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10.1245/ASO.2005.06.011
Annals of Surgical Oncology 12:616-628 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Significant Long-Term Survival After Radiofrequency Ablation of Unresectable Hepatocellular Carcinoma in Patients with Cirrhosis

Chandrajit P. Raut, MD1, Francesco Izzo, MD2, Paolo Marra, MD2, Lee M. Ellis, MD1, Jean-Nicolas Vauthey, MD1, Francesco Cremona, MD2, Paolo Vallone, MD3, Angelo Mastro, MD4, Bruno D. Fornage, MD5 and Steven A. Curley, MD1

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, Texas 77030-4009
2 Division of Surgical Oncology, The G. Pascale National Cancer Institute, Fondazione G. Pascale, Naples 801331, Italy
3 Division of Diagnostic Radiology, The G. Pascale National Cancer Institute, Fondazione G. Pascale, Naples 801331, Italy
4 Division of Medical Oncology, The G. Pascale National Cancer Institute, Fondazione G. Pascale, Naples 801331, Italy
5 Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 13501, Houston, Texas 77030-4009

Correspondence: Address correspondence and reprint requests to: Steven A. Curley, MD; E-mail: scurley{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Radiofrequency ablation (RFA) offers an alternative treatment in some unresectable hepatocellular carcinoma (HCC) patients with disease confined to the liver. We prospectively evaluated survival rates in patients with early-stage, unresectable HCC treated with RFA.

Methods: All patients with HCC treated with RFA between September 1, 1997, and July 31, 2002, were prospectively evaluated. Patients were treated with RFA by using a percutaneous or open intraoperative approach with ultrasound guidance and were evaluated at regular intervals to determine disease recurrence and survival.

Results: A total of 194 patients (153 men [79%] and 41 women [21%]) with a median age of 66 years (range, 39–86 years) underwent RFA of 289 sonographically detectable HCC tumors. All patients were followed up for at least 12 months (median follow-up, 34.8 months). Percutaneous and open intraoperative RFA was performed in 140 (72%) and 54 (28%) patients, respectively. The median diameter of tumors treated with RFA was 3.3 cm. Disease recurred in 103 (53%) of 194 patients, including 69 (49%) of 140 patients treated percutaneously and 34 (63%) of 54 treated with open RFA (not significant). Local recurrence developed in nine patients (4.6%). Most recurrence was intrahepatic. The overall complication rate was 12%. Overall survival rates at 1, 3, and 5 years for all 194 patients were 84.5%, 68.1%, and 55.4%, respectively.

Conclusions: Treatment with RFA can produce significant long-term survival rates for cirrhotic patients with early-stage, unresectable HCC. RFA can be performed in these patients with relatively low complication rates. Confirmation of these results in randomized trials should be considered.

Key Words: Hepatocellular cancer • Radiofrequency ablation • Survival • Unresectable • Cirrhosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) develops most commonly in patients with cirrhosis. Treatment options are limited in most patients with HCC because of liver dysfunction caused by chronic inflammation and cirrhosis. Cirrhosis has a prevalence of 60% to 90% in individuals with HCC.1 Cirrhosis limits the amount of parenchymal resection that will be tolerated and increases the risk of postoperative liver failure and death.2–4 Systemic or regional chemotherapy is palliative at best in a small subset of patients and is associated with significant side effects and reduced quality of life.5 Because resection is not safe in most patients with cirrhosis and HCC, tumor ablation may be considered as an alternative therapy in patients with small-volume disease confined to the liver.

Radiofrequency ablation (RFA) is a thermal treatment technique that produces localized tumor destruction by heating tumor tissue to temperatures exceeding 55°C. Alternating current is passed across the RFA needle electrode arrays deployed directly inside the tumor. When tumor cells are heated rapidly to temperatures >55°C, intracellular proteins denature and the membrane lipid bilayers melt, and this results in direct tumor cell death.6–9 Ionic stimulation induced by the alternating current in tissue surrounding the electrode array produces gradual frictional heating over several minutes and increases the tissue temperature to 80°C to 110°C. This produces coagulative necrosis of the tissue in proximity to the electrode.

