RU2658047C1 - Method of estimation of risk of recurrency of ovarian cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine, in particular oncology, and discloses a method for estimating the risk of recurrence of ovarian cancer in patients after completion of combination therapy. Method includes a cytoreductive surgery and a chemotherapy based on platinum drugs, calculating the probability value by the formula, determined with the help of logistic regression, taking into account the level of the HE-4 oncomarker after the end of first-line chemotherapy, tumor histotypes, category and subcategory of the tumor stage.

EFFECT: method is high sensitive and specific, allows to carry out the forecast of repeated cancer growth up to the clinical appearance of relapse, to optimize the diagnostic algorithm and to take treatment-and-prophylactic steps well-timed.

1 cl, 3 tbl, 1 dwg, 3 ex

Description

The invention relates to medicine, namely to Oncology, and is intended for the diagnosis of preclinical manifestation of recurrence of ovarian cancer after radical treatment.

On the one hand, ovarian cancer is not the most common oncopathology in the world (seventh among the eighteen most common cancers in the world) and not the most aggressive (occurs and grows mainly within the abdominal cavity, is characterized by relative “non-invasiveness” with late involvement of retroperitoneal lymph nodes ), on the other hand, ovarian cancer is one of the main “oncological killers” of the female population in the 21st century: the first place among mortality from oncogynecological diseases and the fifth place with among the mortality of the female population due to cancer pathology (Kensler TW, Spira A., Garber JE et al. / Transformingcancerpreventionthrobghprecisionmedicineandimmune-oncology. // Cancer Prev Res (Phila). - 2016. - 9 (1). - P. 2-10; Winham SJ, Pirie A., Chen YA et al. / Investigation of exomic variants associated with overall survival in ovarian cancer // Cancer Epidemiol Biomarkers Prev. - 2016 .-- V. 1 - Epub ahead of print). The problem of high mortality in ovarian cancer is due to many factors, the most important of which are diagnosis at advanced stages and a high risk of recurrence. According to some reports (Vinokurov V.L. / Cancer of the cervix, uterus and ovary: results and prospects at the Central Research Institute of Radiotherapy of the Ministry of Health of the Russian Federation. // Issue of Oncol. - 2003. - No. 9. - P. 656-663), with cancer ovaries after relapse within three years, all patients die. At the same time, the age of patients with ovarian cancer should be noted: out of 192 patients, 62.5% are under the age of 60 years, 20.2% are under the age of 45, and 9.8% are under the age of 40.

The early detection of relapses makes it possible to conduct secondary cytoreductive operations in combination with various chemotherapy regimens, which, according to some authors, increases patient survival by up to 47% (Poskus E., Strupas K., Guschin V., Sugarbaker PH / Cytoreductivesurgeryand HIPEC intheBalticStates: anintemationalscientificeryery // Viszeralmedizin. - 2014 .-- 30 .-- P. 353-359).

Currently, after completion of the first-line combination therapy, all patients are under dynamic observation, including examination every three months for the first two years, once every four months for the third year, and once every six months for the fourth, fifth years and further to progression. The examination plan includes: determination of the level of tumor marker CA-125 (cancerantigen - cancer antigen), instrumental examination (ultrasound (ultrasound) and computed tomography (CT), positron emission computed tomography (PET CT), mammography and scintigraphy (as indicated). Such an algorithm of actions, without stratification of patients regarding the risk of developing ovarian cancer, is not only ineffective in terms of the timely diagnosis of relapse and makes it impossible to individualize the treatment of ovarian cancer depending on the primary characteristics of the tumor, but also leads to unjustified costs from the state.

In connection with the foregoing, there is a need to develop and integrate into the healthcare system an algorithm for assessing the risk of ovarian cancer recurrence in order to timely predict the likelihood of tumor recurrence.

One approach to predicting recurrence of ovarian cancer is based on an assessment of the morphological characteristics of the primary tumor.

A known method for predicting the recurrence of ovarian cancer, characterized in that the proportion of cells in the S phase of the cell cycle is determined in the ovarian tumor tissue, with a value of this indicator less than 15.9%, a favorable outcome is predicted, and with a value of this indicator more than 15.9%, an unfavorable outcome is predicted (RU 2530556 C1, 10/10/2014).

