RU2712454C1 - Method of treating renal cell carcinoma - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and aims at treating renal cell carcinoma. Combination of preparations is administered to a patient: 3 times a week in amount of 12000000 ME per day and Endoxane. Endoxane is orally administered in amount of 50 mg a day and additionally subcutaneously in amount of 200,000 units a day, twice a week. Computed tomography is performed every 8 weeks. If observing X-ray signs of disease progression, the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced TNF-α (X4) and absolute concentration of natural killers with T-lymphocyte receptors CD3+CD16+56+(X5). Discriminant functions F1 and F2 are calculated from obtained values. If F1>F2 treatment is continued in previous mode. If F2>F1, the patient is transferred to sunitinib therapy. Between 8-week sunitinib cycles, 2-week pause is performed.

EFFECT: invention enables improving survival rates in patients with renal cell carcinoma.

1 cl, 13 tbl, 1 ex

Description

The invention relates to medicine, more specifically to oncology, and may find application in the treatment of malignant neoplasms.

Renal cell cancer accounts for (RCC), according to various authors, 2-4% of all adult tumors. Every year, 338,000 new cases are detected in the world, and 114,000 patients die from this disease. 70-85% of tumors have a histological structure of clear cell cancer. In 30% of patients with initial treatment, distant metastases are detected. In another 30%, they occur during the first year after a radical operation. Metastases are the cause of death in 40% of cases. In the general population of patients with RCC, the five-year survival rate in patients with locally advanced forms is on average 67%, and in the presence of distant metastases - 12%. In specialized centers, where it is possible to use all available options for surgical and drug treatment, as well as very clearly observed intervals of instrumental evaluation of effectiveness, this figure reaches 23%.

Currently, various options for surgical treatment, radiation, drug and cell therapy are used to treat patients with RCC.

The basis for the treatment of patients with local and locally advanced forms of tumors is various surgical options, including open and endoscopic operations, interventional radiological procedures, local hyperthermia and cryoablation. Drug therapy is used only as an auxiliary method in the presence of contraindications for surgical treatment.

In patients with disseminated forms, the surgical treatment is important only as a cytoreduction method to increase the likelihood of a clinical effect when using targeted and immunotherapy. Surgical interventions are also used to stop life-threatening complications arising from the growth of tumor mass.

Currently, the following methods of pathogenetic treatment of patients with disseminated RCC are known:

1. Targeted therapy.

1.1. Tyrosine kinase inhibitors (Sunitinib, Sorafenib, Pazopanib).

1.2. Inhibitors of mTOR (Temsirolimus, Everolimus).

1.3. Angiogenesis Inhibitors (Bevacizumab).

2. Immunotherapy.

2.1. Blockers of co-inhibitory molecules (Nivolumab).

2.2. Cytokines (IL-2, IFN-α).

2.3. Cell therapy.

2.4. Vaccine therapy.

The modern treatment strategy for patients with disseminated RCC includes the consistent use of several lines of drugs. In the first line, they are used that have demonstrated high efficiency in previously untreated patients, in the second - means that have proven to be more effective than analogues in previously treated patients. Starting from the third line, there are no clear instructions on the choice of the drug. Either previously unused drugs or those at different phases of clinical trials are used here. The choice of tactics in this case is completely determined by the attending physician based on the clinical situation. In this case, the basic principle is to use the drug with a different mechanism of action when changing the line of therapy.

The design of clinical trials that determine the use of the drug in a particular line necessarily includes randomization according to the prognosis and histological type of the tumor. To assess the prognosis in patients with disseminated RCC, most studies use a scale developed by Motzer R.J. et al. in 1999 (MSKCC - Memorial Sloan-Kettering Cancer Center scale). It includes 5 parameters: lactate dehydrogenase, hemoglobin, adjusted calcium, Karnovsky status, previous nephrectomy. A favorable prognosis is determined by the absence of risk factors, 1-2 factors - an intermediate forecast, 3 or more - unfavorable. All prognostic systems, including MSKCC, are designed for clear cell cancer, which, according to various authors, accounts for 60% to 90% of kidney tumors. For other histological variants (papillary carcinoma (7% -14%), chromophobic (6% -11%), oncocytoma (7% -10%), tumor of the collecting tubes (<1%)), prognostic factors have not been studied.

Most professional associations include tyrosine kinase inhibitors (Sunitinib, Sorafenib, Pazopanib), an angiogenesis inhibitor (Bevacizumab) in combination with interferon-α, and an mTOR inhibitor (Temsirolimus) as the first line.

Sunitinib underwent clinical trials in patients with clear cell cancer with a favorable and intermediate prognosis. As part of phase III, in the group of 375 patients, the median time to progression was 11 months, in the comparison group (IFN-α) - 5 months. (N. Engl. J. Med. 2007; 356: 115-124).

Sorafenib underwent clinical trials in patients with clear cell cancer with a favorable and intermediate prognosis. As part of phase III, in the group of 451 patients, the median time to progression was 5.5 months, in the comparison group (placebo) - 2.8 months. (J. Clin. Oncol. 2009; 27 (20): 3312-3318).

Pazopanib, a second-generation tyrosine kinase inhibitor, also showed improved long-term treatment outcomes when compared with placebo, inferior to Sunitinib. When compared with placebo in patients with clear cell carcinoma (favorable and intermediate prognosis) in the group of 153 patients, the median time to progression was 11.1 months, in the placebo group - 2.8 months. When compared with Sunitinib, the median time to progression was 8.5 months, and in the comparison group - 9.5 months. (Eur. J. Cancer. 2013; 49 (6): 1287-1296N. Engl. J. Med. 2013; 369 (8): 722-731).

Temsirolimus is a first-generation mTOR inhibitor. mTOR is a component of the universal intracellular signaling pathway of RVCUACT / mTOR, which regulates proliferation, apoptosis and metabolism. Temsirolimus was clinically tested in patients with a poor prognosis. As part of phase III, in the group of 209 patients, the median time to progression was 3.8 months, in the comparison group (IFN-α) - 1.9 months. (N. Engl. J. Med. 2007; 356 (22): 2271-2281).

Bevacizumab has been shown to be effective in combination with IFN-α. As part of phase III, in the group of 369 patients, the median time to progression was 8.5 months, in the comparison group (IFN-α plus placebo) - 5.2 months. (J. Clin. Oncol. 2010; 28 (13): 2137-2143).

In the second line of treatment in most countries, professional associations have recommended the use of two tyrosine kinase inhibitors: Cabosantinib and Lenvatinib; mTOR inhibitor Everolimus and blocker of co-inhibitory molecules Nivolumab.

Everolimus is a second-generation mTOR inhibitor. Historically, it was the first drug used in the second line. In most studies, it is currently used as a comparison drug. As part of phase III, in a group of 272 patients, the median time to progression was 4.6 months, and the median overall survival was 14.8 months. In the comparison group (placebo) - 1.8 and 14.4 months. respectively (Cancer. 2010; 116: 4256-4265).

Cabozantinib is a second generation tyrosine kinase inhibitor. As part of phase III, in the group of 330 patients, the median time to progression was 7.4 months, in the comparison group (Everolimus) - 5.1 months (Lancet. Oncol. 2016; 17: 917-927).

The effectiveness of the combination of Lenvatinib + Everolimus was evaluated in the study E7080-G000-205 (phase II). The frequency of an objective response (the sum of full and partial responses to treatment) was 35% for the combination, 0% for Everolimus and 39% for Lenvatinib. The median time to progression is 12.8 months, 5.6 months. and 9.0 months respectively (Lancet. Oncol. 2015; 16: 1473-1482).

Nivolumab is the first representative of a new class of drugs (blockers of co-inhibiting molecules, checkpoint inhibitors), the mechanism of action of which is associated with a disruption in the interaction between the co-inhibiting molecule and its ligand (PD-1 / PD-L1). Currently, Nivolumab is the only drug in its class that has successfully passed the III phase of clinical trials in patients with locally advanced and disseminated renal cell carcinoma. In a ChekMate 025 study (N. Engl. J. Med. 2015; 373: 1803-1813), which compared the efficacy of Everolimus and Nivolumab, experts recognized that the latter should be considered as the second-line drug of choice. Despite the fact that there were no significant differences in the median time to progression in both groups (4.6 months of Nivolumab and 4.4 months of Everolimus), the median overall survival was significantly greater in the group with Nivolumab (25 months and 19 months. respectively).

Vaccine therapy and various options for cell therapy are currently used only in clinical trials and are not widely used in practice.

A known method of treating RCC through cytokine therapy. The most widely used in the clinic are drugs based on interleukin-2 (IL-2) and interferon-α (IFN-α).

To date, several drugs based on recombinant IL-2 have been developed. Some of them are obtained using E. Coli:

Proleikin (Aldesleukin), Teceleukin, Bioleikin. Others are based on yeast technologies: Roncoleukin, Albuleikin. The most widespread were Proleikin (Aldesleukin) in the USA and Europe and Roncoleukin in the Russian Federation.

Due to the advent of targeted drugs, Proleukin is not used as I line in patients with disseminated forms of renal cell carcinoma and melanoma. Its use, according to the recommendations of the American Association of Clinical Oncology, is limited to the second and subsequent lines. In this case, the drug is used in high-dose mode: 600,000-720,000 IU / kg every 8 hours, up to 15 bolus administrations. To assess the role of high-dose IL-2 in modern combined treatment of patients with renal cell carcinoma, a special register has been created which collects information on patients from more than 40 US clinical centers (PROCLAIMSM, ProleukinObservationRegistrytoEvaluatetheTreatmentPatternsand Clinical Respons einMalignancy). Currently, there are 810 people in this database, and in 356 Proleukin was used in a high-dose regimen in the first line, and was the only treatment option. In this group, patients with a favorable prognosis for M8KSSmedian overall survival was 64.5 months, intermediate - 57.6 months, not favorable - 14 Mec. (J. Immunother. Cancer. 2019; 7: 1-7).

The Russian drug Roncoleukin in clinical studies was studied in the regime of low and medium doses as part of a combination of immuno-and immunochemotherapy. In patients with RCC, the drug was used in combination with IFN-α, TNF-α, cyclophosphamide and, in some cases, with angiogenesis inhibitors. In a group of 300 people who received the drug in a combined mode since 2000, a median survival of 25 months was achieved, and in patients with a favorable prognosis, 42 months. (O.E. Molchanov. Urological sheets; 2018: 8 (3), pp. 67-79).

IFN-α is a pleiotropic cytokine that has been widely used in the treatment of patients with disseminated forms of RCC. It has immunomodulatory, antiviral, antiproliferative and antiangiogenic properties, and also promotes the maturation of antigen-presenting cells. When using IFN-α, the frequency of objective response is 15% (0-29%). As part of the phase III clinical trial, which compared the effectiveness of the combination of IFN-α with vinblastine and vinblastine in mono mode, a median survival of 67.6 weeks was achieved in the study group and 37.8 in the control group. Currently, IFN-α in monotherapy is practically not used in patients with RCC. In modern treatment regimens, it plays the role of a modifier of angiogenesis inhibitors and other drugs.

