Early treatment is the most important factor to improve the prognosis of primary hepatocellular hepatocellular carcinoma. Early stage hepatocellular carcinoma should be surgically resected as much as possible. For unresectable large hepatocellular carcinoma, multi-modality comprehensive treatment can also be used.
For primary liver cancer, radical resection is the most effective treatment; for unresectable liver cancer, surgical or non-surgical combination therapy can be used to shrink the tumor and then perform reduced-stage or 2-stage resection, or to achieve the purpose of slowing down tumor development and prolonging survival; certain types of small liver cancer can be cured by various non-surgical local treatments; for advanced stage patients who cannot tolerate various treatments, liver preservation, improvement of systemic condition and symptomatic treatment should be used. If advanced stage patients cannot tolerate various treatments, they should mainly focus on liver protection, improvement of general condition and symptomatic treatment to reduce pain and improve life quality. For the comprehensive measures such as surgery, chemotherapy, radiotherapy, Chinese medicine, immunotherapy, other supportive therapies and symptomatic treatment, they should be chosen reasonably according to the overall condition in order to achieve the purpose of improving the curative effect.
Chemotherapy of liver cancer
1. Systemic chemotherapy.
Systemic chemotherapy is the most basic method of hepatocellular carcinoma drug treatment and is widely used. It can be administered by oral, intravenous, intraperitoneal, abdominal artery or hepatic artery infusion and enema.
In order to reduce the toxic side effects of systemic chemotherapy and improve the therapeutic effect of hepatocellular carcinoma, many clinical studies have been conducted on the application of drugs and found that combined chemotherapy is more effective and has less side effects than single chemotherapy. Currently, the commonly used chemotherapeutic drugs for liver cancer include fluorouracil (5-Fu) and its derivatives, doxorubicin (Adriamycin), cisplatin (DDP), mitomycin (MMC), etc.
Fluorouracil (5-Fu) is the most commonly used drug for treating digestive system tumors. It is converted into 5-fluorouracil deoxyriboside in the body, which can inhibit thymine nucleotide synthase, block the conversion of uracil deoxyriboside into thymine deoxyriboside, and interfere with DNA biosynthesis.
However, fluorouracil (5-Fu), which is converted to 5-fluorouracil nucleotide in vivo, can be incorporated into RNA to interfere with protein synthesis, and has some therapeutic effects on cells in other phases as well. The efficacy of fluorouracil (5-Fu) alone in hepatocellular carcinoma is inexact. It has been reported that the efficiency of fluorouracil (5-Fu) monotherapy for hepatocellular carcinoma is mostly below 20%, and the survival of patients is 2-5 months. Fluorouracil (5-Fu), a derivative of fluorouracil (5-Fu), has been used in clinical practice since the 1960s, and its side effects were found to be 1/7 to 1/4 of those of fluorouracil (5-Fu), and its chemotherapeutic index was twice that of fluorouracil (5-Fu), with an effective rate of more than 30% in the treatment of hepatocellular carcinoma. It has certain curative effect.
Fluorouracil (5-Fu) is usually 10-12mg/(kg?d) intravenously, and after 3-5 days, the dose can be halved and given intravenously once every other day, the total amount can be 6-8g. Tegafur (FT207) is 800-1200mg/d, divided into four oral doses, and 15-20mg/(kg?d) is given intravenously.
Doxorubicin (Adriamycin) has an anthracycline plane that can be embedded between DNA base pairs and tightly bound to DNA, thus containing high concentrations in nucleic acids. It is a cell cycle non-specific drug due to its chimerism leading to altered DNA spatial structure and inhibition of DNA and DNA-dependent RNA synthesis. The possible reduction of electrons to free groups in the anthracycline ring of doxorubicin (Adriamycin) is highly active and is one of the mechanisms for killing cancer cells.
Doxorubicin (Adriamycin) is currently considered to be one of the most effective chemotherapeutic agents for the treatment of liver cancer.
It enters the body with the highest concentration of aggregation in the liver and long residence time, and this pharmacokinetic feature is favorable for the treatment of hepatocellular carcinoma. The clinical application of doxorubicin (ADM) in the treatment of hepatocellular carcinoma is more frequent, and it is generally believed that it has good efficacy in hepatocellular carcinoma, with apparent and effective rates ranging from 10% to 30%, and can shrink or subside hepatocellular carcinoma. The efficacy of doxorubicin (ADM) in treating hepatocellular carcinoma has a certain relationship with the region, and its efficacy in African hepatocellular carcinoma is better than that in Europe and America. There are also reports that the efficacy of doxorubicin (ADM) is related to HBsAg, and the efficacy is better in HBsAg-positive patients, but the mechanism is unclear.
The significant side effect of doxorubicin (ADM) is the toxic effect on the heart, which has some limitation on the application of doxorubicin (Adriamycin). When long time application or one time high dose treatment, attention should be paid to monitor the patient’s cardiac changes, and if early signs of congestive heart failure or QRS wave group voltage in the limb leads of ECG is lower than 70% of the pre-treatment level are found during treatment, the drug should be stopped immediately.
