ARTICLE
Local Treatment of Unresectable Colorectal Liver
Metastases: Results of a Randomiz ed Phase II Trial
Theo Ruers, Frits Van Coevorden, Cornelis J. A. Punt, Jean-Pierre E. N. Pierie,
Inne Borel-Rinkes, Jonathan A. Ledermann, Graeme Poston, Wolf Bechstein,
Marie-Ange Lentz, Murielle Mauer, Gunnar Folprecht, Eric Van Cutsem,
Michel Ducreux, Bernard Nordlinger; for the European Organisation for
Research and Treatment of Cancer (EORTC) Gastro-Intestinal Tract Cancer
Group, Arbeitsgruppe Lebermetastasen und tumoren in der Chirurgischen
Arbeitsgemeinschaft Onkologie (ALM-CAO), and the National Cancer
Research Institute Colorectal Clinical Study Group (NCRI CCSG)
Affiliations of authors: The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands (TR, FVC); Academic Medical Centre,
University of Amsterdam, Amsterdam, the Netherlands (CP); Leeuwarden Medical Center, Leeuwarden, the Netherlands (JPENP); Universitair Medisch Centrum,
Academisch Ziekenhuis, Utrecht, the Netherlands (IBR); Cancer Research UK and UCL Cancer Trials Centre and UCL Hospitals, London, United Kingdom (JAL); Aintree
University Hospital, Liverpool, United Kingdom (GP); Frankfurt University Hospital and Clinics, Frankfurt, Germany (WB); EORTC Headquarters, Data Management Unit,
Brussels, Belgium (MAL); EORTC Headquarters, Statistics Department, Brussels, Belgium (MM); University Cancer Center, University Hospital Carl Gustav Carus,
Dresden, Germany (GF); Digestive Oncology, University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (EVC); Institut Gustave Roussy, Villejuif, France (MD);
Assistance Publique Hoˆpitaux de Paris, Boulogne-Billancourt, France (BN)
Correspondence to: Prof. Dr. T. Ruers, Division of Surgical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands,
(e-mail: t.ruers@nki.nl).
Abstract
Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit
has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an
aggressive approach.
Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no
extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by
radiofrequency ablation 6 resection. Previously, we reported that the primary end point (30-month overall survival [OS] >
38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to
intention to treat.
Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm
and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the
combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in
favor of the combined modality arm (hazard ratio [HR] ¼ 0.58, 95% confidence interval [CI] ¼ 0.38 to 0.88, P ¼ .01). Three-, five-,
and eight-year OS were 56.9% (95% CI ¼ 43.3% to 68.5%), 43.1% (95% CI ¼ 30.3% to 55.3%), 35.9% (95% CI ¼ 23.8% to 48.2%), re-
spectively, in the combined modality arm and 55.2% (95% CI ¼ 41.6% to 66.9%), 30.3% (95% CI ¼ 19.0% to 42.4%), 8.9% (95%
CI ¼ 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI ¼ 30.3 to 67.8 months) in
the combined modality arm vs 40.5 months (95% CI ¼ 27.5 to 47.7 months) in the systemic treatment arm.
ARTICLE
Received: September 7, 2016; Revised: November 25, 2016; Accepted: January 20, 2017
© The Author 2017. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
For commercial re-use, please contact journals.permissions@oup.com
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JNCI J Natl Cancer Inst (2017) 109(9): djx015
doi: 10.1093/jnci/djx015
First published online March 17, 2017
Article
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Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in
patients with unresectable colorectal liver metastases.
Surgery is the gold standard of treatment in patients with re-
sectable colorectal liver metastases, with reported five-year sur-
vival rates ranging from 40% to 60% (1–3). Only 20% to 30% of
patients with CRC metastases confined to the liver are candi-
dates for surgery (2,4). In others, extensive tumor burden within
the liver or poor anatomical position of the tumors close to criti-
cal vascular or biliary structures precludes resection. In these
patients, systemic therapy is offered with the goal of improving
survival or potentially converting patients into resection candi-
dates (5,6). Although the outcome of systemic therapy is still be-
ing improved and promising biological agents are being
incorporated into treatment protocols, the realistic goal of sys-
temic treatment remains palliative (7–10). It is for this reason
that more aggressive local therapeutic approaches are being
pursued in patients with unresectable colorectal liver
metastases.
