regimen. Systemic chemotherapy may still be considered for patients whose tumors progress while on sorafenib and whose performance status and baseline liver function are sufficient to tolerate it. The side effect profile of any chemotherapy regimen should be considered carefully in patients with advanced liver disease and a short life expectancy. Cytotoxic therapy should be reserved for medically appropriate patients with adequate hepatic function and preferably administered within the context of a clinical trial. Reactivation of viral hepatitis may occur in patients with HCC who are undergoing intensive systemic chemotherapy, so it is important to monitor and maintain antiviral medications during treatment.

### **8. References**

regimen. Systemic chemotherapy may still be considered for patients whose tumors progress while on sorafenib and whose performance status and baseline liver function are sufficient to tolerate it. The side effect profile of any chemotherapy regimen should be considered carefully in patients with advanced liver disease and a short life expectancy. Cytotoxic therapy should be reserved for medically appropriate patients with adequate hepatic function and preferably administered within the context of a clinical trial. Reactivation of viral hepatitis may occur in patients with HCC who are undergoing intensive systemic chemotherapy, so it is important to monitor and maintain antiviral

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**12**

*Italy*

**The Most Important Local and Regional**

**Treatment Techniques of Hepatocellular**

**Carcinoma and Their Effect over**

Federico Cattin, Alessandro Uzzau and Dino De Anna

*Department of General Surgery, University of Udine School of Medicine*

During the last years, many local and regional techniques have been introduced, helping, together with surgery, to treat the hepatocellular carcinoma, and contributing to an important improvement of disease free survival and overall survival of patients affected by this disease. These techniques, suitable also for metastatic lesions, can be performed as exclusive ones or following surgery, and help controlling tumor progression even when it is

Local and regional therapies can be divided into two groups: in the first one we can consider the techniques using heat to obtain their effect, in the second one we consider those using chemotherapic drugs to obtain necrosis of the neoplastic tissue. Necrosis can be obtained through the energy produced by radiofrequency probes, through the alcohol or acetic acid injection or through the injection of embolyzing substances, also together with chemotherapic drugs, into the hepatic artery. Last but not least, the injection of yttrium labeled microspheres is available. These are injected into the hepatic artery and are able to

This is the oldest technique, and it consists in the percutaneous injection of absolute ethanol into the lesion using a fine needle provided with one or more infusion holes. Ethylic alcohol is able to induce a neoplasm coagulative necrosis through cellular dehydration and protein denaturing. Moreover, it causes vascular thrombosis with occlusion of the small vessels which normally feed the tumor. This is a feasible technique for small lesions under 2 centimeters of diameter. Considering these lesions, ethanol has demonstrated its ability to induce a necrosis of more than 95 % of the tumor volume. This result is absolutely similar to

**1. Introduction**

**2. Description**

over any possible surgical approach.

**2.1 Percutaneous ethanol injection**

cytoreduce the tumor through a local irradiation.

The most important techniques nowadays available are:

**a Long Term Overall Survival**

### **The Most Important Local and Regional Treatment Techniques of Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival**

Federico Cattin, Alessandro Uzzau and Dino De Anna *Department of General Surgery, University of Udine School of Medicine Italy*

### **1. Introduction**

224 Hepatocellular Carcinoma – Clinical Research

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octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology

combination with bevacizumab in patients with advanced hepatocellular

During the last years, many local and regional techniques have been introduced, helping, together with surgery, to treat the hepatocellular carcinoma, and contributing to an important improvement of disease free survival and overall survival of patients affected by this disease. These techniques, suitable also for metastatic lesions, can be performed as exclusive ones or following surgery, and help controlling tumor progression even when it is over any possible surgical approach.

Local and regional therapies can be divided into two groups: in the first one we can consider the techniques using heat to obtain their effect, in the second one we consider those using chemotherapic drugs to obtain necrosis of the neoplastic tissue. Necrosis can be obtained through the energy produced by radiofrequency probes, through the alcohol or acetic acid injection or through the injection of embolyzing substances, also together with chemotherapic drugs, into the hepatic artery. Last but not least, the injection of yttrium labeled microspheres is available. These are injected into the hepatic artery and are able to cytoreduce the tumor through a local irradiation.

### **2. Description**

The most important techniques nowadays available are:

### **2.1 Percutaneous ethanol injection**

This is the oldest technique, and it consists in the percutaneous injection of absolute ethanol into the lesion using a fine needle provided with one or more infusion holes. Ethylic alcohol is able to induce a neoplasm coagulative necrosis through cellular dehydration and protein denaturing. Moreover, it causes vascular thrombosis with occlusion of the small vessels which normally feed the tumor. This is a feasible technique for small lesions under 2 centimeters of diameter. Considering these lesions, ethanol has demonstrated its ability to induce a necrosis of more than 95 % of the tumor volume. This result is absolutely similar to

The Most Important Local and Regional Treatment Techniques of

hepatic one, typical of every percutaneous treatment.

heat, the time of exposure and the needle caliber.

tissue vaporization and carbonization5.

happens around the needle.

and 0%6.

**2.3 Radiofrequency ablation**

years (Ohnishi et al.), noticeably higher than the one linked to PEI.

Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival 227

tumor seeding along the needle path4, high level of pain (higher than the one linked to PEI) and then all the risks linked to the puncture of a high vascularized parenchyma, like the

Percutaneous acetic acid injection seems more effective than PEI under a therapeutic point of view: the low pH characteristic of the acid is able to destroy any septum into the nodule, and so tumor necrosis is more homogeneous and safe. For this reason, PAI is healing as much as PEI and radiofrequency ablation if we consider small volume lesions, granting percentages of necrosis close to 95% if nodules are less than 2 cm of diameter5,6. In this case and in selected groups disease free survival rate is 100% and 92% respectively at 1 and 2

3 years and 5 years survival, on the contrary, after exclusive treatment are respectively 40%

Radiofrequency ablation is a technique that induces tissue necrosis through cellular dehydration following a local heat growth. During this procedure, the patient is a part of a real and proper electric circuit, which comprises a generator, a needle to be inserted into the neoplasm, a wide surface plate to be used as an electric outflow, and of course patient's tissues. Heat growth is directly depending on tissue impedance against electric flow, measured in Ohm: as it is quite high, in the immediate surroundings of the entry point into the patient (the needle) a frictional verifiable thermic increase develops. It causes a coagulative necrosis of treated tissues, with a curative effect. Radiofrequency waves swing between 300 KHz and 2500 MHz, and the amount of necrotized tissue is depending on the

A key point for a good radiofrequency procedure is the possibility to control the level of temperature reached during the treatment. In facts, a 55 degrees local temperature, kept for 4-6 minutes, is able to cause an irreversible cellular damage and then apoptosis. A 60-100 degrees local temperature causes an immediate tissue coagulation, as like as the one caused by an electrical scalpel during hemostasis, and then a mythocondrial and cytoplasmic enzymes damage, with a sudden cellular death. A temperature over 100 degrees induces

These different reactions must be considered under the point of view of the different ability damaged tissues have to transmit electricity. At a first time a neoplastic carbonization might seem a valid and final result, but it's fundamental to consider that a carbonized tissue has a higher resistance to electric flow than a damaged or healthy one, and then it provides a protective effect to the surrounding structures, which are shielded from any electric exposure. This is the reason why the technique is ineffective if a tissue carbonization

The system allows to control the temperature reached into the area under treatment, thus avoiding this event. The temperature effective to treatment ranges between 55 and 100 degrees. Needles contain a probe, and any thermic growths are recognized through the continuous measurement of system impedance, direct function of heat growth and tissue change of state. In case of growth, this may be controlled through reducing the energy given

the one obtained with more recent techniques like radiofrequency ablation, which on the contrary gets better results if used on bigger nodules. In facts, in case of lesions 2-5 cm of diameter, PEI is able to produce a necrosis of just 50% of the neoplasm volume, and this percentage becomes inessential in case of even bigger cancers. On the contrary, even today PEI grants a curability percentage similar to that given by radiofrequency or advanced percutaneous techniques if we consider little HCCs.

Difficulties shown by PEI in treating medium and big lesions are characteristic of the injected drug: ethanol is not able to diffuse equally into the tumor, as it can not degrade the fibrous septa which are diffused into the nodule. In a 33% of cases these septa may cause a variable distribution of the drug in the lesion, and then a higher risk of relapse of disease. Moreover, big nodules are often well supplied of blood, and also blood circulation may determine a rapid ethanol wash out from the injected site, lowering the therapeutic effect of PEI. Even if PEI is a ultrasound-guided technique, the needle might be inserted in the peripheral part of the nodule, and then its farthest zones might not receive an adequate concentration of drug. In the end, percutaneous ethanol injection has a limited diffusion outside the lesion, and then it's not amenable to grant an adequate volume of oncologic safety based on healthy hepatic tissue around the tumor. This area has normally the highest probability to hide satellite nodules1,2,3.

Percutaneous ethanol injection is a safe technique, easy, usually well tolerated and feasible also under local anesthesia in outpatients. Sometimes some sessions of therapy are required to achieve a positive oncologic result: most of the protocols schedule eight sessions, once or twice a week, for a whole amount of one or two months of treatment. Complications are linked to the particular kind of technique and to the treated organ: hepatic hematomas, hemoperitoneum, and alcohol diffusion in the blood vessels are the most probable of them, anyhow they are rare and easy to control. Worse complications are described in the Literature in a 0-2% of cases. Among them the tumor seeding along the needle path is included, and this event may happen during all the percutaneous treatments of neoplasm lesions1,4.

3 years and 5 years survival after exclusive treatment are respectively 22% and 0%

### **2.2 Percutaneous acetic acid injection**

Technically similar to the previous, acetic acid is able to enter easily into the cells, dissolve its lipids and destroy collagen. Acetic acid is used in a solution, and its efficacy rises as its concentration rises, until a plateau is reached when the concentration of drug is about 50%. This level has been defined during studies on mice, the exact one in humans has never been detected. Acetic acid has a cytotoxic effect three times higher than ethanol, and this is the reason why it reaches the same therapeutic result needing a lower number of sessions, improving patient's comfort and minimizing the risk of complications. PAI is in the end useful also for bigger lesions than those treated with PEI, as acetic acid spreads into the nodule through the collagen destruction1,3.

In spite of these qualities, PAI is nowadays almost abandoned, turning to the advantage of modern techniques. There are many reasons for this: a remarkable risk of toxicity for intravascular diffusion of acid, considerably higher than the one linked to ethanol, risk of tumor seeding along the needle path4, high level of pain (higher than the one linked to PEI) and then all the risks linked to the puncture of a high vascularized parenchyma, like the hepatic one, typical of every percutaneous treatment.

Percutaneous acetic acid injection seems more effective than PEI under a therapeutic point of view: the low pH characteristic of the acid is able to destroy any septum into the nodule, and so tumor necrosis is more homogeneous and safe. For this reason, PAI is healing as much as PEI and radiofrequency ablation if we consider small volume lesions, granting percentages of necrosis close to 95% if nodules are less than 2 cm of diameter5,6. In this case and in selected groups disease free survival rate is 100% and 92% respectively at 1 and 2 years (Ohnishi et al.), noticeably higher than the one linked to PEI.

3 years and 5 years survival, on the contrary, after exclusive treatment are respectively 40% and 0%6.

