What is the best chemotherapy regimen for TACE treatment of HCC?

Lipiodol Trans-arterial Chemoembolisation of Hepatocellular Carcinoma Optimised by Idarubicin: Preliminary Results

Authors:

Sylvain Favelier,1 Mathieu Boulin,2 Samia Hamza,3,4 Jean-Pierre Cercueil,1,4Violainne Cherblanc,1Côme Lepage,3,4 Patrick Hillon,3,4Bruno Chauffert,5Denis Krausé,1Boris Guiu,1,4

1 Department of Diagnostic and Interventional Radiology, University Hospital, Dijon, France

2Department of Pharmacy, University Hospital, Dijon France

3Department of Hepatology, University Hospital, Dijon, France

4 INSERM U866, University Hospital, Dijon, France

5Department of Oncology, University Hospital, Amiens, France

Corresponding authors:

Department of Diagnostic and Interventional Radiology

Digestive, Thoracic and Oncologic Unit

University Hospital of Dijon

14, rue Paul Gaffarel

21000 Dijon

France

Phone: +33 380 293 686 Fax: +33 380 295 455

Email:

Running Head: TACE Optimisation by Idarubicin

Category: Clinical investigation

Word Count = words (including text)

This paper contains X tables and X figures

Disclaimer: None of the authors has any conflicts of interest to declare regarding this study.

Financial Support: No

Abbreviations:

TACE, Transcatheter arterial chemoembolisation; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; ALP, Alkaline phosphatises; GGT, Gamma glutamyltransferase; 95%CI, 95% confidence interval

Lipiodol Trans-arterial Chemoembolisation of Hepatocellular Carcinoma Optimised by Idarubicin: Preliminary Results

ABSTRACT (XXX words)

Purpose:

Materials & Methods:

Results:

Conclusion:

Keywords: liver cancer; cirrhosis; predictor; survival; chemoembolization

INTRODUCTION

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide [1]. Since only 30% of patients can be treated for cure, palliative treatment options are applied in most cases [2]. For unresectable intermediate-stage HCC, transarterialchemoembolisation (TACE) has a central role [3].Although TACE has been shown to prolong survival in two randomisedcontrolled trials and two meta-analyses[4], this procedure varies highly across centers and interventional radiologists, especially regarding the anticancer drug[5]. Only one randomized trial was designed to compare embolization alone versus TACE (versus best supportive care) for HCC[6]. Unfortunately, this 3-arm trial wasprematurely stoppedbecause TACE was demonstrated to be more efficient than best supportive care. Although there is currently no level one evidence on the benefit of chemotherapy in TACE, the recent introduction of drug-eluting beads helped to demonstrate a clear activity of chemotherapy in both animal [7, 8]and human [9, 10]studies, thanks to the comparison between loaded and unloaded beads.

One of the key theoretic advantages of TACE is tumor exposure to high concentrations of the chemotherapeutic drug [11]. Doxorubicin and cisplatin are the most widely used drugs for TACE [5] although no preclinical study or randomized controlled trial hasever support their use rather than that of other drugs.Since there is still no consensus about the best chemotherapeutic agent, a very recentin vitro study was designed to screen for the best drug, by comparing the cytotoxicity of multiple anticancer drugs on human HCC cell lines. This screening study demonstrated that idarubicin, an anthracyclin commonly used to treat leukemias, was by far the most cytotoxic drug on three HCC cell lines [11]. HCC is considered as one of the most resistant tumor to chemotherapy [12]. This is partly related to the multi-drug resistance (MDR) mechanism causing an increased ATP dependent efflux of drugs from within to outside the cells. Indeed,MDR proteins overexpression may account for resistance to various drugs including doxorubicin and cisplatin[13, 14].Interestingly, besides its high cytotoxic effect,idarubicin has also the ability to overcome multi-drug resistance (MDR)[11]. Furthermore, idarubicin is much more lipophilic than doxorubicin [15], leading to higher penetration through the lipidic double layer of tumor cell membranesand thus, to a higher efficacy. We can take advantage of this higher lipophiliafor TACE of HCC by combining idarubicinwith ethiodized oil which could result in a greater accumulation of the drug in the oily phase, permitting lipiodol to act as a slow-releasing vector.

