European Journal of Cardiovascular Medicine

Hepatocellular Carcinoma (HCC) is a malignant tumor that is sixth most prevalent in the world, accounting for between 500,000 and a million new cases annually. Of the approximately 6,00,000 cases of HCC reported annually worldwide, over 78% are found in Asia.^[1] HCC has a poor prognosis, with a 1-4% 5-year survival rate. Four population-based registries in India show that the mean incidence of HCC is 1.38% for females and 2.77% for males. In India, the prevalence of HCC ranges from 0.2% to 1.6%.^[2,3,4] The only curative treatment is surgical excision of the HCC. About 80–90% of patients having hepatic resection obtain successful excision with negative tumor margins.

Multiple lesions, tumors in inoperable sites and other medical factors that put the patient at low candidate for surgery are all contraindications for hepatic resection . Only 5–15% of HCC patients are candidates for resection,^[5] according to estimates. Patients who have hepatic resection face a number of challenges, including significant postoperative morbidity, a slight risk of mortality and high cost. Another surgical option is liver transplantation.  However, in addition to the difficulties associated with open surgery, there is a scarcity of donors. Given these drawbacks, treating HCC requires an efficient, minimally invasive method that may be repeated as needed to treat recurrent tumors.

A relatively new minimally invasive and relatively low-cost percutaneous thermal ablation like RFA is thought to be the best choice for those with early-stage, small-sized HCC, for whom surgical resection is contraindicated. The principle of RFA is based on converting electrical radiofrequency current into heat, creating a zone of thermal necrosis. A volume of tissue is devitalized under imaging guidance without removing it from the body, resulting in a similar effect to surgery. It is evident that RFA has a wide range of reported effectiveness for complete tumor ablation and lower recurrence rates.

Therefore, this study was conducted with the purpose of identifying the factors leading to better treatment outcomes and the study hopes to achieve this by analyzing preprocedural tumor morphology, Child-Pugh score the technical parameters and correlating them with treatment outcome at follow-up.

To study the correlation of preprocedural tumor morphology (size of the lesion on contrast imaging) with the outcome of RFA (successful ablation or local tumor progression) and to study the correlation of Child-Pugh score and technical parameters with the outcome of RFA.

This was a prospective study conducted over a period from June 2010 to June 2012. The study was approved by the local review board. A written informed consent was obtained from all patients before the procedure. 35 males and 5 females satisfying the aforementioned criteria underwent radiofrequency ablation. Based on the results on the correlation of size of the lesion, Child-Pugh score and technical parameters with the outcome of RFA, from the earlier publication ^[15] and with 95% confidence and 80% power, the minimum sample size came to 30 in each group (successful ablation -30 and local tumor progression - 30). However, during my study period, I could get only 29 cases of successful ablation and 11 cases of local tumor progression.

Inclusion Criteria and Exclusion Criteria

Inclusion criteria were single nodular HCC ≤5cm in maximum diameter, 3 lesions, each ≤3 cm in diameter and Child-Pugh class A or B liver cirrhosis.

Exclusion criteria for the study include lesions >5 cm, main portal venous thrombosis, extrahepatic metastases and Child-Pugh class C liver cirrhosis.

Study Procedure

These patients were diagnosed with hepatocellular carcinoma by different imaging modalities (CT, MRI, and CEUS) and biopsy. The average age of the patient was 63.72 years (45-78 years). None of the patients were seropositive for hepatitis B or C. 25 patients were in Child A score and 15 in Child B.36 HCCs were due to alcohol-induced cirrhosis, and 4 cases were cryptogenic. The mean tumor size of HCCs was 2.83±1.06 cm (range: 1.2 cm ± 5 cm). RFA was done only in proven HCC cases, either with typical imaging features or confirmed with FNAC/liver biopsy. 33 patients were diagnosed with HCC by CT, 3 by MRI, and 3 by CEUS. One case was confirmed with FNAC, which had a doubtful washout in CE-MRI and CEUS. FNA and biopsy were done in 1 and 3 patients, respectively, with doubtful imaging interpretation. HCC most commonly involved the right lobe. Twenty seven  HCCs were located in the right lobe and 12 cases in the left lobe. One case showed bilobar HCC. Serum AFP was elevated in 18 patients, normal in 14 and was not obtained in 8 cases. The inclusion criteria were strictly followed during the entire period of the study, which was based on Milan criteria.