A known group of treatment methods associated with the suppression of the functions of T-regulatory cells (Treg). Treg is a subset of approximately 5-10% of the total number of peripheral lymphocytes in a healthy person. First described in 1995. Currently, they play a key role in preventing the development of autoimmune reactions and immunosuppression in the process of carcinogenesis. In cancer patients, their number increases, which leads to an acceleration of the progression of the disease, and a decrease in the effectiveness of the treatment (WhitesideT.L. Exp.Opin.Ther. Target. 2018; 22 (4): 353-363). In patients with renal cell carcinoma, DenileukinDiftitox (DD) h low-dose cyclophosphamide in combination with an angiogenesis inhibitor is used in clinical practice. These treatment options are considered complementary (Immunother. 2010; 33 (7): 716-722). Their advantage is that they contribute to increasing the effectiveness of the main course of treatment. But a significant drawback is the increased frequency of side effects, which often leads to the cessation of their use.

Significant advantages of modern drugs used in the treatment of patients with disseminated RCC are the ability to improve long-term treatment results and the low incidence of serious side effects. However, a significant drawback is the lack of a method for accurately determining the moment of change of therapy lines in order to obtain the optimal result.

Most researchers studying the clinical features of targeted and immunologic drugs acknowledge that currently existing methods for assessing the immediate outcome of treatment do not allow an accurate assessment of the moment of disease progression. In this regard, in the literature for several years the issue of the need to continue treatment in the previous mode, despite the observation of progression, has been debated. But if in the first works where similar tactics were used in patients receiving tyrosine kinase inhibitors, they only managed to increase the median survival, then with the advent of new generation immunopreparations, it was noted that continued treatment after progression also leads to a decrease in the volume of tumor damage. The term "pseudo-progression" has appeared in the literature. Pseudo-progression is a phenomenon in which, with treatment, there are signs of disease progression, confirmed by instrumental methods, and with continued treatment without changing drugs, a partial or complete response is observed (World. J. Urol. 2018; 36: 1703-1709. J. Clin. Oncol . 2015; 33 (31): 3541-3543).

There is no exact explanation of the pseudo-progression phenomenon. There are several hypotheses in the literature based on the characteristics of the interaction of the tumor and the immune system during treatment. The first is based on the fact that the immune system needs a lot of time to rebuild against the background of stimulation or reduction of suppressor effects. This leads to late clinical effects that occur later than the interval between examination periods. The second hypothesis is based on the assumption that, at the first stage, for the realization of the clinical effect, hyperinfiltration of tumor foci by immune cells is necessary. In computed tomography, this is perceived as progression. This hypothesis is confirmed in several studies where a biopsy of metastases during progression was performed.

According to various authors, the frequency of pseudo-progression in patients with RCC is from 7 to 15%. The maximum number of observations of this phenomenon was noted in studies of the efficacy and safety of Nivolumab in patients with RCC. Pseudo-progression in the treatment of disseminated forms of RCC is also found with the use of Sunitinib. This is apparently due to the fact that part of the effect of that drug is associated with inactivation and a decrease in the concentration of immunocompetent cells (PLOSONE. 2014; 9 (5), e96316: 1-8).

In clinical trials of immunotropic drugs, pseudo-progression was also noted in other tumors, including bladder cancer, melanoma, colorectal cancer and lung cancer. Its frequency in this case varies from 1.7 to 20%.

Accurate differential diagnosis of true and pseudo-progression is one of the key components to increase the effectiveness of the treatment of disseminated forms of RCC. If this phenomenon is not taken into account, then a statement of the fact of progression according to radiological criteria indicates the need to change the line of therapy. If this is pseudo-progression, then the patient stops taking the drug that was effective. If you ignore the fact of x-ray progression and continue taking the drug, then the patient in this case continues to receive ineffective treatment. An increase in the volume of the tumor mass during this period potentially reduces the likelihood of a positive clinical effect when changing the line of therapy. Both options will lead to a deterioration in long-term results of treatment.

The literature traces three strategies to overcome the negative effects of pseudo-progression on long-term treatment outcomes:

1. Continuation of treatment, regardless of the nature of the progression.

2. Improving the algorithms of x-ray diagnostics.

3. Search for molecular biological indicators that would confirm the data of x-ray studies.

The first strategy is fully implemented in the study of the effectiveness and safety of Nivolumab in the framework of I, II and III phases of clinical trials. As part of Phase I, one 72-year-old man with multiple metastases after the Nivolumab cycle showed a decrease in the size of all foci except the pancreas. Continued treatment with him led to a partial response in this focus. Remission lasted 16 months. The data obtained allowed the use of a similar strategy in the development of treatment protocols in the framework of phase II and III of clinical trials. In the ChekMate 025 study (phase 111), 20% (31 people) of patients received a partial response to treatment while continuing treatment, and stable stabilization was achieved in 33% (51 people) (table 1, pseudo-progression rate in patients with disseminated renal cell carcinoma when using Nivolumaba; DAMA. Oncol. 2016; 2 (9): 1179-1186. Eur. Urol. 2017; 72: 368-376)

A significant drawback of this approach, in our opinion, is that patients who have progression confirmed after a follow-up examination continue to receive a drug that has already lost their effectiveness for a long time. During this period, the growth of the tumor mass occurs, and the potential benefit that can be obtained by using the drugs of the next line decreases.

The second strategy for leveling the negative consequences of pseudo-progression is associated with the modification of the radiological criteria for the response of the tumor to treatment.

To evaluate the response of the tumor to treatment in 1981, WHO proposed criteria that included four response options: complete response (CR) - complete disappearance of all foci for a period of at least 4 weeks; partial response (PR) - reduction of all or individual tumor foci by more than 50% in the absence of progression of the rest; disease stabilization (SD) - a decrease of less than 50% or an increase of less than 25% in the absence of new lesions; progression (PD) - an increase of more than 25% in one or more lesions, or the appearance of new ones.

In 2000, in connection with the introduction of computed tomography into widespread clinical practice, the RECIST criteria (ResponseEvaluationCriteriainSolidTumors) were proposed, the concepts of measurable, non-measurable and marker foci were introduced (J. Natl. Cancerlnst. 2000; 92: 205-216).

Measured foci - foci having an axial plane size of at least 10 cm with spiral computed tomography with a slice thickness of 5 mm during reconstruction or a minimum of 20 mm with step computed tomography with a slice thickness of 10 mm.

Non-measurable foci: small (up to 10 mm), bone metastases, leptomeningeal metastases, pericardial and pleural effusions, foci with cystic or necrotic transformation, lymphogenous carcinomatosis of the skin and lungs.

Marker (targeted, target) foci - foci of the largest diameter (up to 5 per organ, up to 10 in total), suitable for accurate repeated measurement. The rest are non-marker. Response criteria according to RECIST: complete response (CR) - complete disappearance of all marker foci; partial response (PR) - a decrease of more than 30% in the sum of the maximum size of foci; disease stabilization (SD) - a decrease of less than 30% or an increase of less than 20% in the absence of new lesions; progression (PD) - the appearance of a new focus or an increase in the sum of the largest sizes by more than 20%.

With the advent of targeted drugs, the nature of the dynamics of the tumor during treatment has changed. In 2009, a modified version of the response criteria appeared - RECISTv 1.1, where for the first time the appearance of new foci was not considered as a sign of disease progression. With the advent of the new generation of immunotropic drugs, a number of modified scales were proposed to evaluate the response of the tumor to treatment: irRC (immune-relatedresponsecriteria), irRECIST (immune-relatedRECIST), iRECIST (immuneRECIST), imRECIST (immune-modifiedRECIST). The principal differences between them are the nature of the measurement of foci (linear dimensions or two mutually perpendicular), the basic size of the foci (5 × 5 mm and more than 10 mm), the number of targeted target lesions in each organ (5 in irRCn 10 in the rest). But all of these scales require confirmation of progression in a subsequent study of 4-8 weeks (Ann. Oncol. 2019; 30: 385-396).

The advantage of these modified regimes for assessing the immediate clinical effect is that the appearance of new foci is not considered an unambiguous sign of progression. The need for repeated examinations to confirm the increase in the size of the foci allows us to differentiate patients with pseudoprogression. A significant drawback is the inability to quickly diagnose true progression. As a result, patients continue to receive treatment that has lost its effectiveness, which negatively affects the prognosis of the disease.

The third strategy involves the search for molecular biomarkers that would help, with greater accuracy than radiological methods, differentiate true and pseudo-progression.

In the literature, there are indications of many molecular biological components, with the help of which it would be possible to monitor the treatment of cancer patients. They are associated with the assessment of histological, serological markers, circulating immune cells, as well as the use of “liquid biopsy” methods, in which circulating DNA and / or circulating tumor cells are evaluated.

Most publications are related to the theoretical justification for the use of certain markers in cancer patients. Four research directions are fundamentally considered: 1) assessment of the biological potential of a tumor: genomic, functional markers, markers of subpopulations of tumor-infiltrating lymphocytes; 2) a quantitative assessment of circulating tumor and immunocompetent cells; 3) phenotypic and functional assessment of circulating tumor and immunocompetent cells; 4) antigen-specific monitoring of T-lymphocytes: binding, clonal activation, characterization of the t-cell receptor (Mol. Med. 2012; 18: 1499-508).

Most studies relate to monitoring various treatment options, as well as the predictive and predictive potential of biomarkers. Only a few studies are devoted to differential diagnosis of true and pseudo-progression. And most of them were carried out with the participation of patients with melanoma and using the methods of "liquid biopsy", evaluating the circulating tumor DNA (Oncol. 2015; 32: 579-586).

Currently, the available literature does not indicate methods that would accurately differentiate between true and pseudo-progression in patients with RCC and thus determine the time to stop treatment with drugs that have lost their effectiveness and start treatment with the next line of drugs.

Closest to the proposed is a method for determining the treatment of locally advanced and disseminated renal cell carcinoma (Patent 2403056 of the Russian Federation), which we took as a prototype.

This method is based on the calculation of the values of discriminant functions that predict the life expectancy of the patient.

The essence of the method proposed by the authors is that for a patient with a histologically confirmed diagnosis of renal cell carcinoma, upon admission to the clinic, a general clinical examination is performed, including computed tomograms, ultrasound, isotopic and radiological examinations, as a result of which the stage of the disease is established.

Immunological examination is carried out in patients with locally prevalent and disseminated forms, determining the absolute concentration of cells with the CD 57+ phenotype in mm3 and the CD4 + CD25 + Treg phenotype in mm3, as well as the level of spontaneous production of interleukin-6 (IL-6) in PG / ml (X3), interleukin - 8 (IL-8) in pg / ml and interferon - γ (IFN - γ) in pg / ml.

Next, the discriminant functions are calculated:

F1 = 0.0003 × X1 + 0.0089 × X2 + 0.0036 × X3 + 0.0125 × X4 - 0.0012 × X5 - 2.197;

F2 = 0.0018 × X1 + 0.0243 × X2 + 0.0096 × X3 + 0.0235 × X4 - 0.001 × X5 - 7.876;

F3 = 0.0234 × X1 + 0.0372 × X2 + 0.0227 × X3 + 0.0561 × X4 - 0.0067 × X5 - 24.608;

F4 = 0.0611 × X1 + 0.0506 × X2 + 0.0415 × X3 + 0.0305 × X4 - 0.0091 × X5 - 63.225,

where X1 is the level of spontaneous production of interferon - γ; X2 - level of spontaneous production of interleukin - 8; X3 - level of spontaneous production of interleukin - 6; X4 is the concentration of cells with the phenotype CD4 + CD25 + Treg; X5 is the concentration of cells with the CD57 + phenotype.

