Hepatocellular carcinoma - Treatment

It is necessary to determine the exact location of the tumor, especially when planning surgical intervention. The method of choice is CT, as well as its combination with angiography. CT can be combined with contrasting of the hepatic artery with iodolipol, which allows detecting 96% of tumors. However, this method complicates diagnostics and is not always necessary.

The only radical method of treating hepatocellular carcinoma is surgery, which involves liver resection or transplantation.

Liver resection

After liver resection, DNA synthesis in liver cells increases, the remaining hepatocytes increase in size (hypertrophy ), and mitoses become more frequent (hyperplasia). A person can survive after removal of 90% of the intact liver.

The operability of hepatocellular carcinoma is low and ranges from 3 to 30%. The success of resection depends on the size of the tumor (no more than 5 cm in diameter), its location, especially in relation to large vessels, the presence of vascular invasion, the presence of a capsule, other tumor nodes and their number. With multiple tumor nodes, a high recurrence rate and low survival are observed.

Cirrhosis is not an absolute contraindication for liver resection, but it causes higher operative mortality and a higher incidence of postoperative complications [45]. Surgical mortality in the presence of cirrhosis reaches 23% (in the absence of cirrhosis it is less than 3%). The operation is contraindicated for patients with Child's group C and in jaundice. When considering indications for liver resection, the age and general condition of the patients are also taken into account.

To search for distant metastases, chest X-ray, CT or MRI of the head, and isotope bone scintigraphy are performed.

Study of the segmental structure of the liver has improved the results of its resection. Ultrasound control during the operation also contributed to its increased effectiveness. The left lobe is relatively easy to resect. Resection of the right lobe is more difficult. In case of small tumors, segmentectomy may be sufficient, while larger tumors require removal of three segments or an entire lobe. In these cases, it is important that the liver function is adequate. The postoperative prognosis is better if the resection is performed within healthy liver tissue, there are no tumor thrombi in the hepatic or portal vein, and there are no visible intrahepatic metastases.

Results of liver resection for hepatocellular carcinoma

Country	Author	Number of patients	Surgical or hospital mortality, %	One-year survival rate, %	Tumor resectability, %
Africa UK	Kew Dunk	46	-	-	5.0-6.5
France	Bismuth	270	15.0	66.0	12.9
USA*	Lim	86	36.0	22.7	22.0
Hong Kong	Lee	935	20.0	45.0	17.6
Japan	Okuda	2411	27.5	33.5	11.9
China	Li	9	11.4	58.6	9
Taiwan	Lees	9	6	84.0	9

* Chinese Americans.

Factors Determining the Success of Liver Resection for Hepatocellular Carcinoma

• Size less than 5 cm
• Defeat of one lobe
• Presence of a capsule
• No vascular invasion
• Initial stages of cirrhosis
• Relatively young age and good general condition of patients.

The probability of recurrence of hepatocellular carcinoma in the remaining liver tissue within 2 years is 57%. In Spain, survival in hepatocellular carcinoma increased from 12.4 months in the untreated control group to 27.1 months after liver resection; in cases where the tumor size did not exceed 5 cm, survival was even longer. Results of recent studies indicate that 1-year survival after liver resection is 55-80%, and 5-year survival is 25-39%.

Liver transplantation

The results of liver transplantation are usually unsatisfactory. If the patient survives the operation, relapses and metastases are often observed, which are facilitated by immunosuppressive therapy administered to prevent graft rejection. Transplantation is performed in cases where resection is impossible: in severe cirrhosis, multiple and large tumor nodes with damage to both lobes of the liver and centrally located tumors. It is not surprising that the condition of patients after liver transplantation is worse than after its resection; liver transplantation should not be performed after resection. Transplantation is effective for single small (no more than 5 cm in diameter) unresectable tumors and the presence of no more than three tumor nodes (no more than 3 cm in diameter). The overall 4-year survival rate is 75%, and the survival rate of patients without relapses is 83%. The results of transplantation are significantly worse in HBsAg-positive patients. In liver cirrhosis, the prognosis is poor.

The best results are achieved in patients in whom hepatocellular carcinoma was detected during a preventive examination or after transplantation performed for other indications. Since 1963, liver transplantation for hepatocellular carcinoma has been performed in more than 300 patients. The 1-year and 5-year survival rates were 42-71% and 20-45%, respectively. The relapse rate is quite high and reaches 65%. It depends on the size of the tumor. For tumors less than 5 cm in diameter, life expectancy is 55±8 months, while for larger tumors it is 24±6 months.

Systemic chemotherapy

The drug of choice is mitoxantrone, which is administered intravenously every 3 weeks. However, positive results are observed in only 27.3% of patients.

Arterial embolization

Catheterization of the hepatic artery through the femoral artery and celiac trunk allows embolization of the vessels feeding the tumor, and the introduction of chemotherapeutic drugs through the catheter creates their high concentrations in the tumor. However, the embolization method is not effective enough due to the development of arterial collaterals.

