Dig Dis Sci DOI 10.1007/s10620-014-3455-1

ORIGINAL ARTICLE

Radiofrequency Ablation Plus Devascularization Is the Preferred Treatment of Hepatocellular Carcinoma with Esophageal Varices Ke Zhang • Li Jiang • Zhe Jia • Yao Zhang Rong He • Zhenhao Ding • Yi Mu



Received: 9 September 2014 / Accepted: 18 November 2014 Ó Springer Science+Business Media New York 2014

Abstract Background Most hepatocellular carcinomas (HCCs) are associated with cirrhosis. Portal hypertension (PHT) and esophageal variceal bleeding (EVB) can limit the patient’s treatment options. Surgical therapy in such patients is challenging. We performed devascularization plus liver resection or radiofrequency ablation (RFA) to treat HCC patients with concomitant EVB resulting from PHT secondary to cirrhosis. Such combined operations have never been reported for the management of HCC patients with variceal esophageal bleeding. Aim To evaluate two different treatment regimens for patients with HCC and EVB. Methods We evaluated 35 BCLC stage 0/A patients with HCC and EVB who underwent either devascularization plus liver resection (Group A) or devascularization plus RFA (Group B). We reviewed the safety and outcomes of the two groups and assessed risk factors for patient survival and tumor recurrence. Results Significant factors for overall survival were surgical approach and Child-Pugh classification. Child-Pugh classification was the only independent risk factor for overall postoperative survival [hazard ratio (HR) 8.320,

Ke Zhang, Li Jiang, and Zhe Jia have contributed equally to this work. K. Zhang  L. Jiang  Z. Jia  R. He  Z. Ding  Y. Mu (&) Department of Hepatobiliary Surgery, Beijing DiTan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing 100015, China e-mail: [email protected] Y. Zhang Department of Ultrasonic Diagnosis, Beijing DiTan Hospital, Capital Medical University, Beijing 100015, China

95 % confidence interval (CI) 1.739–39.799, P = 0.008]. Age was the only independent risk factor for tumor recurrence (HR 4.025, 95 % CI 1.343–12.062, P = 0.013). Conclusions RFA plus devascularization is the preferred treatment of HCC with EVB. RFA plus devascularization should be considered in Child-Pugh class A patients below 50 years of age. Keywords Hepatocellular carcinoma  Portal hypertension  Esophageal varices  Devascularization  Hepatectomy  Radiofrequency ablation

Introduction Most hepatocellular carcinomas (HCCs) are associated with cirrhosis [1]. However, many HCC cases occur in chronic hepatitis B without actually having cirrhosis. Portal hypertension (PHT) and esophageal variceal bleeding (EVB) [2] can limit the patient’s treatment options. Surgical therapy in such patients is challenging. Liver transplantation is considered the best treatment for patients with HCC and EVB within the Milan criteria (single HCC B5 cm or up to 3 nodules each \3 cm) [3]. Due to the shortage of liver donors worldwide, the majority of patients do not receive a liver transplantation. Moreover, many patients with Child-Pugh class A disease do not require transplantation for many years. In these cases, surgical intervention is necessary and may be the only effective treatment. A major concern regarding the surgical treatment of patients with HCC and PHT is whether surgery is safe. Both the European Association for the Study of the Liver (EASL) [4] and the American Association for the Society of Liver Diseases (AASLD) [5] consider hepatectomy a

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risky treatment in HCC patients with PHT. Imamura et al. [6] evaluated factors affecting the postoperative recovery of 1,056 patients treated with hepatectomy and found that PHT was a risk factor for complicated ascites, although it was not associated with an increased risk of postoperative mortality or rate of complications. A retrospective analysis of 217 HCC patients with liver cirrhosis found no difference in the rate of complications, postoperative mortality, and 5-year overall survival of Child-Pugh class A patients with or without PHT [7]. Kawano et al. reported 134 ChildPugh class A/B patients with HCC and cirrhosis treated with liver resection. There was no difference in the prognosis of patients with esophageal varices (n = 31) and those without varices (n = 103) [8]. All these studies suggest that limited hepatic resection is safe for the treatment of HCC patients with esophageal varices. Radiofrequency ablation (RFA) is a widely used, safe, and effective treatment modality for HCC [9, 10]. The effectiveness of RFA is comparable to that of liver resection in patients with HCCs B3 cm in diameter. The minimally invasive nature of the treatment has led to it becoming the first-line treatment for small HCC in patients with compromised liver function or associated severe medical conditions [11]. Nevertheless, RFA can still result in postoperative PHT, and in cases with preoperative EVB induce variceal bleeding and liver failure. Multidisciplinary approaches are still needed to improve the safety and treatment outcomes of these procedures [12]. A reasonable consideration for such patients is the use of gastroesophageal devascularization, the first therapeutic strategy for treating EVB [13, 14]. The use of alternative treatments, particularly endoscopy, transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation, has led to a decrease in the use of gastroesophageal devascularization in the management of variceal bleeding [12, 15]. Devascularization is currently mainly used as a rescue therapy for EVB patients with impaired liver function who failed endoscopic therapy or TIPS treatment. Devascularization is an easy technique with a low mortality and low recurrence rate of variceal bleeding. It remains a major therapeutic option for treating liver cirrhosis patients with PHT and esophageal variceal bleeding [16]. However, esophageal devascularization carries increased morbidity especially in cirrhotic patients [17]. We performed a combination of these operations (liver resection plus devascularization and RFA plus devascularization) to treat HCC patients with concomitant EVB resulting from PHT secondary to cirrhosis. Such combined operations have never been reported for the management of HCC patients with variceal esophageal bleeding. The aim of these operations was to combine the advantages of devascularization and liver resection or RFA and reduce the disadvantages of such techniques. We sought to find a

