RU2751086C1 - Method for evaluating the immediate results of treatment of disseminated renal cell carcinoma - Google Patents

Abstract

FIELD: medicine, oncology in particular.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be applied to the evaluation of the results of treatment of disseminated renal cell carcinoma. A CT scan with contrast enhancement is performed for the patient and the volume of metastatic lung damage is calculated. Then the largest and smallest values of these volumes are selected and the value of the function of the largest total volume of metastatic lesion in two consecutive measurements (F_max) and the value of the function of the smallest total volume of metastatic lesion in two consecutive measurements (F_min). Based on the results of F_min and F_max are calculated, the results of treatment are evaluated.

EFFECT: method allows for an adequate correction of treatment tactics by increasing the accuracy of assessing the immediate results of treatment of patients with disseminated renal cell carcinoma by minimizing the error associated with the technical aspects of the study and the absence of the need to calculate the limit values of volume changes for the differential diagnosis of progression, stabilization and partial response.

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Description

The invention relates to medicine, more precisely to oncology, and can be used in the treatment of malignant neoplasms.

Renal cell carcinoma is, according to various authors, 2 - 4% of all tumors in adults. Every year, 338,000 new cases are diagnosed worldwide, and 114,000 patients die from this disease. 70 - 85% of tumors have a histological structure of clear cell carcinoma. In 30% of patients, distant metastases are detected at the initial visit. Another 30% have them within the first year after radical surgery. Metastases are the cause of death in 40% of cases. In the general population of patients with renal cell carcinoma, 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 the intervals for instrumental assessment of effectiveness are very clearly maintained, this figure reaches 23%.

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

The treatment of patients with local and locally advanced forms of tumors is based on various options for surgical intervention, 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 to surgical treatment.

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

Currently, the following methods of pathogenetic treatment of patients with disseminated renal cell carcinoma are known:

1. Targeted therapy.

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

1.2. MTOR inhibitors (Temsirolimus, Everolimus).

1.3. Angiogenesis inhibitors (Bevacizumab).

2. Immunotherapy.

1.4. Blockers of co-inhibiting molecules (Nivolumab).

1.5. Cytokines (IL-2, IFN-α).

1.6. Cell therapy.

1.7. Vaccine therapy.

The current strategy for the treatment of patients with disseminated renal cell carcinoma includes the sequential use of several lines of drugs. In the first line, those of them are used that have demonstrated high efficiency in previously untreated patients, in the second, agents that have turned out to be more effective compared to analogs in previously treated patients. Starting with the third line, there are no clear instructions on the choice of the drug. Here, either previously unused or drugs that are in different phases of clinical trials are used. The choice of tactics in this case is completely determined by the attending physician based on the clinical situation. In this case, the main principle is to use a drug with a different mechanism of action when changing the line of therapy.

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

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

Sunitinib has undergone clinical trials in patients with clear cell carcinoma with a favorable and intermediate prognosis. In the framework 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 has undergone clinical trials in patients with clear cell carcinoma with a favorable and intermediate prognosis. Within the framework 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 demonstrated improved long-term treatment outcomes when compared with placebo, while being 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, while in the comparison group it was 9.5 months. (Eur. J. Cancer. 2013; 49 (6): 1287-1296. N. 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 PI3K / AKT / mTOR, which regulates the processes of proliferation, apoptosis, and metabolism. Temsirolimus has undergone clinical trials in patients with poor prognosis. In the framework 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. In phase III, the median time to progression was 8.5 months in the group of 369 patients, and 5.2 months in the comparison group (IFN-α plus placebo). (J. Clin. Oncol. 2010; 28 (13): 2137-2143).

In the second line of treatment in most countries, professional associations recommend the use of two tyrosine kinase inhibitors: Cabosantinib and Lenvatinib; the mTOR inhibitor Everolimus; and the blocker of co-inhibiting 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 reference drug. In 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).

Cabosantinib is a second generation tyrosine kinase inhibitor. Within the framework 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 efficacy of the Lenvatinib + Everolimus combination was evaluated in study E7080-G000-205 (phase II). Objective response rates (the sum of complete and partial responses to treatment) were 35% for the combination, 0% for Everolimus, and 39% for Lenvatinib. 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 violation of 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 phase III clinical trials in patients with locally advanced and disseminated renal cell carcinoma. In the study ChekMate 025 (N. Engl. J. Med. 2015; 373: 1803-1813), which compared the effectiveness of Everolimus and Nivolumab, experts recognized that the latter should be considered as the drug of choice in the second line. 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 higher 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 have not received widespread use in practice.

There is a known method of treating RCC through cytokine therapy (J. Immunother. Cancer. 2019; 7: 1-7). The most widespread in the clinic are drugs created on the basis of interleukin-2 (IL-2) and interferon-α (IFN-α). IL-2 is currently recommended for use in the third and subsequent lines of therapy in a high-dose regimen, when other treatment options have been exhausted, in specialized institutions where it is possible to stop the side effects inevitably manifested at high doses. IFN-α is currently used in combination with angiogenesis inhibitors.

Significant advantages of modern drugs used in the treatment of patients with metastatic renal cell carcinoma are the possibility of improving long-term results of treatment and a low incidence of serious side effects. However, a significant drawback is the lack of a way to accurately determine the moment of changing the lines of therapy in order to obtain an optimal result.

The immediate results of treatment in cancer patients with disseminated forms of tumors are assessed using instrumental (computed tomography, magnetic resonance imaging, positron emission tomography) and laboratory (dynamics of biomarkers) methods. To date, no biomarker has been identified in patients with renal cell carcinoma, the concentration of which would strongly correlate with the change in the volume of the tumor mass. Therefore, the basis for assessing the immediate results of treatment in patients with disseminated renal cell carcinoma is instrumental methods.

Currently, there are three groups of instrumental methods for assessing the immediate results of treatment: 1) methods associated with assessing the linear dimensions of tumor foci; 2) methods for assessing the metabolic response of the tumor; 3) methods associated with volumetric tumor foci.

The first group includes the WHO criteria, RECIST (Response Evaluation Criteria in Solid Tumors, criteria for evaluating the response of solid tumors) and their modifications (Table 1: comparison of criteria for evaluating immediate treatment outcomes: WHO, RECIST v. 1.0, RECIST v. 1.1).

To assess the response of the tumor to treatment in 1981. The World Health Organization (WHO) proposed criteria that included four response options: complete response (CR) - complete disappearance of all foci for 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; stabilization of the disease (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% of one or more lesions, or the appearance of new ones (WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization Offset Publication No. 48; Geneva (Switzerland), 1979. Cancer 1981; 47: 207-214).

In 2000, in connection with the introduction of computed tomography (CT) into wide clinical practice, the RECIST v. 1.0, the concepts of measurable, non-measurable and marker foci were introduced (J. Natl. Cancer Inst. 2000; 92: 205-216).

Measured lesions - lesions with a size in the axial plane of more than or equal to 10 cm in spiral computed tomography with a slice thickness of 5 mm or more during reconstruction, or equal to 20 mm in a 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 the foci; stabilization of the disease (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 lesion or an increase in the sum of the largest sizes by more than 20%.

With the advent of targeted drugs, the nature of tumor dynamics during treatment has changed. In 2009, a modified version of the response criteria, RECIST v 1.1 (Eur. J. Cancer. 2009; 45: 228-247), appeared, according to which, in the analysis of CT, targeted foci are identified - foci of the largest diameter, suitable for accurate repeated measurement. In total, no more than five foci are assessed (no more than two per organ). Targeted lesions should be at least 10 mm in diameter in organs, at least 10 mm in length for bone lesions (lytic or mixed lesions) and at least 15 mm for lymph nodes. The rest of the foci are not targeted. To assess the size of metastases in parenchymal organs and bones, the largest diameter of the focus in the axial plane is used, and for lymph nodes, the size of the focus along the short axis.

The categories of overall response to treatment according to RECIST v 1.1: complete response (CR), partial response (PR), stabilization (SD), progression (PD), not assessed (NE).

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

1. Complete answer (CR) - disappearance of all extra-lymphatic targeted foci; 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 diameters of the lesions by at least 30% compared to the primary study.

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

4. Stabilization (SD) - no dynamics of the sum of maximum diameters, as well as its increase or decrease, which does not meet the criteria of PR or PD.

Assessment of non-targeted outbreaks:

1. Complete answer (CR) - the disappearance of all extra-lymphatic non-targeted foci. 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 foci.

The overall response to treatment is assessed by comparing the dynamics of targeted and non-targeted foci (Table 2: Evaluation of the immediate results of tumor treatment according to RECIST v 1.1 criteria).

The emergence of a new generation of drugs aimed at the tumor microenvironment has led to the need to revise the previously developed criteria for assessing the immediate results of tumor treatment. The main problems were associated with the stabilization and progression of the disease. During cytotoxic chemotherapy, most investigators did not consider stabilization as an indicator of clinical response. At the same time, the mechanism of action of targeted and immunologic drugs does not imply rapid cytoreduction, therefore long-term stabilization indicates the achievement of clinical success (J. Clin. Oncol. 2004; 22: 4442-4445. Annu. Rev. Immunol. 2009; 27: 83- 117).

In 2004-2005, 200 experts of different specialties (oncologists, immunologists, radiologists) held a series of seminars on the use of immunotherapeutic agents in cancer patients, as a result of which a number of conclusions were made: 1) the antitumor effects of immunotherapeutic drugs are realized longer than chemotherapy drugs; 2) a response to immunotherapy without changing drugs may occur after a period of progression; 3) it is not recommended to change tactics and stop immunotherapy if signs of progression are detected without confirmation during subsequent examinations according to RECIST v 1.1 criteria; 4) the appearance of new small foci against the background of a decrease in existing ones should be considered as clinically insignificant progression; 5) long-term stabilization should be considered as an indicator of clinical response (J. Immunother. 2007; 30: 1-15). Based on the recommendations of the working group, immunospecific criteria for tumor response to treatment (irRC, immune-specific related response criteria) were developed and validated on a group of 487 patients. As with the WHO criteria, the iRC used two dimensions, new lesions were not considered a clear sign of progression and required confirmation in subsequent studies (Clin. Cancer Res. 2009; 15 (23): 7412-7420).

Measurements in two perpendicular planes are highly variable when different experts are involved. In this regard, Nishini N. et al. Proposed to modify the iRC scale by replacing two perpendicular dimensions with one. The irRECIST scale (immune-related Response Evaluation Criteria in Solid Tumors, immune-related criteria for assessing the response of solid tumors) was created and validated on a group of 57 patients. The authors note the high concordance of both scales (Spearman's correlation coefficient - 0.965), as well as the better reproducibility of irRECIST (95% confidence interval -16.1%; 5.8%) compared to irRC (95% confidence interval -31.3%; 19.7%; Clin Cancer Res 2013; 19 (14): 3936-3943).

Despite the clear advantages of iRECIST over RECIST v.1.1, it has not been validated in large populations and has not found widespread use in clinical practice. Most studies evaluating the efficacy and safety of modern immunotherapeutic drugs between 2010 and 2017 used RECIST v.1.1. Its disadvantages were clearly manifested after pseudo-progression was described in a number of tumors - a phenomenon in which, against the background of treatment, signs of disease progression appear, 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 currently no exact explanation for the phenomenon of pseudo-progression. There are several hypotheses in the literature based on the peculiarities of the interaction between the tumor and the immune system during treatment. The first is based on the fact that the immune system takes a long time to rebuild against the background of stimulation or reduction of suppressive influences. This leads to clinical effects that are realized 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 required. On CT, this is perceived as progression. This hypothesis has been confirmed in several studies where metastases were biopsied during progression. According to various authors, the frequency of pseudoprogression in patients with RCC ranges from 7 to 15%.

The RECIST modification working group, which included oncologists, immunologists, radiologists and regulatory representatives, developed and created a validation plan for the iRECIST scale (Immunotherapy Response Evaluation Criteria in Solid Tumors; immunotherapy criteria for evaluating the response of solid tumors) from 2015 to 2016. The main parameters of iRECIST and RECIST v. 1.1 are the same, but in iRECIST the concepts of “unconfirmed progression” (iUPD) and “confirmed progression” (iCPD) were introduced in iRECIST to identify cases of pseudo-progression. iUPD - newly identified signs of disease progression in the form of an increase in the size and / or number of measurable (target and non-target) and non-measurable foci. To confirm the progression, a second examination is required, which is carried out within 4 to 8 weeks after the initial one. The exception is tumors, which, according to the literature, have a high frequency of pseudo-progression (renal cell carcinoma, melanoma). In this case, a second examination can be carried out at a later date (12-24 weeks). In case of stabilization (iSD, immunological stabilization), decrease (iPR, immunological partial response) or complete disappearance of newly identified foci (iCR, immunological complete response), it is recommended to continue treatment in the same mode. In cases where an iCPD is found during a re-examination, it is recommended to change the treatment tactics.

When using iRECIST, the frequency of examination is usually once every 6 - 12 weeks with a positive dynamics of the lesions during treatment. In routine clinical practice, no more than five target lesions are assessed. Higher volume evaluation is practiced in scientific research (Lancet Oncol. 2017; 18 (3): e143-e152).

Hodi F.S. et al. in 2018 proposed another modified version of the response criteria for those cases when the efficacy and safety of new generation immunotropic drugs is assessed - imRECIST (immune-Modified Response Evaluation Criteria in Solid Tumors; immunomodified criteria for assessing the response of solid tumors; J. Clin. Oncol . 2018; 36: 850-858). The model was created based on the analysis of data obtained in assessing the efficacy and safety of atezolizumab in patients with cancer of the lung, bladder, kidney, and melanoma.

In terms of criteria for assessing lesions, imRECIST is broadly similar to other scales that use a single measurement. The differences relate to the interpretation of the dynamics of measurable and non-measurable foci, which ultimately leads to a more adequate definition of progression-free survival.

In addition to the change in size, the reverse of measured into non-measured foci and vice versa is taken into account. The disappearance of non-measurable lesions along with measurable ones indicates a complete response to treatment. At the same time, their increase does not indicate the progression of the disease as a whole. As with other assessment criteria, confirmation of progression is required after 4-8 weeks. At the same time, when stabilization, partial or complete response was achieved, during re-assessment, the fact of progression was not taken into account when calculating progression-free survival rates.

When comparing RECIST v 1.1 and imRECIST, the rate of achieving the best overall response was 2% higher, the rate of disease control was 8-13% higher, and the median progression-free survival was 1.5 months higher according to the imRECIST criteria. At the same time, the median overall survival was higher when new non-targeted foci appeared; it was lower when using the imRECIST criteria. Thus, the imRECIST criteria in comparison with the standard ones have greater accuracy in assessing long-term treatment outcomes (Table 3: comparison of criteria for assessing immediate treatment outcomes: irRC, irRECIST, iRECIST, imRECIST).

Despite the fact that methods for assessing the effectiveness of direct treatment based on linear measurements are currently standard, and their modern modifications allow taking into account the possibility of pseudoprogression, in the opinion of most experts - radiologists, they have a number of significant drawbacks.

First, in all scales, target foci are selected, and the decision on the nature of the clinical response (partial response, progression, stabilization) is mainly made on the basis of their dynamics. In the presence of multiple small, and also not measurable, foci, their total volume may turn out to be larger than the target ones. Therefore, the long-term results of treatment in this case are determined by the dynamics of the tumor mass, which is not included in the main measurements.