Doxorubicin (ADM) derivative epirubicin (epi-amycin) has a high chemotherapeutic index and low toxicity compared with doxorubicin (ADM), especially in terms of cardiotoxicity and less side effects. Doxorubicin (ADM) is more prone to cardiotoxic reactions when applied at cumulative doses above 550 mg/m2, whereas epirubicin (epi-adriamycin) generally accumulates above 1000 mg/m2 before clinical manifestations of cardiotoxicity are seen. Epirubicin (epi-adriamycin) and doxorubicin (ADM) are for intravascular injection only at a single dose of 60 to 80 mg/m2, repeated every three weeks. The dosage should be reduced when co-administered.
Mitomycin (MMC) is a fermentation product of the actinomycete family, which can covalently bind and cross-link with DNA, thus destroying the cellular DNA structure to achieve the killing effect on cancer cells, and belongs to cell cycle non-specific anticancer drugs. The therapeutic effect of mitomycin on hepatocellular carcinoma is uncertain. In South Africa, it was reported that the application of mitomycin was ineffective in treating hepatocellular carcinoma, and the average survival of patients was only 34 days; however, a report from Japan concluded that mitomycin (MMC) could achieve better results in treating hepatocellular carcinoma, and the survival of patients exceeded one year, and necrosis and fibrosis of cancer foci were seen after treatment. The common dose of mitomycin (MMC) is 4-6mg/time intravenously, 2 times/week. Oral 2-6mg, 1 time/d, 80-120mg as a course of treatment.
At present, combined chemotherapy is still the main treatment for hepatocellular carcinoma. Combined drugs have synergistic anti-cancer effects and the main toxic side effects do not overlap, so it has the characteristics of high efficiency and low toxic side effects. At present, the more commonly used combination chemotherapy regimens in clinical practice are.
①MAF regimen: mitomycin (MMC) 8 mg/m2, IV, day 1, doxorubicin (ADM) 30 mg/m2, IV, day 7, and fluorouracil (5-Fu) 10 mg/kg, IV, days 1-8. Every 3 weeks is a cycle, and 3 cycles are a course of treatment. The sum of complete remission rate (CR) and partial remission rate (PR) of this regimen for hepatocellular carcinoma was 27%.
②FMeA regimen: fluorouracil (5-Fu) 325mg/m2, IV on day 1-5, once every 6 weeks, doxorubicin (ADM) 40-60mg/m2 IV once every 3-4 weeks, and simustine (Me-CCNU ) 150mg/m2, orally on day 1. 6 weeks as a course of treatment, PR was 21.1%. In China, calcium folinic acid (aldehydic folate) and fluorouracil (5-Fu) were applied to treat hepatocellular carcinoma. 500mg/m2 of fluorouracil (5-Fu) was administered orally for 1-5 days, 40-60mg/m2 of doxorubicin (ADM) was administered orally on day 1, 6-8mg/m2 of mitomycin (MMC) was administered orally on day 1, 100mg of calcium folinic acid (aldehydic folate) was administered orally on day 1. The PR was 30% and the one-year survival rate was 20% in 40 patients with moderately advanced primary hepatocellular carcinoma treated with small doses of calcium folinic acid (aldehydic folate) with FM or MAF regimens of intravenous chemotherapy.
2. Transhepatic artery interventional embolization and chemoembolization.
Transhepatic Arterial Embolization (TAE) and Transhepatic Arterial Chemotherapy and Embolization (TACE). Hepatocellular carcinoma starts insidiously, and once detected, it is often in the middle or late stage, and the time for surgery is often lost. The recurrence rate of hepatocellular carcinoma 5 years after surgery is about 90%. These tumors have been treated with transcatheter hepatic artery chemoembolization in recent years, and encouraging results have been achieved.
Normal liver receives dual blood supply from portal vein and hepatic artery, of which about 75% of nutrition comes from portal vein and 25% from hepatic artery, and about 50% of blood oxygen supply each. After blocking the blood flow of hepatic artery, the blood perfusion of hepatocellular carcinoma tissues is reduced by about 90%-95%, while that of normal liver tissues is reduced by about 35%, so it does not cause much damage to normal liver tissues.
At present, this method is mainly used for the treatment of multiple or large tumors that are not suitable for resection, as well as some hepatocellular carcinomas with poor liver function compensation that cannot tolerate surgery and recurrence of hepatocellular carcinoma after surgery. Portal vein branch cancer embolism is not an absolute contraindication, but the therapy should be avoided when liver and kidney functions are severely impaired such as severe jaundice and ascites. The cannula should be inserted beyond the gastroduodenal artery and the right gastric artery, and preferably super-selected to the affected hepatic artery.
