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DOI: 10.1055/s-2005-871199
Local/Regional and Systemic Treatments of Hepatocellular Carcinoma
Dr.
M. Beaugrand
Head of Department of Hepato-Gastroentrol, Hôpital Jean Verdier, Avenue du 14 Juillet
93143 Bondy Cedex, France
Email: secmed.hge@jvr.ap-hop-paris.fr
Publication History
Publication Date:
25 May 2005 (online)
- ABSTRACT
- PERCUTANEOUS TREATMENTS
- INTRA-ARTERIAL TREATMENTS
- SYSTEMIC TREATMENTS
- REFERENCES
ABSTRACT
Screening programs for patients with cirrhosis are designed to detect hepatocellular carcinoma at an early stage when effective treatment is feasible and may provide long-term survival benefits. However, only a minority of these patients will be considered candidates for liver transplantation or surgical resection and hence, most cases will be evaluated for other medical options.
While systemic therapy has never been shown to bear a relevant antitumoral activity with an impact on survival, there are several locoregional options that can achieve a high rate of objective responses (this includes complete necrosis or partial reduction in tumor burden). Percutaneous ablation by any of the available methods (ethanol injection, radiofrequency, microwave, acetic acid injection, laser) is extremely useful in patients with small solitary tumors. Results indicate that 90% of tumors < 2 cm will be completely ablated using the percutaneous approach. However, when tumor size exceeds 3 cm and/or the number of nodules is greater than 3, the rate of treatment success is significantly reduced. In patients with large/multifocal disease, the sole option that has been shown to provide treatment efficacy with moderate improvement in survival is chemoembolization.
New therapeutic agents should target biological mechanisms in a tailored strategy, and the demonstration of beneficial results for patients should be obtained by large, randomized, controled trials comparing active intervention versus no treatment.
Among many types of malignancies, hepatocellular carcinoma (HCC) has several specific characteristics.[1] It occurs in a diseased organ. In the West, 90% of patients have an underlying cirrhosis that is responsible for death in a significant percentage of patients.[2] It is often followed by the emergence of other HCC.[3] Even if not a validated procedure, screening is widely performed in patients with cirrhosis and predisposing factors and allows the recognition of an increasing number of small tumors.[4] It remains for a long period a locoregional disease accessible for locoregional treatments.[5] There is no validated systemic treatment for this tumor. The prognosis of HCC is dependent on many factors[1]: the severity and outcome of the underlying liver disease,[2] the occurrence of other tumors whose factors of prediction are the same as those of the primary,[3] the outcome of the primary tumor, and its response to treatment.
For these reasons, transplantation is the only treatment that can be called curative, but it remains marginal, applying to a small percentage of patients because of the shortage of donors and the stringent indication criteria even for living donor transplantation. This implies that the field of locoregional treatments must be expanded and the results improved if we want to offer some curative options for HCC patients. The locoregional treatments proposed either alone or in association are the following: surgical resection, percutaneous ablation, and transarterial treatment, the third one with only a palliative purpose. Therefore, for the many patients ineligible for transplantation the first question to be answered is, is a curative option possible? If so, the choice is between resection (with so many contraindications) and percutaneous ablation. If not, are transarterial treatments indicated? In this article we examine the results of transcutaneous treatments, then of transarterial treatments, and finally of systemic treatments, having in view principally the results of randomized trials.
#PERCUTANEOUS TREATMENTS
Because of multiple contraindications and the mortality and morbidity of surgery,[1] [2] alternative treatment modalities have been developed, including image guided tumor ablation using chemical (ethanol, acetic acid) or thermal (radiofrequency, microwave, laser and cryoablation) ablative techniques. Single nodular HCCs smaller than 5 cm or as many as three HCC lesions each smaller than 3 cm are generally accepted as an indication for local ablative therapies.
This approach is also used to treat limited recurrences, after surgical resection, or as a bridge to transplantation during the prolonged waiting period. Main contraindications are limited to important ascites, severe hemostasis disorders, platelet count less than 40,000 to 50,000/mm3, prothrombin activity less than 40 to 50%, severe liver impairment, tumoral vein thrombosis, and extrahepatic spread.
#Ethanol
Ethanol induces tumor necrosis by protein denaturation and thrombosis of small vessels. Ethanol ablation is usually performed under ultrasound guidance (as is radiofrequency thermal ablation [RFA]) using 21-gauge needles; 2 to 8 mL of 95% absolute ethanol is injected into several sites inside and around the lesion. Usually an average of four sessions are needed with conventional ethanol ablation to achieve complete necrosis. Treatment-related deaths are rare, with a rate ranging from 0.009 to 0.1%. Severe complications are infrequent and occurred only in 1.3 and 2% of cases in two large series.[3] [4] Early major complications are liver abscess, liver failure, intraperitoneal hemorrhage, cholangitis, and biloma. Tumor seeding along the needle tract has been reported with an incidence ranging from 0 to 1%.[5] Limited intrahepatic vessel thrombosis is also a possible complication.
The rate of complete necrosis is closely correlated with tumor size. Ethanol ablation achieves complete responses of 90 to 100% in HCCs smaller than 2 cm, 70% in HCCs between 3 and 5 cm, and 50% in HCCs larger than 5 cm.[6] [7] [8] [9] [10] [11] [12] The rate of recurrence ranged from 26 to 32%, 51 to 81%, and 60 to 83% at 1, 3, and 5 years, respectively,[7] [8] [9] including local recurrences (around 30%) depending on the size and distant recurrences, which are often new tumors. Long-term survival rates have been reported in large series (Table [1]). A 5-year survival rate of 40 to 65% has been reported in Child A patients with single HCCs smaller than 3 cm. Fair liver function (Child-Pugh A) and small (< 3 cm) and solitary tumors are usually reported as favorable independent prognostic factors.[6] [7] [10] [11] [12] In the study by Livraghi et al, 5-year survival rates were 47, 29, and 0% in patients in Child-Pugh class A (293), B (149), and C (20), respectively.[4]
| References[*] | Technique | Patients[*] | Tumor Characteristics | Mean Follow -Up (months) | Survival Rate (%) | |||
| Size (cm) | % Uni | 1 Year | 3 Years | 5 Years | ||||
| Tateishi et al[21] | RFA | 319 | 61 | 94 | 77 | 54 | ||
| 345a | 40 | 91 | 52 | 38 | ||||
| Lencionib et al[10] | RFA | 206 | 2.8 | 80 | 24 | 97 | 67 | 41 |
| Buscarini et al[16] | RFA | 88 | 3.5 | 89 | 34 | 89 | 62 | 33 |
| Omata et al[12] | EA | 524 | 2.9 | (< 3 cm) | 64 | |||
| Livraghi et al[19] | EA | 246 | < 3 | 36 | 97 | 68 | 40 | |
| 224 | 3-5 | 94 | 57 | 37 | ||||
| 50 | > 5 | 85 | 53 | 30 | ||||
| Lencioni et al[10] | EA | 105 | 22,5 | 96 | 68 | 32 | ||
| Sala et al[11] | EA or RFA | 289 | 84 | 25 | 97 | 72 | 63[†] | |
| 81 | 42 | 14[‡] | ||||||
| Lencionic et al[24] | EA | 50 | 2.8 | 62 | 23 | 96 | 88 (2-year) | |
| RFA | 52 | 2.8 | 77 | 22 | 100 | 98 (2-year) | ||
| Liang et al[28] | MCT | 288 | 3.7 | 63 | 31 | 93 | 51 | |
| EA, ethanol ablation; MCT, microwave technique; RFA, radiofrequency ablation. | ||||||||