(Х3), определяемый путем подсчета общего количества фигур деления на 1000 опухолевых клеток; удельную долю «летальных» форм митозов от общего количества (%) (Х4); количество свободных клеток на 10000 мкм площади стромы (Х5), определяемое анализатором телевизионного изображения; плотность васкуляризации (мкм²) на 1000 мкм² площади стромы (Х6), определяемую при помощи анализатора телевизионного изображения, и срок наступления рецидива (Y) в месяцах определяют по формуле:The patent (RU 2299018 C1, 05.20.2007) describes a method for predicting the duration of a relapse-free period in patients with serous ovarian cancer by assessing the morphological parameters of the tumor: the degree of differentiation of the tumor in points (X1): with a low degree of differentiation - 1 point, with a moderate - 2 points , at high - 3 points; the area of the nucleus of a cancer cell in microns (X2), measured by an eyepiece-micrometer or a television image analyzer; mitotic index

(X3), determined by counting the total number of division patterns per 1000 tumor cells; specific share of “lethal” forms of mitoses from the total number (%) (X4); the number of free cells per 10,000 microns of the stroma area (X5), determined by the television image analyzer; the vascularization density (μm ² ) per 1000 μm ^{2 of} the stroma area (X6), determined using a television image analyzer, and the period of occurrence of relapse (Y) in months is determined by the formula:

Y (month) = (- 30.42) -12.31⋅X1 + 0.04⋅X2-1.61⋅X3 + 1.41⋅X4 + 1.13⋅X5 + 1.29⋅X6.

Close to the claimed technical solution, in the opinion of the applicant, is a method for predicting the recurrence of serous ovarian cancer, described in (RU 2290078 C1, 12/27/2006). The prognosis of relapse is based on the probability value calculated by the formula determined using logistic regression. The formula includes a combination of several variables, which are morphological parameters of the tumor, the probability of re-growth is determined by the formula:

where X1 is the area of the cancer cell (μm), measured by an eyepiece-micrometer or television image analyzer, μm ² ;

X2 - the average ploidy of the nuclei of tumor cells (s) is measured by a photometer in units of the number of sets of chromosomes (s);

X3 - p53 tagging intensity (score):

lack of p53 expression in tumor cells - 0 points;

p53 expression was detected in 1-10% of cells - 1 point;

the oncogen suppressor p53 is visualized in 11-50% of cells - 2 points;

p53 is determined in 51-100% of cancer cells - 3 points;

X4 - the intensity of the labeling of estrogen receptors (score):

lack of expression of progesterone receptors in tumor cells - 0 points;

progesterone receptor expression was detected in 1-10% of cells - 1 point;

progesterone receptors visualized in 11-50% of tumor cells - 2 points;

progesterone receptors determined in 51-100% of cancer cells - 3 points;

X5 - expression value of PCNA (nuclear antigen of proliferating cells),%, determined by the number of PCNA - positive cells in the tumor,

while the final variable Y can take values in the range from 0 to 1,

values of 0≤Y≤0.5 should be regarded as an indicator of a low risk of resuming tumor growth,

while 0.5 <Y≤1 suggests a high probability of recurrence.

Despite some advantages of the method, namely, the possibility of predicting relapse in a patient based on morphological characteristics and a fairly complete set of included variables (cancer cell area, nuclear ploidy, p53 expression, expression of hormonal receptors and PCNA expression), this model is purely morphological and examines the characteristics of the tumor separately, not taking into account the whole complex of clinical factors, such as data from instrumental research methods, features of the first line rapies, tumor marker levels, etc.

Closest to the claimed technical solution is a method for predicting the recurrence of serous ovarian cancer, described in (Rizzuto I., Stavraka Ch., Chatterjee J. et al. / Risk of Ovarian Cancer Relapse Score. A Prognostic Algorithm to Predict Relapse Following Treatment for Advanced Ovarian Cancer // Int J Gynecol Cancer. - 2015 .-- V. 25 - P. 416-422). The prognosis of relapse is based on the probability value calculated by the formula determined using logistic regression. The final formula proposed by the authors includes a combination of several variables, including the stage of the disease according to FIGO (International Federation of Obstetrics and Gynecology - International Federation of Obstetrics and Gynecology), the degree of tumor differentiation, the results of computed tomography (CT) after first-line chemotherapy and the level of tumor marker CA-125 on moment of initial diagnosis.