All patients had laboratory tests performed prior to therapy, including hematocrit, white blood cell count, blood coagulation tests, hepatic function values, and levels of a-fetoprotein. An INR (International Normalized Ratio) of greater than 1.3 or a platelet count of less than 50,000/ml is contraindicated. The aspirin has to be stopped for atleast three days prior to the procedure. Ascites was controlled before the procedure. Our institutional review board approved this study, and each patient or family member provided written and informed consent.

Radio Frequency Ablation Procedure

Patients had radiofrequency ablation following a 4-hour fast, and the procedure was done on an out-patient basis with post-procedure observation. The terminology standardization and reporting guidelines put forward by the International Working Group on Image-Guided Tumor Ablation and the Society of Interventional Radiology Technology Assessment Committee,^[6] served as the foundation for our explanations of the radiofrequency ablation techniques and data evaluation. For all processes, we employed an internally cooled electrode system (Cool-tip, Valleylab). The size, location, and configuration of the index tumor as well as the electrode stock availability determined the type of electrode that the operators chose.

At the time of the trial, five experienced radiologists, each with more than ten years of experience performed the ablation. By fastening one pad to the back and one to the thigh, grounding was accomplished. Following the iodine and alcohol sterilization of the skin, a lancet was used to puncture the skin and local anesthetic 1% lidocaine was injected subcutaneously. Patients also received analgesia by IV injection of 50-100 g of fentanyl citrate (Fentanyl, Mengun) and sedation with 1-2 mg of midazolam (Dormicum, Roche).Six patients had the procedure done under CT guidance, while thirty-four patients had it done under sonographic guidance. Radiofrequency ablation was done in all patients using internally cooled 17-gauge electrodes (Cool-Tip, Valleylab) with an exposed tip of 3.0 cm. The electrode was inserted into the lesion under CT guidance when the lesion was in the hepatic dome or was not apparent on sonography. A Somatom Sensation 64 slice MDCT scanner (Siemens Medical Solutions) was utilized for the CT-guided technique with 110 kVp scanning parameters. 200 mA, 5 mm collimation, and 7 mm/sec table speed. The most likely site of the tumor and the best path to it were determined using the pretreatment diagnostic-workup pictures. A 3.5-MHz convex probe (Sonosite Micromax portable) was utilized for sonographic guidance.

After CT or sonography had verified that the electrodes were properly positioned in the tumor, the electrodes were attached to a 500-KHz monopolar radiofrequency generator (CC-1, Valleylab) that could produce 200W. Circuitry built into the generator monitored tissue impedance using an automated pulsed-radiofrequency method that was regulated by impedance. Vital signs were continually tracked throughout the process.

Normal saline solution at 0°C was infused into the radiofrequency electrode lumen at a pace sufficient to maintain a temperature of 0–20°C using a Watson–Marlow peristaltic pump. When treating tumor nodules with a diameter of less than 3 cm, radiofrequency treatment was administered for 10 to 12 minutes, based on the size of the tumor, using a single electrode placed in the tumor's center. A single radiofrequency electrode was used in the overlap approach (two to four overlaps) for tumors larger than 3 cm. Depending on the size of the tumor, radiofrequency was used for 12 minutes at first and 6 to 12 minutes for successive ablations.

Assessment of Therapeutic Efficacy and Follow-Up Studies

Patients underwent contrast-enhanced CT within 24 hours of the procedure to assess the ablation zone. By comparing the results with pre-treatment CT or MRI, the two skilled radiologists evaluated the therapeutic effectiveness of radiofrequency ablation on posttreatment CT. When a non-enhancing area that was at least as large as the original tumor was observed, tumor necrosis was deemed to be complete. ^[7,8,9] A further ablation session was carried out within three days if persistent tumor was detected on the post-treatment CT scan. After then, an MRI or CT scan was done every three months. All patients underwent blood tests to assess liver function and was monitored for potential procedure-related complications immediately following treatment and during follow-up. We compared the aminotransferase level, bilirubin level, and Child-Pugh score prior to treatment with those during the first three weeks following treatment in order to assess the impact of radiofrequency ablation on hepatic function. The mean follow-up period was 13 months. Recurrence-free survival was defined as the time interval between the date of the initial RFA treatment and the date of a local or distant recurrence.

