THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No.

1, 2000
© 2000 by Am. Coll. of Gastroenterology ISSN 0002-9270/00/$20.00
Published by Elsevier Science Inc. PII S0002-9270(99)00747-9

Treatment of Advanced Hepatocellular Carcinoma

With Tamoxifen and the Correlation With
Expression of Hormone Receptors:
A Prospective Randomized Study
Chi-Leung Liu, M.B.B.S., F.R.C.S. (Edin), Sheung-Tat Fan, M.S., M.D., F.R.C.S. (Edin & Glasg), F.A.C.S.,
Irene Oi-Lin Ng, M.D., F.R.C.Path (U.K.), Chung-Mau Lo, M.S., F.R.A.C.S., F.R.C.S. (Edin),
Ronnie Tung-Ping Poon, M.B.B.S., F.R.C.S. (Edin), and
John Wong, Ph.D., F.R.A.C.S., F.R.C.S. (Edin), F.A.C.S.
Centre of Liver Diseases, and Departments of Surgery and Pathology, University of Hong Kong Medical
Centre, Queen Mary Hospital, Hong Kong, China

OBJECTIVES: A prospective randomized study was per-
formed to test the hypothesis that tamoxifen might improve
the survival of patients with advanced hepatocellular carci-
noma (HCC) and to correlate the response of treatment with
the expression of hormone receptors.
METHODS: One hundred nineteen patients with advanced
and otherwise untreatable HCC were included in a placebo-
controlled, single-blind trial. The patients were randomized
to tamoxifen group (61 patients) and control group (58
patients) and were prescribed with a daily dose of 30 mg of
tamoxifen and placebo, respectively. Immunohistochemical
tests for estrogen and progesterone receptors were per-
formed on the tumor tissues obtained from 66 patients. All
patients were closely monitored and the survival outcome of
the two groups of patients was compared and stratified
according to the hormonal receptor status.
RESULTS: There was no difference in the 1-month mortality
rates (32.8% vs 43.1%, p ⫽ 0.246) and the median survival
(44 days vs 41 days, p ⫽ 0.703) between the tamoxifen
group and the control group. Furthermore, the expression of
hormone receptors in the tumors did not affect the survival
outcome of the patients treated with tamoxifen. None of the
patients who survived longer than 3 months had tumor that
had partial response to tamoxifen treatment on follow-up
imaging study.
CONCLUSIONS: Tamoxifen has no efficacy in the treatment
of patients with advanced HCC and response to treatment
was not affected by the expression of hormone receptors.
(Am J Gastroenterol 2000;95:218 –222. © 2000 by Am.
Coll. of Gastroenterology)
INTRODUCTION
Because of the multifocal nature of hepatocellular carci-
noma (HCC), and its association with chronic liver disease
at a rate of ⬎80% (1, 2), as well as advanced and frequently
systemic disease on presentation, nonresectional treatment
modalities are important in the management of a significant
portion of patients with the disease. The growth of HCC has
been proposed to be modulated by estrogens (3–5), and this
has offered the rationale for evaluating the efficacy of es-
trogen receptor (ER) blockage by tamoxifen. Tamoxifen has
been reported to result in stabilization of the disease in
patients with advanced HCC (6, 7). However, randomized
studies on tamoxifen treatment for HCC has produced con-
flicting results. Two prospective randomized trials (8, 9)
showed significant prolongation of survival in the treatment
group with 1-yr survival rate of 35% and 48.5% compared
with 0% and 9.1% in the control group, respectively. An-
other double-blind placebo-controlled trial with a larger
patient number showed that tamoxifen had no efficacy in the
treatment of patients with advanced HCC (10). Furthermore,
the expression of the hormone receptors in the tumors in
these reports was not studied. Therefore, it was not clear
whether the response of treatment with tamoxifen was de-
termined by hormone receptor status. The objectives of the
present study were to test the hypothesis that tamoxifen
might improve the survival of patients with advanced and
otherwise untreatable HCC and to correlate the response of
treatment with the expression of hormone receptors of the
tumors.
MATERIALS AND METHODS
Between January 1996 to March 1998, 527 patients with
HCC were admitted to the Department of Surgery, Queen
Mary Hospital, Hong Kong. Patients with disease amenable
to hepatic resection, transarterial oily chemoembolization
(TOCE), or percutaneous ethanol injection (PEI) were ex-
cluded from the present study. Patients who had postresec-
tion recurrent disease or any form of previous treatment
AJG – January, 2000
including cryosurgery, TOCE, PEI, hepatic artery ligation,
hepatic arterial embolization, chemotherapy, or hormonal
therapy were also excluded. After evaluation, 130 patients
were considered suitable to be included in the present study.