Secondly, the listed methods imply a high degree of subjectivity of the assessment. Focal boundaries are assessed by researchers in different ways, especially when they differ significantly in qualifications and experience. Such differences can especially strongly affect the assessment of treatment results in borderline situations, when it is necessary to make a differential diagnosis between stabilization and progression.

Thirdly, the maximum size of the foci can depend not only on the actual dynamics of the volume of the tumor mass, but also on the position of the patient during the study, as well as on respiratory movements.

Fourthly, measurements of the linear dimensions and the conclusion about the dynamics of the size of the tumor are based on the assumption of the sphericity of metastatic foci and the uniformity of their growth. At the same time, modern research shows that this is not true. Most of the lesions are irregular in shape and do not increase evenly.

A group of methods for assessing the immediate results of tumor treatment associated with molecular imaging of metabolic processes is known - positron emission tomography (PET, PET, Positron Emission Tomography). When using PET, the distribution of any biomarkers of tumor cells or glucose uptake ( ¹⁸ F-FDG - PET) is assessed, which reflects the metabolic rate, and, as a result, the degree of tumor aggressiveness (Semin. Nucl. Med. 2007; 37: 400-419 ). When carrying out immunotherapy at the first stage, the metabolism of tumor cells is disrupted, and at the second stage, morphological changes are revealed. This pattern allowed Goldfarb L. et al. To create criteria for assessing immediate treatment outcomes based on PET and iRECIST - iPERCIST (EJNMMI Res. 2019; 9: 8). Renal cell carcinoma refers to tumors with a low level of energy metabolism. In addition, there are no specific biomarkers to identify this pathology. In this regard, PET is not widely used in renal cell carcinoma. This study is used in exceptional cases to confirm progression.

There is a group of methods for assessing the immediate results of treatment associated with measuring the volume of tumor foci - volumetry, which can be performed in automatic, semi-automatic or manual modes. With automatic volumetry, calculations are performed entirely by the computer. In the semi-automatic mode, after the stage of calculating the volume, manual correction takes place in order to accurately differentiate the foci located near the anatomical structures. In the manual delineation mode, the selection of foci is carried out by the researcher.

Volumetry is a significantly less subjective method compared to linear estimation methods. In addition, it can be used to estimate the half-doubling period of the foci volumes, which is an important prognostic factor. From a technical point of view, the main task of volumetry is the identification of voxels (an element of a volumetric image containing the value of a raster element in three-dimensional space; an analogue of two-dimensional pixels for three-dimensional space) located at the border of tissues with different X-ray tissue densities (approximately 500 Hounsfield units).

Despite the promise of volumetry, there are a number of technical difficulties that prevent standardization and widespread implementation of this method in clinical practice.

1. Factors associated with the morphological features of the lesions: the size of the lesions, their density, proximity to the anatomical structures. With small linear dimensions of the foci (less than 6 mm), the reproducibility of measurements decreases. This is connected, first of all, with the ratio of the sizes of the voxel and the source. Kuhnigk J.M. et al demonstrated that 41% of the tumor volume is contained in 27 voxels. The rest of the voxels contain both tumor and normal tissue, making it difficult to categorize them (IEEE Trans. Med. Imaging 2006; 25 (4): 417-434). Differentiated lesion density is also a factor that makes volumetry difficult, especially when automatic mode is used. Several studies have demonstrated that the variability of two studies of the same anatomical region in the presence of foci with uneven X-ray density increases the variability of volumetry up to 50% (Eur. Radiol. 2015; 25 (4): 1040-1047). The lesions located near the vessels and pleura are much more difficult to differentiate than intraparenchymal ones. The variability of their estimates is four times higher. In these cases, manual contouring is usually required (Radiology. 2008; 248 (2): 625-631).

2. Factors associated with the patient - respiratory movement and emphysema. The patient's lung volume changes with each breath, even if the breath is held during the exam. The volume estimate can vary from -19% to + 26% (Eur. Radiol. 2009; 19 (4): 800-808). Emphysema can also affect the accuracy of volumetric tumor lesions (Radiology. 2013; 268 (2): 563-571).

3. Factors related to the technical aspects of the study: software, number and type of sensors, contrast agent, slice thickness and type of convolution kernel. Volumetric software from different manufacturers is based on different algorithms. De Hoop B. et al demonstrated that when using different reconstruction algorithms, the 95% confidence interval of measurements is: 16 - 22% (Eur. Radiol. 2009; 19 (4): 800-808). In another study, this rate reached 50% (Acta Radiol. 2014; 55 (6): 691-698). Das M. et al found that the accuracy of volumetry significantly differs when using 16- and 64-slice tomographs (Eur. Radiol. 2007; 17 (8): 1979-1984). A later study revealed a difference in the assessment of lesions (± 18.2%) when using 64-slice devices from different manufacturers (Br. J. Radiol. 2013; 86 (1029): 20130160). Honda O. et al. Demonstrated that the use of different contrast agents is accompanied by a change in measured volume by 20% or more (Radiology. 2007; 245 (3): 881-887). Later, these data were confirmed in another study (Am. J. Roentgenol. 2010; 195 (1): 149-154). Petrou M. and co-authors published data according to which the volumes of lesions, calculated using thin sections (1.25 mm), are 40% larger than using thick ones (5 mm. Am. J. Roentgenol. 2007; 188 (2): 306-312). Similar data were obtained in more recent studies (Radiology. 2008; 247 (2): 400-408. Acad. Radiol. 2013; 20 (2): 173-180). The convolution kernel used in image reconstruction from raw data determines the relationship between spatial resolution and noise in the image. Noise limits the contrast resolution and thus the ability to differentiate objects, the attenuation of which may differ very little from the attenuation of the surrounding background. High resolution convolution kernels improve spatial resolution but also disproportionately increase noise. Soft, or anti-aliasing, kernels lead to a simultaneous reduction in noise and spatial resolution. A number of studies have shown that estimation accuracy and reproducibility in the assessment of foci is better when using high resolution kernels (Radiology. 2007; 245 (3): 881-887. Eur. Radiol. 2010; 20 (5): 1180-1187).

In modern works devoted to volumetry of tumor foci, attempts are made to solve two main problems arising from the use of volumetry: 1) calculation of the measurement error, which arises due to the influence of a large number of factors listed above; 2) calculating the cut-off level of volume changes that differentiates stabilization with progression or partial response (World J. Clin. Onol. 2020; 11 (2): 53-73).

Estimation of the systematic measurement error in volumetry is a fundamental point in the standardization of this method. In all works, which reflect the data on the comparison of one- and two-dimensional measurements and volumetry, the measurement error is carried out, and in some publications the mathematical apparatus for its assessment is given.

Xie X. et al in a study with anthropomorphic phantoms on two different tomographs (Sensation 64, Siemens; Brilliance 64, Phillips) demonstrated that the systematic measurement error is less when using the semi-automatic mode (7.6%) compared to the manual one (26.4 %). At the same time, no significant differences in volumetry between the two devices, with the exception of a slice thickness of 3 mm, were found. 95% confidence interval of inter-scanner variability is ± 41.6%; ± 18.2%; ± 4.9% for lesions 3, 5 and ≥ 8 mm. 95% confidence interval of intrascanner variability is ± 28.6%; ± 13.4%; ± 2.6% for foci 3, 5 and ≥ 8 mm (Br. J. Radiol. 2013; 86: 20130160).

Doo K. et al studied the dependence of the systematic error on the nature of image processing. In their work, they used phantoms with diameters of 5, 8, 10 and 12 mm, simulating frosted glass foci and dense foci (100 more Hounsfield units). Various scanning parameters were used: 10, 20, 30 and 50 mAs. When constructing the image, various filters and iterative reconstruction were used.

The absolute percentage error for all nodes was significantly less when using iterative reconstruction compared with filters (7.5 ± 4.7%; 7 ± 6.9%, respectively, p <0.001). The positive effect of iterative reconstruction is more pronounced at small nodes (p <0.001). The absolute percentage error is significantly less when processing frosted glass nodes when using iterative reconstruction compared to filters (2.9 ± 2%; 4.5 ± 2%, respectively, p <0.001), and this difference is more pronounced with the minimum time scan (11.8 ± 5.9%; 21.3 ± 6.1%, respectively, p <0.001. Br. J. Radiol. 2014; 87: 20130644).

Gavrielides M.A. et al. studied the dependence of the measurement error on the structure of the assessed foci. The study used eight round synthetic phantoms with different sizes and densities of the central and peripheral regions (20 mm / 10 mm; 10 mm / 5 mm; 100 HU (Hounsfield units) / -630 HU; 10 HU / -630 HU; -630 HU / 100 HU; -630 HU / -10 HU). The phantoms were placed in an anthropomorphic phantom, after which a study was carried out with different scanning parameters.

The measurement error with a section thickness of less than 5 mm ranged from -5.1% to 6.6% for the outer layer and from -12.6% to 5.7% for the inner region. According to the model built on the basis of one-dimensional analysis, the magnitude of the measurement error is reliably influenced by: the size of the focus, the slice thickness, the kernel of involution (J. Med. Imag. 2016; 3 (1): 013504).

Hwang E.J. et al. developed and validated a predictive model for lesion malignancy, including various volumetric parameters.

The study included 50 patients (26 men and 24 women) with an average age of 62.6 years (from 32 to 82 years), who were under observation from November 2013 to April 2014. Inclusion criteria were: 1) the presence of metastatic foci in the lungs; 2) computed tomography examination without contrast enhancement; 3) the absence of symptoms of pulmonary damage. The study included patients with renal cell carcinoma (13 people), thyroid cancer (8 people), lung (6 people), colorectal cancer (4 people); with leiomyoma, head and neck tumors, hepatocellular carcinoma - 3 people each; with melanoma, gallbladder cancer, chondrosarcoma, thymus tumor, endometrial cancer, breast cancer, histiocytoma - 1 person each. In three patients, the primary tumor was not detected.

Each patient underwent two sequential scans using a 64-slice tomograph (Brilliance 64, Philips, Netherlands) on the back with full inspiration. Volumetric lesions were subjected to the following criteria: 1) solid structures with a diameter of 4 to 15 mm. 2) lack of cavity and calcification; 3) detected during both scans during the research; 4) surgically removable. A total of 111 lesions were analyzed that met these criteria.

In the course of the study, the authors found that the accuracy of measurements is influenced by 4 calculated parameters: absolute percentage error (APE), sphericity, surface voxel fraction (SVP), boundary voxel fraction (AP). The volume of foci was calculated automatically. The absolute percentage error (APE) was calculated using the formula:

APE = | V ₁ - V ₂ | / V _m x 100, where V ₁ and V ₂ are volumes in two consecutive studies, V _m is the average value of the volume.

By the term "sphericity" the authors mean the degree of closeness of the studied focus to the sphere. It took a value from 0 to 1.

The share of surface voxels (SVP), according to the authors, plays a key role in the generation of errors in the volumetric process. It was calculated using the formula:

SVP = number of surface voxels / total number of segment voxels.

The fraction of boundary voxels (AP) reflects errors associated with differentiation of the focus and surrounding structures. It was calculated using the formula:

AP = number of external voxels> - 400 HU / total number of external voxels. HU - Hounsfield Sedimentation Units.

In order to assess the diagnostic significance of the model, the authors assessed the sensitivity and specificity of two different methods used to assess the growth of metastatic foci: 1) 25% change in the volume of foci (standard method); 2) Individualized score using the 95% APE percentile.

Volumetry of indicator foci was carried out in two consecutive studies. If the increase in volume exceeded the threshold of individual variability corresponding to the 95% APE percentile, the lesion was considered as growing (positive test), if less - as stable (negative test).

To validate the model, a group of patients meeting the following selection criteria was used: 1) patients underwent lung metastasectomy in the period from January 2013 to October 2015; 2) within a year before the operation, the patients underwent computed tomography of the lungs; 3) it was technically possible to compare the remote nodes with the X-ray picture. This group included 41 patients: 25 men and 16 women with an average age of 52 years (from 16 to 77 years). Out of 82 computed tomography examinations, 17 (20, 73%) were performed with contrast enhancement. The average time interval between two computed tomographic studies was 52 days, and between the second study and surgery - 11 days.

After surgical treatment and histological examination of the removed foci, the results of the studies were classified as a positive gold standard (metastatic lesion) or a negative gold standard (non-tumor tissue).

To estimate the 95% APE percentile using one-way quantile regression, the following parameters were included as independent variables: mean lesion volume (V _m ), voxel size, SVP, AP, sphericity.

As a result of univariate analysis, it was revealed that for assessing the 95% percentile of APE, the significant parameters are: SVP, AP, V _m (Table 4: results of one-way quantile regression for assessing the 95% percentile of the percentage error).

When carrying out multivariate analysis (multivariate quantile regression) to estimate the 95% percentile of APE, SVP and AP, the proportion of border voxels, turned out to be significant parameters. Regression formula:

95% APE percentile = 37.82 x SVP + 48.6 x AP - 10.87

Model validation, carried out after surgery, that the developed method has an advantage over the standard method with regard to the assessment of progressive lesions in the lungs (Table 5: model validation including percent error, sphericity and for borderline voxels).

The developed model allows differentiating metastatic and non-metastatic foci with high accuracy (Eur. Radiol. 2017; 27: 3257- 3265).

, где V - объем очага, r - радиус очага. Пороговые значения прогрессирования и частичного ответа рассчитываются в соответствии с критериями RECIST: Уменьшение суммы максимальных размеров на 30% (частичный ответ) соответствует уменьшению объема опухоли на 65%; увеличение суммы максимальных размеров на 20% (прогрессирование) соответствует увеличению объема опухоли на 73% (Radiology. 2002; 225:416-419. Acta Radiol. 2004; 11:1355-1360. Radiol. Med. 2006; 111:365-375). Второй способ связан с расчетом эффективного диаметра очага, который вычисляется автоматически в процессе волюметрии как расстояние между двумя вокселами с одинаковыми характеристиками, которые представляют собой крайние точки шара того же объема, что и очаг (Acta Radiol. 2004; 11:1355-1360). Третий способ предполагает использование специальных математических методов для оценки границы, дифференцирующей стабилизацию, частичный ответ и прогрессирование (Eur. Radiol. 2007;17:2561-2571. Cancer Imaging. 2015;15:17).Currently, there are three known methods for determining the boundaries of changes in the volume of foci, which make it possible to differentiate stabilization with progression or partial response. The first method is based on the assumption that the foci are spherical. The hearth radius is calculated as the average value of the radius of the maximum linear dimension of the hearth and perpendicular to it. The volume is calculated using the standard formula:

, where V is the volume of the focus, r is the radius of the focus. Threshold values for progression and partial response are calculated according to the RECIST criteria: A 30% reduction in the sum of maximum sizes (partial response) corresponds to a 65% reduction in tumor volume; a 20% increase in the sum of maximal sizes (progression) corresponds to a 73% increase in tumor volume (Radiology. 2002; 225: 416-419. Acta Radiol. 2004; 11: 1355-1360. Radiol. Med. 2006; 111: 365-375 ). The second method is related to the calculation of the effective source diameter, which is calculated automatically in the volumetric process as the distance between two voxels with the same characteristics, which represent the extreme points of a sphere of the same volume as the source (Acta Radiol. 2004; 11: 1355-1360). The third method involves the use of special mathematical methods to assess the boundary that differentiates stabilization, partial response and progression (Eur. Radiol. 2007; 17: 2561-2571. Cancer Imaging. 2015; 15: 17).

