Adjuvant Radiotherapy in Centrally Located
Hepatocellular Carcinomas after Hepatectomy
with Narrow Margin (<1 cm): A Prospective
Randomized Study
Weibo Yu, MD, Weihu Wang, MD, Weiqi Rong, MD, Liming Wang, MD, Quan Xu, MD, Fan Wu, MD,
Liguo Liu, MD, Jianxiong Wu, MD
Although radiotherapy (RT) provides potential benefits for patients with hepatocellular carcinomas (HCCs) that are unsuitable for operation, the specific role of adjuvant RT in HCC after
hepatectomy remains ill defined. The current study’s aim was to evaluate the safety and efficacy
of adjuvant RT for centrally located HCCs after narrow-margin (<1 cm) hepatectomy.
STUDY DESIGN: The study included 119 patients with centrally located HCCs who underwent narrow-margin
hepatectomy between July 2007 and March 2012. Patients were prospectively randomized to
receive adjuvant RT (n ¼ 58) or were assigned to a control group (n ¼ 61). Surgical outcomes, safety, and survival rates were evaluated.
RESULTS:
Hepatectomy was successfully performed in all patients. No cases of radiation-induced liver
disease were observed. One-, 3-, and 5-year recurrence-free survival rates were 78.1%, 56.5%,
and 36.9% in the adjuvant RT group and 72.4%, 40.1%, and 16.0% in the control group,
respectively (p ¼ 0.06, log-rank test). Corresponding overall survival rates were 96.2%,
72.6%, 48.4%, and 89.6%, 74.5%, 37.2%, respectively (p ¼ 0.48, log-rank test). One-, 3-,
and 5-year recurrence-free survival rates in patients with small-diameter tumors (5 cm) were
88.8%, 67.4%, 42.9% in the adjuvant RT group and 82.3%, 42.9%, 21.5% in the control
group (p ¼ 0.03, log-rank test). Corresponding overall survival rates were 97.5%, 75.3%,
75.3%, and 94.7%, 84.1%, 65.4%, respectively (p ¼ 0.92, log-rank test).
CONCLUSIONS: Adjuvant RT for centrally located HCCs after narrow-margin hepatectomy was technically
feasible and relatively safe. No significant between-group difference was observed in
recurrence-free and overall survival. The post-hoc subgroup comparison showed that adjuvant
RT improved recurrence-free survival considerably, but not overall survival, in patients with
small HCCs (5 cm). More in-depth studies are needed to validate this finding. (J Am Coll
Surg 2014;218:381e392. 2014 by the American College of Surgeons)
BACKGROUND:
Hepatocellular carcinoma (HCC) is one of the most
common malignancies seen in different regions of the world.
Surgical resection provides the best chance for cure in select
patients.1 However, surgeons have long been perplexed by
high rates of tumor recurrence, which is often the main cause
of long-term treatment failure. The 5-year rate of recurrence
of HCC after resection has been reported to be as high as
70%.2 It has been proposed that the best way to reduce recurrence is to search for improved adjuvant therapies.3
Radiation therapy (RT) is a therapeutic method used in
approximately one third of all cancer patients. However,
there are certain limitations and problems associated with
RT in the treatment of HCC historically. The main problem is related to low whole-liver tolerability to the standard radiation dose (ie, there is a 5% risk of toxicity
Disclosure Information: Nothing to disclose.
Supported by the Key Programs of the Cancer Institute and Hospital,
Chinese Academy of Medical Science (grant number LC2010A15).
Drs Yu and Weihu Wang contributed equally to this work.
Received August 18, 2013; Revised November 24, 2013; Accepted
November 27, 2013.
From the Abdominal Surgery Department, Cancer Institute and Hospital,
Peking Union Medical College, Chinese Academy of Medical Sciences (Yu,
Rong, L Wang, Xu, F Wu, J Wu), the Radiation Oncology Department,
Cancer Institute and Hospital, Peking Union Medical College, Chinese
Academy of Medical Sciences (W Wang), and Hepatobiliary Surgery
Department, China-Japan Friendship Hospital (Liu), Beijing, China.
Correspondence address: Jianxiong Wu, MD, Abdominal Surgery Department, Cancer Institute and Hospital, No. 17 Panjiayuannanli, Chaoyang
District, Beijing, China 100021. email: dr.wujianxiong@yahoo.com
ª 2014 by the American College of Surgeons
Published by Elsevier Inc.