Radiofrequency ablation (RFA) is a treatment modality that
is being increasingly used (11). In patients with unresectable co-
lorectal liver metastases, total tumor clearance from the liver
can often still be obtained by RFA or a combination of RFA plus
resection (12–14). The efficacy of this approach is controversial
because data on the effect on overall survival compared with
the standard of care, systemic treatment, are lacking (11–18). To
deliver compelling evidence on the beneficial effect of such an
aggressive approach, a European intergroup randomized phase
III study (European Organisation for Research and Treatment of
Cancer 40004 CLOCC trial, ClinicalTrials.gov, No. NCT00043004)
was initiated. The trial was designed with overall survival (OS)
as the primary end point.
Patients with unresectable colorectal liver metastases were
randomly assigned to systemic treatment alone (standard arm)
or systemic treatment plus local treatment by RFA with or with-
out additional resection (experimental arm). Because of slow ac-
crual, the study was amended to a randomized phase II trial.
Previously published results of this phase II study showed that
the primary end point, being a 30-month overall survival (OS)
rate greater than 38% in the combined modality arm, was met
(61.7%) (19).
At the time of primary analysis with a median follow-up
time of 4.4 years, median progression-free survival (PFS) was
statistically significantly different between both arms, being
16.8 months in the combined modality arm and 9.9 months in
the systemic treatment–only arm (P ¼ .025) (19). After an ex-
tended follow-up of 9.7 years, we now report on the definitive
impact on overall survival.
Methods
Study Design and Patients
Patients with unresectable colorectal liver–limited metastases
were randomly assigned to systemic treatment alone (standard
arm) or systemic treatment plus local treatment by RFA 6 resec-
tion (experimental arm). The primary end point of this phase II
study was a 30-month OS rate higher than 38% in the combined
modality arm. Using a Fleming design, 76 patients were re-
quired in the experimental arm to reject a 30-month OS rate of
38% or lower under the alternative hypothesis of a 30-month OS
rate of 53% with 90% power, using a one-sided test with a type I
error of 10%.
Secondary end points were progression-free survival (PFS),
overall survival (OS), and health-related quality of life. From
April 2002, patients were recruited from 22 centers in Europe.
The trial was prematurely closed for poor accrual because of
physician’s preferences in treatment modalities in June 2007,
with 60 patients in the experimental arm and 59 patients in the
control arm.
Eligible patients were age 18 to 80 years with a World
Health Organization performance of less than 2 and who pre-
sented with nonresectable colorectal liver metastases without
extrahepatic disease. Nonresectability was defined as no pos-
sibility to completely resect all tumor lesions, as judged by a
multidisciplinary team with at least a hepatobiliary surgeon
and radiologist on board. Patients were eligible only when all
liver lesions could be fully treated by either RFA alone or
combined treatment that consisted of resection of resectable
lesions and RFA of the remaining unresectable lesions. To
allow complete treatment of all liver lesions, the number of
liver metastases had to be less than 10. Full inclusion and ex-
clusion criteria have been previously reported (19). The trial
was approved by the medical ethics committees of all partici-
pating centers. Written informed consent was obtained from
all patients prior to random assignment. Random assignment
(1:1) was done at the EORTC headquarters with the minimiza-
tion technique and was stratified according to center, previous
systemic treatment for liver metastases, previous adjuvant
treatment, and route of random assignment (before or during
surgery).