Then compare the values of discriminant functions (table 2, predicting the life expectancy of the patient by comparing the values of discriminant functions).

Patients with an expected life expectancy of less than 9 months are given the following drugs: Roncoleukin 2 mg intravenously - 3 times a week for 8 weeks, dissolving it in 400 ml of 0.9% NaCl; Interal (interferon-α), 12 million ME intramuscularly every other day, alternating with Roncoleukin - 8 weeks; Xeloda - 1000 mg / m twice a day - 14 days, starting from 8 days after the first injection of Roncoleukin; cyclophosphamide at a dose of 200 mg per day 3 times a week for 3 weeks, starting from 9 days after the first injection of Roncoleukin; Neovastet - 240 ml per day - 8 weeks. Such courses of treatment are carried out before the disease progresses; in case of progression, symptomatic therapy is carried out.

Patients with an expected life expectancy of 9 to 22 months are given the following drugs: Roncoleukin 2 mg intravenously - 3 times a week for 8 weeks, dissolving it in 400 ml of 0.9% NaCl; Interal (interferon-α), 12 million ME intramuscularly every other day, alternating with Roncoleukin - 8 weeks; Xeloda - 1000 mg / m twice a day - 14 days, starting from 8 days after the first injection of Roncoleukin; cyclophosphamide at a dose of 200 mg per day 3 times a week for 3 weeks, starting from 9 days after the first injection of Roncoleukin; Neovastet - 90 ml per day - 8 weeks. Such courses of treatment are carried out before the disease progresses, and in the case of progression, the same treatment is carried out as in the group of patients with a life expectancy of less than 9 months.

Patients with an expected life expectancy of 22 to 36 months are given the following drugs: Roncoleukin 2 mg intravenously - 3 times a week for 8 weeks, dissolving it in 400 ml of 0.9% NaCl; Interal (recombinant interferon-α) at 12 million IU intramuscularly every other day, alternating with Roncoleukin - 8 weeks; Xeloda - 1000 mg / m ² twice a day for 14 days, starting from 8 days after the first injection of Roncoleukin; cyclophosphamide at a dose of 200 mg per day 3 times a week for 3 weeks, starting from 9 days after the first administration of Roncoleukin. During the first twelve months from the start of treatment, such courses are carried out with an interval of 4-6 weeks, for the next twelve months - with an interval of 4-8 months until the disease progresses, and in case of progression, the same treatment is carried out as in the group of patients with predicted life expectancy from 9 to 22 months.

Patients with an expected life expectancy of more than 36 months are given the following drugs: Roncoleukin 2 mg intravenously - 3 times a week for 8 weeks, dissolving it in 400 ml of 0.9% NaCl; Interal (recombinant interferon-α) at 12 million IU intramuscularly every other day, alternating with Roncoleukin - 8 weeks; Xeloda - 1000 mg / m twice a day for 14 days, starting from 8 days after the first injection of Roncoleukin; cyclophosphamide at a dose of 200 mg per day 3 times a week for 3 weeks, starting from 9 days after the first injection of Roncoleukin. During the first twelve months from the start of treatment, such courses are carried out with an interval of 4-6 weeks, during the next twelve months - with an interval of 4-8 months. In the absence of signs of disease progression within 24 months from the start of treatment, Roncoleukin is administered to patients 2 mg intravenously 3 times a week for 8 weeks, dissolving it in 400 ml of 0.9% NaCl, repeating such courses with an interval of 4-8 months in the absence of signs of progression, and with progression, the same treatment is carried out as in the group of patients with a projected life expectancy of 22 to 36 months.

Control computed tomographic and ultrasound examinations are carried out 2 weeks after the end of the next course of treatment and with an interval of 12 weeks thereafter. Osteoscintigraphy was performed no more than 1 time in 24 weeks. During the survey, the dynamics of the measured and non-measured lesions were evaluated using standard RECIST criteria (JNatlCancerlnst. 2000; 92: 205-216).

Thus, the definition of treatment tactics in the prototype was carried out depending on the estimated life expectancy. Long-term monitoring of patients (up to their death) showed the advantage of this method compared to known analogues, including those used earlier in our clinic (the prototype method was developed with the participation of the authors of the present invention). Such tactics improved the long-term results of treatment, however, our further studies, as well as the discoveries made in the field of oncoimmunology, led us to conclude that some of the provisions set forth in the prototype are currently outdated.

So, one of the indicators that is taken into account in the discriminant formulas of the prototype is the concentration of T-regulatory cells (CD4 + CD25 + FoxP3). This is one of the fundamental indicators that reflects the interaction of the tumor and the immune system. In the last 7 years, drugs Nivolumab, Pembrolizumab appeared, one of the main mechanisms of action of which is associated with the depletion or inactivation of T-regulatory cells. In addition, the introduction of metronomic chemotherapy regimens (long-term administration of drugs below the cytotoxic dose) using cyclophosphamide led to the same results (CancerRes. 2012; 72: 3439-3444). This generally changes the forecast, and affects the calculation of life expectancy.

In the prototype, Xeloda is used as a component of chemotherapy. Since the development of the method, many studies have been carried out, including in our clinic, which have demonstrated that the introduction of this drug into the treatment regimen significantly increases its toxicity. At the same time, his contribution to the achievement of the clinical result is small. In connection with the emergence of more effective treatment regimens for patients with RCC, Xeloda has lost its significance in the treatment of this pathology. However, at the time of development of the treatment method described in the prototype, it was the only drug that was widely used in various chemoimmunotherapy regimens and allowed to realize simultaneously cytotoxic and immunomodulating effects.

The prototype also uses the drug Roncoleukin (recombinant yeast IL-2) at low doses (2.0 mg intravenously drip three times a week). Interleukin-2 is known to be a factor in cell proliferation and maturation with the CD25 marker. This receptor is present both on T-helpers of the first type, “triggering” the cellular immune response, and on T-regulatory cells. Thus, this drug can either stimulate or suppress the immune response, depending on what type of cells it interacts with. It is known that the affinity of T-regulatory cells for IL-2 at low doses (60,000-72,000 IU / kg) is higher than that of T-helpers. In this regard, in our clinic and in other institutions, treatment methods have been developed that involve the simultaneous administration of IL-2 and drugs that block T-regulatory cells. In connection with the advent of more effective drugs, such complex methods are not currently used in wide clinical practice. However, at the time of the prototype, this was the most optimal option, combining high efficiency with a low frequency of side effects. In the USA and European countries, when the possibilities of standard treatment options are exhausted, high doses of IL-2 (600000-720000 IU / kg) are used. This treatment regimen leads to anergy of T-regulatory cells by reducing the expression of receptors in the feedback system, and contributes to the achievement of good treatment results.

The prototype uses the drug Neovastet. According to the literature, it is known that in mono mode it is an effective treatment for patients with disseminated RCC in the high-dose regimen (240 ml per day), and in the low-dose regimen (60-90 ml per day) it is not effective (Ann. Oncol. 2002; 13 : 1259-1263). The prototype noted that the combined use of Neovastat with cytokines increases the effectiveness of treatment both in the high-dose mode and in the low-dose mode. Further studies in our clinic in patients with RCC showed that a combination with modern methods of drug treatment of RCC does not lead to an increase in efficiency.

All of the above indicates that in the light of the latest achievements of medical science, the prototype treatment tactics do not correspond to the modern level, being insufficiently effective, although, of course, it has the right to exist and, with some modifications, can be used in medical practice.

The technical result of the present invention is to increase the life expectancy of patients with RCC due to more accurate differential diagnosis of true and pseudo-progression, as well as optimizing the use of drugs.

This result is achieved by the fact that the patient is injected with Alfaron (recombinant IFN-α2c) intramuscularly 3 times a week in the amount of 1,200,000 IU per day and Endoxan, according to the invention, Endoxan (Cyclophosphamide) is administered orally in the amount of 50 mg per day and additionally Refnot subcutaneously in an amount of 200,000 IU per day twice a week, alternating it with Alfarona, such administration of these drugs is carried out in 8-week cycles, after each cycle, a computed tomographic examination is performed, and in the presence of radiological their signs of disease progression in a patient are determined by the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4) and the absolute concentration of natural killer cells with receptors T-lymphocytes (CD3 + CD16 + 56 +, X5), discriminant functions are calculated from the obtained values:

• F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4 - 0.0043 × X5 - 21.6346;

• F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5 - 3.9664; and at F1> F2, pseudo-progression is established in the patient and treatment is continued in the previous mode, and at F2> F1, treatment is carried out with Sunitinib, which is administered in an amount of 50 mg per day orally for 8 weeks with breaks of two weeks until progression.

Having been professionally treating patients with RCC for several years, we studied various immunotherapy options, as well as the fundamental and clinical aspects of the interaction of the tumor and the immune system. In the process of research, we developed and studied various treatment regimens, including cytokines (recombinant IL-2, recombinant TNF-α, recombinant IFN-α), chemotherapy drugs in immunomodulating modes (Xeloda, 5-fluorouracil, cyclophosphamide) and angiogenesis inhibitors (Neovastet). We have investigated the following immunotherapy options:

1. Modes of monotherapy.

- Monotherapy with recombinant yeast IL-2 (Roncoleukin) in various exchange rates. The drug was administered as a long-term intravenous infusion, subcutaneously and inhalation using a compression nebulizer. We have studied low-dose (2-4 mg per administration) and medium-dose (6-8 mg per administration) modes of use of the drug. High-dose regimens (more than 10 mg per administration) were unacceptable due to the high frequency of side effects;

- monotherapy with recombinant IFN-α drugs (Interal, Intron A, Alfarona) in various dosages (from 3,000,000 to 18,000,000 ME).

- monotherapy with a recombinant tumor necrosis factor (Refnot) drug in various dosages (from 100,000 units to 800,000 units).

- monotherapy with cyclophosphamide preparations (Cyclophosphamide, Endoxan) 50, 100 and 200 mg daily and every other day, 400 and 600 mg every other day, 1000 mg once every 5 days.

2. Combined modes.

- The combination of IFN-α with 5-fluorouracil with systemic prolonged 72-hour administration of 5-fluorouracil and with their joint introduction into the renal artery (Pat. 2179859 C1).

- a four-component regimen, including prolonged intravenous administration of recombinant yeast IL-2 (Roncoleukin) at a dose of 2 mg or inhalation at a dose of 4 mg, recombinant IFN-α at a dose of 9 to 15 million ME depending on tolerance, Xeloda at a dose of 1000 mg / m twice a day and cyclophosphamide at a dose of 200 mg per day.

- a four-component scheme in combination with angiogenesis inhibitors (Neovastet in doses of 90 and 240 ml per day).

- a three-component scheme to suppress the immunosuppressive effect caused by T-regulatory cells: cyclophosphamide - 200 mg three times a week, Neovastet 30 ml twice a day orally daily and Roncoleukin - three times a week, simultaneously with cyclophosphamide in an amount of 1 mg intravenously .

- a three-component scheme, including a recombinant tumor necrosis factor - thymosin α1 (Refnot) at a dose of 200,000 units in combination with the preparation of recombinant IFN-α2c (Alpharone) and cyclophosphamide (Endoxan) at a dose of 50 mg per day in metronome mode.