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more suitable treatment option for those patients who are unsuitable for liver transplantation or TIPS. We evaluated the safety and outcomes of these operations in 35 HCC patients with EVB.

Methods Patients Between June 2007 and January 2014, 67 patients with hepatocellular carcinoma (HCC) and concomitant EVB who failed endoscopic treatment were recruited for this study in the Department of Hepatobiliary Surgery at Beijing Ditan Hospital of the Capital Medical University. Endoscopic treatment failure was defined as EVB relapse after a course of sclerotherapy. All EVB cases were evaluated and verified by two independent physicians with at least 5 years of clinical experience in endoscopic diagnosis and therapy. Endoscopic variceal grading was evaluated according to the criterion of the Japan Society for PHT [18], and classified as F1 (small, straight), F2 (moderate sized, tortuous), or F3 (large sized, nodular). Red wale marks (RED) were graded as: (1) RED (-) = absent, (2) RED (?) = small in number and localized, (3) RED (??) = intermediate between (?) and (???), and (4) RED (???) = large in number and circumferential. Thirty-five patients had cirrhosis, HCC, and concomitant esophageal varices. Patients were treated with hepatic resection and devascularization (group A, 19 patients) or RFA and devascularization (group B, 16 patients). The age of the patients in Group A ranged from 33 to 59 years (average 44.8 years). There were 16 men and three women in Group A. The age of the patients in Group B ranged from 27 to 64 years (average 46.4 years) and included 13 men and three women. The selection criteria for these 35 patients with cirrhosis were age less than 65 years; ChildPugh class A/B; BCLC stage 0/A; and no major heart, lung, kidney, or metabolic diseases (Fig. 1). All 35 patients were hepatitis B cirrhosis and diagnosed with HCC before treatment according to EASL guidelines for HCC management [19]. These consisted of (a) demonstration of typical features of HCC with two imaging techniques or positive findings on one imaging study together with an alpha-fetoprotein (AFP) level greater than 400 ng/mL (n = 29) or (b) cytologic and/or histological diagnosis of HCC (n = 6). Liver biopsies were performed when noninvasive criteria were not satisfied. Preoperative tests included blood count, liver function, blood coagulation, AFP, HBV-DNA, and chest x-ray. Nineteen of the 35 patients were BCLC stage 0 and 16 were BCLC stage A. Twenty-nine cases were Child-Pugh class A and six cases were Child-Pugh class B. This study was approved by the

Dig Dis Sci Fig. 1 Flow chart summarizing patient selection. HCC hepatocellular carcinoma, EVB esophageal varices bleeding, LR live resection, RFA radiofrequency ablation, TIPS transjugular intrahepatic portosystemic shunt, TACE transarterial chemoembolization

ethics committee of Beijing Ditan Hospital, Capital Medical University. All patients signed a written consent form and agreed that their medical information may be used in a study. Surgical Procedures All surgical procedures were performed by two surgeons with at least 10 years of experience in our department of hepatobiliary surgery. All patients received general anesthesia with endotracheal intubation. Depending on the blood platelet counts (PLT) levels at the time of anesthesia before surgery, patients received an intravenous infusion of 4–8 U platelets. A left-sided abdominal subcostal oblique incision was used in most patients. An additional abdominal subcostal oblique incision on the right side was also employed when necessary. Portal venous pressure was monitored by gastroepiploic vein puncture. First, splenectomy and devascularization of the upper stomach was performed in accordance with a standard Hassab’s decongestion operation [20]. After another measurement of the portal venous pressure, partial hepatectomy or RFA was performed. Peritoneal drainage catheters were placed at the tail of the pancreas. Patients undergoing hepatectomy had a second peritoneal drainage catheter placed next to the cut surface of the liver.

