Evaluation of Radiofrequency Ablation as a Method for Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma is the fifth most common neoplasm in the World and the third most common cause of cancer related death (1). It accounts for 7.4% of all cancers in males and 3.2% of all cancers in females (2). An early diagnosis of HCC is required for the institution of treatments considered to be curative. On this basis, screening of each patient with liver cirrhosis should be performed by ultrasound and by measurements of serum alphafetoprotein (AFP) at 6-months interval (3).There are different methods for active management of HCC, many factors related to the tumour itself and to the patient may make a tumour unresectable (4). Radio frequency ablation (RFA) is the most common therapy used in patients not suitable for resection. In RFA, an electric current that is passed into the tumour tissue via an electrode tip results in heat generation and coagulative necrosis (5). The advantage of radio frequency is the small number of sessions needed to obtain tumour necrosis (6). The aim of the present study was to evaluate the radiofrequency thermal ablation as a method for treatment of hepatocellular carcinoma.

As we start RFA session a hyper-echoic focus developed around the un-insulated portion of the electrode.This was attributed to tissue vaporization and cavitations.The area of echogenicity was round; most often progressively increased in size over the course of ablation and generally enveloped the entire tumour with variable extensions in the surrounding liver by the end of the treatment.In some cases, the hyper-echoic focus did not develop progressively but appeared rather suddenly and was accompanied with an audible popping sound emanating from the liver.

Cool down:
When the timer runs out the generator well automatically goes into Cool Down mode for 30 seconds (5 minutes on the generator display), when the Cool Down is complete, the temperatures from all leads must be above 70°C, if not we continue ablation for another 5 minutes at target temperature, or we can rotate the device 45 degree to check temperature and continue ablation if still temp below 70°C.

Track ablation:
In most of our cases we ablate the tract before removal of the needle.Post Ablation care: IV antiemetic was given if needed, Strong IV analgesics were given to pain as pethidine hydrochloride 50 mg or tramadol.All patients were observed clinically for 2-3 hours in the Radiology department to detect any acute complications and to start IV fluid.Prophylactic antibiotic were started, amoxicillin-clavulanic acid (augmentin) or ceftazidine (fortum), and metronidazole (flagyl), and continued for 3 days.

Post treatment follow up
All patients underwent dynamic CT scan 1 month after completion of the therapy to detect any residual enhancing tumour tissue.If any area suspicious for viable tissue was detected, the patient was retreated by RFA of this area.Then, follow up CT was done after 3 months, then every 6 months to detect any local recurrence in the ablated tumour or de novo lesion.Alphafetoprotein level was assessed accompanying performance of CT.After 1 month if its level was still elevated, it indicated incomplete tumour ablation.Follow up after complete ablation was to detect any minor elevations which detect recurrence.

Results
Table 1 shows the demographic and clinical data of the studied patients.Thirty one patients had their AFP level above the diagnostic value (200ng/ml), while the remaining 43 patients had AFP level less than 200.The (M ± SD) of serum alphafetoprotein level (AFP) was 12086 ± 7345 ng/ml and ranged between 1.8 ng/ml and 350000 ng/ml, as shown in table 2 which illustrates also the remaining liver profile.All patients were positive for hepatitis C antibody and negative for HbsAg.HbcAb was detected in 7 patients.Abdominal ultrasound findings are shown in table 3. The findings of spiral CT in this study were similar to that of abdominal ultrasound as regard the number, site and diameter of the hepatic focal lesion.In this study, the spiral CT criteria suggestive for HCC were present in 63 cases (85.1%) and absent in 14 cases (14.9%) (they were proved to be HCC by biopsy.Forty two Patients (56.8%) were within Child Pugh class A and 32 patients (43.2%) were within Child Pugh class B (patients in Child class B were with minimal and controlled ascites).Tumour character: The seventy four patients included in the study were divided into 2 groups according to the number of focal lesions in each patient.Sixty eight patients form group I and had only one focal lesion (68 lesions) and the maximum diameter of the tumours was 3 cm or less in 42 patients and was from 3-5 cm in 26 patients.Group II formed of patients with 2 hepatic focal lesions and included 6 patients with 12 focal lesions.In group II, the maximum diameter of the tumours was 3 cm or less in 6 lesions of 6 patients and was from 3-5 cm in another 6 lesions of the same 6 patients (Table 3).

Mean
55. 5  The residual of the tumour was managed by a second session of RFA.All local or distant recurrences were managed by a second RFA session when in suitable site except in one patients was near a biliary radicle, so managed with intralesional ethanol injection.