It is important to note that since 1998 in all patients with disseminated RCC, we studied the immune status in order to assess the prognostic, predictive significance of various parameters, as well as to identify differences in the dynamics of immunological parameters after progression. In patients with blood, the content of lymphocytes, their subpopulations and cytokines was evaluated. Analyzes were carried out in the immunological laboratory of FGUZ VTsERM im. A.M. Nikiforova EMERCOM of Russia on a CytomicsFC 500 laser flow pitometer (BECKMANCOULTERInc, USA) using monoclonal antibodies and consumables from BECKMANCOULTERInc, IMMUNOTECHS.A.S., Protein circuit LLC and Cytokin LLC. The spectrum of the studied parameters and their reference intervals are shown in tables 3 (subpopulations of peripheral blood lymphocytes) and 4 (parameters of the cytokine profile).

The level of lymphocytes and their subpopulations was evaluated in peripheral blood. Analysis of the cytokine profile was carried out in two stages. At the first stage, serum concentration was determined. In the second, a study was conducted in cell culture, where their potential was determined by evaluating the spontaneous and induced production of cytokines. Assessment of lymphocytes, their subpopulations and cytokine profile was carried out at the same time of the day to avoid the influence of circadian oscillations.

From 1998 to 2010, 248 patients with disseminated RCC received various chemoimmunotherapy options. The basic treatment option was a four-component regimen including Roncoleukin, interferon-α, Xeloda and antimetabolite (cyclophosphamide). Therapy was carried out before progression, the emergence of insurmountable complications, or for other reasons not related to medical indications. The component composition and number of chemoimmunotherapy cycles are shown in Table 5 (component composition and number of chemoimmunotherapy cycles in patients of the studied group).

To assess the prognosis of the disease, the MSKCC scale adopted in most studies was used, and we modified the scale with the inclusion of immunological parameters (table 6: risk factors, MSKCC scale).

We created a modified scale using the immune status and MSKCC indicators as variables. As a result of one-way and multi-factor analysis using the Cox proportional risk model, parameters were identified that significantly affect the long-term results of treatment (table 7: multi-factor analysis results in a group of patients with renal cell carcinoma treated with chemoimmunotherapy).

Based on multivariate analysis, an integrated model has been created that includes factors of the MSKCC scale and immunological prognostic factors (table 8: parameters of the prognostic model created on the basis of multivariate analysis).

The model includes determining the prognosis according to the MSKCC scale and evaluating it in combination with immunological risk factors (1, 2-3, more than 3 factors).

As a result, 9 clinical groups were formed with different long-term treatment results (table 9: long-term treatment results for patients with RCC with a different number of immunological prognostic factors)

The best long-term results (median survival of 51 months) were obtained in the subgroup with a favorable prognosis and the least number of immunological risk factors.

In the second stage, starting in 2010, we modified the immunotherapy regimen. The most effective combination, in our opinion, is the combination: a recombinant tumor necrosis factor - thymosin α1 (Refnot) - 200,000 units subcutaneously - twice a week, recombinant interferon-α2c (Alpharone) - 1,200,000 IU intramuscularly three times a week, alternating with Refnotom and cyclophosphamide (Endoxan) 50 mg orally daily.

Refnot is a recombinant form of tumor necrosis factor-α (TNF-α, TNF-α). According to the spectrum of cytotoxic and cytostatic effects, Refnot corresponds to TNF-α, but has 100 times less toxicity. TNF-α is a pleiotropic cytokine that realizes its effects due to two types of receptors: TNFR1 and TNFR2. Through TNFR1, its direct proapoptotic effect on tumor cells and inhibition of angiogenesis is realized. TNFR2 is localized on T-regulatory cells, and according to some authors through this receptor it promotes their maturation. According to our data, the use of the drug Refnot does not increase the concentration of T-regulatory cells in the blood of patients with renal cell carcinoma.

In clinical studies, Refnot demonstrated an increase in the effectiveness of treatment of patients with breast cancer in combination with chemotherapy. In the literature, we did not find mention of the use of Refnot in patients with RCC.

In the course of the study, we studied various options for the use of Refnot in patients: from 100,000 units to 800,000 units for a single administration, 2 or 3 times a week, in mono mode or in combination with other drugs. The greatest effect with minimal toxicity was achieved at a dose of 200,000 units twice a week in a combined mode.

The combination of Refnot with cyclophosphamide increased the effectiveness of treatment. We have studied various dosages of cyclophosphamide in a combined regimen. The metronome modes of cyclophosphamide (50 mg per day for a long time) turned out to be the most optimal. Increasing the dose often led to an increase in hematological toxicity, which led to the need to interrupt the immunotherapy cycle.

We considered it expedient to additionally include IFN-a in the medium-dose regimen (12000000 ME) in the immunotherapy regimen. According to molecular biological studies, IFN-α and TNF-α potentiate each other's action. According to our immunological studies, the combination of cyclophosphamide with IFN-α enhances the effect of the deletion of T-regulatory cells. In this regard, we considered it appropriate to use the specified combination.

From 2010 to 2013, we used the following scheme for 32 patients with RCC: Refnot - 200,000 units subcutaneously - twice a week + Alpharon - 12 million ME intramuscularly three times a week, alternating with Refnot + Endoxan 50 mg orally daily in eight-week cycles. A total of 86 treatment cycles were performed (Table 10. Long-term results of treatment of patients with RCC with a different number of immunological prognostic factors (Refnot + Alfaron + Endoxan).

The indicated three-component scheme is superior in effectiveness to the drugs used in the first line of treatment in patients with disseminated RCC, as well as the chemoimmunotherapy schemes used earlier (table 9).

The development of a method for differential diagnosis of true and pseudo-progression was carried out by analyzing the dynamics of the disease in a group of patients who received various chemoimmunotherapy options from 2005 to 2017, treatment according to an optimized three-component regimen (Refnot + Endoxan + Alfarona) in the first line and Nivolumab in Pliny recommended by the manufacturer doses (3 mg / kg of the mass intravenously drip once every 14 days). According to our data, the dynamics of immunological parameters in patients with renal cell carcinoma against the background of x-ray progression is not associated with the treatment line, but is determined by the biological characteristics of the interaction of the tumor and the immune system at different stages of carcinogenesis. Validation of the technique was carried out on groups of patients who received an optimized three-component scheme or Nivolumab (table 11: development and validation of a method for differential diagnosis of true and pseudo-progression).

The algorithm for developing the differential diagnostic method included three stages. At the first stage, a one-way analysis was carried out, where immunological parameters were included as variables (tables 3, 4), the relationship of individual immunological components with true or pseudo-progression was revealed. At the second stage, a multivariate analysis was carried out in which mutually affecting components were excluded. The results of univariate and multivariate analysis are shown in table 12 (immunological parameters that determine progression and pseudoprogression). The discriminant analysis was carried out using the parameters identified in multivariate.

Spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4), absolute concentration of natural killer cells with T-lymphocyte receptors (CD3 + CD16 + 56+, X5) were used as variables for discriminant analysis. Based on the data obtained, linear classification functions were created:

F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4 - 0.0043 × X5 - 21.6346.

F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5 - 3.9664.

F1 corresponds to pseudo progression, F2 to true progression. When F1> F2, treatment is continued as before. With F2> F1, true progression is confirmed and the patient is recommended to continue treatment using the next-line drug - Sunitinib.

The essence of the method is as follows.

A patient with a histologically confirmed diagnosis of RCC is subjected to a general clinical examination, including osteoscinigraphy and computed tomography of the pelvic organs, abdominal cavity and lungs with contrast enhancement, as a result of which the stage of the disease is established. An eight-week cycle of therapy is carried out for a patient with disseminated RCC as a first line using a combination of Endoxan (cyclophosphamide) - 50 mg per day orally, Alpharone (IFN-α) - IM intramuscularly three times a week, alternating with Refnot - 200,000 units per day twice a week subcutaneously. After 8 weeks, a follow-up examination is performed, including computed tomography of the pelvic organs, abdominal cavity and lungs with contrast enhancement. Evaluation of the effectiveness of treatment is carried out using the criteria of RECISTv 1.1 (Eur. J. Cancer. 2009; 45: 228-247).

When analyzing computed tomograms, targeted foci are distinguished - foci of the largest diameter, suitable for accurate repeated measurement. In total, up to five foci are allocated (no more than two per organ). Target foci should be at least 10 mm in diameter in the organs, at least 10 mm in length for lesions of the bones (lytic or mixed foci) and at least 15 mm for lesions of the lymph nodes. The remaining foci are non-targeted. To assess the size of metastases in the parenchymal organs and bones, the largest focal diameter in the axial plane is used, and for the lymph nodes, the focal size along the short axis.

After an eight-week course of treatment, an assessment is made: 1) of all previously selected targeted lesions (even if their size has ceased to be the largest); 2) all previously selected non-targeted outbreaks; 3) new foci.

Categories of the general response to treatment: complete response (CR), partial response (PR), stabilization (SD), progression (PD), evaluation impossible (NE).

Assessment of the dynamics of targeted lesions is carried out by calculating the sum of their maximum diameters (and the smallest diameter in case of damage to the lymph nodes):

1. The complete answer (CR) is the disappearance of all extralymphatic target lesions; reduction of all pathological lymph nodes to a size along the short axis of less than 10 mm.

2. Partial response (PR) - a decrease in the sum of the maximum diameter of the lesions by at least 30% compared with the initial study.

3. Progression (PD) - an increase in the sum of maximum diameters by at least 20% compared with the smallest sum of maximum diameters (nadir) calculated for any of the studies (including primary). The sum of the maximum diameters should increase by at least 5 mm.

4. Stabilization (SD) - the absence of dynamics of the sum of the maximum diameters, as well as its increase or decrease, which does not meet the criteria of PR or PD.

Assessment of non-targeted lesions:

1. The complete answer (CR) is the disappearance of all extralymphatic non-targeted lesions. Reduction of all pathological lymph nodes to a size along the short axis of less than 10 mm. Normalization of tumor markers.

2. Incomplete response / lack of progression - preservation of at least one non-targeted focus or preservation of tumor markers above normal.

3. Progression (PD) - reliable progression of existing non-targeted lesions.

The overall response to treatment was assessed by comparing the dynamics of targeted and non-targeted lesions (Table 13: overall response to treatment in patients with measurable lesions in the initial examination).

Osteoscintigraphy is carried out with a frequency of once every 24-26 weeks.

If there are signs of disease progression, an immunological examination is performed on the patient, determining the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), and induced production of TNF-α (X4) in the patient's blood ), and the absolute concentration of natural killer cells with T-lymphocyte receptors (CD3 + CD16 + 56 +, X5). Based on the obtained values, discriminant functions are calculated:

F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4 - 0.0043 × X5 - 21.6346;

F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5 - 3.9664.

In the case when F1> F2 y of the patient, pseudo-progression is established and treatment is continued as before, and when F2> F1, the patient is treated with Sunitinib, which is administered at a dose of 50 mg per day orally in the form of eight-week cycles with breaks of two weeks before progression .

The essence of the method is illustrated by examples.

Example 1

Patient Ch, born 1948

10/15/2014. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation. The patient did not show active complaints. General condition is satisfactory. From the anamnesis it is known that 07/14/2011 left-sided nephrectomy in Clinical Hospital No. 122 named after L.G. Sokolova FMBA of the Russian Federation regarding a tumor of the left kidney. Histologically - clear cell renal cell carcinoma (from 07.27.2011). After surgery, he was under the supervision of Clinical Hospital No. 122 named after L.G. Sokolova FMBA of the Russian Federation. On September 17, 2014, according to an X-ray examination, two rounded formations in the left lung were detected with dimensions of 15 mm and 23 mm. An oncologist consultation was recommended, in connection with which he turned to the polyclinic of the Federal State Budgetary Institution "Russian Scientific Center for Scientific and Technological Development" of the Ministry of Health of the Russian Federation.

