Anticancer drug therapy at the NeuroVita Clinical Hospital and our opportunities in the prevention and control of fatal complications.

Drug therapy of malignant tumors (for simplicity, let us use the collective term "chemotherapy") is a therapy that uses drugs to stop the division of tumor cells or to lead to induce their damage and death. It belongs to systemic methods of treatment of oncological diseases.

According to the theory of metastasis of malignant tumors, accepted by the modern oncological scientific community, malignant tumors, even of very small sizes, have the ability to metastasize, i.e., to “send out” tumor cells with the blood and lymph flow to the lymph nodes and organs that are far from the primary tumor, thus spreading the secondary “daughter” tumor foci throughout the human body, affecting the system as a whole. And, if surgery or radiation therapy has a local effect, that is, they eliminate the visible and measurable, as a rule, primary tumor focus, or the organ in which this focus is located, the drug antitumor therapy affects all tumor foci in the body - primary and secondary, visible and invisible, measurable and not measurable. That is, it has an indiscriminate effect on the entire system of the human body as a whole. And this is the positive aspect of drug antitumor treatment. But there are some "cons" in the systemic effect, the toxic side effects or the so-called "adverse events" (AEs): the effect on healthy cells of the whole organism.

The toolkit of a modern oncologist-chemotherapist includes several types of chemotherapy of oncological diseases:

1. Cytostatic and cytotoxic anticancer drug therapy, which it is, in fact, chemotherapy (CT). It is the therapy that uses the drugs that kill tumor cells (cytotoxic) or arrest their proliferation, reproduction and, accordingly, tumor growth (cytostatic). To date, this is the longest known and widely used method of antitumor drug therapy for the most known malignant solid tumors and blood diseases. Unfortunately, cytostatics do not have selective action. And therefore, it is this method of drug treatment that has the greatest number of adverse events, including severe, and even life threatening. In addition, the markers in tumor cells that could indicate the sensitivity of the tumor to a particular drug have not yet been identified. In other words, it is impossible to predict the effectiveness of a particular chemotherapy regimen, but it is always necessary to be prepared for the development of AEs.
2. Targeted therapy (TT) or molecular targeted therapy is the therapy with drugs that selectively interact with certain tumor cell structures. As a result of this interaction, the complex intrapersonalised signaling system is modified, and the division of tumor cells is disrupted. The effect achieved in this case is most often cytostatic, which can last from several months to several years. Most targeted drugs are available in the form of tablets, which allows the patient to take therapy at home, continue their work and live a normal life, and not be tied to a hospital bed. In addition, TT, is much less likely than CT to cause severe adverse events, although it has its own set of side effects. Its negative points are: firstly, not every patient is eligible for TT - in the tumor cells the molecular “targets” must be identified for targeting drug to “get into”. Otherwise, not only the desired positive effect is not achieved, but, on the contrary, the patient's condition may worsen. Therefore, the "targeted" therapy is appointed only if there are strict indications, after molecular biological, molecular genetic tests of tumor cells for the "targets". Modern studies of the molecular biological characteristics of tumors contribute to the identification of an increasing number of "targets", and TT is used for tumors of various localizations (lung cancer, breast cancer, stomach and gastroesophageal junction cancer, melanoma, liver cancer, colorectal cancer, kidney cancer, gastrointestinal stromal tumors, etc.). And, secondly, the need for long-term use of TT sooner or later leads to the accumulation of toxicity, with very unpleasant manifestations for the patient, which may require a break or even complete discontinuation of the drug.
3. Hormonal antitumor therapy (HT) is used to treat or prevent progression in hormone-sensitive, hormone-dependent tumors (breast cancer, prostate cancer, neuroendocrine tumors), as well as to relieve symptoms in functionally active, biologically active substances expressing tumors (carcinoids of various localizations). In such cases, tumor cells have receptors on their surface, which are affected by hormones produced in the human body. This stimulates the proliferation of tumor cells, growth and metastasis of tumors. The principle of action of antitumor synthetic hormones is based on the blocking of these receptors and the termination of hormonal stimulation of tumor cells. The “pluses” of such therapy include the possibility of treatment outside the hospital, low toxicity and, accordingly, a good quality of life, and at the same time, the possibility of long-term control of the disease even in the presence of metastatic forms or long-term prevention of relapse. However, only some types of cancer are hormone-dependent, so HT is prescribed, as well as targeted, only in the case of clear indications.
4. Antitumor immunotherapy (IT) (medication) is therapy with drugs based on substances of natural and synthetic origin that affect the human immune system. These drugs have different mechanisms of action and “points of application”, for example, stimulation of the production of antitumor immune cells and an increase in their antitumor activity, or correction of immunodeficiency conditions associated both with the action of the tumor itself and with side effects of antitumor treatment, or blocking of protective mechanisms tumor cells. For more than 25 years, the cytokines (interferons, interleukin, etc.) have been used in oncological practice to treat metastatic forms of certain types of tumors, for example, melanoma, kidney cancer. However, those doses of drugs that showed high antitumor efficacy of treatment also demonstrated high toxicity, and therefore the maximum allowable dosages have been revised and indications for use were limited.
   