Prasad S.R. et al published the results of a study comparing measurements of one, two lesion sizes and calculated volumetric data to assess the immediate results of treatment. Of the 38 patients included in the study, 12 with one size measurement and 13 with two measurements obtained discordant results in relation to volumetry. In 6 patients with a partial response, according to one and two measurements after volumetry, the response was classified as stabilization. In 2 patients with stabilization according to linear measurements according to volumetric data, a partial response was stated. In 4 patients with progression according to linear measurements, the response was changed to stabilization after volume assessment. The authors concluded that volumetry has better classifying power compared to linear measurements (Radiology. 2002; 225: 416-419). Several groups of researchers later came to similar conclusions (Acta Radiol. 2004; 11: 1355-1360. Radiol. Med. 2006; 111: 365-375).

Dicken V. et al. Conducted a study comparing the effectiveness of different methods of measuring the size of the lesion in assessing the immediate results of treatment. The study was conducted on a group of patients with metastatic renal cell carcinoma (174 people) who received immunotherapy with interferon-α preparations as part of the second phase of clinical trials. A total of 726 computed tomographic examinations were carried out. In the course of the work, the diameters of the foci were measured using three algorithms: a) manual measurement of the maximum sizes of foci; b) automatic measurement of dimensions; c) an estimate of the effective diameter. According to the authors, the use of the effective diameter to assess the dynamics is characterized by the maximum number of coincidences with the participation of two researchers (87.6%) compared with automatic (86.2%) and manual measurements (63.9%). In addition, of all measurement options, only the effective diameter makes it possible to accurately estimate the minimum dynamics of the lesion size (10% or 1 mm). The authors come to the conclusion that it is necessary to integrate this type of measurement into modern scales for assessing immediate results of treatment (Acta Radiol. 2004; 11: 1355-1360).

Marten K. et al published the results of a study in which the calculation of the limiting values of changes in the volume of foci using the Bland-Altman method (Stat. Meth. Med. Res. 1999; 8: 135-160). It involved 50 patients with various tumors, including esophageal cancer (13 people), non-small cell lung cancer (10 people), colorectal cancer (7 people), melanoma (3 people), transitional cell bladder cancer (3 people) , chondrosarcoma (2 people), renal cell carcinoma (2 people) and one person each with cancer of the stomach, pharynx, breast, histiocytoma, leiomyosarcoma, osteoarcoma, chorionic carcinoma, pleural sarcoma, synovial sarcoma, and sarcoma of unknown etiology 202 metastatic lesions were assessed (from 1 to 5 in each patient).

The median volume before treatment was 182.22 mm ³ (3.16 to 5159.13 mm ³ ) and 124.79 mm ³ (0 to 6359.23 mm ³ ) after treatment. In the study, automatic volumetry was performed by two specialists. In 7 solid nodes in two series of measurements (1.7%), manual correction was required due to their location near anatomical structures (vessels, pleura). The variability of measurements when comparing the results obtained by both specialists ranged from -17.9 to 13.2% for the first and from -11.1 to 4.8% for the second. The variability in two measurements by one specialist over a short time interval ranged from - 16.9 to 13.2% for the first and from - 21.3% to 3.9% for the second.

During the study, at the first stage, the immediate results of treatment were assessed using various boundaries that determine the area of stabilization: from 70% to 20% with a step of 5%. At the second stage, using the Bland-Altman method, the optimal value of the boundaries characterizing the stabilization of the disease was determined.

A total of 50 patients underwent 400 evaluations (2 researchers, 2 studies) of the immediate results of treatment. When 70% was used as the stabilization limit, disease progression was stated in 13 patients, stabilization in 28, partial response in 7, and complete response in 2. As the border decreased, the number of patients with stabilization decreased, and increased with progression and partial response. When the 20% level was used as a boundary, stabilization was noted only in 9 patients (a decrease by 67.9%), in 21 (an increase by 61.5%) - progression, and in 18 (an increase by 157.1%) - a partial response. When using the border of 60% and 65% of the classification of the response by both investigators in the two series of measurements were identical.

At the second stage, the researchers calculated the optimal estimate boundary (≥ 35%). At the same time, when the number of metastases is ≥ 3, the highest values of agreement in the classification of immediate treatment results (stabilization, progression, partial response) with RECIST are achieved (Eur. Radiol. 2007; 17: 2561-2571).

Beaumont H. et al. To assess the optimal boundary determining stabilization, partial response and progression in volumetry, conducted a study based on data from the Quantitative Imaging Biomarker Alliance (QIBA) and using a multiparameter mathematical model based on the Geary transformation. Hinkel (Radiology. 2011; 258: 906-914. CT Tumor Volume Change Profile. [Http://qibawiki.rsna.org/index.php?title=CT_Volumetry_Biomarker_Ctte]. Biometrika. 1969; 56: 635-639. Manage Sci 1975; 21: 1338-41. Am Stat. 1993; 47: 259-64).

The model was developed using 10,000 lesion volumetry samples from the Numerical Imaging Biomarker Alliance database and validated on a real retrospective clinical group of 10 patients who participated in multicenter studies for which there were data from 5 or more sequential computed tomography studies.

The scan thickness varied from 1 to 7 mm. Most often, scanning was carried out with a thickness of 5 mm (87%). The study was carried out on 10 tomographs of various manufacturers (Siemens, General Electric, Toshiba). Voxel sizes varied from 0.5 to 1 mm. The median, minimum and maximum linear dimensions of the lesions in the group were 40 mm, 11 mm and 117 mm, respectively. The dynamics of volumes was assessed in a semi-automatic mode; after the stage of automatic volumetry, manual correction of the contouring was carried out. A total of 426 outbreaks were assessed. Partial response to treatment was diagnosed in 68 cases, progression in 67 cases; in other cases, stabilization. The mean lesion volume in the study was 29.446 cm ³ , the median was 30.719 cm ³ (range from 0.195 cm ³ to 380.976 cm ³ ). The sizes of most foci varied from 1 to 100 cm ³ .

The stabilization limits calculated according to the model with volumetry were -35%; + 55%. In this case, the corresponding size limits of the effective diameter were -13%; + 16%. Disease progression was ascertained with an increase in volume by 55% or an increase in effective diameter by 16%; the partial answer is with a decrease of 35% and 16%, respectively. Model consistency was assessed using Monte Carlo simulations (R Foundation for Statistical Computing; 2011, p. 409). In a real clinical group, 97.1% of the estimates coincided with the proposed model (Cancer Imaging. 2015; 15:17).

Immediate treatment outcome models based on lesion volumetry have a number of advantages over criteria based on linear measurements. They allow minimizing the subjectivity of the assessment (increasing the reproducibility of the result) and assessing the dynamics of non-spherical foci. But, despite this, models with an estimate of volumes have a number of disadvantages. First, in the algorithms proposed to date for calculating the limits differentiating stabilization, progression, and partial response, there is no assessment of the effect of section thickness, convolution kernel, and software used. Conversely, studies that estimate the error associated with the technical aspects of the study use data obtained from recalculating the RECIST criteria, taking into account the assumption of sphericity of the lesions. This creates conditions for significant errors during volumetry and assessment of immediate treatment results. Second, most models take into account the volumes of only a small number of foci. But even in those few studies where full volumetry with manual correction is performed, the measurement accuracy increases sharply with a decrease in the number and an increase in the size of the evaluated metastases. This, of course, negatively affects the diagnostic value of such an approach. According to a number of authors, including ours, small foci are characterized by the highest growth rate. Thirdly, the proposed models did not track the relationship of immediate treatment results with long-term results in comparison with criteria using linear measurements, while among the latter, similar comparisons were made (imRECIST. Clin. Oncol. 2018; 36: 850-858).

The closest to the proposed method is the method proposed by a group of authors who, by calculation, revealed the optimal level of changes in the volume of foci, which allows us to differentiate stabilization with progression or partial response, which we used as a prototype (Vogel MN, Schmuker S., Maksimovic O. et al. Reduction in growth threshold for pulmonary metastases: an opportunity for volumetry and its impact on treatment decisions // Br. J. Radiol. 2012; 85: 959-964).

The essence of the proposed method lies in the fact that, by calculation, using the method of comparing two studies with Bland-Altman calculations, they identified the boundaries of volume changes (± 38%) for differentiating stabilization with progression and partial response, and demonstrated that their application adequately reflects clinical changes and allows you to make a decision about changing treatment tactics.

The study involved 58 patients (36 men, 22 women) with an average age of 55.7 years (from 20 to 93 years), who were under the supervision of the Tübinger University Hospital with colorectal (15 people), renal cell (5 patients) cancer, breast cancer of the testis, lung (4 people), cancer of the bladder and stomach (2 people) and other nosological forms (7 people). All patients received various options for drug therapy and were under dynamic observation. In the group, 203 metastatic foci were analyzed.

Computed tomography study was carried out according to the standard technique after intravenous injection of 120 ml of Ultravist 300 (Schering AG, Germany) on a 64-slice multislice computed tomograph (Sensation 64; Siemens Medical Solutions, Germany). Scanning parameters: 120 kVP, 140 mAs, collimation - 0.6 mm, rotation - 0.5 s ^-1 . The scan was performed with full inspiration. The table rotation speed was 6 mm, the rotation time was 0.75 s. Slice thickness during reconstruction - 3 mm.

To increase the contrast of anatomical structures, the tumor size was assessed in the “pulmonary window” using an electronic caliper and a volume assessment software (OncoTREAT, Germany). In all patients, two specialists sequentially assessed the dynamics of the five largest foci with a minimum diameter of 4 mm. To increase the reliability, radiologists did not have information about the results of each other's studies, as well as about the results of previous studies. The study used semi-automatic volumetry.

, где r - радиус очага, увеличение суммы линейных размеров на 20% (прогрессирование) соответствует увеличению объема на 73%, а уменьшение на 30% (частичный ответ) соответствует уменьшению объема на 65%. Второй способ представлял собой расчет пограничных значений изменения объема с использованием метода Бланда-Альтмана. Метод представляет собой расчет минимальных значений параметра, при котором в двух сериях измерений выявляется максимальное число совпадений. Расчет выявил, что оптимальными значениями границ стабилизации при волюметрии являются ± 38%. Использование метода Бланда-Альтмана в ряде других исследований привело к расчету сходных значений границ стабилизации (Eur. Radiol. 2007; 17:2561-71. Am. J. Roentgenol. 2009;192:1657-61). The linear dimensions of the lesions were assessed according to the RECIST criteria. Volumetry was performed in two ways. The first was the volumetric equivalent of RECIST. Taking into account the assumption of the sphericity of the foci and the calculation of the volume by the formula

, where r is the radius of the focus, an increase in the sum of linear dimensions by 20% (progression) corresponds to an increase in volume by 73%, and a decrease by 30% (partial response) corresponds to a decrease in volume by 65%. The second method was the calculation of the boundary values of the change in volume using the Bland-Altman method. The method is the calculation of the minimum values of the parameter, at which the maximum number of coincidences is revealed in two series of measurements. The calculation revealed that the optimal values of the stabilization boundaries for volumetric measurements are ± 38%. The use of the Bland-Altman method in a number of other studies has led to the calculation of similar values of the stabilization boundaries (Eur. Radiol. 2007; 17: 2561-71. Am. J. Roentgenol. 2009; 192: 1657-61).

Research results. The average value of the volume of 203 metastatic foci before the start of the study was 4.24 mm ³ (range: 0.1 - 73.4 mm ³ ), after treatment - 3.72 mm ³ (range: 0 - 86.06 mm ³ ). The average value of the diameter of the lesions before the start of treatment was 16.06 mm (range: 4.2 - 75.83 mm), after - 15.59 mm (range: 0 - 113.89 mm).

When evaluating 174 lesions in 58 patients, both investigators equally classified the nature of the response to treatment according to the RECIST criteria. In 4 patients, a complete response to treatment was stated, in 2 - a partial response, in 40 - stabilization of the disease, and in 12 - progression.

Volumetry using the boundaries of the volumetric analogue RECIST (+ 73%; -65%) revealed progression in 12 patients, stabilization in 40, and partial response in 2.

Volumetry using cut-off values calculated by the Bland-Altman method made it possible to ascertain progression in 18 patients, stabilization in 28, and partial response in 8.

In 15 (17%) of 58 patients, the results of treatment were assessed differently using different methods. At the same time, in 8 (13%), this led to opposite decisions to continue (stabilization or partial response) or change therapy (progression). Two subgroups (with the same and different assessment of the response by three methods) did not statistically differ in any of the parameters (age; size, localization and quality of foci segmentation).

When using the RECIST criteria, differences in the assessment of linear dimensions between researchers were found in 6 patients, and in 5 of them it became necessary to make a decision on changing tactics. In volumetry using the volumetric analogue RECIST, the differences concerned 13 people, and in 7 it was necessary to make a decision on changing tactics. In case of volumetry with cut-off values calculated by the Bland-Altman method, the differences affected 11 patients, and in 7 it became necessary to make a decision to change the tactics. In 9 patients, the differences related to all three assessment methods, and in 3 there was a need to make a decision to change the treatment tactics (Table 6: patients with discordant results when using three assessment methods: correlation with the overall assessment of the result at the University Hospital Tübinger, decision making and changing tactics treatment).

In 52 (90%) of 58 patients, the direction of the dynamics of the tumor mass (increase in volume, stabilization, decrease in volume, disappearance of metastases) was the same in the linear assessment of both types of volumetry. Taking into account the standards that determine the tactics of treatment, the decision to change the line of therapy was made when the progression was confirmed by all three methods. With progression, ascertained using one or two methods, treatment tactics were changed only in the presence of serious side effects.

In comparison with other known analogs, the method for assessing the immediate results of treatment, proposed in the prototype, allows: 1) to more accurately determine the boundaries of volume changes for differential diagnosis of progression, stabilization and partial response; 2) has better reproducibility; 3) have a clinical focus: the results of the studies are considered not only in theoretical terms, but also form the basis for making a decision on changing treatment tactics.

According to the authors themselves, their work has a number of limitations and disadvantages: 1) patients with different nosological forms took part in the study, and the size of each subgroup is small; 2) most of the work is based on retrospective material; 3) the relationship with long-term results was traced only in a small number of patients.

In our opinion, in addition to the limitations associated with validation noted by the authors themselves, the method also has a number of significant disadvantages that are currently common to all groups of studies related to volumetry: 1) the volume assessment was not carried out in all foci; from the field of view of the researchers, small metastases have dropped out, which have a high growth rate; 2) the proposed algorithm did not allow comparing studies with different section thickness; 3) the influence of the technical parameters of the study, the involution kernel of the software used was not taken into account.

The technical result of the present invention is to improve the accuracy of assessing the immediate results of treatment of patients with disseminated renal cell carcinoma by minimizing errors associated with the technical aspects of the study (slice thickness, software, type of tomograph) and the absence of the need to calculate the limiting values of volume changes for differential diagnosis of progression , stabilization and partial response.