The calculation of the risk of relapse is as follows. After the initial diagnosis of ovarian cancer and hospitalization of the patient, the level of the tumor marker CA-125 is determined within the framework of standard examinations. Further, in the presence of appropriate indications, combination therapy is carried out, including primary cytoreductive surgery, in some cases neoadjuvant chemotherapy and, without fail, adjuvant chemotherapy based on platinum drugs. After the initial cytoreductive surgery, neoadjuvant (according to indications) and adjuvant (without fail) chemotherapy based on platinum preparations, a corresponding histopathological study is carried out, according to the results of which the final stage of the tumor is determined according to FIGO (http://www.uicc.org/sites /main/files/atomsfiles/TNM_7_FIGO_OVARY_2014.pdf). Samples for a histopathological study are tissues removed during the initial cytoreductive surgery (ovaries, fallopian tubes, uterus, part of the greater omentum and lymph nodes). Depending on the totality of pathological and clinical data (instrumental studies, ultrasound, CT, osteoscintigraphy, magnetic resonance imaging, etc.), staging of the tumor is performed according to FIGO. The assignment of research results to a specific stage of the tumor is shown in table 1.

In addition, the degree of histological differentiation of the tumor by a four-stage system is determined

Grade 1 (G1) - highly differentiated,

Grade 2 (G2) - moderately differentiated,

Grade 3 (G3) - low differential,

Grade 4 (G4) - undifferentiated tumors.

In this study, since undifferentiated tumors were considered as a category of histotypes, only the first three types of histotypes were included in the analysis.

In determining the histological degree of tumor malignancy, the Nottingham gradation system is used, which reflects the following signs: the degree of cell polymorphism, nuclear hyperchromia, mitotic activity, and the ability of cells to form various structures (Silverberg SG. / Histopathologic grading of ovarian carcinoma: a reviewand proposal. // IntJGynecolPathol - 2000 .-- 19 (1). - P. 7-15).

After the end of the last course of adjuvant chemotherapy, a CT scan of the pelvic organs is carried out for the presence of a residual tumor / tumors. All these patient data are recorded, and after the end of the last chemotherapy course, the scale is calculated as follows. For clarity, the algorithm for assessing the risk of recurrence of ovarian cancer by the prototype method is presented in table 2.

The value of the initial constant was determined using logistic regression and is -2.8899 (Step A). If there is a residual tumor / tumors on CT, 2.951 are added to this figure, in the absence of a residual tumor - 0 (Step B). If the level of the tumor marker CA-125 at the time of the initial diagnosis was higher than 200 units / ml, then 1.0541 is added to the resulting amount, if not, then 0 (Step C). In stage I tumors, as determined by FIGO, 0 is added to the amount obtained, in stage II — 0.8935, in stage III — 1.8536, and stage IV — 2.5540 (Step D). And finally, with a highly differentiated tumor, 0 is added to the sum obtained, with a moderately differentiated tumor - 0.3122, and with a low-grade tumor - 1.1800 (Step E). After calculating the sum of the initial constant and the four indicated clinical and pathological characteristics, the final value is determined by the following formula:

Scale ROVAR = 1 / (1 + exp (sum of steps AE),

where ROVAR is riskofovariancancerrelapsescore is the risk scale for ovarian cancer recurrence.

After calculating the scale, risk is divided into low, moderate and high, depending on the value:

if the obtained value is in the range of 0-0.33, a low risk of tumor recurrence is predicted;

if the obtained value is in the range of 0.34-0.67, a moderate risk of tumor recurrence is predicted;

if the obtained value is ≥0.68, a high risk of tumor recurrence is predicted.

The proposed scale is applicable only to patients with ovarian cancer who were treated with first-line combination therapy, including primary cytoreductive surgery and chemotherapy based on platinum drugs, so the described method is only suitable for patients with a diagnosis of ovarian cancer who received combination therapy first line, including primary cytoreductive surgery and chemotherapy based on platinum drugs.

The indisputable advantages of the proposed method are a wide range of clinical and morphological characteristics included in the initial analysis kit (degree of differentiation, level of tumor marker CA-125 at the time of initial diagnosis, CT results after completion of the first-line chemotherapy course) and stratification of the risk of recurrence to low, moderate and high, depending on the value of the ROVAR scale. However, in the method chosen as a prototype, the role of tumor markers is considered extremely narrowly (the level of the tumor marker HE-4 (humanepidimisantigen 4-antigen of human epididymis) is not considered. In addition, the role of ultrasound examination, which, in view of the practicality and cheapness of the study, is much more often carried out in Russian clinics compared to CT.

