MODERN PRINCIPLES OF CORRECTION OF HEMATOLOGICAL TOXICITY OF POLYCHEMOTHERAPY OF MALIGNANT TUMORS (LITERARY REVIEW)

Kobilov O.R.
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 PRINCIPLES OF CORRECTION OF HEMATOLOGICAL TOXICITY OF POLYCHEMOTHERAPY OF MALIGNANT TUMORS (LITERARY REVIEW)

Abstract

Hematological toxicity continues to be one of the urgent problems of modern tumors’ chemotherapy (CT). In addition to malignant cells, normal body cells with high regenerative activity, in particular bone marrow cells, also fall into the zone of influence of cytostatics. Among the modern means of combating the hematological toxicity of chemotherapy, various inducers of colony-stimulating factors remain, a promising direction is their combination with extracorporeal methods that reduce the toxic effect of antitumor therapy.

Аннотация

Гематологическая токсичность продолжает оставаться одной из актуальных проблем современной химиотерапии (ХТ) опухолей. В зону влияния цитостатиков попадают, помимо злокачественных клеток, также нормальные клетки организма с высокой регенеративной активностью, в частности клетки костного мозга. Среди современных средств борьбы с гематологической токсичностью ХТ по-прежнему остаются различные индукторы колониестимулирующих факторов, перспективным направлением является их сочетание с экстракорпоральными методами, снижающими токсическое влияние противоопухолевой терапии.

Ключевые слова: гематологическая токсичность, химиотерапия, злокачественные опухоли.
Keywords: hematological toxicity, chemotherapy, malignant tumors.

Currently, due to the increase in the number of effective and affordable anticancer drugs, chemotherapy (CT) has developed into a full-fledged scientific discipline with its own methodology and experimental base. Thanks to the development of this field of oncology, a number of oncological diseases can be cured by using chemotherapy alone. Also, CT, as a component of the complex treatment of breast cancer, colorectal cancer, sarcomas of soft tissues and bones, as well as patients with disseminated forms of solid tumors, significantly increases the effectiveness of treatment. At the same time, most chemotherapy, acting cyclically, have the maximum damaging effect on rapidly dividing cells. In addition to tumor cells, normal tissue cells with high regenerative activity, in particular bone marrow cells, fall into this category.

Various studies have shown that for cancer of the esophagus, cardiac section of the stomach, lungs and cervix, an increase in the intensity of spontaneous chemiluminescence of blood serum is characteristic, which increases in the absence of the effect of antitumor therapy. The predominance of the production of activated oxygen metabolites as a result of an increase in their formation or depletion of antioxidants, accompanied by activation of destructive processes, is called “oxidative stress”. Thus, for many types of tumors, the activation of lipid peroxidation (LP) processes is an important pathogenetic factor that negatively affects the effectiveness of treatment and the prognosis of the disease. With malignant growth, an imbalance develops between the intensity of production of antioxidant enzymes and free radical oxidation, as well as the level of functional activity of the antioxidant defense system.

As a consequence of these processes, among the most common side effects of chemotherapy, myelotoxicity, that is, a damaging effect on the bone marrow, is noted. Myelotoxicity leads to a decrease in the number of leukocytes, neutrophils, platelets and red blood cells, which reduces the body’s natural defense against infection. An equally common side effect of chemotherapy is a decrease in hemoglobin, which causes anemia, which also worsens the tolerance of the infection. Hematological complications of antitumor chemotherapy of varying severity are found in 88% of cancer patients. Factors affecting the depth and frequency of suppression of hematopoiesis are due to: 1) hematopoiesis reserve, which is affected by previous irradiation or chemotherapy, the presence of metastases in the bone marrow, the patient’s age, degree of exhaustion of the patient; 2) the type, doses and methods of administration of the used chemotherapeutic drugs, the intervals between the courses of chemotherapy and the somatic status of the patient.

The development of infection with neutropenia requires massive antibacterial therapy with broad-spectrum drugs. Despite the treatment, the mortality rate during the development of such complications varies from 5 to 20%. In the case of thrombocytopenia, the only method of symptomatic therapy remains the transfusion of blood components, which is associated with the risk of additional complications. Also, thrombopoietic growth factors are currently being studied for these purposes, but they have not yet found clinical use.
In addition to obvious infectious and hemorrhagic complications, a serious consequence of severe or prolonged myelosuppression may be delaying the next course of treatment or reducing the dose of drugs. Given the existence of a direct relationship between the total dose of the drug and the therapeutic effect, such changes in planned therapy can lead to a decrease in the overall effectiveness of the treatment.

In recent years, the concept of the approach to the treatment of Hodgkin’s lymphoma (HL) has changed significantly, while a detailed study of prognostic factors, as well as an understanding of the nature and extent of late complications of chemotherapy, have played an important role. Maintaining the planned dose rate for Hodgkin’s lymphomas is an essential task of chemotherapy, therefore, the prophylactic use of granulocyte colony stimulating factor (G-CSF) is widely used in the BEACOPP and BEACOPP-14 regimens. A multicenter study to evaluate the effectiveness of the BEACORP-14 regimen for advanced HL using G-CSF as planned support showed that chemotherapy was manageable and dose reduction of cytostatics was rare. Acute toxicity was moderate, leukopenia, thrombocytopenia and anemia (WHO grade 3-4) were noted in 75%, 23%, 65%, respectively, infections — in 12% of cases, 3 deaths were recorded during drug therapy.

