In most patients with primary liver cancer (PLC), treatment options are limited by the liver dysfunction caused by chronic inflammation and cirrhosis. Although surgical resection is the gold-standard treatment, alternative treatment options are necessary for most patients with unresectable PLC. Transarterial chemoembolization (TACE) is a regional therapy widely used since the 1980s for unresectable PLC.1-3 It is not a curative treatment modality and is based on the therapeutic principle of regional chemotherapy and partial obstruction of the blood supply. Complete necrosis was previously observed in only 30%-64% of the patients with PLC who received TACE before resection,3-5 without destruction of the surrounding rim of nontumorous liver tissue.
Since the first report on radiofrequency ablation (RFA) of PLCs by Rossi et al6 in 1995, RFA has been performed principally in patients with small PLC (<4.0 cm in diameter).7 In recent years, the use of RFA has also been considered for the treatment of medium (3.1-5.0 cm) and large (>5.0 cm) PLCs.8 Apart from the technologic developments aiming to increase the efficacy of ablative therapy for large PLCs, recent research interest has been directed toward the combination of transarterial and local ablative therapies. It has been demonstrated that TACE combined with RFA (TACE plus RFA) was superior to TACE or RFA alone9 for improving survival of patients with hepatocellular carcinomas larger than 3.0 cm. However, there have not been many studies regarding TACE as an adjuvant therapy after RFA for treatment of PLC. In the present study, the outcome of the combination of RFA and TACE for unresectable PLC was retrospectively evaluated to study the necessity and feasibility of this combined modality.
From May 2003 to March 2008, a total of 127 consecutive PLC patients with a median age of 56.4±8.8 years (range: 37-72 years) underwent RFA plus TACE in our hospital. The inclusion criteria of these patients were as follows: All patients were deemed to have unresectable PLCs based on clinical characteristics such as (a) the presence of severe cirrhosis with inadequate functional hepatic reserve to tolerate the necessary hepatic resection, (b) the tumor proximity to major vascular structures precluding a margin-negative resection, (c) the focal or multifocal lesions (no more than 5 foci) should be confined in the liver without distant metastasis, (d) the diameter of the main tumor was no more than 10 cm, and (e) the liver function should be Child-Pugh class A or B. The contraindication of this treatment regimen included diffuse multifocal (more than 5 foci) lesions in the whole liver, portal vein thrombosis, or Child-Pugh class C liver function. The clinical characteristics of all patients are listed in Table.
Patients were treated using the RITA 1500 generator (RITA Medical Systems Inc., Mountain View, CA, USA). This system consists of a generator that supplied up to 150 W of power and a multitined expandable electrode (StarBurst XL, RITA). The multitined expandable electrode consisted of a 15-gauge insulated cannula, 15 to 25 cm in length, that contains nine individual electrode tines deployed in situ after ultrasound-guided placement of the needle electrode into the liver tumor. Depending on tumor size, shape, and location, a defined treatment strategy was adopted that consisted of a mathematical protocol, an individualized protocol, and adjunctive measures. RFA was performed percutaneously for patients with small or medium tumors in the liver parenchyma, by laparoscopic approach for patients with small or medium tumors on the liver surface, and through laparotomy for other circumstance, including for patients with tumors proximal to major vascular structures and large tumors.
For tumors no larger than 3.0 cm in diameter, the multitined expandable electrode was deployed into the center of the tumor. Each application of RFA energy lasted for 15-25 minutes to gain a 5.0 cm ablation zone. For medium tumors (3.1-5.0 cm), multiple overlapping zones of ablation were needed for the destruction of the tumor and a surrounding rim of nontumorous liver. The multitined expandable electrode was first deployed at the most posterior interface (monitored ultrasonographically) between tumor and normal liver parenchyma. It was redeployed at 1.0-2.1 cm intervals from the tumor center (Figure 1). Optimal positioning of the electrode permits complete destruction of a tumor 3.1-5.0 cm in diameter, including at least a 1.0 cm rim of normal liver parenchyma, following 6 ablations.
For tumors larger than 5.0 cm, more multiple overlapping zones of ablation are needed. For patients with more than one lesion, the tumors were ablated separately. The Pringle maneuver (i.e., temporary hepatic arterial and portal venous occlusion by means of direct compression of the vessels) was used during RFA for tumors with a rich blood supply at laparotomy. The ablative area was monitored and controlled during the procedure with real-time ultrasound. Vital signs were continuously monitored during the procedure and for 1 hour following.