The objective of the invention is the creation of a new method for assessing the risk of recurrence of ovarian cancer in patients after completing first-line combination therapy, including cytoreductive surgery and chemotherapy based on platinum drugs, expanding the range of known methods for assessing the risk of recurrence of ovarian cancer and allowing to assess the risk of recurrence of ovarian cancer in patients more more complex than in the prototype method, and also use ultrasound diagnostics instead of computed tomography Ostik, more practical and easy to use, and less denezhnozatratnuyu.

The technical result of the invention is the use of additional characteristics in predicting the onset of relapse, established on the basis of the probability value calculated by the formula determined using the logistic regression, namely the level of the tumor marker HE-4 after the end of chemotherapy of the first line, tumor histotype, and not only categories but also subcategories of the tumor stage. The expansion of the range of characteristics used in predicting the onset of relapse allows a more comprehensive, comprehensive assessment of the risk of recurrence of ovarian cancer in patients. The technical result is the use of ultrasound diagnostics, which although inferior to CT in terms of sensitivity and specificity for the diagnosis of formations in the pelvic area, is at the same time more practical and quick, does not require complex technical skills of the researcher, as well as a specially equipped room and conditions , like CT, is practically not accompanied by radiation from the patient, which is why it is safer and less costly.

The technical result also consists in the implementation of a method for assessing the risk of recurrence of ovarian cancer in patients after completion of the first-line combination therapy, including cytoreductive surgery and chemotherapy based on platinum drugs according to the invention, the method includes:

determination of the stage of the tumor according to FIGO,

determination of the degree of tumor differentiation,

determination of the level of tumor marker CA-125 at the time of the initial diagnosis,

detection of residual tumor (s) after first-line therapy,

calculating the probability of a relapse on the basis of a formula determined using logistic regression using an algorithm that takes into account certain individual characteristics of the patient,

division of risk into low, moderate and high, depending on the value obtained,

at which

additionally determine the level of tumor marker HE-4 after the end of first-line chemotherapy and the histotype of the tumor,

the detection of residual tumors (tumors) after the first-line therapy is carried out by the method of ultrasound diagnosis,

the calculation of the probability of relapse occurs according to the presented algorithm:

step A: the value of the initial constant, determined using logistic regression, is -3.346;

step B: value is added to the value of the initial constant depending on the stage of ovarian cancer determined according to FIGO, taking into account not only the category, but also the subcategory of the stage:

at stage IA add 0,

at stage IB, 0.621 is added,

in stage IC, 0.930 is added,

at stage IIA add 1.005,

in stage IIB, 1,200 are added,

in stage IIIA add 1,238,

in stage IIIB, 1.412 is added,

at stage IIIC add 1,503,

at stage IVA, 1.605 is added,

in stage IVB, 1.637 is added;

step C: to the amount obtained in steps A-B, the value is added depending on the specific histotype of the tumor:

in the case of endometroid histotype add 0,

clear cell - add 0.3510,

mucinous - add 0.5215,

undifferentiated - add 0.7900,

serous - add 0.8600,

another - 0.4100 is added;

step D: to the amount obtained in steps AC, add a value depending on a certain degree of tumor differentiation:

in the case of a highly differentiated tumor (G1) add 0,

moderately differentiated (G2) - add 0,583,

low differentiated (G3) - add 1,342;

step E: the value obtained in steps AD is added depending on the presence or absence of residual tissue of the residual tumor (s) determined by ultrasound:

if available add 2.5,

in the absence - add 0;

step F: add the value to the amount AE obtained in steps, depending on the level of the CA-125 tumor marker, determined at the time of diagnosis, before the combination therapy:

in case the indicator was <200 U / ml, add 0,

if ≥200 U / ml - add 1,207;

step G: add to the amount obtained in steps A-F, depending on the level of tumor marker HE-4, determined after combination therapy:

in case the indicator was ≤35 pmol / l, add 0,

if> 35 pmol / l - add 1,0479;

determine the index of individual risk of recurrence of ovarian cancer according to the following formula:

IRRRYA = 1 / (1 + exp (sum of steps A-G)),

where IRRI is the index of individual risk of recurrence of ovarian cancer;

risk division into low, moderate and high is carried out depending on the obtained value of the IRRRY:

if the obtained value of the IRRI is in the range of 0-0.39, the risk of recurrence of ovarian cancer is assessed as low;

if the obtained value of the IRRI is in the range of 0.40-0.85, the risk of recurrence of ovarian cancer is assessed as moderate;

if the obtained value of the IRRI is in the range of 0.86-1.00, the risk of recurrence of ovarian cancer is assessed as high.

