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Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma

Original Paper
Accepted: August 6, 2008 Published online: September 17, 2008 Chemoembolization Combined with
Pravastatin Improves Survival in Patients
with Hepatocellular Carcinoma

Hannah Graf a Christoph Jüngst g Gundula Straub a Selin Dogan f Ralf-Thorsten Hoffmann b Tobias Jakobs b Maximilian Reiser b Tobias Waggershauser b Thomas Helmberger d Andreas Walter e Autar Walli c Dietrich Seidel c Burkhard Göke a Dieter Jüngst a Departments of a Medicine II, b Radiology and c Clinical Chemistry, Klinikum Grosshadern, Ludwig Maximilian University, d Department of Radiology, Klinikum Bogenhausen, and e Department of Surgery, Klinikum der Barmherzigen Brüder, Munich , and f Department of Internal Medicine, Klinikum Landshut, Landshut , Germany; g Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich , Switzerland Key Words
survival was significantly longer in HCC patients treated by Pravastatin ؒ Hepatocellular carcinoma ؒ TACE and pravastatin (20.9 months, 95% CI 15.5–26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0
months, 95% CI 10.3–13.7). Conclusion: Combined treat-
ment of chemoembolization and pravastatin improves sur-
vival of patients with advanced HCC in comparison to pa- Background/Aims: Pravastatin, a 3-hydroxy-3-methylgluta-
tients receiving chemoembolization alone.
ryl coenzyme A reductase inhibitor, has been shown to in- hibit growth and to induce apoptosis in human hepatocel- lular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, Hepatocellular carcinoma (HCC) is one of the most which prompted us to test the efficacy of pravastatin in pa- frequent malignancies and annually accounts for as many tients with advanced HCC. Methods: We investigated pro-
as 1 million deaths worldwide [1–4] . Most patients have 2 spectively a cohort of 183 HCC patients who had been diseases – chronic liver disease and HCC – and complex selected for palliative treatment by transarterial chemo- interactions between them have major implications for embolization (TACE). Fifty-two patients received TACE com- diagnosis, prognosis and the management of HCC.
bined with pravastatin (20–40 mg/day) and 131 patients The clinical course of patients with HCC is deter- received chemoembolization alone. Six independent pre- mined by both liver function and the extent of the HCC. dictors of survival according to the Vienna survival model for Transarterial chemoembolization (TACE) is a minimally HCC were equally distributed in both groups. Results: Dur-
invasive procedure that has a demonstrated ability to re- ing the observation period of up to 5 years, 31 (23.7%) out of duce systemic toxicity, increase local effects and improve 131 patients treated by TACE alone and 19 (36.5%) out of 52 overall therapeutic results, particularly in the treatment patients treated by TACE and pravastatin survived. Median of unresectable hepatocellular carcinoma [5–10] .
Department of Medicine II, Klinikum Grosshadern Ludwig Maximilian University, Marchioninistrasse 15 DE–81377 München (Germany), Tel. +49 89 7095 2376, Fax +49 89 7095 5374 E-Mail In addition to their cholesterol-lowering effects, statins with multifocal large ( 1 8 cm tumor nodules) and diffuse growing such as fluvastatin and pravastatin inhibit tumor cell tumors were not included for TACE.
All TACE procedures were performed under angiographic growth [11–14] . More recently it was demonstrated that control (Multistar TOP and Axiom Artis dTA, Siemens, Munich, pravastatin reduces progression and limits metastatic Germany) and under local anesthesia. After inserting a 4-Fr pig- diffusion in a rat model of very aggressive HCC [15] . A tail catheter into the femoral artery via a microincision in the clinical study by Kawata et al. [16] , the only one conduct- groin, a panviscerography was performed to detect potential ab- ed so far, showed that pravastatin prolongs survival of errant or additional hepatic and possibly tumor-feeding arteries. After identifying the tumor-feeding arteries, a 4-Fr catheter (e.g. patients with advanced HCC when applied after treat- cobra configuration) for selective use or a superselective micro- ment with TACE and oral 5-fluorouracil. Nevertheless, catheter, which could be placed through the primary 4-Fr cathe- the benefit of pravastatin in HCC patients has still not ter, were directed as close as possible to the tumor-feeding vessels. been characterized, which prompted us to test the effi- The embolizing moiety was prepared by extensive mixing be- cacy of pravastatin in a large cohort of patients with ad- tween 2 syringes, typically 3–5 ml lipiodol, microparticles of 150–500 ␮ m (e.g. Contour SE € , Boston Scientific, Ratingen, Germany) vanced HCC who had been selected for TACE.
