Predictors of survival after laparoscopic radiofrequency thermal ablation of hepatocellular cancer

Transcription

1 Surg Endosc (2005) 19: DOI: /s z Ó Springer Science+Business Media, Inc Predictors of survival after laparoscopic radiofrequency thermal ablation of hepatocellular cancer A prospective study E. Berber, 1 S. Rogers, 2 A. Siperstein 1 1 Department of General Surgery, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA 2 Department of General Surgery, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110, USA Received: 5 April 2004/Accepted: 2 December 2004/Online publication: 11 March 2005 Abstract Background: Most patients with hepatocellular carcinoma (HCC) are not candidates for hepatic resection or liver transplantation. Radiofrequency ablation (RFA) provides local control for unresectable HCC with minimal morbidity. The aim of this prospective study is to determine factors predicting survival in patients with HCC undergoing RFA. Methods: Sixty-six consecutive patients with HCC who were not candidates for a curative liver resection and were free of extrahepatic disease underwent laparoscopic RFA. The relationship between demographic, clinical, laboratory, and surgical parameters and survival was assessed using univariate Kaplan-Meier survival and multivariate Cox proportional hazards model. Results: The median Kaplan-Meier survival for all patients was 25.3 months after RFA. Although alfa fetal protein (AFP), bilirubin, ascites, and were statistically significant predictors of survival by univariate analysis, only the and AFP were independent predictors by multivariate analysis. Conclusions: This study determines which patients do best after RFA and shows that RFA can provide significant survival for patients with unresectable HCC while also forming a bridge to liver transplantation. RFA has become the first line of treatment in the management of these patients. Key words: Radiofrequency thermal ablation Primary liver tumors Laparoscopic Survival Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and causes almost 1 million deaths annually throughout the world. It is a Correspondence to: A. Siperstein potential complication in cirrhotic patients and a common cause of death. Approximately 6000 new cases are diagnosed each year in the United States, and there is a huge population at risk, with 2.7 million people with chronic hepatitis C virus infection. Evidence also indicates that the incidence and mortality rate of HCC are increasing in the United States and Europe [2, 4, 6, 7, 11, 23]. Complete surgical excision offers the best chance for long-term survival but is suitable for only 9 27% of patients because resectability in cirrhosis is limited by the diminished functional reserve of the liver and the attendant risk for intraoperative bleeding and postoperative liver failure [11, 16]. Hepatic resection is further contraindicated because of multifocal bilateral disease, tumor proximity to major vascular or biliary structures, or technical inaccessibility of the tumor. Due to the multifocal nature of HCC in cirrhotic patients, there is also a significant rate of intrahepatic recurrence after resection [3]. Long-term survival after resection is limited by recurrent tumor and progression of liver disease [12, 16]. Liver transplantation is the other alternative, potentially curative option for the treatment of HCC. Nevertheless, there is substantial morbidity and mortality. Although some centers report <5% surgical mortality, most published reports have found rates of 10 20% [8, 15]. The severe shortage of donor organs, the length of waiting time for a suitable donor organ, and selection criteria are additional factors limiting the use of liver transplantation for the treatment of HCC [6, 16]. Systemic or regional chemotherapy is at best palliative in a small number of patients, with significant side effects and reduced quality of life [6]. Previous studies have documented the efficacy of radiofrequency ablation (RFA) for providing local control with low morbidity in patients with unresectable HCC [1, 6, 9, 10, 21]. Nevertheless, there are no data on

2 711 prognostic factors for survival. The aim of this prospective study is to determine factors that may predict survival in patients with HCC at the time of RFA. Patients and methods This was a prospective study. From September 1997 to September 2003, 400 patients underwent laparoscopic RFA of primary and metastatic liver tumors. Of these, 66 consecutive patients were treated for HCC. Seven patients who underwent RFA as a bridge to transplantation, two patients undergoing concomitant liver resections, and two patients lost to follow up were excluded, leaving 55 patients with 98 liver rumors for analysis. These patients were not candidates for a curative liver resection and were free of extrahepatic disease. Surgical technique Our technique for performing laparoscopic RFA has been described in detail elsewhere [5, 20]. The procedure was performed under general anesthesia. A diagnostic laparoscopy was first performed with a biopsy of any suspicious extrahepatic disease. Laparoscopic ultrasonography of the liver