However, 11 of them defaulted on treatment and follow-up
soon after randomization. Therefore, 119 patients were left
for analysis. The diagnosis was confirmed in 64 patients
with histology by tru’cut biopsy and in 26 patients with
cytology by fine-needle aspiration. In the remaining 29
patients, because of the presence of gross ascites, grossly
deranged clotting profile or patient’s refusal to biopsy, the
diagnosis was made with raised ␣-fetoprotein (AFP) of
more than 1000 ng/ml (normal ⬍20 ng/ml) together with
typical CT findings. The patients were randomized by draw-
ing consecutive sealed envelopes into tamoxifen group and
control group, and were prescribed with a daily oral dose of
30 mg of tamoxifen and placebo, respectively. The patients
were blind to the result of randomization and treatment.
Informed consent was obtained from all patients and the
study protocol was approved by the Hospital Ethics Com-
mittee.
All patients were closely monitored for the progress of the
disease, drug compliance, and side effects of treatment and
were seen at least every 4 wk. Monthly liver biochemistry
and serum AFP level were monitored. Indocyanine green
(ICG) clearance test and CT abdomen was performed for all
patients before randomization and after the first month of
treatment and every 3 months thereafter for monitoring of
liver function and the progress of disease. When the general
condition of the patients deteriorated, they were admitted to
the hospital for care and oral medications were supervised.
The response to treatment and disease progression were
defined by interval CT according to the criteria of the World
Health Organization: partial response, reduction in total
tumor load of ⬎50%; no change, reduction of ⬍50% or
increase of ⬍25%; and progressive disease, increase of
⬎25% (11).
After tumor tissues were obtained with ultrasound-guided
tru’cut biopsy or fine-needle aspiration, immunohistochem-
ical tests for ER and and progesterone receptor (PR) were
performed using the streptavidin– biotin complex method
and monoclonal antibodies to ER (DAKO, Glostrup, Den-
mark) and PR (Abbott Laboratories, Chicago, IL) were
used. A breast carcinoma known to be positive for ER and
PR was used as a positive control in each batch of staining.
A negative control was performed by replacing the primary
antibody with normal rabbit serum. Semiquantitative asse-
sement of the immunostaining was performed as 1% to
20%, 21% to 50%, and ⬎50% tumor cells positive for
hormone receptor. The examination was carried out by a
pathologist who was blind to the treatment given to the
patients.
Statistical analysis was performed by ␹2 test or Fisher’s
exact test to compare discrete variables and Mann-Whitney
U test was used to compare continuous variables. Survival
duration was calculated from the date of randomization and
Tamoxifen and Advanced Hepatocellular Carcinoma 219
treatment until the date of death. Survival analysis was
performed by the Wilcoxon statistical method. All p values
⬍0.05 were considered to indicate statistical significance.
Statistical analysis was made with SPSS for Windows com-
puter software (SPSS Inc., Chicago, IL). The patient sample
size calculation was performed according to the results
reported in the two previously published trials with favor-
able results (8, 9). Expecting a 5% 1-yr survival rate in the
control group, aiming to achieve a 30% 1-yr survival rate in
the tamoxifen group, and requiring a level of statistical
significance of 0.05 and a power of 0.9, 120 patients were
planned to be included in the study.
RESULTS
After randomization, 61 patients were included in the ta-
moxifen group and 58 patients were included in the control
group. Both groups of patients were identical with regard to
age, sex, liver function, ICG clearance test, Child’s–Pugh
grading (12), tumor size, tumor node metastasis (13), and
Okuda staging (14), and performance status according to
Eastern Cooperative Oncology Group (grade 0 to 4) (Table
1) (15). Upon follow-up, no significant side effects of treat-
ment were recorded in any of the patients. The overall
survival outcome of the 119 patients was poor with median
survival of only 44 days, and 45 patients (20 in the tamox-
ifen group and 25 in the control group) survived less than 1
month from the time of inclusion into the study. The
1-month mortality rate was comparable in the tamoxifen
group (32.8%) and in the control group (43.1%) (p ⫽
0.246). The causes of death in both groups of patients were
listed in Table 2. Nine months after the completion of the
study, 118 patients have died and only one patient in the
tamoxifen group survived for 20 months since treatment.
The median survival of the tamoxifen group was 44 days
and was not significantly different from that of the control
group (41 days, p ⫽ 0.703). The response to treatment was
summarized in Table 3 and was not different in both groups
of patients (p ⫽ 0.586). None of the 27 patients who
survived more than 3 months had partial response to treat-
ment. After the 45 patients with short survival of less than
30 days were excluded retrospectively, the median survival
of the 41 patients in the tamoxifen group was 67 days. This
was not significantly different from that of 82 days of the 33
patients in the control group (p ⫽ 0.39). The analysis of the
survival results of the 47 patients who survived more than
60 days showed that the survival of the 25 patients in the
tamoxifen group (median 98 days) was not different from
that of the 22 patients in the control group (median 105
days) (p ⫽ 0.359).