Patients with HCC treated with surgical resection have a 5-year overall survival (OS) rate of approximately 37%.10 Those with low-volume disease meeting the Milan criteria and treated with liver transplantation have a 4-year OS rate of 75%.11 However, those with unresectable HCC treated with medical or supportive care have a median survival of only 9 months, a 1-year survival rate of 44%, and a 3-year survival rate of 13% to 26%.12–14 Although surgical extirpation is not an option in these patients, the role of RFA and its effect on survival in this subset of patients have not been established.

We have previously published the initial results of a prospective study of RFA in patients with unresectable HCC.15 We now present the first published data on long-term survival rates in an expanded cohort of patients. We also report the local tumor control rate, patterns of failure, and treatment-related complications.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After approval by the institutional review boards at the University of Texas M. D. Anderson Cancer Center in Houston, TX, and the G. Pascale National Cancer Institute in Naples, Italy, all patients with unresectable HCC treated with RFA between September 1, 1997, and July 31, 2002, were prospectively evaluated. All patients were deemed to have unresectable hepatic disease on the basis of tumor multifocality, tumor proximity to major vascular structures precluding a margin-negative resection, or the presence of severe cirrhosis with functional hepatic reserve inadequate to tolerate the necessary hepatic resection. Patients with tumor abutting a major portal or hepatic vein branch or the inferior vena cava were included, but patients were excluded if the tumor involved either the main right or left bile duct (or both) or if there was evidence of extrahepatic disease. Patients were treated with ultrasound (US)-guided RFA by using a percutaneous or open intraoperative approach based on the severity of cirrhosis and the safest approach in the judgment of the treating surgeon (see below).

All patients were evaluated with a baseline history and physical examination and serum laboratory tests consisting of a complete blood count, platelets, coagulation profile, electrolytes, renal panel, albumin, alanine aminotransferase, aspartate aminotransferase, {gamma}-glutamyl transferase, alkaline phosphatase, total bilirubin, serum alfa fetoprotein, and hepatitis B and C virus serologies. Patients were excluded if their platelet count was <40,000/µL or if the prothrombin time was >1.5 times normal, unless platelet or fresh-frozen plasma transfusion, respectively, corrected the abnormal laboratory value. Pretreatment imaging was obtained with either computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis and a chest radiograph. HCC was confirmed histologically by either prior intraoperative biopsy or by CT- or US-guided percutaneous fine-needle aspiration. Core biopsy of the liver documented cirrhosis in all 194 patients. The clinical severity of the cirrhosis was scored by using the Child-Turcotte-Pugh system.

Patients with small cancers easily imaged on transabdominal US and with cirrhosis too severe to tolerate laparotomy were considered for percutaneous US-guided RFA. All patients undergoing percutaneous RFA were treated in the operating room by a surgeon with intravenous anesthesia consisting of propofol (3–6 mg/kg/hour) and remifentanil (.05–.075 µg/kg/minute). A biopsy guide attached to the transabdominal US probe was used to assist radio-frequency (RF) needle electrode placement for percutaneous treatment.

Patients with larger tumors, those abutting major intrahepatic blood vessels, or those near the liver capsule where percutaneous treatment could produce thermal injury to adjacent organs were treated during an open surgical procedure. Intraoperative US was used to identify, count, and characterize the nature of and vascular proximity of the hepatic lesions and to place the RF needle into the lesions to be treated in these patients. Hepatic resection, when performed, was generally performed immediately before RFA of additional tumors.

RFA was administered with the RF 2000 or 3000 generator system (Boston Scientific Corp., Natick, MA). This system consists of a generator supplying up to 100 W (RF 2000) or 200 W (RF 3000) of power, a LeVeen monopolar array needle electrode (3.5- and 4.0-cm maximum array diameter), and four indifferent dispersive grounding electrode pads applied to the patient’s skin. The LeVeen electrode is a 15-gauge, 15- to 25-cm-long insulated cannula containing 10 individual hook-shaped electrode arms to be deployed in situ. For tumors <2.5 cm in diameter, the multiple array was deployed into the center of the tumor. For larger lesions, the array was deployed first at the most posterior interface (sonographically) between the tumor and the liver parenchyma; after treatment, the array was withdrawn and redeployed anteriorly at 1.5- to 2.0-cm intervals in the tumor. Optimal positioning of the electrode permitted complete destruction of the tumor and a 1-cm zone of surrounding liver parenchyma.

