Microwave ablation versus transarterial chemoembolization in large ...

Scandinavian Journal of Gastroenterology. 2015; 50: 479–484

ORIGINAL ARTICLE

Microwave ablation versus transarterial chemoembolization in large hepatocellular carcinoma: prospective analysis

ASHRAF OMAR ABDELAZIZ1, MOHAMED MAHMOUD NABEEL1, TAMER MAHMOUD ELBAZ1, HEND IBRAHIM SHOUSHA2, EMAN MEDHAT HASSAN1, SHERIF HAMDY MAHMOUD1, NOHA ALI RASHED1, MOSTAFA MOHAMED IBRAHIM1 & AHMED HOSNI ABDELMAKSOUD3 1

Endemic Medicine and Hepatogastroenterology Department, Cairo University, Cairo, Egypt, 2Endemic Hepatogastroenterology Department, Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt, and 3 Diagnostic and Interventional Radiology Department, Cairo University, Cairo, Egypt

Abstract Objective. Limited therapies are offered for large hepatocellular carcinoma (HCC). It carries dismal prognosis and efforts tried changing its management from a palliative to a curative mode. Transarterial chemoembolization (TACE) is a palliative procedure that may have survival benefit if compared to non-management of large lesions. Microwave ablation (MWA) has emerged as a relatively new technique with promise of larger and faster ablation. We aim to evaluate the efficacy and safety of percutaneous MWA versus TACE for large tumors (5–7 cm) and to assess their effects on local tumor progression and survival. Patients and methods. Sixty-four patients with large lesions are managed in our multidisciplinary HCC clinic and were divided into two groups treated either by MWA or TACE. Complete response rate, local recurrence, de novo lesions, and overall survival analysis are compared between both procedures. Results. Both groups were comparable as regards the demographic and ultrasonographic features. MWA showed higher rates of complete ablation (75%) with fewer sessions, lower incidence of tumor recurrence (p = 0.02), development of de novo lesions (p = 0.03), occurrence of post-treatment ascites (p = 0.003), and higher survival rates (p = 0.04). The mean survival of the microwave group was 21.7 months with actuarial probability of survival at 12 and 18 months 78.2% and 68.4%, respectively. The mean survival of the TACE group was 13.7 months with actuarial probability of survival at 12 and 18 months being 52.4% and 28.6%, respectively. Conclusion. MWA showed better results than TACE in the management of large HCC lesions.

Key Words: hepatocellular carcinoma, microwave ablation, survival, transarterial chemoembolization.

Introduction Hepatocellular carcinoma (HCC) is a primary liver tumor that has long been of poor prognosis. However, it is still potentially curable with various management regimens that depend on tumor and patient-related factors [1]. Recently, many efforts focused on ways to save patients and change the therapeutic aims from palliative to curative potentials. Malignant hepatic focal lesions that are more than 5 cm in size are considered as large lesions. More than

70% of tumors belong to this category [2]. Currently, there is no standard treatment for such unresectable lesions, certainly if associated with advanced tumor stage, multicentricity, or poor liver condition [3,4]. Transarterial chemoembolization (TACE) evolved as the standard therapy for such patients who are considered as not eligible for curative therapies [5,6]. Primarily, it has a palliative effect as it does not achieve complete tumor necrosis, raising the possibility of tumor recurrence [7,8]. Although the reports declared unsatisfactory clinical outcomes with repeated TACE

Correspondence: Hend Ibrahim Shousha, Endemic Hepatogastroenterology Department, Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt. Tel: +20 1005738455. Fax: +20 0225326543. E-mail: [email protected]

(Received 4 November 2014; revised 6 December 2014; accepted 18 December 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.1003397