*Follow up of Laboratory investigation:
As regards the liver enzymes, ALT was significantly elevated one month after RFA sessions (92.8 ± 36.4 IU/L) more than before ablation (P < 0.01), the same was noticed for AST which was also significantly higher (98 ±32.5 IU/L ) (P<0.01).During the second follow up done after 3 months, ALT and AST returned to base line levels.Three months after RFA, serum albumin was higher and ranged between 2.8-4.5 gm/dl with (M ± SD: 0.2± 0.4gm/dl), serum bilirubin was lower and ranged between 0.6-1.9mg/dl with (M ± SD: 0.9±0.4gm/dL).Before treatment with RFA serum A FP values were elevated (>200ng/mL) in 31patients (41.8%).Table 6 shows the patients with AFP level>200 during the follow up period after ablation.There were no fatal complications related to RFA treatment.Nearly all the patients experienced post-ablation right hypochondrial pain that was controlled by analgesics, and nausea (70 patients, 94.5%), which was controlled by antiemetics Also, nearly all experienced post -ablation pyrexia for 1-3 days, which was controlled by antipyretics.
Only one patient developed pneumothorax due to ablation of Sub-diaphragmatic tumour and another 2 patients developed ascites within the first week post ablation.
At the end of this study after one year, survival analysis was evaluated.Two patients (2.7%) died as result of advanced liver disease.So, overall survival rate was 97.2% (72/74 patients).Disease free survival rate was 79.7% as thirteen patients (17.6%) survived with recurrent HCC and fifty nine patients (79.7%) were disease free over the follow up period (Table 7).

Survival status Number of patients %
Disease

Discussion
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world and the third most common cause of cancer related death.Currently, it is the leading cause of death among cirrhotic patients (1).The studies carried out on hepatocellular carcinoma are scarce in Egypt.Nevertheless, they presumed an upward trend for HCC among chronic liver disease (CLD) patients (9).
For the last two decades several minimally invasive interventional ablative techniques aiming at providing local destruction of the tumour have been developed.Radiofrequency thermal ablation (RFA) is a more recently developed for local tissue ablation.This retrospective study was performed on 74 patients with hepatocellular carcinoma attending Hepatoma unit of Ain Shams University during the period between January 2004 and January 2006.
In this study, it was found that the number of male patients was higher than females (57 male and 17 females) with ratio 3.4:1 and this agrees with Sherlock and Dooley 2002 who reported that in patients with HCC males exceed females in a ratio of 4-6:1(2).Also, Marrero, 2003 stated that male population both black and white is primarily affected (10).
The newly developed persistent right hypochondrial dull aching pain was the most common complaint of patients included in this study (78.3%).This is a very important finding and it meets the finding of Hillebrand and Sandowski, 2000 who found that although the percentage of patients having specific signs and symptoms differs in highincidence and low incidence areas of HCC, the most common complaint remains abdominal pain (4).Pain is frequent but rarely severe and is felt as a non-specific, continuous dull ache in the epigastrium, right upper quadrant, or the back.Severe pain is due to perihepatitis or involvement of the diaphragm (2).The etiology of chronic liver disease in patients of the study was hepatitis viruses' infection (HBV and/or HCV).In Egypt, HCV seroprevalence is 55% among children who had received blood transfusions and 67% among patients on renal dialysis, and is 10% among sexually transmitted disease patients (11).
In this study, 67 patients (90.5%) were positive for HCV antibody.The prevalence of HCV antibody positive patient with HCC was found to be 62% in Spain, 65% in Italy, 29% in South Africa and 29% in United States (12).
In this study all patients were negative for HBsAg but when HBcAb IgG was assessed (which indicates past infection with HBV), it was found that HBcAb IgG was positive in 7 patients (9.5%) of the study.these results agree also with El-Zayadi et al., 2001 who placed Egypt among the countries of intermediate prevalence for HBV as HBV accounts for 10-30% of CLD and HBsAg carriage was reported in 5.6% (9).Owing to the use of ultrasound surveillance in patients with hepatic cirrhosis, HCC is diagnosed in an increasing number of patients at an early asymptomatic stage (13) .Patients with early stage HCC should be considered for any of the available curative treatment options including surgical resection, liver transplantation and percutaneous techniques of tumour ablation (14) .In the recent decade, ultrasound guided percutaneous ethanol injection (PEI), as a local therapy for hepatic tumours, has gradually been replaced by intraoperative or percutaneous RFA (15) .RFA was considered by many authors as superior to other existing loco regional therapies as percutaneous ethanol injection (PEI), transarterial chemoembolization (TACE) and microwave ablation (16) .
In the present studying RFA was used to treat 80 tumours in 74 patients.The 80 tumours included 48 tumours (60%) less than 3 cm in diameter and 32 tumours (40%) 3-5cm in diameter.
Generally, a single ablation of 5cm in diameter could successfully destroy liver tumour smaller than 3cm plus the safety margin of 0.5-1cm (17) .In the present study, after one month of RFA , all the 48 tumours (100%) less than 3cm in diameter shoed complete ablation while 26/32 (81.3%) of tumours between 3-5cm showed complete ablation and 6 tumours (18.7%) showed residual viable tumour tissue (i.e.partial or incomplete ablation).In a study by Chen et al. 2005 (17) , cases with tumours larger than 3.5cm in diameter accounted for 61.8% (207/335 cases) of their study population, and they got 85.9% response rate (178/207 cases), results nearly similar to the results of the present study.The whole complete response rate for all tumours was 92.5% (74/80 tumours), the 6 incompletely ablated tumours (7.5%) were larger than 3cm in diameter.These results are also near the results of Chen et al. 2005 who reported 94.8% (723/763 tumours) total ablation rate of the initial RFA.Of the 40 incompletely ablated tumours, 33 (82.5%) were larger than 3.5cm (17) .These data support the fact that the most important factor for efficacy of RFA is the size of the tumour and the RFA could successfully ablate smaller liver tumours.Sala et al 2004 (18) supports this by the results of their study as they reported initial complete response of 96% in tumours 2cm or smaller and this figure decreased to almost 50% in multinodular or large HCC and this figure is similar to that reported by most referral groups (19) .All cohort studies assessing percutaneous ablation report the appearance of viable tumour tissue within the treated nodule or its vicinity after initial complete response (20) .This was met in our study as, three months after ablation local recurrence occurred in three patients in group I. Six months after ablation, 4 patients (2 in each group) showed distant recurrence and 2 other patients in group II showed another distant recurrence after one year.This event is heterogeneously defined (distance from the main nodule, location in the same segment) and named (21) .This is usually termed local recurrence or local tumour progression (21) .Sala et al 2004 reported local tumour progression in 76 patients in their series of 192 patients after initial complete response with a 1, 3, 5 years probability of 26%, 56%, and 74% respectively.Most were detected early in the follow up, but 34% were registered at 2 years and 13% were detected beyond 3 years (18) .Unfortunately, results of our study can not be compared with results of Sala et al 2004 as the follow up period here is only one year.
Even tumours 2cm or smaller can present with late failure and studies in resected tumours explain this: one third of tumours with 3cm or smaller present microscopic vascular invasion or satellites, which will almost likely not be affected by ablation and emerge as failure early or late during follow up (22) .At the end of the follow up period in our study (1year), the overall survival rate was 97.3% i.e. 72 patients alive and 2 patients died due to disease progression.Fifty nine patients (79.7%) represented the disease free survival while 13 patients (17.5%) lived with either local or distant recurrence.The one year overall survival in our study was 97% which is similar to that of Shina et al., 2005 (23) but less than Lencioni et al., 2003 (24) which was 100%.However our results are higher than those of Lin et al., 2004 (25) and Lin et al., 2005 (26)  In this series nearly all the patients experienced post-ablation minor complication as right hypochondrial pain that was controlled by analgesics and nausea, which was controlled by