The examination revealed the following changes.

10/20/2014. Osteoscintigraphy - without pathology.

10/20/2014. Isotopic renography, a function of the right kidney, is within normal limits. On the left is the function curve.

10/23/2014. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 20 mm was determined. In the left lung there are two foci measuring 15 × 15 × 28 mm and 15 × 15 × 15 mm.

10.24.2014. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

As a result of the examination, the diagnosis was established: renal cell carcinoma of the left kidney TxN0M0. 07/14/2011 - left-sided nephrectomy. Progression: metastases in the right lung from 09/17/2014, metastases to the paraaortic lymph nodes from 10.23.2014.

Target foci:

1. The left lung: a) 15 × 15 × 28 mm; b) 15 × 15 × 15 mm.

2. Lymph nodes: 45 × 20 mm.

Sum of maximum diameters: 28 mm + 20 mm + 15 mm = 63 mm.

From October 27, 2014 to December 21, 2014, an eight-week treatment cycle was conducted on an outpatient basis in the following mode: Alfaron - I intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

10/27/2014, 10/29/2014, 10/31/2014, 11/03/2014, 11/05/2014, 11/11/2014, 11/10/2014, 12/12/2014, 11/14/2014, 11/17/2014, 11/19/2014, 11/21/2014, 11/24/2014. 2014, 12/26/2014, 11/28/2014, 12/12/2014, 3/12/2014, 12/05/2014, 12/12/2014, 10/12/2014, 12/12/2014, 12/15/2014, 12/17/2014, 12/19/2014, Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

10/28/2014, 10/30/2014, 11/4/2014, 6/11/2014, 11/11/2014, 11/13/2014, 11/18/2014, 11/20/2014, 11/25/2014, 11/27/2014, 2/12/2014, 4/12/2014, 9/12. 2014, 12/11/2014, 12/16/2014, 12/18/2014 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From October 27, 2014 to December 21, 2014, Endoxan was administered at a dose of 50 mg per day orally.

12/30/2014. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 20 mm was determined. In the left lung there are two foci measuring 15 × 15 × 31 mm and 15 × 15 × 16 mm.

01/12/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory.

The course of treatment was satisfactory. After the introduction of Alfarona, a short-term (up to four hours) temperature increase was noted, about the body up to 37.5 ° -38 ° C, stopped by taking paracetamol.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 15 × 15 × 31 mm; b) 15 × 15 × 16 mm.

2. Lymph nodes: 45 × 20 mm.

Sum of maximum diameters: 31 mm + 16 mm + 20 mm = 67 mm. In a previous study, the sum of the maximum diameters is 63 mm. Growth + 6.3%, which met the criteria for stabilization.

From January 12, 2015 to March 8, 2015, an eight-week treatment cycle was conducted on an outpatient basis in the following mode: Alfaron - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

01/12/2015, 01/14/2015, 01/16/2015, 01/19/2015, 01/21/2015, 01/23/2015, 01/26/2015, 01/28/2015, 01/30/2015, 02/02/2015, 4/02/2015, 6/02/2015, 9/02. 2015, 02/11/2015, 02/13/2015, 02/16/2015, 02/18/2015, 02/20/2015, 02/23/2015 02/25/2015, 02/27/2015, 02/03/2015, 03/04/2015, 03/03/2015 Alfaron was administered at a dose of 1,200,000 ME intramuscularly according to the instructions.

01/13/2015, 01/15/2015, 01/20/2015, 01/22/2015, 01/27/2015, 01/29/2015, 02/03/2015, 02/05/2015, 02/10/2015, 02/12/2015, 02/17/2015, 02/19/2015, 02/24/2015. 2015, 02/26/2015, 03/03/2015, 03/05/2015 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 12.01.2015 to 8.03.2015, Endoxan was administered at a dose of 50 mg per day orally.

03/10/2015. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 50 × 20 mm in size was determined. In the left lung there are two foci measuring 17 × 18 × 35 mm and 15 × 16 × 18 mm.

03/12/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the introduction of Alfarona, a short-term (up to four hours) increase in body temperature to 37.5 ° -38 ° C was observed, which was stopped by taking paracetamol.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 17 × 18 × 35 mm; b) 15 × 16 × 18 mm.

2. Lymph nodes: 50 × 20 mm.

Sum of maximum diameters: 35 mm + 18 mm + 20 mm = 73 mm. Nadir (the minimum value during the study) of the sum of the maximum diameters is 63 mm. An increase of + 15.9%, which met the criteria for stabilization.

From March 16, 2015 to May 10, 2015, an eight-week treatment cycle was carried out on an outpatient basis in the following mode: Alpharon - I intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

03/16/2015, 03/18/2015, 03/20/2015, 03/23/2015, 03/25/2015, 03/27/2015, 03/30/2015, 1/4/2015, 04/04/2015, 04/06/2015, 04/08/2015, 04/10/2015, 04/13/2015. 2015, 04/15/2015, 04/17/2015, 04/20/2015, 04/22/2015, 04/24/2015, 04/27/2015 04/29/2015, 05/01/2015, 05/04/2015, 05/06/2015, 05/08/2015, Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

03/17/2015, 03/19/2015, 03/24/2015, 03/26/2015, 03/31/2015, 02/04/2015, 7/04/2015, 04/09/2015, 04/14/2015, 04/16/2015, 04/21/2015, 04/23/2015, 04/28/2015. 2015, 04/30/2015, 05/05/2015, 05/07/2015 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From March 16, 2015 to May 10, 2015, Endoxan was administered at a dose of 50 mg per day orally.

05/12/2015. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 50 × 20 mm in size was determined. In the left lung there are two foci measuring 18 × 18 × 36 mm and 15 × 17 × 22 mm.

05/14/2015. Osteoscintigraphy - without pathology.

05/15/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the introduction of Alfarona, a short-term (up to four hours) increase in body temperature to 37.5 ° was observed, stopped by taking paracetamol.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 18 × 36 mm; b) 15 × 17 × 22 mm.

2. Lymph nodes: 50 × 20 mm.

Sum of maximum diameters: 36 mm + 22 mm + 20 mm = 78 mm. The nadir of the sum of the maximum diameters is 63 mm. Growth + 23.8%, which met the criteria for progression.

Given that the patient according to computed tomographic examination revealed signs of disease progression, an immunological study was conducted.

05/20/2015. The immunogram. IL-10 (spontaneous production) - 80 pg / ml, IL-8 (induced production) - 1995 pg / ml, IL-4 (spontaneous production) - 75 pg / ml, TNF-α (induced production) - 952 pg / ml, CD3 + CD16 + 56 + - 254 / mm ³ .

05/22/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 80 + 0.026 × 1995 + 0.0246 × 75 + 0.0019 × 952 - 0.0043 × 254 - 21.6346 = 37.4;

• F2 = 0.0144 × 80 + 0.0006 × 1995 + 0.0012 × 75 + 0.0004 × 952 + 0.0161 × 254 - 3.9664 = 2.9.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From 8/25/2015 to 07/19/2015, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

05/25/2015, 05/27/2015, 05/29/2015, 06/06/2015, 06/06/2015, 06/06/2015, 06/08/2015, 06/10/2015, 06/06/2015, 06/15/2015, 06/17/2015, 06/19/2015, 06/22/2015. 2015, 06/24/2015, 06/26/2015, 06/29/2015, 07/07/2015, 07/03/2015, 07/07/2015 07/08/2015, 07/10/2015, 07/13/2015, 07/15/2015, 07/17/2015 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

05/26/2015, 05/28/2015, 06/06/2015, 06/06/2015, 06/09/2015, 06/11/2015, 06/16/2015, 06/18/2015, 06/23/2015, 06/25/2015, 06/30/2015, 02/07/2015, 7/07. 2015, July 9, 2015, July 14, 2015, July 6, 2015 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From May 25, 2015 to July 19, 2015, Endoxan was administered at a dose of 50 mg per day orally.

07/21/2015. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 40 × 20 mm in size was determined. In the left lung there are two foci measuring 18 × 17 × 35 mm and 15 × 17 × 22 mm.

07/23/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the administration of Alfarona, a short-term (up to four hours) increase in body temperature to 37.5 ° С was noted, which was stopped by paracetamol administration.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 17 × 35 mm; b) 15 × 17 × 22 mm.

2. Lymph nodes: 40 × 20 mm.

Sum of maximum diameters: 35 mm + 22 mm + 20 mm = 77 mm.

Compared with the previous study, there was a tendency toward a decrease in the size of foci. The nadir of the sum of the maximum diameters is 63 mm. Compared with nadir, an increase of + 22.2% was noted, which met the criteria for progression.

Given that the patient according to computed tomography studies compared with nadir (study from 10/23/2014), the disease progressed, an immunological examination was performed.

07/30/2015. The immunogram. IL-10 (spontaneous production) - 53 pg / ml, IL-8 (induced production) - 1965 pg / ml, IL-4 (spontaneous production) - 30 pg / ml, TNF-α (induced production) - 542 pg / ml, CD3 + CD16 + 56 + - 78 / mm ³ .

07/31/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 53 + 0.026 × 1965 + 0.0246 × 30 + 0.0019 × 542 - 0.0043 × 78 - 21.6346 = 34;

• F2 = 0.0144 × 53 + 0.0006 × 1965 + 0.0012 × 30 + 0.0004 × 542 + 0.0161 × 78 - 3.9664 = -0.52.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From 08/03/2015 to 09/27/2015, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

08/03/2015, 08/05/2015, 08/08/2015, 08/10/2015, 06/12/2015, 08/14/2015, 08/17/2015, 08/19/2015, 08/21/2015, 08/24/2015, 08/26/2015, 08/28/2015, 08/31/2018. 2015, 02.09.2015, 09.09.2015, 09.09.2015, 09.09.2015, 09.09.2015, 09.09.2015, 09.16.2015, 09.09.2015, 09.21.2015, 09.23.2015, 09.25.2015, Alfaron was administered in a dose of 12000000 million ME intramuscularly according to the instructions.

08/04/2015, 08/06/2015, 08/11/2015, 08/13/2015, 08/18/2015, 08/20/2015, 08/25/2015, 08/27/2015, 09/09/2015, 09/03/2015, 09/08/2015, 09/10/2015, 09/15/2015. 2015, 09/17/2015, 09/22/2015, 09/24/2015 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 03/08/2015 to 09/27/2015, Endoxan was administered at a dose of 50 mg per day orally.

09/29/2015. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 40 × 20 mm in size was determined. In the left lung there are two foci measuring 18 × 17 × 35 mm and 15 × 17 × 22 mm.

10/10/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the administration of Alfarona, a short-term (up to four hours) increase in body temperature to 37 ° C was observed, which did not require pharmacological correction.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 17 × 35 mm; b) 15 × 17 × 22 mm.

2. Lymph nodes: 40 × 20 mm.

Sum of maximum diameters: 35 mm + 22 mm + 20 mm = 77 mm.

Compared to the previous study, no dynamics were noted.