Anatomic or nonanatomic liver resections were performed according to the extent and location of the tumor, hepatic function, and the preference of the surgeon. Intraoperative ultrasonography was routinely performed to confirm the characteristics of the HCC, to study its relationship with vascular and biliary structures, to evaluate the remnant liver for additional tumors, and to guide the resection. The Pringle maneuver was routinely used, with clamping and unclamping times of 10 and 5 min, respectively. This technique was used repeatedly throughout the entire procedure. Hemostasis of the surface of the raw liver was achieved with sutures. According to the guidelines of the International Union Against Cancer, complete resection, designated as R0, was defined by the absence of microscopic tumor invasion of the margins of the resected area (tumor-free margins 1 mm for all lesions detected). All resected specimens were evaluated using a conventional histopathological examination. The cellular differentiation of HCC was graded from I to IV, according to Edmondson–Steiner’s classification. The 6th edition Union Internationale Contre le Cancer (UICC) Tumor Node Metastasis (TNM) classification was used for staging [21]. The liver was exposed to allow the surgeons to examine the tumors completely during RFA. The diaphragm and the heart were protected appropriately, and RFA was performed under ultrasound guidance. The RFA device model

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used in this study was the US CTRF-220 cooled electrodes RF system. The ultrasound model used was the L0GIQ.S6 (General Electric, Inc., Fairfield, CT). The RFA procedures were performed by one radiologist with 5 years’ experience in interventional therapy at the start of the study. The methods were the same as those described in other research reports [22]. Ultrasound imaging was performed 10 min after the RFA procedures, and the images showed the tumors to be completely ablated. The ablated zones (hyperechoic zone on image) included a 1–1.5 cm margin around the tumors. Enhanced abdominal CT or MRI was performed 1 month after RFA procedure. According to the CT or MRI results, the RFA was classified as complete ablation (indicated by the absence of enhancing tissue in the tumor site) or incomplete ablation (enhancing tissue still observed in the tumor site).

the appearance of new HCC in the untreated liver or metastases [25]. Preferred therapy for recurrent tumors was percutaneous RFA, liver transplantation, liver resection, or TACE, depending on disease conditions and patient preference. Esophagogastroduodenoscopy was performed 3 months after surgery to examine the esophagus and stomach for varices. Postoperative recurrent varices greater than F2 or RED-positive were treated with sclerotherapy. An annual endoscopy was performed in patients with no varices seen. Postoperative variceal hemorrhage was defined as bleeding from esophageal varices, excluding variceal hemorrhage due to recurrent tumor thrombus in the main trunk of the portal vein.

Efficacy and Follow-Up

Statistical analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL). Mann–Whitney U test was used to compare differences of continuous variables. The corresponding data were presented as Mean ± standard deviation (SD). Categorical variables and frequencies were compared using Fisher’s exact test. P values \0.05 were deemed to indicate statistical significance. Overall survival was evaluated from the day of operation to the day of death or to the most recent follow-up visit. Recurrence-free survival was computed from the day of surgery to the first follow-up visit with clear evidence of a tumor or the most recent follow-up visit. Univariate analysis was performed to identify clinical and biological parameters, and tumor factors predicting overall and recurrence-free survivals. Survival curves were computed according to the Kaplan– Meier method and compared by the log-rank test. Univariate Cox proportional hazards model was fitted to each variable. All variables with a P value\0.05 were subjected to multivariate analysis to assess their value as independent predictors.

Operative morbidity and mortality were defined as complications and deaths that occurred within 30 days after surgery. Postoperative hepatic dysfunction was defined as hyperbilirubinemia, or serum total bilirubin (TBIL) level over 5.0 mg/dL, and persistent ascites or pleural effusion [23]. Major complications were defined as complications that were life threatening, that led to substantial morbidity or disability, or that lengthened the hospital stay [24]. All other complications were considered minor. Fever was defined as an axillary temperature more than 38.5 °C. Ascites was defined as clinically detectable abdominal fluid or as abdominal drainage output (when present) of 500 mL or more per day. All patients were followed until March 2014. After the patients were discharged from the hospital, they were followed monthly at the outpatient clinic. Routine testing included electrolyte and CBC tests, liver function tests, assessment of AFP levels, and imaging. Blood HBV-DNA levels were determined every 3 months after surgery. Patients with a positive HBV test (C500 copies/mL) before surgery and patients that converted from a negative HBV test before surgery to a positive result after surgery received antiviral nucleoside analogue therapy. Abdominal CT or MRI was performed 1 month after treatment. If no functional tumor was seen, ultrasound was performed every month, and enhanced abdominal CT or MRI was performed every 3 months. If no recurrence, metastasis, or new neoplasms were seen after 6 months, ultrasound was performed every 3 months from then on, and a CT or MRI was performed every 6 months. Local tumor recurrence was defined as the appearance of tumor growth around the original ablated area in the RFA cases and at the resected liver surface after resection in the surgical resection cases. Distant recurrence was defined as

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Statistical Analysis

Results The baseline characteristics of the patients are reported in Table 1. There were no significant differences in the two groups of patients with respect to preoperative age, gender, severity of variceal grading, tumor characteristics, liver function, AFP levels, or blood laboratory test results. There were no significant differences in the two groups of patients with respect to duration of surgery, intraoperative blood loss, units of blood received, free portal venous pressure before and after devascularization, or duration of postoperative hospital stay. There were no cases of residual tumor after surgery and no postoperative death within 30 days of surgery. No hepatic encephalopathy or liver

Dig Dis Sci Table 1 Demographic and clinical characteristics of the two groups

MELD score, the model for endstage liver disease score AFP alpha-fetoprotein, WBC white blood cell counts, PLT blood platelet counts, ALT alanine aminotransferase, AST aspartate aminotransferase, TBIL total bilirubin, ALB serum albumin, CHE cholinesterases, PTA prothrombin activity, FPP free portal pressure a A total of 37 tumor lesions

Group A (n = 19)

Group B (n = 16)

P value

Gender (M/F)

16/3

13/3

1.000

Age (years)

44.8 ± 8.0

46.4 ± 10.3

0.540

HBV-DNA (copies/mL) (\500/C500)

10/9

9/7

1.000

Varicose vein grading (F2/F3)

2/17

4/12

0.379

Red wale marks (?/??/???)

