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Use of tamoxifen in advanced-stage hepatocellular carcinoma

Use of Tamoxifen in Advanced-Stage Hepatocellular
Carcinoma

A Systematic Review
Anna K. Nowak,
M.B.B.S., Ph.D.
BACKGROUND. Hepatocellular carcinoma (HCC) is the third most common cause of
Martin R. Stockler,
M.B.B.S., M.Sc.
cancer mortality worldwide. Survival is poor for patients with advanced-stage HCC, Pierce K. H. Chow,
M.B.B.S.
and small trials of tamoxifen for patients with this disease have shown conflicting Michael Findlay,
results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen-containing arm with a nontamoxifen-containing 1 National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Syd- METHODS. Eligible trials were identified from the Cochrane Hepato-Biliary Group
ney, Camperdown, New South Wales, Australia.
register and other databases. Studies were selected for inclusion and their meth- 2 Sydney Cancer Centre, Royal Prince Alfred and odologic quality assessed by three independent reviewers. Hazard ratios (HR) were Concord Repatriation General Hospitals, Camper- derived for overall survival where possible. Metaanalysis was performed using a 3 Department of General Surgery, Singapore Gen- RESULTS. The authors identified 10 randomized trials with a total of 1709 patients.
eral Hospital, Singapore, Republic of Singapore.
Use of tamoxifen had no effect on median survival (HR, 1.05; 95% confidence 4 Cancer Trials New Zealand, University of Auck- interval, 0.94 –1.16; P ϭ 0.4) or tumor response rate. The findings were stable in sensitivity analyses and were not affected by publication bias or inclusion of low-quality studies or studies reported in abstract form only. Few adverse events or withdrawals were noted.
CONCLUSIONS. There was no support for the therapeutic use of tamoxifen in
advanced HCC, nor for its use as a control arm in future clinical trials. Cancer 2005;
103:1408 –14. 2005 American Cancer Society.
KEYWORDS: anti-estrogen, hepatocellular carcinoma, liver, neoplasm, systemic
therapy, tamoxifen.

Worldwide, hepatocellular carcinoma (HCC) is one of the most
common causes of death from malignant disease. Although less common in Western populations, it is a significant cause of death ineastern Asia and sub-Saharan Africa.1 The etiology is believed to beassociated primarily with cirrhosis, due to chronic infection with Dr. Anna Nowak is the recipient of the 2003Medical Oncology Group of Australasia/Novartis hepatitis B or hepatitis C viruses, alcohol consumption, aflatoxin, or hemachromatosis. People with HCC generally present with advanced-stage disease, although, more recently, some high-risk populations The current study is based on a Cochrane review have been targeted for screening, but the outlook is still poor in most prepared for the Cochrane Hepato-biliary Group.37 Address for reprints: Martin R. Stockler, M.B.B.S., A variety of therapeutic modalities have been used in these pa- NHMRC Clinical Trials Centre, University of Sydney, tients.2 Surgery for early-stage disease results in some long-term Locked Bag 77, Camperdown, New South Wales survivors. However, the wide applicability of resection is often limited 1450, Australia; Fax: (011) 612-9562-5000; E- by the poor synthetic function of the cirrhotic liver. The major prob- lem after resection or local ablation is tumor recurrence, which often Received August 26, 2004; revision received De- occurs in the first 24 months after surgery.3,4 Long-term results similar cember 7, 2004; accepted December 8, 2004.
to those for surgery have been reported with nonsurgical local abla- 2005 American Cancer SocietyDOI 10.1002/cncr.20963Published online 2 March 2005 in Wiley InterScience (www.interscience.wiley.com).
Tamixofen for Advanced HCC/Nowak et al.