### **2.3 Radiofrequency ablation**

226 Hepatocellular Carcinoma – Clinical Research

the one obtained with more recent techniques like radiofrequency ablation, which on the contrary gets better results if used on bigger nodules. In facts, in case of lesions 2-5 cm of diameter, PEI is able to produce a necrosis of just 50% of the neoplasm volume, and this percentage becomes inessential in case of even bigger cancers. On the contrary, even today PEI grants a curability percentage similar to that given by radiofrequency or advanced

Difficulties shown by PEI in treating medium and big lesions are characteristic of the injected drug: ethanol is not able to diffuse equally into the tumor, as it can not degrade the fibrous septa which are diffused into the nodule. In a 33% of cases these septa may cause a variable distribution of the drug in the lesion, and then a higher risk of relapse of disease. Moreover, big nodules are often well supplied of blood, and also blood circulation may determine a rapid ethanol wash out from the injected site, lowering the therapeutic effect of PEI. Even if PEI is a ultrasound-guided technique, the needle might be inserted in the peripheral part of the nodule, and then its farthest zones might not receive an adequate concentration of drug. In the end, percutaneous ethanol injection has a limited diffusion outside the lesion, and then it's not amenable to grant an adequate volume of oncologic safety based on healthy hepatic tissue around the tumor. This area has normally the highest

Percutaneous ethanol injection is a safe technique, easy, usually well tolerated and feasible also under local anesthesia in outpatients. Sometimes some sessions of therapy are required to achieve a positive oncologic result: most of the protocols schedule eight sessions, once or twice a week, for a whole amount of one or two months of treatment. Complications are linked to the particular kind of technique and to the treated organ: hepatic hematomas, hemoperitoneum, and alcohol diffusion in the blood vessels are the most probable of them, anyhow they are rare and easy to control. Worse complications are described in the Literature in a 0-2% of cases. Among them the tumor seeding along the needle path is included, and this event may happen during all the percutaneous treatments of neoplasm

3 years and 5 years survival after exclusive treatment are respectively 22% and 0%

Technically similar to the previous, acetic acid is able to enter easily into the cells, dissolve its lipids and destroy collagen. Acetic acid is used in a solution, and its efficacy rises as its concentration rises, until a plateau is reached when the concentration of drug is about 50%. This level has been defined during studies on mice, the exact one in humans has never been detected. Acetic acid has a cytotoxic effect three times higher than ethanol, and this is the reason why it reaches the same therapeutic result needing a lower number of sessions, improving patient's comfort and minimizing the risk of complications. PAI is in the end useful also for bigger lesions than those treated with PEI, as acetic acid spreads into the

In spite of these qualities, PAI is nowadays almost abandoned, turning to the advantage of modern techniques. There are many reasons for this: a remarkable risk of toxicity for intravascular diffusion of acid, considerably higher than the one linked to ethanol, risk of

percutaneous techniques if we consider little HCCs.

probability to hide satellite nodules1,2,3.

**2.2 Percutaneous acetic acid injection**

nodule through the collagen destruction1,3.

lesions1,4.

Radiofrequency ablation is a technique that induces tissue necrosis through cellular dehydration following a local heat growth. During this procedure, the patient is a part of a real and proper electric circuit, which comprises a generator, a needle to be inserted into the neoplasm, a wide surface plate to be used as an electric outflow, and of course patient's tissues. Heat growth is directly depending on tissue impedance against electric flow, measured in Ohm: as it is quite high, in the immediate surroundings of the entry point into the patient (the needle) a frictional verifiable thermic increase develops. It causes a coagulative necrosis of treated tissues, with a curative effect. Radiofrequency waves swing between 300 KHz and 2500 MHz, and the amount of necrotized tissue is depending on the heat, the time of exposure and the needle caliber.

A key point for a good radiofrequency procedure is the possibility to control the level of temperature reached during the treatment. In facts, a 55 degrees local temperature, kept for 4-6 minutes, is able to cause an irreversible cellular damage and then apoptosis. A 60-100 degrees local temperature causes an immediate tissue coagulation, as like as the one caused by an electrical scalpel during hemostasis, and then a mythocondrial and cytoplasmic enzymes damage, with a sudden cellular death. A temperature over 100 degrees induces tissue vaporization and carbonization5.

These different reactions must be considered under the point of view of the different ability damaged tissues have to transmit electricity. At a first time a neoplastic carbonization might seem a valid and final result, but it's fundamental to consider that a carbonized tissue has a higher resistance to electric flow than a damaged or healthy one, and then it provides a protective effect to the surrounding structures, which are shielded from any electric exposure. This is the reason why the technique is ineffective if a tissue carbonization happens around the needle.

The system allows to control the temperature reached into the area under treatment, thus avoiding this event. The temperature effective to treatment ranges between 55 and 100 degrees. Needles contain a probe, and any thermic growths are recognized through the continuous measurement of system impedance, direct function of heat growth and tissue change of state. In case of growth, this may be controlled through reducing the energy given

The Most Important Local and Regional Treatment Techniques of

Fig. 2. A typical lesion suitable for radiofrequency during surgery

important.

Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival 229

Radiofrequency is a versatile technique. It may be provided as an exclusive treatment, through percutaneous needle insertion, or it may follow surgery during an operation as a way to treat satellite lesions or to eliminate metastatic liver nodules during non hepatic surgery. Radiofrequency ablation as an exclusive technique may be provided under local anesthesia or conscious sedation. In some centers radiofrequency is used during surgery as a way to treat the surgical resection surface: it allows a coagulative necrosis of surface cells,

Radiofrequency has a number of possible complications, linked to the needle insertion into the nodule and to the necrosis following the treatment. Complications described in Literature are, in order of probability, hepatic hematomas or hemoperitoneum needing blood supply, hepatic abscesses caused by necrosis infection and needing percutaneous drainage, thermic bile duct damages needing biliary drainage, hemothoraxes, bowel perforations caused by needle mispositioning, necrosis of organs close to liver due to thermic damage (especially when treating superficial liver lesions), hepatic failure. Neoplastic seeding along the needle path is quite high as a risk (about 2% of procedures), but it can be avoided keeping the system working during the needle extraction, and then performing a real and proper radiofrequency ablation over the tissues which have been in contact to the needle itself. To reach a good result, a temperature of about 75 degrees is

thus providing a bigger oncologic safety than that obtained through resection itself.

to the patient. Due to this, the complete time of treatment might grow up from 4-6 minutes. In our clinical experience, the medium length is about 10-12 minutes, but in some centers sessions lasting up to 30 minutes are performed.

Radiofrequency ablation therapy is a good option in hepatocellular carcinomas either alone, or in combination with surgery, and, even having different technical principles, it is a valid and modern alternative to percutaneous ethanol injection. It is able to reach the same results even through a lower number of treatment sessions, also for lesions more than 2 centimeters of diameter, or metastatic. Especially in these cases this technique has its best advantages in comparison to PEI, and represents a step forward in comparison to other percutaneous procedures.

Using a single needle, the volume of treated hepatic tissue is quite narrow, about 1.8 cm3. This volume may be enhanced using more powerful generators and needles chilled with saline, which allows a tissue impedance reduction and a growth of heat diffusion and energy delivery. Then, the use of multiple needles or single hooked needles is possible5,7.

Using these devices, the treated volume may rise up to 3 cm3 and over. It's better in any case to use a single hooked needle, as it grants a similar treated volume if compared to multiple needles, but it has a bigger treatment evenness.

Fig. 1. Radiofrequency over resected liver

to the patient. Due to this, the complete time of treatment might grow up from 4-6 minutes. In our clinical experience, the medium length is about 10-12 minutes, but in some centers

Radiofrequency ablation therapy is a good option in hepatocellular carcinomas either alone, or in combination with surgery, and, even having different technical principles, it is a valid and modern alternative to percutaneous ethanol injection. It is able to reach the same results even through a lower number of treatment sessions, also for lesions more than 2 centimeters of diameter, or metastatic. Especially in these cases this technique has its best advantages in comparison to PEI, and represents a step forward in comparison to

Using a single needle, the volume of treated hepatic tissue is quite narrow, about 1.8 cm3. This volume may be enhanced using more powerful generators and needles chilled with saline, which allows a tissue impedance reduction and a growth of heat diffusion and energy delivery. Then, the use of multiple needles or single hooked needles is possible5,7.

Using these devices, the treated volume may rise up to 3 cm3 and over. It's better in any case to use a single hooked needle, as it grants a similar treated volume if compared to multiple

sessions lasting up to 30 minutes are performed.

needles, but it has a bigger treatment evenness.

Fig. 1. Radiofrequency over resected liver

other percutaneous procedures.

Radiofrequency is a versatile technique. It may be provided as an exclusive treatment, through percutaneous needle insertion, or it may follow surgery during an operation as a way to treat satellite lesions or to eliminate metastatic liver nodules during non hepatic surgery. Radiofrequency ablation as an exclusive technique may be provided under local anesthesia or conscious sedation. In some centers radiofrequency is used during surgery as a way to treat the surgical resection surface: it allows a coagulative necrosis of surface cells, thus providing a bigger oncologic safety than that obtained through resection itself.

Radiofrequency has a number of possible complications, linked to the needle insertion into the nodule and to the necrosis following the treatment. Complications described in Literature are, in order of probability, hepatic hematomas or hemoperitoneum needing blood supply, hepatic abscesses caused by necrosis infection and needing percutaneous drainage, thermic bile duct damages needing biliary drainage, hemothoraxes, bowel perforations caused by needle mispositioning, necrosis of organs close to liver due to thermic damage (especially when treating superficial liver lesions), hepatic failure. Neoplastic seeding along the needle path is quite high as a risk (about 2% of procedures), but it can be avoided keeping the system working during the needle extraction, and then performing a real and proper radiofrequency ablation over the tissues which have been in contact to the needle itself. To reach a good result, a temperature of about 75 degrees is important.

Fig. 2. A typical lesion suitable for radiofrequency during surgery

The Most Important Local and Regional Treatment Techniques of

radiofrequency ablation is a valid exclusive treatment8.

also for non-surgical patients in the immediate future9.

**2.4 Cryotherapy**

procedures.

Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival 231

procedure. This is the reason why 3 and 5 years survival rates after exclusive treatment are, respectively, 56-83% and 40-52%. Anyways, these rates are similar to surgical ones in case of surgery following disease relapse. This is the reason why, in these cases, nowadays

It consists in positioning a cryogenic probe into the nodule and then in its freezing up to a temperature between -100 and -196 degrees by using liquid nitrogen. The procedure lasts about 15 minutes until the tumor and healthy surrounding tissue frostbite is reached, through the development of cytoplasmic ice crystals, the cellular volume growth and the break of cytoplasmic membranes. Cold as a therapeutic agent against hepatocellular carcinoma makes also use of a particular cellular response to temperature decrease: cryoablation is able to inhibit cellular growth by stimulating a sort of cryoimmunity and by producing cytokines activating the natural killer cells, able to control tumor proliferation. This activation, typical of cryotherapy, is not visible in any other therapy against HCC.