5/10/4

3/6/7

0.421

Numbers of the nodule (single/2)

18/1

15/1

1.000

Tumor locationa (left lateral lobe/left inner leaf/right anterior/posterior lobe of the right) The greatest tumor dimension (mm)

8/1/4/7

2/2/8/5

0.127

22.7 ± 10.5

20.4 ± 9.0

0.595

BCLC stages (0/A)

9/10

10/6

0.500

Child-Pugh class (A/B)

17/2

12/4

0.379

MELD score (\9/9–10/[10)

12/5/2

10/4/2

1.000

AFP levels (ng/mL) (\200/C200)

15/4

13/3

1.000

WBC (9109/L)

2.4 ± 0.7

2.2 ± 0.7

0.476

PLT (9109/L)

57.0 ± 22.8

56.3 ± 30.3

0.518

ALT (U/L)

25.5 ± 10.1

21.0 ± 9.2

0.197

AST (U/L)

30.2 ± 9.8

26.7 ± 10.4

0.175

TBIL (lmol/L)

16.5 ± 5.4

18.6 ± 12.3

0.778

ALB (g/L)

37.7 ± 3.0

38.0 ± 4.8

0.882

CHE (U/L)

3,947.7 ± 982.7

3,617.3 ± 1,170.6

0.321

PTA (%)

74.5 ± 15.8

69.2 ± 13.7

0.408

Duration of surgery (min)

275.3 ± 60.0

296.6 ± 72.3

0.369

Intraoperative blood loss (mL) Intraoperative blood transfusion (yes/no)

573.7 ± 366.0 6/13

406.3 ± 60.0 5/11

0.181 1.000

FPP pre-devascularization (cmH2O)

37.6 ± 3.9

37.6 ± 5.9

0.538

FPP post-devascularization (cmH2O)

29.8 ± 6.6

31.0 ± 4.2

0.561

Duration of postoperative hospital stay (day)

24.4 ± 12.4

20.9 ± 10.6

0.266

failure was observed. Preoperative hypersplenism resolved after surgery in all patients. Increased white blood cell counts (WBC) after surgery, which rose to a peak on the first postoperative day ([10.0 9 109/L), all gradually decreased and returned to normal levels after 14 days (4.0–10.0 9 109/L) (Fig. 2a). PLT levels were 100.0 9 109/L or above by 3 days after surgery (Fig. 2b). In this study, each needle electrode radiofrequency ablation costs $ 2,200, but no significant difference was found regarding the total cost between the two treatment groups (group A vs group B) during surgery and postoperative hospital stay ($ 6,240 ± 760 vs. $ 6,690 ± 520, P = 0.053). Severe postoperative complications included gastrointestinal bleeding, ascites, abdominal infection, lung infection, pleural effusion, portal vein thrombosis, incision infection, and wound dehiscence. Fourteen patients in group A had postoperative ascites, whereas only six patients in group B had ascites (P = 0.044). Nine patients from group A developed pulmonary infections, but none in group B (P = 0.001). There was no significant difference

in the development of other serious complications in the two groups (Table 2). After hepatectomy, the incidence of biliary fistula occurring in the liver section has been reported to be 3.6–12 % [26]. In this study, there was no postoperative biliary fistula among the 19 cases of liver resection. Liver function was evaluated daily for 14 days after surgery. On day one, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) peaked in both groups. ALT and AST levels in group A were significantly higher than those of group B (ALT 232.5 ± 108.1 vs. 94.9 ± 65.2 U/L, P \ 0.001; AST 259.5 ± 132.9 vs. 165.0 ± 105.7 U/L, P = 0.028). On day three, ALT and AST declined as compared to day one, but ALT and AST levels in group A were still significantly higher than those in group B (ALT 130.5 ± 79.7 vs. 68.1 ± 39.2 U/L, P = 0.004; AST 127.9 ± 107.6 vs. 68.4 ± 37.3 U/L, P = 0.047). Both ALT and AST decreased progressively after 3 days, and no significant differences between the two groups were seen after day 3 (Fig. 3a, b). Postoperative

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Fig. 2 White blood cell counts (WBC) and blood platelet counts (PLT) of the two groups in preoperative and postoperative time: a WBC (9109/L), b PLT (9109/L)

Table 2 Post-operation complications of the two groups Group A (n = 19)