1 Key: anon-naïve, bintention-to-treat, crandomized controlled trial, dconventional or higher dose ethanol ablation.
Ethanol ablation can be performed safely in elderly patients. No significant difference was reported in the survival rates after ethanol ablation in patients older than 70 years.[13] The most prominent advantages of ethanol ablation are a low cost and a low rate of complications. Major limitations of this technique are the presence of fibrous septa inside the lesion, limiting the spread of ethanol, and irregular diffusion outside the limits of the lesion, precluding a security margin. Multiple sessions are needed to achieve a complete response, and efficacy substantially decreases for tumors larger than 3 cm.[4] [6] A single-session higher ethanol ablation technique has been used to extend the size of necrosis. This technique increases the rate of major complications, particularly in patients with poor liver function.[14] As a whole, although no randomized study has been performed, ethanol injection and resection seemed to provide similar survival rates.
#Acetic Acid
Acetic acid with higher necrotizing power has been proposed as an alternative to ethanol, to decrease the number of sessions.[15] A randomized trial including 60 patients reported better local control and improved survival rates with acetic acid (2-year survival rate of 92% versus 63% with ethanol ablation).[15]
#Radiofrequency Thermal Ablation
RFA is the most extensively studied thermal ablation technique. RFA achieves thermal coagulation using an alternating electric current. Various advances in RF electrodes and techniques, such as cooled-tip electrodes, expandable electrodes, and pulsed delivery of RA energy, allow complete necrosis of spherical lesions ∼3 to 5 cm in diameter and also reduce the number of sessions.[16] Complication rates associated with RFA are higher than those with ethanol (Table [2]). Large studies showed mortality rates ranging from 0.1 to 0.5% and severe complication rates from 0 to 12%.[17] [18] Early major complications included intraperitoneal bleeding, liver abscess, intestinal perforation, pneumothorax, bile duct stenosis, and needle tract seeding, the last with an incidence around 0.5%.[19] Higher rates of major complications occurred for treatment of lesions adjacent to the gastrointestinal tract, particularly the colon, and hepatic helum, which are considered contraindications.[20] Caution is needed for tumors adjacent to the gallbladder or diaphragm.
| Radiofrequency Ablation | Ethanol Ablation | ||||
| Livraghi[*] et al[69] | Lencioni et al[10] | Giorgio et al[17] | Rhim[*] et al[18] | Di Stasi[*] et al[3] | |
| Patients | 2320 (1610 HCC) | 206 (all HCC) | 336 (287 HCC) | 1139 (1303 HCC) | 1066 (all HCC) |
| Needle | Internally cooled | Expandable | Saline enhanced | Internally cooled | |
| Number of sessions, patients | 1, 5 | 1, 2 | 1, 1 | 1, 1 | 6, 7 |
| Mean tumor size (cm) | 3.1 | (< 5) | 3.6 | 3.1 | |
| Deaths | 6 (0.3%) | 0 | 1 (0.3%) | 1 | 1 (0.09%) |
| Major complications | 54 (2%) | 3 (2%) | 3 (0.9%) | 1.8%[*] | 34 (3.2%) |
The effectiveness of RFA has been assessed by several studies. For small tumors, complete necrosis is usually observed after one session in 88 to 98% of cases, and for tumors of 3 to 5 cm, in 80 to 90% of cases. Long-term survival and outcomes of RFA in HCC have been reported in two studies: a 5-year overall survival rate of 54% in 319 naïve patients by Tateishi et al[21] and a 5-year survival rate of 41% by Lencioni et al.[10]
Predictors of complete response are small size and well-differentiated and noninfiltrative HCCs. In a series of 126 HCCs larger than 3 cm, complete necrosis was observed in 61% of tumors smaller than 5 cm and in 24% of those larger than 5 cm. In the same study, for tumors smaller than 5 cm, complete response rates decreased from 51 to 22% for infiltrative forms.[22]
Combined therapy (Pringle maneuver: occlusion of tumor blood supply prior to RFA) has been tested to increase the area of necrosis, but there was a higher rate of complications.
Two randomized studies have shown that RFA can achieve more effective local tumor control than ethanol injection with fewer sessions. The overall and local recurrence-free survival rates are significantly higher with RFA, and the treatment assigned was an independent survival prognostic factor in two randomized studies.[23] [24] When treating tumors larger than 2 cm, safety margins necessary to sterilize microscopic disease in the tissue surrounding the tumor are more often achieved with RFA than with ethanol ablation. Therefore, RFA emerged as the most powerful method for percutaneous treatment of early-stage HCC, allowing fewer treatment sessions with lower local recurrence rates, particularly in nodules larger than 3 cm. Despite this overall superiority, RFA also has some limitations, carrying a risk of severe complications for the treatment of lesions adjacent to the colon wall or the large bile ducts and a risk of failure for lesions adjacent to large vessels because of the heat sink phenomenon.
#Microwaves
The microwave ablative technique is used principally in Japan and China. Compared with ethanol ablation, microwave ablation has been reported to be superior for local control of small HCCs.[25] [26] The thermally coagulated area produced by microwaves is smaller than that produced by RFA. In a study including 77 patients with small HCCs randomly assigned to the microwave ablative technique or RFA, the same rates of complete ablation and complications were observed. Shorter time was counterbalanced by a greater number of sessions (1.1 versus 2.4) to achieve complete necrosis.[27] A large series including 288 patients with HCCs treated by microwave ablation reported a 1-, 3-, and 5-year survival of 92%, 72%, and 51%, respectively.[28]
#Laser
With laser ablation, high-energy light is delivered inside the tumor, resulting in tumor coagulation. A large area of necrosis (6 to 7 cm) can be expected with simultaneous use of multiple probes or diffuse-tip fibers.[29] Treatment time is usually longer than for RFA and can exceed 1 hour. In a series of 74 patients with 92 small HCCs reported by Pacella et al, cancer-free survival rates ranged from 73% to 24% over 1 to 4 years.[30] Complications are similar to those observed with RFA.