381
ISSN 1072-7515/13/$36.00
http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.030
382
Yu et al
Adjuvant Radiotherapy of Central Liver Cancer
Abbreviations and Acronyms
AFP
¼ a-fetoprotein
3D-CRT ¼ 3-dimensional conformal radiotherapy
technique
HCC
¼ hepatocellular carcinoma
RT
¼ radiation therapy
TACE ¼ transarterial chemoembolization
after 28 Gy in 2-Gy fractions given for primary liver cancer). Patients are exposed to the risk of liver toxicity with
the traditional standard doses and are unlikely to derive
much benefit from low-dose radiation therapy.4,5
The development of a 3-dimensional conformal technique (3D-CRT) and intensity-modulated radiotherapy
(RT) techniques enables higher doses of radiation to be delivered to the target area and thereby spare the majority of the
liver from irradiation damage.6 A series of retrospective and
prospective studies indicates that RT has become a safe and
effective local therapy that is of potential benefit to patients
who are unable to undergo surgery.7-12 However, the specific
role of RT as adjuvant therapy has not yet been clearly established. The reasons for recurrence of HCC after radical hepatectomy are complex, which means that adjuvant RT
focused on the surgical site alone might not necessarily provide any advantage.
Centrally located HCC is traditionally characterized as being sited in Couinaud segments IV, V, or VIII of the liver.13
Extensive major hepatectomy or mesohepatectomy were
often recommended for this type of HCC.14-19 We previously proposed a revised definition that defines centrally
located HCC as carcinoma-adjoined hepatic hilum, <1
cm from major vascular structures (including the IVC,
main portal branches, and main trunks of the hepatic veins),
that is usually located in Couinaud segment I, IV, V, VIII, or
at the junction of the central segments. Since 2006, we have
begun to explore the outcomes of hepatectomy undertaken
for complex centrally located HCC and performed using selective and dynamic region-specific vascular occlusion techniques.20 To date, this procedure has been performed safely
in >200 patients. However, it was often difficult to gain an
adequate resection margin due to the specific tumor location.
Based on our revised definition, the resection margins for
most cases should be <1 cm (narrow margin). In addition,
for some patients, we have no choice but to carefully dissect
and resect the tumor away from the vascular surface because
the tumor had adhered to the major vascular structures (nullmargin resection).21
From an oncologic point of view, a narrow margin
<1 cm is not safe and is often associated with higher rates
of recurrence and shorter patient survival.22 On the other
hand, it is also believed that most intrahepatic recurrences
J Am Coll Surg
arise from multicentric carcinogenesis and are distant
from the resection margin.23 To address this issue, a series
of retrospective and prospective studies were undertaken
to investigate the effect of surgical margin on tumor
recurrence.21,24-36 However, no consensus has been
reached. We previously observed that there was a certain
risk of short-term recurrence in some cases. Therefore, in
our series of patients, we conventionally stitched several
silver marks on the tumor cutting surface to facilitate
accurate orientation for postoperative RT.
There are few reports on postoperative adjuvant RT for
HCC. This prospective study was designed to evaluate
the safety and efficacy of adjuvant RT for centrally
located HCC after narrow margin (<1 cm) hepatectomy
(inscription number: ChiCTR-TRC-12002717, who.int/
ictrp).
METHODS
Patients
Between July 2007 and March 2012, one hundred and
forty-two consecutive patients (17 to 75 years of age)
diagnosed with centrally located HCC at the Cancer
Institute and Hospital of Chinese Academy of Medical
Science were considered for enrollment in the study.
The diagnostic criteria for HCC used in the study were
in accordance with the American Association for the
Study of Liver Diseases’ 2005 guidelines. All patients
had preoperative serum a-fetoprotein (AFP) levels
>200 ng/mL or a typical enhancement pattern (arterial
enhancement and portal/delayed washed out) on dynamic
imaging of hepatic mass(es) 2 cm, or cytologic/histologic evidence of HCC.37
Preoperative procedures included hematology, routine
liver and renal function and coagulation tests, screening
for hepatitis B/C virus markers, and determination of
serum AFP, carcinoembryonic antigen, and carbohydrate
antigen 199. Abdominal CT scan with contrast or MRI
was also routinely undertaken. The Barcelona Clinic Liver
Cancer staging classification was used for tumor staging.
Child-Pugh criteria were used for liver function evaluation.
