover, of therecurrence-free survivors at 5 years (n = 87), 56.3 %(n = 49) had previously developed recurrences and had
achieved a cancer-free status after repeat resections(Table 2). Although recent effective chemotherapy has
prolonged the OS of patients with recurrence, chemotherapy alone cannot realize the primary goal of a cure forpatients with recurrences. Thus, the number of patients

0.4

0.6

0.8

1.0

0.8

1.0

RFS probability

1.0

n = 154, r = 0.700
0.0

0.2

0.4

0.6

TSF probability

who could be cured even after a repeat resection was
notable, and most patients received a survival benefit fromrepeat surgical management, even after a relapse event(Fig. 4). Using this new composite endpoint, the correlation
between TSF and OS was shown to be much stronger thanthat between RFS and OS.
This study had several limitations. The first limitation isthe difficulty in establishing standard criteria for repeat
resections after relapse from technical or oncological perspectives, although our center’s staff members haveadopted a consistent policy using a multidisciplinary
approach. The definition of ‘re-resectability’ differs
according to each institution’s policy, and the new ‘TSF’
endpoint would be difficult to apply to conventional practice across multicenters. However, if ‘re-resectability’ wasto be determined by a central evaluation, TSF could be a
promising surrogate endpoint for OS in future multicentricclinical trials. The most important points of this study are
the unreliability of RFS and the clinical significance ofrepeat surgery. We believe that repeat resection should be
regarded as an absolutely necessary strategy in the overallOptimal Endpoint for CLM Overall Management
FUNDINGOS probability
1.0

Relapse resectable pts (n = 152)
Relapse unresectable pts (n = 128)0.8

HR 0.24 (95% Cl: 0.17–0.34)
Log-rank P < 0.0001

No Grant support or other funding was received.

DISCLOSURE Masaru Oba, Kiyoshi Hasegawa, Yutaka Matsuyama, Junichi Shindoh, Yoshihiro Mise, Taku Aoki, Yoshihiro
Sakamoto, Yasuhiko Sugawara, Masatoshi Makuuchi, and Norihiro
Kokudo have no conflicts of interest to declare.

0.6

REFERENCES
0.4

0.2

0

2

Number at risk
152
128

4

76
17

6
Time (year)

8

31
2

10

12

8
0

FIG. 4 Comparison of OS in all relapse patients (n = 280) after
initial CLM resection: relapse resectable patients (n = 152) versus
relapse unresectable patients (n = 128). OS overall survival, CLM
colorectal liver metastasis

management of CLM, as the first relapse event after an
initial hepatic resection does not necessarily indicate surgical treatment failure.
The second limitation concerns a problem in the study
design, since our results are based on a retrospectively
selected patient analysis and the correlations between theefficacy of adjuvant treatment and the TSF and the true
endpoint cannot be measured.19–21 However, the current
study was based on prospectively collected data, and during the investigation period patients were treated using thesame approach and the same perioperative management.
Because our results represent a unified strategy at a single
specialized center, our conclusion should be valid to somedegree, although another prospective study is needed toconfirm the validity of our results. If future adjuvant
treatment truly prevents or delays the time to first relapse,
to show that this efficacy translates into an OS benefit, theprolongation of the DFS or PFS could be accepted as a
useful endpoint on its own.
CONCLUSIONSThe current study confirmed that the TSF, a new composite endpoint including the possibility of repeat
resections, was associated with the OS and could be apotential surrogate for long-term outcome. Actually, theRFS does not clinically reflect the OS in the overall management of patients with resectable CLM, who could becandidates for a potential cure even if a recurrence has
occurred.

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