The nadir of the sum of the maximum diameters is 63 mm. Compared with nadir, an increase of + 22.2% was noted, which met the criteria for progression.

Given that the patient according to computed tomography studies compared with nadir (study from 10/23/2014), the disease progressed, an immunological examination was performed.

10/06/2015. The immunogram. IL-10 (spontaneous production) - 16 pg / ml, IL-8 (induced production) - 1923 pg / ml, IL-4 (spontaneous production) - 17 pg / ml, TNF-α (induced production) - 914 pg / ml, CD3 + CD16 + 56 + - 411 / mm ³ .

10/10/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 16 + 0.026 × 1923 + 0.0246 × 17 + 0.0019 × 914 - 0.0043 × 411 - 21.6346 = 29.7;

• F2 = 0.0144 × 16 + 0.0006 × 1923 + 0.0012 × 17 + 0.0004 × 914 + 0.0161 × 411 - 3.9664 = 4.4.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From October 12, 2015 to December 6, 2015, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

10/12/2015, 10/14/2015, 10/16/2015, 10/19/2015, 10/21/2015, 10/23/2015, 10/26/2015, 10/28/2015, 10/30/2015, 2/11/2015, 4/11/2015, 6/11/2015, 9/10. 2015, 11/11/2015, 11/13/2015, 11/16/2015, 11/18/2015, 11/20/2015, 11/23/2015, 11/25/2015, 11/27/2015, 11/30/2015, 2/12/2015, 4/12/2015, Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

10/13/2015, 10/15/2015, 10/20/2015, 10/22/2015, 10/27/2015, 10/29/2015, 11/3/2015, 5/11/2015, 10/11/2015, 12/11/2015, 11/17/2015, 11/19/2015, 11/24/2015. 2015, November 26, 2015, December 1, 2015, December 3, 2015, Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From October 12, 2015 to December 6, 2015, Endoxan was administered at a dose of 50 mg per day orally.

12/07/2015. Osteoscintigraphy - without pathology.

12/08/2015. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 40 × 20 mm in size was determined. In the left lung there are two foci measuring 18 × 18 × 39 mm (with a central decay of 7 mm in diameter) and 15 × 16 × 19 mm.

12/10/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the administration of Alfarona, a short-term (up to four hours) increase in body temperature to 37 ° C was observed, which did not require pharmacological correction.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 18 × 39 mm; b) 15 × 16 × 19 mm.

2. Lymph nodes: 40 × 20 mm.

Sum of maximum diameters: 39 mm + 19 mm + 20 mm = 78 mm.

Compared with the previous study, an increase in one of the lesions with the appearance of central necrosis and a decrease in the second lesion were noted.

The nadir of the sum of the maximum diameters is 63 mm. Compared to nadir, an increase of + 23.8% was observed, which met the criteria for progression.

Given that the patient according to computed tomography studies compared with nadir (study from 10/23/2014), the disease progressed, an immunological examination was performed.

12/17/2015. The immunogram. IL-10 (spontaneous production) - 41 pg / ml, IL-8 (induced production) - 1620pg / ml, IL-4 (spontaneous production) - 49 pg / ml, TNF-α (induced production) - 998 pg / ml , CD3 + CD16 + 56 + - 289 / mm ³ .

12/18/2015. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 41 + 0.026 × 1620 + 0.0246 × 49 + 0.0019 × 998 - 0.0043 × 289 - 21.6346 = 24.8;

• F2 = 0.0144 × 41 + 0.0006 × 1620 + 0.0012 × 49 + 0.0004 × 998 + 0.0161 × 289 - 3.9664 = 2.7.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From 8/21/2015 to 02/14/2016, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

12/21/2015, 12/23/2015, 12/25/2015, 12/28/2015, 12/30/2015, 01/01/2016, 4/01/2016, 6/01/2016, 8/01/2016, 01/11/2016, 01/13/2016, 01/15/2016, 01/18/2016. 2016, 01/20/2016, 01/22/2016, 01/25/2016, 01/27/2016, 01/29/2016, 01/02/2016, 02/03/2016, 02/05/2016, 02/08/2016, 02/10/2016, 02/12/2016 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

12/22/2015, 12/24/2015, 12/29/2015, 12/31/2015, 5.01.2016, 7.01.2016, 12.01.2016, 01/14/2016, 01/19/2016, 01/21/2016, 01/26/2016, 01/28/2016, 2.02. 2016, 02/02/2016, 02/09/2016, 02/11/2016 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From December 21, 2015 to February 14, 2016, Endoxan was administered at a dose of 50 mg per day orally.

02.16.2016. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes 40 × 20 mm in size was determined. In the left lung there are two foci measuring 14 × 12 × 28 mm and 13 × 15 × 18 mm.

02/19/2016. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory.

The course of treatment was satisfactory. After the administration of Alfarona, a short-term (up to four hours) increase in body temperature to 37 ° C was observed, which did not require pharmacological correction.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 14 × 12 × 28 mm; b) 13 × 15 × 18 mm.

2. Lymph nodes: 40 × 20 mm.

Sum of maximum diameters: 28 mm + 18 mm + 20 mm = 66 mm. Compared with the previous study, a decrease in both foci was noted.

The nadir of the sum of the maximum diameters is 63 mm. Compared to nadir, an increase of + 4.8% was observed, which met the criteria for stabilization.

From 8/22/2016 to 04/17/2016, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

02/22/2016, 02.24.2016, 02.26.2015, 02.29.2016, 02.03.2016, 03.03.2016, 03.03.2016, 03.03.2016, 03.11.2016, 03.14.2016, 03.16.2016, 03.03.2016, 03.21.2016. 2016, 03.23.2016, 03.25.2016, 03/28/2016, 03/30/2016, 04/04/2016, 04/04/2016, 04/06/2016, 04/08/2016, 04/11/2016, 04/13/2016, 04/15/2016 Alfaron was administered in a dose of 12000000 ME intramuscularly according to the instructions.

02/23/2016, 02/25/2016, 03/03/2016, 03/03/2016, 03/08/2016, 03/10/2016, 03/15/2016, 03/17/2016, 03/22/2016, 03/24/2016, 03/29/2016, 03/31/2016, 04/05/2016. 2016, 04/07/2016, 04/12/2016, 04/14/2016 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 02/22/2016 to 04/17/2016, Endoxan was administered at a dose of 50 mg per day orally.

04/20/2016. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there are two lesions measuring 8 × 10 × 16 mm and 12 × 14 × 16 mm.

04/28/2016. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. After the administration of Alfarona, a short-term (up to four hours) increase in body temperature to 37 ° C was observed, which did not require pharmacological correction.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 8 × 10 × 16 mm; b) 12 × 14 × 16 mm.

2. Lymph nodes: 40 × 15 mm.

Sum of maximum diameters: 16 mm + 16 mm + 15 mm = 47 mm.

Compared with the previous study, there was a decrease in the size of both foci in the lungs and a decrease in the size of the lymph nodes.

The nadir of the sum of the maximum diameters is 63 mm. Compared to nadir, a decrease of 34% was observed, which met the criteria for a partial response.

From 08/05/2016 to 06/26/2016, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 ME intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

05/05/2016, 05/04/2016, 05/06/2016, 05/09/2016, 05/11/2016, 05/13/2016, 05/16/2016, 05/18/2016, 05/20/2016, 05/23/2016, 05/25/2016, 05/27/2016, 05/30/2016. Alfaron was administered at a dose of 12,000,000 on 2016, 1.06.2016, 06.06.2016, 06.06.2016, 06.06.2016, 06.06.2016, 06.06.2016, 06.15.2016, 06.17.2016, 06.20.2016, 06.22.2016, 06.24.2016 ME intramuscularly according to the instructions.

05/05/2016, 05/05/2016, 05/10/2016, 05/12/2016, 05/17/2016, 05/19/2016, 05/24/2016, 05/26/2016, 05/31/2016, 06/06/2016, 06/07/2016, 06/09/2016, 06/14/2016. 2016, 06/16/2016, 06/21/2016, 06/23/2016 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 02/05/2016 to 06/26/2016, Endoxan was administered at a dose of 50 mg per day orally.

06/28/2016. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there are two foci measuring 8 × 8 × 12 mm and 12 × 14 × 14 mm.

06/30/2016. Osteoscintigraphy - without pathology.

07/05/2016. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. There were no episodes of fever against the background of taking immunotherapy.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 8 × 8 × 12 mm; b) 12 × 14 × 14 mm.

2. Lymph nodes: 40 × 15 mm.

The sum of the maximum diameters: 12 mm + 14 mm + 15 mm = 41 mm.

Compared with the previous study, there was a decrease in the size of both foci in the lungs and a decrease in the size of the lymph nodes.

The nadir of the sum of the maximum diameters is 47 mm (study dated 04/20/2016). Compared to nadir, a decrease of 14.6% was observed, which met the criteria for stabilization.

From 8/11/2016 to 09/04/2016, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

07/11/2016, 07/13/2016, 07/15/2015, 07/18/2016, 07/20/2016, 07/22/2016, 07/25/2016, 07/27/2016, 07/29/2016, 01/08/2016, 08/03/2016, 08/05/2016, 08.08. 2016, 08/10/2016, 08/12/2016, 08/15/2016, 08/17/2016, 08/19/2016, 08/22/2016, 08/24/2016, 08/26/2016, 08/29/2016, 08/31/2016, 02/09/2016 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

07/12/2016, 07/14/2016, 07/19/2016, 07/21/2016, 07/26/2016, 07/28/2016, 02/08/2016, 08/08/2016, 08/09/2016, 08/11/2016, 08/16/2016, 08/18/2016, 08/23/2016. 2016, 08/25/2016, 08/30/2016, 09/09/2016 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 11/11/2016 to 09/04/2016, Endoxan was administered at a dose of 50 mg per day orally.

09/06/2016. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there are two foci measuring 8 × 8 × 12 mm and 12 × 14 × 14 mm.

09/09/2016. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 8 × 8 × 12 mm; b) 12 × 14 × 14 mm.

2. Lymph nodes: 40 × 15 mm.

The sum of the maximum diameters: 12 mm + 14 mm + 15 mm = 41 mm.

Compared to the previous study (nadir), no dynamics were noted that met the stabilization criteria.

From September 12, 2016 to November 6, 2016, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

09/12/2016, 09/14/2016, 09/16/2015, 09/19/2016, 09/21/2016, 09/09/2016, 09/26/2016, 09/28/2016, 09/30/2016, 10/03/2016, 10/05/2016, 10/07/2016, 10/10. 2016, 12.10.2016, 10/14/2016, 10/17/2016, 10/19/2016, 10/21/2016, 10/24/2016, 10/26/2016, 10/28/2016, 10/31/2016, 2/11/2016, 4/11/2016 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

09/13/2016, 09/15/2016, 09/20/2016, 09/22/2016, 09/27/2016, 09/29/2016, 10/04/2016, 10/06/2016, 10/11/2016, 10/13/2016, 10/18/2016, 10/20/2016, 10/25/2016. 2016, 10/27/2016, 11/11/2016, 11/03/2016 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From September 12, 2016 to November 6, 2016, Endoxan was administered at a dose of 50 mg per day orally.

November 9, 2016. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there are two foci measuring 6 × 6 × 7 mm and 12 × 12 × 12 mm.

11/11/2016. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 6 × 6 × 7 mm; b) 12 × 12 × 12 mm.