The inclusion criteria were as follows: centrally located
HCC with no preoperative RT; resectable lesion that could
be completely removed, at the same time retaining a sufficient residual liver tissue to maintain adequate function;
compensated cirrhosis or no cirrhosis; Child-Pugh liver function class A; and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients who had undergone
transarterial chemoembolization (TACE) were eligible for
enrollment in the study, provided this form of therapy ended
at least 4 weeks before study entry. We excluded such patients
with presence of distant metastasis; resection margin 1 cm;
Vol. 218, No. 3, March 2014
Yu et al
palliative resection with tumor residual; and non-HCC
confirmed by postoperative pathology.
All eligible patients provided written informed consent.
The study was approved by the Ethical Committee of the
Cancer Institute and Hospital of the Chinese Academy of
Medical Science and was performed in accordance with
principles of Good Clinical Practice and Declaration of
Helsinki guidelines (1975, revised in 1983).
Hepatectomy procedure
Patients were selected as being suitable candidates for hepatectomy by a multidisciplinary team. All patients underwent
hepatectomy for removal of complex centrally located HCC
using a selective and dynamic region-specific vascular occlusion technique. The first step of the procedure was to ligate
and divide the ligaments around the liver to make it movable.
Then, intraoperative ultrasonography was used to define the
tumor location and display the vessels to be manipulated
during resection. According to tumor size, location, and degree of hepatic cirrhosis, individual resection ranges were
selected, including central resection (removal of segments
IV, V and VIII), right anterior sectorectomy (removal of segments V and VIII), segment IV resection, caudate lobe resection, or nonanatomical resection.
We performed a precise hepatic hilar dissection before
resecting the tumor. Depending on the transection area,
the left or right portal vein and hepatic artery were
dissected in the hilum and encircled with vessel tapes.
When liver parenchymal dissection was performed on
the right side of the Cantlie line, the right hepatic artery
and portal vein were occluded intermittently and the left
area was free from clamping. When the dissection was
performed on the left side of the Cantlie line, similar
occlusion was applied on the left hepatic artery and portal
vein and the right area was free from clamping. A
dynamic procedure was used for hepatic blood flow,
such that outflow occlusion was applied only when necessary and the IVC was occluded only in emergency situations. In cases where tumors adhered to major vascular
structures, we carefully dissected and resected lesions
away from the vascular surface using a Cavitron Ultrasonic Surgical Aspirator to avoid cutting major vascular
structures and prevent postoperative liver failure.
After tumor removal, we conventionally stitched
several silver marks on tumor cutting surface, making
provisions for accurate orientation of postoperative RT.
All of the operations were completed by the same
surgical team in an attempt to standardize operative
quality and safety.
After tumor removal, the specimen was examined to
measure resection margin (the shortest distance from
the edge of the tumor to the plane of liver transection).
Adjuvant Radiotherapy of Central Liver Cancer
383
Randomization
Before discharge, those postoperative patients who had
recovered well and who had adequate hepatic and renal
function, an Eastern Cooperative Oncology Group Performance Status of 0 or 1, no fever and no active sepsis,
were prospectively randomized to receive adjuvant RT or
were assigned to a control group. The simple randomization procedure was done without stratification by
computer-generated random numbers between 0 and 1.
Odd values of the first decimal place of the random number were assigned adjuvant RT group, and even values
(including zero) were assigned no RT.
Blinding procedures
This is a randomized, open-label study. Blind and
dummy techniques were not used because they were
not feasible, given the nature of the treatment.
Adjuvant radiotherapy
The tumor cutting bed was indicated by silver marks applied
during the operation. The clinical treatment volume was
defined as the tumor cutting bed plus a 1-cm margin.
This was expanded by 0.5 to 1 cm for the final planning
treatment volume. Three-dimensional conformal radiation
therapy plans were generated for each patient. In all patients,
the goal was for at least 95% of the clinical treatment volume
to receive 100% of the dose. The plans were optimized independently and reviewed by at least 2 physicians (a dosimetrist and a physicist). The target total dose was 60 Gy
delivered using 2 Gy/fraction, 5 days per week.
