Niyozova Sh.Kh.
Assistant department of oncology of Tashkent Medical Academy
Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, c. Tashkent
MODERN OPPORTUNITIES FOR CORRECTION OF HEPATOTOXIC SYNDROME FOR POLYCHEMOTHERAPY OF SOLID TUMORS (LITERARY REVIEW)
Аннотация
Современная химиотерапия (ХТ), как компонент комплексного лечения злокачественных опухолей, позволяет успешно бороться с новообразованиями, но по-прежнему остаётся проблема её токсического действия на различные системы и органы больного. Одним из главных побочных действий ХТ является её гепатотоксичность, которая стала встречаться чаще в связи с использованием высокодозных режимов. Однако, арсенал гепатопротекторов в последние годы продолжает пополняться новыми препаратами, а также новыми подходами на основе снижения токсических эффектов ХТ с помощью экстракорпоральных методов и плазмафереза.
Abstract
Modern chemotherapy (CT), as a component of the complex treatment of malignant tumors, allows you to successfully fight against neoplasms, but the problem of its toxic effect on various systems and organs of the patient still remains. One of the main side effects of chemotherapy is its hepatotoxicity, which has become more common in connection with the use of high-dose regimens. However, the arsenal of hepatoprotectors in recent years continues to be replenished with new drugs, as well as new approaches based on the reduction of toxic effects of chemotherapy using extracorporeal methods and plasmapheresis.
Ключевые слова: химиотерапия, солидные опухоли, гепатотоксический синдром.
Keywords: chemotherapy, solid tumors, hepatotoxic syndrome.
In recent years, anticancer chemotherapy has become increasingly important in the treatment of malignant neoplasms. With disseminated forms of solid tumors, chemotherapy is the main treatment method, and in the early stages it is successfully used as a component of the complex effect. The main conditions for creating effective therapeutic programs are still the development of new cytotoxic drugs and their combinations that selectively act on tumor cells. As a rule, cytostatic agents are used in high doses, as a result of which the maximum destruction of tumor cells is achieved. This made it possible to increase the effectiveness of chemotherapy for malignant neoplasms of various localizations: non-small cell lung cancer, colorectal cancer, germinogenic malignant tumors of the ovaries and testicles, breast cancer, etc., however, it also caused a wide range of adverse reactions.
Among the side effects of anticancer treatment, liver dysfunction previously occupied a negligible place, but with the advent of new highly effective anti-blastoma drugs, as well as the introduction of high-dose chemotherapy into oncological practice, such complications came to the fore. With maintenance chemotherapy with small doses of cytostatics, the hepatotoxicity of anti-blastoma drugs often has a long latent asymptomatic course, manifested by an isolated increase in the activity of serum transaminases. In this regard, liver damage can be diagnosed only with an in-depth examination and often already in the long term. At the same time, the frequency of hepatotoxicity during chemotherapy varies from 14.3 to 100%.
Direct hepatotoxicity is due to the toxicity of the substance itself, indirect — of its metabolites. The basis of direct toxic damage to hepatocytes is the formation of a large number of toxic substances and highly reactive molecules with the participation of enzyme systems that enhance peroxidation (LP) in the membranes, which in turn is accompanied by an increase in their permeability, impaired balance of cellular ions, a decrease in ATP level, and a violation of vital important functions and, as a consequence, the development of cell necrosis. This mechanism of liver cell cytolysis is a substrate of most acute and chronic drug hepatitis. It has been revealed that the damaging effect of etoposide and paclitaxel on the liver is based on the activation of lipid peroxidation and inhibition of microsomal oxidation. In this regard, the use of hepatoprotective agents with antiradical activity for the correction of cytostatic hepatotoxicity is promising. Among hepatoprotective drugs with a similar mechanism of action, both synthetic and substances of natural origin are known.
Antitumor drugs characterized by predictable hepatotoxicity include 5-fluorouracil, leucovorin, oxaliplatin, irinotecan, cytarabine, nitrosourea preparations, taxanes, etc. The most studied are the toxic effects that limit the conduct of specific therapy from rapidly renewing cellular systems (hematopoietic tissue, epithelium of the oral cavity and gastrointestinal tract, hair follicles, reproductive organs). An important aspect in rehabilitation, and therefore in improving the quality of life of patients who underwent chemotherapy, is a thorough study of the long-term effects of the toxic effects of cytostatics on various organs and systems. The negative effect of hepatotoxicity on the results of treatment of cancer patients is expressed in an increase in the incidence of postoperative complications and perioperative blood transfusions, as well as in an increase in mortality of patients after surgery.
Hepatotoxicity of anticancer drugs is also due to the low selectivity of the action of most cytostatics, leading to damage to normal cells by toxic agents. This causes a variety of liver damage and is accompanied by functional disorders of various organs. The mechanisms of drug damage to the liver during chemotherapy include impaired metabolic processes in hepatocytes, toxic destruction of subcellular structures, induction of immune responses, carcinogenesis, impaired blood supply to hepatocytes, exacerbation of previously existing hepatocellular disorders.