All patients were followed up to detect acute or chronic complications related to the RFA treatment. Those treated with percutaneous RFA underwent a dynamic contrast-enhanced CT or MRI of the abdomen 1 week after treatment to assess for viable, incompletely treated tumor (as evidenced by persistent contrast-enhanced tumor tissue). If any areas suggestive of viable tumor were detected, then the patient was immediately retreated with percutaneous RFA to the area of concern. A CT or MRI of the abdomen, a chest radiograph, and the same battery of laboratory studies were obtained 1 month after treatment and then every 3 months up to 3 years in all HCC patients treated with RFA.

Statistical analysis was performed with a signed rank test and analysis of variance (GraphPad Instat version 3.05; GraphPad Software, San Diego, CA). Significance was determined at the 95% confidence interval. Survival times were estimated by using the method of Kaplan and Meier (SPSS for Windows version 11.5.0; SPSS Inc., Chicago, IL).16


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
All surviving patients were followed up for at least 12 months after RFA of HCC. A total of 194 patients, 153 men (79%) and 41 women (21%), were included in this study. RFA was performed percutaneously in 140 (72%) patients and via laparotomy (open RFA) in 54 (28%) patients. There was no difference in sex distribution between patients treated with a percutaneous versus an open intraoperative RFA. The median age was 66 years (range, 39–86 years). Patients treated with percutaneous RFA (median age, 68 years; range, 46–86 years) were older than those treated with open RFA (median age, 65 years; range, 39–82 years; P < .01).

Risk factors for cirrhosis are listed in Table 1Go. The Child-Turcotte-Pugh class at the time of RFA treatment was A in 110 patients (57%), B in 49 patients (25%), and C in 35 patients (18%). Patients treated with open RFA generally had clinically less severe cirrhosis; 51 (94%) of 54 were Child class A. In contrast, virtually all patients with more severe cirrhosis were treated with percutaneous RFA. There were more Child B patients in the percutaneous RFA group (n = 46; 33%) compared with the open RFA group (n = 3; 6%; P < .0001). All of the Child class C patients were treated with percutaneous RFA.


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  		TABLE 1. Etiological factors and severity of cirrhosis in 194 hepatocellular cancer patients treated with radiofrequency ablation (RFA)
 
Treatment of Tumors
RFA was used to treat 289 sonographically detectable HCC tumors in the 194 patients (Table 2Go). After diagnosis of new clinically detectable recurrent hepatic tumors without extrahepatic recurrence of disease, 59 patients underwent repeat RFA (percutaneous). After a second intrahepatic recurrence, 22 patients underwent a third RFA session (percutaneous). Thus, 194 patients underwent a total of 279 RFA sessions (Fig. 1Go).


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  		TABLE 2. Tumor number, size, and T stage in patients with hepatocellular cancer treated with radiofrequency ablation (RFA)
 

Figure 1
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  		FIG. 1. A total of 194 cirrhotic patients with hepatocellular carcinoma (HCC) underwent 279 radiofrequency ablation (RFA) treatments. Initial RFA treatments were percutaneous in 140 patients and open in 54 patients. Immediate repeat treatment was necessary in 4 patients treated percutaneously because of incomplete tumor ablation. After disease recurrence at new sites in the liver, 59 patients underwent a second RFA session. After a second intrahepatic recurrence, 22 patients underwent a third RFA session.

 
The mean number of tumors treated was 1.5. Patients treated with open RFA had a greater mean number of tumors treated as compared with those treated with percutaneous RFA (1.8 vs. 1.4; P < .01). The median tumor diameter was 3.3 cm. There was no difference in median tumor diameter in patients treated with a percutaneous approach (3.0 cm) versus an open approach (4.0 cm). Tumors treated percutaneously had a lower T stage than those treated with an open approach (P < .05). There was no imaging evidence (by CT, MRI, or US) of major portal or hepatic venous invasion by tumor in any of the lesions treated with RFA.