Toxicity was evaluated according to the National Cancer
Institute Common Terminology Criteria for Adverse
Events, version 3.0. Hematologic adverse effects were
graded using the Radiation Therapy Oncology Group
Morbidity Scoring Criteria. Radiation-induced liver disease
was defined as a minimum 2-fold increase in anicteric elevation of alkaline phosphatase (ALP) levels and nonmalignant
ascites, or a minimum 5-fold increase in transaminase levels
above the normal upper limit or relative to pretreatment
levels. Acute toxicity was defined as events occurring during
treatment or within the first month after treatment. Late
toxicity was assessed at least 3 months after treatment.38,39
Follow-up
After discharge from hospital, all patients were followed
at 3-month intervals for the first year and at 4- to
6-month intervals thereafter. The follow-up program
included serum AFP assays, liver function tests, abdominal ultrasonography, and chest x-rays.
Enhanced CT was performed every 6 months for surveillance of recurrence. Bone scanning was undertaken
when necessary. In cases where a suspicious recurrent or
384
Yu et al
Adjuvant Radiotherapy of Central Liver Cancer
J Am Coll Surg
Figure 1. Flow chart of the study and randomization of eligible patients underwent narrow-margin
hepatectomy. RT, radiotherapy.
metastatic lesion was detected, MRI or hepatic angiography was used to confirm the diagnosis.
The diagnosis of tumor recurrence was based on typical
imaging features mentioned previously, an increase in
AFP levels, or development of extrahepatic metastasis.
Fine-needle aspiration/biopsies were not necessarily
undertaken to assess recurrences.
The treatment of recurrence depended on the characteristics of the recurrent tumor, the patient’s general condition, and the consensus of the multidisciplinary team.
Regional therapy or systemic therapy were used as alternative methods for treating recurrences.
End points
Patients were followed until death or until the censoring
date (November 2012). The primary and secondary
outcomes were recurrence-free survival and overall survival, respectively, both calculated from the date of
randomization. Patients lost to follow-up were censored
at the date of the last observation. Death not related to
recurrence was not considered as an end point for the
recurrence-free survival calculation, but was included
and censored in the estimation of date of death.
Sample size determination
Sample size was computed using the recurrence-free
survival as the main end point. For HCC patients who
underwent hepatectomy with narrow margin (<1 cm),
the 5-year recurrence-free survival was estimated to be
approximately 22.5%, based on previously published
studies.40 We predicted that adjuvant RT would minimize recurrence and metastatic rate associated with
Vol. 218, No. 3, March 2014
Yu et al
Adjuvant Radiotherapy of Central Liver Cancer
385
Figure 2. Recurrence-free survival curves for adjuvant radiotherapy (RT) and control groups
(p ¼ 0.06, log-rank test).
narrow or null margin surgery similar to those achieved
with wide margin surgery. Therefore, for patients who
underwent narrow-margin hepatectomy combined with
adjuvant RT, the 5-year recurrence-free survival was estimated to be approximately 52.7%, based on a previous
study of wide-margin hepatectomy (>1 cm).32 Using a
2-sided test with 90% power at a significance level of
5%, the minimal sample size needed to detect a significant difference was calculated to be 58 patients in each
treatment group. We randomized 119 patients into this
study.
Statistical analysis
Statistical analysis was performed using SAS software,
version 9.2 (SAS Institute). Comparisons between groups
were undertaken on an intention-to-treat basis. Normally
distributed continuous data were presented as means and
SDs. Categorical variables were compared using the chisquare test or Fisher’s exact test, and continuous variables
were compared using the Student’s t-test.
Overall survival and disease-free survival rates were
evaluated by the Kaplan-Meier method, and compared
using the stratified log-rank test. Considering that tumor
size was an independent risk factor for survival, a post-hoc
subset analysis based on tumor size (5 cm) was performed. In all cases, statistical significance was defined
as p < 0.05.
RESULTS
Patients
We screened 142 consecutive patients who met the diagnostic criteria for centrally located HCC. Fourteen
patients were excluded from the study for the reasons
shown in Figure 1. The remaining 128 patients underwent hepatectomy. Nine patients were excluded from
the analysis. Two were found to have other pathologies
on histologic examination of resected specimens, 2 underwent wide margin resection (>1 cm), and 5 had postoperative complications or inadequate hepatic function.
A total of 119 patients were randomized: 58 to the
adjuvant RT group and 61 to the control group. Seven
patients failed to complete adjuvant RT for the reasons
stated in Figure 2. In the control group, 1 patient had a
protocol violation and another was lost to follow-up. All
9 patients were included in the intention-to-treat analysis.
The demographic and baseline characteristics of the
119 patients in the final analysis are shown in Table 1.
