Local Ablative Therapy for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with an annual occurrence of at least one million new cases. Even this figure represents an underestimate, since cancer statistics are far from complete in many countries with a high incidence of HCC [1]. Common etiological factors for HCC include hepatitis B virus, hepatitis C virus, chronic alcoholism, and aflatoxin.

The generally accepted “curative” treatment for HCC is liver resection. A close correlation between HCC and liver cirrhosis has long been recognized. In the presence of cirrhosis, hepatic resection raises special problems due to the high risks of hemorrhage, limited liver reserve, lack of regenerative properties of the cirrhotic parenchyma, and predisposition of the patients to sepsis due to multiple immunological defects. The perioperative mortality ranges from 0.5 % to 21.5 % [2] [3] , with a median of around 5 - 10 % for cirrhotic liver resection.

As an alternative to liver resection, local ablative therapy has been used to treat small HCCs confined to the liver. For technical reasons, it cannot be used in patients with too many tumors. This form of treatment is particularly suitable for patients who are not candidates for liver resection due to poor liver function, and in those with recurrent HCC after liver resection when further surgery cannot be performed. Local ablation is contraindicated in patients with gross ascites, marked coagulopathy, and obstructive jaundice, as there is a risk of postprocedural intra-abdominal bleeding and bile peritonitis. Increased risks of bleeding and tumor seeding have to be considered when HCCs are situated on the surface of the liver or protruding out of it, although these risks are minimal [4].

Percutaneous ethanol injection (PEI) was first reported by Sugiura et al. in 1983 [5]. Since then, it has become the most commonly used form of local ablative therapy, and many studies of it have been published. PEI is a form of intralesional treatment carried out under ultrasound guidance using ethanol to destroy the tumor. The treatment is usually repeated twice a week for four to six sessions. Follow-up serum alpha-fetoprotein testing, ultrasound, and computed tomography are usually used to monitor the therapeutic response. Additional PEI treatment is given in patients with incomplete tumor necrosis. Ethanol induces cellular dehydration, coagulative necrosis, and vascular thrombosis, causing tumor cells to die. The side effects of PEI are mainly pain, fever, and a transient rise in liver enzymes. Other systemic side effects are minimal. Nonrandomized studies have shown that PEI is associated with three-year survival rates of 55 - 77 % [4] [6] [7] [8] . However, there is a high rate of post-treatment recurrence within the liver - in the range of 50 % within two years [6] [8] . Two randomized and controlled trials have shown that PEI does not have any impact on patient survival. In one trial, PEI was evaluated against no treatment [9], while the other trial evaluated PEI plus transarterial chemoembolization against transarterial chemoembolization alone [10]. However, these two studies were conducted in patients with large HCCs, which are usually regarded as unsuitable for PEI treatment. A meta-analysis combining the two studies showed that the survival effect one year after PEI was not significant using the Der Simonian and Laird method (mean 38 % difference, 95 % CI - 30 to 100 %, not significant), but was significant using the Peto et al. method (10.7 means odds ratio, 95 % CI 2 to 58 %, P < 0.01) [11]. Thus, although nonrandomized studies showed good results, the number of randomized studies is insufficient for firm conclusions to be drawn regarding PEI treatment for HCC.

Ultrasound-guided percutaneous acetic acid treatment was reported by Ohnishi et al. in 1994, with good results [12]. There is a theoretical advantage of acetic acid over ethanol treatment, in that acetic acid diffuses into the tumor better. In a subsequent randomized controlled study carried out by the same group of researchers, percutaneous acetic acid injection was shown to be better than PEI [13].

Other forms of local ablative therapy for HCC that have been less well studied include intratumoral injection of glass microspheres containing yttrium-90 [14], percutaneous laser [15] [16] , percutaneous radiofrequency electrocautery [17] [18] , intralesional hyperthermic saline [19] [20] , and intralesional distilled water [21]. All of these procedures have the advantages that the treatment approach is less invasive than in open surgery and that more nontumorous liver tissue can be preserved. The latter aspect is particularly important in patients with cirrhotic livers with marginal liver function. However, the encouraging initial results with these treatment options should be regarded as preliminary, and further evaluation of the procedures needs to be carried out in order to determine their true value in the treatment of HCC. In addition, concerns have been expressed about the possible side effects of these procedures, especially on the potential radiation hazard associated with percutaneous injection of glass microspheres containing yttrium-90 [22].

Microwave tissue coagulation is one of the many forms of local ablative therapy that can be used to treat small HCCs. It has become popular in Japan in recent years, and is worth more detailed scrutiny. Microwave tissue coagulation was first reported by Tabuse et al. in 1985 to cut down on the blood loss during hepatic parenchymal transection in liver resection in open surgery [23]. The microwave coagulator generates and transmits microwave energy for medical use to a monopolar-type needle electrode, which is inserted into the liver at a point along the line of the anticipated liver transection. As a result of the absorption of microwaves, thermal energy is produced, and tissue coagulation occurs around the electrode. The coagulation reaches a depth corresponding to the length of the electrode; electrodes of various lengths are available. The coagulated liver tissue appears as yellowish-whitish zones on the liver surface around the electrode. At the end of the coagulation, smooth withdrawal of the electrode is ensured by activating the dissociation apparatus, which induces hydrolysis and tissue dissociation. The process of coagulation-dissociation is repeated until the whole liver transection plane is coagulated. The liver can then be transected by blunt dissection using a pair of artery forceps, with minimal blood loss [24]. A natural development in microwave tissue coagulation is to use the method to destroy unresectable HCCs during laparotomy [25] [26] - much in the same way as in cryosurgery, but using the other end of the temperature scale to kill the tumor cells. Following promising results with laparotomy and microwave coagulation for unresectable HCC, it is logical to use microwave coagulation therapy to treat small HCCs using a minimally invasive approach. This is possible in one of three forms:

Laparoscopic microwave coagulation therapy 27 28 29 30 . Percutaneous microwave coagulation therapy 31 32 . Thoracoscopic microwave coagulation therapy 33 34 .

Laparoscopic microwave coagulation therapy can be carried out under direct laparoscopic vision, or under ultrasound guidance. Although it appears to be more invasive than percutaneous microwave coagulation therapy, lesions that cannot be treated via the percutaneous route (e.g., on the inferior surface of liver near abdominal organs such as the stomach or intestine) or those in which percutaneous treatment is technically difficult (e.g., near the diaphragm) can be dealt with laparoscopically. The two articles published in this issue of Endoscopy by Abe et al. and Seki et al. provide further evidence that laparoscopic microwave coagulation therapy can provide good results in the treatment of small HCCs. Thoracoscopic microwave coagulation therapy is mainly used for HCCs that lie just adjacent to the diaphragm.

Although it has been claimed that microwave coagulation therapy can provide results comparable to those with liver resection [35], the effects of the treatment must still be regarded as preliminary. Microwave coagulation therapy has its limitations, and the results when larger lesions are treated using this method are poorer than those with liver resection. As reported by Abe et al. in this issue of Endoscopy, significant complications such as hepatic infarction and pneumothorax can occur, and local recurrence of HCC within the liver still remains a concern. Local ablative therapy using microwave coagulation therapy requires further evaluation in a randomized prospective trial, in order to determine its true place in the management of small HCCs.

References

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