To our knowledge, idarubicin has never been used intra-arterially to treat liver tumors and especially HCC. Therefore, we designed this preliminary human study to evaluate the safety and efficacy of lipiodol-TACE using idarubicin.

PATIENTS AND METHODS

Patients

The approval of the institutional review board was obtained to retrospectively evaluate the combination of idarubicin and lipiodol TACE of unresectable HCC.

Twenty-one consecutive patients treated by lipiodol TACE for a HCC at our institution between January 2010 and June 2010 were enrolled in this study. Indications for TACE were decided for all patients at our weekly multidisciplinary meeting of digestive oncology in the presence of interventional radiologists, gastroenterologists, hepatic surgeons, radiation therapistsand oncologists. Inclusion criteria were : Patients were diagnosed using either a liver biopsy or non-invasive AASLD criteria [16], Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1 or 2, preserved liver function (Child-Pugh class A or B7), platelet count >50 x 109/l, cardiac ejection fraction>50%. Exclusion criteria were candidacy for liver resection, biliary tract dilation, bilioenteric anastomosis, hepatofugal blood flow, thrombus within the main portal vein, extrahepatic metastases, serum creatinine level ≥150 µmol/l (renal failure), allergy to iodine-containing agents, pregnancy and previous treatment by TACE. Patients gave their informed consent for the TACE procedure.

Liver involvement was assessed on baseline imaging data (CT or MRI) obtained within one month before TACE. Baseline liver enzymes (AST [Aspartate aminotransferase], ALT [Alanine aminotransferase], ALP [Alkaline phosphatases], GGT, total bilirubin, prothrombin) were systematically obtained within 7 days before the first TACE session.

Idarubicin-lipiodolEmulsion: in vitro evaluation

The emulsion was prepared by mixing an equal volume of iodized oil (lipiodol; Guerbet, Aulnay-sous-Bois, France) and 1mg/ml idarubicin(Zavedos®, Pfizer, Paris, France) through a 3-way tap from one 5-ml syringe to another one (10 passages). The physical stability of the idarubicin-ethiodized oil emulsion was examined at 37°C. Thirty minutes after the preparation, the phase separation for idarubicin-ethiodized oil emulsion was limited (5% aqueous solution and 95% persisting emulsion). The size distribution of the droplets of idarubicin-ethiodized oil emulsion was 20-100 µm, as measured by an inverted fluorescent microscope (λexcitation=485 nm) associated with AxoVision image analysis software for acquisition and image processing (Cell Observer, Carl Zeiss, Paris, France) (Fig. 1).

TACE procedure

TACE was performed through a femoral access with a 5-F catheter. The patency of the portal branches was confirmed during the venous phase of an injection into the superior mesenteric artery. Then, selective catheterisation of the proper hepatic artery was performed. When accessory hepatic arteries were present, they were catheterised successively. Digital subtraction angiography and arterial CT imaging (when available) were used to plan the treatment. Depending on the degree of liver involvement, selective catheterisation of the artery feeding the tumors was performed. A microcatheter was used when needed. As detailed above, a mixture of 10-mg idarubicinand 10-ml iodized oil was injected in about 5 min, followed by the injection of a particulate embolic agent of the radiologist’s choice (gelatin sponge (Curaspon®, Curamedical B.V., Amsterdam, Netherlands) or unloaded beads (Embozene™, Celonova Biosciences, Paris, France) until stasis.

In cases of unilobar disease, the artery feeding the affected lobe was selectively catheterized with a microcatheter when needed (2.7-F or 2.4-F Progreat; Terumo Europe, Leuven, Belgium). In case of bilobar tumor involvement, one lobe was treated during the first TACE session while the other one was treated 6 weeks later. A cycle of TACE was defined as the one, two or more sessions required to treat all liver nodules. Patients received systematic antiemetic medication using ondansetron (8 mg) and on-demand pain medication.