Group B (n = 16)

P value

1

1

1.000

Major complication Gastrointestinal bleeding Abdominal fluid

14

6

0.044

Abdominal infection

3

3

1.000

Lung infection

9

0

0.001

Moderate/severe hydrothorax

7

3

0.285

Portal vein thrombosis

8

7

1.000

Rupture of incision

1

0

1.000

Incision infection

4

2

0.666

16

9

0.132

Minor complication Fever ([38.5 °C)

TBIL levels rose slowly in the first 3 days after surgery, reached a peak on day 3, and then declined. TBIL levels in group A were significantly higher than those of group B on days 3 and 7 (day 3: 28.8 ± 7.4 vs. 22.7 ± 11.1 lmol/L, P = 0.031; day 7: 27.0 ± 8.4 vs. 21.5 ± 11.0 lmol/L, P = 0.040). After day 7, there was no significant difference between the two groups’ TBIL levels (Fig. 3c). Serum albumin (ALB) remained within the normal range after surgery (C35 g/L), and there was no significant difference in the ALB level of the two groups (Fig. 3d). The postoperative cholinesterases (CHE) levels were lower than preoperative levels. There was no significant difference in the two groups’ CHE levels on day 1. CHE levels in group A were significantly lower than those of group B on days 3 and 7 (day 3: 3,104.8 ± 559.2 vs. 3,741.3 ± 831.9 U/L, P = 0.029; day 7: 2,968.8 ± 746.5 vs. 3,557.1 ± 1,027.7 U/L, P = 0.040). No difference was seen after day 7 (Fig. 3e). The

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postoperative prothrombin activity (PTA) levels were lower than before surgery. No significant differences in PTA levels were observed between the two groups during the first 3 days. On day 7, the PTA levels in group A were significantly lower than those in group B (59.8 ± 10.2 vs. 67.6 ± 7.3 %, P = 0.024). No difference in PTA levels was seen after day 7 (Fig. 3f). The median follow-up in 35 patients was 32 months (range 2–81 months). No cases were lost to follow-up. No esophageal varices were seen in 32 patients by endoscopy 3 months after surgery. Residual varices were found in 2 patients. These resolved after the patients received 1–2 treatments with sclerotherapy. One patient had a variceal hemorrhage. No varices were seen after three rounds of sclerotherapy. This patient died 27 months after surgery from tumor recurrence complicated with liver failure. Only one patient developed portal vein thrombosis with cavernous transformation of the portal system after surgery. This patient had recurrent variceal hemorrhage 23 months after surgery. The varices were significantly smaller after four treatments with sclerotherapy, and no further variceal bleeding was seen. The median postoperative follow-up time for group A was 32 months (range 2–81 months) and for group B was 30.5 months (range 2–74 months). Two deaths were observed in group A during follow-up at 17 and 27 months due to tumor recurrence complicated with liver failure. Seven patients died in group B during follow-up. Two cases died at 6 and 33 months, respectively, due to tumor recurrence. Another two cases died at 17 and 33 months, respectively, due to tumor recurrence complicated with liver failure. Three patients died of liver failure at four, 52, and 57 months. The estimated 1-, 3-, and 5-year overall

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Fig. 3 Liver function parameters of the two groups in preoperative and postoperative time: a alanine aminotransferase (ALT), b aspartate aminotransferase (AST), c total bilirubin (TBIL), d serum albumin (ALB), e cholinesterases (CHE), f prothrombin activity (PTA)

Fig. 4 Kaplan–Meier curves showing a overall survival and b recurrence-free survival after surgery

survival rates after surgery for group A were 100, 85.6, and 85.6 %, respectively. The estimated 1-, 3-, and 5-year overall survival rates after surgery for group B were 86.7, 58.5, and 29.3 %, respectively (P = 0.026) (Fig. 4a). Univariate analysis was performed on factors that could affect overall patient survival, including gender, age, surgical approaches, tumor size, BCLC staging, Child-Pugh classification, the model for end-stage liver disease (MELD) score, AFP, CHE, WBC and PLT levels, intraoperative blood loss, intraoperative blood transfusion, free portal pressure before and after devascularization, presence

of severe postoperative complications, and postoperative HBV-DNA levels. Risk factors for overall survival were surgical approach and Child-Pugh classification (Table 3). Child-Pugh classification was the only independent risk factor for overall survival (Multivariate analysis) (Table 3). Seven cases in Group A developed tumor recurrence, including six cases with single hepatic metastases and one with multiple liver metastases (2 metastases). Median relapse time for group A was 6 months (range 3–57 months). Tumor recurrence in group B consisted of six cases with one case of surgical site recurrence, one case of multiple liver metastases

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Dig Dis Sci Table 3 Cox proportional hazard regression analysis of risk factors for overall survival in all patients

Risk factors

Univariate HR

Multivariate

95 % CI

P value 0.321

Gender (male)

2.040

0.499–8.345

Age (C50 years)

2.730

0.731–10.200

0.135

Surgical approaches

4.954

1.023–23.981

0.047

Tumor size (C30 mm)