There were 99 men and 20 women with a mean age of
54.36 10.69 years. More than 90% of patients had
hepatitis B or C virus infection and 88% had liver
cirrhosis of varying severity.
For tumors that adhered to the major portal or hepatic
vein structures, we performed null-margin resection. This
accounted for 72.3% of cases. As shown in Table 1, the 2
groups were well matched with respect to baseline disease
386
Table 1.
Yu et al
J Am Coll Surg
Adjuvant Radiotherapy of Central Liver Cancer
Demographic and Baseline Characteristics of the Patients
Variables
Age, y, mean SD
Sex, male/female, n
Chronic hepatitis, n
Nil
Hepatitis B virus
Hepatitis C virus
Hepatitis B þ hepatitis C virus
Cirrhotic liver, yes/no, n
Alcohol intake, yes/no, n
Alanine aminotransferase, U/L, mean SD
Serum albumin, g/L, mean SD
a-Fetoprotein, >25 ng/mL/25 ng/mL, n
Vascular adhesion, null margin, n
Nil
PV adhesion
HV adhesion
PV þ HV adhesion
BCLC staging, n
A
B
C
No. of tumor sites, n
1
2
Tumor diameter, cm, mean SD
Differentiation, n
Well
Moderate
Poor
Presence of satellite nodules, yes/no, n
Liver capsule invasion, yes/no, n
Blood vessel invasion, yes/no, n
Preoperative TACE, yes/no, n
Adjuvant RT group (n ¼ 58)
Control group (n ¼ 61)
p Value
53.1 10.5
51/7
55.5 10.7
48/13
0.22
0.18
0.08
5
52
0
1
51/7
26/32
37.6 20.7
42.4 4.1
24/34
3
53
5
0
54/7
16/45
40.2 23.1
40.7 4.3
27/34
18
12
18
10
15
12
25
9
38
15
5
34
21
6
52
6
4.7 2.6
53
8
5.6 3.7
5
40
10
2/56
36/22
7/51
8/50
4
40
16
6/55
37/24
8/53
10/51
0.92
0.03
0.53
0.02
0.75
0.71
0.54
0.64
0.12
0.59
0.27
0.87
0.86
0.69
Continuous variables were expressed as mean SD and compared by Student’s t test. Categorical variables were compared by the chi-square test or Fisher’s
exact test, as appropriate.
BCLC, Barcelona Clinic Liver Cancer Staging Classification; HV, hepatic vein; PV, portal vein; RT, radiotherapy; TACE, transarterial chemoembolization.
characteristics. The majority of patients had a single
tumor site with a diameter <5 cm. Approximately two
thirds of patients had moderately differentiated lesions
mostly involving the liver capsule. Fifteen percent of
patients had undergone preoperative TACE.
Operative variables and perioperative outcomes
Operative and postoperative variables are summarized in
Table 2. The number of patients that underwent central
resection, right anterior sectorectomy, segment IV resection, caudate lobe resection, and nonanatomical resection
were 18, 36, 34, 4, and 27, respectively. There were no
between-group differences for resection margin, operative
time, and warm ischemia time. Thirty-three patients
required blood transfusion.
There were no cases of massive hemorrhage, but bile
leakage occurred in 4 patients, each of whom had tumors
that adhered to intrahepatic Glisson structures. Six
patients had transient liver impairment (Child’s C status
on postoperative day 7). There was no 30-day operative
mortality in this study.
Adjuvant radiotherapy and toxicity
Fifty-eight patients were allocated to receive adjuvant RT
and 51 of them received planning doses (56.90 3.60
Gy; range 46 to 60 Gy). The median interval between
Yu et al
Vol. 218, No. 3, March 2014
Table 2.
Adjuvant Radiotherapy of Central Liver Cancer
387
Operative Variables and Perioperative Outcomes
Variables
Adjuvant RT group (n ¼ 58)
Control group (n ¼ 61)
8
20
18
1
11
0 (0e0.8)
258.7 76.5
23.5 8.5
15/43
0/58
1/57
2/56
0/58
10
16
16
3
16
0 (0e0.9)
221.2 64.3
21.7 10.1
19/42
0/61
3/58
4/57
0/61
Extent of liver resection, n
Segments IV, V, and VIII
Segments V and VIII
Segment IV
Caudate lobe resection
Nonanatomical resection
Resection margin, cm, median (range)
Operative time, min, mean SD
Warm ischemia time, min, mean SD
Blood transfusion, yes/no, n
Postoperative massive hemorrhage, yes/no, n
Postoperative bile leakage, yes/no, n
Transient liver impairment, yes/no,y n
30-day operative mortality, yes/no, n
p Value
0.62
0.65*
0.71
0.76
0.52
d
0.62
0.68
d
Normal distributed continuous variables were expressed as mean SD and compared by Student’s t test. Categorical variables were compared by chi-square
test or Fisher’s exact test as appropriate.