Follow-up

Liver imaging was systematically performed by MRI (3T Siemens Trio TIM, Erlangen, Germany). Baseline imaging was performed 7 days or any hospitalisation within the month after TACEpossibly, probably, or definitely attributed to TACE. Secondary endpoints were tumor response according to modified Response Evaluation Criteria In Solid Tumors (mRECIST) at MRI 1 month after completion of the first cycle of TACE, time to treatment failure and overall survival.

Statistical analysis

Categorical variables were described using percentages. Continuous variables were expressed as means and standard deviations. Because several patients had repeated TACE sessions, biological data from all sessions were not pooled. The serum levels of liver enzymes were compared before and after the first TACE session using the Wilcoxon signed-rank test. Time to treatment failure (TTTF) was defined as the time from the first TACE session to TACE discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death. OS was defined as the time from the first TACE session to death (all causes). Survival curves were estimated using the Kaplan-Meier method and compared using log-rank tests. All analyses were performed using Stata software version 10.0 (Stata corporation, College Station, TX, USA). A p-value below .05 was considered significant.

RESULTS

Baseline characteristics

The baseline characteristics of the 21 patients are listed in Table 1. Mean age was 68,6 ± 8,6 years. All patients were cirrhotic and the cause for cirrhosis was alcohol abuse in 7 patients (33,3%), viral in 6 patients (28,6%), NASH in 3 patients (14,3%), NASH / viral or alcohol in 3 patients (14,3%), and hemochromatosis in 2 patients (9,5%). All patients had a PS of 0-1 and the majority had a Child-Pugh A class liver function (85.7%). Most patients (81%; 17/21) had a multifocal HCC. The mean total tumour size was 97,6± 62,9 cm, and the largest nodule size 51,3 ±23 cm.The mean baseline serum level of liver enzymes was 15,63 ± 10,8 µmol/l for total bilirubin, 57,0 ± 31,4 IU/l for ALT, 58,2 ± 31,1 IU/l for AST, 275,2 ± 237,6 IU/l for GGT, 128,2 ± 60,6 IU/l for ALP and 76,5 ± 21,5% for PT.

TACE procedure

TACE could be performed in all cases without technical failure. A total of 55 sessions were performed, representing 22 TACE cycles, including four patients who underwent one session for unilateral disease, fourteen who underwent 2-3 sessions and three patient who underwent >3 sessions for bilateral disease. In all sessions, 100% of the lipiodol-idarubicin emulsion could be injected. Embolisation was conducted using gelfoam in 83.4% (46/55) and 250µm- calibrated microspheres in 16.4% (9/55) of patients.

TACE-Related toxicity

Median hospital duration was 4 days (range: 3 – 14). Post-embolization syndrome was observed after 30.9% (17/55) of sessions.

No patient died from a TACE-related complication. At least one grade ≥3 AEoccurred in 19% (4/21) of patients. One patient experienced a severe TACE-related toxicity (grade 4 with prolonged hospitalisation) due to severe hypoxia requiring intubation after the second TACE session. Treatment was changed tosorafenib in this patient. Corresponding grade 3 AEs were: one renal failure associated with global cardiac decompensation, one lobar pneumonia requiring antibiotherapy (this patient was rehospitalised within the month following TACE session), and in another patient, hepatic pain necessitating morphin administration during 2 days.

At 1 month after the first TACE session, serum level of liver enzymes was 19.9 ± 14.2 µmol/l for total bilirubin, 71.2 ± 70.1 IU/l for ALT, 58,2 ± 31,1 IU/l for AST , 211.5 ± 151.2 IU/l for GGT, 180.1 ± 135.1 IU/l for ALP and 78.8 ± 19.2% for PT. These levels did not significantly differ from those recorded before TACE, except for GGT (significantly lower after TACE, p=0.037) and ALP (significantly higher after TACE, p=0.042).