0.778

0.161–3.760

0.755 0.942

BCLC stages (A)

1.050

0.280–3.932

11.899

2.501–56.610

0.002

MELD score (C10)

0.910

0.188–4.420

0.907

Intraoperative blood loss (C500 mL)

0.685

0.183–2.557

0.573

Intraoperative blood transfusion

0.429

0.113–1.629

0.214

FPP pre-devascularization (C40 cmH2O)

2.747

0.682–11.057

0.155

FPP post-devascularization (C30 cmH2O)

5.436

0.679–43.512

0.111

Child-Pugh classification (B)

AFP (C200 ng/mL)

1.506

0.309–7.331

0.612

CHE (\4,000 U/L)

0.547

0.113–2.651

0.454

WBC (\2.5 9 109/L)

2.352

0.599–9.239

0.220

PLT levels (\50 9 109/L)

2.306

0.287–18.551

0.432

Most recently value of postoperative follow-up period

Postoperative HBV-DNA levels (C500 copies/mL)a

0.488

0.061–3.910

0.499

HR hazard ratio, CI confidence interval, MELD score the model for end-stage liver disease score, FPP free portal pressure, AFP alpha-fetoprotein, CHE cholinesterases, WBC white blood cell counts, PLT blood platelet counts

Postoperative ascites

1.015

0.268–3.836

0.983

Moderate-to-severe postoperative pleural effusion

1.627

0.323–8.199

0.555

Postoperative portal vein thrombosis

0.919

0.228–3.705

0.906

Postoperative pulmonary infection

0.335

0.042–2.684

0.303

Postoperative abdominal infection

1.779

0.367–8.633

0.475

a

and hilar lymph node metastases, three cases of single hepatic metastasis, and one case of multiple liver metastases (2 metastases). Median relapse time for group B was 9 months (range 2–31 months). The estimated recurrence-free 1-, 3-, and 5-year survival rates after surgery for group A were 72.2, 66.7, and 50.0 %, respectively. The estimated recurrence-free 1-, 3-, and 5-year survival rates after surgery for group B were 80.8, 49.8, and 49.8 %, respectively. There was no difference in the recurrence-free survival of the two groups (Fig. 4b). Risk factors for recurrence-free survival were gender, age, surgical approach, tumor size, BCLC stage, Child-Pugh classification, MELD score, AFP, and postoperative HBVDNA levels. Only age was an independent risk factor for recurrence-free survival (Univariate analysis) (Table 4). The treatment options for BCLC Stage 0 and Stage A are different. Stratified analysis of overall survival and recurrencefree survival for each patient with different BCLC staging. The results suggest that the overall survival and recurrence-free survival were not statistically different between the two groups of patients with BCLC Stage 0 and Stage A (Figs. 5, 6). Edmondson grade and UICC-TNM stage of HCC tumors were determined for 19 patients in group A. Seven

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HR

95 % CI

P value

3.568

0.699–18.228

0.1226

8.320

1.739–39.799

0.008

Table 4 Univariate Cox proportional hazard regression analysis of risk factors for recurrence-free survival in all patients Risk factors

HR

95 % CI

P value

Gender (male)

1.540

0.416–5.707

0.518

Age (C50 years)

4.025

1.343–12.062

0.013

Surgical approach

1.228

0.408–3.695

0.715

Postoperative HBV-DNA levels (C500 copies/mL)a

1.531

0.420–5.581

0.519

Tumor size (C30 mm)

0.814

0.223–2.975

0.755

BCLC stages (A)

0.950

0.319–2.830

0.926

Child-Pugh classification (B)

3.328

0.837–13.225

0.088

MELD score (C10) AFP (C200 ng/mL)

1.414 1.850

0.421–4.755 0.568–6.022

0.575 0.307

a

Most recently value of postoperative follow-up period

HR hazard ratio, CI confidence interval, MELD score the model for end-stage liver disease score, AFP alpha-fetoprotein

cases were Edmondson grade I, 10 were grade II, and two were grade III. Fourteen cases were UICC-TNM stage I and five stage II. Seven tumor recurrences in group A were classified for Edmondson grade and UICC-TNM stage.

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Fig. 5 Kaplan–Meier curves showing overall survival stratified with BCLC stage a group A and b group B

Fig. 6 Kaplan–Meier curves showing recurrence-free survival stratified with BCLC stage a group A and b group B

Two were Edmondson grade I, four were grade II, and one was grade III. Four were UICC-TNM stage I and three were stage II. Neither Edmondson grade nor UICC-TNM stage were risk factors for recurrence-free survival (Univariate analysis) (Table 5). Thirteen patients developed recurrent HCC. One case was treated with liver transplantation, three with RFA, four with TACE, and five with TACE plus RFA. Six patients died during follow-up. One died of liver failure (treated with RFA), two died of tumor recurrence (one treated with TACE Table 5 Univariate Cox proportional hazard regression analysis of pathologic factors for recurrence-free survival in group A patients Risk factors

HR

95 % CI

P value

Edmondson grading (II and III)

3.968

0.462–34.098

0.209

UICC-TNM (II)

3.723

0.734–18.872

0.112

HR hazard ratio, CI confidence interval, UICC Union Internationale Contre le Cancer, TNM tumor node metastasis

and one treated with TACE plus RFA), and three died of tumor recurrence complicated with liver failure (one treated with TACE and two treated with TACE plus RFA).