2. Lymph nodes: 40 × 15 mm.

The sum of the maximum diameters: 7 mm + 12 mm + 15 mm = 34 mm.

Compared with the previous study, a decrease in the size of both foci was noted.

The nadir of the sum of the maximum diameters is 41 mm (study dated 04/20/2016). Compared with nadir, a decrease of 20.1% was observed, which corresponded to stabilization criteria.

From 11/14/2016 to 8/01/2017, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

11/14/2016, 11/16/2016, 11/18/2016, 11/21/2016, 11/23/2016, 11/25/2016, 11/28/2016, 11/30/2016, 12/12/2016, 12/05/2016, 12/07/2016, 12/9/2016, 12/12. On 2016, 12/14/2016, 12/16/2016, 12/19/2016, 12/21/2016, 12/23/2016, 12/26/2016, 12/28/2016, 12/30/2016, 02/01/2017, 01/01/2017, 6.01.2017 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

11/15/2016, 11/17/2016, 11/22/2016, 11/24/2016, 11/29/2016, 12/01/2016, 6/12/2016, 12/08/2016, 12/13/2016, 12/15/2016, 12/20/2016, 12/22/2016, 12/27/2016. 2016, December 29, 2016, January 3, 2017, January 5, 2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 11/14/2016 to 8/01/2017, Endoxan was administered at a dose of 50 mg per day orally.

01/11/2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there are two foci measuring 6 × 6 × 7 mm and 12 × 12 × 12 mm.

01/16/2017. Osteoscintigraphy - without pathology.

01/18/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 6 × 6 × 7 mm; b) 12 × 12 × 12 mm.

2. Lymph nodes: 40 × 15 mm.

The sum of the maximum diameters: 7 mm + 12 mm + 15 mm = 34 mm.

Compared with the previous study (nadir), no dynamics were noted that met the stabilization criteria.

From January 23, 2017 to March 19, 2017, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

01/23/2017, 01/25/2017, 01/27/2017, 01/30/2017, 02/01/2017, 02/03/2017, 02/06/2016, 02/08/2017, 02/10/2017, 02/13/2017, 02/15/2017, 02/17/2017, 02/20/2017. 2017, 02.22.2017, 02.24.2017, 02.27.2017, 1.03.2017, 03.03.2017, 03.03.2017, 8.03.2017, 10.03.2017, 03.13.2017, 03.15.2017, 03.17.2017 Alfaron was administered at a dose of 12000000 ME intramuscularly according to the instructions.

01/24/2017, 01/26/2017, 01/31/2017, 02/02/2017, 02/07/2017, 02/02/2017, 02/14/2017, 02/16/2017, 02/21/2017, 02/23/2017, 02/28/2017, 02/03/2017, 7/03. 2017, March 9, 2017, March 14, 2017, March 16, 2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From January 23, 2017 to March 19, 2017, Endoxan was administered at a dose of 50 mg per day orally.

03/21/2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 40 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 12 × 12 mm.

03/24/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 12 × 12 mm.

2. Lymph nodes: 40 × 15 mm.

Sum of maximum diameters: 12 mm + 15 mm = 27 mm.

Compared with the previous study (nadir, the sum of the maximum diameters is 34 mm), one of the foci in the lungs disappeared and the sum of the maximum diameters decreased by 25.9%, which met the stabilization criteria.

From April 3, 2017 to May 28, 2017, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

04/03/2017, 04/05/2017, 04/04/2017, 04/10/2017, 04/12/2017, 04/14/2017, 04/17/2017, 04/19/2017, 04/21/2017, 04/24/2017, 04/26/2017, 04/28/2017, 1.05. 2017, 05/05/2017, 05/05/2017, 05/05/2017, 05/10/2017, 05/12/2017, 05/15/2017, 05/17/2017, 05/19/2017, 05/22/2017, 05/24/2017, 05/26/20 Alfaron was administered at a dose of 12,000,000 ME intramuscularly according to the instructions.

04/04/2017, 04/06/2016, 04/11/2016, 04/13/2017, 04/18/2017, 04/20/2017, 04/25/2017, 04/27/2017, 05/05/2017, 05/04/2017, 05/09/2017, 05/11/2017, 05/16. 2017, 05/18/2017, 05/23/2017, 05/25/2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From April 3, 2017 to May 28, 2017, Endoxan was administered at a dose of 50 mg per day orally.

05/31/2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 12 × 12 mm.

02.06.2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 12 × 12 mm.

2. Lymph nodes: 40 × 15 mm.

Sum of maximum diameters: 12 mm + 15 mm = 27 mm.

Compared to the previous study (nadir), no dynamics were noted that met the stabilization criteria.

From June 5, 2017 to July 30, 2017, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

06/05/2017, 06/06/2017, 06/09/2017, 06/12/2017, 06/14/2017, 06/16/2017, 06/19/2017, 06/21/2017, 06/23/2017, 06/26/2017, 06/28/2017, 06/30/2017, 3.07. 2017, 07/07/2017, 07/07/2017, 07/07/2017, 07/12/2017, 07/14/2017, 07/17/2017, 07/19/2017, 07/21/2017, 07/24/2017, 07/26/2017, 07/28/2017 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

06/06/2017, 06/08/2016, 06/13/2016, 06/15/2017, 06/20/2017, 06/22/2017, 06/27/2017, 06/29/2017, 07/04/2017, 07/06/2017, 07/11/2017, 07/13/2017, 07/18/2017. 2017, 07/20/2017, 07/25/2017, 07/27/2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From 05.06.2017 to 07.30.2017, Endoxan was administered at a dose of 50 mg per day orally.

08/08/2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 12 × 12 mm.

08/03/2017. Osteoscintigraphy - without pathology.

08/08/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 12 × 12 mm.

2. Lymph nodes: 40 × 15 mm.

Sum of maximum diameters: 12 mm + 15 mm = 27 mm.

Compared with the previous study and nadir (03/21/2017), no dynamics were noted, which met the stabilization criteria.

From August 7, 2017 to October 1, 2017, an eight-week treatment cycle was carried out: Alpharone - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

08/08/2017, 08/09/2017, 08/11/2017, 08/14/2017, 08/16/2017, 08/18/2017, 08/21/2017, 08/23/2017, 08/25/2017, 08/28/2017, 08/30/2017, 09/09/2017, 4/09. 2017, September 6, 2017, September 8, 2017, September 11, 2017, September 13, 2017, September 15, 2017, September 18, 2017, September 20, 2017, September 22, 2017, September 25, 2017, September 27, 2017, September 29, 2017, were administered Alfaron in a dose of 1,200,000 ME intramuscularly according to the instructions.

08/08/2017, 08/10/2017, 08/15/2016, 08/17/2017, 08/22/2017, 08/24/2017, 08/29/2017, 08/31/2017, September 5, 2017, September 7, 2017, September 12, 2017, September 14, 2017, September 19. 2017, September 21, 2017, September 26, 2017, September 28, 2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From August 7, 2017 to October 1, 2017, Endoxan was administered at a dose of 50 mg per day orally.

10/03/2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 10 × 10 mm.

10/06/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 10 × 10 mm.

2. Lymph nodes: 40 × 15 mm.

Sum of maximum diameters: 10 mm + 15 mm = 25 mm.

Compared with the previous study, a decrease in the size of the lesion in the lung was noted. Compared to nadir (03/21/2017 - 27 mm.) - reduction in size - 8%, which met the stabilization criteria.

From October 9, 2017 to December 3, 2017, an eight-week treatment cycle was carried out: Alpharone - 12,000,000 ME intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

10/09/2017, 10/11/2017, 10/13/2017, 10/16/2017, 10/18/2017, 10/20/2017, 10/23/2017, 10/25/2017, 10/27/2017, 10/30/2017, 11/01/2017, 11/03/2017, 6.11. Alfaron was administered at a dose of 12,000,000 on 2017, 11/08/2017, 11/10/2017, 11/13/2017, 11/15/2017, 11/17/2017, 11/20/2017, 11/22/2017, 11/24/2017, 11/27/2017, 11/29/2017, 12/01/2017. ME intramuscularly according to the instructions.

10/10/2017, 10/12/2017, 10/17/2017, 10/19/2017, 10/24/2017, 10/26/2017, 10/31/2017, 2/11/2017, 11/11/2017, 11/09/2017, 11/14/2017, 11/16/2017, 11/21. 2017, 11/23/2017, 11/28/2017, 11/30/2017 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From October 9, 2017 to December 3, 2017, Endoxan was administered at a dose of 50 mg per day orally.

December 5, 2017. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 10 × 10 mm. In the right lung there is a lesion measuring 8 × 8 × 10 mm.

12/08/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Two new lesions were revealed in the patient: in the right lung and in the liver, which met the criteria for progression.

Given that the patient according to computed tomography studies showed progression of the disease, an immunological examination was performed.

12/14/2017. The immunogram. IL-10 (spontaneous production) - 38 pg / ml, IL-8 (induced production) - 1743 pg / ml, IL-4 (spontaneous production) - 43 pg / ml, TNF-α (induced production) - 892 pg / ml, CD3 + CD16 + 56 + - 220 / mm ³ .

12/15/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 38 + 0.026 × 1743 + 0.0246 × 43 + 0.0019 × 892 - 0.0043 × 220 - 21.6346 = 27.7;

• F2 = 0.0144 × 38 + 0.0006 × 1743 + 0.0012 × 43 + 0.0004 × 892 + 0.0161 × 220 - 3.9664 = 1.6.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From the 12/18/2017 to the 11/02/2018, an eight-week treatment cycle was carried out: Alfaron - 1,200,000 ME intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

12/18/2017, 12/20/2017, 12/22/2017, 12/25/2017, 12/27/2017, 12/29/2017, 01/01/2018, 3.01.2018, 5.01.2018, 8.01.2018, 01/10/2018, 01/01/2018, 01/15/2018. 2018, 01/17/2018, 01/19/2018, 01/22/2018, 01/24/2018, 01/26/2018, 01/29/2018, 01/31/2018, 02/02/2018, 02/05/2018, 02/02/2018, 02/09/2018 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

12/19/2017, 12/21/2017, 12/26/2017, 12/28/2017, 02/01/2018, 01/01/2018, 01/01/2018, 01/01/2018, 01/16/2018, 01/18/2018, 01/23/2018, 01/25/2018, 01/30/2018. 2017, 02/01/2018, 02/06/2017, 02/08/2018 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From December 18, 2017 to February 11, 2018, Endoxan was administered at a dose of 50 mg per day orally.

02/12/2018. Osteoscintigraphy - without pathology.

02/14/2018. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 10 × 10 mm. In the right lung there is a lesion measuring 8 × 8 × 10 mm.

02.16.2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 10 × 10 mm.

2. Right lung: 8 × 8 × 10 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 10 mm + 10 mm + 15 mm + 6 mm = 41 mm.

Compared with nadir (10.3.2017 - 25 mm), the sum of maximum diameters increased by 64%, which met the criteria for progression.

Given that the patient according to computed tomography studies showed progression of the disease, an immunological examination was performed.

02/21/2018. The immunogram. IL-10 (spontaneous production) - 68 pg / ml, IL-8 (induced production) - 2522 pg / ml, IL-4 (spontaneous production) - 38 pg / ml, TNF-α (induced production) - 1264 pg / ml, CD3 + CD16 + 56 + - 278 / mm ³ .