The inventive method of assessing the risk of recurrence of ovarian cancer in patients after completing first-line combination therapy, including cytoreductive surgery and chemotherapy based on platinum drugs, is as follows. Like the prototype method, the claimed method is suitable exclusively for patients after the end of the first-line combination therapy, including cytoreductive surgery and platinum-based chemotherapy.

When assessing the risk of recurrence of ovarian cancer, six individual patient characteristics are used:

the level of tumor marker CA-125 at the time of the initial diagnosis (before therapy),

FIGO tumor stage,

tumor histotype,

the degree of tumor differentiation,

the presence or absence of residual tumor (s) after first-line therapy, which is determined by ultrasound after chemotherapy,

and the level of tumor marker HE-4 after the end of first-line chemotherapy.

After the initial diagnosis of ovarian cancer and hospitalization of the patient, the level of the tumor marker CA-125 is determined within the framework of standard examinations. When assessing the activity of CA-125, the criteria defined by G.J. were used. Rustin, M. Quinn, T. Thigpen et al. And the International Gynecological Cancer Group (GCIG - Gynecologic Cancerlnter Group) (2004), as well as those described in (Bast RC Jr., Klug TL, St. John E. et al. / A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer // N. Engl. J. Med. - 1983. - V. 309 - P. 883-887). Further, in the presence of appropriate indications, combination therapy is carried out, including primary cytoreductive surgery, neoadjuvant chemotherapy (if indicated) and adjuvant chemotherapy (without fail) based on platinum preparations. After the initial cytoreductive surgery, an appropriate

pathological examination, after which the final staging of the tumor is carried out according to FIGO (as in the prototype method), similarly to the prototype, the degree of histological differentiation of the tumor according to a three-stage system (highly differentiated, moderately differentiated, low and undifferentiated) is determined, and the histotype of the tumor is determined (Kurman RJ, Carcangiu ML, Herrington CS, et al. / WHOclassificationoftumoursoffemalereproductiveorgans. // Lyon: IARCPress, 2014). After the end of the last course of adjuvant chemotherapy, an ultrasound examination of the pelvic organs is carried out for the presence of residual tumors (tumors) using any transvaginal ultrasound apparatus, for example, Pentax (Toukio, Japan), Toshiba (Tokyo, Japan), HitachiAloka (Tokyo, Japan) ), Philips (Amsterdam, Netherlands), and also determine the level of the HE-4 tumor marker after the end of first-line chemotherapy using the method described (Nolen B., Velikokhatnaya L., Marrangoni A. et al. / Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass // Gynecol. Oncol. - 2010 .-- V. 117 (3) - P. 440-445). All these patient data are recorded, and after the end of the last chemotherapy course, the individual risk index for ovarian cancer recurrence is calculated as follows. For convenience, the algorithm for calculating the specified index is shown in table 3.

The value of the initial constant is determined using logistic regression and is -3.346 (Step A).

At step B, the value of the initial constant is added depending on the stage of ovarian cancer determined by FIGO, and not only the category, but also the subcategory, is taken into account:

at stage IA add 0,

at stage IB - 0.621,

at stage IC - 0.930,

at stage IIA - 1.005,

at stage IIB - 1,200,

at stage IIIA - 1.238,

at stage IIIB - 1.412,

at stage IIIC - 1,503,

at stage IVA - 1,605,

at stage IVB - 1,637.

In step C, the value obtained in steps AB is added depending on the specific histotype of the tumor:

in the case of endometroid histotype add 0,

clear cell - 0.3510,

mucinous - 0.5215,

undifferentiated - 0.7900,

serous - 0.8600,

another - 0.4100.

In step D, the value obtained in steps AC is added depending on the degree of tumor differentiation:

in the case of a highly differentiated tumor (G1) add 0,

moderately differentiated (G2) - 0.583,

low grade (G3) - 1.342.

In the presence of residual tissue of residual tumor (s) determined by ultrasound, 2.5 is added to the amount obtained in steps A-D, and 0 in the absence (Step E).

In step F, 0 is added to the sum obtained in steps AE if the level of the CA-125 tumor marker determined at the time of diagnosis was <200 U / ml before combination therapy if ≥200 U / ml - 1.207.