#Cryoablation Technique
Cryoprobes are directly targeted into the tumor tissue. Rapid freezing leads to ice formation. This technique was mainly used for the management of liver metastasis and performed under open surgery. More recently a percutaneous approach using multiple cryoprobes has been tested, allowing an ablation size greater than 5 cm. Few data are available. In 78 patients treated with cryoablation by a percutaneous approach, the 1-, 3-, and 5-year survival rates were 64%,40%, and 27%.[31] The complication rate might be higher than with RFA. In addition, specific complications have been observed such as cracking of the liver resulting in significant hemorrhage in cirrhotic patients and a cryoshock phenomenon that occurred in ∼1% of patients and was associated with a high risk of death.[32]
#Perspectives on Transcutaneous Treatments
Percutaneous ablative treatments are effective in the management of small HCCs (< 3 cm) in cirrhotic patients, with overall survival rates similar to those observed with resection. Thermal techniques, especially RFA, are favored over chemical ablative therapies as they achieve larger and more predictable areas of necrosis in fewer sessions, especially for tumors larger than 2 cm.
Large (> 4 cm) and infiltrative tumors are a major limitation of local ablative techniques. For infiltrative forms, a new approach using intra-arterial ethanol injection has been proposed.[33]
Improvement of ablation techniques such as bi- or multipolar electrodes for RFA[34] and improvement in guidance techniques such as magnetic resonance imaging (MRI) allowing real-time monitoring of tissue temperature[35] are under investigation and would allow safer and more extended ablation in the future. Controlled trials with different thermal systems are needed to better definite their place. Transcutaneous treatments and particularly thermal ablation are clearly evolving and in the near future will compete with resection for the ablation of larger well-limited tumors. These increases in performance will probably carry a higher rate of complications because of the extent of tumor necrosis and the respective indications with surgery will have to be defined.
#INTRA-ARTERIAL TREATMENTS
A wide spectrum of transarterial procedures has been proposed for targeting treatments in HCC patients, mainly transarterial chemotherapy, transarterial Lipiodol®-targeted chemotherapy, transarterial embolization, transarterial injection of radioactive iodine, and transcatheter arterial chemoembolization (TACE). The three latter procedures have principally been subjected to randomized evaluation.[36]
#Transarterial Chemoembolization
The complete procedure of TACE associates injection in the hepatic artery of a cytotoxic drug mixed with lipiodol (ethiodized oil), an oily contrast medium, followed by embolization usually using absorbable gelatin (Gelfoam) particles. The rationale of TACE is the following. Cytotoxic drugs achieve higher intratumoral concentrations when injected in the hepatic artery, and lipophilic or amphiphilic anticancer drugs when mixed with lipiodol are thought to be liberated progressively inside the tumor. Lipiodol, when injected by the arterial route, is specifically transported into the tumor as a result of arterial hypervascularization and may remain there for weeks or even months, presumably because of the absence of Kupffer cells. The most frequently used cytotoxic drugs are cisplatin and doxorubicin, which are amphiphilic and supposed to be retained at least for a few hours in lipiodol, allowing increased contact with tumoral tissue, a point that has not been clearly demonstrated. Lipiodol remains embolized in the tumoral vessels and contributes to ischemic necrosis of the tumor in addition to the injection into the hepatic artery of metallic coils or Gelfoam particles; the latter induce a transient obstruction of the hepatic artery and are the most widely (but not exclusively) used. The whole procedure, which can be repeated in case of recurrence, induces a profound ischemia of the tumor, as it is arterially hypervascularized in 85% of cases with a minimal portal blood supply, but also has an ischemic effect on the nontumorous liver, the extent of which depends upon the quality of portal blood supply and the selectivity of the embolization process. The injection of cytotoxic drugs mixed with lipiodol but not followed by embolization has not shown any substantial antitumoral effect, suggesting that ischemia plays a major role in tumor necrosis.[37] The results are usually assessed at 1 month or more by computed tomography scan or MRI with vascular injection, taking into account the area of necrosis in comparison with preprocedure imaging.
#Results of Nonrandomized Studies: Antitumoral and Side Effects
Since the introduction of TACE more than 20 years ago, its effect in patients with unresectable HCC has been reported in a large number of papers. Even if nonrandomized studies were unable to provide an estimation of survival benefit, they helped to demonstrate three important points.
First, TACE has an obvious antitumoral effect, allowing in most cases a partial or even macroscopically complete tumor necrosis as assessed by the examination of resected liver specimens. However, histological examination still finds viable tumor cells, explaining the high rate of recurrence. The extent of tumor necrosis can be predicted by morphological findings: the size of the tumor (the smaller the better), the degree of arterial hypervascularization (the greater the better), and the presence of a capsule or a pseudocapsule limiting the tumor without external spreading. After the procedure, the uptake and long-term retention of lipiodol® inside the tumor are also important predictors of a good response.[37]
Second, side effects of TACE are very frequent and often severe. Postembolization syndrome, which is associated with abdominal pain and fever, is extremely frequent, especially when large tumors are treated. Fever is usually related to tumor necrosis, bacterial superinfection being a rare event. Prevention of bacterial infection by systemic antibiotics is still debated but might be justified in case of large tumors. The postembolization syndrome usually fades in a few days. An increase in serum transaminase level is frequent and may be pronounced, being the hallmark of hepatic ischemia of the tumorous and often also nontumorous liver. More important, deterioration of liver function may occur in patients with cirrhosis, rarely resulting in complications such as jaundice, ascites, encephalopathy, or even renal failure and death. The potential occurrence of such complication has lead to defining contraindications such as poor liver function or inadequate portal flow, but even when these contraindications are absent a deterioration in liver status may occur and its predictive factors are still poorly known. Progressive liver atrophy may follow repeated procedures, which are justified only in case of recurrence after an initial response. Complications resulting from ischemia of neighboring organs mainly related to aberrant arterial embolization have been reported, such as acute cholecystitis, stenosis of the biliary tract, acute pancreatitis, or gastroduodenal ulcerations responsible for gastrointestinal hemorrhage. Liver abscess can also develop in case of large tumor necrosis. Finally, complications related to the cytotoxic drugs used are , such as neutropenia, a factor favoring severe bacterial infection in patients with cirrhosis, or gastric intolerance and vomiting induced by cisplatin. A durable asthenia is frequent, and the quality of life of these patients (although not objectively assessed) may be markedly worsened for several weeks after each procedure.
Third, major contraindications to TACE have been identified to avoid massive liver necrosis and complications of cirrhosis: inadequate portal flow and poor liver function. Inadequate portal flow can result from either troncular or plurisegmental portal obstruction, arterioportal fistula inside the tumor, or hepatofugal or stagnant portal flow. Poor liver function is more ill defined. Predictive factors of liver decompensation after TACE are Child-Pugh class, serum bilirubin, prothrombin time, and serum aspartate aminotransferase level. The number of treatment sessions can also be predictive, particularly for renal failure. As a whole, Child-Pugh class C is considered a contraindication, and patients in Child-Pugh class B are clearly at risk for severe complications. Risk factors among Child-Pugh A patients have not been properly studied, and little is known in particular about the role of activity and cause of the underlying liver disease.