Cryotherapy allows to visualize with millimetric precision the limit between treated area and surroundings during routine radiologic controls. Low temperature action in facts is extremely zone-specific, and as it grows over the freezing limit for hepatic cells, it's possible to meet healthy tissue, not damaged and well distinguishable from the treated area. So knowing exactly how much volume has been treated allows to plan possible further

Cryotherapy, very promising, is now performed in the operatory room as a surgical time during hepatic resection. This is due to the dimension of probes, bigger than those of radiofrequency ablation. Technical evolution has brought to project and production of thinner probes, available for percutaneous use. This could make this technique available

Any of the two different approaches has of course pros and cons. Cryotherapy during surgery is made considering the possibility to explore all the parts of the abdomen and of the liver, looking for satellite nodules. Then, it's possible the exact positioning of the probe into the tumor, even if it is in areas not reachable through percutaneous puncture or close to other organs. Percutaneous cryotherapy is possible also for outpatients, allows a rapid recovery and an easy pain control. Percutaneous treatment requires two therapy sessions9,10. A real comparison between cryotherapy and the most used percutaneous technique – radiofrequency – is difficult to be done. The most important reason is the fact that nowadays radiofrequency is performed mostly as an exclusive and percutaneous technique, while cryotherapy is still a therapeutic option during surgery. Anyways, there is a number of capabilities which might make it even more effective once reached an adequate technical ability. First, cryotherapy induces the production of a group of cytokines inhibiting cellular growth, while radiofrequency induces the production of substances stimulating the relapse of disease. Second, cryotherapy shows an exact limit between treated and non-treated areas, and then allows to control the adequacy of treatment, while radiofrequency creates a shaded border. Third, during cryotherapy it's possible to verify, using ultrasounds, the blistering of ice crystals, and then assess the efficacy of therapy. Fourth, the procedure can be performed

using multiple needles, without modifying the shape of the treated volume.

The strongest limit of this procedure is the presence of blood vessels more than 5 mm of diameter nearby the target lesion. Vessels can reduce the treatment efficacy through heat loss, and may be impossible to reach the 55 degrees temperature mandatory for the technique to be effective. Moreover, even if it's more effective than the previously described techniques, also radiofrequency is affected by the presence of collagen septa into the nodules: even if it's true that heat can destroy collagen, these septa can shield the tissue behind them form thermic effects. This is the reason why it's always impossible to predict the exact final amount of treated volume.

In the end, the only possibility to be certain to avoid any tumor relapse is to be sure to have destroyed every neoplastic cell. This is of course impossible. Heat damage induces the production of tissue growth factors by the cells surrounding the damaged ones, and these substances are the most important factors of disease relapse if any tumor cell survived the

Fig. 3. A lesion suitable for percutaneous radiofrequency

procedure. This is the reason why 3 and 5 years survival rates after exclusive treatment are, respectively, 56-83% and 40-52%. Anyways, these rates are similar to surgical ones in case of surgery following disease relapse. This is the reason why, in these cases, nowadays radiofrequency ablation is a valid exclusive treatment8.

### **2.4 Cryotherapy**

230 Hepatocellular Carcinoma – Clinical Research

The strongest limit of this procedure is the presence of blood vessels more than 5 mm of diameter nearby the target lesion. Vessels can reduce the treatment efficacy through heat loss, and may be impossible to reach the 55 degrees temperature mandatory for the technique to be effective. Moreover, even if it's more effective than the previously described techniques, also radiofrequency is affected by the presence of collagen septa into the nodules: even if it's true that heat can destroy collagen, these septa can shield the tissue behind them form thermic effects. This is the reason why it's always impossible to predict

In the end, the only possibility to be certain to avoid any tumor relapse is to be sure to have destroyed every neoplastic cell. This is of course impossible. Heat damage induces the production of tissue growth factors by the cells surrounding the damaged ones, and these substances are the most important factors of disease relapse if any tumor cell survived the

the exact final amount of treated volume.

Fig. 3. A lesion suitable for percutaneous radiofrequency

It consists in positioning a cryogenic probe into the nodule and then in its freezing up to a temperature between -100 and -196 degrees by using liquid nitrogen. The procedure lasts about 15 minutes until the tumor and healthy surrounding tissue frostbite is reached, through the development of cytoplasmic ice crystals, the cellular volume growth and the break of cytoplasmic membranes. Cold as a therapeutic agent against hepatocellular carcinoma makes also use of a particular cellular response to temperature decrease: cryoablation is able to inhibit cellular growth by stimulating a sort of cryoimmunity and by producing cytokines activating the natural killer cells, able to control tumor proliferation. This activation, typical of cryotherapy, is not visible in any other therapy against HCC.

Cryotherapy allows to visualize with millimetric precision the limit between treated area and surroundings during routine radiologic controls. Low temperature action in facts is extremely zone-specific, and as it grows over the freezing limit for hepatic cells, it's possible to meet healthy tissue, not damaged and well distinguishable from the treated area. So knowing exactly how much volume has been treated allows to plan possible further procedures.

Cryotherapy, very promising, is now performed in the operatory room as a surgical time during hepatic resection. This is due to the dimension of probes, bigger than those of radiofrequency ablation. Technical evolution has brought to project and production of thinner probes, available for percutaneous use. This could make this technique available also for non-surgical patients in the immediate future9.

Any of the two different approaches has of course pros and cons. Cryotherapy during surgery is made considering the possibility to explore all the parts of the abdomen and of the liver, looking for satellite nodules. Then, it's possible the exact positioning of the probe into the tumor, even if it is in areas not reachable through percutaneous puncture or close to other organs. Percutaneous cryotherapy is possible also for outpatients, allows a rapid recovery and an easy pain control. Percutaneous treatment requires two therapy sessions9,10.

A real comparison between cryotherapy and the most used percutaneous technique – radiofrequency – is difficult to be done. The most important reason is the fact that nowadays radiofrequency is performed mostly as an exclusive and percutaneous technique, while cryotherapy is still a therapeutic option during surgery. Anyways, there is a number of capabilities which might make it even more effective once reached an adequate technical ability. First, cryotherapy induces the production of a group of cytokines inhibiting cellular growth, while radiofrequency induces the production of substances stimulating the relapse of disease. Second, cryotherapy shows an exact limit between treated and non-treated areas, and then allows to control the adequacy of treatment, while radiofrequency creates a shaded border. Third, during cryotherapy it's possible to verify, using ultrasounds, the blistering of ice crystals, and then assess the efficacy of therapy. Fourth, the procedure can be performed using multiple needles, without modifying the shape of the treated volume.

The Most Important Local and Regional Treatment Techniques of

Fig. 4. A lesion following a TACE treatment seen with MR imaging

Chemoembolization does not show the complications typical of the percutaneous procedures with direct tumor puncture. Anyways, considering the loss of healthy liver tissue after TACE, it's mandatory to have a blood liver function test before performing the treatment, as destruction of a volume of liver, even if small in some cases, could bring to

radiological contrast by itself13.

unresolved13,14.

Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival 233

also be easily recognized also during a CT scan control without contrast because it is a

As said, chemoembolizing treatment is generally performed linking a drug to a resin microsphere. This process is obviously not necessary to obtain just the embolization of the blood vessel going to the tumor. There is a debate in the Literature whether there is a real need to link the drug to the resin, or not, as the resin alone is able to close the vessel and maybe to eliminate the lesion. Some studies show an almost comparable 3 years overall survival between the first and the second therapeutic option, some other suggest to perform a more complete procedure, and this is the reason why the discussion remains

The most important complications typical of this procedure are the same of all the other percutaneous techniques. Using smaller probes than those used during intra-operatory approach (about 3.5 mm of diameter) has minimized the worst complication following cryotherapy, which is the rupture of the frozen area and then the following bleeding. Even if this event is possible after any cryogenic probe insertion, the probability of it is directly proportional to the dimension of the used needles. Another complication is the local and systemic thermic shock, with MOF and disseminated intravascular coagulation. In Literature this event has a risk of 1% of incidence using the old needles, close to 0% using the new smaller ones.

As this is a new technique, and as it is now performed during surgery, it's difficult to provide survival rates linked to its exclusive use. Anyways, in the Literature some Authors show a 3 years survival of about 35%11.

### **2.5 Chemoembolization (TACE)**

This technique is performed through puncture of the common femoral artery and retrograde reach of a selected branch of the hepatic artery, or percutaneously through puncture of an infuse-a-port previously inserted into the right vessel. It consists in injecting resin microspheres linked to a chemotherapic drug (a cocktail of Mitomycin C, Adriamycin and Cisplatinum) or alone (in this case is correct to call the procedure not chemoembolization but only "embolization"). These spheres close the artery which provides blood to the liver volume in which there is the tumor. Occlusion causes an ischemic necrosis of the nodule and of the healthy surrounding tissue, and the presence of the chemotherapic drugs allows a lasting treatment. This technique is indicated especially for multifocal neoplasms, normally more than four nodules, but is useful also for a lower number of big lesions, or in any case of non surgical disease12.

The possibility of using TACE for treatment of all the non surgical patients makes it good for those who would have a light risk of liver failure in case of surgery, and this is the reason why this technique is a good option for all the Child B and C patients. More indications are the absence of vascular and periepatic infiltration and no extra-hepatic spread of disease. In all these cases, also according to the BCLC score, chemoembolization might be considered as a first line treatment for hepatocellular carcinoma.

During the first therapeutic trials, in order to gain a complete treatment, big volumes of hepatic healthy tissue were embolized together with the neoplasm. This could bring to a real risk of organ failure, especially in those patients with low liver function. This is the reason why technological evolution has helped physicians to embolyze liver arteries in an always more selective way, thus trying to perform selective procedures, even less invasive. The collaboration between CT scan techniques and intra-operatory angiography allows the selection of just the sub-segmentary arteries bringing blood to the lesion. Nowadays also the digital angiography is available, able to give clear images during the procedure, tridimensional if needed. Superselective chemoembolization, as it is performed in very little vessels, requires a new carrier of the chemotherapic drug. So, in this case it's impossible to use the standard resin microspheres, but a different material, once used in radiology for hepatic contrast images and no longer in use, which is Lipiodol. This material, thick and able to link to HCC cells, has a disposition to settle and stay into the treated area, and it can

The most important complications typical of this procedure are the same of all the other percutaneous techniques. Using smaller probes than those used during intra-operatory approach (about 3.5 mm of diameter) has minimized the worst complication following cryotherapy, which is the rupture of the frozen area and then the following bleeding. Even if this event is possible after any cryogenic probe insertion, the probability of it is directly proportional to the dimension of the used needles. Another complication is the local and systemic thermic shock, with MOF and disseminated intravascular coagulation. In Literature this event has a risk of 1% of incidence using the old needles, close to 0% using

As this is a new technique, and as it is now performed during surgery, it's difficult to provide survival rates linked to its exclusive use. Anyways, in the Literature some Authors

This technique is performed through puncture of the common femoral artery and retrograde reach of a selected branch of the hepatic artery, or percutaneously through puncture of an infuse-a-port previously inserted into the right vessel. It consists in injecting resin microspheres linked to a chemotherapic drug (a cocktail of Mitomycin C, Adriamycin and Cisplatinum) or alone (in this case is correct to call the procedure not chemoembolization but only "embolization"). These spheres close the artery which provides blood to the liver volume in which there is the tumor. Occlusion causes an ischemic necrosis of the nodule and of the healthy surrounding tissue, and the presence of the chemotherapic drugs allows a lasting treatment. This technique is indicated especially for multifocal neoplasms, normally more than four nodules, but is useful also for a lower number of big lesions, or in any case

The possibility of using TACE for treatment of all the non surgical patients makes it good for those who would have a light risk of liver failure in case of surgery, and this is the reason why this technique is a good option for all the Child B and C patients. More indications are the absence of vascular and periepatic infiltration and no extra-hepatic spread of disease. In all these cases, also according to the BCLC score, chemoembolization

During the first therapeutic trials, in order to gain a complete treatment, big volumes of hepatic healthy tissue were embolized together with the neoplasm. This could bring to a real risk of organ failure, especially in those patients with low liver function. This is the reason why technological evolution has helped physicians to embolyze liver arteries in an always more selective way, thus trying to perform selective procedures, even less invasive. The collaboration between CT scan techniques and intra-operatory angiography allows the selection of just the sub-segmentary arteries bringing blood to the lesion. Nowadays also the digital angiography is available, able to give clear images during the procedure, tridimensional if needed. Superselective chemoembolization, as it is performed in very little vessels, requires a new carrier of the chemotherapic drug. So, in this case it's impossible to use the standard resin microspheres, but a different material, once used in radiology for hepatic contrast images and no longer in use, which is Lipiodol. This material, thick and able to link to HCC cells, has a disposition to settle and stay into the treated area, and it can

might be considered as a first line treatment for hepatocellular carcinoma.

the new smaller ones.

show a 3 years survival of about 35%11.