TABLE 1
Search Strategy

Register
Search strategy
Search date
Cochrane Hepato-Biliary Group Controlled Trials (carcinoma OR neoplasm* OR cancer) AND (hepat* OR liver) AND (tamoxifen OR antiestrogen* OR anti-estrogen) Cochrane Central Register of Controlled Trials (carcinoma OR neoplasm$ OR cancer) AND (hepat$ OR liver) AND (tamoxifen OR antiestrogen* OR anti-estrogen) (exp CARCINOMA/OR exp Neoplasms/) AND (exp Liver/OR hepat$.mp) AND (exp Tamoxifen/OR exp EstrogenAntagonists/) Abstracts from the Annual Scientific Meeting of the American Society of Clinical Oncology tive therapies such as percutaneous ethanol injec- Eligibility Criteria for Inclusion in the Review
tion,5 radiofrequency ablation,6 and transarterial che- Study type
Unconfounded, truly randomized trials
moembolization.7 In addition, numerous cytotoxicagents have been investigated in trials comprising pa- Treatment with any dose or duration of tamoxifen with tients with HCC,8 and tumor response rates with sys- or without other treatment modalities versus a temically administered cytotoxic drugs are generally control arm using placebo, no intervention, bestsupportive care, or the same other treatment low, although they may be slightly higher when drugs are administered regionally, with or without emboli- zation.9 Any benefit from cytotoxic therapy must be Diagnosis of HCC according to the definitions of weighed against the associated toxicity.
individual trials (histology, cytology, or clinicalcriteria [e.g., typical imaging, raised AFP level, Ͼ 5 On the basis of the finding that some HCCs have ϫ upper limit of normal, and a history of chronic estrogen receptors (ER),10,11 several trials of the anti- estrogen, tamoxifen, have been conducted. The earli- Trials recruiting patients with apparently resected est trials were small and had conflicting results. Al- disease (testing tamoxifen as an adjuvant treatment)and trials recruiting patients with advanced or though tamoxifen has been used in both women and unresectable disease (testing tamoxifen as treatment men with malignant disease, its putative mode of ac- for advanced disease) were both eligible for tion raises the question of whether its efficacy differs inclusion; analyses were to be stratified according to There have been 3 systematic reviews of ran- domized controlled trials of treatments for HCC: hepatocellular carcinoma; AFP: ␣-fetoprotein.
HCC.12–14 Whereas the 2 earlier reviews12,13 showeda marginal increase in survival with the use of ta-moxifen in advanced HCC, both noted that further MATERIALS AND METHODS
large, well designed trials were needed to answer A search by the secretariat of the Cochrane Hepato- this question. The most recent review included fur- Biliary Group used the search strategy described in ther large trials and did not show any survival ben- Table 1. References of review articles and identifiedtrials were also searched, and experts in the field con- efit or antitumor effect for tamoxifen,14 and the tacted, but no further trials were identified.
authors noted that only the trials assessed as lower Titles of trials identified through this search strat- egy were screened for possible eligibility, and the pro- The current review extended the search beyond spectively defined eligibility criteria (Table 2) were Medline and added larger, more recent trials. The applied to each trial by 3 independent reviewers, with primary objective was to assess the effect of tamoxifen disagreements resolved by discussion. Our search on overall survival in patients with HCC. The second- identified 42 reports, of which 19 were considered ary objectives were to assess the effects of tamoxifen potentially eligible. After further screening of the on quality of life, tumor response, and treatment tox- methods sections of the studies, 10 studies were in- icity and, in addition, to assess whether there is an cluded. Reasons for excluding trials included the fol- interaction between gender and the effects of tamox- lowing: no comparison group without tamoxifen,15–17 ifen on the overall survival or response rate.
confounded controls that added another drug to treat- CANCER April 1, 2005 / Volume 103 / Number 7
TABLE 3
Study Characteristics

evaluable patients
Control arm
Experimental arm
Quality grade
Reference
i.v.: intravenous.
a Inadequate information available in abstract to classify quality.
ment in place of tamoxifen,18 studies that were not the basis of actual (where available) or estimated max- actually assessing the effect of tamoxifen,19 studies imum and minimum follow-up times. To calculate an that were assessing the affect of combination hor- overall estimate of effect but avoid including the con- monal therapy with tamoxifen and medroxyprogester- trol group twice, the 3-arm study26 was analyzed using one acetate,20 studies in which the outcome measures one-half of the control group numbers as controls for were unsuitable for analysis,21 studies with nonran- each of the 2 experimental arms. A fixed-effect model domized allocation to treatment and control arms,22,23 was used to calculate a pooled hazard ratio (HR) for and publications that were found to be review articles.