Commonly used chemotherapeutic agents include fluorouracil (5-Fu), doxorubicin (Adriamycin), carboplatin, mitomycin, methotrexate, etc. Embolization agents commonly used are iodine oil and absorbent gelatin sponges, and drug microspheres have also been used in large numbers in clinical practice. Methods include sandwich method, double artery embolization method, combined arterial and portal vein therapy and arterial boost chemotherapy. The treatment can be repeated after 1 to 2 months. The purpose of the 1st TAE is to block the arterial blood supply to the tumor, and the 2nd one is to block the established collateral circulation. It is also repeated for a total of 3 to 10 times, but repeated TAE treatment can lead to liver function impairment and aggravate portal vein pressure, making the disease worse.
According to the results of pathological studies, preoperative and postoperative TAE treatment only has varying degrees of necrosis on the main tumor and does not kill viable cancer cells in the daughter tumor, within the envelope, and in the portal vein cancer thrombus. Therefore, preoperative TAE is not advocated for resectable hepatocellular carcinoma, and it is also inappropriate to use TAE as a routine method to prevent tumor recurrence after surgery. It has been reported that the survival rate of primary liver cancer treated with repeated TAE can reach 26.5%, but generally it can only control and shrink the tumor temporarily. Therefore, it is advisable to strive for resection of unresectable hepatocellular carcinoma after repeated TAE shrinkage.
1. Indications for TAE or TACE.
Absolute indications include.
(1) Hepatocellular carcinoma only invades the tertiary branches of portal vein.
(2) Those who are not suitable for surgical resection if their liver function is ChildA-B.
(3) For those who are suitable for surgical resection, TAE treatment is feasible as preoperative treatment, which can further improve the surgical resection rate, reduce intraoperative bleeding and improve postoperative survival.
(4) Internal bleeding from ruptured liver cancer. Broadly speaking, TAE or TACE treatment is feasible for those whose tumors account for less than 70% of the liver volume and no cancer embolism in the main portal vein. For those with large amount of ascites and severe esophageal varices, symptomatic treatment can be given first to reduce ascites and TAE treatment after injection of sclerosing agent or ligation of varices, which are relative indications for TAE treatment.
2. Contraindications for TAE or TACE.
(1) The volume of hepatocellular carcinoma accounts for more than 70% of the total volume of the liver.
(2) Iodine allergy.
(3) Portal vein trunk cancer thrombosis.
(4) Severe organ insufficiency, such as serious impairment of heart, liver, lung and kidney function.
(5) Coagulation mechanism disorder, accompanied by serious bleeding tendency.
(6) Combined with serious infections, diabetes and other complications and cannot be effectively controlled.
3.Chemotherapy drugs.
Commonly used chemotherapy drugs include fluorouracil (5-Fu), doxorubicin (ADM), epirubicin (epi-amycin), cisplatin (DDP), mitomycin (MMC), etc. The combination application scheme is consistent with systemic combination chemotherapy, and the dose of drugs is generally greater than that of systemic drugs.
(1) Chemotherapy and embolization therapy: chemotherapy drugs are injected via hepatic artery, cisplatin (DDP) 80mg/m2 or doxorubicin (ADM) 50mg/m2 or doxorubicin (ADM) 40mg/m2 + cisplatin (DDP) 70mg/m2, mixed with iodized oil and slowly perfused, so that the cancer foci are hit by both ischemia and chemotherapy drugs. At present, this treatment is an optimal treatment for patients with hepatocellular carcinoma that cannot be removed surgically.
(2) Chemotherapy with hepatic artery ligation: The mechanism of tumor treatment is the same as chemoembolization, and it is mainly used to treat patients with hepatocellular carcinoma that can no longer be surgically removed during open exploration.
(3) Slow-release drugs: Chemotherapeutic drugs are made into small slow-release particles or wrapped with liposomes to increase the concentration of drugs in the tumor foci and prolong the duration in order to improve the therapeutic effect.
(4) Miniature arterial pump drug delivery: The drug is delivered through the miniature arterial pump embedded under the skin to maintain high concentration of drugs in liver cancer tissues, which is conducive to the killing of tumor cells, with the advantages of convenience, simplicity and less complications.
(5) Vasoconstrictors: Some studies have pointed out that when systemic vasoconstrictors are applied at the same time as hepatic artery administration, the amount of blood in cancer tissues is relatively more than that in normal liver tissues after applying vasoconstrictors due to poor regulation of diastole and contraction of new blood vessels in hepatocellular carcinoma, and the concentration of anticancer drugs entering cancer tissues is higher. Therefore, vasoconstrictors can be used as potentiating agents for arterial perfusion chemotherapy. Some people applied angiotensin II-mediated hepatic artery boosting chemoembolization (IHCE) to treat primary hepatocellular carcinoma, and the results showed that 57% of hepatocellular carcinoma shrank by more than 50% after IHCE treatment, while only 33.4% after TAE treatment.