Of the 54 patients treated with open RFA, 22 (41%) underwent additional hepatic resection, whereas 32 (59%) were treated with open RFA alone. A wedge resection was performed in 3 patients, a single hepatic segment was resected in 14 patients, a left lateral segmentectomy was performed in 3 patients, a left hepatectomy was performed in 1 patient, and a right hepatectomy was performed in 1 patient. Cholecystectomy was performed in six patients to facilitate either resection or RFA of an adjacent segment. An adrenalectomy was also performed in one patient.

Tumor Recurrence
Tumor ablation was complete in all 54 patients treated with open RFA, with no evidence of residual viable tumor on the first postoperative CT or MRI scan. Of the 140 patients treated with percutaneous RFA, 4 (3%) had evidence of residual viable tumor on the first posttreatment imaging study, thus necessitating immediate repeat treatment with percutaneous RFA of the suspicious areas (Fig. 1Go).

At a median follow-up of 34.8 months, HCC recurred in 103 (53%) of the 194 patients. HCC recurred in 69 (49%) of 140 patients after percutaneous RFA, in 20 (63%) of 32 patients after open RFA without hepatic resection, and in 14 (64%) of 22 patients after open RFA with hepatic resection (Table 3Go). Local recurrence was identified in four patients (3%) after percutaneous RFA and in five patients (16%) after open RFA without resection. HCC recurred at other intrahepatic sites in 63 patients (45%) after percutaneous RFA, in 11 patients (34%) after open RFA without resection, and in 14 patients (64%) after open RFA with resection. Overall, 98 (95%) of the 103 recurrences occurred in the liver (local, other intrahepatic, or intrahepatic with distant recurrence). Of the 59 patients with recurrent hepatic disease who underwent repeat RFA, 36 (61%) developed a second recurrence (Table 4Go). Again, the dominant pattern of recurrence was intrahepatic; 34 (95%) of the 36 second recurrences were in the liver (with or without distant recurrence).


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  		TABLE 3. Patterns of disease recurrence after radiofrequency ablation (RFA) in 194 patients with hepatocellular cancer
 

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  		TABLE 4. Patterns of second recurrence after radiofrequency ablation (RFA) in 194 patients with hepatocellular cancer
 
Morbidity and Mortality After RFA
Table 5Go lists the deaths and complications in our patient cohort. Mortality and morbidity rates were calculated on the basis of cumulative RFA treatments. After 279 RFA sessions in our 194 patients, there were 4 (1%) treatment-related deaths, all in patients who underwent open RFA with hepatic resection. Two patients developed hepatic insuffciency and died 10 and 39 days after operation. In addition to RFA, they had undergone a segmentectomy and a right hepatectomy, respectively. Another patient developed hepatorenal syndrome and died after 30 days. The final patient developed ascites, pneumonia, and multiorgan system failure and died after 10 days. There were no treatment-related deaths in the patients with recurrent disease who underwent a second or third RFA procedure. There were no deaths in the 172 patients treated with RFA alone.


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  		TABLE 5. Complications associated with radiofrequency ablation (RFA) in 194 patients with hepatocellular cancer
 
Major treatment-related complications developed after 34 (12%) of 279 RFA treatments. Complications observed in the patients treated percutaneously included incomplete ablation (four patients, described previously), hemorrhage into the ablated tumor, subcapsular hematoma, ascites, hydropneumothorax, pleural eNusion, ventricular fibrillation, and persistent fever for >2 weeks. Complications observed in patients treated with open RFA included hemorrhage from the incision, ascites, biloma, pneumothorax, and atrial fibrillation. Ascites was successfully treated with diuretic therapy. Symptomatic pleural eNusions, hydropneumothorax, and pneumothorax were treated with chest thoracostomy drainage. Ventricular fibrillation developed at the conclusion of percutaneous RFA treatment in one patient; this was successfully treated with a single electrical discharge from transthoracic cardioversion paddles. The patient with persistent fevers for >2 weeks had no evidence of infection at the ablation site (after repeated aspirations of the treated tumor). It should be noted that RFA with hepatic resection resulted in complications such as hemorrhage from the incision and biloma, as well as the complications resulting in the four treatment-related deaths.