was then performed, and the size and location of all suspected tumors were determined using a 7.5-MHz Aloka (Wallingford, CT, USA) rigid, linear, side-viewing 10-mm laparoscopic transducer and the Aloka 5500 ultrasound machine. Under ultrasound guidance, 18-gauge core biopsies were performed of the suspected metastatic foci for histologic confirmation using a springloaded biopsy gun (Microvasive). A minimum of two ports were required, one for the laparoscope and one for the ultrasound transducer. The radiofrequency thermoablation catheter was then placed percutaneously into the lesion and the prongs were deployed under laparoscopic ultrasound guidance. During the initial part of the study, RITA Medical Systems (Mountainview, CA, USA) Model 30 (four prongs) and Model 70 (seven prongs) 3-cm catheters were used with the 50-W generator for ablation. In the latter half of the study, the second-generation RFA technology consisting of a 5-cm ablation catheter (nine prongs) and a 150-W generator (RITA Medical Systems Starburst XL ablation catheter and the Model 1500 generator) was used. The 7-cm RITA Medical Systems Starburst XLI catheter was also used in the study. In most cases, patients were monitored overnight and discharged home the morning following surgery. Within 1 week prior to surgery, triphasic CT scans of the liver (noncontrast, arterial, and portal venous) were performed. Preoperative laboratory tests included a complete blood count, renal panel, liver function tests, coagulation studies, and serum alfa feto protein (AFP) levels. Follow-up studies included liver CT scan and laboratory tests repeated at 1 week and every 3 months postoperatively. Statistical analysis In order to determine parameters at the time of the RFA that might predict survival, a number of variables were analyzed, including age, gender, the time interval between the diagnosis of liver metastases and RFA, largest tumor size, number of tumors, serum albumin, total bilirubin and serum AFP levels, prothrombin time/international normalized ratio (INR), the presence of ascites, and ification [22]. Survival time was measured in months following RFA. Cutpoints for continuous measures (age, number of lesions, tumor size, and bilirubin, albumin, and AFP levels) were applied to convert these into ordinal-scale predictors in order to correspond with clinical categories used in the published literature or to create subgroups with more evenly distributed numbers of patients. Because all predictors were coded as either ordinal data or categorical data (e.g., gender), univariate Kaplan-Meier survival analyses were applied. Any predictors that were significant at p 0.10 in the Kaplan-Meier univariate analyses were candidates for entry into a multivariate Cox proportional hazards model. Data were analyzed using Statview on a Macintosh (OS 9.2.1). Table 1. Child-Turcotte criteria a Criterion Class A Class B Class C Ascites None Easily controlled Poorly controlled Bilirubin (mg/dl) <2 2 3 >3 Albumin (g/dl) > <3 Nutrition Excellent Good Poor Encephalopathy None Minimal Advanced a The worst criterion was used to assign a given patient to one of the classes Table 2. Child-Turcotte-Pugh grading Child-Turcotte criteria [22] were used to classify the patients into the A, B and C classes. The worst criterion was used to assign a given patient to a certain class (Tables 1 and 2). The Child-Turcotte-Pugh grading system was also used to assign each patient a numerical score based on individual criteria. Encephalopathy was not included as a factor in the analysis because only one patient had such a history. Likewise, all patients had either good or excellent nutritional status and thus nutrition was not included in the analysis. Results Score Criteria Encephalopathy (grade) None I or II III or IV Ascites None Mild Moderate Bilirubin (mg/dl) Albumin (g/dl) > Protime (sec) INR < >2.3 INR, international normalized ratio The demographic, clinical, and surgical characteristics of the patients are given in Table 3. Seven patients (11%) had repeat ablations for recurrent disease in follow up. The median Kaplan-Meier survival for all patients was 25.3 months after RFA treatment (Fig. 1). Survival rates at 1, 2, and 3 years were 78, 48 and 38%, respectively. Univariate analysis identified ascites, bilirubin, AFP, and ChildÕs score as significant determinants of survival (Table 4). Patients without ascites had a median survival of 29 months versus 6.9 months for those with ascites (p = ) (Fig. 2). Those patients with a bilirubin of < 2 mg/dl had a survival of 25.2 versus 5.9 months of those with >2 mg/dl (p < 0.05) (Fig. 3). Patients with an AFP <400 ng/ml had improved survival compared to those with an AFP >400 of 25.2 versus 6.7 months, respectively (p < 0.05) (Fig. 4). Patients in Child A classification had a median survival of 29 months compared to 14.7 months for those in Child B and 5.9 months for those in Child C classification (p < 0.001) (Fig. 5). There was no survival advantage based on age, gender, the time interval between the diagnosis of liver metastases and RFA, tumor size and number, serum albumin, and prothrombin time/inr.