Although tumor tissues were obtained in 64 patients with
tru’cut biopsy and 26 patients with fine-needle aspiration,
adequate tissues were available only in 66 patients for
immunohistochemical tests for ER and PR. Among these 66
patients, ER was found to be positive in 18 patients (27.3%)
and PR was found to be positive in 20 patients (30.3%). All
220 Liu et al. AJG – Vol. 95, No. 1, 2000

Table 1. Cllinical and Pathological Data of Control Group (58 Patients) and Tamoxifen Group (61 Patients)
Tamoxifen Group Control Group
(n ⫽ 61) (n ⫽ 58) p Value
Male sex 51 55 0.077
Age (yr)* 57 (25–85) 60 (36–83) 0.318
Hepatitis B carrier 46 47 0.561
Tumor size (cm)* 8 (1.5–19) 8 (1.6–14) 0.588
Bilirubin (␮mol/L)* 26 (8–645) 30 (7–216) 0.452
Prothrombin time (s)* 12.0 (9.9–18.3) 12.2 (9.9–23.1) 0.385
AFP (ng/ml)* 3,879 (2–2,082,300) 1,377 (1–813,300) 0.675
ICG at 15 min (%)* 28 (3.4–86.1) 33.2 (5–95) 0.466
Child’s-Pugh Grading 0.386
A 37 28
B 16 21
C 8 9
TNM staging 0.138
Stage II 0 2
Stage III 13 8
Stage IVa 32 38
Stage IVb 16 10
Okuda staging 0.669
Stage I 4 6
Stage II 44 39
Stage III 13 13
ECOG performance status (14)* 1 (0–3) 1 (0–3) 0.737
* Values expressed in median with range in parentheses.
AFP ⫽ ␣-fetoprotein; ICG ⫽ indocyanine green retention; ECOG ⫽ Eastern Cooperative Oncology Group.

ER- and PR-positive tumors showed cytoplasmic positivity. beyond curative surgical resection or any other effective
Few patients had tumors that had a high concentration of local therapy including TOCE and PEI. The advantages of
hormone receptor of ⬎50% (Table 4). In the tamoxifen hormonal therapy with tamoxifen treatment are that it is
group, the median survival of the 10 patients who had cheap, simple to prescribe, and has minimal side effect.
ER-positive tumors was 33 days. The survival of these 10 Early reports with antiestrogenic treatment have been shown
patients was not different from that of the 26 patients with to result in stabilization of the disease in patients with
ER-negative tumors, with the median survival of 50 days advanced HCC (6, 7). Several prospective randomized trials
(p ⫽ 0.584). The survival result of treatment was also found (8, 9, 16) compared the survival rates of tamoxifen-treated
to be unaffected by the expression of PR of the tumors. The patients with that of untreated controls and showed a sig-
median survival of the eight patients with PR-positive tu- nificant improvement of survival in tamoxifen-treated pa-
mors was 80 days and was not different from that of the 28 tients. However, it was observed that the patients included in
patients with PR-negative tumor, which was 40 days (p ⫽ these studies were not blind to the result of randomization
0.254). Furthermore, the expression of the hormone recep- and treatment. In addition, a small number of patients might
tors did not affect the survival outcome of the patients in the
control group.