After a catheter was inserted percutaneously into the hepatic artery using Seldinger's technique,3 digital subtraction angiography was performed to show tumor dissection and arterial maps. The celiac artery and mesenteric artery were catheterized to assess the hepatic vascular anatomy, followed by injection of 500-1000 mg 5-FU, 20-40 mg mitomycin C, and 20-40 mg adriamycin by way of the hepatic and collateral arteries supplying the tumor. A mixture of 5-10 ml of Lipiodol and 20 mg of adriamycin were subsequently administered.
All patients were followed up for detecting acute or chronic complications related to the RFA treatment. One month after RFA, 3 weeks after TACE, and then every 3 to 6 months for up to 3 years, a CT scan of the abdomen and serum α-fetoprotein (AFP) tests were routinely performed. During the follow-up period, patients may have received other adjuvant treatments, such as traditional Chinese medicine and antiviral treatments acquired elsewhere, as they were not prohibited.
The local 3-dimensional ablation zone was evaluated by contrast CT scanning one month after RFA. Tumor necrosis was considered complete when no foci of enhancement were seen within the tumor or at its periphery.8 The authors created a scale to further classify local tumor ablation in response to RFA. The classification was as follows: (1) complete ablation (for a single nodular tumor) defined as complete tumor necrosis with an ablative margin 0.5-1.0 cm wide (Figure 2); (2) nearly complete ablation (for a single nodular tumor) defined as complete tumor necrosis with some ablative margin less than 0.5 cm wide or (for 2-3 nodules <5 cm) 100% complete tumor necrosis not considering ablative margin; and (3) partial ablation (for a single nodular tumor) defined as less than complete tumor necrosis, residual tumors found after RFA, or metastases were left unablated, or for patients with more than 3 tumors (indicating micro multi-nodular metastasis) or with tumor emboli in the branch of portal vein, hepatic vein, or bile duct.
Data were analyzed using the SPSS statistical software package, version 11.5 (SPSS, Inc., USA). A P value <0.05 was considered statistically significant.
RFA was performed percutaneously in 16 (13.5%) patients, by laparoscopic approach in 19 (15.7%), and through laparotomy in the other 92 (72.4%). Technical success of RFA was achieved in all 127 patients with no severe treatment-related complications. Ascites occurred and persisted for more than 1 week in 13 cases, and all patients recovered within one month following proper treatment. Other operations conducted simultaneously with RFA included ligation of splenic artery for hypersplenia in 23 cases, cholecystectomy in 13, and incision of the common bile duct to withdraw cancer embolus in 3. The diagnosis of PLC was confirmed histologically either by ultrasound-guided percutaneous fine-needle aspiration in 25 cases or by intraoperative biopsy in 102. One hundred and thirteen cases were of hepatocellular carcinoma and the other 14 were cholangiocarcinoma.
According to the contrast CT scanning one month after RFA, the RFA response of the 127 cases was classified as complete ablation in 48 cases, nearly complete ablation in 28, and partial ablation in 51. Most of the patients, 96.2% (25/26) with <3.0 cm diameter tumors and 57.6% (19/33) with 3.1-5.0 cm diameter tumors, achieved complete ablation. RFA could be particularly problematic in large tumors when multiple overlapping zones of ablation are needed for the destruction of the tumor and a surrounding rim of nontumorous liver, which requires a longer duration to manage RFA. It took 6 hours for us to manage RFA for one patient with two large tumors (9 cm and 6 cm in diameter). Fewer of the patients with large tumors could achieve complete ablation (6%, 4/68) or nearly complete ablation (19%, 13/68). Analysis by Spearman's method showed that the relationship between the main tumor diameter and RFA response was significantly correlated (r=0.819, P<0.01).
One to two months after RFA, the first-time TACE and subsequent iodized-oil CT scan at 3 weeks were performed to further evaluate the results of RFA. Evidence of incompletely treated tumors, residual lesions, or metastasis were found on the iodized CT scan after TACE in only 10.4% (5/48) of the patients that gained complete ablation, 14.3% (4/28) of the patients that gained nearly complete ablation, and in 76.5% (39/51) for those patients that only achieved partial ablation. The 3-dimensional evaluation of RFA response by contrast CT scan was almost identical with that of the iodized CT scan. For those 90 cases with elevated AFP values higher than 25 μg/L, AFP values dropped to less than 25 μg/L in 55.6% (51/90) of the cases 3 months after RFA plus the first TACE.