Procedures
Patients assigned to the combined modality therapy received
complete treatment of all liver metastases either by RFA alone
or by RFA in combination with resection. The optimal strategy
to obtain adequate local treatment was decided upon by the
hepatobiliary surgeon and the multidisciplinary team. RFA
procedures were carried out according to the guidelines of the
manufacturer of the ablation device used during open sur-
gery, laparoscopically, or percutaneously. Quality control for
RFA and surgery required specialized liver surgeons and radi-
ologists to assess the suitability of patients for ablation and
full documentation of the lesions treated. From April 2002 to
October 2005, systemic treatment in both study arms con-
sisted of 5-FU/LV/oxaliplatin. After October 2005, bevacizu-
mab was added when it became accepted as the standard of
care in most participating centers. Treatment of 5-FU/LV/
oxaliplatin consisted of the FOLFOX 4 regimen while bevaci-
zumab was administered at 5 mg/kg body weight once every
two weeks. Detailed systemic treatment regimens were re-
ported previously (19).
In the systemic treatment arm only, no additional local
treatment options were allowed except for resection when
unresectable disease was converted to resectable disease by
systemic treatment. In both study arms, treatment was started
within four weeks of random assignment and systemic
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treatment after RFA was planned within four to eight weeks af-
ter the procedure.
Systemic treatment in both arms was administered for six
months unless there was disease progression or unacceptable
toxicity. After protocol treatment, any further systemic treat-
ment was at the discretion of the multidisciplinary team.
Patients were assessed for PFS and OS every six weeks during
protocol treatment, every three months after treatment for a pe-
riod of two years, and every six months thereafter. Disease pro-
gression was assessed using contrast-enhanced CT scan by the
local radiologist according to RECIST 1.0. Recurrence at the RFA
site was defined by the appearance on CT imaging of one or more
new lesions along the margin of the ablated lesion or at least a
20% increase in the longest diameter of the RFA-treated lesion.
Statistical Analysis
Follow-up duration was computed fromthetimeofrandomassign-
ment to the date of last follow-up. Patients who died were censored
at the date of death. PFS was defined as the time interval between
thedateofrandomassignmentandthedateofprogression(orre-
currence) of the disease or death, whichever occurred first. OS was
defined as the time interval between the date of random assign-
ment and the date of death. Patients who were still event free at
the last visit were censored at the date of last follow-up.
The updated analyses of PFS and OS are intent-to-treat anal-
yses. Overall PFS and OS were estimated by the Kaplan-Meier
method and compared by a two-sided log-rank test. The level of
statistical significance was set to .05.
Additional sensitivity univariate analyses of OS, adjusting
for baseline factors, that is, number of liver metastases (4vs
>4) and synchronicity (synchronous vs metachronous), were
performed to correct for a potential prognostic effect on the re-
sults. OS was compared between arms using a two-sided log-
rank test stratified for the baseline factor. Possible heterogeneity
of the results in these subgroups was tested by means of a
Cochran’s Q test. A graphical display of the results is provided us-
ing Forest plots. To determine any possible influence of second-
ary treatments on OS, survival duration after initial disease
progression was analyzed in progressive patients (for whom
death was not the first recorded event, 55 and 43 patients in the
systemic treatment and in the combined modality arms, respec-
tively). Survival duration after initial disease progression was
computed as the time interval between the date of first progres-
sion and the date of death. Patients who were still alive at the
last visit were censored at the date of last follow-up. Survival du-
ration after initial disease progression was estimated by the
Kaplan-Meier method and compared between treatment arms by
a two-sided log-rank test.
The analysis of the time to hepatic progression and to extra-
hepatic progression was performed using the competing risk
methodology in the intent-to-treat population as exploratory
analyses. The cumulative incidence of the event of interest (in-
cluding the occurrence of the event and a simultaneous pro-
gression at another site) was estimated and compared by
means of a Gray test (20). In these analyses, death in absence of
hepatic or extrahepatic progression, respectively, was consid-
ered the only competing risk.
Results
A total of 119 patients were randomly assigned to either sys-
temic treatment alone or combined modality treatment
(systemic plus local treatment). Patient and tumor characteris-
tics appeared balanced between both arms (Table 1).