Disease Status and Survival
The disease status of all 194 patients is known (Table 6Go). Of note, one patient who underwent percutaneous RFA died several months later from anaphylactic shock while undergoing hepatic artery chemoembolization for recurrent disease and is listed in the dead from other cause group. Patients with recurrent disease who are currently disease free after repeat RFA or who were disease free at the time of death from unrelated causes after repeat RFA are classified as no evidence of recurrent disease or dead from other cause, respectively. None of the 194 patients underwent hepatic arterial embolization or chemoembolization before RFA, nor had they received any other regional or systemic therapies. None of the 194 patients received adjuvant regional or systemic therapy after RFA. As noted previously, HCC recurred in the liver, at distant sites, or both in 103 of the 194 patients treated with RFA. In 59 (57.3%) of these 103, the disease was confined to the liver and was treated with a second session of RFA to ablate the newly diagnosed hepatic tumors. Overall, 50 (25.7%) of the 194 patients ultimately received regional and/or systemic chemotherapy when diagnosed with recurrent HCC not amenable to treatment with RFA or other local therapies.


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  		TABLE 6. Disease status and survival rates in 194 hepatocellular cancer patients treated with radiofrequency ablation (RFA)
 
Disease-free survival (DFS) and OS rates for our cohort of 194 patients are listed in Table 6Go and graphed in Fig. 2Go. The median DFS was 17.4 months. One-year, 3-year, and 5-year DFS rates were 58.5%, 43.1%, and 33.1%, respectively. Median OS has not yet been achieved. One-year, 3-year, and 5-year actuarial OS rates were 84.8%, 68.1%, and 55.4%, respectively. The 5-year actuarial OS rate for the 185 patients with T1 or T2 disease was 57.8%.


Figure 2
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  		FIG. 2. Disease-free (A) and overall (B) survival curves in 194 patients after radiofrequency ablation (RFA) of hepatocellular carcinoma. The median disease-free survival (DFS) was 17.4 months. DFS rates at 1, 3, and 5 years were 58.5%, 43.1%, and 33.1%, respectively. Median overall survival (OS) was not achieved. OS rates at 1, 3, and 5 years were 84.8%, 68.1%, and 55.4%, respectively.

 
Survival by treatment is shown in Table 6Go and Fig. 3Go. After percutaneous RFA, the median DFS was 30.8 months. One-year, 3-year, and 5-year DFS were 58.6%, 49.9%, and 33.7%, respectively. Median OS has not yet been achieved. One-year, 3-year, and 5-year actuarial OS were 87.6%, 74.3%, and 57.5%, respectively. In patients who underwent open RFA without hepatic resection, the median DFS was 13.9 months. One-year, 3-year, and 5-year DFS were 65.6%, 34.1%, and 34.1%, respectively. The median OS was 49.8 months. One-year, 3-year, and 5-year actuarial OS were 90.6%, 55.1%, and 45.9%, respectively. In patients who underwent open RFA with hepatic resection, the median DFS was 11.4 months. One-year, 3-year, and 5-year DFS were 43.3%, 7.2%, and 7.2%, respectively. The median OS was 24.2 months. One-year, 3-year, and 5-year actuarial OS were 58.0%, 44.8%, and 44.8%, respectively. DFS was significantly lower in patients who underwent open RFA with hepatic resection when compared with those who underwent RFA alone (either percutaneous or open) at 1, 3, and 5 years (P < .05). OS was lower at 1 year for those who underwent open RFA with hepatic resection versus the other two groups (P < .05). At 3 years, those who underwent open RFA (with or without hepatic resection) had lower OS (P < .05). Finally, 5-year actuarial OS rates were statistically similar (not significant).


Figure 3
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  		FIG. 3. Disease-free (A) and overall (B) survival curves after percutaneous radiofrequency ablation (RFA; solid line), open RFA without hepatic resection (hatched line), and open RFA with hepatic resection (dashed line) in 194 hepatocellular cancer patients with cirrhosis.