Table 1 .
Demographic and clinical data of the studied patients.

Table 2 .
Laboratory findings of the studied patients. www.intechopen.com

Table 3 .
Tumour character in the studied patients: During the first follow up done one month after ablation, 68 patients (91.9%) showed complete ablation no evidence of residual and 6 patients (8.1 %) showed incomplete ablation [ 3 patients in group I and 3 patients in group II, all of them with lesion diameter 3-5cm] (

Table 4
. Results of RFA after one month During the second follow up done after 3 months, 71 patients (95.9 %) had no evidence of local or distant recurrence.Local recurrence occurred in 3 patients in group I (4.1%).During the third follow up done after 6 months, 70 patients (94.6%) showed no evidence of recurrence and 4 patients (5.4%) [2 patients in group I and 2 patients in group II] had a new focal lesion at distant sites of the liver.During the fourth follow up done after 12 months, 72 patients (97.3%) showed no evidence of recurrence and 2 patients (2.7%) had a new focal lesion at other sites of the liver both were in group II (

Table 5 .
Results of 3, 6 and 12 months follow up after RFA

Table 6 .
Patients with AFP>200ng/ml before and after RFA.

Table 7 .
Survival rates evaluation in the study (90% , 93% respectively ).At the end of the study (1 year ) ,15 patients (18.9% ) lived with either local recurrence or denovo lesion.Lin et al., 2003 reported 18% local recurrence at the end of their study (2 year ) while over the same period Lncioni et al ., 2003 reported only 4% local recurrence and no report on denovo lesions.