This result is achieved by the fact that in the known method for assessing the dynamics of the volumes of metastatic foci in the lungs of a patient, the volume of metastatic lesions of the lungs is calculated by the formulas:

; V₂ =

;V ₁ =

; V ₂ =

;

where V ₁ is the total volume of the initial metastatic lesion, i is the number of the lesion at the initial study, vi is the volume of the lesion at the initial study, n1 is the number of lesions at the initial study, V ₂ is the total volume of the metastatic lesion after the treatment cycle, j is the number of the lesion at the study after the treatment cycle, vj - the volume of the lesion in the study after the treatment cycle, n2 - the number of lesions after the treatment cycle;

select the largest (Vmax) and smallest (Vmin) values from these volumes and calculate the value of the volume functions taking into account the system error using the formulas:

+183/dк + 49);F _max =

+ 183 / d to + 49);

+183/dl + 49),F _min =

+ 183 / d l + 49),

- объем очага в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях,

- объем очага в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях, nmax - число метастатических очагов в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях, nmin - число метастатических очагов в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях, dк - диаметр очага в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях, dl - диаметр очага в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях,

- толщина среза, where, F _max is the value of the function of the largest total volume of metastatic lesion in two successive measurements, F _min is the value of the function of the smallest total volume of metastatic lesion in two successive measurements,

- the volume of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements,

is the volume of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements, nmax is the number of metastatic lesions in the measurement with the largest total volume of metastatic lesion in two successive measurements, nmin is the number of metastatic lesions in the measurement with the smallest total volume of metastatic lesion at two successive measurements, d to - the diameter of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements, d l - the diameter of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements,

- slice thickness,

and if F_max- F_min> 0 and V_one > V₂, then this is regarded as a partial response to treatment, if F_max- F_min> 0 and V_one <V_2,then this is regarded as progression, if F_max- F_min< 0 for any ratios V_one and V₂ - as process stabilization.

Having been professionally treating patients with renal cell carcinoma for a number of years, we evaluated the long-term and immediate results using various assessment criteria, including RECIST and RECIST v 1.1. Starting in 2010, as an additional method of examination, we began to assess the dynamics of foci in the lungs by calculating their volume in manual, semi-automatic and automatic modes.

The development of a method for assessing the immediate results of treatment of patients with renal cell carcinoma included three stages. At the first stage, an algorithm was created for estimating the absolute error in calculating the volume of foci. On the second, a model was created to assess the dynamics of volumes in absolute terms. In the third, the model was validated.

To determine the factors affecting the magnitude of the absolute volumetric error, the reconstruction was performed by two radiologists three times with different slice thicknesses (0.5; 1.5; 3; 5 mm) and different convolution cores (FC07; FC14). The study was carried out on 64-slice computed tomographs of various manufacturers (Aquillion One, Aquillion CX, Toshiba; Sensation 64, Siemens). Various preparations were used for contrast enhancement: Ultravist 300 (Schering AG, Germany), Omnipak 240 (GE Healthcare AS, Norway). For volumetry, software from various manufacturers was used (LMS Lung, Median Technologies; Lung CARE ^® , Siemens). Scanning was carried out with a voltage per tube of 120 kV and a pitch of 1.

For each lesion and the combination of slice thickness and convolution kernel, the measurement error was calculated as the difference between the measured and reference (slice thickness 0.5 mm; convolution kernel FC14) volumes. The assessment of the degree of influence of the factor on the measurement error was carried out using regression analysis. The following parameters were chosen for univariate analysis: the volume of the lesion, the localization of the lesion (intrapulmonary, juxtavascular, juxtapleural lesions), the effective lesion diameter, the slice thickness, the convolution kernel, the software used, the contrast enhancement, the tomograph used.

As a result of univariate analysis, it was revealed that the magnitude of the absolute volumetric error is influenced by the volume of the lesion (p = 0.003), the effective diameter of the lesion (p = 0.026), the slice thickness (p <0.005), the convolution kernel (p <0.001), and the localization of the lesion. (p = 0.045). As a result of multivariate regression analysis, it was revealed that the absolute value of the volume measurement error is influenced by: the volume of the focus, the effective diameter of the focus, the slice thickness, the convolution kernel (Table 7: factors affecting the magnitude of the absolute volumetric error; the results of multivariate analysis).

To calculate the absolute error in measuring the volume, the following formula was obtained:

.

...

t - slice thickness, d - effective lesion diameter - parameter calculated using special computer tomograph software (LMS Lung, Median Technologies; Lung CARE ^® , Siemens). It represents the diameter of a conditional ball of the same volume as the studied focus.

Thus, taking into account the data of multivariate analysis, the proposed formula for calculating the absolute error makes it possible to compare studies performed on different computer tomographs with different slice thicknesses, using different software products and with different technical parameters of the study.

Volumetry was performed in a semi-automatic mode. The volumes were calculated using the computer tomograph software. If necessary, in cases where the foci were located near the vessels or serous membranes, and it was not possible to accurately assess their boundaries in an automatic mode, manual correction of the contouring was carried out.

After evaluating the volume of each focus, their values were summed up:

; V₂ =

;V ₁ =

; V ₂ =

;

where V ₁ is the total volume of the initial metastatic lesion, i is the number of the lesion at the initial study, vi is the volume of the lesion at the initial study, n1 is the number of lesions at the initial study, V ₂ is the total volume of the metastatic lesion after the treatment cycle, j is the number of the lesion at the study after the treatment cycle, vj is the volume of the lesion in the study after the treatment cycle, n2 is the number of lesions after the treatment cycle.

Further, we compared the values of the total lesion volumes in two consecutive studies; of them, the largest (Vmax) and the smallest (Vmin) were selected, after which the absolute error of the total volume values was calculated.

In a study with a large lesion volume (Vmax), the value of the absolute error was subtracted from the calculated volume for each lesion, after which the obtained indicators were summed up:

+183/dк + 49);F _max =

+ 183 / d to + 49);

- объем очага в исследовании, где область поражения больше, nmax - число метастатических очагов и dк - диаметр очага в исследовании, где область поражения больше;

толщина среза. where, F _max is the value of the function that corresponds to the minimum possible volume of the tumor mass, calculated taking into account the absolute error in the study where the affected area is larger,

- the volume of the focus in the study, where the affected area is larger, nmax is the number of metastatic foci and d to - the diameter of the focus in the study, where the affected area is larger;

slice thickness.

In a study with a smaller lesion volume (Vmin), the value of the absolute error was summed up with the calculated volume for each lesion, after which the obtained indicators were summed up:

+183/dl + 49),F _min =

+ 183 / d l + 49),

- объем очага в исследовании, где область поражения меньше, nmin - число метастатических очагов и dl - диаметр очага в исследовании, где область поражения меньше;

- толщина среза.where F _min is the value of the function that corresponds to the maximum possible volume of the tumor mass, calculated taking into account the absolute error in the study where the affected area is smaller,

- the volume of the focus in the study, where the affected area is smaller, nmin is the number of metastatic foci and d l is the diameter of the focus in the study, where the affected area is smaller;

- slice thickness.

Further, the values of the functions F _max and F _min were compared, and if their difference was greater than zero, then the differences in the tumor volume in two consecutive studies were significant and progression (if the total volume of lesions was greater in a later study) or a partial response (if the total the volume of lesions is greater in the early study), and if it is less than zero, then the differences were not significant and the stabilization of the process was stated. As in other criteria for assessing the immediate results of treatment, a complete response was ascertained with the complete disappearance of metastatic foci.

To develop a prognostic model, the study used data from 46 patients who were under the supervision of the Federal State Budgetary Institution “RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation in the period from 2014 to 2018. Of these women - 27 (59%), men - 19 (41%), the female / male ratio is 1.4. The age of the patients included in the study was 61 ± 7.5 years (from 41 to 82). Most - 39 people (85%) belonged to the age category from 50 to 69 years.

Patients of the study group on an outpatient basis in the first line received Sutent (sunitinib) 50 mg per day for 8 weeks with a break of 2 weeks (25 patients, 54%), as well as various options for chemoimmunotherapy (21 patients, 46%), the main of which there were two regimens: 1) Alfarona (recombinant IFN-α) 9 million IU intramuscularly three times a week in combination with Avastin (bevacizumab) at a dose of 10 mg / kg intravenously once every 14 days; 2) Alfarona (recombinant IFN-α) 9 million IU three times a week intramuscularly in combination with Refnot (recombinant TNF-α - thymosin α1) at a dose of 200,000 IU subcutaneously twice a week and Endoxan (cyclophosphamide) at a dose of 50 mg orally daily ...

With progression against the background of chemoimmunotherapy in the second line, patients received: 1) tyrosine kinase inhibitors (12 people, 26%): Sutent 50 mg per day for 8 weeks with a break of 2 weeks or Votrient (pazopanib) at a dose of 400 - 800 mg per day depending on tolerance; 2) blockers of co-inhibiting molecules (11 people, 24%) - Opdivo (Nivolumab) - 240 mg intravenously once every 2 weeks. With progression against the background of Sutent, patients received Opdivo (5 people, 11%) or other blockers of co-inhibiting molecules (4 people, 9%) as part of clinical trials.

The model was validated using a group of patients under observation from 1998 to 2010. Data on the study of the effectiveness of various regimens of chemoimmunotherapy and the studied prognostic factors in this group were published earlier (Urological Bulletin. 2018; 8 (3): 67-79). A total of 81 people took part in the study. Of these women - 46 (57%), men - 35 (43%), the female / male ratio is 1.3. The age of the patients included in the study was 57 ± 9.5 years (from 45 to 73). Most - 72 people (89%) also belonged to the age category from 50 to 69 years.

In the validation group, patients in the first and second lines received various options for chemotherapy, including recombinant interleukin-2, recombinant interferon-α, 5-fluorouracil, capecitabine, and cyclophosphamide. 10 people (12%) from the second line validation group received Sutent (sunitinib) 50 mg per day for 8 weeks with a break of 2 weeks.

Evaluation of the immediate results of treatment was carried out using the developed method and standard criteria RECIST v 1.1 (table 2). During the observation of patients, 181 definitions of immediate treatment results were made in the group, the data of which were used to develop the method and 318 definitions in the validation group.

When analyzing the immediate results of treatment, it was revealed that when assessing according to the RECIST v 1.1 criteria and according to the developed method, the rate of progression significantly differs in the research group (31 definitions (17%) - RECIST v 1.1 and 76 definitions (42%) - the developed method; p < 0.05) and stabilization (106 determinations (61%) - RECIST v 1.1 and 52 determinations (27%) - developed method; p <0.05). In the validation group, significant differences in frequency were observed in subgroups with progression (48 determinations (15%) - RECIST v 1.1 and 119 determinations (37%) - developed method; p <0.05), stabilization (229 determinations (72%) - RECIST v 1.1 and 106 definitions (33%) - developed method; p <0.05) and partial response (39 definitions (12%) - RECIST v 1.1 and 91 definitions (29%) - developed method; p <0.05) ... The fundamental question from the point of view of determining the tactics of treatment is the differential diagnosis of stabilization and progression. Progression requires a change in drugs and or administration regimens. With stabilization and partial response, treatment continues as before. The developed method allows for more accurate differentiation of stabilization and progression, which is shown in the development and validation groups (table 8: immediate treatment results in the development and validation groups).

Long-term treatment outcomes in the study group and the validation group were assessed using the standard prognostic scale developed by Motzer R.J. with coauthors in 1999 (MSKCC scale - Memorial Sloan-Kettering Cancer Center; Memorial Sloan and Kettering Cancer Center). It includes 5 parameters: lactate dehydrogenase, hemoglobin, corrected calcium, Karnovsky status, previous nephrectomy. A favorable prognosis is determined by the absence of risk factors, 1-2 factors are an intermediate prognosis, 3 or more are unfavorable (table 9: risk factors, MSKCC scale).

In the research group, in the subgroup with a favorable prognosis (12 people), the median overall survival (37 months) is significantly less than in the subgroup where, using the developed method, the assessment of immediate treatment results was adjusted towards an improved prognosis (from progression to stabilization). and from stabilization to partial response; 42 months, p <0.05). Similar patterns were found in the validation group: median overall survival in the subgroup with a favorable prognosis (23 people) - 42 months; the median overall survival in the subgroup where, using the developed method, the assessment of the immediate results of treatment was adjusted towards an improved prognosis (from progression to stabilization and from stabilization to a partial response) - 48 months.

In the subgroup with an unfavorable prognosis, both in the experimental (7 people) and in the validation group (9 people), the median overall survival (7 months - the research group; 9 months - the validation group) is significantly greater than in the subgroups where using the developed method the assessment of the immediate results of treatment was adjusted towards a worsening prognosis (from stabilization to progression and from a partial response to stabilization: 4 months in the research group, p <0.05; 6 months in the validation group, p <0.05).

In the subgroup with an intermediate prognosis in both study groups, significant differences were revealed in the overall survival rates in the case of correction of the assessment of immediate treatment results in the direction of improving the prognosis (from progression to stabilization and from stabilization to partial response). In the event of a worsening prognosis (from a partial response to stabilization and from stabilization to progression), this pattern remains only for the research group.

Medina of overall survival in the subgroup with an intermediate prognosis and in the research (25 people, 19 months) and in the validation group (40 people, 16 months) is significantly less than this indicator in the subgroup, where, according to the proposed method, the assessment of the immediate treatment results was corrected in the direction of improving the prognosis (23 months - the research group, 21 months - the validation group) and significantly more when calculating this indicator without taking into account the data of patients in whom the correction was made (17 months - the research group, 14 months - the validation group).

Medina of overall survival in the subgroup with an intermediate prognosis and in the research group (25 people, 19 months) is significantly higher compared to this indicator in the subgroup, where, according to the proposed method, the assessment of the immediate results of treatment was corrected towards a worsening prognosis (17 months) and significantly less when calculating this indicator without taking into account the data of patients in whom the correction was made (22 months). In the validation group, no similar patterns were found, but there was a tendency to an increase in the difference in the studied indicators. Such differences are due to two circumstances: 1) a small number of patients in these subgroups; 2) in the research group, changes in the assessment of immediate results entailed a change in treatment tactics, while the validation group was retrospective (Table 10: long-term results of treatment in the development groups (46 people) and validation (81 people), taking into account changes in the assessment of immediate the results of treatment when using the developed method).

The developed method for determining the immediate results of treatment allows for accurate differential diagnosis of disease progression and stabilization, which also leads to a change in long-term treatment results.

The essence of the method is as follows.

A patient with a histologically confirmed diagnosis of renal cell carcinoma before the start of treatment and then every 8-12 weeks undergo a computed tomography study with contrast enhancement.

In order to assess the immediate results of treatment in a patient, the volume of metastatic lesions of the lungs is calculated according to the formulas:

; V₂ =

;V ₁ =

; V ₂ =

;

where V ₁ is the total volume of the initial metastatic lesion, i is the number of the lesion at the initial study, vi is the volume of the lesion at the initial study, n1 is the number of lesions at the initial study, V ₂ is the total volume of the metastatic lesion after the treatment cycle, j is the number of the lesion at the study after the treatment cycle, vj is the volume of the lesion in the study after the treatment cycle, n2 is the number of lesions after the treatment cycle.