*Compared by Wilcoxon test.
y
Child’s C status on postoperative day 7.
RT, radiotherapy.
surgery and initiation of RT was 48 days. The toxicity
associated with RT is summarized in Table 3. Dermatitis,
vomiting, diarrhea, and gastroduodenal ulcer were
seldom observed. Four patients (7.8%) experienced grade
2 fatigue and 2 patients (3.9%) complained of grade 2
nausea. Myeloid suppression was the most common toxic
effect (n ¼ 32); however, grade 3 myeloid suppression
developed in only 1 patient (1.9%). Toxicity usually
occurred in the acute stage; late toxicity was rare. There
were no cases of radiation-induced liver disease.
Recurrence
Recurrence developed in 24 patients (41.3%) in the adjuvant RT group and 31 patients (50.8%) in the control
group (p ¼ 0.30, chi-square test). There were no
between-group differences in intrahepatic and extrahepatic recurrence, or single lesion and multiple lesion of
intrahepatic recurrence (Table 4).
Table 3. Observed Toxicity during and after Adjuvant
Radiotherapy (n ¼ 51)
Toxicity grade*
0
1
2
3
Dermatitis
Fatigue
Nausea
Vomiting
Diarrhea
Gastroduodenal ulcer
Myeloid suppression
Radiation-induced liver disease
49
39
40
50
50
51
19
51
2
8
9
1
1
0
18
0
0
4
2
0
0
0
13
0
0
0
0
0
0
0
1
0
*Based on the National Cancer Institute Common Terminology Criteria
for Adverse Events (version 3.0).
Thirty-four patients received TACE as the main initial
therapy for recurrence. Nine patients received potentially
curative treatment for recurrence of HCC, including
radiofrequency ablation in 7 patients and surgery in 2.
No patients underwent liver transplantation.
The 1-, 3-, and 5-year recurrence-free survival rates for
all the patients were 75.2%, 48.3%, and 27.8%, respectively. The percentages were 78.1%, 56.5%, and
36.8%, respectively, in the RT group and 72.4%,
40.1%, and 16.0%, respectively, in the control group
(Fig. 2). The differences were not statistically significant
(log-rank test, p ¼ 0.06).
Survival
Median follow-up was 41 months. In the adjuvant RT
group, 11 patients died as a result of tumor progression
and 1 patient suffered a fatal myocardial infarction. In
the control group, causes of death were tumor progression
(12 patients) and liver failure (1 patient).
The 1-, 3-, and 5-year overall survival rates for all
patients were 92.8%, 73.1%, and 48.3%, respectively.
The percentages were 96.2%, 72.6%, and 48.4%, respectively, in the adjuvant RT group and 89.6%, 74.5%, and
37.2%, respectively in the control group (Fig. 3). The difference was not statistically significant (log-rank test,
p ¼ 0.48).
Subgroup analysis
We further analyzed a subgroup of patients with small
HCC tumors (diameter 5 cm), including 45 patients
in adjuvant RT subgroup and 40 patients in control
388
Table 4.
Yu et al
J Am Coll Surg
Adjuvant Radiotherapy of Central Liver Cancer
Characteristics and Treatment of Recurrent Hepatocellular Carcinoma
Variables
Adjuvant RT group (n ¼ 58)
Control group (n ¼ 61)
p Value
24
21
14
7
3
41
31
26
16
10
5
22
0.30
>0.99
0.72
0.72
0.78
d
0.73
16
4
0
1
3
18
3
2
2
6
No. of recurrences
Intrahepatic recurrence*
Single lesion of intrahepatic recurrence
Multiple lesion of intrahepatic recurrence
Extrahepatic recurrence*
Median recurrence-free survival time, mo
Treatment for recurrencey
TACE
RFA
Surgery
Molecular targeted therapy
Supportive treatment
Variables were compared by the chi-square test or Fisher’s exact test as appropriate.
*The first recurrences that were recorded.
y
The initial treatment for the first recurrence.