In general, with BEACOPP-14 and the enhanced variant, anemia was diagnosed in 70% and 66%, leukopenia in 80% and 98%, thrombocytopenia in 27% and 70%. However, unlike young patients, acute toxicity during chemotherapy was significantly higher in elderly patients, as a result, fewer elderly patients received the intended full dose of cytostatics: 75% versus 91%.

Neutropenia is the most common hematological complication of chemotherapy in cancer patients, due to damage to the granulocyte germ. The presence of neutropenia is associated with a high risk of bacterial infection: in 20% or more patients, bacteremia is recorded with a decrease in the number of neutrophils in the blood. The appearance of fever in these patients directly correlates with the intensity of chemotherapy. More than 20% of patients with FN( febrile neutropenia )recorded bacteremia with a decrease in the number of neutrophils in the blood to a number less than 1.0 × 109 / l. This condition poses a threat to the life of patients, as if improperly treated, it can lead to septic shock and death. Neutropenia of the III-IV degree is the main limiting factor preventing the onset of chemotherapy and causing the need to reduce the doses of chemotherapy, delay and / or cancel treatment.

Acute granulocytopenia appears on the 6-12th day after the introduction of most myelosuppressive chemotherapy drugs. The restoration of normal values occurs in 10-14 days. Megakaryocytes are affected later, therefore platelet suppression is usually observed 4 or 5 days after granulocytopenia, and their normal level is restored a few days after the normalization of the number of leukocytes. Mitomycin C and nitrosourea derivatives have a unique ability to cause delayed bone marrow suppression, which usually appears on the 28-42th day with the restoration of bone marrow function on the 40-60th day after treatment. In 10-40% of patients with solid tumors and in 80-100% of patients with malignant diseases of the blood system who received chemotherapy in standard doses, the so-called febrile neutropenia develops.

To reduce the side effects of chemotherapy, several factors should be considered. So, myelosuppression is characteristic of many chemotherapy drugs, but some do not have this effect, for example, bleomycin and vincristine. Individual factors significantly affect the risk of toxic effects on the bone marrow. In patients with a low baseline level of leukocytes or platelets, with previous courses of chemotherapy or radiation, old age and a decrease in bone marrow reserve, when prescribing chemotherapy, their myelosuppressive profile is taken into account. For example, if the excretion of a myelotoxic drug depends on its excretion by the kidneys, then a patient with impaired renal function will have a higher level of the drug in the blood and an increased risk of myelosuppression. If the drug is used in combination, then to prevent additional toxic effects, lower doses should be used than with monotherapy.

The study of the role of hematopoietic factors in the prevention and correction of myelosuppression began in the mid-80s of the twentieth century, and now they have found wide clinical application. The use of CSF, which causes rapid proliferation of progenitor cells into mature differentiated blood cells, can reduce the number of life-threatening infectious complications developing in patients with neutropenia, while the use of granulocyte-macrophage (GM) CSF and G-CSF does not prevent the development thrombocytopenia. Despite the pronounced effectiveness of CSF, their use for prophylactic or therapeutic purposes is often limited by the development of side effects, as well as the high cost of drugs. Severe inhibition of bone marrow hematopoiesis with the development of infectious complications leads to inhibition of immunity, which, in turn, exacerbates the course of the tumor process. In this regard, the question arises of introducing into clinical use drugs with a direct or indirect effect on the hematopoiesis system. Russian scientists have developed drugs that can indirectly restore hematopoiesis without directly affecting bone marrow stem cells. Among them, the drugs of the new class of pseudopeptides (dicarbamine) and thiopoietins (glutoxim) are most interesting.

The prophylactic use of CSF is recommended in patients with more than 40% risk of febrile neutropenia. This category includes patients receiving high-dose chemotherapy and chemotherapy with a high dose intensity, when the interval between cycles is reduced to 14 days. Repeated injections of CSF after chemotherapy cycles can shorten the duration of neutropenia, as well as reduce the risk of febrile neutropenia in subsequent chemotherapy cycles in patients with previous episodes of febrile neutropenia. The addition of CSF to antibacterial regimes during febrile neutropenia does not significantly improve the outcome of treatment, however, the appointment of cytokines in the debut of a proven infection is justified. Non-glycolized G-CSF (Neupogen) is prescribed at a dose of 5 μg / kg body weight per day subcutaneously or intravenously. Glycosylated G-CSF (granocyte) is prescribed at a dose of 150 mcg / m2 per day subcutaneously or intravenously. Non-glycolized GM-CSF (leukomax) — at a dose of 5 to 10 mcg / kg body weight per day subcutaneously and intravenously. All CSF are administered until a steady increase in the number of granulocytes is observed, after which the dose is reduced to zero within three days.