At least one TACE was performed after RFA for each patient. Afterwards, TACE was given every 3-6 months (no more than 3 times in total) if the RFA response was classified as nearly complete ablation, partial ablation, or for those classified as complete ablation when metastasis or a new lesion was found. All patients were followed for 5-48 months (median, 15 months; mean, 18.9±12.4 months). By the end of the follow-up period, thirty-one patients died as a result of recurrent PLC, 19 patients died of liver dysfunction, and 7 others were lost in follow-up and were treated as deaths. Life table analysis showed that the total survival rates after RFA plus TACE at 1, 2, and 3 years were 83.1%, 55.7%, and 43.7%, respectively. The survival rates after RFA plus TACE at 3 years for patients with tumors <3 cm, 3.1-5.0 cm, or >5.0 cm in diameter were 69.8%, 59.6%, and 12.2%, respectively (Figure 3, χ2=27.4, P <0.01). The survival rates after RFA plus TACE at 3 years for the complete ablation, nearly complete ablation, or partially ablation groups were 78.6%, 28.1%, and 0%, respectively (Figure 3, χ2=39.1, P <0.01).
Metastasis or new lesions (Figure 2) were found in 16 of the 48 cases of complete ablation 3-44 months after RFA (median recurrence time, 24 months; mean, 22.4±11.3 months). Metastasis or new lesions were found in 18 cases of the nearly complete ablation group 3-39 months after RFA (median recurrence time, 16.5 months; mean, 14.9±9.8 months). One, two, and three-year disease-free survival rates for the complete ablation and nearly complete ablation groups were 93.3%, 76.1%, 50.5%, and 69.0%, 32.0%, 21.3%, respectively (χ2=11.260, P <0.01). Kaplan-Meier log-rank analysis showed that the tumor diameter, liver function, histopathology, and RFA response were statistically significant factors influencing survival rates (P <0.01). The factors of gender, age, type of hepatitis, and AFP level relative to survival rate did not reach statistical significance (P >0.05). The four statistically significant factors (above) were analyzed using multivariate Cox regression analysis. RFA response (Wald=24.709, P <0.01) and liver function (Wald=8.990, P <0.01) were statistically significant variables influencing survival time as determined by the Cox regression model.
Effect of RFA on unresectable PLC
The principle and mechanism of RFA are the same as thermal ablation,10 although the needle electrode may be designed differently. Novel RFA needle electrode designs have been developed with multitined expandable electrodes that are deployed from the needle tip into the tumor. In contrast to the small area of tumor tissue ablation created by a simple needle electrode, multitined expandable electrodes can produce a zone of coagulative necrosis up to 5.0 cm in diameter. RITA Medical Systems has recently introduced the third generation of multitined expandable electrodes, by which the authors could produce a zone of coagulative necrosis up to 7.0 cm in diameter following a single ablation. RFA can produce a predictable area of necrosis that encompasses not only the tumor tissue but also the capsule and a margin of surrounding liver tissue, and RFA can also reveal a resection of the lesion functionally. In a sense, this is equivalent to a limited hepatic resection, better than TACE11 or percutaneous ethanol injection (PEI) alone.12 This approach is more useful than microwave coagulation13 as a thermal ablative therapy, and hence RFA has been proposed to be a curative treatment for small PLCs (<3.0 cm). The authors even achieved complete ablation for most of the tumors (75%, 44/59) no larger than 5.0 cm (<3.0 cm or 3.1-5.0 cm) in diameter, which resulted in a satisfactory 3-year survival rate when combined with TACE. Even for tumors larger than 5.0 cm in diameter, which usually show poor progress, the 3-year survival rate after RFA plus TACE reached 12.2%. These results indicate that RFA for large tumors is also applicable. Compared with TACE used alone, RFA showed the characteristics of rapid local exterminate ablation. It has been previously demonstrated that no other therapy is more effective than RFA for the treatment of large infiltrating hepatocellular carcinoma.8 In order to achieve a possibly curative therapy by complete ablation, the authors suggested RFA be chosen as the first option for unresectable PLC.