**2.5 Chemoembolization (TACE)**

of non surgical disease12.

also be easily recognized also during a CT scan control without contrast because it is a radiological contrast by itself13.

As said, chemoembolizing treatment is generally performed linking a drug to a resin microsphere. This process is obviously not necessary to obtain just the embolization of the blood vessel going to the tumor. There is a debate in the Literature whether there is a real need to link the drug to the resin, or not, as the resin alone is able to close the vessel and maybe to eliminate the lesion. Some studies show an almost comparable 3 years overall survival between the first and the second therapeutic option, some other suggest to perform a more complete procedure, and this is the reason why the discussion remains unresolved13,14.

Fig. 4. A lesion following a TACE treatment seen with MR imaging

Chemoembolization does not show the complications typical of the percutaneous procedures with direct tumor puncture. Anyways, considering the loss of healthy liver tissue after TACE, it's mandatory to have a blood liver function test before performing the treatment, as destruction of a volume of liver, even if small in some cases, could bring to

The Most Important Local and Regional Treatment Techniques of

*Journal of hepatology*, 52 (3), 380-388

art. *Liver transplantation*, 10 (2), Suppl 1, S91-S97

hepatocellular carcinoma. *Hepatology*, 27, 67-72

*American journal of roentgenology*, 174, 323-331

carcinoma. *International journal of surgery*, 9 (2), 188-191

adjuvants. *Technology cancer research and treatment*, 3, 103-111

*surgical oncology*, 14 (8), 2319-29

*radiology*, 1997, 7, 514-519

procedures, avoiding the bad ones.

**3. Conclusions**

**4. References**

357

447

1339

disease.

quite the same of chemoembolization18.

Hepatocellular Carcinoma and Their Effect over a Long Term Overall Survival 235

method, creating a sort of radioembolization, able to present the good actions of the two

Survival curves characteristic of Yttrium microspheres treatment as an exclusive one are

Most of the techniques described have been performed in our institution, each one according to their indication, to treat hepatic lesions after surgery. We have noticed a growth of disease free survival and overall survival, experiencing how a combined approach to hepatocellular carcinoma is nowadays the most effective way to treat this

[1] Germani, G. et al. (2010), Clinical outcomes of radiofrequency ablation, percutaneous

[2] Vilana, R. et al. (1992), Tumor size determines the efficacy of percutaneous ethanol

[3] Lencioni, R. et al. (1997), Long-term results of percutaneous ethanol injection therapy for

[4] Stigliano, R. et al. (2007), Seeding following percutaneous diagnostic and therapeutic

[5] Lencioni, R. et al. (2004), Percutaneous ablation of hepatocellular carcinoma: state of the

[6] Ohnishi, K. et al. (1998), Prospective randomized controlled trial comparing

[7] Goldberg, S.N. et al. (2000), Thermal ablation therapies for focal malignancies: a unified

[8] Choi, D. et al. (2007), Percutaneous radiofrequency ablation for recurrent hepatocellular

[9] Chen, H.W. et al. (2011), Ultrasound-guided percutaneous cryotherapyof hepatocellular

[10] Han, B. et al. (2004), Improved cryosurgery by useof thermophysical and inflammatory

[11] Adam, R. et al. (2002), A comparison of percutaneous cryosurgery and percutaneous

alcohol and acetic acid injection for hepatocellular carcinoma: a meta-analysis.

injection for the treatment of small hepatocellular carcinoma. *Hepatology*, 16, 353-

hepatocellular carcinoma in cirrhosis: a European experience. *European journal of*

approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. *Cancer treatment review*, 33, 437-

percutaneous acetic acid injection and percutaneous ethanol injection for small

approach to underlying principles, techniques and diagnostic imaging guidance.

carcinoma after hepatectomy: long-term results and prognostic factors. *Annals of*

radiofrequency for unresectable hepatic malignancies. *Archives of surgery*, 137, 1332-

organ failure. Moreover a pre-treatment angiographic study is required, looking for vascular anatomic variations or aberrant vessels, which could keep the lesion fed also after the procedure and cause a drug wash out. A pre-treatment angiographic study is important also, on the contrary, to look for anatomic variations to avoid possible ischemic necrosis of other organs close to the liver and not directly involved in the treatment.

The characteristic possibility of TACE to treat also big lesions is the reason why survival after exclusive treatment is a direct consequence of neoplasm dimension. In case of small lesions a survival of 59% after 5 years is described. In case of nodules more than 5 centimeters in diameter, 3 years and 5 years survival are respectively of 27% and 20%, as reported in the Literature15.

### **2.6 Yttrium microspheres embolization**

This is a real and proper radioembolization, based on the finding that neoplastic liver tissue, as much as the metastatic one coming from other organs, is sensitive to therapeutic radiations. On the contrary, healthy liver tissue can be able to resist to cumulative doses even higher than 3000 Gy. Radioembolization is performed using two possible devices, which are resin microspheres covered with 90Y, similar to those used for chemoembolization, or glass microspheres covered with the same radioactive material. In the USA, resin spheres are FDA authorized for any therapeutic use, while glass spheres are allowed only in case of non-surgical disease. In Europe both devices are allowed16.

Procedures linked to the Yttrium microspheres treatment are strictly similar to those characteristic of chemoembolization, the only important difference is the fact the intraarterial drug injection does not require the vessel embolization. In this way the production of some cytokines is avoided, among them there is also the factor 1α hypoxia induced and VEGF, able to stimulate the disease relapse over eventual not completely treated areas. This is the reason why there are some extended indications for this procedure in comparison with TACE: it's possible to perform it even in case of Portal Vein thrombosis, which is a contraindication for chemoembolization as it could bring to ischemic hepatitis, and it's particularly indicated for big lesions. Moreover, Yttrium microspheres appear easier to be tolerated than TACE, as they reduce post-treatment fever and post-chemotherapic diarrhea. On the contrary, patients who underwent this procedure often experience asthenia, and must be kept isolated for at least 24 hours as they are a source of ionizing dangerous waves. The general bearability of the treatment, anyways, makes it a valid option also for patients with a low performance status16,17.

In the Literature there are always more papers trying to make a comparison between TACE and Yttrium microspheres. The two treatments are in facts quite similar, and results over disease free survival and overall survival are comparable. Today it's still difficult to project equivalence studies, as they require a very big sample population to give significant statistic results. It's demonstrated that radiometabolic treatment brings to an important improvement in terms of time to progression, which is the time between the treatment and the disease relapse. Moreover, if there is an adequate structure to accommodate them, older or weak people are some of the best patients to receive this treatment.

In the end, considering the wide amount of contact points between TACE and Yttrium microspheres treatment, technical evolution is moving towards the creation of a unifying method, creating a sort of radioembolization, able to present the good actions of the two procedures, avoiding the bad ones.

Survival curves characteristic of Yttrium microspheres treatment as an exclusive one are quite the same of chemoembolization18.

### **3. Conclusions**

234 Hepatocellular Carcinoma – Clinical Research

organ failure. Moreover a pre-treatment angiographic study is required, looking for vascular anatomic variations or aberrant vessels, which could keep the lesion fed also after the procedure and cause a drug wash out. A pre-treatment angiographic study is important also, on the contrary, to look for anatomic variations to avoid possible ischemic necrosis of

The characteristic possibility of TACE to treat also big lesions is the reason why survival after exclusive treatment is a direct consequence of neoplasm dimension. In case of small lesions a survival of 59% after 5 years is described. In case of nodules more than 5 centimeters in diameter, 3 years and 5 years survival are respectively of 27% and 20%, as

This is a real and proper radioembolization, based on the finding that neoplastic liver tissue, as much as the metastatic one coming from other organs, is sensitive to therapeutic radiations. On the contrary, healthy liver tissue can be able to resist to cumulative doses even higher than 3000 Gy. Radioembolization is performed using two possible devices, which are resin microspheres covered with 90Y, similar to those used for chemoembolization, or glass microspheres covered with the same radioactive material. In the USA, resin spheres are FDA authorized for any therapeutic use, while glass spheres are allowed only in case of

Procedures linked to the Yttrium microspheres treatment are strictly similar to those characteristic of chemoembolization, the only important difference is the fact the intraarterial drug injection does not require the vessel embolization. In this way the production of some cytokines is avoided, among them there is also the factor 1α hypoxia induced and VEGF, able to stimulate the disease relapse over eventual not completely treated areas. This is the reason why there are some extended indications for this procedure in comparison with TACE: it's possible to perform it even in case of Portal Vein thrombosis, which is a contraindication for chemoembolization as it could bring to ischemic hepatitis, and it's particularly indicated for big lesions. Moreover, Yttrium microspheres appear easier to be tolerated than TACE, as they reduce post-treatment fever and post-chemotherapic diarrhea. On the contrary, patients who underwent this procedure often experience asthenia, and must be kept isolated for at least 24 hours as they are a source of ionizing dangerous waves. The general bearability of the treatment, anyways, makes it a valid option also for patients

In the Literature there are always more papers trying to make a comparison between TACE and Yttrium microspheres. The two treatments are in facts quite similar, and results over disease free survival and overall survival are comparable. Today it's still difficult to project equivalence studies, as they require a very big sample population to give significant statistic results. It's demonstrated that radiometabolic treatment brings to an important improvement in terms of time to progression, which is the time between the treatment and the disease relapse. Moreover, if there is an adequate structure to accommodate them, older

In the end, considering the wide amount of contact points between TACE and Yttrium microspheres treatment, technical evolution is moving towards the creation of a unifying

or weak people are some of the best patients to receive this treatment.

other organs close to the liver and not directly involved in the treatment.

reported in the Literature15.

**2.6 Yttrium microspheres embolization**

with a low performance status16,17.

non-surgical disease. In Europe both devices are allowed16.

Most of the techniques described have been performed in our institution, each one according to their indication, to treat hepatic lesions after surgery. We have noticed a growth of disease free survival and overall survival, experiencing how a combined approach to hepatocellular carcinoma is nowadays the most effective way to treat this disease.