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so that definite regulatory rules are needed to determine success from failure [9], some recent randomized trials reported improved survival rates of patients with unresectable lesions managed with TACE [5,6]. Patients with unfavorable criteria for liver transplantation can be operated after downstaging using TACE [10]. Local ablative modalities emerged as a better therapeutic option for nonsurgical patients with early HCC due to their easy performance, safety, effectiveness, and gained long-term survival rates [11]. Microwave ablation (MWA), one of the thermal ablative techniques, afforded the capacity to perform larger and faster ablations that even exceeded the limitations of radiofrequency ablation through guarded consistent higher intratumoral temperatures [12]. The larger ablation zones given by the microwave technique opened the gate to possibly consider it as a curative rather than palliative technique for large lesions [13]. Thereby, we aimed in our study to determine the safety and efficacy of TACE versus microwave therapy for ablation of large lesions (more than 5 cm) and prospectively follow up the patients to identify the survival benefits offered by such techniques. Patients and methods We started enrollment of patients since February 2012. Sixty-four eligible patients presented to our multidisciplinary HCC clinic, Cairo University (Egypt), seeking for management of large lesions. HCC diagnosis is revised according to EASL guidelines, and AASLD updated practice guidelines for management of HCC and BCLC guidelines [14-16]. The study was in compliance with the ethics principles of the declaration of Helsinki with GCP guidelines. A written informed consent is obtained from all studied patients and they were divided to two groups. They were randomly divided into two groups using the online randomization http://www.graphpad.com/ quickcalcs/index.cfm. The first group (TACE group) included 32 patients managed by TACE for their large lesions. The second group (microwave group) included another 32 patients treated by microwave ablative technique. All patients were Child Pugh A (or B) with three or less focal lesions, the largest lesion being measured 5–7 cm. All patients were revised for number and site of lesions with certainty that lesions could be managed by either technique. A proper coagulation profile (platelet count exceeding 50,000/cm3 and prothrombin concentration more than 60%) is a prerequisite before management. Excluded patients were Child C patients, patients with portal vein thrombosis or distant metastases, inacceptable coagulation profile, or lesions outfitting

the inclusion criteria. Further contraindications included intractable systemic infection, leucopenia (white blood cell count 2.0 mg/dl), hepatic encephalopathy, performance status >2, hepatofugal flow, and biliary obstruction. In addition, we excluded patients whose lesions can be managed by a certain technique while not feasible by the other technique. Microwave ablation The procedures were ultrasonography guided using a Hitashi EUB-5500 machine with a 3.5–5 MHz probe. We used an HS AMICA microwave machine (HS Hospital service S.P.A. Roma, Italy), so-called AMICA GEM machine. It operated at a frequency of 2450 MHz and 14-gauge (150 mm and 200 mm) cooled shift electrodes (AMICA-probes) were used to deliver the microwave energy into liver tissue. TACE procedure Patients in the TACE group were treated using a common femoral artery catheterization, followed by super-selective catheterization of the feeding artery (arteries) and injection of intra-arterial doxorubicin (50 mg) mixed with lipiodol (5–10 ml). Injection of embolic materials (as gelfoam or PVA particles) was used in cases of tumor shunting until complete occlusion of the shunt and was followed by injection of the chemoembolic material. Lipiodol permits the drug to concentrate in the tumor and is retained for weeks. Immediately after TACE, a non-contrast computed tomography (CT) scan is performed to confirm the proper location of the combined chemotherapy/lipiodol. TACE is repeated at 1–2-month intervals, depending on the tumor burden and response. Follow-up All patients were early assessed after the ablative procedures for complications. Contrast-enhanced (triphasic) CT imaging is performed 4 weeks postablation and every 3 months during the follow-up period. Response to treatment was rated as complete when CT scans showed no contrast enhancement inside the lesion in the arterial phase. Partial response rate is considered when CT scans showed areas of enhancement within the boundaries of the original lesion in the arterial phase. We looked for possible primary recurrence or de novo lesions. Finally, we assessed the therapeutic efficacy, safety, as well as the overall survival in relation to both techniques.

Microwave versus TACE in large HCC Table I. Demographic and ultrasonographic features of the studied groups.

Number of patients Age (years) Gender Male Female Child-Pugh Child A Child B Performance status 0 1 Viral markers HBV HCV Alphafetoprotein (ng/ml) Median Range Number of tumors Single Two Three Site of tumors Right lobe Left lobe Both lobes Size of the tumors Mean (cm)

TACE group

Microwave ablation group

32 55.5 ± 9.4

32 56.8 ± 5.7

23 (71.9%) 9 (28.1%)

26 (81.2%) 6 (18.8%) 0.1

20 (62.5%) 12 (37.5%)

Table II. Success rate of both procedures.

p-Value

0.5 0.3

481

Ablation rate Complete ablation Partial ablation Number of sessions (mean ± SD)

TACE group

Microwave ablation group

13 (40.6%) 19 (59.4%) 2.9 ± 0.9

24 (75%) 8 (25%) 1.2 ± 0.4

p-Value 0.005

0.001

No procedure related major complications.