Limitation of RFA for unresectable PLC
The size of the ablated area was largely determined by the current intensity and length, the gauge of the electrode tip, and the duration of energy applied. This effectively limits the area of tissue that can be ablated by a single RFA. Using contrast CT scans, several studies have shown complete tumor necrosis in 80% to 90% of PLCs smaller than 5.0 cm after a single session of RFA,14 while the complete ablation rate for larger tumors was less favorable. Complete necrosis was achieved significantly less frequently in infiltrating tumors and tumors larger than 5.0 cm in diameter.8 A study of RFA for the treatment of 126 cases of PLC 3.1-9.5 cm in diameter (mean, 5.4 cm)8 reported a complete necrosis rate of 48%, even with the use of a clustered electrode. Locoregional recurrences were reported to be frequent after RFA for hepatocellular carcinoma.15
According to the principal of surgical oncology, a 0.5-1.0 cm rim of normal liver (surgical margin) around the tumor should be treated to gain curative effectiveness.16 Creating overlapping ablation fields can be used to ablate tumors up to 5.0 cm, but it is not easy. To gain a 7.0 cm ablation zone requires twelve 5.0-cm ablations, according to the mathematic and overlapping model established by Chen et al.17 Using a modified model and selecting a proper approach, the authors still required six 5.0-cm ablations to gain a 7.0 cm ablation zone.
The results of the RFA response are usually classified as complete ablation or partial ablation,10 which is not sufficient for evaluation and further treatment direction in the authors' opinion. In the present study, RFA response was classified as complete ablation, nearly complete ablation, or partial ablation. Cox regression showed that the RFA response classification was the primary statistically significant variable relative to survival time, with the exception of liver function (a non-treatment variable). The 3-year disease-free survival rate of the complete ablation group (50.3%) was significantly higher than the nearly complete ablation group (21.3%). These results indicated that this novel classification of RFA response was better for predicting long-term survival.
The present study also revealed that the larger the tumor was, the less completely the tumor was ablated and poorer the resulting progress, further indicating that RFA for treatment of medium and large tumors is limited. Simultaneously, it indicated that the combination of multimodality after RFA to control residual foci or micro-metastasis was necessary for patients with medium or large PLCs that could not be completely ablated.
Combined treatment with RFA and TACE
The treatment procedure and principals of RFA and TACE are obviously different. A novel approach that combines locoregional therapies is transarterial embolization prior to local hyperthermic ablation.18 This is of benefit because the cooling effect of the blood flow is one of the main limiting factors for thermal ablation. Hence, transarterial occlusion of the blood supply before heat ablation by percutaneous or laparoscopic approach may significantly increase the size of the ablation area. Some reports have shown better results for TACE followed by RFA than for RFA alone.9,11 Others suggest that preoperative TACE reduces long-term survival rate after hepatic resection for resectable hepatocellular carcinoma.19 Whether pre-RFA TACE reduces long-term survival rates after RFA requires further study. Clinically, for those tumors that need to be ablated by way of an intraoperative approach, especially medium and large tumors, the main blood supply of PLC (derived from the hepatic artery) could be controlled by the Pringle maneuver. Generally speaking, in the authors' opinion, it is not necessary to perform TACE before RFA to occlude the hepatic blood supply that could easily be controlled by the Pringle maneuver, unless it is to perform RFA by a percutaneous or laparoscopic approach for special cases with excessive blood supply, where TACE is an adjuvant to the subsequent RFA.
The present study shows that RFA alone is not effective for the treatment of large tumors, because most of these cases (51/68) only achieved partial ablation. Even for the patients that gained complete ablation or nearly complete ablation, 3-year disease-free survival rates were very low (50.5% and 21.3%, respectively). Peritumoral fibrotic tissue that is interposed between the main tumor and satellite lesions may limit heat diffusion from the tumor's center.8 The high rate of local recurrence may be due to residual cancer cells not killed by RFA or adjacent microscopic satellite tumor nodules. Although the majority of recurrent tumors after RFA could be new lesions, possibly related to multicentric hepatocarcinogenesis of cirrhosis14 determined by the biology of the tumor.
It has been demonstrated that postoperative adjuvant TACE can prolong the survival of patients with risk factors for residual tumors.20 In our hospital, adjuvant TACE is usually performed after liver resection for patients with PLC. Consequently, adjuvant TACE is routinely performed after RFA for patients with unresectable PLC. Considering the advantages and disadvantages of using RFA or TACE1-3 alone, the authors prefer a two-step modality. RFA should be the first-line exterminate treatment for unresectable PLC, and TACE could be used as an adjuvant therapy after RFA, especially for medium and large PLC, to eradicate the peripheral viable tissue and micro-metastasis. The number of TACE reiterations depends on the RFA response as measured oncologically. For completely ablated tumors, the recurrence and metastasis rate is low and one-time TACE is necessary for both evaluation and treatment of micro-metastasis before recurrence or metastasis is verified by imaging. For those cases that could only achieve nearly complete ablation, recurrence or metastasis is frequent and multi-time TACE is necessary. For those cases that could only be partially ablated, multi-time TACE and multimodality21 treatments are required.
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