#Results of Randomized Studies: Effects on Tumor Growth and Side Effects
Two randomized trials have assessed precisely these effects and confirmed the previous results from nonrandomized trials: a French multicentric trial.[38] and the Barcelona trial.[39] In the Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH) trial from France, significant inhibition of tumor growth was observed: 53% of the treated patients and 14% of controls had a decrease in tumor size, and an increase in tumor size was observed in 50% of controls versus 9% of treated patients (p < 0.007). A decrease in the incidence of portal obstruction was also demonstrated in 7% of treated patients versus 27% of controls (p < 0.002). A similar outcome was observed for serum α-fetoprotein levels. This trial also confirmed the high incidence of side effects. Despite severe selection criteria (only 12% of encountered patients were included), impairment of liver function was observed in 60% of patients following TACE: 58% experienced increased bilirubinemia and 12% overt decompensation of cirrhosis, either ascites or encephalopathy resulting in death in one case. The scheduled repetition of TACE every 3 months could have contributed to the poor tolerance, as repeated courses of TACE may induce liver atrophy. Postembolization liver failure seemed less common in the Barcelona trial performed by Llovet et al, but both trials reported the same rate of side effects related to ischemia of neighboring organs, such as ischemic cholecystitis.
#EFFECTS ON SURVIVAL
Five trials assessed the influence of TACE on survival in a randomized way, controls being either nontreated or treated by tamoxifen, which was later shown to have no influence on survival (Table [3]). The first trial by Pelletier et al[40] explored the influence of doxorubicin and gel sponge powder injection into the hepatic artery. The survival rate, although not significantly different, was actually lower in the treated group. The method of TACE used in that trial was later criticized because embolization by gel sponge powder was considered to have more deleterious effects on liver function than embolization by gel sponge particles. Furthermore, in a randomized trial comparing three different methods of TACE, Kasugai et al[41] found that the association of cisplatin and lipiodol resulted in more frequent tumor necrosis than doxorubicin mixed or not with lipiodol in patients who were subsequently embolized with gel sponge particles. Thus, in a second randomized trial versus conservative treatment performed by a French cooperative group, the effects of TACE using cisplatin mixed or not with lipiodol and gel sponge particles were tested.[38] Survival was not different between the two groups even when main prognostic factors were taken in account aside from the treatment in a Cox model. Nevertheless, limited benefit in survival in the treated group was observed. Considering the obvious antitumoral effect of TACE, this benefit could have been related to treatment but was counterbalanced by many side effects of TACE contributing to a decreased, although not objectively assessed, quality of life. A negative result was observed in a second trial by Pelletier et al comparing TACE according to the same procedural protocol versus no intra-arterial treatment in patients receiving tamoxifen in both groups.[42] These three negative trials were from France and included patients with mostly alcoholic cirrhosis.
| Authors | Year | Treatment | n | Survival Rate (%) | P [*] |
| Pelletier et al[40] | 1990 | Doxorubicin + gelatin-sponge powder | 21 | 24[†] | NS |
| Conservative treatment | 21 | 31 | |||
| GRETCH[38] | 1995 | Cisplatin + Lipiodol + gelatin-sponge particles | 50 | 62[†] | NS |
| Conservative treatment | 46 | 43.5 | |||
| Pelletier et al[42] | 1998 | Cisplatin + Lipiodol + gelatin-sponge particles + tamoxifen | 37 | 45[†] | NS |
| Tamoxifen | 36 | 58 | |||
| Bruix et al[44] | 1998 | Gelatin-sponge + metallic coils | 40 | 49[†] | NS |
| Conservative treatment | 40 | 50 | |||
| Doxorubicin + Lipiodol + gelatin-sponge particles | 40 | 63[†] | 0.02 | ||
| Gelatin-sponge particles | 37 | 50 | |||
| Conservative treatment | 35 | 27 | |||
| Lo et al[43] | 2002 | Cisplatin + Lipiodol + gelatin-sponge particles | 37 | 57[†] | 0.02 |
| Conservative treatment | |||||
| NS, not significant. | |||||
8 Versus conservative treatment.
Two later trials including mainly patients with viral liver disease reported different results. The first one, by Llovet et al,[39] compared three groups of Spanish patients, a control group and two treated groups, one treated by embolization alone and the second by TACE using lipiodol and doxorubicin. Criteria of inclusion similar to those of the French multicentric trial were selective, allowing the inclusion of only 12% of patients. The benefit in survival of patients treated by TACE compared with nontreated controls was statistically significant (Table [1]). The main discrepancies between both trials were the following. In the Spanish trial a small but significant imbalance between the control and the treated group according to serum bilirubin levels was observed; doxorubicin was used instead of cisplatin, and the cause of the underlying liver disease was hepatitis C virus (HCV) in more than 80% of the patients in contrast to 20% in the French trial. The last point might explain differences between both trials in the rate of postembolization hepatic failure as the tumoral response rate was similar. The last trial, by Lo et al,[43] concerned Chinese patients, 80% of them with hepatitis B virus (HBV) liver disease. The percentage of patients with cirrhosis was not reported. In this trial again, a survival benefit was observed between treated and untreated patients but this difference was mainly achieved in patients in Okuda stage I with tumors less than 5 cm in diameter, a condition in which radiofrequency ablation could now be considered a therapeutic option prior to TACE.
#ARTERIAL EMBOLIZATION
Arterial embolization alone has been investigated in two randomized trials from Barcelona. The first one, by Bruix et al,[44] investigated the results of embolizing the hepatic artery by Gelfoam particles and metallic coils and the second one, by Llovet et al,[39] by Gelfoam particles. Neither demonstrated a survival benefit. It must be emphasized that lipiodol was not used in the embolization procedure. Therefore, in the latter trial differences with TACE could hardly be attributed to the effects of cisplatin alone.
#RADIOACTIVE IODINE MIXED WITH LIPIODOL
A mixture of radioactive iodine and lipiodol (Lipiocis; Cisiointernational, Saclay, France®) has been proposed for targeting internal radiotherapy in patients with HCC, but limited data are available (Table [2]). The overall procedure is complex and costly. Patients are isolated for several days as a radioactivity safety measure after each procedure. Severe side effects such as pneumonia and liver failure may occur. Efficacy is dependent on lipiodol retention inside the tumor. A small randomized trial involving patients with HCC and portal vein thrombosis[45] suggested a benefit in survival but has yet to be confirmed. A larger trial comparing TACE and Lipiocis did not show any difference in survival between both groups, but Lipiocis seemed to be better tolerated.[46] Unfortunately, no control group of untreated patients was available.
#WHAT ROLE FOR TACE OR EMBOLIZATION IN THE TREATMENT OF ADVANCED HCC?