3 712 Table 3. Demographical, clinical, laboratory, and surgical data of the study patients a Age (yr) 62.3 ± 1.4 Gender (male:female) 44:11 Time to RFA (mo) b 7.1 ± 1.5 Bilirubin (mg/dl) 1.3 ± 0.2 Albumin (g/dl) 3.5 ± 0.1 Ascites Absent 39 Present 16 A 28 B 16 C 11 INR 1.12 ± 0.02 No. of tumors 1.8 ± 0.2 Largest tumor size (cm) 4.1 ± 0.2 AFP (ng/ml) 875 ± 359 RFA, radiofrequency thermal ablation, INR, International normalized ration; AFP, alfa feto protein. a Data are expressed as mean ± SEM. b Time to RFA designates the time interval between the diagnosis of liver tumors and RFA Fig. 1. The overall Kaplan-Meier survival in the study. The median survival was 2.1 years after the radiofrequency thermal ablation treatment. Table 4. Results of the univariate Kaplan-Meier survival analysis Variable No of patients Median survival a p value Gender Female 11 Undefined 0.62 Male Age (yr) < > Time to RFA (yr) < > Albumin (g/dl) Undefined < Bilirubin (mg/dl) < > Ascites Absent Present A < B C AFP (ng/dl) < > INR (ng/ml) < > No. of tumors > Largest tumor size (cm) < > a Survival is expressed as months after the radiofrequency ablation procedure RFA, raidofrequency thermal ablation; AFP, alfa feto protein; INR, international normalized ratio Multivariate analysis identified only the ChildÕs score and AFP level as statistically significant determinants of survival at the time of RFA (Table 5). A of B was associated with an 8.3 times greater mortality risk compared with a of A, and a of C was associated with a 33.5 times greater mortality risk. Thus, there was a trend toward a higher Child score to be associated with an increasing mortality risk. Serum AFP level was a significant predictor of mortality risk because an AFP level >400 ng/ml was associated with a 5.7 times greater mortality compared with an AFP level <20 ng/ml. There was also a trend for increasing serum AFP levels to be associated with an increased mortality risk. Although there was a trend for increasing levels of serum bilirubin to be associated with a higher mortality risk, this was not statistically significant. Multivariate analysis using Child-Pugh grade as a continuous variable indicated that as Child-Pugh grade increased by one unit, mortality risk increased 1.52 times (HR = 1.520; p < 0.001; 95% confidence interval, ). Fig. 2. Kaplan-Meier survival of patients with ascites versus patients without ascites. Discussion This is the first study to report on the predictors of survival in patients with HCC undergoing RFA and one of the largest series providing survival data in the literature. The overall median survival was 2.1 years, with

4 713 Table 5. Multivariate Cox Proportional Hazards Model Parameter p value Hazard ratio 95% confidence interval Bilirubin (>2 mg/dl) Ascites B < C < AFP >400 < AFA, alfa feto protein Fig. 3. Kaplan-Meier survival curves of patients with bilirubin <2 mg/ dl versus those with bilirubin >2 mg/dl at the time of RFA. Fig. 4. Kaplan-Meier survival based on serum AFP level at the time of RFA. Fig. 5. Kaplan-Meier survival according to ification. survival at 1, 2, and 3 years being 78, 48, and 38%, respectively. There are few data in the literature regarding survival after RFA for HCC. In one study, the overall survival of 30 patients with HCC undergoing percutaneous RFA was 92% at 1 year, 75% at 2 years, and 60% at 3 years [9]. In another study from France, the 6-month survival was 78% and 1-year survival 61% (n = 18) [1]. The natural history of HCC is short, with a 3-year survival rate of only 12% [17]. The median survival of all HCC patients in the SEER database between 1992 and 1996 was 0.6 years [7]. After resection of HCC, actuarial survival at 1, 3, and 5, years has been reported to range between 62 and 90%, 35 and 75%, and 17 and 53%, respectively [16]. In the largest resection series in the literature (n = 54), the median survival was 39 months, with 1-, 3-, and 5-year survival rates of 81, 54, and 37%, respectively [8]. Recent data demonstrated a 3-year survival of 50 70% for patients who undergo total hepatectomy and transplantation for HCC [8, 15, 19]. After percutaneous alcohol injection, the 3-year survival is 63% for patients with solitary tumors and 31% for those with multiple tumors [13]. Five-year survival rates for patients with tumor size 5 cm range between 24 and 40% [14]. Although it is not possible to compare our survival results with these modalities because of the different