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 the contrast of the hepatic artery with iodolipol, which makes it possible to detect 96% of tumors. However, this method complicates the diagnosis and is not always necessary.

The only radical treatment for hepatocellular carcinoma is surgical, which consists of resection or liver transplantation.

Liver resection

After liver resection, the synthesis of DNA in liver cells is enhanced, the remaining hepatocytes increase in size (hypertrophy ), mitoses (hyperplasia) increase . A person can survive after removing 90% of unchanged liver.

Operability in hepatocellular carcinoma is low and ranges from 3 to 30%. The success of resection depends on the size of the tumor (diameter no more than 5 cm), its localization, especially in relation to large vessels, the presence of germination in the vessels, the presence of a capsule, other tumor nodes and their number. With multiple tumor nodes, there is a high incidence of relapse and a low survival rate.

Cirrhosis is not an absolute contraindication for carrying out a liver resection, but it causes a higher operational mortality and a higher incidence of postoperative complications [45]. Operational mortality in the presence of cirrhosis reaches 23% (in the absence of cirrhosis it is less than 3%). Operation is contraindicated in patients of group C on Child and with jaundice. When considering the 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, as well as isotope scintigraphy of the bones are performed.

The study of the segmental structure of the liver improved the results of her resection. The ultrasound control during the operation also helped to increase its effectiveness. The left share is relatively easy to resect. Resecting the right lobe is more difficult. For small tumors, segmentectomy can be limited, larger tumors require the removal of three segments or a whole lobe. In these cases, it is important that the liver function is adequate. Postoperative prognosis is better if the resection is performed within a 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 in hepatocellular carcinoma

A country	Author	Number of patients	Operational or hospital mortality,%	Annual survival rate,%	Resectivity of tumor,%
Africa Great Britain	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	6th	84.0	9

* Americans of Chinese origin.

Factors determining the success of liver resection in hepatocellular carcinoma

• Size less than 5 cm
• The defeat of one share
• Presence of a capsule
• Absence of germination in blood vessels
• The 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, life expectancy in hepatocellular carcinoma increased from 12.4 months in the control group of untreated patients to 27.1 months after liver resection; in cases where the tumor size did not exceed 5 cm, the life expectancy was even greater. The results of recent studies indicate that the survival rate for 1 year after liver resection is 55-80%, and the 5-year survival rate is 25-39%.

Liver transplantation

The results of liver transplantation are usually unsatisfactory. If the patient survives after the operation, relapses and metastases are often observed, which is facilitated by immunosuppressive therapy, carried out for the purpose of prevention of graft rejection. Transplantation is performed in cases when resection is not possible: with severe cirrhosis, multiple and large tumor nodes with lesions of both lobes and centrally located tumors. It is not surprising that the condition of patients after liver transplantation is worse than after resection; after resection, liver transplant should not be performed. Transplantation is effective for single small (no more than 5 cm 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. With cirrhosis, the prognosis is poor.

The best results can be achieved in patients in whom hepatocellular carcinoma was detected during a preventive examination or after transplantation performed on other indications. Since 1963, liver transplantation for hepatocellular carcinoma has been performed in more than 300 patients. The annual and 5-year survival rates were respectively 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 with a diameter less than 5 cm, the life expectancy is 55 ± 8 months, while for larger tumors, 24 ± 6 months.

Systemic chemotherapy

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

Arterial embolization

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

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

The procedure of embolization is performed under local or general anesthesia and under the "cover" of antibiotic therapy. The portal vein must be passable. The branch of the hepatic artery feeding the tumor is embolized with gelatin foam. Sometimes additional drugs, for example doxorubicin, mitomycin or cisplatin are added. The tumor is subjected to complete or partial necrosis. Embolization with gelatin cubes in combination with the introduction of a steel helix improves the survival rates somewhat, but for the final evaluation of the method, prospective controlled trials are necessary.

Side effects of embolization of the hepatic artery include pain (can be intense), fever, nausea, encephalopathy, ascites and a significant increase in serum transaminase activity. Other complications include the formation of an abscess and the embolization of arteries that feed healthy tissue.

Introduction of microcapsules of mitomycin C into the arteries of the tumor allows to achieve positive results in 43% of cases.

Glass microspheres with yttrium-90 can be used as a strong internal source of tumor irradiation if there is no extrahepatic venous blood shunting.

Hepatocellular carcinoma is insensitive to radiation therapy.

The results of embolization are ambiguous. In some patients, it does not have a significant effect, others allow prolonging life. The prognosis depends on the form of the tumor, its size, germination in the portal vein, the presence of ascites and jaundice. Tumors that do not have a capsule are resistant to embolization. This method of treatment is most effective in carcinoid liver tumors, in which it is possible to achieve significant clinical improvement and reduce their size.

Iodized oil

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

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

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

Percutaneous Injection of Ethyl Alcohol

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

Ethanol can be administered before the forthcoming liver resection, and with tumor recurrence, the administration can be repeated. Alcoholization is used in the presence of multiple tumor sites, as well as to stop bleeding when the tumor is ruptured.

Percutaneous injections of ethanol in hepatocellular carcinoma

• Tumors with a diameter of not more than 5 cm
• No more than three tumor centers
• Local anesthesia
• Visual monitoring by ultrasound or CT
• Introduction 2-12 ml of undiluted ethanol

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

The use of labeled antibodies

A radioisotope associated with monoclonal antibodies to antigens on the surface of a tumor cell is injected intravenously or into the hepatic artery. Conjugating with such antibodies, antitumor agents, for example ¹³¹ I-ferritin, can be selectively delivered to tumor tissue. At present, there is no convincing evidence of the effectiveness of this method of treatment.

Immunotherapy

Tumor growth may be due to the inability of the host organism to provide an immune response sufficient to lyse a significant number of tumor cells. Stimulation of the immune response by 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.

The use of hormonal drugs

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

[1], [2], [3], [4], [5], [6]