### **4. References**

**13**

 *Japan*

Kiyoshi Mochizuki

**Radiofrequency Ablation for Hepatocellular**

*Department of Gastroenterology and Hepatology, Kansai Rousai Hospital, Hyogo*

**Carcinoma at the Dome of the Liver: A Review**

Hepatocellular carcinoma is the third-leading cause of global cancer-related mortality. Major causes of this disease are hepatotropic viruses including hepatitis B and C viruses, nonalcoholic steatohepatitis, alcohol, autoimmunity, primary biliary cirrhosis, primary sclerosing cholangitis, vascular disorders and so on (Olsen et al., 2010). These factors related to hepatitis lead the patients to the high-risk group for decompensated liver cirrhosis and hepatocellular carcinoma during their clinical course in 20–30 years. Interferon or other medical therapy for each disease have been accommodating better conditions of the liver and make it possible to prolong their lives. However, the possibility of the occurrence of hepatocellular carcinoma could not have been completely avoided in

Recently, the improvements of surveillance techniques and disease awareness have led to earlier diagnosis and more appropriate treatment for liver tumors. Surgical therapy could be curative treatment to avoid local recurrence, but many patients are unable to undergo surgical resection due to severely compromised liver function or multiple tumors. Moreover, frequent recurrence of heparocellular carcinoma makes it hazardous for the patients to undergo surgical therapy repeatedly to maintain the liver function after the treatment. Thus, non-surgical interventional therapy has been introduced to control hepatocellular carcinoma and have played an important role in the treatment of hepatocellular carcinoma (Livraghi et al, 1999; Poon et al, 2002). These locoregional therapies including transcatheter arterial chemoembolization, percutaneous ethanol injection therapy, percutaneous radiofrequeny ablation therapy and others, have been making significant contributions to reduce the decrease of the liver function and to maintain the condition of the patients (Poon et al, 2002; Buix et al, 2004; Orland et al, 2009). Radiofrequency ablation has provided one of the greatest recent advances in the treatment of hepatocellular carcinoma because of the improvement of the local control and the patient survival. Radiofrequency ablation is reported as a minimally invasive and effective treatment for small hepatocellular carcinoma and now this treatment is the most widely used technique of the therapy for hepatocellular carcinoma worldwide. Many studies have established the effectiveness of radiofrequency ablation in treating hepatocellular carcinoma (McGhana &Dodd, 2001; Livraghi et al, 2003; Lencioni et al, 2005; Tateishi et al, 2005; Choi et al, 2007)

and have achieved to expand the indications for radiofrequency ablation.

**1. Introduction**

these patients during their lifetime.

### **Radiofrequency Ablation for Hepatocellular Carcinoma at the Dome of the Liver: A Review**

Kiyoshi Mochizuki

*Department of Gastroenterology and Hepatology, Kansai Rousai Hospital, Hyogo Japan*

### **1. Introduction**

236 Hepatocellular Carcinoma – Clinical Research

[12] Takayasu, K. (2010), Chemoembolization for unresectable Hepatocellular carcinoma in

[13] Matsui, O. et al. (1994), Subsegmental transcatheter arterial embolization for small

[14] Bronowicki, J.P. et al. (1994), Transcatheter oily chemoembolization for hepatocellular

[15] Coldwell, D. et al. (2010), Radioembolization in the treatment of unresectable liver

[16] Salem, R. et al. (2011), Radioembolization results in longer time-to-progression and

[17] Leelawat, K. et al. (2008), The effect of doxorubicin on the changes of serum vascular

[18] Virmani, S. et al. (2008), Comparison of hypoxia-induced factor 1α expression before

carcinoma: A 4-year study of 127 French patients. *Cancer*, 74, 16-24

hepatocellular carcinomas: Local therapeutic effect and 5-year survival rate. *Cancer*

tumors: experience across a range of primary cancers. *American journal of clinical*

reduced toxicity compared with chemoembolization in patients with hepatocellular

endothelial growth factor (VEGF) in patients with hepatocellular carcinoma after transcatheter arterial chemoembolization (TACE). *Journal of medical association of*

and after transcatheter arterial embolization in rabbit VX2 liver tumors. *Journal of*

Japan. *Oncology*, 78 (suppl.1), 135-141

*oncology*, online first (November 30)

*Thailand*, 91, 1539-1543

carcinoma. *Gastroenterology*, 140, 497-507

*vascular interventional radiology*, 19, 1483-1489

*chemotherapy and pharmacology*, 33 (suppl), 84-88

Hepatocellular carcinoma is the third-leading cause of global cancer-related mortality. Major causes of this disease are hepatotropic viruses including hepatitis B and C viruses, nonalcoholic steatohepatitis, alcohol, autoimmunity, primary biliary cirrhosis, primary sclerosing cholangitis, vascular disorders and so on (Olsen et al., 2010). These factors related to hepatitis lead the patients to the high-risk group for decompensated liver cirrhosis and hepatocellular carcinoma during their clinical course in 20–30 years. Interferon or other medical therapy for each disease have been accommodating better conditions of the liver and make it possible to prolong their lives. However, the possibility of the occurrence of hepatocellular carcinoma could not have been completely avoided in these patients during their lifetime.

Recently, the improvements of surveillance techniques and disease awareness have led to earlier diagnosis and more appropriate treatment for liver tumors. Surgical therapy could be curative treatment to avoid local recurrence, but many patients are unable to undergo surgical resection due to severely compromised liver function or multiple tumors. Moreover, frequent recurrence of heparocellular carcinoma makes it hazardous for the patients to undergo surgical therapy repeatedly to maintain the liver function after the treatment. Thus, non-surgical interventional therapy has been introduced to control hepatocellular carcinoma and have played an important role in the treatment of hepatocellular carcinoma (Livraghi et al, 1999; Poon et al, 2002). These locoregional therapies including transcatheter arterial chemoembolization, percutaneous ethanol injection therapy, percutaneous radiofrequeny ablation therapy and others, have been making significant contributions to reduce the decrease of the liver function and to maintain the condition of the patients (Poon et al, 2002; Buix et al, 2004; Orland et al, 2009). Radiofrequency ablation has provided one of the greatest recent advances in the treatment of hepatocellular carcinoma because of the improvement of the local control and the patient survival. Radiofrequency ablation is reported as a minimally invasive and effective treatment for small hepatocellular carcinoma and now this treatment is the most widely used technique of the therapy for hepatocellular carcinoma worldwide. Many studies have established the effectiveness of radiofrequency ablation in treating hepatocellular carcinoma (McGhana &Dodd, 2001; Livraghi et al, 2003; Lencioni et al, 2005; Tateishi et al, 2005; Choi et al, 2007) and have achieved to expand the indications for radiofrequency ablation.

Radiofrequency Ablation for Hepatocellular Carcinoma at the Dome of the Liver: A Review 239

undetectable region in the liver and lead the physicians to have difficulties in such treatment. Hepatocellular carcinoma can locate in every lobe of the liver, and sometimes locates under the diaphragm dome and this could often be the key factor affecting the effectiveness or the insufficiency of this treatment (Koda et al, 2003; Kang et al, 2009). It may be unavoidable in such cases to make unintended burns to the diaphragm neighboring or close to the target tumor because physicians should burn larger area including

**4. Reported complications including a diaphragmatic hernia in the literature,**

Mulier et al. reviewd the complication of radiofrequency ablation from 82 reports of 3670 cases and reported that the prevalence of diaphragm burn was estimated as 0.1% (5 out of 3670) (Mulier et al, 2002). However, Head HW et al. reported that 5 (17%) in 29 radiofrequency ablation cases of hepatocellular carcinoma adjacent to the diaphragm had right shoulder pain and 3 cases showed thickening of the diaphragm induced by the thermal effect of radiofrequency ablation (Head et al, 2007). It is also reported that the symptom of diaphragm injury manifests as referred right shoulder pain that occurs during the treatment and can last up to 2 weeks after the ablation (Livraghi et al, 2003). It may be unavoidable in cases that hepatocellular carcinomas locate under the diaphragm dome to make unintended burn to the diaphragm because of the environmental and technical factors (Kang et al, 2009). The unintended burn of the limited area of the diaphragm may not induce any significant phenomena in the short term except in a few cases, but Curly et al. analyzed the data of 608 cases and emphasized the risk of the late complications of the radiofrequency ablation treatment (Curley et al, 2004). It should be known that radiofrequency ablation could induce

hepatocellular carcinoma in order to gain the safety margin around it.

**4.1 A review of diaphragmatic hernia reported in the literature**

serious combined diseases more than several months after the treatment.

**radiofrequency ablation for hepatocellular carcinoma**

Child-Pugh class A liver cirrhosis.

**4.2 Case report: Diaphragmatic hernia twenty months after percutaneous**

In August, 2006, we experienced one case of a 50-year-old man with hepatitis B virus infection who underwent radiofrequency ablation for hepatocellular carcinoma of 2.2 cm in diameter located in the segment VIII area of his liver adjacent to the diaphragm (Figure 1a). The tumor could be almost fully scanned ultrasonographically and it was located just under the costal region close to the costpleural angle. Laboratory tests showed his liver function as

Ultrasound-guided radiofrequency ablation was performed using RITA Medical System 1500 RF generator attached to a 15-gauge Starburst XL model 90 probe needle for 20 minutes and the needle was expanded to 4cm in a stepwise manner. There was no technical problem and enough ablation area around hepatocellular carcinoma could be achieved with a safety margin of the necrotic area (Figure 1b). He did not feel nausea and did not complained about a thermal effect like right shoulder pain which could be a sign of diaphragm damage (Livraghi et al, 2003). After the procedure, he was discharged in a week without any adverse effects. He had been under observation in our hospital regularly and medicated by entecavir

**and the case report**

However, one of the most characteristic complications of this therapy is that related to the thermal effect. We experienced a case that developed diaphragmatic hernia due to the thermal effect of radiofrequency ablation twenty months after the treatment for a tumor located in the segment VIII area of his liver. Patients who have undergone radiofrequency ablation for hepatic tumors adjacent to the diaphragm should be carefully followed up for possible damage of the diaphragm, even after the long postoperative intervals. Recently, the artificial ascites technique has been developed and introduced in this field. This technique could be approved for the prevention of the diaphragmatic damage and the thermal complications of the surrounding organs.

### **2. Radiofrequency ablation for hepatocellular carcinoma**

Radiofrequency ablation includes the methods of tumor necrosis through the direct placement of the needles into the tumor under the ultrasonographical guide and the usage of alternating electrical current to create ionic agitation and frictional heating leading to the tissue damage. The benefits of this therapy include excellent local control comparable to surgical resection, low morbidity, repeatability for recurrence, preservation of liver function, and few complications (Livraghi et al, 1999; Poon et al, 2002).

Although radiofrequency ablation is considered safe (Curley et al, 2000; Livraghi et al, 2000; Wood et al, 2000), some serious complications have been reported. These include bleeding from costal or hepatic artery, pneumothorax or puncture of surrounding organ, infection, pain, nausea or vomiting, and so on (Curley et al, 2000; Livraghi et al, 2000; Wood et al, 2000). One of the most characteristic and unpredictable complications of this therapy is that induced by heat conduction. Even though the needle could be inserted into the appropriate lesion under the ultrasonographic guide, because the ablated area should be larger than the tumor and involving the whole tumor, it is difficult to grasp the ablated area around the tumor and the environmental situation precisely during the treatment. The ablation produce microbubbles due to heating up in the tissue surrounding the tumor resulting in occurrence of difficulty in grasping the precise ablated area. If the physicians could release the needle from the ultrasonographic transducer during the treatment, it could be possible to grasp roughly the area from other view points. However, high echoic area of microbubbles is not always identical to ablated area and sometimes expands beyond the thermal margin of the effective thermal area. Three-dimensional analysis with radiological study should be helpful to evaluate the ablated area, but it is impossible to predict before the treatment because of the existence of environmental factors of the ablated area including blood flow and respiratory movement of the liver.