Even if TACE is only a palliative treatment, it has an obvious antitumoral effect and it could improve survival[47] in selected patients. Furthermore, a meta-analysis has demonstrated an overall benefit in survival, which is not the case for embolization alone and for various medical treatments. We can therefore conclude that there is a place for TACE as palliative treatment for HCC, but we still need to answer additional important questions concerning the procedure itself, the selection of eligible candidates, and the future of TACE.
#SYSTEMIC TREATMENTS
A wide range of systemic treatments have been tested in patients with HCC.[48] Cytotoxic drugs (so-called chemotherapy) and more recently hormonal treatments were the more widely tested, the former mainly in phase II trials.
#Cytotoxic Drugs
Cytotoxic drugs as a whole are poorly tolerated in cirrhotic patients, inducing a high rate of septic complications and, for cisplatin, renal failure. HCC is usually chemoresistant.[48] [49] One possible explanation is overexpression of P-glycoprotein, the product of the multiple drug resistance gene present in tumor cells. In phase II studies, the response rates for single agents vary between 0 and 30% with a very low rate of durable responses.[48] These studies were usually performed in selected patients with fair liver function or without cirrhosis. Despite selection, severe side effects were frequent. The association of various cytotoxic drugs did not seemed to improve the results, and the more recent cytotoxic agents did not yield better results.
Randomized trials including a nontreated arm are scarce. Doxorubicin was tested in two randomized trials with control patients receiving either no treatment or tamoxifen, which could be currently considered a placebo. The first trial demonstrated a statistically significant benefit in survival that was very limited and hampered by numerous severe side effects impairing the quality of life. No significant survival was demonstrated at 1 year for doxorubicin (Adriamycin) in the meta-analysis performed by Mathurin et al.[49] 5-Fluorouracil and its derivative tegafur were evaluated in a randomized trial including a nontreated control group.[5] This study demonstrated an improvement in 1-year survival in the treated group. However, this result is not in accordance with the absence of survival benefit with intra-arterial treatments using the same drugs, and a bias related to the small number of patients can be suspected.
Because of low tumor response rates, absence of unequivocal improvement in survival, and high rate of severe side effects, systemic chemotherapy cannot be recommended and its routine use must be firmly discouraged in patients with advanced HCC, particularly those with cirrhosis. The efficacy of new cytotoxic drugs should be assessed only by phase II and III trials in selected patients.
#Tamoxifen
Mainly because of the presence of estrogen nuclear receptors in tumor cells, it has been hypothesized that the growth of HCC might be enhanced by estrogens. Similarly to what has been shown in breast cancer, estrogen antagonists could therefore slow the tumor growth and increase survival. Tamoxifen, an antiestrogenic drug effective in the treatment of breast cancer, has subsequently been tested in patients with advanced HCC.
Several randomized controlled trials have been published. Two of the first studies reported an increase in survival in treated patients but were obviously underdimensioned.[50] [51] In contrast, larger and more recent trials reported negative results,[52] [53] [54] [55] [56] [57] and two meta-analyses found no antitumoral effect and no survival benefit in treated patients.[47] [48] [49] Consequently, tamoxifen should be considered ineffective in patients with advanced HCC.[59] [60] It must be stressed that this conclusion was reached after randomization of more than 1000 patients. The detrimental effect on clinical research of the publication of underdimensioned positive trials is well illustrated by the example of tamoxifen.
#Megestrol
Although the presence of mutated estrogen receptors in tumor cells is controversial, megestrol was shown to improve survival and slow tumor growth in a small randomized trial[61] in which patients were included on the basis of the presence of such receptors in tumor cells. This result has to be confirmed.
#Antiandrogens
Because of the marked male predominance of HCC, relatively high levels of androgen receptors in tumor cells, and antitumoral effects in vitro, antiandrogens have been tested in patients with advanced HCC. Various luteinizing hormone-releasing hormone (LH-RH) agonists and peripheral androgen antagonists, mostly in combination as recommended for the treatment of prostatic cancer, have been used. Phase II trials provided disappointing results secondarily confirmed by randomized trials.[62] [63] No survival benefit was found in treated patients compared with controls. Moreover, in the two larger trials, an increased but not significant mortality rate was observed in treated patients, suggesting a lack of sensitivity of tumoral cells to antiandrogens and a possible deleterious effect of androgen deprivation on the nontumoral liver parenchyma. Consequently, antiandrogens must not be prescribed in advanced HCC.
#Octreotide
Somatostatin receptors have been identified in liver tissue and particularly in HCC cells. As somatostatin is credited with some antitumoral effects on neuroendocrine tumors bearing receptors, its use (or the use of somatostatin analogues) was attempted in patients with advanced HCC although no influence on proliferation or apoptosis of tumoral hepatocytes has ever been demonstrated. Conflicting results have been obtained. Two randomized trials have been published with opposite results. Kouroumalis et al[64] reported increased survival in patients treated by octreotide versus nontreated controls (median survival 13 versus 4 months, p = 0.002), but Yuen et al,[65] testing long-acting octreotide, did not demonstrate any benefit (median survival 1.9 months in both groups). Both trials included a small number of patients, and the results of larger randomized trials are needed before any conclusion can be reached.
#Interferon Alfa
Interferon alfa (INFa) is routinely used as an antiviral drug. Because of antiangiogenic and presumably antiproliferative properties (although not demonstrated in different HCC cell lines), INFa in association or not with cytotoxic drugs has been used to treat advanced HCC. Two randomized trials have been published. In the first one, from China, patients mostly with HBV liver disease were assigned to receive either INFa in very high doses (50 million units/m2 three times a week) or conservative management. A significant but slight survival benefit was demonstrated (median survival 14.5 versus 7.5 weeks, p < 0.02), and the tolerance was surprisingly reported to be fair.[66] In a subsequent Spanish trial,[67] patients with mostly HCV-related cirrhosis and a more advanced age were randomly assigned to receive either INFa (3 million units three times a week) or conservative management. No benefit in terms of tumor progression and overall survival was reported, although survival was slightly improved in the treated group. Tolerance was poor and the rate of dropout was high, reflecting the general experience with this treatment in patients with cirrhosis. INFa may also have contributed to the poor treatment tolerance without increasing the response rate. Therefore, INFa cannot be recommended for the treatment of advanced HCC.
#Pravastatin
As a result of the cytostatic activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductas inhibitors, Kawata et al[68] investigated the effects of pravastatin (40 mg/day) in a small number of patients with advanced HCC. A significant increase in survival was observed (median survival 18 versus 9 months, p = 0.006). This result needs to be confirmed.
#Linoleic Acid
The cytostatic effects of essential fatty acid have been well documented in vitro in HCC cells. However, in a small randomized trial using a dietary supplement of gamma-linolenic acid versus placebo in patients with advanced HCC, no effect on survival was observed.