patient populations treated, the survival rate achieved with RFA in our study is encouraging. All patients treated in our study had cirrhosis and were not candidates for surgery because of unresectable disease, limited hepatic functional reserve, or medical comorbidites. A number of studies have been conducted to examine determinants of survival after resection of HCC. Some of the prognostic parameters suggested by these studies include the presence of venous infiltration, the absence of tumor encapsulation, and surgical resection margin <1 cm [12]; blood loss, surgical resection margin, intrahepatic metastasis, portal vein invasion, and extent of hepatic resection [18]; and ification, age, and serum alanine aminotransferase levels [17]. In the largest resection study to date [8], the factors most influential on long-term survival by univariate analysis were preoperative AFP level, surgical margin positive for tumor, vascular invasion, and size of largest tumor. The independent determinants by multivariate analysis, on the other hand, were positive margin, AFP >2000 ng/ml, and vascular invasion. The limited number of patients with Child B or C hepatic function status who underwent resection (n = 10) was believed to be the reason why ification did not significantly predict outcome (p = 0.09) in this study. ification is being used extensively by physicians to assess the severity of disease in patients with liver disease as well as to determine the risk for surgical procedures based on an estimation of the hepatic functional reserve [22]. This is a simple classification and all of the criteria are available at the time of referral of patients to our RFA program. Our aim in this

5 714 study was to identify factors at the initial presentation of patients that could be used to estimate their survival after RFA. One of our major study questions was whether the ification, used to assess the severity of liver disease, could also be used as a predictor of survival. Therefore, in addition to a number of demographic, clinical, and surgical parameters, we focused on ification as well as the individual Child criteria. In accordance with the literature, we did not find an effect of age or gender on survival. On the other hand, our study showed that the criteria used to assess the severity of liver disease also translated to long-term prognosis in patients with HCC undergoing laparoscopic RFA. When individually analyzed, each worse Child criterion was associated with a shorter median survival, although statistical significance was only reached for bilirubin and ascites by univariate analysis. Because alone is such a powerful factor, it proved to profoundly affect survival in both univariate and multivariate analyses. B was associated with an eight times greater mortality risk compared with A, and C was associated with a 34 times greater mortality risk. Moreover, a 1 point increase in the Child-Pugh grade was associated with a 1.52 times increased mortality risk. Since bilirubin and ascites are components of the, they were not found to be independent predictors of mortality by the multivariate analysis. On the other hand, the large confidence interval for the suggests that studies with a larger number of patients are required to increase the power of the current study. We did not find the number or the largest size of tumors treated with RFA to affect survival. This underscores the importance of hepatic functional reserve in patients with HCC undergoing RFA in determining long-term prognosis. Serum AFP level was shown to influence survival after liver resection [8]. Likewise, our study also shows that increasing serum AFP level is associated with shorter survival after RFA, by both univariate and multivariate analyses. A serum AFP level >400 ng/ml was associated with a 5.7 times greater mortality compared with a serum AFP level <20 ng/ml. In conclusion, this study determined which patients with HCC do best after RFA. and AFP levels are independent predictors of survival. These results show that RFA can provide significant survival for patients with unresectable hepatocellular cancer while also forming a bridge to liver transplantation. In our institution, RFA has become the first line of treatment in the management of these patients. Acknowledgment. We thank Philip Ituarte, PhD, MPH, for his assistance with the statistical analyses. References 1. 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