Tamoxifen in the Treatment of Hepatocellular Carcinoma: 5-Year Results of the CLIP-1 Multicentre Randomised Controlled Trial

Perrone, Francesco; Gallo, Ciro; Daniele, Bruno; Gaeta, G. B.; Izzo, Francesco; Capuano, Gaetano; Adinolfi, Luigi Elio; Mazzanti, Roberto; Farinati, F.; Elba, Silvana; Piai, G.; Calandra, Maria; Stanzione, Marcello; Mattera, D.; Aiello, Andrea; Sio, Ilario de; Castiglione, Francesca; Russo, Monica Lo; Persico, Marcello; Felder, Mitchell S.; Manghisi, O. G.; Maio, Ermelinda De; Maïo, Massimo Di; Pignata, Sandro

doi:10.2174/1381612024607063

Cited by 51 publications

(34 citation statements)

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“…In a further 5 trials, either histologic diagnosis or an elevated ␣-fetoprotein level together with imaging suggestive of HCC was accepted. 27,29,[31][32][33] In these studies, a diagnosis was made without histology or cytology examinations in 17%, 14%, 17%, 25%, and 24% of patients, respectively. A further 2 studies accepted similar criteria for diagnosis, but did not report the number of diagnoses made without histology or cytology.…”

Section: Effect Of Tamoxifen Treatment On Overall Survivalmentioning

confidence: 98%

“…The methodologic quality of the studies was variable, with a low risk of bias in 3 trials (Grade A: 27%), 26,28,29 a low to moderate risk in 3 trials (Grade B1: 27%), 27,30,31 and moderate to high risk in 3 trials (Grade B2: 18%). [32][33][34] Inadequate information was available to classify 1 further study, published in abstract form only.…”

Section: Quality Of the Studiesmentioning

confidence: 99%

“…Median survival in the control arm ranged from just over 1 month 33 to 12 months 34 in groups without any previous surgical treatment, and as high as 16 months in the study allowing previous surgery. 29 Funnel plots suggest the possibility of publication bias, as there were several small trials with positive results, but no corresponding small trials with negative results. The inclusion of unpublished and unidentified small trials with negative results could potentially show an overall detrimental effect of tamoxifen.…”

Section: Effect Of Tamoxifen Treatment On Overall Survivalmentioning

confidence: 99%

“…36 In the trials identified, the daily dose of tamoxifen varied, ranging from 20 mg in 5 trials, 27,28,30,32,35 30 mg in 1 trial, 33 40 mg in 2 trials, 29,31 to 60 mg in 1 trial. 34 A single 3-arm study randomized patients to 2 high-dose levels of tamoxifen, 60 or 120 mg daily, or placebo.…”

Section: Effect Of Tamoxifen Dosagementioning

confidence: 99%

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Use of tamoxifen in advanced‐stage hepatocellular carcinoma

Nowak

Stockler

Chow

et al. 2005

Cancer

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BACKGROUNDHepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Survival is poor for patients with advanced‐stage HCC, and small trials of tamoxifen for patients with this disease have shown conflicting results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen‐containing arm with a nontamoxifen‐containing arm in advanced HCC.METHODSEligible trials were identified from the Cochrane Hepato‐Biliary Group register and other databases. Studies were selected for inclusion and their methodologic quality assessed by three independent reviewers. Hazard ratios (HR) were derived for overall survival where possible. Metaanalysis was performed using a fixed‐effect model.RESULTSThe authors identified 10 randomized trials with a total of 1709 patients. Use of tamoxifen had no effect on median survival (HR, 1.05; 95% confidence interval, 0.94–1.16; P = 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.CONCLUSIONSThere 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. © 2005 American Cancer Society.

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Section: Effect Of Tamoxifen Treatment On Overall Survivalmentioning

confidence: 98%

Section: Quality Of the Studiesmentioning

confidence: 99%

Section: Effect Of Tamoxifen Treatment On Overall Survivalmentioning

confidence: 99%

Section: Effect Of Tamoxifen Dosagementioning

confidence: 99%

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Use of tamoxifen in advanced‐stage hepatocellular carcinoma

Nowak

Stockler

Chow

et al. 2005

Cancer

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“…The results of these trials have been conflicting and inconclusive. [9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC.…”

mentioning

confidence: 99%

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

et al. 2002

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In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P ‫؍‬ .011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed. H epatocellular carcinoma (HCC) is an important malignancy worldwide. In many parts of the Asia-Pacific region, the age-standardized mortality is in excess of 20 per 100,000. Surgery currently offers the only chance of prolonged survival, but only 10% to 15% of HCCs are operable at diagnosis. 1,2 There is currently no proven treatment modality that prolongs survival in patients with inoperable HCC. 3 Estrogen receptor (ER)-positive HCC responds to treatment with tamoxifen (TMX), 4 but more than 50% of HCCs are ER negative, including HCCs found in southeast Asia. 5-8 TMX at dosages relevant for ER-positive breast carcinoma (20-60 mg/d) was nevertheless used in a number of phase 3 trials in which the ER status of HCC was not determined. The results of these trials have been conflicting and inconclusive. [9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC. 18,19 This multicenter trial was designed to test this hypothesis and

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Hepatocellular Carcinoma

Palmer¹,

Johnson²

2006

TNM Online

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Hepatocellular carcinoma (HCC) is a common tumor that is responsible for over 5% of all cancer deaths worldwide. It is highly malignant and therapy has, to date, had little impact on overall survival. Although the natural history of the disease and the essential prognostic variables are now clearly defined, we must recognize that the overall prognosis is universally poor, with most patients dying within one year of diagnosis. Part of the reason for this dismal state of affairs is that, as well as having HCC, at least 75% of patients will have an associated chronic liver disease, usually at the stage of cirrhosis. The tumor and the chronic liver disease have independent natural histories and both contribute significantly to the patient's prognosis. In a disease such as HCC, where a significant proportion of patients will die within a few weeks of diagnosis, accurate prognostication is important. Information on the expected course of the disease is essential to provide a time frame in which these unfortunate patients can sort out their affairs. In reviewing prognostic factors it is important to bear in mind that the tumor is relatively rare in the West where the incidence is only in the order of 1–2/100,000 compared to over 50/100,000 in many areas of Africa and the Far East. There is therefore a tendency for patients in the West to be referred to a few specialist centers, and this process can be the source of considerable bias in reported series. For example, the figure for the rate that HCC can be resected with curative intent, an essential determinant of prognosis, has been reported to be up to 40% in series from Western surgical units. This may reflect, however, the fact that only those patients who the referring physician perceives to be good candidates for resection are referred and operated upon. The “true” rate is nearer to 10%. Another consequence of the wide geographic variation is that surgeons in high‐incidence areas may have significantly more experience of operating on HCC in cirrhotic livers and may expect better results.

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Tamoxifen in the Treatment of Hepatocellular Carcinoma: 5-Year Results of the CLIP-1 Multicentre Randomised Controlled Trial

Abstract: the update of the present study confirms that tamoxifen is not effective in prolonging survivals, both in advanced patients and in those potentially curable and that the CLIP score is able to predict prognosis.

Cited by 51 publications

References 0 publications

Use of tamoxifen in advanced‐stage hepatocellular carcinoma

Use of tamoxifen in advanced‐stage hepatocellular carcinoma

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

Hepatocellular Carcinoma

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