RFA, radiofrequency ablation; RT, radiotherapy; TACE, transarterial chemoembolization.
subgroup. There was no between-group difference in the
ratio of patients who underwent null-margin resection
(29 in adjuvant RT group and 27 in control group;
p ¼ 0.82, chi-square test). The 1-, 3-, and 5-year
recurrence-free survival rates in this subgroup were
85.8%, 56.2%, and 33.4%, respectively. The percentages
were 88.8%, 67.4%, and 42.9%, respectively, in the
adjuvant RT group and 82.3%, 42.9%, and 21.5%,
respectively, in the control group (Fig. 4). The difference
between the groups was statistically significant (log-rank
test, p ¼ 0.03).
The 1-, 3-, and 5-year overall survival rates among
patients with small HCC tumors were 96.2%, 78.8%,
and 71.6%, respectively. The percentages were 97.5%,
Figure 3. Overall survival curves for adjuvant radiotherapy (RT) and control groups (p ¼ 0.48,
log-rank test).
Vol. 218, No. 3, March 2014
Yu et al
Adjuvant Radiotherapy of Central Liver Cancer
389
Figure 4. Recurrence-free survival curves for adjuvant radiotherapy (RT) and control subgroups
with hepatocellular carcinoma 5 cm in diameter (p ¼ 0.03, log-rank test).
75.3%, and 75.3%, respectively, in the adjuvant RT
group and 94.7%, 84.1%, and 65.4%, respectively, in
the control group (Fig. 5). This difference was not significant (log-rank test, p ¼ 0.92).
DISCUSSION
Surgical resection remains the most effective treatment
modality for HCC. Many postoperative procedures
have been investigated as strategies to reduce recurrence.
These include TACE, molecular targeted therapy, and
adjuvant iodine-131 lipiodol therapy. However, the success of these interventions is variable.41-49
The role and status of RT as postoperative adjuvant
therapy for HCC is not clearly defined. The liver has
low tolerance for RT, which is reduced by the presence
of cirrhosis, which means that traditional RT can only
be used in small doses that minimize the risk of liver
toxicity.4,5 Research also suggests that multiple clones of
premalignant cells are harbored in damaged liver tissue,
which might be responsible for multicentric carcinogenesis. In addition, intrahepatic dissemination before
surgery is not unusual and is associated with recurrence.23,50,51 If this is true, then adjuvant RT focused on
surgical site alone would not be sufficient.
Other studies have found evidence that a resection
margin <1 cm might be an adverse prognostic factor.
Both anatomic and nonanatomic hepatectomy for HCC
are generally undertaken to ensure a safe resection margin
(>2 cm).22,24,29,31,32,34 Consequently, the additional value
of adjuvant RT might be reduced in patients who have
undergone safe margin resection.
Centrally located HCC is often situated in the deeper
portions of the liver and adjoins main vascular structures.
Sometimes combined resection and reconstruction of
major veins is involved because of tumor invasion, making
hepatectomy more difficult. In this study, all eligible
patients underwent hepatectomy with narrow margin
(<1 cm). Surgical safety and outcomes are comparable
with other studies previously reported for mesohepatectomy.13-19,52 Several patients underwent preoperative
TACE due to large tumors. But cases of substantial reductions in tumor size were rare. This procedure also increased
operative difficulties and risk of liver damage. The indication
of neoadjuvant therapy for HCC still needs to be explored.
It has been shown that 3D-CRT spares nontarget tissue
and maintains adequate coverage and dose of the clinical
treatment volume.6-12 In a multicenter retrospective study
of 398 patients with HCC, RT was performed predominantly using the 3D-CRT (81.9%), mostly with a total
doses 45 Gy after failure of other treatments. The biologically effective dose (>53.1 Gy) was shown by multivariate
analysis to be a significant prognostic factor associated with
increased 2-year overall survival.9 Another study of 158
390
Yu et al
Adjuvant Radiotherapy of Central Liver Cancer
J Am Coll Surg
Figure 5. Overall survival curves for adjuvant radiotherapy (RT) and control subgroups with
hepatocellular carcinoma 5 cm in diameter (p ¼ 0.92, log-rank test).