25 (78.1%) 7 (21.9%) 0.6

20 (62.5%) 12 (37.5%)

18 (56.2%) 14 (43.8%)

2 (6.2%) 27 (84.4%)

1 (3.1%) 30 (93.8%)

0.5 0.2 0.5

71.2 3–6660

200 13–1400

0.4

24 (75%) 1 (3.1%) 7 (21.9%)

23 (71.9%) 5 (15.6%) 4 (12.5%)

25 (78.1%) 4 (12.5%) 3 (9.4%)

31 (96.9%) 1 (3.1%) 0 (0%)

5.9 ± 0.8

5.7 ± 0.6

0.1

0.06

0.2

Statistical analysis We reported the numerical data as means ± standard deviation (SD). Categorical data are represented as counts and percentages. The student t-test and the Chi-square test are used when appropriate. Statistical significance is considered if the probability of occurrence by chance is 5% or less (p < 0.05). Survival analysis using the Kaplan–Meier method is performed from the date of primary diagnosis to the date of last follow-up or death. Results In our prospective study, 64 patients diagnosed as HCC with large lesions were managed either by TACE (n = 32) or microwave technique (n = 32). During randomization, two patients were recruited for microwave but the lesions were technically difficult for management due to their site and so were excluded from study. They were not shifted to TACE to avoid randomization bias. All studied patients were assessed for success rate, complications, recurrence, and overall survival.

First, we assessed the general characteristics and demographic features of both studied groups. No statistically significant difference was detected as regards their age, gender, Child Pugh score, performance status, viral markers, as well as alpha fetoprotein. Moreover, both groups were comparable for their ultrasonographic features of the focal lesions. No statistically significant difference was noticed for the number, site, and size of the lesions. The mean value of the size of the lesions was 5.9 ± 0.8 cm for TACE group and 5.7 ± 0.6 cm for the microwave group (p = 0.2) (Table I). The success rate achieved by the microwave technique was significantly higher. Seventy-five percent of lesions were completely ablated by the microwave versus 40.6% only by TACE (p = 0.005). In addition, a lesser number of needed sessions to achieve complete ablation were demonstrated in the microwave group (p = 0.001) (Table II). No major procedurerelated complications were evidenced by either procedure. The follow-up data of the studied groups were in favor of the microwave technique (Table III). This technique was associated with a statistically significant lower incidence of tumor recurrence (p = 0.02), development of de novo lesions (p = 0.03), and post-treatment ascites (p= 0.003) than TACE group. Finally, we performed a survival analysis of the studied groups (Table IV, Figure 1). During the follow-up period, 21 patients died in the TACE group (65.6%). Causes of death were liver failure (n = 15), spontaneous bacterial peritonitis (n = 3), hepatorenal syndrome (n = 2), and hematemesis (n = 1). In the microwave group, mortality was recorded in five cases (15.6%) and the causes of death were hematemesis Table III. Follow-up data of the studied groups. TACE group Recurrence 3/13 (23%) De novo lesions 14/32 (43.8%) Portal vein thrombosis 3/32 (9.4%) Post-treatment ascites 15/32 (46.9%)

Microwave p-Value ablation group 5/24 (20.8%) 6/32 (18.8%) 1/32 (3.1%) 4/32 (12.5%)

0.02 0.03 0.3 0.003

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Table IV. Overall survival of studied patients. TACE group (n = 32)

Microwave ablation group (n = 32)

p-Value

Overall mean survival of total patients (n = 64) 15.4 months 1 year 63.6% 1.5 year 38.7% Overall survival Mean 13.7 months Mean 21.7 months 0.04 12 months 52.4% 78.2% 18 months 28.6% 68.4%