 
Survival by Child-Turcotte-Pugh classification is shown in Fig. 4Go. DFS at 1 year was similar in Child class A (60.0%) and B (63.0%) patients and was lower in class C (46.6%) patients (P < .05); at 3 years, it was similar in all three groups (A, 41.2%; B, 50.1%; and C, 39.0%; not significant), and at 5 years it was greater in class B patients (50.1%) compared with class A (30.9%) and C (31.2%) patients (P < .05). OS at 1 and 3 years was similar regardless of Child classification (1 year: A, 81.6%; B, 93.2%; and C, 82.9%; 3 years: A, 69.2%; B, 69.2%; and C, 61.2%; not significant). At 5 years, OS was greater in class A (64.1%) and class B (57.7%) patients than in class C (20.7%) patients (P < .05).


Figure 4
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  		FIG. 4. Disease-free (A) and overall (B) survival curves by Child-Turcotte-Pugh classification in 194 hepatocellular cancer patients with cirrhosis.

 
Survival by tumor (T) stage is shown in Fig. 5Go. Median DFS and OS rates were not generally different. The 3-year DFS rate for patients with T1tumors was greater than for those with T2 tumors (P < .05). The 5-year OS rates for patients with T1 and T2 tumors were greater than for those with T3 tumors (P < .05).


Figure 5
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  		FIG. 5. Disease-free (A) and overall (B) survival curves by tumor stage (tumor-node-metastasis system) in 194 hepatocellular cancer patients with cirrhosis.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although the incidence of HCC in Western countries is relatively low when compared with other solid-tumor malignancies, it is the fifth most common malignancy worldwide, with approximately 1 million new cases diagnosed annually.1,17,18 Treatment options are limited. Only 10% to 30% of affected individuals are suitable for hepatic resection or transplantation.10,19,20

The reported median survival rate of individuals who undergo hepatectomy for resectable HCC is 39 months, with 1-, 3-, and 5-year survival rates of 81%, 54%, and 37%, respectively.10,21 In noncirrhotic patients with disease meeting transplantation criteria who undergo hepatic resection, 5-year DFS and OS rates of 54.8% and 70.0%, respectively, have been recently reported.22 Liver transplantation provides some of the best survival rates after surgical extirpation for low-volume disease meeting the Milan criteria (solitary liver nodule not exceeding 5 cm in maximal diameter or two or three tumors not exceeding 3 cm in maximal diameter).11 Transplantation remains the treatment of choice for patients with early HCC and decompensated cirrhosis; it offers a cure for both malignancy and cirrhosis. However, limited organ availability makes this treatment unavailable for most patients with early-stage HCC. In contrast, patients with unresectable disease who are treated with medical or best supportive care have a median survival of 9 months, with 1-year and 3-year survival rates of 44% and 13% to 26%, respectively.12–14 In our 185 patients with T1 or T2 tumors who met current criteria for transplantation, the actuarial 5-year OS rate was 57.8%. This supports the use of RFA to control early-stage HCC in patients awaiting transplantation to remove a diseased liver at risk of harboring multifocal HCC or developing new malignant tumors.

We have previously shown that RFA can be performed with low morbidity and mortality rates in selected cirrhotic HCC patients with unresectable disease.15 The current report is the first to define 5-year actuarial survival rates in an expanded cohort of these patients. With a median follow-up of 34.8 months, we have not yet established the median OS after RFA for early-stage unresectable HCC. Five-year OS is 55.4%. These compelling survival data suggest that RFA for unresectable HCC results in patient survival rates comparable—if not superior—to those for resection for HCC and that it is significantly better than nonoperative management. Also, resection is usually considered only for low-risk patients: specifically, those with Child class A cirrhosis and a functional hepatic reserve adequate to tolerate resection. In contrast, all patients in our cohort had unresectable disease on the basis of tumor location or severity of cirrhosis (43% of our patients had Child class B or C cirrhosis). Thus, our survival data were obtained in inoperable patients, who generally have a worse prognosis. Giovannini et al.23 recently reported DFS rates at 1 and 3 years of 82.1% and 70.3%, respectively, and OS rates at 1 and 3 years of 96.2% and 94.2%, respectively, after RFA in 56 patients with cirrhosis after a mean follow-up of 14 months. However, the shorter follow-up interval and smaller patient number confound any meaningful comparison between their study and ours.