Embolization is used for unresectable tumors, tumor recurrences, and in some cases as a preliminary stage before performing resection. This method can be used as an emergency measure for intra-abdominal bleeding caused by tumor rupture.

The embolization procedure is performed under local or general anesthesia and under the "cover" of antibacterial therapy. The portal vein must be patent. The branch of the hepatic artery feeding the tumor is embolized with gelatin foam. Sometimes additional drugs are administered, such as doxorubicin, mitomycin or cisplatin. The tumor undergoes complete or partial necrosis. Embolization with gelatin cubes in combination with the introduction of a steel coil slightly improves survival rates, but prospective controlled studies are needed for a final assessment of the method.

Side effects of hepatic artery embolization include pain (which may be severe), fever, nausea, encephalopathy, ascites, and significant increases in serum transaminase levels. Other complications include abscess formation and embolization of arteries supplying healthy tissue.

The introduction of mitomycin C microcapsules into tumor arteries allows achieving positive results in 43% of cases.

Yttrium-90 glass microspheres can be used as a strong internal source of tumor irradiation if extrahepatic venous shunting of blood does not occur.

Hepatocellular carcinoma is insensitive to radiation therapy.

The results of embolization are ambiguous. In some patients it does not produce a significant effect, while in others it prolongs life. The prognosis depends on the tumor shape, its size, invasion into the portal vein, the presence of ascites and jaundice. Tumors that do not have a capsule are resistant to embolization. This treatment method is most effective for carcinoid liver tumors, where it is possible to achieve significant clinical improvement and a decrease in their size.

Iodized oil

Iodolipol, which is iodized poppy seed oil, remains in the tumor for 7 days or more after its introduction into the hepatic artery, but does not linger in healthy tissue. Iodolipol is used to diagnose very small tumors. The degree of tumor contrast and its duration is an important prognostic factor. Iodolipol is used for selective delivery of lipophilic cytostatics to the tumor - epirubicin, cisplatin or ¹³¹ I-iodolipol. These drugs increase the life expectancy of patients, while there is no significant difference in effectiveness between them. The drugs can be re-administered after 3-6 months. Such therapy is effective for small tumors.

Arterial embolization with iodolipol in combination with a chemotherapy drug can serve as adjuvant therapy after liver resection. Despite the improvement in the condition of patients, the method does not reduce the frequency of relapses and prolong the life of patients.

Unfortunately, viable tumor cells often remain within the tumor and in the surrounding tissue, so a complete cure is impossible.

Percutaneous injection of ethyl alcohol

Small tumor nodes (no more than 5 cm in diameter), if there are no more than three of them, can be treated by percutaneous administration of undiluted alcohol under visual control with ultrasound or CT. Such treatment can be performed on an outpatient basis. The drug is administered 2 times a week, 2-12 ml each. The course of treatment includes 3 to 15 procedures. For large tumors, a single administration of 57 ml of alcohol under general anesthesia is possible. However, such treatment is not recommended for advanced liver cirrhosis. Alcohol causes thrombosis of the arteries that feed the tumor, its ischemia, and coagulation necrosis of the tumor tissue. The method is used only for encapsulated tumors. In rare cases, complete tumor necrosis is observed. The effectiveness of the treatment is monitored using MRI.

Ethanol can be administered before the upcoming liver resection, and in case of tumor recurrence, the administration can be repeated. Alcoholization is used in the presence of multiple tumor foci, as well as to stop bleeding in case of tumor rupture.

Percutaneous ethanol injections in hepatocellular carcinoma

• Tumors with a diameter of no more than 5 cm
• No more than three tumor foci
• Local anesthesia
• Visual control using ultrasound or CT
• Introduction of 2-12 ml of undiluted ethanol

Side effects are similar to those observed after embolization. Three-year survival in patients with liver cirrhosis of Child's group A is 71%, in patients of group B - 41%.

Use of labeled antibodies

A radioisotope linked to monoclonal antibodies to antigens on the surface of a tumor cell is administered intravenously or into the hepatic artery. By conjugating these antibodies, antitumor agents, such as ¹³¹ I-ferritin, can be selectively delivered to tumor tissue. There is currently no convincing evidence for the effectiveness of this treatment.

Immunotherapy

Tumor growth may be due to the inability of the host to mount an immune response sufficient to lyse a significant number of tumor cells. Stimulation of the immune response with autologous lymphokine-activated killer cells in combination with interleukin-2 causes tumor lysis. The treatment is well tolerated, but its effectiveness has not yet been proven.

Use of hormonal drugs

Experimental studies have shown that male and female sex hormones affect chemically induced carcinomas. Patients with hepatocellular carcinoma have estrogen and androgen receptors on the surface of tumor cells. There is a report that tamoxifen (10 mg twice daily) significantly increases the survival of patients with hepatocellular carcinoma, but further studies have not confirmed this.

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