Response, Time to Treatment Failure (TTTF) and Overall Survival (OS)

One month after the end of the first cycle of TACE, no progression was encountered, 4 patients (24%) exhibited stable disease, 12 (57%) exhibited a partial response, and 5 (19%) had a complete response.

Median follow-up lasted 8.4 months (range: 3.2–19 months). Treatment failure occurred before data cut-off in 9 patients. Median TTTF was 16.7 months. At 6 months, 94.7% (95%CI: 68.1% - 99.2%) of patients did not reached treatment failure, whereas treatment failure was not reached in 50.6% (95%CI: 21.6% - 73.9%) of patients at 1 year (Figure 2). Six patients died before the data cut-off. OS was 83.5% (95%CI: 57%-94.4%) at 1year.

DISCUSSION

To our knowledge, no previous study has been published using idarubicin injected intra-arterially. Therefore, safety data are crucial. There are very few papers reporting reliable toxicity data in conventional TACE. Given its prospective collection of AEs in the two arms (drug-eluting beads and lipiodol-TACE), the phase II randomised PRECISION V trial which is the largest published study on TACE to date, may serve as a standard for comparison of AEs.In our study, the 19%-occurrence of ≥3 AE compares favorably to the 29.6% incidence of serious AEs (defined as events resulting in death; immediately life-threatening; resulting in permanent/significant disability/incapacity; requiring or extending inpatient hospitalization or congenital anomaly/birth defects) reported in the Precision V trial [17] with doxorubicin lipiodol-TACE. In another paper reporting on the same trial[18], the overall incidence of the postembolisation syndrome was higher than that reported here (72%vs 30.9%). In our study, serum level of AST, ALT and bilirubin returned to baseline levels after 1month, as reported in PRECISION V [18].Unfortunately, no data was provided in this trial regarding serum levels of GGT and ALP.Interestingly, in our series we did not observe dilated bile ducts, portal vein narrowing, portal veinous thrombosis or biloma/liver infarct after TACE, whereas such liver/biliary toxicities have been reported in a recent paper [19]. Therefore, toxicity profile of idarubicin used for lipiodol-TACE does not seem to be different from that observed with doxorubicin. Although the number of patients is limited, patient rate with an objective response (76%) also compares favourably to those reported with doxorubicin either in PRECISION V (43.5% in cTACE)[17] orin a large retrospective study on cTACE using doxorubicin, cisplatin and mitomycin C(64%) [20]. However, it should be kept in mind 1) that tumor response has not been validated as a surrogate for overall survival and 2) that only phase III studies could demonstrate a superiority of idarubicin over doxorubicin for TACE of HCC.

A systematic review published by Marelli et al. showed that the most widely used drugs for TACE were doxorubicin (36%), cisplatin (31%) and epirubicin (12%) [10]. However, until recently, there was no rationale to use one drug over another one. Indeed, systemic chemotherapy is considered ineffective in HCC [2, 12] and thus, cannot bring help to select the best anticancer agent to use for TACE. Moreover, only two randomized controlled trials were designed to compare drugs (doxorubicin versus epirubicin) but failed to demonstrate superiority in survival[21, 22].