Next, the largest (Vmax) and the smallest (Vmin) values of these volumes are selected and the value of the volume functions is calculated taking into account the system error using the formulas:

+183/dк + 49);F _max =

+ 183 / d to + 49);

+183/dl + 49),F _min =

+ 183 / d l + 49),

- объем очага в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях,

- объем очага в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях, nmax - число метастатических очагов в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях, nmin - число метастатических очагов в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях, dк - диаметр очага в измерении с наибольшим суммарным объемом метастатического поражения при двух последовательных измерениях, dl - диаметр очага в измерении с наименьшим суммарным объемом метастатического поражения при двух последовательных измерениях,

- толщина среза.where, F _max is the value of the function of the largest total volume of metastatic lesion in two successive measurements, F _min is the value of the function of the smallest total volume of metastatic lesion in two successive measurements,

- the volume of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements,

is the volume of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements, nmax is the number of metastatic lesions in the measurement with the largest total volume of metastatic lesion in two successive measurements, nmin is the number of metastatic lesions in the measurement with the smallest total volume of metastatic lesion at two successive measurements, d to - the diameter of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements, d l - the diameter of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements,

- slice thickness.

If F_max- F_min> 0 and V_one > V₂, then this is regarded as a partial response to treatment, if F_max- F_min> 0 and V_one <V_2,then this is regarded as progression, if F_max- F_min< 0 for any ratios V_one and V₂ - as process stabilization.

In parallel, the immediate results of treatment are assessed using the generally accepted criteria RECIST v 1.1 (Eur. J. Cancer. 2009; 45: 228-247), according to which, in the CT analysis, targeted foci are identified - foci of the largest diameter suitable for accurate repeated measurement. In total, up to five foci are isolated (no more than two per organ). Targeted lesions should be at least 10 mm in diameter in organs, at least 10 mm in length for bone lesions (lytic or mixed lesions) and at least 15 mm for lymph nodes. The rest of the foci are not targeted. To assess the size of metastases in parenchymal organs and bones, the largest diameter of the focus in the axial plane is used, and for lymph nodes, the size of the focus along the short axis.

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

1. Complete answer (CR) - disappearance of all extra-lymphatic targeted foci; 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 diameters of the lesions by at least 30% compared to the primary study.

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

4. Stabilization (SD) - no dynamics of the sum of maximum diameters, as well as its increase or decrease, which does not meet the criteria of PR or PD.

Assessment of non-targeted outbreaks:

1. Complete answer (CR) - the disappearance of all extra-lymphatic non-targeted foci. 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 foci.

The overall response to treatment is assessed by comparing the dynamics of targeted and non-targeted lesions (Table 2: General response to treatment in patients with measurable lesions at baseline).

With stabilization, full and partial response, the treatment tactics does not change. With progression, it becomes necessary to use the drugs of the next line. If there are differences in the evaluation of the results according to the RECIST v 1.1 criteria and according to the developed method, the latter is preferred. But, taking into account the requirements of the regulator, in this case, in order to make a decision on the tactics of treatment, a decision of the council is necessary.

The essence of the method is illustrated by examples.

Example 1.

Patient K, born in 1968

09/16/2019. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. He did not show any active complaints. The general condition is satisfactory. From the anamnesis it is known that on October 18, 2017, according to the CT scan, a neoplasm of the right kidney with dimensions of 11 x 16 cm was revealed. On November 9, 2017, a right-sided nephrectomy was performed at the Murmansk Oncological Dispensary. Histologically - clear cell renal cell carcinoma (from 15.11.2017). After surgery, he was under the supervision of the Murmansk Oncological Dispensary. After surgery, a CT scan of the abdominal cavity and lungs was performed once every six months. During the control examination according to CT data from 07/31/2019, signs of disease progression were revealed in the form of the appearance of foci in the left lung with diameters of 11 and 14 mm. In this regard, the patient turned to the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation.

The examination revealed the following changes.

24.09.2019. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 16 x 17 mm and 16 x 11 mm. In the right lung there are two lesions measuring 14 x 18 mm and 19 x 11 mm. In both lungs, there are multiple small foci up to 7 mm in diameter.

1.10.2019. A patient at an outpatient appointment of the Federal State Budgetary Institution "RNTSRHT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation.

As a result of the examination, the diagnosis was made: renal cell carcinoma of the left kidney T2N0M0. 11/9/2017 - right-sided nephrectomy. Histologically - clear cell renal cell carcinoma (conclusion of 11/15/2017). Progression: metastases in the left lung from 07/31/2019. Progression from 09/24/2019: an increase in the size and number of foci in both lungs.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 16 x 17 mm; b) 16 x 11 mm.

2. Right lung: a) 14 x 18 mm; b) 19 x 11 mm.

Sum of maximum dimensions: 17 mm + 16 mm + 18 mm + 19 mm = 70 mm.

Automatic volumetry revealed 15 foci: 1) d ₁ = 10 mm; V ₁ = 528.6 mm ³ ; 2) d ₂ = 6 mm; V ₂ = 116.1 mm ³ ; 3) d ₃ = 8 mm; V ₃ = 272.1 mm ³ ; 4) d ₄ = 7 mm; V ₄ = 183.1 mm ³ ; 5) d ₅ = 6 mm; V ₅ = 116.1 mm ³ ; 6) d ₆ = 5 mm; V ₆ = 67.9 mm ³ ; 7) d ₇ = 5 mm; V ₇ = 67.9 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 5 mm; V ₉ = 67.9 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 4 mm; V ₁₁ = 35.5 mm ³ ; 12) d ₁₂ = 4 mm; V ₁₂ = 35.5 mm ³ ; 13) d ₁₃ = 3 mm; V ₁₃ = 15.6 mm ³ ; 14) d ₁₄ = 3 mm; V ₁₄ = 15.6 mm ³ ; 15) d ₁₅ = 3 mm; V ₁₅ = 15.6 mm ³ ;

, V _i - объем очага. Total volume: V =

, V _i is the volume of the focus.

528.6 mm³(V_one) + 116.1 mm³(V₂) + 272.1 mm³(V₃) + 183.1 mm³(V_four) + 116.1 mm³(V_five) + 67.9 mm³(V₆) + 67.9 mm³(V₇) + 67.9 mm³(V_eight) + 67.9 mm³(V_nine) + 67.9 mm³(V₁₀) + 35.5 mm³(V_eleven) + 35.5 mm³(V₁₂) + 15.6 mm³(V₁₃) + 15.6 mm³(V_fourteen) +15.6 mm³(V_fifteen) = 1673.7 mm³...

The patient had not previously received systemic therapy; therefore, the use of the first-line drug, Sunitinib, was recommended.

Recommended:

1. Sunitinib - 50 mg per day orally for 10 weeks with a break of 2 weeks after the fourth.

2. Computed tomographic examination with contrast enhancement at the end of the treatment cycle.

3. Attendance with the survey results.

From 10/7/2019 to 11/3/2019 and from 11/18/2019 to 12/15/2019, the patient received Sunitinib 50 mg per day orally according to the instructions.

12/18/2019. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 17 x 17 mm and 18 x 11 mm. In the right lung there are two lesions measuring 14 x 18 mm and 21 x 11 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

12/24/2019. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. There were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 17 x 17 mm; b) 18 x 11 mm.

2. Right lung: a) 14 x 18 mm; b) 21 x 11 mm.

Sum of maximum dimensions: 17mm + 18mm + 18mm + 21mm = 74mm.

Compared to the first study, after the start of Sunitinib (09/24/2019 - 70 mm), the sum of the maximum sizes increased by 5.7%, which met the criteria for stabilization.

Automatic volumetry revealed: 1) an increase in the number of foci; 2) multidirectional dynamics of volumes.

Revealed 17 foci: 1) d ₁ = 8 mm; V ₁ = 272.1 mm ³ ; 2) d ₂ = 6 mm; V ₂ = 116.1 mm ³ ; 3) d ₃ = 7 mm; V ₃ = 183.1 mm ³ ; 4) d ₄ = 7 mm; V ₄ = 183.1 mm ³ ; 5) d ₅ = 7 mm; V ₅ = 183.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 6 mm; V ₇ = 116.1 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 5 mm; V ₉ = 67.9 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 5 mm; V ₁₁ = 67.9 mm ³ ; 12) d ₁₂ = 5 mm; V ₁₂ = 67.9 mm ³ ; 13) d ₁₃ = 4 mm; V ₁₃ = 35.5 mm ³ ; 14) d ₁₄ = 4 mm; V ₁₄ = 35.5 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 3 mm; V ₁₆ = 15.6 mm ³ ; 17) d ₁₇ = 2 mm; V ₁₇ = 5.2 mm ³ .

, V _i - объем очага.Total volume: V =

, V _i is the volume of the focus.

272.1 mm³(V_one) + 116.1 mm³(V₂) + 183.1 mm³(V₃) + 183.1 mm³(V_four) + 183.1 mm³(V_five) + 116.1 mm³(V₆) + 116.1 mm³(V₇) + 67.9 mm³(V_eight) + 67.9 mm³(V_nine) + 67.9 mm³(V₁₀) + 67.9 mm³(V_eleven) + 67.9 mm³(V₁₂) + 35.5 mm³(V₁₃) + 35.5 mm³(V_fourteen) + 35.5 mm³(V_fifteen) + 15.6 mm³(V_sixteen) + 5.2 mm³(V₁₇) = 1636.8 mm³...

In the previous study (09.24.2019), the calculated volume was 1673.7 mm ³ . Thus, the largest value of the volume in two consecutive studies (Vmax, 09.24.2109) - 1673.7 mm ³ ; the smallest (Vmin, 12/18/2019) - 1636.8 mm. The slice thickness for both examinations is 5 mm.

Calculation of the function Fmax.

+183/dк + 49) =

+183/dк) + 15 x 34.F _max =

+ 183 / d k + 49) =

+ 183 / d k) + 15 x 34.

F _max = 528.6 + 18.3 + 116.1 + 30.5 + 272.1 + 22.9 + 183.1 + 26.1 + 116.1 + 30.5 + 67.9 + 36.6 + 67.9 + 36.6 + 67.9 + 36.6 + 67.9 + 36.6 + 67.9 + 36.6 + 35.5 + 45.8 + 35.5 + 45.8 + 15 .6 + 61 + 15.6 + 61 +15.6 + 61 + 510 = 2769.47 mm ³ .

Calculation of the function Fmin.

+183/dl + 49) =

183/dl) + 17 x 64.F _min =

+ 183 / d l + 49) =

183 / d l ) + 17 x 64.

F_min = 272.1 + 22.9 + 116.1 + 30.5 + 183.1 + 26.1 + 183.1 + 26.1 + 183.1+ 26.1 + 116.1 + 30.5 + 116.1 + 30.5 + 67.9 + 36.6 + 67.9 + 36.6 + 67.9 + 36.6 + 67 .9 + 36.6 + 67.9 + 36.6 + 35.5 + 45.8 + 35.5 + 45.8 + 35.5 + 45.8 + 15.6 + 61 + 5.2 + 91 .5 + 1088 = 3031.36 mm³...

F _max - F _min = 2769.47 - 3031.36 = -266.89 <0, which, according to the developed method, corresponded to stabilization.

The patient was advised to continue the treatment as before.

From 12/30/2019 to 01/26/2019 and from 02/10/2020 to 03/08/2020 on an outpatient basis, the patient received 50 mg of Sunitinib per day orally according to the instructions.

03/12/2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 16 x 15 mm and 14 x 11 mm. In the right lung there are two lesions measuring 14 x 18 mm and 19 x 11 mm. In both lungs, there are multiple small foci up to 7 mm in diameter.

03/17/2020. A patient at an outpatient appointment of the Federal State Budgetary Institution "RNTSRHT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment endured satisfactorily there were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 16 x 15 mm; b) 14 x 11 mm.

2. Right lung: a) 14 x 18 mm; b) 19 x 11 mm.

Sum of maximum dimensions: 16 mm + 14 mm + 18 mm + 19 mm = 67 mm.

Compared to the previous study (12/18/2019 - 74 mm), the sum of the maximum dimensions decreased by 9%. Compared to the nadir (the minimum value during the observation - September 24, 2019 - 70 mm), the sum of the maximum dimensions decreased by 4%, which corresponded to the stabilization criteria.

Automatic volumetry revealed 17 foci: 1) d ₁ = 8 mm; V ₁ = 272.1 mm ³ ; 2) d ₂ = 6 mm; V ₂ = 116.1 mm ³ ; 3) d ₃ = 6 mm; V ₃ = 116.1 mm ³ ; 4) d ₄ = 7 mm; V ₄ = 183.1 mm ³ ; 5) d ₅ = 7 mm; V ₅ = 183.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 6 mm; V ₇ = 116.1 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 5 mm; V ₉ = 67.9 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 4 mm; V ₁₁ = 35.5 mm ³ ; 12) d ₁₂ = 4 mm; V ₁₂ = 35.5 mm ³ ; 13) d ₁₃ = 4 mm; V ₁₃ = 35.5 mm ³ ; 14) d ₁₄ = 4 mm; V ₁₄ = 35.5 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 3 mm; V ₁₆ = 15.6 mm ³ ; 17) d ₁₇ = 2 mm; V ₁₇ = 5.2 mm ³ .

Total volume: 1504, 9 mm ³ (calculation as during the previous visit - 12/24/2019).

The largest value of the volume in two consecutive studies (Vmax, 12/18/2019) - 1636.8 mm ³ ; the smallest (Vmin, 03/12/2020) - 1504.9 mm. The slice thickness in both studies was 5 mm.

F _max = 2880.32; Fmin = 2922.14 (calculation as in the previous visit - 12/24/2019).

F _max - F _min = 2880.32 - 2922.14 = -41.82 <0, which, according to the developed method, corresponded to stabilization.

The patient was advised to continue the treatment as before.

From 03/23/2020 to 04/19/2020 and from 05/04/2020 to 05/31/2020 on an outpatient basis, the patient received Sunitinib 50 mg per day orally according to the instructions.

06/03/2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 18 x 15 mm and 16 x 14 mm. In the right lung, there are two lesions measuring 22 x 16 mm and 23 x 19 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

8.06.2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. He noted increased fatigue.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 18 x 15 mm; b) 16 x 14 mm.

2. Right lung: a) 22 x 16 mm; b) 23 x 19 mm.

Sum of maximum dimensions: 18 mm + 16 mm + 22 mm + 23 mm = 79 mm.

Compared to the nadir (03/12/2020 - 67 mm), the sum of the maximum dimensions increased by 18%, which corresponded to the stabilization criteria.

Automatic volumetry revealed 17 foci: 1) d ₁ = 13 mm; V ₁ = 1156.8 mm ³ ; 2) d ₂ = 11 mm; V ₂ = 702.4 mm ³ ; 3) d ₃ = 13 mm; V ₃ = 1156.8 mm ³ ; 4) d ₄ = 12 mm; V ₄ = 910.8 mm ³ ; 5) d ₅ = 7 mm; V ₅ = 183.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 6 mm; V ₇ = 116.1 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 5 mm; V ₉ = 67.9 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 4 mm; V ₁₁ = 35.5 mm ³ ; 12) d ₁₂ = 4 mm; V ₁₂ = 35.5 mm ³ ; 13) d ₁₃ = 4 mm; V ₁₃ = 35.5 mm ³ ; 14) d ₁₄ = 4 mm; V ₁₄ = 35.5 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 3 mm; V ₁₆ = 15.6 mm ³ ; 17) d ₁₇ = 2 mm; V ₁₇ = 5.2 mm ³ .