The most common drug damage to the liver during chemotherapy are steatohepatitis and vascular damage (sinusoidal obstruction syndrome, peliosis, veno-occlusive disease). As a rule, doctors face these complications when conducting high-dose chemotherapy regimens. In addition, the development of tubular cholestasis and sclerosing cholangitis is possible. Timely recognition and treatment of such complications as minimal hepatic encephalopathy (MPE) is important, since it can be a harbinger of clinically pronounced hepatic encephalopathy, and psychomotor disturbances noted in MPE reduce the quality of life and patient performance.
Thus, inhibition of metabolism resulting from damage to hepatocytes creates the conditions for further damage and impaired liver function, a vicious circle is formed. In such a situation, one has to either reduce the dose of the cytostatic agent, as a result of which the therapeutic effect is further reduced, and toxicity remains at the level of the full dose of the drug, or interrupt treatment, which may contribute to the development of relapse of the tumor process. In clinical practice, a number of indicators are used to establish the degree of hepatotoxicity, in particular, levels of alkaline phosphatase (ALP), bilirubin, gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin in the blood.
Hepatoprotectors — a group of heterogeneous drugs that prevent the destruction of cell membranes and stimulate the regeneration of hepatocytes, thereby exerting a positive effect on liver function. They increase the resistance of the liver to pathological effects, enhance its detoxification function by increasing the activity of enzyme systems (including cytochrome P450 and other microsomal enzymes), and also contribute to the restoration of its functions in various injuries (including toxic ones). Moreover, the proven clinical efficacy of hepatoprotectors in various conditions is contradictory. In oncological practice, the arsenal of hepatoprotectors currently used by clinicians is small. These include: heptral (S-ademethionine), ursodeoxycholic acid (UDCA), Hepa-Merz (L-ornithine-L-aspartate), flumecinol (zixorin). Hepatoprotectors with essential phospholipids are drugs with unproven effectiveness.
An important specific antidote for dose-dependent hepatotoxicity is N-acetylcysteine (other sulfhy dryl ofl group donors), which is effective in stopping an overdose of acetaminophen. In other cases of hepatotoxicity, treatment is delayed or discontinued with symptomatic therapy. CIS countries are considered to be hepatoprotectors, primarily, preparations of essential phospholipids (EPL), which have a positive effect on the structure of hepatocyte membranes. One of the ways to reduce the toxic effects of cytostatics on the liver is the use of drugs with a narrowly targeted protective effect on hepatoprotective liver cells.
Among hepatoprotectors, S-ademethionine (Heptral drug) is characterized by the most multifunctional effect on various parts of the metabolism in the liver, and its choice is based on the principles of evidence-based medicine. There is a wide clinical evidence base for the use of this drug. S-ademethionine is a chemically active compound that plays a key role in metabolic processes such as transmethylation, transulfonation, aminopropylation, and has detoxifying, antioxidant, antidepressant, neuroprotective, regenerating, choleretic and cholekinetic effects in the body. S-ademethionine is synthesized in the liver from adenosine and methionine, and is found in all body media. In a number of studies, heptral was recommended as an accompanying therapy in the treatment of hepatotoxicity that arose during cytostatic PCT.
One of the methods that have been used successfully for a long time for the treatment of allergic diseases, as well as intoxication, is therapeutic plasmapheresis (PPh), which consists in the removal of blood plasma containing antibodies responsible for the development of the disease, circulating immune complexes, cytokines, and cellular metabolism products. The main mechanism that provides the therapeutic effect of PPh is the deplasia of cellular elements. Together with the plasma, pathological elements adsorbed on the surface of the cells are removed, the vital activity of the cells changes, new interactions with other cells and regulatory facts arise.
Modern methods of extracorporeal immunopharmacotherapy (EIPHT) are inherently an effective extension of therapeutic PF. If with the latter, the cellular elements are immediately returned to the patient immediately after their separation from the plasma, then with EIPHT there is an additional isolation of the leukocyte fraction, which is then treated externally with a certain drug aimed at increasing or decreasing (depending on the disease) the functional activity of the cells participating in the inflammation and immune responses. Oncological patients with pronounced concomitant pathology, advanced age, immunosuppression, aggravated by radiation or chemotherapy, make up a special group of patients who are shown to perform EIPHT. When performing traumatic and volumetric surgical interventions, secondary postoperative immunodeficiency can contribute to the development of purulent-septic complications.
All of the above confirms the urgency of the problem of hepatotoxicity during chemotherapy in patients with solid tumors and is the unconditional basis for conducting special studies in this area. Despite the relatively large number of works devoted to this topic, the list of hepatoprotectors used in the clinic is small: the most commonly used drugs contain essential phospholipids, silymarin, vitamins and amino acids. The issue of pharmacological correction of toxic disorders in the liver caused by cytostatics, based on the mechanism of their cytotoxic action, as well as the study of the morphological and functional state of the liver in the long term after antitumor therapy, remains topical.
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