Table 3. Response to Treatment of the 119 Patients With
Advanced HCC Included in the Study According to the Criteria
DISCUSSION of the World Health Organization (11)
Tamoxifen Control
Despite efforts of screening for early detection, most of the
Group Group
patients with HCC presented at an advanced stage, which is (No. of (No. of
Patients) Patients)
(%) (%) p Value
Table 2. Causes of Death of the 119 Patients With Advanced
HCC Included in the Study At 1 month from treatment
Number of patients survived 41 33 0.296
Tamoxifen Group Control Group Partial response 0 (0) 0 (0)
Cause of Death (n ⫽ 61) (%) (n ⫽ 58) (%) No change 36 (87.8) 26 (78.8)
Malignant cachexia 52 (85.3) 53 (91.3) Progressive disease 5 (12.2) 7 (21.2)
Gastrointestinal bleeding 5 (8.2) 2 (3.5) At 3 months from treatment
Hepatic failure 2 (3.3) 3 (5.2) Number of patients survived 14 13 0.586
Multiorgan failure 1 (1.6) 0 (0) Partial response 0 (0) 0 (0)
Not applicable (still surviving) 1 (1.6) 0 (0) No change 8 (57.1) 6 (46.2)
Total 61 (100) 58 (100) Progressive disease 6 (42.9) 7 (53.8)
AJG – January, 2000
Table 4. Hormone Receptor Status of Control Group (30
Patients) and Tamoxifen Group (36 Patients)
Tamoxifen Control
Group Group
(n ⫽ 36) (n ⫽ 30) p Value
Estrogen receptor 0.775
Negative 26 22
1–20% 4 5
21–50% 3 1
⬎50% 3 2
Progesterone receptor 0.444
Negative 28 18
1–20% 5 8
21–50% 1 2
⬎50% 2 2
have resulted in statistical bias. On the contrary, a prospec-
tive randomized double-blind study with a larger number of
patients later reported by Castells et al. (10) did not confirm
the effectiveness of tamoxifen in the treatment of HCC and
the survival of patients was not modified by tamoxifen
administration. However, a meta-analysis pooling these four
randomized clinical trials in HCC reported a significant
survival advantage with tamoxifen at 1 yr (17). More re-
cently, a large multicenter Italian trial on 477 patients re-
ported that tamoxifen was not effective in prolonging sur-
vival of patients with HCC and the median survival of
tamoxifen group (15 months) was comparable to that of
control group (16 months) (18). This multicenter report
included patients from 30 institutions and the heterogenicity
of the patients created a major drawback. The fact that more
than 70% of the patients in the study received other forms of
therapy including hepatic resection and liver transplantation
made the interpretation of the results difficult.
The present study included a pure group of patients with
advanced HCC and they did not receive any other form of
treatment. The results of the present study was consistent
with the experience reported by Castells et al. (10) and
tamoxifen was found to have no efficacy in the treatment of
patients with advanced HCC. A major difference observed
in the results between the two studies was the short median
survival of our patients (about 1.5 months vs about 6
months). To avoid statistical bias, we did not purposefully
exclude any patients with advanced disease, in the elderly
age group or with impairment of liver function. The median
survival of the patients included in the present study was
similar to that of patients with advanced HCC without
treatment previously reported from Hong Kong (7.5 wk)
(19) and from Japan (1.6 months) (14). The reason for the
difference in survival results of the two studies was obscure
and it was uncertain whether our patients had more ad-
vanced disease or it was related to the difference in the
natural course of disease between Chinese and Spanish
patients. In fact, 78% of our patients had HCC related to
chronic hepatitis B infection and the corresponding figure
was only 3% in the Spanish report. It could be argued that
the negative results of our trial might be related to inclusion
Tamoxifen and Advanced Hepatocellular Carcinoma 221
of patients with very advanced disease, and short survival of
our patients could have precluded the recognition of a ben-
eficial effect. However, when patients who survived less
than 30 days in the study were retrospectively excluded, the
results were not changed. Similar results were also observed
when patients with survival less than 60 days were ex-
cluded.
The frequency of ER-positive cancers in the present se-
ries was 28% (Table 4) and was higher than that reported in
European patients (15%) (20). The survival outcome of
patients in the control group of the present study was found
unrelated to the expression of hormone receptors. The find-
ing was consistent with those reported in the literature that
the survival outcome was related to the pathological char-
acteristics of the tumors rather than the expression of ER
(21, 22). In addition, better survival outcome in female
patients after hepatic resection was also found unrelated to
expression of hormone receptors (23).
It was previously suspected that the lack of efficacy of
tamoxifen treatment could be related to the low proportion
of patients having ER-positive tumors. Assuming that tu-
mors could have responded to treatment, the overall results
were diluted by a large proportion of patients bearing ER-
negative tumors. In the five randomized studies (8 –10, 16,
18) reported previously on treatment of HCC with tamox-
ifen, hormone receptor analysis was unfortunately not per-
formed. Therefore, it was not sure whether the differences in
response to treatment were due to the difference in hormone
receptor expression. However, the results of the present
study clearly showed that the survival outcome of treatment
with tamoxifen was not related to the expression of ER or
PR of the tumors. Whether this could be the result of low
expression of ER in HCC (22) or expression of mutated ER
(24) was not clear.
In conclusion, tamoxifen has no efficacy in the treatment
of patients with advanced HCC and response to treatment
was not affected by the expression of hormone receptors.
Further studies are required to investigate the efficacy of
tamoxifen treatment in patients with less advanced disease
or in the form of combination therapy together with other
treatment modalities including TOCE and PEI.
Reprint requests and correspondence: C. L. Liu, M.B.B.S.,
Department of Surgery, University of Hong Kong Medical Centre,
Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.
Received Mar. 29, 1999; accepted Aug. 5, 1999.
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