(n = 3), hepatorenal syndrome (n = 1), and sepsis (n = 1). The overall survival was 15.4 months from the date of diagnosis. The mean survival of the microwave group was 21.7 months with actuarial probability of survival at 12 and 18 months being 78.2% and 68.4%, respectively. Survival analysis was statistically significant (p = 0.04) when compared to the TACE group who had a lower survival rate (13.7 months) as well as lower 12- and 18-month survival (52.4% and 28.6%, respectively). There was no significant difference in the overall survival between Child A and B patients (mean survival 15.9 vs. 14.4 months, respectively, p-Value = 0.4) and also among patients with single, two, and three lesions (mean survival was 15.8 vs. 11.3 vs. 13.5 months, respectively, p-Value = 0.5). Discussion HCC with lesions exceeding 5 cm proposes a real challenging problem. Several studies mentioned the rare possibility to achieve complete ablation of large lesions due to limited ablation zones [17]. For patients with good performance status and acceptable liver condition (as represented by the Child Pugh score), it is harder to accept the aim of tumor

palliation with a true enthusiasm to reach a curative end point if possible. For that reason, we enrolled our prospective study to manage large HCC lesions using the widely nominated TACE in such conditions versus the locally ablative microwave modality. Our two divided groups were comparable as regards the demographic and the ultrasonographic features, which may avoid the appearance of biased results as much as possible. The rationale to use TACE for HCC ablation is the delivery of a local and concentrated dose of chemotherapeutic agents directly into the arterial feeder of the tumor and the embolization using either permanent or temporary particulate materials to reduce washout [10]. The use of TACE is very debatable with various potential benefits and disadvantages. Repeated TACE sessions may reduce the total volume of the viable tumor [18] with a possible positive impact on the quality of life and may be survival. However, the subtotal ablation allows tumor recurrence, de novo lesions, and damage of liver function reserve [7]. Considering microwave, its mechanism is based on the generation of friction heat. That heat leads to coagulation and cellular death after reaching the intratumoral temperature above 60 [19]. Role of MWA for small lesions is no more questionable as proved by many papers [11,20,21] but its role in lone management of large lesions is the point of discussion. In our study, large lesions were completely ablated in 75% and 40.6% of cases by microwave and TACE procedures, respectively. A lesser number of sessions were needed by the microwave technique to gain complete ablation. In addition, patients managed by microwave showed a lower incidence of recurrence, appearance of de novo lesions, or even occurrence of hepatic decompensation (as represented by

Survival functions Type of treatment

1.0 p-Value = 0.04

Cum survival

0.8

Microwave TACE Microwave-censored TACE-censored

0.6 0.4 0.2 0.0 0

5

10 15 20 Survival_time

25

30

Figure 1. Kaplan–Meier survival analysis of the studied groups.

Microwave versus TACE in large HCC appearance of post-treatment ascites). Similar rates of complete ablation were presented by different studies concerned with MWA of large lesions and ranged between 69% and 81.8%. Their incidences of local recurrence were 10.5–40.9% [12,22,23]. Still our rates of complete ablation of large lesions by TACE were higher than literally reported by many studies. TACE has an additional benefit to ablate lesions that are sometimes technically difficult due to their site that hinders percutaneous introduction and ablation. Biolata et al. achieved complete control in 25–35% of their cases [24], while much lower rates were documented by Paul et al. who clarified that 4.8% only of their studied patients gained the complete ablation as the ablated lesions still contained viable tumor cells [25]. This difference may be related that all our cases were performed using superselective catheterization for feeding arterial vessels, either from hepatic artery or parasitic supply from different suppliers. This allowed higher ablation rates and lower complication rates than usually published. However, the superselective maneuver did not really prevent the high incidence of post-treatment ascites. This is believed to be related to the management of large lesions with frequent number of sessions that surely can affect the liver. Of course, the success to achieve complete ablation has its direct impact on survival rates. The overall survival of patients treated by microwave was significantly higher than patients treated with TACE (21.7 and 13.7 months, respectively). The 12- and 18-month survival of patients managed by microwave and TACE were 78.2%, 68.4%, 52.4%, and 28.6%, respectively. These impressive results highlight the positive curative role of microwave to ablate unresectable large lesions with a definite beneficial survival time. While TACE per se shows lower success rates, our rates of partial ablation (59.4%) could be satisfactory if they were compared to symptomatic palliative management [26,27]. If aiming potential curative role, TACE needs to be used in a multimodality manner. Many studies showed that the lone management of large lesions by TACE provides lesser success rates than gained by other regimens such as surgery [28-31]. Better results were published when TACE was part of multimodality therapy with various techniques such as alcohol injection [32], radiofrequency ablation [7], laser therapy [33], sorafenib [34], and MWA [35]. TACE assisted to reduce the tumor size and controlled (or eliminated) the micro-metastases that may be undetectable by different imaging modalities [7]. Finally, we conclude the obvious superiority of microwave in management of large lesions. This

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