and farmorubicin (1 mg/kg b.w.). The embolizing agent was then injected slowly under fluoroscopic control to avoid retrograde embolization of nontarget areas due to back spill. As soon as sta- Patients and Methods
sis within the tumor vessels occurred, the injection was stopped. Treatment was terminated if, over 5–10 min, a flow within the Our prospective cohort included 183 HCC patients (149 males tumor vessels was no longer detectable. Otherwise another injec- and 34 females, mean age 64 8 10 years) who were diagnosed and tion was performed. In cases of several main feeders these vessels staged in our institution between 2003 and 2008. Patients with early HCC (1 nodule ! 5 cm or 3 nodules ! 3 cm each) and im- One day after the procedure a baseline CT was performed to paired liver function who were considered for orthotopic liver document the storage of the embolizing agent within the tumor. transplantation were not evaluated in this investigation. Follow-up studies by triphasic (native, arterial and portal-venous) To address the problem of selection bias we determined in the contrast-enhanced CT were performed incorporating the general cohort of 183 HCC-patients 6 independent predictors of survival. clinical situation of the patient 6–12 weeks after the initial proce- These included bilirubin ( 1 2 mg/dl), portal vein thrombosis, pro- dure, and a new TACE was performed if there were signs of ‘de- thrombin time ( ! 70%), ␣ -fetoprotein (AFP, 1 125 kU/l), tumor storage’ with revascularization of the treated tumor, or if new tu-mass 1 50% and enlarged lymph nodes, according to the Vienna survival model for HCC (VISUM-HCC) [17] .
Systemic Therapy with Pravastatin . Fifty-two HCC patients Prior to therapy, 138 HCC patients presented with VISUM (41 men and 11 women, mean age 66 8 10 years) received 20–40 stage 1 (0–2 points), while 30 patients were classified as stage 2 (3 mg pravastatin as a single dose daily in addition to chemoembo- points) and 15 patients as stage 3 (4–6 points). All patients selected for TACE had advanced HCC and did not fit into the surgical criteria either for resection (due to bilateral Follow-Up and Statistical Analysis disease, inoperability due to cardiopulmonary risk factors, unre- Survival was set as the primary endpoint of the study. Follow- sectability due to proximity of the tumors to large vessels or im- up every 3–6 months was computed as starting from the begin- paired liver function) or liver transplantation (according to the ning of the treatment and was maintained until death or the last Milan criteria: fewer than 3 nodules ! 3 cm in diameter or a single visit before March 2008. Patients received clinical examination, HCC ! 5 cm in diameter) or for combined treatment with chemo- blood analysis including AFP and imaging techniques (ultra- embolization and radiofrequency ablation (tumor size ! 5 cm, sound, spiral CT or magnetic resonance imaging alternatively). fewer than 4–5 tumor nodules, no significant extrahepatic Upon detection of treatment failure or recurrence, patients were spread).
Disease extension was assessed using ultrasound, computed Probability curves obtained via the Kaplan-Meier method tomography (CT) and magnetic resonance imaging.
were compared using the log rank test, and for group comparisons Diagnosis of HCC was confirmed via needle biopsy or via ra- the ␹ 2 and Mann-Whitney tests were performed. diological criteria (2 coincident imaging techniques) or combined Calculations were done with SPSS package (SPSS Inc., Chica- criteria (1 imaging technique associated with elevated AFP levels go, Ill., USA) and the level of significance was set at p ! 0.05.
according to the Barcelona EASL Conference 2000 [18] ). Written informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declara-tion of Helsinki, as reflected in a priori approval by the institu- Table 1 depicts the characteristics of the 2 groups of Treatment Procedures Transarterial Chemoembolization . Patients not suitable for HCC patients. No significant difference between the 2 surgery or combined treatment with TACE and radiofrequency groups was detected concerning age, sex, etiology of liver ablation were considered for chemoembolization alone. Patients cirrhosis, VISUM score, AFP, presence of portal-vein Table 1. Characteristics of 183 HCC patients prior to treatment
with TACE alone or TACE and pravastatin
Fig. 1. Survival rates determined by Kaplan-Meier of HCC pa-
tients treated by combined TACE and pravastatin (n = 52) or TACE alone (n = 131). Statistical evaluation by log rank test showed an improved survival of patients treated by TACE and pravastatin compared to TACE alone (p = 0.003). Statistical analysis showed a significantly (p = 0.003) improved survival time in the subgroup of patients treat- ed with chemoembolization and pravastatin (median 20.9 months, 95% CI 15.5–26.3) compared to patients treated with chemoembolization alone (median 12.0 Kaplan-Meier plots of the 2 groups of HCC patients are illustrated in figure 1 and demonstrate the marked survival benefit to HCC patients of treatment with che- moembolization combined with pravastatin as compared HBV = Hepatitis B virus; HCV = hepatitis C virus. Discussion
thrombosis, bilirubin levels, prothrombin times and the The management of HCC has improved in recent number of TACE treatments. Enlarged perihepatic lymph years. However, many treatments for HCC have only lim- nodes were significantly (p = 0.016) more frequent in ited impact on outcome since most patients with HCC HCC patients treated with TACE and pravastatin. Fur- suffer from 2 diseases: chronic liver disease, usually at the thermore, table 1 illustrates survival time (median and stage of cirrhosis, and HCC [19] . Thus, both the extent of 95% CI) in the 183 patients with HCC who received TACE HCC and the grade of liver dysfunction affect the prog- alone or TACE combined with pravastatin. During the nosis of HCC patients. Therefore, most prognostic scores observation period of up to 5 years, 31 (23.7%) out of 131 include parameters of liver function.
patients treated by TACE alone and 19 (36.5%) out of 52 An independent evaluation of prognostic scores in a patients treated by TACE and pravastatin survived.