In step G, 0 is added to the sum obtained in steps A-F if the HE-4 tumor marker determined after combination therapy was ≤35 pmol / L; if> 35 pmol / L, 1.0479 is added.

After calculating the sum of the initial constant and the six indicated clinical and pathological characteristics, the final value of the index of individual risk of recurrence of ovarian cancer is determined by the following formula:

IRRRYA = 1 / (1 + exp (sum of steps A-G)),

where IRRI is the index of individual risk of ovarian cancer recurrence.

The final variable of the IRRRIA can take values in the range from 0 to 1, the values 0≤IRRRID≤0.39 should be regarded as an indicator of a low risk of resuming tumor growth, 0.40 <IRRRID≤0.85 - moderate, while 0.86 И HYDRRID 1 1.0 indicates a high probability of recurrence.

Thus, after calculating the IRRI index, the risk of ovarian cancer recurrence is assessed as low, moderate and high, depending on the value of the obtained value of the IRRI index:

if the value of the IRRI index is in the range of 0-0.39, the risk of recurrence of ovarian cancer is assessed as low;

if the value of the IRRI index is in the range of 0.40-0.85, the risk of recurrence of ovarian cancer is assessed as moderate;

if the value of the IRRI index is in the range of 0.86-1.0, the risk of recurrence of ovarian cancer is estimated as high.

The value of the IRRRY index can be calculated manually according to the above algorithm. For the convenience of evaluating the recurrence of ovarian cancer and reducing time costs, the IRRR index can be calculated using special computer programs, for example, the computer program “Algorithm for assessing the individual risk of recurrence of ovarian cancer” ©, which instantly calculates the IRRR index after entering the above six individual indicators into the program the patient.

To assess the reliability of the proposed method (Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine // Clinical Chemistry. - 1993 - 39 (8). - P. 561-577), as well as to determine such diagnostic characteristics As sensitivity and specificity, 1103 patients were studied (average age: 60.26 ± 14.38 years; interquartile range: 51-72. As a result, it was found that the AUC (areaunderthecurve - area under the curve) was 0.761 (95% CI : 0.733-0.789), and since for any AUC value> 0.5 it is considered that the classifier (in this case, the IRRR index) classifies the population correctly , then the given AUC value indicates the reliability of the diagnostic tool.It should also be noted that the closer the AUC value to the maximum value, i.e. to unity, the higher the reliability of the test.The low risk of recurrence (with a threshold value of 0.39) was predicted with a specificity of 25.5% (only such a percentage of patients with a low risk for 5 years had a relapse) and with a sensitivity of 97%, a moderate risk of recurrence (with a threshold value of 0.84) was predicted with a specificity of 54% and with a sensitivity of 74.5 %, and accordingly high th the risk of recurrence (at a threshold value 0.996) is predictable with the specificity was 98.2% (pritakom value at such percentage of patients had a relapse), and with a sensitivity of 6.3% (a value of the index was only in 6.3% of subjects).

The invention is illustrated by examples of specific performance.

Example 1

Patient R., 45 L., diagnosed with ovarian cancer T _1a N ₀ M ₀ .

A radical cytoreductive surgery was performed, as well as a first-line chemotherapy course based on platinum drugs.

Defined by:

FIGO - IA stage of ovarian cancer;

the degree of tumor differentiation is moderately differentiated (G2);

the level of CA-125 in the blood at the time of initial diagnosis before treatment was 34 U / ml (determined on an IMx analyzer AbbotGmbHDiagnositka (Wiesbaden, Germany); criteria used by GJ Rustin, M were used to evaluate the activity of CA-125 Quinn, T. Thigpen et al. And the International Gynecological Cancer Group (GCIG - GynecologicCancerInterGroup) (2004), as well as those described by B (Bast RC Jr., Klug TL, St. John E. et al. / A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer // N. Engl. J. Med. - 1983. - V. 309 - P. 883-887));

the level of HE-4 after adjuvant chemotherapy of the first line based on platinum preparations - 19 pmol / l (determined by the method described in (Nolen B., Velikokhatnaya L., Marrangoni A. et al. / Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass // Gynecol. Oncol. - 2010 .-- V. 117 (3) - P. 440-445);

morphological-serous histotype of the tumor (determined by the method (Kurman RJ, Carcangiu ML, Herrington CS, et al. / WHO classification of tumors of female reproductive organs. // Lyon: IARC Press, 2014));

absence of residual tissue (determined by transvaginal ultrasound examination with a cavity probe on a Pentax apparatus (Tokyo, Japan) after first-line chemotherapy.