Statistical Analysis

Statistical Computer software SPSS (Statistical Package for Social Sciences) version 20 and Microsoft Excel 2007 were used for the statistical analysis in this study. The Kaplan-Meier technique was used to determine the median patient survival periods. The Chi-square test served as the foundation for the statistical analysis. A p-value of less than 0.05 is regarded as significant.

There were 35 males and 5 females in this study. The highest number in age group criteria was within 60 to 70 years old. A statistically significant association was observed in the size of the lesion with the outcome. <3 cm lesions showed 89.66% complete response. >3 cm lesions showed 63.64% CR. >3 cm lesions showed 36.36% local tumor progression. <3 cm lesions showed 10.34% LTP. No association was noted with other variables like Child-Pugh criteria, technical parameters like size of the needle, fresh or reused needle, and the time of ablation on outcome (Table). The median follow-up period was 5 months (range: 1–22 months). The median recurrence-free survival period was 6 months.

Figure shows median recurrence free survival curve plotted by Kaplan-Meier method. The median follow-up period was 5 months(range of 1 to 22 months). The  overall median reccurrence free survival period was 6 months.

Radiofrequency ablation of the liver is a promising technique for treatment of HCC. There are a variety of factors that contribute to variations in stated success rates, such as the equipment utilized, operator expertise, and patient selection. RFA is not a good treatment for diffuse or infiltrative forms of HCC and should only be used as a stand-alone intervention for unresectable localized or multifocal tumors. A single nodular HCC with a maximum diameter of ≤5 cm, <3 lesions with a diameter of ≤3 cm each, and patients with Child-Pugh class A or B liver cirrhosis were the criteria used to select patients for RFA. Our study which included 40 HCC patients treated between June 2010 and June 2012 revealed that the tumor size had the greatest impact on RFA's therapeutic success. Out of the 40 cases, 29 tumors (72.5%) showed complete response(CR). 88.5% of the lesions in the CR category were ≤3 cm showing that RFA can successfully ablate small tumors.  We could also achieve 42.9% CR in >3 cm lesions, showing that many larger lesions can also be ablated. A study by Laspas et al. showed the success rate of ablation was 87.3%, while 41% of lesions were managed with repeat RFA due to tumour residue, and the survival rates at 1, 2, 3, 4, and 5 years were 94%, 86%, 73%, 64%, and 51%, respectively.^[10] A work undertaken by Yulri Park et al. showed the local therapeutic efficacy of RFA was 99%. Tumour progression was detected in 23.9% of the cases during follow-up. The estimated rates of local tumour progression at 1, 2, and 3 years were 12.9%, 23.1%, and 27.6%, respectively.^[11]

Needle size (ablation zone) was not related to the outcome of this study. The RFA needle can be reused two times (total of three sittings) safely as revealed in the results that fresh/reused needle did not have any statistically significant difference on the outcome. Cool-tip radiofrequency electrode (Covidien) used in our department has an advantage over other manufacturers. The internal cooling is believed to prevent desiccation and charring around the needle tip and thereby facilitating re-use. Though re-use is not recommended by the manufacturer, economic reasons compel us to do so. Ablation time also did not show any statistical association with the outcome.

RFA is a safe procedure. One patient with segment VII HCC close to the diaphragm developed minimal hydropneumothorax. No other complications were noted during post-procedure imaging. Post-ablation syndrome occurred in 6 patients and was medically managed. One left lobe HCC close to the heart was completely ablated without any complications. Another case of left lobe HCC showing segment III surface lesion close to stomach was ablated using an 8 mm x 4 cm balloon placed between the stomach and left lobe to avoid thermal injury to the bowel. Postprocedural check CT showed no complications, and the follow up imaging showed CR with no thermal injury to the stomach. Ablation was also performed safely in a subdiaphragmatic HCC by artificially creating pleural effusion. Re-ablation was recommended in cases with local tumor progression(LTP) and intrahepatic distant recurrence (IDR); only two patients underwent the same for IDR. Five patients with LTP underwent TACE, out of which one was combined with repeat RFA. Survival curves were plotted by the Kaplan-Meier method with a log-rank test. The median follow-up period was 5 months (range: 1-22 months). The overall median recurrence-free survival period was 6 months. Many patients who had a complete response on imaging at one month did not come for further follow up. This could have contributed to the apparently poor recurrence-free survival observed by us. In the study by Zytoon et al., consisting of 40 HCC patients, the overall median recurrence-free survival after RFA was 13 months with a median follow-up period of 24.1±15.7 months.^[12]