The results of the NADIR study showed that maintenance therapy with long-acting lipegfilgrastim (Lonquex), a new glycopegylated G-CSF, is characterized by clinical efficacy and tolerability in primary and secondary prevention of FN in patients with various tumors receiving cytostatic chemotherapy in real clinical practice. A pharmacoeconomic study showed that Lonquex, with clinical efficacy and the lowest cost-effectiveness ratio, is considered the preferred alternative to the available G-CSF drugs.

Thrombocytopenia as a complication of chemotherapy also presents a clinical problem, the most formidable manifestations of which are hemorrhages, often fatal, especially in the presence of concomitant infection. Thrombocytopenia is the result of inhibition of a megakaryocytic germ due to CT. Transfusions of thromboconcentrate are carried out strictly according to indications and in an adequate dose. It should be remembered that about a third of patients who regularly received platelet transfusions have anti-platelet and anti-leukocyte antibodies most often against HLA-system antigens, which is caused by an admixture of leukocytes in the platelet concentrate. This leads to a decrease in both the number of platelets and their lifespan. Therefore, an important aspect of the preparation of thromboconcentrate is its purification from impurities of leukocytes.

Thanks to modern filtration technologies, it is possible to obtain thromboconcentrate with an admixture of <1% of the initial number of leukocytes. As a result, the proportion of alloimmunized patients decreased from 30-40% to 15-20%. The use of leukocyte filters is an expensive procedure and is not recommended in widespread oncological practice. Another technology that prevents HLA alloimmunization is irradiation of platelet concentrate with ultraviolet rays. With developed refractoriness to platelet transfusions, the introduction of high doses of gamma globulin and / or massive platelet transfusions is also recommended. In order to stimulate thrombocytopoiesis, thrombopoietin may be used. However, more often thrombopoietin is administered according to special indications in patients after high-dose chemotherapy with hematopoietic stem cell transplantation.

Attempts to stimulate a platelet germ with various recombinant cytokines (IL-1, IL-3, IL-6, IL-11, GM-CSF), as well as their possible combinations for the activation of megakaryocytes and their predecessors, were unsuccessful. When using recombinant cytokines, a significant toxic effect was observed, adverse side reactions were observed, manifested in a decrease in blood pressure, in the appearance of signs of a systemic inflammatory reaction, etc. The next step undertaken by specialists was the use of a recombinant form of thrombopoietin. Several control studies were performed in patients with NHL with unfavorable prognostic indicators, after several cycles of chemotherapy (ifosfamide, etoposide, carboplatin), with the need for transfusions of thromboconcentrate. According to these studies, the use of a recombinant growth factor and differentiation of megakaryocytes has reduced the need for transfusion of thrombus suspension. Studies of modified recombinant forms of thrombopoietin were stopped when autoimmune antibodies to the drug were detected.

In a randomized study conducted by Chissov V.I., Reshetov I.V. et al., it was shown that the drug sodium nucleospermate affects cellular immunity, stimulating the active release of cytokines GM-CSF. Enhances the proliferation and differentiation of bone marrow progenitor cells of neutrophils, lymphocytes, red blood cells, eosinophils, monocytes, megakaryocytes. GM-CSF actively stimulates megakaryocytopoiesis, followed by an increase in platelet count in the blood. Thus, the search for an affordable and effective stimulator of the platelet germ of hematopoiesis in cancer patients remains topical in oncology to the present.

Anemia can cause a significant deterioration in the quality of life and tolerance to CT. In addition, red blood cell transfusions, used to correct anemia, carry the risk of transmission of many viruses, including hepatitis viruses and human immunodeficiency. Anemic syndrome in cancer patients in the post-cytostatic period, primarily due to a decrease in the concentration of hemoglobin and red blood cells in the blood due to bone marrow failure. Indications for transfusion of red blood cells in these patients vary significantly. For each patient, this issue is resolved individually. There is only one strict indication for blood transfusion — the clinical need for a short period of time to increase tissue oxygenation. In this case, other factors are also taken into account: a rapid drop in hemoglobin level, the general status of the patient, his age. The red blood cells volume required for transfusion is determined based on the available hemoglobin concentration.

As a result of the development of the malignant process in the patient’s body, the decay products of the tumor accumulate, and the use of chemoradiotherapy has an additional toxic effect on the basic systems of life. The methods of extracorporeal immunopharmacotherapy (EIPHT) allow combining the direct immunomodulating effect on the patient’s body with the detoxifying effect of plasmapheresis. Modern EIPHT methods are inherently an effective extension of therapeutic PPh (plasmapheresis). 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.

Despite the proven feasibility of using CSF in carrying out various chemotherapy regimens, at present, most patients with solid tumors in the CIS countries do not receive them. Not more than 6–10% in Russia of potentially needy patients have the opportunity to receive preventive support for CSF, which is 7–10 times lower than in Europe and the USA. Obviously, there is a high need for the most rational use of limited material resources aimed at the drug supply of cancer patients. This is largely due to economic reasons. In such a situation, it seems interesting to study new generics and indirect hematopoietic inducers, which will significantly reduce the cost of drugs and increase their availability for patients.

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