Tumor recurrence was identified in 53% of our patients after initial RFA and in 61% of patients with recurrent disease after second RFA. Recurrence rates after RFA are similar to those after resection. By way of comparison, Cha et al.24 reported a recurrence rate of 55% after a median follow-up of 26 months in patients undergoing resection. Although it has been recently reported that RFA is an effective treatment for tumors measuring up to 8.0 cm, long-term follow-up data are not available to determine whether recurrences are more likely with large tumors after RFA intended for cure.25 Analysis of our prospective database reveals that there is a direct correlation between an increased incidence of local recurrence, meaning incomplete tumor destruction, and increasing tumor size. More than 95% of local recurrences in our studies occur in tumors >4 cm in diameter, and these results have been corroborated by other investigators.15,26

HCC recurred at a site of previous RFA in 9 (5%) of 194 patients treated. This relatively modest rate of local recurrence reflects meticulous attention to the completeness of ablation by the surgeon. One significant disadvantage to RFA is the inability to confirm the extent of successful coagulation. Other studies27,28 have reported rates of local recurrence after RFA for HCC of 19% to 36%. Such high recurrence rates cause concern and are usually due to persistence of tumor at the ablation site after RFA. Successful RFA relies on the painstaking application of overlapping zones of tumor ablation to ensure destruction of tumor along with a surrounding rim of hepatic parenchyma. Furthermore, we emphasize the need for a surgeon with a thorough understanding of oncological principles to perform the RFA treatment (even for percutaneous RFA) and to do so with continuous US guidance and treatment monitoring to minimize the risk of incomplete ablation.

Not surprisingly, the most common site of recurrence was at new sites in the liver. Intrahepatic recurrences were identified in 45% of patients after initial RFA and in 56% after second RFA for recurrence. Nevertheless, just as recurrent resectable HCC can be treated with repeat resection, recurrent disease that is unresectable may be successfully treated with repeat RFA or other regionally directed therapy. HCC is frequently multifocal in the liver, and close follow-up is necessary in the first 2 to 3 years after RFA to detect the development of new hepatic lesions that were clinically undetectable at the time of initial RFA.

Complications were identified in 14% of patients after initial treatment. This rate was higher in patients who also underwent hepatic resection. The overall complication rate including repeat RFA treatments for new tumors was 12%. The scope of complications presented here is similar to those previously reported.29,30 The mortality rate of 1% reflects the four patients who died after RFA combined with liver resection.

A potential criticism of this study is the inclusion of patients treated in essentially three different ways—namely, by percutaneous RFA, open RFA without hepatic resection, and open RFA with hepatic resection. Those who underwent resection in addition to RFA had multiple tumors, but all could not be safely resected. Survival curves separating these three groups show poor short-term (1-year) survival with intervention involving any partial hepatic resection, as one would expect in patients with cirrhosis. Nevertheless, the 5-year OS in this subset is still 44.8%. At 5 years, the OS curves for the three different treatment groups did not differ significantly. This implies that the initial difference in OS is due to a combination of the assumed larger volume of disease (taking into account the disease resected) and the morbidity of hepatic resection in patients with cirrhosis. The convergence of the survival curves at 5 years reflects the utility of aggressive liver-directed therapy for HCC in cirrhotic patients, even when resection is combined with RFA to eradicate all sonographically detectable disease.

It is not known how survival duration after RFA compares to that after hepatic resection for resectable disease. A direct comparison between these treatments cannot be accurately assessed without a prospective randomized clinical trial. Such a trial is currently under way in Europe, and a multi-institutional trial in the United States is planned.

In conclusion, RFA is a useful therapeutic option to treat early-stage, unresectable HCC. Patients with unresectable HCC confined to the liver may have improved long-term survival with RFA. Our survival numbers compare favorably to reported values for patients with resectable disease treated with major hepatic resection. Our local recurrence rates are lower than those reported elsewhere in the literature. This reflects meticulous ablative techniques when this procedure is performed by experienced surgical oncologists.


   FOOTNOTES
 
Presented at the 57th Annual Cancer Symposium of the Society of Surgical Oncology, New York, New York, March 18–21, 2004.

Received for publication June 7, 2004. Accepted for publication February 23, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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