The Child-Pugh score did not show any statistically significant association with the efficacy of RFA in this study. Out of 25 Child A and 15 Child B patients who underwent RFA, one Child B patient with CR developed IDR and died due to decompensation one year after the procedure. No other mortality occurred. The median recurrence-free survival period of Child A and B patients in our study was 8 and 6 months, respectively. In the study by Sang Seok Lee et al. with 257 patients for a 5-year period, 1-year survival rates for Child A and B patients are 63.5% and 36.9% respectively, and their median survival periods in months are 20.8 and 9.5, respectively.^[13] The same study showed 1-year, 3-year and 5-year survival rates in patients with Child -Pugh class A or B after RFA in TNM stages I and II are 81.8%, 36.4%, and 27.3%, respectively, and the overall median survival rate was 27 months. In our study, the 1-year survival rate after RFA for Child A and B was 61% and 50%, respectively. Our results are not in agreement with the above study due to our small patient population and shorter duration of study.

Odd's ratio showed >3 cm lesions had 10 times the risk for local tumor progression. Out of 11 cases showing LTP, 7 lesions >3 cm were close to blood vessels. Because the incidence of LTP is known to correlate with tumor size, local tumor progression is more common in cases with larger HCCs. Therefore, larger lesions require longer ablation times, multiple needle passes/overlapping ablation zones, and reablation or in combination with TACE. Another factor that could have contributed to LTP is an overcautious approach to lesions in proximity to blood vessels. In the vicinity of large vessels, needles may be placed as close as achievable to the vessel without damaging it. It has been recommended by Chen MH et al. that the area where the feeding artery is entering should be ablated first.^[14] For larger lesions undergoing RFA, deepest ablations were performed before the superficial ones, minimizing the possibility of microbubbles obscuring the visualization of the deeper portions of the tumor. Despite all these factors, we could achieve CR in 50% of lesions close to vessels. Cumulative rates of LTP at 1 year are 25%, and this is in line with the study done by Yulri Park et al. However, our data does not show any particular trend towards greater local tumor progression in HCCs near blood vessels. HCCs are known to recur, and the cumulative rates of IDR at 1 year are 12.5%. 

Thus, for early HCC, RFA is an effective locoregional treatment option as it is minimally invasive and safe. Because this was a single-center study, it's possible that the findings will not hold up well in different contexts. Careful thought should be given to variations in the criteria, procedures, and RFA equipment before extrapolating the study's findings to patients at other institutions. The amount of care provided by the facility and the radiologists' level of skill may also have an impact on the course of treatment.

In this study, 60% of patients did not turn up for periodic follow-up imaging which was a major limitation of this study. This was probably the reason for our reduced overall median recurrence-free survival period of 6 months. The outcome of RFA who were lost on follow-up could not be determined. Another limitation was our selection bias in cases for RFA. Some patients with lesions deemed difficult for RFA were triaged towards TACE. These include larger lesions, ill-defined, diffuse lesions, lesions close to large blood vessels, gall bladder, near hepatic flexure, and subcapsular and subdiaphragmatic HCCs. This bias can lead to RFA appearing much more effective than it actually is. However, it is well known that RFA is relatively ineffective in large and diffuse lesions, and so our study does reflect a real-life scenario. Lastly, our study had a small sample size and a short follow-up period. A study consisting of a larger number of patients and longer follow-up is necessary, as regular long-term surveillance is essential for early detection and eradication of local tumor progression and intrahepatic distant recurrence.

The preprocedural tumor morphology showed a statistically significant association with outcome. HCCs ≤ 3 cm showed a complete response of 88.5%. Overall complete response was noted in 72.5% of cases. Even > 3 cm tumors also showed CR of 42.9%. Tumors >3 cm showed 10 times the risk for Local Tumor Progression (LTP) . LTP was seen in 27.5% of lesions. More than 3 cm lesions showed 57.1%  LTP. The overall median recurrence free survival period was 6 months. The Child-Pugh score of patients and technical parameters did not show any statistical association with outcome. The 1-year survival rate of Child A and B patients was 61% and 50% respectively.

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