Central European cohort of patients with HCC has been presented recently [20] . The Child-Turcotte-Pugh score, progressive disease [22] . Potential mechanisms of resis-Okuda score, VISUM-HCC score, Chevret score, Barce- tance to cytotoxic drugs include the activation of the Ras/ lona clinic liver cancer classification and cancer of the Raf/MEK/ERK signal transduction cascade [11] and the liver Italian program score were calculated. All scores increase of cholesterol levels in cancer cells [23, 24] . The performed similarly to the Okuda score in the receiver enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reduc-operating characteristic analysis.
tase (HMG-CoAR) is known to catalyze, the rate-limit- In our prospective study we used the new VISUM- ing step in the mevalonate pathway, leading to the pro- HCC survival model [17] to characterize the cohorts of duction of isoprenoids. Isoprenoids are involved both in patients who had received treatment by chemoemboliza- the activation of Ras and in cholesterol synthesis [25] . tion alone or chemoembolization and pravastatin. The 6 Thus, HMG-CoAR is a rational molecular target for in-independent predictors of survival according to VISUM- novative antineoplastic treatment of HCC. HCC were equally distributed in both groups ( table 1 ). In addition to their cholesterol-lowering effects, statins However, the main problem of our study is that it is not such as fluvastatin and pravastatin inhibit tumor cell randomized or blinded. Indeed, most patients receiving growth [11–14] . Statins have also been shown to synergis-the additional application of pravastatin were selected by tically enhance the effects of chemotherapy and to over-the principal investigators (B.G. and D.J.) after admission come chemoresistance [26–33] . Moreover, morbid obe- to the hospital. They represent a cohort of patients with sity has been shown to be associated with increased cho-advanced HCC suitable for treatment by transarterial lesterol and HMG-CoAR levels and with liver cancer [34, chemoembolization. As illustrated in table 1 , the 6 inde- 35] . Accordingly, HMG-CoAR inhibition by pravastatin pendent predictors of survival according to VISUM-HCC prolonged the survival of patients with advanced HCC in were equally distributed between patients receiving a randomized clinical trial [16] .
TACE alone or combined with pravastatin. Thus, it is not Several preclinical trials confirm an anticancer effi- likely that a selection bias has affected the outcome of the cacy of statins, investigating the mechanisms leading to growth inhibition [36] . In a recent study, Sutter et al. [22] The success of chemoembolization relies on the fact showed that HMG-CoAR inhibitors decreased the prolif- that HCC derives its blood supply predominantly from eration of HCC cells by inducing apoptosis and cell cycle the hepatic artery, whereas the surrounding liver receives arrest. The authors suggest that the inhibition of HMG- both portal and arterial blood. Chemoembolization re- CoAR by statins is a promising novel approach for the quires catheterization of the segmental hepatic artery treatment of HCC that warrants further evaluation. This supplying the tumor and performance of an arterio- has been done in our study and our data show that pa- tients with advanced HCC have a more favorable long- Chemotherapeutic agents are then injected intra-arte- term survival if combined treatment with chemoemboli- rially and the hepatic artery is then occluded by injection zation and pravastatin is administered. These results are of material to obstruct the flow [6, 7, 21] .
in accordance with the previous randomized controlled The theoretical benefits of this approach include de- trial and support a wider application of pravastatin in livery of a high concentration of chemotherapy to the tu- HCC patients selected for chemoembolization.
mor, a marked increase in contact time between drugs and tumor cells and high rates of first-pass extraction. Thus, the drugs are concentrated in the liver and tumor Acknowledgements
while systemic effects are minimized. However, chemo-embolization is generally considered as palliative treat- The authors are grateful to Birgit Eberlein and Viera Stefanek for secretarial help. Parts of the data presented here were included ment because it does not achieve complete necrosis of the in the MD thesis of H.G. This paper is dedicated to Gustav Paumgartner on the occasion of his 75th birthday.
Thus, our patients treated with chemoembolization alone showed a less favorable prognosis in the long term. As illustrated in figure 1 , within the first year the sur-vival is about 50%, but only a few patients survived to the end of the 3-year follow-up. Drug resistance is one of the major problems of che- motherapy, which causes treatment failure and leads to References
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