Total volume: 4744.4 mm ³ (calculation as during the visit 12/24/2019)

The largest value of the volume in two consecutive studies (Vmax, 06/03/2020) - 4744.4 mm ³ ; the smallest (Vmin, 03/12/2020) - 1504.9 mm. The slice thickness in both studies was 5 mm.

F _max = 5960.63; Fmin = 2922.14 (calculated as during the visit on 12/24/2019).

F _max - F _min = 5960.63 - 2922.14 = 3038.49> 0, which, according to the developed method, corresponded to progression.

According to RECIST v 1.1. the patient has stabilization. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - progression. A consultation was held. It was recommended to change tactics and continue treatment using the drug recommended in the second line - Nivolumab (Opdivo) at a dose of 3 mg / kg body weight intravenously twice a week for eight weeks.

The patient's weight is 67 kg. Dose of the drug for a single administration: 67 x 3 = 201 mg (2 vials of 10 ml - 200 mg).

06/15/2020, 06/29/2020, 07/13/2020, 07/27/2020 on an outpatient basis, Nivolumab was administered at a dose of 200 mg (2 vials of 10 ml) as a 60-minute intravenous infusion, dissolving 0.9% in 400 ml NaCl.

08/11/2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 15 x 12 mm and 12 x 11 mm. In the right lung, there are two lesions measuring 17 x 16 mm and 12 x 10 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

08/14/2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. There were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 15 x 12 mm; b) 12 x 11 mm.

2. Right lung: a) 17 x 16 mm; b) 12 x 10 mm.

Sum of maximum dimensions: 15mm + 12mm + 17mm + 12mm = 56mm.

Compared to the original study (09/24/2019 - 70 mm), the sum of the maximum dimensions decreased by 20%, which met the stabilization criteria.

Automatic volumetry revealed 14 foci: 1) d ₁ = 13 mm; V ₁ = 1156.8 mm ³ ; 2) d ₂ = 11 mm; V ₂ = 702.4 mm ³ ; 3) d ₃ = 13 mm; V ₃ = 1156.8 mm ³ ; 4) d ₄ = 12 mm; V ₄ = 910.8 mm ³ ; 5) d ₅ = 7 mm; V ₅ = 183.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 6 mm; V ₇ = 116.1 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 5 mm; V ₉ = 67.9 mm ³ ; 10) d ₁₀ = 4 mm; V ₁₀ = 35.5 mm ³ ; 11) d ₁₁ = 4 mm; V ₁₁ = 35.5 mm ³ ; 12) d ₁₂ = 4 mm; V ₁₂ = 35.5 mm ³ ; 13) d ₁₃ = 4 mm; V ₁₃ = 35.5 mm ³ ; 14) d ₁₄ = 3 mm; V ₁₄ = 15.6 mm ³ .

Total volume: 4635.7 mm ³ (calculation as during the visit 12/24/2019).

The largest value of the volume in two consecutive studies (Vmax, 06/03/2020) - 4744.4 mm ³ ; the smallest (Vmin, 08/11/2020) - 4635.7 mm. The slice thickness in both studies was 5 mm.

F _max = 5960.63; Fmin = 4761.21 (calculation as during the visit on 12/24/2019).

F _max - F _min = 5960.63 - 4761.21 = 1199.42> 0, which, according to the developed method, corresponds to a partial answer.

According to RECIST v 1.1. the patient has stabilization. According to volumetric data and evaluation of the immediate results of treatment according to the developed method, this is a partial answer. It was recommended to continue treatment as usual.

08/17/2020, 08/31/2020, 09/14/2020, 09/28/2020 on an outpatient basis, Nivolumab was administered at a dose of 200 mg (2 vials of 10 ml) as a 60-minute intravenous infusion, dissolving 0.9% in 400 ml NaCl.

10/14/2020. Computed tomography research. Slice thickness - 3 mm. Computed tomograph - Aquillion One, Toshiba. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 12 x 12 mm and 12 x 11 mm. In the right lung there are two lesions measuring 11 x 10 mm and 12 x 10 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

10/16/2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. There were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 12 x 12 mm; b) 12 x 11 mm.

2. Right lung: a) 11 x 10 mm; b) 12 x 10 mm.

Sum of maximum dimensions: 12mm + 12mm + 11mm + 12mm = 47mm.

Compared to the original study (09/24/2019 - 70 mm), the sum of the maximum dimensions decreased by 33%, which met the criteria for a partial response.

Automatic volumetry revealed 16 foci: 1) d ₁ = 7 mm; V ₁ = 183.1 mm ³ ; 2) d ₂ = 11 mm; V ₂ = 702.4 mm ³ ; 3) d ₃ = 8 mm; V ₃ = 272.1 mm ³ ; 4) d ₄ = 10 mm; V ₄ = 528.6 mm ³ ; 5) d ₅ = 9 mm; V ₅ = 386.2 mm ³ ; 6) d ₆ = 9 mm; V ₆ = 386.2 mm ³ ; 7) d ₇ = 9 mm; V ₇ = 386.2 mm ³ ; 8) d ₈ = 9 mm; V ₈ = 386.2 mm ³ ; 9) d ₉ = 8 mm; V ₉ = 272.1 mm ³ ; 10) d ₁₀ = 8 mm; V ₁₀ = 272.1 mm ³ ; 11) d ₁₁ = 8 mm; V ₁₁ = 272.1 mm ³ ; 12) d ₁₂ = 8 mm; V ₁₂ = 272.1 mm ³ ; 13) d ₁₃ = 7 mm; V ₁₃ = 183.1 mm ³ ; 14) d ₁₄ = 3 mm; V ₁₄ = 15.6 mm ³ ; 15) d ₁₅ = 2 mm; V ₁₅ = 5.2 mm ³ ; 16) d ₁₆ = 2 mm; V ₁₆ = 5.2 mm ³ .

Total volume: 4528.4 mm ³ (calculation as during the visit on 12/24/2019).

The largest value of the volume in two consecutive studies (Vmax, 08/11/2020) - 4635.7 mm ³ ; the smallest (Vmin, 10/14/2020) - 4528.4 mm. The slice thickness in the study on 08/11/2020 was 5 mm, in the study on 10/14/2020 - 3 mm.

F _max = 5576.13; Fmin = 5722.13 (calculation as during the visit on 12/24/2019).

F _max - F _min = 5576.13 - 5722.13 = - 146 <0, which, according to the developed method, corresponded to stabilization.

According to RECIST v 1.1. the patient has a partial answer. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - stabilization. It was recommended to continue treatment as usual.

10/19/2020, 10/26/2020, 11/9/2020, 11/23/2020 on an outpatient basis, Nivolumab was administered at a dose of 200 mg (2 vials of 10 ml) as a 60-minute intravenous infusion, dissolving 0.9% in 400 ml NaCl.

12/14/2020. Computed tomography research. Slice thickness - 3 mm. Computed tomograph - Aquillion One, Toshiba. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 14 x 12 mm and 13 x 12 mm. In the right lung there are two lesions measuring 12 x 11 mm and 14 x 11 mm. In both lungs, there are multiple small foci up to 9 mm in diameter.

12/18/2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 14 x 12 mm; b) 13 x 12 mm.

2. Right lung: a) 12 x 11 mm; b) 14 x 11 mm.

Sum of maximum dimensions: 14mm + 13mm + 12mm + 14mm = 53mm.

Compared to the nadir (10/14/2020 - 47 mm), the sum of the maximum dimensions increased by 13%, which corresponded to the stabilization criteria.

Automatic volumetry revealed 16 foci: 1) d ₁ = 10 mm; V ₁ = 528.6 mm ³ ; 2) d ₂ = 11 mm; V ₂ = 702.4 mm ³ ; 3) d ₃ = 12 mm; V ₃ = 910.8 mm ³ ; 4) d ₄ = 10 mm; V ₄ = 528.6 mm ³ ; 5) d ₅ = 9 mm; V ₅ = 386.2 mm ³ ; 6) d ₆ = 9 mm; V ₆ = 386.2 mm ³ ; 7) d ₇ = 9 mm; V ₇ = 386.2 mm ³ ; 8) d ₈ = 9 mm; V ₈ = 386.2 mm ³ ; 9) d ₉ = 8 mm; V ₉ = 272.1 mm ³ ; 10) d ₁₀ = 8 mm; V ₁₀ = 272.1 mm ³ ; 11) d ₁₁ = 8 mm; V ₁₁ = 272.1 mm ³ ; 12) d ₁₂ = 8 mm; V ₁₂ = 272.1 mm ³ ; 13) d ₁₃ = 7 mm; V ₁₃ = 183.1 mm ³ ; 14) d ₁₄ = 3 mm; V ₁₄ = 15.6 mm ³ ; 15) d ₁₅ = 2 mm; V ₁₅ = 5.2 mm ³ ; 16) d ₁₆ = 2 mm; V ₁₆ = 5.2 mm ³ .

Total volume: 5512.6 mm ³ (calculation as during the visit on 12/24/2019).

The largest value of the volume in two consecutive studies (Vmax, 12/14/2020) - 5512.6 mm ³ ; the smallest (Vmin, 10/14/2020) - 4528.4 mm. The slice thickness in both studies was 3 mm.

F _max = 6658.1; Fmin = 5722.13 (calculation as during the visit on 12/24/2019).

F _max - F _min = 6658.1 - 5722.13 = 935.97> 0, which, according to the developed method, corresponded to progression.

According to RECIST v 1.1. the patient has stabilization. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - progression. A consultation was held. It was recommended to change tactics and continue treatment using the drug recommended in the third line - Everolimus - 10 mg per day orally according to the instructions.

The patient is currently alive. It is under the supervision of the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation. 37 months have passed since the diagnosis of renal cell carcinoma. During the observation period, the immediate results of treatment were assessed six times using volumetry according to the developed method and according to the RECIST v. 1.1. In two cases, the assessment was the same. In three cases, the correction was in the direction of worsening the prognosis: in two - from stabilization to progression, which required a change in treatment tactics; and in one - from a partial response to stabilization. In one case, the correction took place in the direction of improving the forecast: from stabilization to a partial response.

Example 2.

Patient A, born in 1959

01/27/2020. A patient at an outpatient appointment of the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "Ministry of Health of the Russian Federation The patient had no active complaints. The general condition is satisfactory.

From the anamnesis it is known that on June 25, 2018, according to the CT scan, a neoplasm of the right kidney with dimensions of 10 x 12 cm was revealed. On July 5, 2018, a right-sided nephrectomy was performed at the St. Petersburg City General Hospital No. 2. Histologically - clear cell renal cell carcinoma (from 11.07.2018). After surgery, he was under the supervision of a district oncologist. A CT scan of the abdomen and lungs was performed once every six months. During the control examination according to CT data from December 10, 2019, signs of disease progression were revealed in the form of the appearance of a new focus in the left lung with a diameter of 21 mm. In this regard, the patient turned to the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation.

The examination revealed the following changes.

01/29/2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 25 x 16 mm and 7 x 5 mm. In the right lung - a lesion measuring 14 x 10 mm. In both lungs, there are multiple small foci up to 5 mm in diameter.

02/04/2020. A patient at an outpatient appointment of the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation.

As a result of the examination, the diagnosis was made: renal cell carcinoma of the right kidney T3N0M0. 07/05/2018 - right-sided nephrectomy. Histologically - clear cell renal cell carcinoma (conclusion from 11.07.2018). Progression: metastasis in the left lung from 10.12.2019. Progression from 01/29/2020: an increase in the size and number of foci in both lungs.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 25 x 16 mm; b) 7 x 5 mm.

2. Right lung: a) 14 x 10 mm.

Sum of maximum dimensions: 25mm + 7mm + 14mm = 46mm.

Automatic volumetry revealed 22 lesions: 1) d ₁ = 20 mm; V ₁ = 4198.6 mm ³ ; 2) d ₂ = 8 mm; V ₂ = 272.1 mm ³ ; 3) d ₃ = 12 mm; V ₃ = 910.8 mm ³ ; 4) d ₄ = 7 mm; V ₄ = 183.1 mm ³ ; 5) d ₅ = 6 mm; V ₅ = 116.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 5 mm; V ₇ = 67.9 mm ³ ; 8) d ₈ = 5 mm; V ₈ = 67.9 mm ³ ; 9) d ₉ = 4 mm; V ₉ = 35.5 mm ³ ; 10) d ₁₀ = 4 mm; V ₁₀ = 35.5 mm ³ ; 11) d ₁₁ = 4 mm; V ₁₁ = 35.5 mm ³ ; 12) d ₁₂ = 4 mm; V ₁₂ = 35.5 mm ³ ; 13) d ₁₃ = 3 mm; V ₁₃ = 15.6 mm ³ ; 14) d ₁₄ = 3 mm; V ₁₄ = 15.6 mm ³ ; 15) d ₁₅ = 3 mm; V ₁₅ = 15.6 mm ³ ; 16) d ₁₆ = 3 mm; V ₁₆ = 15.6 mm ³ ; 17) d ₁₇ = 3 mm; V ₁₇ = 15.6 mm ³ ; 18) d ₁₈ = 2 mm; V ₁₈ = 5.2 mm ³ ; 19) d ₁₉ = 2 mm; V ₁₉ = 5.2 mm ³ ; 20) d ₂₀ = 2 mm; V ₂₀ = 5.2 mm ³ ; 21) d ₂₁ = 2 mm; V ₂₁ = 5.2 mm ³ ; 22) d ₂₂ = 2 mm; V ₂₂ = 5.2 mm ³ .

, V _i - объем очага.Total volume: V =

, V _i is the volume of the focus.

4198.6 mm³(V_one) + 272.1 mm³(V₂) + 910.8 mm³(V₃) + 183.1 mm³(V_four) + 116.1 mm³(V_five) + 116.1 mm³(V₆) + 67.9 mm³(V₇) + 67.9 mm³(V_eight) + 35.5 mm³(V_nine) + 35.5 mm³(V₁₀) + 35.5 mm³(V_eleven) + 35.5 mm³(V₁₂) + 15.6 mm³(V₁₃) + 15.6 mm³(V_fourteen) +15.6 mm³(V_fifteen) + 15.6 mm³(V_sixteen) +15.6 mm³(V₁₇) + 5.2 mm³(V_eighteen) + 5.2 mm³(V_nineteen) + 5.2 mm³(V_twenty) + 5.2 mm³(V₂₁) + 5.2 mm³(V₂₂) = 6179 mm³...

The patient had not previously received systemic therapy; therefore, the use of the first-line drug, Sunitinib, was recommended.

Recommended:

1. Sunitinib - 50 mg per day orally for 10 weeks with a break of 2 weeks after the fourth.

2. Computed tomographic examination with contrast enhancement at the end of the treatment cycle.

3. Attendance with the survey results.

From 02/10/2020 to 03/08/2020 and from 03/23/2020 to 04/19/2020 the patient received Sunitinib 50 mg per day orally according to the instructions.