In the combined modality arm (n ¼ 60), three patients
were ineligible, two had more advanced disease than allowed
per protocol, and one showed liver metastases that were
considered resectable at baseline (Figure 1). Of the 60 patients
randomly assigned to combined modality, two patients did not
receive any local treatment because of patient refusal (n ¼ 1) or
ineligibility (n ¼ 1); for one patient, no treatment data are avail-
able. Local treatment in the 57 remaining patients consisted of
RFA only in 30 patients, RFA plus resection in 26 patients, and
resection only in one patient (Table 2). In 51 patients, local treat-
ment was combined with planned systemic treatment. Six
patients did not receive any systemic treatment because of fast
disease progression (n ¼ 2), patient death (n ¼ 1), or postopera-
tive complications (n ¼ 3).
In the systemic treatment arm (n ¼ 59), all patients started
systemic therapy. One patient was considered ineligible; this
patient showed resectable disease on the initial CT scan and
was resected after the start of systemic treatment. Six addi-
tional patients underwent liver resection as intended by the
protocol because unresectable disease was converted by sys-
temic treatment into resectable disease. In the systemic treat-
ment arm, the median number of systemic treatment cycles was
10 (range ¼ 1–12), in the combined modality arm 8.5 (range ¼
0–12).
After a similar long-term follow-up in both arms at a me-
dian of 9.7 years, 92 of 119 (77.3%) patients had died, 53 of 59
(89.8%) patients in the systemic treatment arm and 39 of 60
(65.0%) patients in the combined modality arm (Table 3).
Nearly all patients died due to progressive disease (PD), 49 pa-
tients in the systemic treatment arm and 35 patients in the
combined modality arm. Only five patients were lost to follow-
up, two patients in the systemic treatment arm and three pa-
tients in the combined modality arm.
Patients in the combined modality arm had a statistically
significantly longer OS as compared with the patients in the
systemic treatment arm (HR ¼ 0.58, 95% CI ¼ 0.38 to 0.88, P ¼
.01) (Figure 2). Three-, five-, and eight-year OS rates were 56.9%
(95% CI ¼ 43.3% to 68.5%), 43.1% (95% CI ¼ 30.3% to 55.3%), and
35.9% (95% CI ¼ 23.8% to 48.2%) in the combined modality arm
and 55.2% (95% CI ¼ 41.6% to 66.9%), 30.3% (95% CI ¼ 19.0% to
42.4%), and 8.9% (95% CI ¼ 3.3% to 18.1%) in the systemic treat-
ment arm. The median overall survival was 45.6 months (95%
CI ¼ 30.3 to 67.8 months) for the combined modality arm and
40.5 months (95% CI ¼ 27.5 to 47.7 months) for the systemic
treatment arm.
As previously reported, PFS was statistically significantly
prolonged in the combined modality arm as compared with the
systemic treatment arm (HR ¼ 0.57, 95% CI ¼ 0.38 to 0.85, P ¼
.005) (Figure 3). Median PFS was improved from 9.9 months (95%
CI ¼ 9.1 to 12.9 months) to 16.8 months (95% CI
¼ 11.0 to 21.9
months).
After this long-term follow-up, 45 patients in the combined
modality arm had recurrent disease or had died compared with
57 patients in the systemic treatment arm. In the combined mo-
dality arm, apart from the three patients who were lost to
follow-up without progression, 12 patients did not experi-
ence any recurrence or death. The minimum follow-up in
these 12 patients was 7.9 years. In the systemic treatment
arm, one patient was lost to follow-up without progression and
only one patient did not experience any progression after a
follow-up duration of 10.8 years.
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Three-, five-, and eight-year PFS rates in the combined mo-
dality arm were 27.7% (95% CI ¼ 16.9% to 39.5%), 24.2% (95% CI ¼
14.1% to 35.7%), and 22.3% (95% CI ¼ 12.7% to 33.7%), respec-
tively (Figure 3). In the systemic treatment arm, three-, five-,
and eight-year PFS rates were 11.9% (95% CI ¼ 5.2% to 21.5%),
5.9% (95% CI ¼ 1.6% to 14.4%), and 2.0% (95% CI ¼ 0.2% to 9.0%),
respectively. Among patients who experienced progression, six
and three patients in the combined modality arm and in the
systemic treatment arm, respectively, were still alive during the
last follow-up. In the systemic treatment arm, the six patients
who underwent liver resection because nonresectable disease
was converted by systemic treatment into resectable disease all
developed recurrence.