#Perspectives on Systemic Treatments
Up to now, systemic treatments of HCC have been deceptive in two ways. First, no medical treatment emerges. Cytotoxic drugs used on an empirical basis are poorly effective, and their antitumoral effects are hampered by numerous and life-threatening side effects. Hormonal treatment seems ineffective. Second, much time and money have been spent in the false hope of confirming positive results from underdimensioned or ill-designed trials. These two pitfalls must be avoided in the future. The choice of new drugs must be made on a more rational and detailed basis, and therapeutic trials need to obey more precise rules. New drugs must respond to a pathophysiological mechanism and have to be tested in in vitro or animal models before entering clinical trials. Candidate compounds must also prove not harmful to the nontumoral liver. At present, different types of drugs are under scrutiny. In view of the highly vascular nature of HCC, a promising approach might be the use of antiangiogenic agents, but one must be cautious about their role in livers with cirrhotic parenchyma that strongly express vascular endothelial growth factor (VEGF), probably as a secondary response to ischemia. Cyclooxygenase 2 inhibitors exhibit a strong antitumoral effect in vitro but could induce apoptosis in the nontumoral liver; their effectiveness in patients has not currently been assessed. As epidermal growth factor could play a role in the growth of HCC, antagonists of the tyrosine kinase epidermal growth factor receptors are also potential candidates.
Long-term perspectives would probably include tailored treatments selected on the basis of gene expression. The mechanism of hepatocarcinogenesis may differ from case to case depending in part on the cause of cirrhosis. The expression of genes in each tumor could be assessed by DNA microarrays or proteomics in the future, making it possible to tailor treatment according to each gene profile. While waiting for these promising perspectives, we still have to manage HCC patients in the least aggressive way and to include them in therapeutic trials.
#REFERENCES
- 1 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001; 35 421-430
- 2 Trinchet J C, Beaugrand M. Treatment of hepatocellular carcinoma in patients with cirrhosis. J Hepatol. 1997; 27 756-765
- 3 Di Stasi M, Buscarini L, Livraghi T et al.. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J Gastroenterol. 1997; 32 1168-1173
- 4 Livraghi T, Giorgio A, Marin G et al.. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology. 1995; 197 101-108
- 5 Ishii H, Okada S, Okusaka T et al.. Needle tract implantation of hepatocellular carcinoma after percutaneous ethanol injection. Cancer. 1998; 82 1638-1642
- 6 Vilana R, Bruix J, Bru C, Ayuso C, Sole M, Rodes J. Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology. 1992; 16 353-357
- 7 Shiina S, Tagawa K, Niwa Y et al.. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol. 1993; 160 1023-1028
- 8 Hasegawa S, Yamasaki N, Hiwaki T et al.. Factors that predict intrahepatic recurrence of hepatocellular carcinoma in 81 patients initially treated by percutaneous ethanol injection. Cancer. 1999; 86 1682-1690
- 9 Khan K N, Yatsuhashi H, Yamasaki K et al.. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol. 2000; 32 269-278
- 10 Lencioni R, Della Pina C, Bartolozzi C. Percutaneous image-guided radiofrequency ablation in the therapeutic management of hepatocellular carcinoma. Abdom Imaging. 2005; , In press
- 11 Sala M, Llovet J M, Vilana R et al.. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology. 2004; 40 1352-1360
- 12 Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology. 2004; 127 S159-S166
- 13 Teratani T, Ishikawa T, Shiratori Y et al.. Hepatocellular carcinoma in elderly patients: beneficial therapeutic efficacy using percutaneous ethanol injection therapy. Cancer. 2002; 95 816-823
- 14 Livraghi T, Benedini V, Lazzaroni S, Meloni F, Torzilli G, Vettori C. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer. 1998; 83 48-57
- 15 Ohnishi K. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatogastroenterology. 1998; 45(suppl 3) 1254-1258
- 16 Buscarini L, Buscarini E, Di Stasi M, Vallisa D, Quaretti P, Rocca A. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long-term results. Eur Radiol. 2001; 11 914-921
- 17 Giorgio A, Tarantino L, de Stefano G et al.. Percutaneous sonographically guided saline-enhanced radiofrequency ablation of hepatocellular carcinoma. AJR Am J Roentgenol. 2003; 181 479-484
- 18 Rhim H. Percutaneous radiofrequency ablation therapy for patients with hepatocellular carcinoma during occlusion of hepatic blood flow: comparison with standard percutaneous radiofrequency ablation therapy. Cancer. 2003; 98 433-435
- 19 Livraghi T, Meloni F. Treatment of hepatocellular carcinoma by percutaneous interventional methods. Hepatogastroenterology. 2002; 49 62-71
- 20 Meloni M F, Goldberg S N, Moser V, Piazza G, Livraghi T. Colonic perforation and abscess following radiofrequency ablation treatment of hepatoma. Eur J Ultrasound. 2002; 15 73-76
- 21 Tateishi R, Shiina S, Teratani T et al.. Percutaneous radiofrequency ablation for hepatocellular carcinoma. Cancer. 2005; 103 1201-1209
- 22 Livraghi T, Goldberg S N, Lazzaroni S et al.. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology. 2000; 214 761-768
- 23 Lin S M, Lin C J, Lin C C, Hsu C W, Chen Y C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology. 2004; 127 1714-1723
- 24 Lencioni R A, Allgaier H P, Cioni D et al.. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003; 228 235-240
- 25 Seki T, Wakabayashi M, Nakagawa T et al.. Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with percutaneous ethanol injection therapy. Cancer. 1999; 85 1694-1702
- 26 Horigome H, Nomura T, Saso K, Itoh M. Standards for selecting percutaneous ethanol injection therapy or percutaneous microwave coagulation therapy for solitary small hepatocellular carcinoma: consideration of local recurrence. Am J Gastroenterol. 1999; 94 1914-1917
- 27 Shibata T, Iimuro Y, Yamamoto Y et al.. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology. 2002; 223 331-337
- 28 Liang P, Dong B, Yu X et al.. Prognostic factors for survival in patients with hepatocellular carcinoma after percutaneous microwave ablation. Radiology. 2005; 235 299-307
- 29 Vogl T J, Straub R, Eichler K, Woitaschek D, Mack M G. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology. 2002; 225 367-377
- 30 Pacella C M, Bizzarri G, Magnolfi F et al.. Laser thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology. 2001; 221 712-720
- 31 Zhou X D, Tang Z Y. Cryotherapy for primary liver cancer. Semin Surg Oncol. 1998; 14 171-174
- 32 Seifert J K, Morris D L. World survey on the complications of hepatic and prostate cryotherapy. World J Surg. 1999; 23 109-114
- 33 Seror O, N’Kontchou G, Haddar D et al.. Large infiltrative hepatocellular carcinomas: treatment with percutaneous intraarterial ethanol injection alone or in combination with conventional percutaneous ethanol injection. Radiology. 2005; 234 299-309
- 34 Tacke J, Mahnken A, Roggan A, Gunther R W. Multipolar radiofrequency ablation: first clinical results. Rofo. 2004; 176 324-329