patients indicated that total dose was the most significant
factor for tumor response, with response rates of 29.2%,
28.6%, and 77.1% being achieved at doses of <40, 40 to
50, and >50 Gy, respectively.53 A third study in 45 HCC
patients with major portal vein occlusion reported a
median total dose of 61.2 Gy, with 39 of 45 patients
(86.7%) receiving doses higher than 64 Gy. The relatively
high-irradiated dose contributed to a favorable response
rate of 62.3%. Nausea and abdominal pain were the most
common acute and late toxic effects. No clinically significant radiation-induced liver disease was noted.39
In our study, the tumor cutting bed was indicated by silver marks during surgery to assist accurate orientation for
3D-CRT. Total doses ranged from 46 to 60 Gy. Myeloid
suppression was the most common toxic effect, but only
1 patient had acute grade 3 myeloid suppression. No other
grade 3 or higher toxicity and no cases of radiation-induced
liver disease were observed. The findings provided evidence
of safety for postoperative RT of centrally located HCC.
The intention-to-treat analysis showed no significant differences in recurrence-free survival rates between the adjuvant
and control groups. Theoretically, postoperative RT should
improve the local control rate. Some patients in our study
had poor treatment compliance and gave up adjuvant RT
by themselves. Although there is no standardized preventive
treatment for patients who have undergone narrow-margin
resection, the “traditional adjuvant therapies,” including
preventive TACE or systematic therapies, were not be
excluded for ethical reasons in the study. These factors might
have impacted the analysis to some extent. In this study,
typical resection margin recurrence was not common and
will also require more extensive research.
Subgroup analysis of patients with small HCC lesions
showed that recurrence-free survival was significantly
longer with adjuvant RT than in the control group,
implying that the benefit of adjuvant RT was more prominent in lesions 5 cm in diameter. However, this is
a post-hoc nonrandomized subgroup comparison, and
this finding should be validated in more in-depth studies.
The removal of large tumors is associated with increased
postoperative morbidity and mortality, which is often exacerbated by cirrhosis. It is likely that larger intrahepatic
tumors begin to spread to other hepatic sites before the start
of adjuvant RT. Therefore, RT aimed at improving the
local control rate would not necessarily prevent the recurrence of these large lesions. In addition, large tumors are
often associated with larger parenchymal transection planes
and require major hepatectomy, which complicates the accurate location of adjuvant RT. Identification of biologybased predictors of outcomes in patients with HCC will
contribute to more effective use of adjuvant RT.
Effective therapeutic strategies for recurrent HCC are
critical in prolonging survival after resection of HCC.
Repeat hepatectomy, TACE, radiofrequency ablation,
Vol. 218, No. 3, March 2014
Yu et al
systematic therapies, and molecular targeted therapy are all
available. However, the management of patients with recurrent HCC is dependent on numerous factors, including
physical conditions; liver function grade; and number,
size, and location of tumors. The absence of large randomized controlled trials comparing different treatment models
means that the current evidence is not sufficient to determine the best initial therapy or to develop a standardized
guideline for recurrent HCC. Also, our study protocol
lacked a standardized approach to guide the management
of patients with recurrence. We were unable to demonstrate
differences in 1-, 3-, and 5-year overall survival rates (irrespective of lesion size) between adjuvant RT group and control groups. We believe that differences in initial therapies
for recurrence of HCC might have impacted overall survival
to some degree. Therefore, changes in recurrence-free survival were not reflected in overall survival.
CONCLUSIONS
Adjuvant RT for centrally located HCC after hepatectomy
with narrow margin was technically feasible and acceptably
safe. Patients who received adjuvant RT had recurrencefree and overall survival after narrow-margin hepatectomy
for centrally located HCC similar to patients in the
control group. However, the post-hoc subgroup comparison showed that adjuvant RT significantly improved
recurrence-free survival in patients with small HCC lesions
(5 cm), although overall survival was not increased. We
still need more carefully designed prospective clinical trials
to confirm whether the potential is realized to improve the
prognosis of patients.
Author Contributions
Study conception and design: Yu, W Wang, J Wu
Acquisition of data: Yu, W Wang, Rong, L Wang, Xu, F
Wu, Liu
Analysis and interpretation of data: Yu, W Wang, Rong,
L Wang, Liu, J Wu
Drafting of manuscript: Yu, W Wang, J Wu
Critical revision: W Wang, Rong, Liu, J Wu
Acknowledgment: The authors would like to acknowledge
Professor Yexiong Li, Professor Jing Jin, and the faculty of
Radiation Oncology Department at Cancer Institute and
Hospital of Chinese Academy of Medical Science for their
participation in the study.
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