The liver as first site of recurrence (with or without extrahe-
patic disease) was observed in 28 of 60 (46.7%) patients in the com-
bined modality arm and in 46 of 59 (78.0%) of those in the
systemic treatment arm. In the combined modality arm, in 56 pa-
tients treated with radiofrequency ablation, nine patients (16.1%)
experienced a first liver recurrence at a site treated by RFA.
Extrahepatic progression only as first progression was observed in
25.0% of patients (15/60) in the combined modality arm and 13.6%
of patients (8/59) who received systemic treatment alone (Table 3).
Furthermore, given the small sample size, it was impossible
to completely eliminate the possibility of small imbalances in
baseline characteristics, for example, in the number of lesions
or synchronicity. To correct for a potential prognostic effect of
baseline factors on the results, we conducted additional sensi-
tivity analyses. The results of the sensitivity analyses of OS ad-
justing for the number of liver metastases (4vs>4) and
synchronicity (synchronous vs metachronous) show that the
difference in OS between both arms remains statistically signifi-
cant. No heterogeneity in the results in patients with four or
fewer liver metastases vs more than four liver metastases or in
patients with synchronous vs metachronous liver metastases
was observed (Supplementary Figures 1 and 2, available online).
To determine any possible influence of secondary treat-
ments on OS, survival after initial disease progression was ana-
lyzed. Median survival after disease progression was 21.0
months (95% CI ¼ 16.2 to 30.5 months) in the systemic treatment
arm only and 19.5 months (95% CI ¼ 14.3 to 32.3 months) in the
combined modality arm (HR ¼ 0.86, 95% CI ¼ 0.56 to 1.31, P ¼ .48)
(Supplementary Figure 3; Supplementary Table 1, available on-
line). With death in absence of hepatic progression considered
the only competing risk, the cumulative incidence of hepatic
progressions at one, three, and five years were 31.0% (95%
CI ¼ 19.1% to 42.9%), 58.6% (95% CI ¼ 45.9% to 71.3%), and 62.1%
(95% CI ¼ 49.6% to 74.6%) in the combined modality arm vs
51.7% (95% CI ¼ 38.9% to 64.6%), 86.2% (95% CI ¼ 77.3% to 95.1%),
and 88.2% (95% CI ¼ 79.8% to 96.6%) in the systemic treatment
arm (P < .001) (Figure 4). The cumulative incidence of extrahe-
patic progressions at one, three, and five years was 24.1% (95%
CI ¼ 13.1% to 35.1%), 55.2% (95% CI ¼ 42.4% to 68.0%), and 60.4%
(95% CI ¼ 47.8% to 72.9%) for the combined modality arm and
20.9% (95% CI ¼ 10.4% to 31.5%), 45.5% (95% CI ¼ 32.6% to 58.5%),
and 60.2% (95% CI ¼ 47.4% to 73.1%) for the systemic treatment
arm (P ¼ .73) (Figure 5). With regard to local recurrence after
RFA, in total 11 lesions (in nine patients) out of 170 RFA-treated
lesions showed a local recurrence at the RFA site as first pro-
gression. In addition, three lesions (in two patients) recurred af-
ter initial progression at another site.