The risk of ovarian cancer recurrence is assessed taking into account the data obtained, calculating the IRRR index according to the algorithm shown in table 3

IRRRYA = 1 / (1 + EXP - (0 + 0.086 + 0.583 + 0 + 0 + 0-3.346)) = 1 / (1 + EXP (1.903)) = 0.129 and comparing the obtained index value with intervals characteristic

for low (0-0.39), moderate (0.40-0.85) and high (0.86-1.0) risk of ovarian cancer recurrence: 0.1290.39, which corresponds to a low risk of recurrence.

According to the ROC analysis (figure 1), this value of the IRRRY index corresponds to 100% sensitivity and 7.3% specificity.

In this patient, a relapse of ovarian cancer was not recorded during the five-year follow-up period.

Example 2

Patient K., 50 L., diagnosed with ovarian cancer Ti _c N ₀ M ₀ .

Individual indicators are determined by the methods specified in example 1.

A radical cytoreductive surgery was performed, as well as a first-line chemotherapy course based on platinum drugs.

Defined by:

FIGO - IC stage of ovarian cancer;

the degree of tumor differentiation is moderately differentiated (G2);

level of CA-125 at the time of initial diagnosis, before treatment - 35 units / ml;

the level of HE-4 after adjuvant chemotherapy of the first line based on platinum preparations - 29 pmol / l;

morphologically serous histotype of the tumor;

the presence of residual tissue by ultrasound after first-line chemotherapy based on platinum preparations.

The risk of ovarian cancer recurrence is assessed taking into account the data obtained, calculating the IRRI index according to the presented algorithm IRRI = 1 / (1 + EXP (0.93 + 0.86 + 0.583 + 2.5-3.346)) = 1 / (1 + EXP (-1.527)) = 1 / 1.21 = 0.82,

and comparing the obtained index value with the intervals typical for low (0-0.39), moderate (0.40-0.85) and high (0.86-1.0) risk of ovarian cancer recurrence: the obtained value (IRRI = 0.82) lies in the range of 0.40-0.85, on the basis of which it is determined that the patient has a moderate risk of recurrence.

According to the ROC analysis (figure 1), the value of the IRRI index, equal to 0.82, corresponds to 77.4% of sensitivity and 49.9% of specificity.

During the five-year follow-up period, the patient did not have a relapse of ovarian cancer.

Example 3

Patient B., 53 g., Diagnosed with Ovarian Cancer T _3c N ₀ M ₀ .

Individual indicators are determined by the methods specified in example 1.

A radical cytoreductive surgery was performed, as well as a first-line chemotherapy course based on platinum drugs.

Defined by:

FIGO - IIIC ovarian cancer stage;

the degree of tumor differentiation is low-grade (G2);

level of CA-125 at the time of initial diagnosis, before treatment - 126 units / ml;

the level of HE-4 after adjuvant chemotherapy of the first line based on platinum preparations - 42 pmol / l;

morphologically undifferentiated histotype of the tumor;

the presence of residual tissue by ultrasound after first-line chemotherapy based on platinum preparations.

An assessment of the risk of recurrence of ovarian cancer is carried out taking into account the data obtained, calculating the IRRR index:

IRRI = 1 / (1 + EXP (1.503 + 1.342 + 0 + 1.0479 + 0.79 + 2.5-3.346)) = 1 / (1 + EXP (-3.0779)) = 1 / 1.02156 = 0.9789,

and comparing the obtained index value with the intervals typical for low (0-0.39), moderate (0.40-0.85) and high (0.86-1.0) risk of ovarian cancer recurrence. The obtained value (IRRI = 0.9789) lies in the range of 0.86-1.0 (0.9789> 0.86), which corresponds to a high risk of recurrence.

On the coordinate table of the ROC curve (Figure 1), the value 0.9789 corresponds to 42.5% sensitivity and 93.6% specificity.

During the observation period, the patient had a recurrence of ovarian cancer (13 months after the initial diagnosis).