overall survival, using the derived observed minus ex- Methodologic quality was assessed independently pected number of events and the variance obtained by 3 reviewers using a modified subset of the MERGE for each trial.25 The 95% confidence intervals (95% CI) criteria,24 based on standard criteria to assess the de- were calculated for individual and aggregate estimates gree to which the study is susceptible to bias. The criteria specifically take into account concealment oftreatment allocation, generation of the allocation se- quence, blinding of treatment delivery, comparability Of the 10 trials selected, 8 were fully reported, 2 were between groups at baseline, inclusion of all random- published in abstract form only, and 1709 patients ized participants in the analysis, withdrawals from the were included (Table 3). Nine studies examined the trial, and valid assessment of end points. A global effect of tamoxifen versus placebo or no treatment on rating of quality and susceptibility to bias was then outcomes that included overall survival. One study assigned as follows: A) all or most criteria fulfilled: randomized patients to 2 different doses of tamoxifen where not fulfilled, it is believed very unlikely that the in 2 arms in addition to the control arm.26 A single conclusions of the study would be altered; B1)some study examined the effect of adding tamoxifen to che- criteria are fulfilled: where not fulfilled, it is believed unlikely that the conclusions of the study would bealtered; B2) some criteria are fulfilled: where not ful- Quality of the Studies
filled, it is believed likely that the conclusions of the The methodologic quality of the studies was variable, study would be altered; C) few or no criteria are ful- with a low risk of bias in 3 trials (Grade A: 27%),26,28,29 filled: where not fulfilled, it is believed very likely that a low to moderate risk in 3 trials (Grade B1: the conclusions of the study would be altered.
27%),27,30,31 and moderate to high risk in 3 trials Survival data were obtained indirectly using the (Grade B2: 18%).32–34 Inadequate information was methods described by Parmar et al.,25 by recording available to classify 1 further study, published in ab- actuarial survival proportions at predetermined time stract form only.35 Six studies were placebo con- points from Kaplan–Meier curves or tables. Censoring trolled,26,28,30,31,33,34 although the study by Liu et al.
was accounted for by adjusting the numbers at risk on was single-blinded only,33 and the adequacy of blind- Tamixofen for Advanced HCC/Nowak et al.
treatment, and as high as 16 months in the studyallowing previous surgery.29 Funnel plots suggest the possibility of publication bias, as there were several small trials with positiveresults, but no corresponding small trials with nega-tive results. The inclusion of unpublished and uniden-tified small trials with negative results could poten-tially show an overall detrimental effect of tamoxifen.
None of the three trials showing a low potential forbias showed any survival benefits for tamoxifen. How- FIGURE 1. Effect of tamoxifen on overall survival.
ever, this may be confounded by the use of higherdoses of tamoxifen in the studies showing the lowestpotential for bias.
ing in a further 2 studies was unclear.30,34 The remain- The stratification of analyses according to stage of der were either not placebo controlled27,29.32 or this disease (i.e., postresection vs. advanced disease) was planned, but could not be performed as no studiesincluded only postresection patients. Analysis using Patient Characteristics
only studies with histologic or cytologic confirmation The characteristics of patients in these 10 trials ap- of the diagnosis was also planned originally. However, peared similar. Their mean age ranged from 60 to 67 only 1 study, of 61 patients and overall poor quality, years in the 9 studies testing tamoxifen alone, but was fulfilled these criteria,30 and hence this analysis was lower (52 years) in the study testing tamoxifen with not done. In a further 5 trials, either histologic diag- doxorubicin.27 Most patients were male in all studies nosis or an elevated ␣-fetoprotein level together with (range, 71– 89%). Underlying liver disease was re- imaging suggestive of HCC was accepted.27,29,31–33 In ported in 98 –100% of patients. Most studies excluded these studies, a diagnosis was made without histology patients with advanced concomitant liver disease, or cytology examinations in 17%, 14%, 17%, 25%, and with all studies including Ͻ 25% of patients with 24% of patients, respectively. A further 2 studies ac- Child–Pugh Stage C liver disease, and Ͻ 25% of pa- cepted similar criteria for diagnosis, but did not report tients with Okuda Stage III disease. Only 1 study re- the number of diagnoses made without histology or ported including patients who had previously under- cytology.26,28 Criteria for the diagnosis of HCC were gone either surgery (5% of patients) or chemotherapy Effect of Tamoxifen Treatment on Overall Survival
Effect of Tamoxifen Dosage
In metaanalysis, overall survival was not affected by It has been hypothesized previously that higher doses the addition of tamoxifen (odds ratio, 1.05; 95% CI, of tamoxifen could be more effective by invoking es- 0.94 –1.16; P ϭ 0.4) (Fig. 1). This comparison showed trogen receptor-independent mechanisms of tumor no significant statistical heterogeneity (P ϭ 0.2). One inhibition.36 In the trials identified, the daily dose of trial of 420 patients was necessarily excluded from the tamoxifen varied, ranging from 20 mg in 5 tri- metaanalysis because it reported insufficient data.35 als,27,28,30,32,35 30 mg in 1 trial,33 40 mg in 2 trials,29,31 to However, it is unlikely that the availability of these 60 mg in 1 trial.34 A single 3-arm study randomized data would change the overall review conclusions, as patients to 2 high-dose levels of tamoxifen, 60 or 120 the trial showed no significant difference in median mg daily, or placebo.26 In subgroup analysis, there was survival between the tamoxifen and control arms.