Discussion
In this randomized phase II trial, we found that a combination
of aggressive local treatment plus systemic treatment, as com-
pared with systemic treatment alone, improved both progres-
sion-free survival and overall survival in patients with
unresectable colorectal liver metastases. The addition of local
Table 1. Baseline characteristics
Patient and tumor
characteristics
Local plus
systemic treatment
(n ¼ 60)
Systemic
treatment
(n ¼ 59)
No. (%) No. (%)
Age, y
Median (range) 64 (31–79) 61 (38–79)
Sex
Male 37 (61.7) 42 (71.2)
Female 23 (38.3) 17 (28.8)
WHO performance status
0 47 (78.3) 47 (79.7)
1 13 (21.7) 12 (20.3)
No. of liver metastases
1 15 (25.0) 7 (11.9)
2 6 (10.0) 4 (6.8)
3 8 (13.3) 7 (11.9)
4 9 (15.0) 8 (13.6)
5 6 (10.0) 10 (16.9)
6 3 (5.0) 9 (15.3)
7 6 (10.0) 8 (13.6)
8 3 (5.0) 2 (3.4)
9 4 (6.7) 4 (6.8)
Median 4.0 5.0
Synchronicity of liver metastases
Metachronous metastases 37 (61.7) 31 (52.5)
Synchronous metastases* 23 (38.3) 28 (47.5)
Time from surgery for primary
cancer to random assignment, d
Median (range) 290 (28–1802) 308 (30–2754)
T stage of primary cancer
pT2 9 (15.0) 4 (6.8)
pT3 42 (70.0) 48 (81.4)
pT4 9 (15.0) 6 (10.2)
Unknown 0 (0.0) 1 (1.7)
N stage of primary cancer
pN0 17 (28.3) 21 (35.6)
pN1 22 (36.7) 24 (40.7)
pN2 20 (33.3) 12 (20.3)
Unknown 1 (1.7) 2 (3.4)
Adjuvant chemotherapy
for primary cancer†
No 50 (83.3) 49 (83.1)
Yes 10 (16.7) 10 (16.9)
Prior chemotherapy for
metastatic disease†
No 51 (85.0) 51 (86.4)
Yes 9 (15.0) 8 (13.6)
Previous liver surgery for
CRC metastases
No 51 (85.0) 49 (83.1)
Yes 9 (15.0) 10 (16.9)
Route of random assignment†
Before surgery 46 (76.7) 44 (74.6)
During surgery 14 (23.3) 15 (25.4)
*Liver metastases detected within three months after primary cancer diagnosis.
CRC ¼ colorectal cancer; WHO ¼ World Health Organization.
†Stratification factors.
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treatment using RFA was clinically beneficial and was associated
with a statistically significant improvement in overall survival (P ¼
.01). Patients were followed for a minimum of 7.8 years, and only
five patients (4.2%) were lost to follow-up. Almost all deaths were
due to progressive disease.
The current analysis, after a median follow up time of 9.7
years, extends the initial analysis on the primary end point of
30-month overall survival. At 30 months, overall survival in the
experimental arm (61.7%) and the control arm (57.6%) was com-
parable, both being higher than expected. At the time of original
study design (late 1990s), figures on overall survival of patients
with liver-limited colorectal metastases were scarce, which has
led to a very conservative estimation of overall survival (21,22).
At the time of the initial analysis, a statistically significant
60 allocated to local treatment
+ systemic treatment
57 eligible
3 ineligible
59 started systemic treatment
59 allocated to systemic treatment
58 eligible
1 ineligible (resectable)
119 patients randomly assigned
2 patients did not receive local
treatment
1 eligible (patient’s refusal)
1 ineligible (bone
metastases at baseline)
1 unknown
57
p
atients received local treatment
6 patients did not receive adjuvant
chemotherapy
6 eligible (patient
progression [n = 2], patient
death [n = 1], surgery
complications [n = 3])
51 patients received
s
y
stemic treatment
45 events for PFS:
28 liver (recurrence at a site treated by
RFA [n = 9], elsewhere in liver [n = 18],
unknown [n = 1])
15 elsewhere (primary, lung, regional,
other)
2 deaths (cardiovascular disease;
multiple organ failure (RFA/surgery
complication))
39 patients died
35 progressive disease
1 cardiovascular disease
1 other (multiple organ failure,
RFA/surgery complication)
2 unknown
53 patients died
49 progressive disease
4 unknown
57 events for PFS:
46 liver
8 elsewhere (primary, lung, regional,
other)
2 unknown site
1 death (unknown cause)
1 ineligible resected
6 patients converted into
resectable and resected
2 patients had surgery plus RFA after PD
(major protocol violations)
Figure 1. CONSORT flow diagram. PD ¼ progressive disease; PFS ¼ progression-free survival; RFA ¼ radiofrequency ablation.
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