- 35 Mahnken A H, Buecker A, Spuentrup E et al.. MR-guided radiofrequency ablation of hepatic malignancies at 1.5 T: initial results. J Magn Reson Imaging. 2004; 19 342-348
- 36 Trinchet J C, Ganne-Carrie N, Beaugrand M. Review article: intra-arterial treatments in patients with hepatocellular carcinoma. Aliment Pharmacol Ther. 2003; 17(suppl 2) 111-118
- 37 Takayasu K, Shima Y, Muramatsu Y et al.. Hepatocellular carcinoma: treatment with intraarterial iodized oil with and without chemotherapeutic agents. Radiology. 1987; 163 345-351
- 38 A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma . Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. N Engl J Med. 1995; 332 1256-1261
- 39 Llovet J M, Real M I, Montana X et al.. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359 1734-1739
- 40 Pelletier G, Roche A, Ink O et al.. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol. 1990; 11 181-184
- 41 Kasugai H, Kojima J, Tatsuta M et al.. Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil. Gastroenterology. 1989; 97 965-971
- 42 Pelletier G, Ducreux M, Gay F et al.. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol. 1998; 29 129-134
- 43 Lo C M, Ngan H, Tso W K et al.. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002; 35 1164-1171
- 44 Bruix J, Llovet J M, Castells A et al.. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998; 27 1578-1583
- 45 Raoul J L, Guyader D, Bretagne J F et al.. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med. 1994; 35 1782-1787
- 46 Raoul J L, Guyader D, Bretagne J F et al.. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology. 1997; 26 1156-1161
- 47 Llovet J M, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003; 37 429-442
- 48 Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol. 2004; 5 409-418
- 49 Mathurin P, Rixe O, Carbonell N et al.. Review article: overview of medical treatments in unresectable hepatocellular carcinoma-an impossible meta-analysis?. Aliment Pharmacol Ther. 1998; 12 111-126
- 50 Farinati F, Salvagnini M, de Maria N et al.. Unresectable hepatocellular carcinoma: a prospective controlled trial with tamoxifen. J Hepatol. 1990; 11 297-301
- 51 Martinez Cerezo F J, Tomas A, Donoso L et al.. Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. J Hepatol. 1994; 20 702-706
- 52 Chow P K, Tai B C, Tan C K et al.. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002; 36 1221-1226
- 53 Castells A, Bruix J, Bru C et al.. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology. 1995; 109 917-922
- 54 Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet. 1998; 352 17-20
- 55 Liu C L, Fan S T, Ng I O, Lo C M, Poon R T, Wong J. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol. 2000; 95 218-222
- 56 Madden M V, Krige J E, Bailey S et al.. Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. Gut. 1993; 34 1598-1600
- 57 Chang J M, Tzeng W S, Pan H B, Yang C F, Lai K H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study. Cancer. 1994; 74 2449-2453
- 58 Koda M, Murawaki Y, Mitsuda A et al.. Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma: a randomized control study. Cancer. 2001; 92 1516-1524
- 59 Riestra S, Rodriguez M, Delgado M et al.. Tamoxifen does not improve survival of patients with advanced hepatocellular carcinoma. J Clin Gastroenterol. 1998; 26 200-203
- 60 Simonetti R G, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997; 8 117-136
- 61 Villa E, Ferretti I, Grottola A et al.. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer. 2001; 84 881-885
- 62 Grimaldi C, Bleiberg H, Gay F et al.. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol. 1998; 16 411-417
- 63 Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire . Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated by tamoxifen. Hepatology. 2004; 40 1361-1369
- 64 Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos O N. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut. 1998; 42 442-447
- 65 Yuen M F, Poon R T, Lai C L et al.. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology. 2002; 36 687-691
- 66 Lai C L, Lau J Y, Wu P C et al.. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology. 1993; 17 389-394
- 67 Llovet J M, Sala M, Castells L et al.. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000; 31 54-58
- 68 Kawata S, Yamasaki E, Nagase T et al.. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84 886-891
- 69 Livraghi T, Solbiati L, Meloni M F et al.. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology. 2003; 226 441-451
Dr.
M. Beaugrand
Head of Department of Hepato-Gastroentrol, Hôpital Jean Verdier, Avenue du 14 Juillet
93143 Bondy Cedex, France
Email: secmed.hge@jvr.ap-hop-paris.fr
REFERENCES
- 1 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001; 35 421-430
- 2 Trinchet J C, Beaugrand M. Treatment of hepatocellular carcinoma in patients with cirrhosis. J Hepatol. 1997; 27 756-765
- 3 Di Stasi M, Buscarini L, Livraghi T et al.. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J Gastroenterol. 1997; 32 1168-1173
- 4 Livraghi T, Giorgio A, Marin G et al.. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology. 1995; 197 101-108
- 5 Ishii H, Okada S, Okusaka T et al.. Needle tract implantation of hepatocellular carcinoma after percutaneous ethanol injection. Cancer. 1998; 82 1638-1642
- 6 Vilana R, Bruix J, Bru C, Ayuso C, Sole M, Rodes J. Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology. 1992; 16 353-357
- 7 Shiina S, Tagawa K, Niwa Y et al.. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol. 1993; 160 1023-1028
- 8 Hasegawa S, Yamasaki N, Hiwaki T et al.. Factors that predict intrahepatic recurrence of hepatocellular carcinoma in 81 patients initially treated by percutaneous ethanol injection. Cancer. 1999; 86 1682-1690
- 9 Khan K N, Yatsuhashi H, Yamasaki K et al.. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol. 2000; 32 269-278
- 10 Lencioni R, Della Pina C, Bartolozzi C. Percutaneous image-guided radiofrequency ablation in the therapeutic management of hepatocellular carcinoma. Abdom Imaging. 2005; , In press
- 11 Sala M, Llovet J M, Vilana R et al.. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology. 2004; 40 1352-1360
- 12 Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology. 2004; 127 S159-S166
- 13 Teratani T, Ishikawa T, Shiratori Y et al.. Hepatocellular carcinoma in elderly patients: beneficial therapeutic efficacy using percutaneous ethanol injection therapy. Cancer. 2002; 95 816-823
- 14 Livraghi T, Benedini V, Lazzaroni S, Meloni F, Torzilli G, Vettori C. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer. 1998; 83 48-57
- 15 Ohnishi K. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatogastroenterology. 1998; 45(suppl 3) 1254-1258
- 16 Buscarini L, Buscarini E, Di Stasi M, Vallisa D, Quaretti P, Rocca A. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long-term results. Eur Radiol. 2001; 11 914-921
- 17 Giorgio A, Tarantino L, de Stefano G et al.. Percutaneous sonographically guided saline-enhanced radiofrequency ablation of hepatocellular carcinoma. AJR Am J Roentgenol. 2003; 181 479-484
- 18 Rhim H. Percutaneous radiofrequency ablation therapy for patients with hepatocellular carcinoma during occlusion of hepatic blood flow: comparison with standard percutaneous radiofrequency ablation therapy. Cancer. 2003; 98 433-435