02/28/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 68 + 0.026 × 2522 + 0.0246 × 38 + 0.0019 × 1264 - 0.0043 × 278 - 21.6346 = 50;

• F2 = 0.0144 × 68 + 0.0006 × 2522 + 0.0012 × 38 + 0.0004 × 1264 + 0.0161 × 278 - 3.9664 = 3.5.

F1> F2, which met the criteria for pseudo progression.

Continued treatment as before. From March 5, 2018 to April 29, 2018, an eight-week treatment cycle was carried out: Alfaron - 1,200,000 IU intramuscularly three times a week; Refnot - 200,000 units subcutaneously twice a week, alternating with Alfarona; Endoxan - 50 mg per day orally.

March 5, 2018, March 7, 2018, March 9, 2018, March 12, 2018, March 14, 2018, March 16, 2018, March 19, 2018, March 21, 2018, March 23, 2018, March 26, 2018, March 28, 2018, March 30, 2018, 2.04. 2018, April 4, 2018, April 6, 2018, April 9, 2018, 04/11/2018, 04/13/2018, 04/16/2018, 04/18/2018, 04/20/2018, 04/23/2018, 04/25/2018, 04/27/2018 Alfaron was administered in a dose of 1,200,000 ME intramuscularly according to the instructions.

March 6, 2018, March 8, 2018, March 13, 2018, March 15, 2018, March 20, 2018, March 22, 2018, March 27, 2018, March 29, 2018, April 3, 2018, April 5, 2018, April 4, 2018, April 12, 2018, April 17, 2018. 2018, 04/19/2018, 04/24/2018, 04/26/2018 Refnot was administered at a dose of 200,000 units subcutaneously according to the instructions.

From March 5, 2018 to April 29, 2018, Endoxan was administered at a dose of 50 mg per day orally.

05/04/2018. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 10 × 10 mm. In the right lung there is a lesion measuring 8 × 10 × 12 mm.

05/11/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of the use of immunopreparations, episodes of an increase in body temperature were not observed.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 10 × 10 mm.

2. Right lung: 8 × 10 × 12 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 10 mm + 12 mm + 15 mm + 6 mm = 43 mm.

Compared with nadir (10.3.2017 - 25 mm), the sum of the maximum diameters was increased by 72%, which met the criteria for progression.

Given that the patient according to computed tomography studies showed progression of the disease, an immunological examination was performed.

05/15/2018. The immunogram. IL-10 (spontaneous production) - 110 pg / ml, IL-8 (induced production) - 543 pg / ml, IL-4 (spontaneous production) - 85 pg / ml, TNF-α (induced production) - 1100 pg / ml, CD3 + CD16 + 56 + - 312 / mm ³ .

05/18/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 68 + 0.026 × 2522 + 0.0246 × 38 + 0.0019 × 1264 - 0.0043 × 278 - 21.6346 = 1.8;

• F2 = 0.0144 × 68 + 0.0006 × 2522 + 0.0012 × 38 + 0.0004 × 1264 + 0.0161 × 278 - 3.9664 = 3.5.

F2> F1, which met the criteria for progression.

Given that, according to a CT scan, the patient showed signs of disease progression, which is also confirmed by the values of discriminant functions, continued treatment using the next-line drug - Sunitinib.

From May 21, 2018 to June 17, 2018 and from July 2, 2018 to July 29, 2018, the patient received Sunitinib 50 mg per day orally.

07/31/2018. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 9 × 10 mm. In the right lung there is a lesion measuring 8 × 8 × 8 mm.

08/03/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. There were no side effects with Sunitinib.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 9 × 10 mm.

2. Right lung: 8 × 8 × 8 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 10 mm + 8 mm + 15 mm + 6 mm = 39 mm.

Compared with the first study after starting taking Sunitinib (05/04/2018 - 41 mm), the sum of the maximum diameters decreased by 5%, which met the stabilization criteria.

From August 6, 2018 to September 2, 2018 and from September 17, 2018 to October 14, 2018, the patient received Sunitinib 50 mg per day orally.

10/16/2018. Osteoscintigraphy - without pathology.

10/18/2018. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 9 × 9 × 9 mm. In the right lung there is a lesion measuring 7 × 8 × 8 mm.

10.24.2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. Against the background of Sunitinib, an increase in pressure to 160/90 mm was noted. A pharmacological correction was carried out with Enap at 10 mg per day, against which blood pressure returned to normal. Sunitinib dose adjustment was not required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 9 × 9 × 9 mm.

2. Right lung: 7 × 8 × 8 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 9 mm + 8 mm + 15 mm + 6 mm = 38 mm. Compared with nadir, after starting taking Sunitinib (07/31/2018 - 39 mm), the sum of the maximum diameters decreased by 2.6%, which met the stabilization criteria.

From October 29, 2018 to November 25, 2018 and from December 10, 2018 to January 6, 2019, the patient received Sunitinib 50 mg per day orally.

01/11/2019. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring 6 mm in diameter. In the right lung there is a lesion measuring 7 × 6 × 5 mm.

01/17/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. He continued to take Enap at 10 mg per day. Blood pressure 120-130 / 90 mm. Sunitinib dose adjustment was not required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 6 × 6 × 6 mm.

2. Right lung: 7 × 6 × 5 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 6 mm + 7 mm + 15 mm + 6 mm = 34 mm.

Compared with the previous study, a decrease in the size of both lesions in the lungs was noted. Compared with nadir, after starting taking Sunitinib (10/18/2018 - 38 mm), the sum of the maximum diameters decreased by 11.8%, which met the stabilization criteria.

From January 21, 2019 to February 17, 2019 and from March 4, 2019 to March 31, 2019, the patient received Sunitinib 50 mg per day orally.

04/04/2019. Osteoscintigraphy - without pathology.

04/04/2019. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring less than 5 mm in diameter. In the right lung there is a lesion measuring 5 × 6 × 5 mm.

04/11/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. He continued to take Enap at 10 mg per day. Blood pressure 120-130 / 90 mm. Sunitinib dose adjustment was not required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 5 × 5 × 5 mm.

2. Right lung: 5 × 6 × 5 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 5 mm + 6 mm + 15 mm + 6 mm = 32 mm.

Compared with the previous study, a decrease in the size of both lesions in the lungs was noted. Compared with nadir, after starting taking Sunitinib (01/11/2019 - 34 mm), the sum of the maximum diameters decreased by 6.2%, which met the stabilization criteria.

From April 15, 2019 to May 12, 2019 and from May 27, 2019 to June 23, 2019, the patient received Sunitinib 50 mg per day orally.

06/26/2019. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring less than 5 mm in diameter. In the right lung there is a lesion measuring 5 × 6 × 5 mm.

07/04/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. He continued to take Enap at 10 mg per day. Blood pressure 120-130 / 90 mm. Sunitinib dose adjustment was not required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 5 × 5 × 5 mm.

2. Right lung: 5 × 6 × 5 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 5 mm + 6 mm + 15 mm + 6 mm = 32 mm.

Compared to the previous study, no dynamics were noted. Compared with nadir, after starting taking Sunitinib (01/11/2019 - 34 mm), the sum of the maximum diameters decreased by 6.2%, which met the stabilization criteria.

From July 8, 2019 to August 4, 2019 and from August 19, 2019 to September 15, 2019, the patient received Sunitinib 50 mg per day orally.

09/17/2019. Computed tomography study. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a focus of 6 mm in diameter of a rounded shape. At the L1-L2 level, a chain of enlarged lymph nodes with a size of 45 × 15 mm was determined. In the left lung there is a lesion measuring less than 5 mm in diameter. In the right lung there is a lesion measuring 5 × 6 × 5 mm.

07/04/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

No active complaints. General condition is satisfactory. The course of treatment was satisfactory. He continued to take Enap at 10 mg per day. Blood pressure 120-130 / 90 mm. Sunitinib dose adjustment was not required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. Left lung: 5 × 5 × 5 mm.

2. Right lung: 5 × 6 × 5 mm.

3. Lymph nodes: 40 × 15 mm.

4. Liver: 6 × 6 × 6 mm.

The sum of the maximum diameters: 5 mm + 6 mm + 15 mm + 6 mm = 32 mm.

Compared to the previous study, no dynamics were noted. Compared with nadir, after starting taking Sunitinib (01/11/2019 - 34 mm), the sum of the maximum diameters decreased by 6.2%, which met the stabilization criteria.

According to computed tomographic examination of the patient, the stabilization of the disease. Treatment continued as before: Sunitinib 50 mg per day orally for 8 weeks with 2-week intervals.

The patient is alive and continues to be observed at the Federal State Budget Scientific Institution "Scientific Center for Chemistry and Medicine" of the Ministry of Health of the Russian Federation. 59 months have passed since the start of treatment. The time to progression was 43 months.

To date, the proposed method has been clinically tested in 78 patients with disseminated and locally advanced renal cell carcinoma treated in the first line: 16 (21%) patients with a favorable prognosis; 32 (41%) - with an intermediate and 9 (38%) - with an unfavorable prognosis according to MSKCC. Data from 38 patients were used to develop the method, 46 for validation. In all patients, when radiological signs of disease progression were detected, differential diagnosis was performed between true and pseudo-progression by calculating discriminant functions on average 5 times (from 2 to 16) during treatment. The median time to progression in the group was 27 months. In the subgroup with a favorable prognosis - 37 months, with an intermediate - 26 months and not favorable - 9 months, which significantly exceeds the results of the prototype and known analogues. More than half of patients (42 people) who received treatment in accordance with the developed method are currently alive. Median survival in the group is not achieved. The middle group is not reached. The average life expectancy of deceased patients in the subgroup with a favorable prognosis was 51 months, with an intermediate - 31 months. The median survival in the subgroup with an unfavorable prognosis was 11 months.

The method in comparison with known analogues has several significant advantages:

1. Improves the immediate results of treatment of patients with disseminated renal cell carcinoma.

2. Increases the life expectancy of patients.

3. Based on the use of modern advances in molecular biology and cellular immunology.

4. It has a significantly lower number of side effects compared to other treatment options.

A method for the treatment of renal cell carcinoma was developed in the group of molecular biological prognosis and individualization of treatment of the Federal State Budget Scientific Center "Russian Scientific Center for Reconstructive Surgery" of the Ministry of Health of the Russian Federation named after Acad. A.M. Granova and to date has passed clinical testing in 78 patients with a positive result.

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

A method for the treatment of renal cell cancer

Claims (3)

A method for the treatment of renal cell carcinoma, comprising administering Alfaron intramuscularly 3 times a week in an amount of 1,200,000 IU per day and Endoxan, characterized in that Endoxan is administered orally in an amount of 50 mg per day and additionally Refnot subcutaneously in an amount of 200,000 units per day two once a week, alternating it with Alfarona, such administration of these drugs is carried out in cycles of 8 weeks, after each cycle, performing a computer-tomographic examination, and in the presence of radiological signs of progression, the disease Evidence in the patient determines the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4) and the absolute concentration of natural killer cells with T-lymphocyte receptors CD3 + CD16 + 56 + (X5), the discriminant functions are calculated from the obtained values: • F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4 - 0.0043 × X5 - 21.6346; • F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5 - 3.9664; and at F1> F2, pseudo-progression is established in the patient and treatment continues as before, and at F2> F1 the treatment is carried out with sunitinib, which is administered in an amount of 50 mg per day orally for 8 weeks with breaks of 2 weeks until progression.