### **3. Technical difficulties for hepatocellular carcinoma situated at the dome of the liver**

Because all of the procedures for the liver diseases under ultrasonographic guidance need to be performed with the fully clear detection of the target site, insufficient and poor imaging of ultrasonography means the hardly successful treatment. However, ultrasonographic visualization of the whole tumor under the diaphragm is not always possible due to the atrophy of the right lobe of the cirrhotic liver and the normal respiratory expansion of the lung over the liver causing the acoustic shadow. Therefore, the deformity or the atrophy of the liver due to the chronic inflammation and the damage would make ultrasonographically

However, one of the most characteristic complications of this therapy is that related to the thermal effect. We experienced a case that developed diaphragmatic hernia due to the thermal effect of radiofrequency ablation twenty months after the treatment for a tumor located in the segment VIII area of his liver. Patients who have undergone radiofrequency ablation for hepatic tumors adjacent to the diaphragm should be carefully followed up for possible damage of the diaphragm, even after the long postoperative intervals. Recently, the artificial ascites technique has been developed and introduced in this field. This technique could be approved for the prevention of the diaphragmatic damage and the thermal

Radiofrequency ablation includes the methods of tumor necrosis through the direct placement of the needles into the tumor under the ultrasonographical guide and the usage of alternating electrical current to create ionic agitation and frictional heating leading to the tissue damage. The benefits of this therapy include excellent local control comparable to surgical resection, low morbidity, repeatability for recurrence, preservation of liver function,

Although radiofrequency ablation is considered safe (Curley et al, 2000; Livraghi et al, 2000; Wood et al, 2000), some serious complications have been reported. These include bleeding from costal or hepatic artery, pneumothorax or puncture of surrounding organ, infection, pain, nausea or vomiting, and so on (Curley et al, 2000; Livraghi et al, 2000; Wood et al, 2000). One of the most characteristic and unpredictable complications of this therapy is that induced by heat conduction. Even though the needle could be inserted into the appropriate lesion under the ultrasonographic guide, because the ablated area should be larger than the tumor and involving the whole tumor, it is difficult to grasp the ablated area around the tumor and the environmental situation precisely during the treatment. The ablation produce microbubbles due to heating up in the tissue surrounding the tumor resulting in occurrence of difficulty in grasping the precise ablated area. If the physicians could release the needle from the ultrasonographic transducer during the treatment, it could be possible to grasp roughly the area from other view points. However, high echoic area of microbubbles is not always identical to ablated area and sometimes expands beyond the thermal margin of the effective thermal area. Three-dimensional analysis with radiological study should be helpful to evaluate the ablated area, but it is impossible to predict before the treatment because of the existence of environmental factors of the ablated area including blood flow and

**3. Technical difficulties for hepatocellular carcinoma situated at the dome of**

Because all of the procedures for the liver diseases under ultrasonographic guidance need to be performed with the fully clear detection of the target site, insufficient and poor imaging of ultrasonography means the hardly successful treatment. However, ultrasonographic visualization of the whole tumor under the diaphragm is not always possible due to the atrophy of the right lobe of the cirrhotic liver and the normal respiratory expansion of the lung over the liver causing the acoustic shadow. Therefore, the deformity or the atrophy of the liver due to the chronic inflammation and the damage would make ultrasonographically

complications of the surrounding organs.

respiratory movement of the liver.

**the liver**

**2. Radiofrequency ablation for hepatocellular carcinoma**

and few complications (Livraghi et al, 1999; Poon et al, 2002).

undetectable region in the liver and lead the physicians to have difficulties in such treatment. Hepatocellular carcinoma can locate in every lobe of the liver, and sometimes locates under the diaphragm dome and this could often be the key factor affecting the effectiveness or the insufficiency of this treatment (Koda et al, 2003; Kang et al, 2009). It may be unavoidable in such cases to make unintended burns to the diaphragm neighboring or close to the target tumor because physicians should burn larger area including hepatocellular carcinoma in order to gain the safety margin around it.

### **4. Reported complications including a diaphragmatic hernia in the literature, and the case report**

### **4.1 A review of diaphragmatic hernia reported in the literature**

Mulier et al. reviewd the complication of radiofrequency ablation from 82 reports of 3670 cases and reported that the prevalence of diaphragm burn was estimated as 0.1% (5 out of 3670) (Mulier et al, 2002). However, Head HW et al. reported that 5 (17%) in 29 radiofrequency ablation cases of hepatocellular carcinoma adjacent to the diaphragm had right shoulder pain and 3 cases showed thickening of the diaphragm induced by the thermal effect of radiofrequency ablation (Head et al, 2007). It is also reported that the symptom of diaphragm injury manifests as referred right shoulder pain that occurs during the treatment and can last up to 2 weeks after the ablation (Livraghi et al, 2003). It may be unavoidable in cases that hepatocellular carcinomas locate under the diaphragm dome to make unintended burn to the diaphragm because of the environmental and technical factors (Kang et al, 2009). The unintended burn of the limited area of the diaphragm may not induce any significant phenomena in the short term except in a few cases, but Curly et al. analyzed the data of 608 cases and emphasized the risk of the late complications of the radiofrequency ablation treatment (Curley et al, 2004). It should be known that radiofrequency ablation could induce serious combined diseases more than several months after the treatment.

### **4.2 Case report: Diaphragmatic hernia twenty months after percutaneous radiofrequency ablation for hepatocellular carcinoma**

In August, 2006, we experienced one case of a 50-year-old man with hepatitis B virus infection who underwent radiofrequency ablation for hepatocellular carcinoma of 2.2 cm in diameter located in the segment VIII area of his liver adjacent to the diaphragm (Figure 1a). The tumor could be almost fully scanned ultrasonographically and it was located just under the costal region close to the costpleural angle. Laboratory tests showed his liver function as Child-Pugh class A liver cirrhosis.

Ultrasound-guided radiofrequency ablation was performed using RITA Medical System 1500 RF generator attached to a 15-gauge Starburst XL model 90 probe needle for 20 minutes and the needle was expanded to 4cm in a stepwise manner. There was no technical problem and enough ablation area around hepatocellular carcinoma could be achieved with a safety margin of the necrotic area (Figure 1b). He did not feel nausea and did not complained about a thermal effect like right shoulder pain which could be a sign of diaphragm damage (Livraghi et al, 2003). After the procedure, he was discharged in a week without any adverse effects. He had been under observation in our hospital regularly and medicated by entecavir

Radiofrequency Ablation for Hepatocellular Carcinoma at the Dome of the Liver: A Review 241

Computed tomography revealed the prolapsed large intestine and the omentum through a defect on the right diaphragm (Figure 2a, 2b), and emergency surgery was performed to close the hole in the diaphragm following the diagnosis of diaphragmatic hernia. The operation showed that the ascending and transverse colon had been herniated into the right pleural cavity through the diaphragmatic hole which measured 5x3 cm in diameter (Figure 3) and no apparent invasion of hepatocellular carcinoma around the hole was observed. Although the colon was perforated in the pleural cavity and induced pyothorax after the operation, he recovered with the intense care using antibiotics and drainage

Fig. 3. The photograph taken during the surgery. (adapted from Nawa T et al).

In our case, the location of the diaphragm defect was apparently different from that of congenital diaphragmatic hernia and his clinical history showed that nothing other than the radiofrequency ablation could be the cause of the diaphragmatic perforation. The repeated treatments of transcatheter arterial chemoembolization against hepatocellular carcinoma recurrence during twenty months might accelerate the atrophy of the right lobe of his liver (Figure 4, a-d). This atrophic change could be thought to make the space between the liver

It is often a problem of radiofrequency ablation using an expandable electrode that all of the multiple tips of the needle cannot always be detected under ultrasonography because the tips are multidirectional meaning there is a risk of puncture of vessels or other organs close to a tumor beyond the possible scan area. However, diaphragmatic hernia was reported not only in the case of expandable electrodes but also in the case of a single straight electrode. Therefore, the thermal effect for the diaphragm could not always be induced by the direct

Because this complication was observed in the cases of hepatocellular carcinoma located in the segment IV, VII or VIII close to the diaphragm, it should be recommended to follow carefully such cases, especially with the apparent atrophic change of the right lobe of the

This photograph is showing the hole in the diaphragm.

and the diaphragm for his large intestine to access to the hole.

liver, as the high-risk groups of diaphragmatic hernia.

puncture of expandable electrode.

(Nawa et al, 2010).

to control hepatitis B virus replication. Since multiple recurrence lesions were detected in the segment VIII later, he was treated with transcatheter arterial chemoembolization therapy in April, 2007 and in February, 2008.

Fig. 1. 50-year-old man with hepatocellular carcinoma. (adapted from Nawa T et al).

Twenty months later after the radiofrequency ablation treatment in April 2008, he was admitted to our hospital emergency department because of severe right hypochondralgia and dyspnea.

Fig. 2. Computed tomography scan obtained at the hospital emergency department twenty months later after the radiofrequency ablation therapy. (adapted from Nawa T et al).

to control hepatitis B virus replication. Since multiple recurrence lesions were detected in the segment VIII later, he was treated with transcatheter arterial chemoembolization therapy

Fig. 1. 50-year-old man with hepatocellular carcinoma. (adapted from Nawa T et al).

a. Arterial phase computed tomography scan obtained prior to the radiofrequency ablation shows enhancing nodule (black arrows) in the segment VIII of the liver. b. Portal phase computed tomography scan obtained after the radiofrequency ablation

Twenty months later after the radiofrequency ablation treatment in April 2008, he was admitted to our hospital emergency department because of severe right hypochondralgia

Fig. 2. Computed tomography scan obtained at the hospital emergency department twenty months later after the radiofrequency ablation therapy. (adapted from Nawa T et al).

a. Computed tomography scan shows the prolapsed large intestine and the omentum in

b. Coronal multidetector computed tomography image of his chest shows the portion of the large intestine in the right lower thorax, indicating the anatomic relationship of the

diaphragmatic defect (white arrow) and the surrounding organs.

in April, 2007 and in February, 2008.

shows the ablation zone (A).

his right pleural cavity (white arrows).

and dyspnea.

Computed tomography revealed the prolapsed large intestine and the omentum through a defect on the right diaphragm (Figure 2a, 2b), and emergency surgery was performed to close the hole in the diaphragm following the diagnosis of diaphragmatic hernia. The operation showed that the ascending and transverse colon had been herniated into the right pleural cavity through the diaphragmatic hole which measured 5x3 cm in diameter (Figure 3) and no apparent invasion of hepatocellular carcinoma around the hole was observed. Although the colon was perforated in the pleural cavity and induced pyothorax after the operation, he recovered with the intense care using antibiotics and drainage (Nawa et al, 2010).

Fig. 3. The photograph taken during the surgery. (adapted from Nawa T et al). This photograph is showing the hole in the diaphragm.

In our case, the location of the diaphragm defect was apparently different from that of congenital diaphragmatic hernia and his clinical history showed that nothing other than the radiofrequency ablation could be the cause of the diaphragmatic perforation. The repeated treatments of transcatheter arterial chemoembolization against hepatocellular carcinoma recurrence during twenty months might accelerate the atrophy of the right lobe of his liver (Figure 4, a-d). This atrophic change could be thought to make the space between the liver and the diaphragm for his large intestine to access to the hole.

It is often a problem of radiofrequency ablation using an expandable electrode that all of the multiple tips of the needle cannot always be detected under ultrasonography because the tips are multidirectional meaning there is a risk of puncture of vessels or other organs close to a tumor beyond the possible scan area. However, diaphragmatic hernia was reported not only in the case of expandable electrodes but also in the case of a single straight electrode. Therefore, the thermal effect for the diaphragm could not always be induced by the direct puncture of expandable electrode.

Because this complication was observed in the cases of hepatocellular carcinoma located in the segment IV, VII or VIII close to the diaphragm, it should be recommended to follow carefully such cases, especially with the apparent atrophic change of the right lobe of the liver, as the high-risk groups of diaphragmatic hernia.