Discussion Most patients with HCC and esophageal varices have an advanced state of liver cirrhosis. HCC patients with esophageal varices have a much shorter life expectancy than those with HCC alone. Esophageal variceal hemorrhage is the most life threatening complication for such patients [27]. Esophagogastric varices in HCC patients frequently rupture as a result of the development of intratumoral fistulas or tumor progression [28]. Surgical intervention is necessary to manage these acute episodes. However, surgical treatment of such patients is challenging. We evaluated the safety, effectiveness, and outcome of combined operations (liver resection plus devascularization

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versus RFA plus devascularization) for the treatment of HCC patients with concomitant EVB. In our study, 35 patients with cirrhosis and EVB were BCLC stage 0/A HCC. All patients showed normal recovery after surgery. No deaths, liver failure, hepatic encephalopathy, or overwhelming postsplenectomy infection (OPSI) occurred after surgery. Although the use of RFA electrodes increases an extra $ 2,200 expense, RFA combined devascularization did not significantly increase the total cost of treatment during surgery and postoperative hospitalization. Hypersplenism resolved after surgery. WBC levels increased and peaked on day 1 ([10.0 9 109/ L) and declined thereafter to normal levels (4.0–10.0 9 109/L) (Fig. 2a) by day 14. PLT levels returned to 100.0 9 109/L or above (Fig. 2b) by day 3. These data support the use of combined operations in HCC patients with EVB. Two of 35 cases had gastrointestinal bleeding within 30 days after surgery, as suggested by black stools and a positive fecal occult blood test. Endoscopic examination of these two patients revealed gastric erosions. Bleeding stopped after conventional medical treatment. Three cases of esophageal varices appeared within 3 months after surgery, including one case of esophageal variceal hemorrhage and two cases of residual varices. All varices responded well to sclerotherapy. Only one case of variceal hemorrhage occurred after the first 3 months of follow-up. These data support the use of combined operations as an effective way of reducing the rate of recurrent postoperative variceal hemorrhage [29]. Zhang et al. [30] found there was a 47.83 % chance of PHT patients with liver cirrhosis who received devascularization therapy developing portal vein thrombosis. In our study, 43 % cases (15/35) showed postoperative portal vein thrombosis. Ultrasound imaging of portal vein blood flow showed that most thrombosis occurred in the splenic vein stump (nine cases). A mural thrombus that occupied less than 1/3 of the lumen diameter of the veins occurred in the other six cases. Clinical symptoms in patients with thrombosis included prolonged postoperative fever, no abdominal pain, and intestinal ischemia and necrosis. Portal vein thrombosis generally diminished after 3–6 months (11 cases). Among the nine patients with splenic vein thrombosis, seven showed decreased length of thrombosis stump, which was not evident in the other two patients. For the six patients with portal vein thrombus, thrombus disappeared in one patient, three patients showed reduced thrombosis, one remained the same, and one developed into portal cavernous transformation (PVCT) with variceal hemorrhage. This PVCT patient had a rapidly increasing PLT level after surgery (reached 1,051.0 9 109/L at day 14). Zou et al. [31] found that treatment of these patients with heparin for seven days after devascularization surgery significantly reduced the

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development of portal vein thrombosis. Our patients did receive this type of prophylactic treatment. The goal of combined splenectomy on hepatocellular carcinoma patients with concomitant portal hypertension is to correct the thrombocytopenia caused by splenic sequestration and to reduce the risk of postoperative bleeding in the surgical site [32]. It has been reported that combined splenectomy can reduce the load of bilirubin metabolism and may be beneficial to postoperative liver function recovery [33]. On the contrary, there is nearly 50 % incidence of portal vein thrombosis with splenectomy [30]. In theory, if the spleen is to be retained and only gastric coronary vein and short gastric vein ligations are performed, not only can the operation time be reduced, but also the risk of portal vein thrombosis. However, this strategy still needs further validation in future studies. In a case series of patients with hepatocellular carcinoma and portal hypertension, we have performed gastric coronary vein and short gastric vein ligations and retained the spleen while performing partial hepatectomy. These patients only had mild hypersplenism without significant splenomegaly (WBC 3.0–4.0 9 109/L, PLT 50–100 9 109/L). The postoperative recovery was uneventful without portal vein thrombosis over the 3-month follow-up period. However, for splenomegaly patients with concomitant hypersplenism (WBC \3.0 9 109/L, PLT \50 9 109/L), we still advocate intraoperative spleen removal. We evaluated the risk of liver injury with these procedures. Patients in group A with small HCCs located on the surface of the liver were treated with limit hepatic resection. Patients had larger tumors or more central tumors were treated with RFA plus devascularization. Even limited hepatic resection had a substantial impact on the liver function of our patients (Table 2). Patients in group A more frequently developed ascites (73.7 vs. 37.5 %, P = 0.044) and pulmonary infections (47.4 vs. 0, P = 0.001) after resection. ALT and AST levels were also significantly higher in group A than group B within 72 h of surgery (Fig. 3a, b). TBIL levels were higher in group A than group B on days 3 and 7 (Fig. 3c). PTA and CHE are sensitive indicators of liver function with a short serum half-life. PTA levels were lower in group A than group B on day 7 (Fig. 3f), and CHE levels were lower in group A on days 3 and 7 (Fig. 3e). These data support the use of RFA plus devascularization to minimize liver damage and decrease the incidence of postoperative complications. The operative time and blood loss was almost the same in the two treatment groups. The overall survival of group A was higher than that of group B (Fig. 4a). Recurrencefree survival was almost the same. Tumor recurrence and liver failure were the two main causes of patient death. Child-Pugh grade was the major risk factor for death (Table 3). The average survival of patients with