   

Relatively recently, antitumor immune therapy drugs, immune checkpoints inhibitors (ICI), have entered the practice of oncologists-chemotherapists. Normally, immune checkpoints in human blood lymphocytes regulate the work of lymphocytes and protect the body from pathologically strong, excessive reactions of the immune system, the so-called autoimmune reactions. Cancer cells use these checkpoints to suppress the reproduction and activity of cytotoxic T-lymphocytes and protect themselves from them. ICIs block this protective mechanism, which contributes to the activation of antitumor T-lymphocytes and the destruction of tumor cells. In addition, ICIs show good results in the treatment of tumors containing a large number of mutations in their genome. As with targeted therapy, the appointment of ICIs is preceded by specialized tests of tumor cells and lymphocytes surrounding the tumor for the presence of "application points" for ICIs. ICI therapy is currently used in the treatment of many tumors - melanoma, small cell lung cancer, adenocarcinoma and squamous cell lung cancer, adenocarcinoma of the stomach and esophagogastric junction, esophageal cancer, pancreatic adenocarcinoma, colorectal cancer, squamous and glandular head and neck cancers, breast cancer, body and cervix cancer, liver, kidney, bladder cancer.

ICI therapy, like any drug therapy, is not completely safe. One of the main AEs of this therapy is immune-mediated reactions, which are, in fact, autoimmune reactions against healthy human cells. The second dangerous AE in this type of therapy is the phenomenon of "hyper-progression" of the tumor, when, in response to therapy, rapid proliferation of tumor cells begins, new metastatic foci develop, resulting in a rapid increase in the volume of the tumor mass in the patient's body. According to researchers, this phenomenon occurs in 13-15% of cases, the mechanism of development of hyper-progression in response to ICT therapy is currently being studied.

The listed possibilities of CT are well known, widely used in oncological practice both as independent methods of treatment and in combination with each other or with local methods of treatment (surgery, radiotherapy) in the programs of combined and complex treatment.

As follows from the above, no matter how precise the mechanisms of action of chemotherapy drugs are, nevertheless, they all have some toxicity, the ability to damage healthy cells of the body and, most of all, the hematopoietic system, and, therefore, the human immune system. Immunodeficiency in cancer patients already exists by the beginning of treatment: it is the defects in antitumor immunity that allow the development of a “tumor disease”. The greater the mass of tumor cells in the body, the stronger the immunodeficiency, since atypical cells have the ability to produce immunosuppressive factors. Any component of antitumor treatment programs (major surgical interventions, radiation therapy, chemotherapy), in addition to the therapeutic effect, exacerbates immunosuppression.

At the NeuroVita Clinical Hospital, oncological diseases are treated in accordance with the Russian and international clinical guidelines and standards for the treatment of malignant tumors, based on the principles of evidence-based medicine. Chemotherapy is carried out along with maintenance drug therapy, detoxifying intravenous ozone therapy between courses. But, in addition, the patients of our hospital have a unique opportunity to receive personalized protecting chemotherapy in the conditions of bioprophylaxis of especially frequent adverse events (complications), which protection of the patient's immune system from the immunosuppressive effect of chemotherapy drugs, maintain a good quality of life, observe time and dose regimens, which is especially important during CT. For the bioprophylaxis of adverse events, the patient's own (autologous) hematopoietic personalised therapy (autocells) are isolated before or between the stages of standard programs of drug or radiation treatment. Patients who have fully completed all stages of treatment or have reached a stable course of the disease are offered personalized dendritic antitumor vaccines to prevent tumor recurrence and distant metastasis. Additionally, depending on the indications based on the immunological status of the patient, it is possible to select immunomodulatory therapy regimens, which can be prescribed simultaneously with chemotherapy. The decision to use the above methods of bioprophylaxis is taken jointly with the oncologist-immunologist individually for each patient.