Radiofrequency Ablation for Hepatocellular Carcinoma at the Dome of the Liver: A Review 243

1. The location of the puncture site should be defined first as a clearly visible point in the liver with ultrasonography usually at the sixth to eighth intercostal space along the anterior to middle axillary line. It is necessary to avoid around the radiofrequency ablation puncture site for the artificial ascites puncture site since radiofrequency ablation treatment should be started during the artificial ascites procedure before the ascites spreads to other or lower abdominal cavity. If it is difficult to avoid the ablation puncture site for the artificial ascites puncture site, it is able to start making the artificial ascites at that site and try other sites after gaining a solution space in the abdominal cavity since there should be more puncture sites to make the ascites after gaining it. 2. After the administration of the local anesthesia at the skin of the puncture site, an 18 gauge sheathed needle would be prepared to insert into the peritoneal space. If the outer sheath has a side hole for infusion, it would be much easier and faster to achieve enough volume of ascites. The pneumoperitoneum needle can be used for the puncture

of the appropriate site instead of the sheathed needle for this procedure.

inspiration and expiration could help a successful placement of the sheath.

diabetic patients, saline could be used instead of glucose solution.

volume of ascites above ventral side of the target liver surface.

the physician should stop infusion and retry the puncture.

**5.3 The other issues of artificial ascites technique**

the change of abdominal pressure.

**5.3.1 Learning of the knack of artificial ascites procedure**

3. Patients are asked to perform inspiration to move the liver downward and then to hold the breath for a while. Oxygen administration could be helpful for the patients to hold the breath. The physician inserts the 18-gauge sheathed needle into the parenchyma of the liver (Figure 5a) and removes the inner stylet of the sheathed needle (Figure 5b). 4. Next, the patients are asked to perform full expiration so that the needle sheath can slip away from the hepatic capsule and located in the perihepatic intraperitoneal space (Figure 5c). If the needle sheath could not slip away from the liver, further deep

5. After the placement of the outer sheath into the peritoneal cavity, 500-1500 ml of 5% glucose solution could be infused until the tumor is fully visualized and the path for the radiofrequency ablation electrode could be clearly developed (Figure 5d). In case of

a. The puncture directed in the dorsal space of the liver without direct puncture of the liver parenchyma could be selected, but it may take longer time to achieve enough

b. Even though the needle sheath could not slip away from the liver parenchyma at step 4), the solution infusion could be started slowly. Sometimes, a blood back flow is seen after stylet removal through the needle sheath, but if the blood flow does not come from a hepatic artery, usually the solution infusion can be started. The back flow of the solution infusion from the liver parenchyma would make the ultrasonographically visible thin layer of the solution showing faint blinking streams around the liver (Figure 4e, 4f). At that time, respiratory movement might affect the drip infusion while it stops during the time of the expiration and it starts during the time of the inspiration due to

c. If an outflow of the blinking stream through hepatic vein could be observed (Figure 4g),

**5.2 Procedure of artificial ascites**

Fig. 4. Computed tomography scan obtained after the radiofrequency ablation therapy. (adapted from Nawa T et al).

Computed tomography obtained in August, 2006, (a); in November, 2006,(b); in March, 2007, (c); in May, 2007, (d). The serial computed tomography scans are showing the gradual atrophic change of the liver causing to space between the diaphragm and the liver.

### **5. Technical solution for radiofrequency ablation for hepatocellular carcinoma at the dome of the diaphragm: The techniques of artificial ascites**

### **5.1 The purpose of the artificial ascites technique**

Radiofrequency ablation is difficult to perform if a tumor is located under the diaphragm because this region is often invisible or is poorly visible on ultrasonography. Local ablation therapy under laparoscopy or thoracoscopy could be a possible treatment in such case, but it is more invasive than percutaneous procedure and other special equipment would be needed. The artificial pleural or peritoneal effusion has been explored as a beneficial treatment option that offers excellent local control through visualization of hepatocellular carcinoma under the diaphragm (Katayama et al, 2002; Uehara et al, 2007; Rhim et al, 2008). It was meaningful that this method has been reported to be effective to keep enough space between the liver and the adjacent organs including the diaphragm by a solution that can cool down the local ablated area by circulating in the peritoneal space. The procedure of artificial ascites technique is briefly shown below.

### **5.2 Procedure of artificial ascites**

242 Hepatocellular Carcinoma – Clinical Research

Fig. 4. Computed tomography scan obtained after the radiofrequency ablation therapy.

**carcinoma at the dome of the diaphragm: The techniques of artificial ascites**

Radiofrequency ablation is difficult to perform if a tumor is located under the diaphragm because this region is often invisible or is poorly visible on ultrasonography. Local ablation therapy under laparoscopy or thoracoscopy could be a possible treatment in such case, but it is more invasive than percutaneous procedure and other special equipment would be needed. The artificial pleural or peritoneal effusion has been explored as a beneficial treatment option that offers excellent local control through visualization of hepatocellular carcinoma under the diaphragm (Katayama et al, 2002; Uehara et al, 2007; Rhim et al, 2008). It was meaningful that this method has been reported to be effective to keep enough space between the liver and the adjacent organs including the diaphragm by a solution that can cool down the local ablated area by circulating in the peritoneal space. The procedure of

Computed tomography obtained in August, 2006, (a); in November, 2006,(b); in March, 2007, (c); in May, 2007, (d). The serial computed tomography scans are showing the gradual

atrophic change of the liver causing to space between the diaphragm and the liver.

**5. Technical solution for radiofrequency ablation for hepatocellular**

**5.1 The purpose of the artificial ascites technique**

artificial ascites technique is briefly shown below.

(adapted from Nawa T et al).

### **5.3 The other issues of artificial ascites technique**

### **5.3.1 Learning of the knack of artificial ascites procedure**

Fig. 5. The diagrams show the procedure to obtain artificial ascites during radiofrequency

a. The insertion of the 18-gauge sheathed needle into the parenchyma of the liver.

g. The unsuccessful streams of solution outflowing to the hepatic vein

the peritoneal cavity would disappear in 3 to 7 days in our experience.

effect to the abdominal wall or gastrointestinal tract(Kondo et al, 2006).

c. The placement of the outer needle sheath in the perihepatic intraperitoneal space. d. The achievement of the artificial ascites that can visualize the whole tumor and the path

e. The faint blinking streams of the back flow of the solution infusion from the outer

d. It is reported that oxygen saturation decreased by only 2.3% even in performing artificial pleural effusion (McGhana & Dodd, 2001) and most of the solution infused into

e. Artificial ascites technique can be used in the cases that hepatocellular carcinoma is located at ventral or dorsal side beneath the liver capsule in order to avoid the thermal

The infusion should not be vigorously performed until enough thickness (about 2 to 5 mm) of the layer could be detected because such infusion often causes the sheath dislocation from the first placed site and produces an unintended inflow to the abdominal wall. The physicians often notice such inflow with the swelling of the puncture site or an ultrasonographic thickening of the abdominal wall. In this case, the physicians should also remove the sheath as soon as possible and retry the puncture, but it often becomes more difficult to insert from the same site because the abdominal wall becomes thicker than the distance that the puncture needle can reach. Therefore, the physicians should try to find

If the patients have histories of abdominal operation or peritonitis, the adhesions between the liver and the abdominal wall might be hazardous to have successful artificial ascites. In

b. The removal of the inner stylet of the sheathed needle.

**5.3.2 Technical pitfalls of artificial ascites procedure**

another appropriate site for a puncture or try it again another day.

**5.3.3 Out of the indication of artificial ascites**

sheath needle in the liver parenchyma. f. The faint blinking streams around the liver.

ablation.

for the RFA electrode.

Fig. 5. The diagrams show the procedure to obtain artificial ascites during radiofrequency ablation.

### **5.3.2 Technical pitfalls of artificial ascites procedure**

The infusion should not be vigorously performed until enough thickness (about 2 to 5 mm) of the layer could be detected because such infusion often causes the sheath dislocation from the first placed site and produces an unintended inflow to the abdominal wall. The physicians often notice such inflow with the swelling of the puncture site or an ultrasonographic thickening of the abdominal wall. In this case, the physicians should also remove the sheath as soon as possible and retry the puncture, but it often becomes more difficult to insert from the same site because the abdominal wall becomes thicker than the distance that the puncture needle can reach. Therefore, the physicians should try to find another appropriate site for a puncture or try it again another day.

### **5.3.3 Out of the indication of artificial ascites**

If the patients have histories of abdominal operation or peritonitis, the adhesions between the liver and the abdominal wall might be hazardous to have successful artificial ascites. In

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those cases, the other locoregional treatments like transcatheter arterial chemoembolization, percutaneous ethanol injection therapy, or computed tomography guided radiofrequency ablation could be suitable procedures to treat the patients.

### **6. Conclusion**

The patients who have undergone radiofrequency ablation for hepatic tumors adjacent to the diaphragm should be carefully followed up for possible diaphragmatic hernia, even after the long postoperative intervals. The artificial ascites technique can be used not only to visualize the whole HCC under the diaphragm, but also to reduce the unavoidable and unintended thermal complications of the diaphragm and the surrounding organs if successfully performed.

### **7. References**

those cases, the other locoregional treatments like transcatheter arterial chemoembolization, percutaneous ethanol injection therapy, or computed tomography guided radiofrequency

The patients who have undergone radiofrequency ablation for hepatic tumors adjacent to the diaphragm should be carefully followed up for possible diaphragmatic hernia, even after the long postoperative intervals. The artificial ascites technique can be used not only to visualize the whole HCC under the diaphragm, but also to reduce the unavoidable and unintended thermal complications of the diaphragm and the surrounding organs if

Bruix J, Sala M, Llovet JM. (2004). Chemoembolization for hepatocellular carcinoma.

Choi D, Lim HK, Rhim H, Kim YS, Lee WJ, Palk SW, Koh KC, Lee JH, Choi MS, Yoo BC.

Curley SA, Marra P, Beaty K, Ellis LM, Vauthey JN, Abdalla EK, Scalfe C, Raut C, Wolff R,

Head HW, Dodd III GD, Dalrymple NC, Prasad SR, El-Merhi FM, Freckleton MW, Hubbard

Kang TW, Rhim H, Kim EY, Kim Ys, Choi D, Lee Wj, Lim HK (2009). Percutaneous

Katayama K, Ohka Y, Uemura A, Shinzaki S, Egawa S, Naito M, Ishibashi K, Kamoi R.

Koda M, Ueki M, Maeda N, Murawaki Y. (2003). Diaphragmatic perforation and hernia after

Kondo Y, Yoshida H, Shiina S, Tateishi R, Teratani T, Omata M. (2006). Artificial ascites

Am J Roentgenol 179. 1, (Jul 2002), 102-104. 0361-803X.

gastrointestinal tract. Br J Surg 93. 10, 1277-1292, 0007-1323.

(2007). Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series. Eur Radiol 17. 3, (Mar 2007), 684-692, 0938-7994. Curley SA, Izzo F, Ellis LM, Nicolas Vaughey J, Vallone P. (2000). Radiofrequency ablation

of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 232. 3, (Sep 2000),

Choi H, Loyer E, Vallone P, Flore F, Scordino F, De Rosa V, Orlando R, Pignata S, Daniele B, Izzo F. (2004). Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients. Ann Surg 239. 4, (Apr 2004), 450-458,

LG. (2007). Percutaneous radiofrequency ablation of hepatic tumors against the diaphragm: frequency of diaphragmatic injury. Radioilogy 243. 3, (Jun 2007), 877-

radiofrequency ablation for the hepatocellular carcinoma abutting the diaphragm: assessment of safety and therapeutic efficacy. Korean J Radiol 10. 1, (Jan-Feb 2009),

(2002). Saline injection into the pleural cavity to detect tumors of the hepatic dome with sonography; A new approach for treatment of hepatocellular carcinoma. AJR

hepatic radiofrequency ablation. AJR Am J Roentgenol 180. 6, (Jun 2003), 1561-1562.

technique for percutaneous radiofrequency ablation of liver cancer adjacent to the

Gastroenterology 127. 5, (Nov 2004), S179-188, 0016-5085.

ablation could be suitable procedures to treat the patients.