Very recently, a preclinical cytotoxicity study compared the cytotoxicity of anticancer agents on human HCC cell lines in order to select the best candidate for TACE. Eleven chemotherapeutic agents were tested, including the most frequently used for TACE. Among them, idarubicin (an anthracyclin) was by far the most cytotoxic. The superiority of idarubicin (especially over doxorubicin) was observed most notably on the SNU-449 cell line, known for its resistance to various chemotherapeutic agents [14]. The greater cytotoxicity of idarubicincan be explained by two different mechanisms: 1) idarubicin has a higher hepatic penetration compared to other anthracyclines[27]. This may be related to its high lipophilicity, enabling easier intracellular penetration through the cell membrane composed of a double layer of lipids.2)idarubicin has the ability to overcome the multidrug resistance (MDR) system [28]. The MDR mechanism consists in pumping drugs out of cells and is classically observed in HCC [14, 39, 40]. Both the higher lipophilicity and the ability to overcome MDR could account for a greater accumulation of idarubicin in HCC cells, and therefore a greater efficacy. Interestingly, idarubicinused orally (5mg/days for 21-days periods) to treat HCC has been demonstrated to be safe and active [33], but has never been used intra-arterially so far. Idarubicin is a key-drug used in hematology to treat acute leukemias [31] with a known toxicity profile, mainly hematological and cardiac. Interestingly in our study, we did not observe any grade 3/4 cardiac or hematologicial AE. This is not surprising given the dose used in this series (10mg). Cardiac toxicities of idarubicin and doxorubicin occur when total cumulative dose are 93 mg/m2 and 550 mg/m2 respectively. For example, with a mean 1.8m2-patient, we can theoretically administer 18 sessions of TACE using 10mg of idarubicin before reaching cumulative cardiac toxicity. Our 10mg-dose is far from the doses of idarubicin used in hematology (commonly 12 mg/m2 each day for 3 consecutive days, or 8mg/m2 each day for 5 consecutive days) which are frequently marrow suppressive. But, if we chose to administer only 10mg idarubicin for cTACEbased on these safety data, we are not sure whether or not this dose is optimal. In oncology, only phase-I studies with escalation dose allow to determine the maximum-tolerated dose and then, the optimal dose for treatment. But, to our knowledge, this scientific approach has never been used for TACE treatment since no phase I TACE study has been published so far. This lack of phase I TACE studies certainly accounts for the wide variations in dose used for TACE in the litterature[5], as it is the case for example with doxorubicin whose doses range between 50-150mg / session.

Although a very recent monocentric and retrospective study performed in Asia showed a benefit in response and survival for DEB-TACE over cTACE[23], there is still no level one evidence of the superiority of drug-eluting beads. Here we report on cTACE using a lipiodol/idarubicin emulsion. We took advantage of the higher lipophilicity of idarubicin, resulting in a great accumulation of the drug in the oily phase thereby permitting lipiodol to act as a slow-releasing vector. Favoulet et al. demonstrated that lipiodol-doxorubicin emulsion was completely separated into two phases (oil and aqueous) after 20 minutes[24]. On the contrary, the phase separation for lipiodol-idarubcin emulsion was very limited (5% aqueous solution and 95% persisting emulsion) and fluorescent electronic microscopy showed that idarubicin was inside and at the periphery of lipid droplets due to drug/lipid ionic interactions. This enhanced emulsion stability is certainly an advantage to increase the contact time of the drug with cancer cells, as previously reported[24].

This study has several limitations including its retrospective design, the limited number of patients, and the relatively short follow-up. As previously mentioned, we used an empiric dose based on IV safety data of idrubicin. This dose might not be the optimal dose. Interestingly, idarubicin can also be loaded in drug-eluting beads thanks to similar ionic properties than doxorubicin. We are conducting a phase I study to determine the maximum tolareted dose of idarubicin-loaded beads. When the data will be available, the optimal dose for idarubicin will be known.

In conclusion, idarubicin is safe and effective in cTACE of HCC. This warrants further studies to determine the potential of this drug to replace doxorubicin for TACE. Idarubicin could be an attractive option to prevent from doxorubicin shortage.

FIGURE LEGENDS

Figure 1

The emulsion was prepared by mixing an equal volume of iodized oil and 1mg/ml idarubicin through a 3-way tap from one 5-ml syringe to another one (10 passages) (A). The physical stability of the idarubicin-ethiodized oil emulsion was examined at 37°C. Thirty minutes after the preparation, the phase separation for idarubicin-ethiodized oil emulsion was limited (5% aqueous solution and 95% persisting emulsion), compared with emulsion at H0 (B).Fluorescent micrograph showing the presence of idarubicin (shown in red) on the inner surface of droplets(C).The droplets diameter was 20-100µm.

Figure 2

5cm unifocal HCC in a 60-year old patient before (A) and after (B) lipiodol TACE using idarubicin.

Figure 3

Time to treatment failure (TTTF)

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