an overall survival trend favoring the control arms Exclusion of the single trial published in abstract with higher doses of tamoxifen (Fig. 2). The HR for form only for which results were available30 did not overall survival was lowest for trials of tamoxifen 20 affect the results of the analysis (HR, 1.05; 95% CI, mg daily (HR, 0.88; 95% CI, 0.69 –1.44; P ϭ 0.71), 0.94 –1.17; P ϭ 0.4). Median survival for both experi- higher in trials of tamoxifen 40 mg daily (HR, 1.00; 95% mental and control arms was available for all studies CI, 0.85–1.19; P ϭ 1.0), higher still in trials of tamoxifen reviewed, but was very variable, suggesting that the 60 mg daily (HR, 1.03; 95% CI, 0.81–1.31; P ϭ 0.8), and patient groups were more heterogeneous than the highest in the single trial of tamoxifen 120 mg daily patient characteristics suggested. Median survival in (HR, 1.29; 95% CI, 1.04 –1.6; P ϭ 0.02). There is unlikely the control arm ranged from just over 1 month33 to 12 to be a place for further trials of tamoxifen dose esca- months34 in groups without any previous surgical CANCER April 1, 2005 / Volume 103 / Number 7
rubicin alone, and 16% in the group receiving doxo-rubicin plus tamoxifen, a difference that was not sta-tistically significant. There is no evidence thattamoxifen can produce objective tumor responses.
Quality of Life
Quality of life was examined in only 1 study using a
validated tool (the European Organization for Re-
search and Treatment of Cancer QLQ-C30 question-
naire), but the data were not presented in detail.26 The
authors commented that there were no appreciable
differences in global quality of life between the treat-
ment groups and that scores seemed somewhat lower
with the highest dose of tamoxifen (120 mg). Thus,
there is no evidence that tamoxifen can produce qual-
ity-of-life benefits in these patients.
Toxicity
Treatment toxicity was not described as a predefined
outcome in any study and was reported inconsis-
FIGURE 2. Effect of tamoxifen dosage on overall survival.
tently. Reports of 2 trials made no mention of toxici-ty,27,30 whereas reports of 3 trials only included com-ments that treatment was “well tolerated” or had Effect of Gender on Overall Survival
“negligible” or “minimal” toxicity.28,31,33 Reports of 3 The influence of gender on treatment effects was not trials described minor side effects such as diarrhea, an a priori objective in any of the trials. One trial thrombophlebitis, vertigo, and hot flashes in a few reported no difference in survival between men and patients.32,34,35 The 2 largest trials reported toxicity in women in post-hoc analysis.28 One trial reported a more detail.26,29 Chow et al.26 graded toxicity as mild, significant benefit of tamoxifen for men without major moderate, or severe, with 3% of patients developing hepatic insufficiency (P ϭ 0.02) but no benefit for moderate or severe toxicity, with equal numbers receiv- women (P ϭ 0.59).35 There were insufficient data for a ing tamoxifen and placebo, and in this trial 1.5% of metaanalysis on these subgroups. There was no com- patients receiving tamoxifen withdrew from treatment ment on gender differences in the only study to report because of toxicity. The CLIP-1 investigators29 reported estrogen receptor status in tumors.33 Furthermore, ER that 10% of patients receiving tamoxifen developed tox- status did not correlate with outcome in this trial.