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Child-Pugh class A was about three times higher than that of patients with Child-Pugh class B (68 vs. 21.5 months). Child-Pugh grade was the only independent risk factor for overall survival [hazard ratio (HR) 8.320, 95 % confidence interval (CI) 1.739–39.799, P = 0.008] (Table 3). Maximum treatment efficacy was seen with Child-Pugh class A. Further studies with larger numbers of patients are needed to examine the relatively higher overall survival rate in group A. Size of tumor is a prognostic factor in patients with HCC and a limiting factor in RFA. Tumor size in group A ranged from 9 to 45 mm and in group B ranged from 10 to 35 mm. The liver resection margin in group A ranged from 10 to 20 mm. Recurrence-free survival in group B was comparable to that of group A. RFA was associated with a similar outcome as hepatic resection in patients with localized HCC and tumor diameters less than 30 mm, similar to previous reports [34]. BCLC staging is key to long-term prognosis of a specific treatment strategy. Stratified analysis of BCLC staging showed that, for BCLC Stage 0 and Stage A patients, neither overall survival nor recurrence-free survival was statistically different between the two groups (Figs. 5, 6). This suggests liver resection and RFA are comparable treatment strategies for BCLC Stage 0/A HCC patients. Most of the patients enrolled in this study had localized HCC with good liver function and relatively low AFP levels. Only age was a risk factor for tumor recurrence in these patients (HR 4.025, 95 % CI 1.343–12.062, P = 0.013) (Table 4). Patients aged less than 50 had a 2.5 times longer recurrence-free survival than patients aged above 50 (62.7 vs. 24.5 months). Therefore, age less than 50 years should be considered when selecting treatment. Postoperative HBV-DNA levels are a risk factor for tumor recurrence in HCC patients with liver cirrhosis [35, 36]. HBV-DNA levels were monitored in our patients, and treatment started if patients were HBV-DNA positive. Only 17 % (6/35) of patients had a positive postoperative HBVDNA test result. This may explain why HBV-DNA status was not a risk factor for tumor recurrence in our study. HCC tumor differentiation and staging are important risk factors for tumor recurrence. In our group A patients, neither Edmondson grading nor UICC-TNM was a risk factor for tumor recurrence (Table 5). This may be due to their low Edmondson grade (Grade I–II, 17/19) and UICCTNM stage (stage I–II, 19/19). We chose RFA, TACE, or TACE plus RFA to treat patients with tumor recurrence. Among 13 recurrent cases, only one received liver transplantation. The overall effectiveness of treatment was not satisfactory. Almost 50 % of patients died during follow-up. Their median survival after tumor recurrence was 12 months (range 2–31 months). Seventy-eight patients with recurrent HCC tumors treated

with hepatic resection were reviewed. Hepatic resection was the best therapy for small localized recurrent HCC with good liver function [37]. Matsuda et al. [38] reported that repeat hepatic resection or ablation were suitable treatments for patients with recurrent multicentric cancer. In conclusion, both hepatic resection with devascularization and RFA with devascularization were effective in the treatment of early BCLC stage 0/A HCC associated with esophageal varices. RFA with simultaneous devascularization was preferred as there was less injury to the liver, less impact on liver function, fewer postoperative complications, more cost-effective, and comparable recurrence-free survival as compared to hepatic resection. Child-Pugh class A patients below 50 years of age are ideal candidates for RFA plus devascularization therapy. Acknowledgments This study was funded in full by the Beijing Municipal Science and Technology Commission Capital Characteristic Clinical Application Research (No. Z121107001012169) and Capital Medical University, Beijing Ditan Hospital Research Fund Project (No. QN2011-04). Conflict of interest

None.

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Radiofrequency ablation plus devascularization is the preferred treatment of hepatocellular carcinoma with esophageal varices.

Most hepatocellular carcinomas (HCCs) are associated with cirrhosis. Portal hypertension (PHT) and esophageal variceal bleeding (EVB) can limit the pa...
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