04/28/2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 25 x 18 mm and 9 x 7 mm. In the right lung there are two lesions measuring 15 x 12 mm and 10 x 8 mm. In both lungs, there are multiple small foci up to 7 mm in diameter.

04/30/2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 25 x 18 mm; b) 9 x 7 mm.

2. Right lung: a) 15 x 12 mm; b) 10 x 8 mm.

Sum of maximum dimensions: 25mm + 9mm + 15mm + 10mm = 59mm.

Compared to the first study (01/29/2020 - 46 mm), the sum of the maximum sizes increased by 32%, which met the criteria for progression.

Automatic volumetry revealed 30 foci: 1) d ₁ = 12 mm; V ₁ = 910.8 mm ³ ; 2) d ₂ = 9 mm; V ₂ = 386.2 mm ³ ; 3) d ₃ = 17 mm; V ₃ = 2580.9 mm ³ ; 4) d ₄ = 11 mm; V ₄ = 702.4 mm ³ ; 5) d ₅ = 7 mm; V ₅ = 183.1 mm ³ ; 6) d ₆ = 6 mm; V ₆ = 116.1 mm ³ ; 7) d ₇ = 6 mm; V ₇ = 116.1 mm ³ ; 8) d ₈ = 6 mm; V ₈ = 116.1 mm ³ ; 9) d ₉ = 6 mm; V ₉ = 116.1 mm ³ ; 10) d ₁₀ = 6 mm; V ₁₀ = 116.1 mm ³ ; 11) d ₁₁ = 5 mm; V ₁₁ = 67.9 mm ³ ; 12) d ₁₂ = 5 mm; V ₁₂ = 67.9 mm ³ ; 13) d ₁₃ = 5 mm; V ₁₃ = 67.9 mm ³ ; 14) d ₁₄ = 4 mm; V ₁₄ = 35.5 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 4 mm; V ₁₆ = 35.5 mm ³ ; 17) d ₁₇ = 4 mm; V ₁₇ = 35.5 mm ³ ; 18) d ₁₈ = 4 mm; V ₁₈ = 35.5 mm ³ ; 19) d ₁₉ = 4 mm; V ₁₉ = 35.5 mm ³ ; 20) d ₂₀ = 4 mm; V ₂₀ = 35.5 mm ³ ; 21) d ₂₁ = 3 mm; V ₂₁ = 15.6 mm ³ ; 22) d ₂₂ = 3 mm; V ₂₂ = 15.6 mm ³ ; 23) d ₂₃ = 2 mm; V ₂₃ = 5.2 mm ³ ; 24) d ₂₄ = 2 mm; V ₂₄ = 5.2 mm ³ ; 25) d ₂₅ = 2 mm; V ₂₅ = 5.2 mm ³ ; 26) d ₂₆ = 2 mm; V ₂₆ = 5.2 mm ³ ; 27) d ₂₇ = 2 mm; V ₂₇ = 5.2 mm ³ ; 28) d ₂₈ = 2 mm; V ₂₈ = 5.2 mm ³ ; 29) d ₂₉ = 2 mm; V ₂₉ = 5.2 mm ³ ; 30) d ₃₀ = 2 mm; V ₃₀ = 5.2 mm ³ .

Total volume: 5753 mm ³ (calculation as during the previous visit - 02/04/2020).

The largest value of the volume in two consecutive studies (Vmax, 01/29/2020) - 6179 mm ³ ; the smallest (Vmin, 04/28/2020) - 5753 mm ³ . The slice thickness in both studies was 5 mm.

F _max = 8080.13; Fmin = 9104.2 (calculation as in example 1 during the visit on 12/24/2019).

F _max - F _min = 8080.13 - 9104.2 = - 1024.07 <0, which, according to the developed method, corresponded to stabilization.

According to RECIST v 1.1. the patient has progression. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - stabilization. A consultation was held. It was recommended to continue treatment as usual.

From 05/11/2020 to 06/07/2020 and from 06/22/2020 to 07/19/2020 the patient received Sunitinib 50 mg per day orally according to the instructions.

21.07.2020. Computed tomography research. Slice thickness - 3 mm. Computed tomograph - Aquillion One, Toshiba. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 18 x 15 mm and 11 x 9 mm. In the right lung there are two lesions measuring 12 x 10 mm and 11 x 8 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

07.24.2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. There were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 18 x 15 mm; b) 11 x 9 mm.

2. Right lung: a) 12 x 10 mm; b) 11 x 8 mm.

Sum of maximum dimensions: 18mm + 11mm + 12mm + 11mm = 52mm.

Compared to the nadir (01/29/2020 - 46 mm), the sum of the maximum dimensions increased by 7%, which corresponded to the stabilization criteria.

Automatic volumetry revealed 28 foci: 1) d ₁ = 12 mm; V ₁ = 910.8 mm ³ ; 2) d ₂ = 10 mm; V ₂ = 528.6 mm ³ ; 3) d ₃ = 16 mm; V ₃ = 2152.7 mm ³ ; 4) d ₄ = 10 mm; V ₄ = 528.6 mm ³ ; 5) d ₅ = 8 mm; V ₅ = 272.1 mm ³ ; 6) d ₆ = 8 mm; V ₆ = 272.1 mm ³ ; 7) d ₇ = 7 mm; V ₇ = 183.1 mm ³ ; 8) d ₈ = 6 mm; V ₈ = 116.1 mm ³ ; 9) d ₉ = 6 mm; V ₉ = 116.1 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 5 mm; V ₁₁ = 67.9 mm ³ ; 12) d ₁₂ = 5 mm; V ₁₂ = 67.9 mm ³ ; 13) d ₁₃ = 5 mm; V ₁₃ = 67.9 mm ³ ; 14) d ₁₄ = 5 mm; V ₁₄ = 67.9 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 4 mm; V ₁₆ = 35.5 mm ³ ; 17) d ₁₇ = 4 mm; V ₁₇ = 35.5 mm ³ ; 18) d ₁₈ = 4 mm; V ₁₈ = 35.5 mm ³ ; 19) d ₁₉ = 4 mm; V ₁₉ = 35.5 mm ³ ; 20) d ₂₀ = 4 mm; V ₂₀ = 35.5 mm ³ ; 21) d ₂₁ = 4 mm; V ₂₁ = 35.5 mm ³ ; 22) d ₂₂ = 3 mm; V ₂₂ = 15.6 mm ³ ; 23) d ₂₃ = 3 mm; V ₂₃ = 15.6 mm ³ ; 24) d ₂₄ = 3 mm; V ₂₄ = 15.6 mm ³ ; 25) d ₂₅ = 3 mm; V ₂₅ = 15.6 mm ³ ; 26) d ₂₆ = 3 mm; V ₂₆ = 15.6 mm ³ ; 27) d ₂₇ = 3 mm; V ₂₇ = 15.6 mm ³ ; 28) d ₂₈ = 3 mm; V ₂₈ = 15.6 mm ³ .

Total volume: 5777.9 mm ³ (calculation as during the visit on February 4, 2020).

The largest value of the volume in two consecutive studies (Vmax, 07/21/2020) - 5777.9 mm ³ ; the smallest (Vmin, 04/28/2020) - 5753 mm ³ . Slice thickness in the study on 04/28/2020 - 5 mm; in the study on July 21, 2020 - 3 mm.

F _max = 8024.3; Fmin = 9104.2 (calculation as in example 1 during the visit on 12/24/2019).

F _max - F _min = 8024.3 - 9104.2 = - 1079.9 <0, which, according to the developed method, corresponded to stabilization.

According to RECIST v 1.1. the patient has stabilization. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - stabilization. It was recommended to continue treatment as usual.

From 07/27/2020 to 08/23/2020 and from 09/07/2020 to 10/04/2020 the patient received Sunitinib 50 mg per day orally according to the instructions.

6.10.2020. Computed tomography research. Slice thickness - 5 mm. Computer tomograph - Sensation 64, Siemens. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 20 x 17 mm and 11 x 11 mm. In the right lung there are two lesions measuring 12 x 10 mm and 11 x 9 mm. In both lungs, there are multiple small foci up to 8 mm in diameter.

9.10.2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. Blood pressure increased periodically to 160/90. It was stopped by taking antihypertensive drugs.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 20 x 17 mm; b) 11 x 11 mm.

2. Right lung: a) 12 x 10 mm; b) 11 x 9 mm.

Sum of maximum dimensions: 20mm + 11mm + 12mm + 11mm = 54mm.

Compared to the nadir (01/29/2020 - 46 mm), the sum of the maximum diameters increased by 17%, which corresponded to the stabilization criteria.

Automatic volumetry revealed 20 foci: 1) d ₁ = 18 mm; V ₁ = 3062.6 mm ³ ; 2) d ₂ = 10 mm; V ₂ = 528.6 mm ³ ; 3) d ₃ = 16 mm; V ₃ = 2152.7 mm ³ ; 4) d ₄ = 15 mm; V ₄ = 1774.6 mm ³ ; 5) d ₅ = 8 mm; V ₅ = 272.1 mm ³ ; 6) d ₆ = 8 mm; V ₆ = 272.1 mm ³ ; 7) d ₇ = 7 mm; V ₇ = 183.1 mm ³ ; 8) d ₈ = 6 mm; V ₈ = 116.1 mm ³ ; 9) d ₉ = 6 mm; V ₉ = 116.1 mm ³ ; 10) d ₁₀ = 5 mm; V ₁₀ = 67.9 mm ³ ; 11) d ₁₁ = 5 mm; V ₁₁ = 67.9 mm ³ ; 12) d ₁₂ = 5 mm; V ₁₂ = 67.9 mm ³ ; 13) d ₁₃ = 4 mm; V ₁₃ = 35.5 mm ³ ; 14) d ₁₄ = 4 mm; V ₁₄ = 35.5 mm ³ ; 15) d ₁₅ = 4 mm; V ₁₅ = 35.5 mm ³ ; 16) d ₁₆ = 4 mm; V ₁₆ = 35.5 mm ³ ; 17) d ₁₇ = 3 mm; V ₁₇ = 15.6 mm ³ ; 18) d ₁₈ = 3 mm; V ₁₈ = 15.6 mm ³ ; 19) d ₁₉ = 3 mm; V ₁₉ = 15.6 mm ³ ; 20) d ₂₀ = 3 mm; V ₂₀ = 15.6 mm ³ .

Total volume: 8886.4 mm ³ (calculation as during the visit on February 4, 2020).

The largest value of the volume in two consecutive studies (Vmax, 6.10.2020) - 8886.4 mm ³ ; the smallest (Vmin, 21.07.2020) - 5777.9 mm ³ . Slice thickness in the study 07/21/2020 - 3 mm; in the study on 6.10.

F _max = 10288.22; Fmin = 8528.3 (calculation as in example 1 during the visit on 12/24/2019).

F _max - F _min = 10288.22 - 8528.3 = 1759.92> 0, which, according to the developed method, corresponded to progression.

According to RECIST v 1.1. the patient has stabilization. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - progression. A consultation was held. It was recommended to change tactics and continue treatment using the drug recommended in the second line - Nivolumab (Opdivo) at a dose of 3 mg / kg body weight intravenously twice a week for eight weeks.

The patient's weight is 63 kg. Dose of the drug for a single administration: 63 x 3 = 189 mg (2 vials of 10 ml - 200 mg).

10/12/2020, 10/26/2020, 11/9/2020, 11/23/2020 on an outpatient basis, Nivolumab was administered at a dose of 200 mg (2 vials of 10 ml) as a 60-minute intravenous infusion, dissolving 0.9% in 400 ml NaCl.

3.12.2020. Computed tomography research. Slice thickness - 3 mm. Computed tomograph - Aquillion One, Toshiba. In the area of the bed of the right kidney, no pathological formations were revealed. The left kidney is without pathology. Abdominal organs - no pathology. In the left lung there are two lesions measuring 22 x 19 mm and 12 x 11 mm. In the right lung, there are two lesions measuring 14 x 12 mm and 14 x 11 mm. In both lungs, there are multiple small foci up to 9 mm in diameter.

9.12.2020. A patient at an outpatient appointment of the FSBI "RNTSRKhT named after acad. A.M. Granova "of the Ministry of Health of the Russian Federation. The treatment was tolerated satisfactorily. There were no side effects.

Targeted foci (RECIST v 1.1):

1. Left lung: a) 22 x 19 mm; b) 12 x 11 mm.

2. Right lung: a) 14 x 12 mm; b) 14 x 11 mm.

Sum of maximum dimensions: 22mm + 12mm + 14mm + 14mm = 62mm.

Compared to the nadir (01/29/2020 - 46 mm), the sum of the maximum sizes increased by 35%, which met the criteria for progression.

Automatic volumetry revealed 26 foci: 1) d ₁ = 10 mm; V ₁ = 528.6 mm ³ ; 2) d ₂ = 11 mm; V ₂ = 702.4 mm ³ ; 3) d ₃ = 9 mm; V ₃ = 386.2 mm ³ ; 4) d ₄ = 8 mm; V ₄ = 272.1 mm ³ ; 5) d ₅ = 9 mm; V ₅ = 386.2 mm ³ ; 6) d ₆ = 9 mm; V ₆ = 386.2 mm ³ ; 7) d ₇ = 9 mm; V ₇ = 386.2 mm ³ ; 8) d ₈ = 9 mm; V ₈ = 386.2 mm ³ ; 9) d ₉ = 9 mm; V ₉ = 386.2 mm ³ ; 10) d ₁₀ = 9 mm; V ₁₀ = 386.2 mm ³ ; 11) d ₁₁ = 9 mm; V ₁₁ = 386.2 mm ³ ; 12) d ₁₂ = 9 mm; V ₁₂ = 386.2 mm ³ ; 13) d ₁₃ = 9 mm; V ₁₃ = 386.2 mm ³ ; 14) d ₁₄ = 8 mm; V ₁₄ = 272.1 mm ³ ; 15) d ₁₅ = 8 mm; V ₁₅ = 272.1 mm ³ ; 16) d ₁₆ = 8 mm; V ₁₆ = 272.1 mm ³ ; 17) d ₁₇ = 8 mm; V ₁₇ = 272.1 mm ³ ; 18) d ₁₈ = 8 mm; V ₁₈ = 272.1 mm ³ ; 19) d ₁₉ = 8 mm; V ₁₉ = 272.1 mm ³ ; 20) d ₂₀ = 8 mm; V ₂₀ = 272.1 mm ³ ; 21) d ₂₁ = 8 mm; V ₂₁ = 272.1 mm ³ ; 22) d ₂₂ = 7 mm; V ₂₂ = 183.1 mm ³ ; 23) d ₂₃ = 7 mm; V ₂₃ = 183.1 mm ³ ; 24) d ₂₄ = 7 mm; V ₂₄ = 183.1 mm ³ ; 25) d ₂₅ = 6 mm; V ₂₅ = 116.1 mm ³ ; 26) d ₂₆ = 5 mm; V ₂₆ = 67.9 mm ³ .

Total volume: 8275.4 mm ³ (calculation as during the visit on 02/04/2020).

The largest value of the volume in two consecutive studies (Vmax, 6.10.2020) - 8886.4 mm ³ ; the smallest (Vmin, 3.12.2020) - 5275.4 mm ³ . Slice thickness in the study on October 6, 2020 - 5 mm; in the study on December 3, 2020 - 3 mm.