Thus, a new method for assessing the risk of recurrence of ovarian cancer in patients after the end of the first-line combination therapy, including cytoreductive surgery and platinum-based chemotherapy, is claimed. The method expands the range of known methods for assessing the risk of recurrence of ovarian cancer and can be used in everyday practice of departments of hospitals, oncology clinics, specialized centers, etc. The inventive method allows to assess the risk of recurrence of ovarian cancer in patients more comprehensively than in the prototype method using a multilevel analysis to consider all prognostic risk markers, their interaction with each other and the impact on the overall result. In addition, the method allows you to replace computed tomography with ultrasound diagnostics, more practical and easy to use, and less costly.

The inventive method has high sensitivity and specificity and allows to stratify patients into groups of high, moderate and low risk. Integration of the claimed method into a plan for the dynamic monitoring of patients after the end of first-line therapy will optimize the diagnostic algorithm and take timely therapeutic and preventive measures against recurrence of ovarian cancer. Application of the method at the stage of “Dianamic observation” and “Plan of therapeutic measures” of the diagnostic algorithm will allow us to review the frequency of outpatient visits and the range of instrumental research methods, similarly leading to optimization of work according to the criteria of “price-quality”. The use of automated calculation of the index of individual risk of ovarian cancer recurrence using specialized computer programs will make the practical use of the proposed method the most optimal, allowing you to automatically distribute patients to one or another group of dynamic observation.

Claims (49)

A method for assessing the risk of ovarian cancer recurrence in patients after completion of the first-line combination therapy, consisting of cytoreductive surgery and platinum-based chemotherapy, including: determination of the stage of the tumor according to FIGO, determination of the degree of tumor differentiation, determination of the level of tumor marker CA-125 at the time of the initial diagnosis, detection of residual tumor (s) after first-line therapy, calculating the probability of a relapse on the basis of a formula determined using logistic regression using an algorithm that takes into account certain individual characteristics of the patient, differentiation of the risk of relapse into low, moderate and high, depending on the obtained value of the probability of relapse, characterized in that: additionally determine the level of tumor marker HE-4 after the end of first-line chemotherapy and the histotype of the tumor, the detection of residual tumors (tumors) after the first-line therapy is carried out by the method of ultrasound diagnosis, the calculation of the probability of a relapse is carried out according to the algorithm: step A: the value of the initial constant, determined using logistic regression, is -3.346; step B: value is added to the value of the initial constant depending on the FIGO stage of ovarian cancer, taking into account the subcategory of the stage: at stage IA add 0, at stage IB, 0.621 is added, in stage IC, 0.930 is added, at stage IIA add 1.005, in stage IIB, 1,200 are added, in stage IIIA add 1,238, in stage IIIB, 1.412 is added, at stage IIIC add 1,503, at stage IVA, 1.605 is added, in stage IVB, 1.637 is added; step C: to the amount obtained in steps A-B, the value is added depending on the specific histotype of the tumor: in the case of endometroid histotype add 0, clear cell - add 0.3510, mucinous - add 0.5215, undifferentiated - add 0.7900, serous - add 0.8600, another - 0.4100 is added; step D: to the amount obtained in steps AC, add a value depending on a certain degree of tumor differentiation: in the case of a highly differentiated tumor, add 0, moderately differentiated - add 0.583, low-grade - add 1,342; step E: add the value to the amount obtained in steps A-D depending on the presence or absence of residual tissue of residual tumor (s) determined by ultrasound: if available add 2.5, in the absence - add 0; step F: add the value to the amount AE obtained in steps, depending on the level of the CA-125 tumor marker, determined at the time of diagnosis, before the combination therapy: if the indicator is <200 U / ml, add 0, if the indicator is ≥200 U / ml, add 1,207; step G: add to the amount obtained in steps A-F, depending on the level of tumor marker HE-4, determined after combination therapy: if indicator ≤35 pmol / l, add 0, if the indicator> 35 pmol / l, add 1,0479; determine the probability of relapse - the index of individual risk of recurrence of ovarian cancer (IRRR) according to the formula: IRRRYA = 1 / (1 + exp (sum of steps A-G)); differentiation of the risk of recurrence of ovarian cancer is carried out taking into account the calculated index of individual risk of recurrence of ovarian cancer: if the obtained value of the index of individual risk of ovarian cancer recurrence is in the range of 0-0.39, the risk of recurrence of ovarian cancer is assessed as low; if the obtained value of the index of individual risk of ovarian cancer recurrence is in the range of 0.40-0.85, the risk of recurrence of ovarian cancer is assessed as moderate; if the obtained value of the index of individual risk of recurrence of ovarian cancer is in the range of 0.86-1.00, the risk of recurrence of ovarian cancer is assessed as high.

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