icity, and 4% stopped tamoxifen because of toxicity. Asurprising absence was that none of the trial reports Objective Tumor Responses and -Fetoprotein
described thromboembolic events. This may reflect ei- Responses
ther coagulopathy from underlying liver disease or lack Assessment of tumor or serologic response was not an of rigor in reporting adverse events.
a priori objective of any trial. Radiologic response wasreported in only 4 trials,27,28,30,33 and in these, tumor DISCUSSION
response rates were not affected by the addition of We identified 10 randomized trials testing tamoxifen tamoxifen. Although the response criteria were not in 1709 people with HCC and found no evidence of defined, Coll et al.30 reported no partial responses (PR) benefit. There were no apparent effects on survival, and similar rates of progressive disease between tumor response rate, or quality of life. Furthermore, treated and untreated groups (78% vs. 79%). Castells et the trials with the least risk of bias tended to show that al.28 reported 1 PR (World Health Organization crite- tamoxifen was associated with increased mortality, ria) in the placebo group and the development of whereas the trials with the largest risk of bias showed progressive disease was not different between the 2 groups. Liu et al.33 reported no PRs and similar rates of Funnel plots suggested publication bias, with sev- progressive disease at 3 months (54% without tamox- eral small positive trials and no corresponding small ifen vs. 43% with tamoxifen). In the single trial com- negative trials. It is possible that there are additional, bining tamoxifen with chemotherapy, Melia et al.27 small, unpublished negative trials. Their inclusion reported a PR rate of 11% in the group receiving doxo- would improve the rigor of the current review, but Tamixofen for Advanced HCC/Nowak et al.
would not affect its conclusion, namely, that the avail- 12. Mathurin P, Rixe O, Carbonell N, et al. Review article: over- able evidence argues against use of tamoxifen in HCC.
view of medical treatments in unresectable hepatocellular Many trials identified were of low methodologic carcinoma—an impossible meta-analysis? Aliment Pharma-col Ther. 1998;12:111–126.
quality, with only two trials assessed as showing a low 13. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment potential for bias. Our findings that tamoxifen seemed of hepatocellular carcinoma: a systematic review of ran- to increase mortality in high-quality trials but have the domized controlled trials. Ann Oncol. 1997;8:117–136.
opposite effect in low-quality trials support the con- 14. Llovet JM, Bruix J. Systematic review of randomized trials for tention that low-quality trials are susceptible to bias.
unresectable hepatocellular carcinoma: chemoemboliza-tion improves survival. Hepatology. 2003;37:429 – 442.
However, we were not able to determine whether the 15. Group d’Etude et de Traitment de Carcinome Hepatocellu- difference in treatment response was due to the meth- laire. A multicenter randomized trial of anti-androgenic odologic quality of the trials or the dose of tamoxifen, (AA) treatment (leuproprelinϩ flutamideϩ tamoxifen vs ta- as this finding is confounded by the use of higher moxifen) in patients with unresectable hepatocellular carci- doses of tamoxifen in the better-quality trials.
noma (HCC) [abstract]. Hepatology. 1998;28:249A.
16. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresect- These data argue against the use of tamoxifen in able hepatocellular carcinoma with lipiodol chemoemboli- advanced HCC. Further research on the effects of ta- zation: a multicenter randomized trial. Groupe CHC.
moxifen in HCC is probably unwarranted. Tamoxifen J Hepatol. 1998;29:129 –134.
should not be used as a control arm in trials in HCC.
17. Schachschal G, Lochs H, Plauth M. Controlled clinical trial Future promising interventions should be tested in of doxorubicin and tamoxifen versus tamoxifen mono- large, well designed, randomized controlled clinical therapy in hepatocellular carcinoma. Eur J GastroenterolHepatol. 2000;12:281–284.
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tocellular carcinoma with tamoxifen and the correlation

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