- 19 Livraghi T, Meloni F. Treatment of hepatocellular carcinoma by percutaneous interventional methods. Hepatogastroenterology. 2002; 49 62-71
- 20 Meloni M F, Goldberg S N, Moser V, Piazza G, Livraghi T. Colonic perforation and abscess following radiofrequency ablation treatment of hepatoma. Eur J Ultrasound. 2002; 15 73-76
- 21 Tateishi R, Shiina S, Teratani T et al.. Percutaneous radiofrequency ablation for hepatocellular carcinoma. Cancer. 2005; 103 1201-1209
- 22 Livraghi T, Goldberg S N, Lazzaroni S et al.. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology. 2000; 214 761-768
- 23 Lin S M, Lin C J, Lin C C, Hsu C W, Chen Y C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology. 2004; 127 1714-1723
- 24 Lencioni R A, Allgaier H P, Cioni D et al.. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003; 228 235-240
- 25 Seki T, Wakabayashi M, Nakagawa T et al.. Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with percutaneous ethanol injection therapy. Cancer. 1999; 85 1694-1702
- 26 Horigome H, Nomura T, Saso K, Itoh M. Standards for selecting percutaneous ethanol injection therapy or percutaneous microwave coagulation therapy for solitary small hepatocellular carcinoma: consideration of local recurrence. Am J Gastroenterol. 1999; 94 1914-1917
- 27 Shibata T, Iimuro Y, Yamamoto Y et al.. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology. 2002; 223 331-337
- 28 Liang P, Dong B, Yu X et al.. Prognostic factors for survival in patients with hepatocellular carcinoma after percutaneous microwave ablation. Radiology. 2005; 235 299-307
- 29 Vogl T J, Straub R, Eichler K, Woitaschek D, Mack M G. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology. 2002; 225 367-377
- 30 Pacella C M, Bizzarri G, Magnolfi F et al.. Laser thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology. 2001; 221 712-720
- 31 Zhou X D, Tang Z Y. Cryotherapy for primary liver cancer. Semin Surg Oncol. 1998; 14 171-174
- 32 Seifert J K, Morris D L. World survey on the complications of hepatic and prostate cryotherapy. World J Surg. 1999; 23 109-114
- 33 Seror O, N’Kontchou G, Haddar D et al.. Large infiltrative hepatocellular carcinomas: treatment with percutaneous intraarterial ethanol injection alone or in combination with conventional percutaneous ethanol injection. Radiology. 2005; 234 299-309
- 34 Tacke J, Mahnken A, Roggan A, Gunther R W. Multipolar radiofrequency ablation: first clinical results. Rofo. 2004; 176 324-329
- 35 Mahnken A H, Buecker A, Spuentrup E et al.. MR-guided radiofrequency ablation of hepatic malignancies at 1.5 T: initial results. J Magn Reson Imaging. 2004; 19 342-348
- 36 Trinchet J C, Ganne-Carrie N, Beaugrand M. Review article: intra-arterial treatments in patients with hepatocellular carcinoma. Aliment Pharmacol Ther. 2003; 17(suppl 2) 111-118
- 37 Takayasu K, Shima Y, Muramatsu Y et al.. Hepatocellular carcinoma: treatment with intraarterial iodized oil with and without chemotherapeutic agents. Radiology. 1987; 163 345-351
- 38 A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma . Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. N Engl J Med. 1995; 332 1256-1261
- 39 Llovet J M, Real M I, Montana X et al.. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359 1734-1739
- 40 Pelletier G, Roche A, Ink O et al.. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol. 1990; 11 181-184
- 41 Kasugai H, Kojima J, Tatsuta M et al.. Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil. Gastroenterology. 1989; 97 965-971
- 42 Pelletier G, Ducreux M, Gay F et al.. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol. 1998; 29 129-134
- 43 Lo C M, Ngan H, Tso W K et al.. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002; 35 1164-1171
- 44 Bruix J, Llovet J M, Castells A et al.. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998; 27 1578-1583
- 45 Raoul J L, Guyader D, Bretagne J F et al.. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med. 1994; 35 1782-1787
- 46 Raoul J L, Guyader D, Bretagne J F et al.. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology. 1997; 26 1156-1161
- 47 Llovet J M, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003; 37 429-442
- 48 Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol. 2004; 5 409-418
- 49 Mathurin P, Rixe O, Carbonell N et al.. Review article: overview of medical treatments in unresectable hepatocellular carcinoma-an impossible meta-analysis?. Aliment Pharmacol Ther. 1998; 12 111-126
- 50 Farinati F, Salvagnini M, de Maria N et al.. Unresectable hepatocellular carcinoma: a prospective controlled trial with tamoxifen. J Hepatol. 1990; 11 297-301
- 51 Martinez Cerezo F J, Tomas A, Donoso L et al.. Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. J Hepatol. 1994; 20 702-706
- 52 Chow P K, Tai B C, Tan C K et al.. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002; 36 1221-1226
- 53 Castells A, Bruix J, Bru C et al.. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology. 1995; 109 917-922
- 54 Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet. 1998; 352 17-20
- 55 Liu C L, Fan S T, Ng I O, Lo C M, Poon R T, Wong J. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol. 2000; 95 218-222
- 56 Madden M V, Krige J E, Bailey S et al.. Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. Gut. 1993; 34 1598-1600
- 57 Chang J M, Tzeng W S, Pan H B, Yang C F, Lai K H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study. Cancer. 1994; 74 2449-2453
- 58 Koda M, Murawaki Y, Mitsuda A et al.. Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma: a randomized control study. Cancer. 2001; 92 1516-1524
- 59 Riestra S, Rodriguez M, Delgado M et al.. Tamoxifen does not improve survival of patients with advanced hepatocellular carcinoma. J Clin Gastroenterol. 1998; 26 200-203
- 60 Simonetti R G, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997; 8 117-136
- 61 Villa E, Ferretti I, Grottola A et al.. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer. 2001; 84 881-885
- 62 Grimaldi C, Bleiberg H, Gay F et al.. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol. 1998; 16 411-417
- 63 Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire . Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated by tamoxifen. Hepatology. 2004; 40 1361-1369
- 64 Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos O N. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut. 1998; 42 442-447
- 65 Yuen M F, Poon R T, Lai C L et al.. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology. 2002; 36 687-691
- 66 Lai C L, Lau J Y, Wu P C et al.. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology. 1993; 17 389-394
- 67 Llovet J M, Sala M, Castells L et al.. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000; 31 54-58
- 68 Kawata S, Yamasaki E, Nagase T et al.. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84 886-891
- 69 Livraghi T, Solbiati L, Meloni M F et al.. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology. 2003; 226 441-451
Dr.
M. Beaugrand
Head of Department of Hepato-Gastroentrol, Hôpital Jean Verdier, Avenue du 14 Juillet
93143 Bondy Cedex, France
Email: secmed.hge@jvr.ap-hop-paris.fr