**6. Conclusion**

successfully performed.

381-391, 0003-4932.

0003-4932.

884, 0033-8419.

34-42, 1229-6929.

0361-803X.

**7. References**

**14**

*Japan*

**Transcatheter Arterial Chemo-Embolization**

**with a Fine-Powder Formulation of Cisplatin for Unresectable Hepatocellular Carcinoma**

*Division of Gastroenterology and Hepatology, Department of Internal Medicine*

Hepatocellular carcinoma (HCC) is the cancer with the sixth highest incidence in the world.1 The incidence of this cancer has increased significantly in the United States, Japan and several European countries over the last two or three decades. HCC as a cause of death is also increasing throughout the world.2-5 Development of new treatments for HCC has helped to improve patient prognosis.6, 7 Transcatheter arterial chemoembolization (TACE) is one such treatment, and has been applied to patients with multiple or unresectable HCC.8, 9 However, HCC has been reported to progress within the short period of multiple sessions of TACE into a complicated condition, even though the treatment is temporarily effective. In recent years, TACE using an emulsion of doxorubicin (ADM) with lipiodol (LPD) (ADM-LPD emulsion) followed by embolization with gelatin sponge has commonly been employed for HCC treatment.10, 11 However, the tumors have been demonstrated to show a high frequency of recurrence after TACE.9, 12, 13 Cisplatin (CDDP), a platinum compound, is an effective anticancer agent used in the treatment of various malignancies.14 Researchers have recently reported that TACE using a suspension of CDDP in LPD may be more effective against unresectable HCC than that using ADM-LPD emulsion.15, 16 Moreover, a fine-powder formulation of CDDP (DDPH, IA-call; Nipponkayaku, Tokyo, Japan) has also

been available since 2004 as a therapeutic agent for intra-arterial infusion in Japan.

In this article, we report the results of a retrospective comparative review of TACE using a suspension of DDPH in LPD (DDPH-LPD suspension) and an emulsion of ADM in LPD, in terms of the response rate (RR), progression-free survival (PFS) and overall survival (OS). Moreover, we analyzed prognostic factors in patients undergoing TACE using DDPH-LPD

We reviewed 468 consecutive HCC patients who had undergone TACE using DDPH or ADM between April 2004 and September 2008 at the Hospital of Iwate Medical

**1. Introduction**

suspension or ADM-LPD emulsion.

**2. Methods 2.1 Patients**

Kazuhiro Kasai and Kazuyuki Suzuki

*Iwate Medical University*

Wood TF, Rose DM, Chung M, Allegra DP, Foshag LJ, Bilchik AJ. (2000). Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol 7. 8, (Sep 2000), 593-600, 1068-9265.

### **Transcatheter Arterial Chemo-Embolization with a Fine-Powder Formulation of Cisplatin for Unresectable Hepatocellular Carcinoma**

Kazuhiro Kasai and Kazuyuki Suzuki

*Division of Gastroenterology and Hepatology, Department of Internal Medicine Iwate Medical University Japan*

### **1. Introduction**

248 Hepatocellular Carcinoma – Clinical Research

Wood TF, Rose DM, Chung M, Allegra DP, Foshag LJ, Bilchik AJ. (2000). Radiofrequency

complications. Ann Surg Oncol 7. 8, (Sep 2000), 593-600, 1068-9265.

ablation of 231 unresectable hepatic tumors: indications, limitations, and

Hepatocellular carcinoma (HCC) is the cancer with the sixth highest incidence in the world.1 The incidence of this cancer has increased significantly in the United States, Japan and several European countries over the last two or three decades. HCC as a cause of death is also increasing throughout the world.2-5 Development of new treatments for HCC has helped to improve patient prognosis.6, 7 Transcatheter arterial chemoembolization (TACE) is one such treatment, and has been applied to patients with multiple or unresectable HCC.8, 9 However, HCC has been reported to progress within the short period of multiple sessions of TACE into a complicated condition, even though the treatment is temporarily effective. In recent years, TACE using an emulsion of doxorubicin (ADM) with lipiodol (LPD) (ADM-LPD emulsion) followed by embolization with gelatin sponge has commonly been employed for HCC treatment.10, 11 However, the tumors have been demonstrated to show a high frequency of recurrence after TACE.9, 12, 13 Cisplatin (CDDP), a platinum compound, is an effective anticancer agent used in the treatment of various malignancies.14 Researchers have recently reported that TACE using a suspension of CDDP in LPD may be more effective against unresectable HCC than that using ADM-LPD emulsion.15, 16 Moreover, a fine-powder formulation of CDDP (DDPH, IA-call; Nipponkayaku, Tokyo, Japan) has also been available since 2004 as a therapeutic agent for intra-arterial infusion in Japan.

In this article, we report the results of a retrospective comparative review of TACE using a suspension of DDPH in LPD (DDPH-LPD suspension) and an emulsion of ADM in LPD, in terms of the response rate (RR), progression-free survival (PFS) and overall survival (OS). Moreover, we analyzed prognostic factors in patients undergoing TACE using DDPH-LPD suspension or ADM-LPD emulsion.

### **2. Methods**

### **2.1 Patients**

We reviewed 468 consecutive HCC patients who had undergone TACE using DDPH or ADM between April 2004 and September 2008 at the Hospital of Iwate Medical

Transcatheter Arterial Chemo-Embolization with a Fine-Powder

(Gelpart; Nipponkayaku, Tokyo, Japan) were used for all patients.

disease not qualifying for classification as CR, PR, or PD.

for Adverse Events, version 3.0 (CTCAE v3.0).

**2.6 Evaluation of therapeutic effects**

with 3-10 mL of LPD.

**2.4 Treatment regimen**

of LPD not allowed to exceed 10 mL.

patient could no longer be treated.

**2.5 Post-treatment assessment**

Formulation of Cisplatin for Unresectable Hepatocellular Carcinoma 251

The ADM/LPD emulsion was prepared by the following procedure: 10-30 mg of ADM was dissolved in 1-2 mL of a contrast medium (Iomeron; Eisai, Tokyo, Japan) and then mixed

The dosages of LPD and the anticancer drugs were adjusted depending on tumor size, number of tumors, degree of liver impairment and renal function, with the maximum dose

The patient enrolment period for the DDHP and ADM groups extended from May 2006 to September 2008 and April 2004 to September 2008, respectively. All patients provided fully informed consent prior to TACE. In terms of embolization agents, gelatin sponge particles

After TACE, additional RFA or OPE therapy was provided to patients who met the following inclusion criteria: the presence of up to three tumors with none exceeding 30 mm in diameter or a solitary tumor less than 50 mm in diameter. Regardless of the additional therapy requirement, all patients were followed up with US, CT and/or MRI after 1 month, then every 3 months thereafter. TACE was undertaken again when relapse of treated lesions and/or new hepatic lesions were detected. These patients received additional TACE using the same agent during the follow-up period. TACE or TACE with additional therapy (RFA or OPE) was repeated until complete regression of the tumor was obtained, or until the

Tumor response was assessed by US, CT and/or MRI, conducted 1 month from the start of treatment and every 3 months thereafter. We regarded LPD accumulation in the tumor as representing a necrotic area, based on previous reports of such LPD retention areas corresponding to the necrotic areas on CT.20-23 By measurement of the two largest perpendicular diameters of the tumor, we classified tumor response into four categories using the following criteria: complete response (CR), complete disappearance or 100% necrosis of all tumors; partial response (PR), reduction and/or necrosis, with a decrease of at least 50% in all measurable lesions; progressive disease (PD), an increase in tumor size exceeding 25% of all measurable lesions or appearance of a new lesion; stable disease (SD),

Toxicity was evaluated using the National Cancer Institute–Common Terminology Criteria

We analyzed outcomes in the DDPH and ADM groups in terms of RR, PFS and OS in September 2008. In addition, we also evaluated all patients for survival using uni- and multivariate analyses. Duration of response was calculated from the date of the start of treatment to the date of documented progression. Survival time was calculated from the

date of the start of treatment to the date of death or last day of follow-up.

University. HCC was diagnosed based on distinctive findings on ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) and angiography, and serum levels of des-γ-carboxy prothrombin (DCP) and α-fetoprotein (AFP). Histological examination was not always applied. Liver function was evaluated according to the Child-Pugh classification.17 Tumor stage was judged by the TNM classification established by the International Union Against Cancer.18 The extent of portal vein invasion was classified as follows: Vp0, no invasion of the portal vein; Vp1, invasion of the third or more distal branch of the left or right portal vein; Vp2, invasion of the second branch of the portal vein; Vp3, invasion of the first branch of the portal vein; and Vp4, invasion of the trunk of the portal vein.

We excluded 18 patients with serum bilirubin levels over 3.0 mg/dL, 12 patients with extrahepatic metastasis, and 30 patients with uncontrolled ascites. In addition, we excluded 77 patients who had undergone repeated sessions of TACE using different regimens, and 44 patients who showed disease progression and received hepatic arterial infusion chemotherapy (HAIC) and/or systemic chemotherapy as additional therapy.

A final total of 287 HCC patients were enrolled in this study. All of the enrolled patients met the eligibility criteria for inclusion in the analysis described in the next paragraph. Patients were divided into two groups: one group consisting of 120 patients who had undergone TACE using DDPH-LPD suspension (DDPH group); and another group consisting of 167 patients who had undergone TACE using an emulsion of LPD with ADM (ADM group). Of the 120 patients in the DDPH group, 44 had also received various additional therapies such as radiofrequency ablation (RFA) or surgical operation (OPE) after TACE, and 76 patients had undergone TACE alone during the study period. Similarly, 79 patients of the ADM group had received various additional therapies such as RFA or OPE after TACE, and 88 patients had undergone TACE alone without any other therapies during the study period.

Informed consent was obtained from all patients. The study protocol was approved by the Ethics Committee of Iwate Medical University and the study was conducted in accordance with the Declaration of Helsinki 1975.

### **2.2 Eligibility criteria**

Eligibility criteria for patients in this study were as follows: 1) no evidence of extrahepatic metastasis; 2) no evidence of active heart or renal diseases meeting the contraindications for ADM and CDDP therapy, respectively; 3) Eastern Cooperative Oncology Group (ECOG) performance status (PS)19 level 0-2; 4) no uncontrolled ascites or pleural effusion; and 5) total serum bilirubin (T-Bil) less than 3 mg/dL. The presence of underlying liver disease such as hepatitis or cirrhosis was confirmed by laboratory, radiological examinations and pathological examinations. We classified chronic hepatitis patients into Child-Pugh class A, because chronic hepatitis is a known pre-cirrhotic condition.

### **2.3 Preparation of the agents for TACE**

We used DDPH or ADM (Adriacin; Kyowa Hakko Kogyo, Tokyo, Japan) mixed with LPD (iodized oil; Andre Guerget, Aulnay-sous-Bois, France).

The DDPH/LPD suspension was prepared by mixing 50 mg of DDPH into 3-10 mL of LPD.

The ADM/LPD emulsion was prepared by the following procedure: 10-30 mg of ADM was dissolved in 1-2 mL of a contrast medium (Iomeron; Eisai, Tokyo, Japan) and then mixed with 3-10 mL of LPD.

The dosages of LPD and the anticancer drugs were adjusted depending on tumor size, number of tumors, degree of liver impairment and renal function, with the maximum dose of LPD not allowed to exceed 10 mL.