F _max = 10288.22; Fmin = 10372.79 (calculation as in example 1 during the visit on 12/24/2019).

F _max - F _min = 10288.22 - 10372.79 = - 84.57 <0, which, according to the developed method, corresponded to stabilization.

According to RECIST v 1.1. the patient has progression. According to volumetric data and evaluation of the immediate results of treatment according to the developed method - stabilization. A consultation was held. It was recommended to continue treatment as usual.

The patient is currently alive. It is under the supervision of the Federal State Budgetary Institution "RNTSRKhT im. acad. A.M. Granova "of the Ministry of Health of the Russian Federation. 30 months have passed since the diagnosis of renal cell carcinoma. During the observation period, the immediate results of treatment were assessed four times using volumetry according to the developed method and according to the RECIST v. 1.1. In one case, the score was the same. In one case, the correction was in the direction of a worsening prognosis: from stabilization to progression, which required a change in treatment tactics. In two cases, the correction was in the direction of improving the prognosis: from progression to stabilization.

To date, the method has been clinically tested on 127 patients. Data from 46 of them were used to develop a method for assessing the immediate results of treatment of disseminated renal cell carcinoma, 81 - for validation.

The method improves the accuracy of assessing the immediate results of the treatment of disseminated renal cell carcinoma. Compared to the standard method (RECIST v 1.1), the rate of progression significantly differs (development group: RECIST v 1.1 - 17%, developed method - 42%; validation group: RECIST v 1.1 - 15%, developed method - 37%), stabilization ( development group: RECIST v 1.1 - 61%, developed method - 27%; validation group: RECIST v 1.1 - 72%, developed method - 33%) and partial response (validation group: RECIST v 1.1 - 12%, developed method - 29 %).

When analyzing long-term results, two patterns were revealed:

1. When correcting the immediate results of treatment using the developed method towards improvement (from progression to stabilization and from stabilization to a partial response), the median overall survival with a favorable prognosis according to MSKCC is significantly less than in the subgroup where the correction took place (study group; 37 months and 42 months; validation group: 42 months and 48 months, respectively).

Similar patterns were found in the MSKCC intermediate prognosis group (research group; 19 months and 23 months; validation group: 16 months and 21 months, respectively).

2. When correcting the immediate results of treatment using the developed method towards deterioration (from stabilization to progression and from a partial response to stabilization), the median overall survival with an unfavorable prognosis according to MSKCC is significantly higher compared to the subgroup where the correction took place (research group; 7 months and 4 months; validation group: 9 months and 7 months, respectively).

A similar pattern was found in the research group with an interim prognosis according to MSKCC (19 months and 17 months, respectively).

The method has a number of significant advantages in comparison with known analogs:

1. Allows you to more accurately differentiate stabilization with partial response and progression.

2. Allows you to compare studies conducted with different slice thickness and different software.

3. Does not require precise definition of the boundaries of volume changes differentiating stabilization, progression and partial response.

4. Due to adequate correction of treatment tactics, it contributes to the improvement of long-term results of treatment.

5. Includes volumetry of all foci identified during the study, which makes it possible to more accurately assess the dynamics of the tumor mass.

A method for assessing the immediate results of treatment of disseminated renal cell carcinoma has been developed in the Department of Basic Research and the Group of Molecular Biological Prediction and Treatment Individualization of the Federal State Budgetary Institution “RNTSRKhT im. acad. A.M. Granov "of the Ministry of Health of the Russian Federation and has now been clinically tested in 127 patients with a positive result.

Table 1. WHO RECIST v1.0 RECIST v1.1 Assessment method Two dimensions. The sum of the perpendicular maximum sizes of the foci One dimension. The sum of the largest sizes of target foci Sum of the largest sizes of target foci and chains of lymph nodes along the short axis Number of foci assessed All hearths Target foci: no more than 10 in total (no more than 5 in an organ) Target foci: no more than 5 in total (no more than 2 in an organ) Full answer Disappearance of all lesions for at least four weeks Disappearance of all lesions for at least four weeks. Chain of lymph nodes along the short axis less than 10 mm Partial Answer ≥ 50% reduction from baseline or nadir for at least four weeks ≥ 30% reduction from baseline or nadir for at least four weeks Lack of new measurable and non-measurable foci Stabilization Any options that do not meet the criteria for progression and partial response Progression ≥ 25% increase over nadir ≥ 20% increase over nadir ≥ 20% increase over nadir (not less than 5 mm) Emergence of new measurable or progression of non-measurable lesions Link WHO Handbook for Reporting Results of Cancer Treatment. World health
Organization Offset Publication No. 48; Geneva (Switzerland) 1979 Cancer 1981; 47:
207-214 J. Natl. Cancer Inst. 2000; 92: 205-216 Eur. J. Cancer. 2009; 45: 228-247

RECIST (Response Evaluation Criteria in Solid Tumors) - criteria for evaluating the response of solid tumors.

Table 2. Targeted foci Non-targeted foci New foci The general answer CR CR - CR CR not CR / not PD - PR CR NE - PR PR Not PD or NE - PR SD Not PD or NE - SD PD any +/- PD Any PD +/- PD Any Any + PD

CR = complete response, PR = partial response, SD = stabilization, PD = progression, NE = undetectable.

Table 3. irRC, 2009 irRECIST, 2013 iRECIST, 2017 imRECIST, 2018 Assessment method Two dimensions. The sum of the perpendicular maximum sizes of the foci One dimension. The sum of the largest sizes of target foci Number of foci assessed Target foci: no more than 10 in total (no more than 5 in an organ) Target foci: no more than 5 in total (no more than 2 in an organ) New measurable lesions Progression is not a criterion. The sizes of the new foci are summed up with the previously existing ones. Response is assessed using the criteria: unconfirmed progression (iUPD) and confirmed progression (iCPD) Progression is not a criterion. The sizes of the new foci are summed up with the previously existing ones. New non-measurable lesions New is not a criterion for progression. Disappearance (along with measurables) - complete response criterion New is not a criterion for progression. Disappearance (along with measurables) - complete response criterion Full answer Disappearance of measurable and non-measurable foci Partial Answer Reduction of the size of the measured lesions by more than 50% compared to the baseline. Lack of new measurable and non-measurable foci Reduction of the size of the measured lesions by more than 30% compared to the baseline. Lack of new measurable and non-measurable foci Stabilization Any options that do not meet the criteria for progression and partial response Progression Increase in size of measured lesions ≥ 25% compared to nadir An increase in the size of the lesions measured ≥ 20% compared to the nadir (minimum 5 mm) Confirmation of progression Yes Yes ¹ Yes ² Yes ³ Link Clin. Cancer Res. 2009; 15 (23): 7412-7420. Clin. Cancer Res. 2013; 19 (14): 3936-3943. Lancet Oncol. 2017; 18 (3): e143-e152 J. Clin. Oncol. 2018; 36: 850-858

¹ Confirmation required 4–12 weeks after primary progression; ² requires confirmation 4–8 weeks after primary progression; ³ requires confirmation 4 to 8 weeks after primary progression.

iUPD (immune unconfirmed progressive disease) - unconfirmed progression (immunotherapy);

iCPD (immune unconfirmed progressive disease) - confirmed progression (immunotherapy);

irRECIST (immune-related Response Evaluation Criteria in Solid Tumors) - immunity-related criteria for evaluating the response of solid tumors; iRECIST (Immunotherapy Response Evaluation Criteria in Solid Tumors) - immunotherapeutic criteria for evaluating the response of solid tumors; irRC (immune-specific related response criteria) - immune-specific response criteria; imRECIST (immune-Modified Response Evaluation Criteria in Solid Tumors) - immunomodified criteria for evaluating the response of solid tumors.

Table 4. Variable Coefficient P Constant P Log V _m (mm ³ ) - 5.95 <0.01 47.31 <0.01 Sphericity 45.79 <0.01 -12.62 0.196 SVP 44.21 <0.01 -9.69 <0.01 AP 70.77 <0.01 14.11 <0.01 Voxel volume (mm ³ ) 10.30 0.498 18.98 <0.01

APE is the absolute percentage error, V _m is the average volume of the segmented node, SVP is the fraction of surface voxels, AP is the fraction of border voxels.

Table 5. Standard method Metastatic foci Non-metastatic foci Amount Growing lesions (test positive) 66 four 70 Stable lesions (test negative) 34 7 41 Amount 100 eleven 111 APE 95% percentile method Metastatic foci Non-metastatic foci Amount Growing lesions (test positive) 75 four 79 Stable lesions (test negative) 25 7 32 Amount 100 eleven 111

APE - absolute percentage error

Table 6. No. RECIST V (+73% / - 65%) V (± 38%) OO The decision to change tactics Correction of tactics Exodus one SD SD PD PD Not Yes (PE) - 2 SD SD PD PD Yes Yes - 3 SD SD PR PR Not Not SD four SD SD PD SD Yes Not SD five SD SD PR SD Not Yes (PE) - 6 SD SD PR PR Not Not PD 7 SD SD PR PR Not Not PR eight SD SD PD PD Yes Increased dose PD nine SD SD PR SD Not Died - 10 SD PD PD PD Yes Yes - eleven PD SD SD PD Yes Yes - 12 PD SD SD PD Yes Yes - 13 SD PD PD PD Yes Yes - fourteen PD SD PD PD Not Yes - fifteen PD SD PD PD Yes Yes -

RECIST - Response Evaluation Criteria in Solid Tumors PD - disease progression; PR - partial answer; SD - disease stabilization; V - volumetry; OO - general assessment of the treatment outcome; PE - side effects.

Table 7. Parameter β k% p Kernel convolution (FC07; FC14) 0.003 32.2 0.001 Slice thickness (0.5; 1.5; 3; 5 mm) 0.002 10.3 0.036 Volume (mm ³ ) -0.001 37.4 0.027 Effective diameter (mm) 0.003 20.1 0.041

β is the coefficient of the regression equation; k - coefficient of influence of the parameter.

Table 8. Group Treatment response RECIST v. 1.1., N (%) Volumetry, n (%) p Development, 46 people
(181 definition of immediate result) PD 31 (17%) 76 (42%) <0.05 SD 106 (61%) 52 (27%) <0.05 PR 40 (22%) 49 (29%) > 0.05 CR 4 (2%) 4 (2%) > 0.05 Validation, 81 people (318 definitions of immediate outcome) PD 48 (15%) 119 (37%) <0.05 SD 229 (72%) 106 (33%) <0.05 PR 39 (12%) 91 (29%) <0.05 CR 2 (1%) 2 (1%) > 0.05

RECIST - Response Evaluation Criteria in Solid Tumors PD - disease progression; PR - partial answer; SD - disease stabilization; n is the number of definitions of the immediate results of treatment; p is the significance of differences in response rate to treatment when assessed using volumetry and according to RECIST v. 1.1.

Table 9. Risk factor Risk Interval Lactate dehydrogenase > 1.5 times higher than normal (N <200 U / l) Hemoglobin <normal (<13 g / dl - men;
<11.5 g / dl - women) Corrected Calcium (Calcium Concentration - 0.707 x Albumin Concentration) > 10 mg / dl Karnovsky status <80% Prior nephrectomy Not

Table 10. MSKCC (n) Me, month Correction of the answer (n) Me (corr), month Me (without corr), month p Development group BP (12) 37 PD - SD (2; 5%) 42 34 <0.05 ^* ;
> 0.05 ** SD - PR (6; 16%) PR - SD (1) - - - Multidirectional (1) - - - PP (25) nineteen PD - SD (1) 23 17 <0.05 ^* ;
<0.05 ** SD - PR (5; 26%) SD - PD (4; 21%) 17 22 <0.05 ^* ;
<0.05 ** PR - SD (1) Multidirectional (3; 16%) eighteen twenty > 0.05 ^* ;
> 0.05 ** NP (9) 7 PD - SD (1) - - - PR - SD (1) four nine <0.05 ^* ;
> 0.05 ** SD - PD (4; 57%) Validation group BP (23) 42 PD - SD (5; 12%) 48 39 <0.05 ^* ;
> 0.05 ** SD - PR (4; 10%) PR - SD (2; 5%) 42 41 > 0.05 ^* ;
> 0.05 ** PP (40) sixteen PD - SD (3; 19%) 21 fourteen <0.05 ^* ;
> 0.05 ** SD - PR (2; 13%) SD - PD (2; 13%) nine 17 > 0.05 ^* ;
> 0.05 ** PR - SD (1) Multidirectional (2; 13%) fourteen fifteen > 0.05 ^* ;
> 0.05 ** NP (18) nine PD - SD (1) 6 12 <0.05 ^* ;
<0.05 ** SD - PD (3; 33%) PR - SD (1) - - -

MSKCC - Memorial Sloan-Kettering Cancer Center; Memorial Sloan and Kettering Cancer Center; n is the number of patients; PD - disease progression; PR - partial answer; SD - disease stabilization; BP - favorable prognosis according to MSKCC criteria; PP - interim forecast according to MSKCC criteria; NP - unfavorable prognosis according to MSKCC criteria; Me is the median overall survival; Me (corr) - median overall survival in subgroups where there was a correction in the assessment of the immediate outcome of treatment using volumetry; Me (without corr) - median overall survival in subgroups without taking into account the data of patients who had a correction in the assessment of immediate treatment results using volumetry; - reliability of the differences between Me and Me (corr); ** - reliability of differences Me and Me (without corr).

Claims (8)

A method for assessing the immediate results of treatment of patients with disseminated renal cell carcinoma, including performing a computed tomography study with contrast enhancement and assessing the volume of tumor foci in the lungs, characterized in that the volume of metastatic lesions of the lungs is calculated in the patient according to the formulas V ₁ =

; V ₂ =

; where V ₁ is the total volume of the initial metastatic lesion, i is the number of the lesion at the initial study, vi is the volume of the lesion at the initial study, n1 is the number of lesions at the initial study, V ₂ is the total volume of the metastatic lesion after the treatment cycle, j is the number of the lesion at the study after the treatment cycle, vj - the volume of the lesion in the study after the treatment cycle, n2 - the number of lesions after the treatment cycle; select the largest (Vmax) and smallest (Vmin) values from these volumes and calculate the value of the volume functions taking into account the system error using the formulas F _max =

+ 183 / d to + 49); F _min =

+ 183 / d l + 49), where, F _max is the value of the function of the largest total volume of metastatic lesion in two successive measurements, F _min is the value of the function of the smallest total volume of metastatic lesion in two successive measurements,

- the volume of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements,

Is the volume of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements, nmax is the number of metastatic lesions in the measurement with the largest total volume of metastatic lesion in two successive measurements, nmin is the number of metastatic lesions in the measurement with the smallest total volume of metastatic lesion at two successive measurements, d to - the diameter of the lesion in the measurement with the largest total volume of metastatic lesion in two successive measurements, d l - the diameter of the lesion in the measurement with the smallest total volume of metastatic lesion in two successive measurements,

- slice thickness, and if F_max- F_min> 0 and V_one > V₂, then this is regarded as a partial response to treatment, if F_max- F_min> 0 and V_one <V_2,then this is regarded as progression, if F_max- F_min< 0 for any ratios V_one and V₂ - as process stabilization.

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