RU2789500C1 - Method for predicting the progression of cervical cancer in patients with stage iib - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncogynecology, and can be used to predict the progression of cervical cancer in stage IIB patients. After neoadjuvant chemotherapy, the level of CD44 expression is determined intraoperatively in the tumor tissue by immunohistochemical method. At its level above 25%, the development of disease progression is predicted within 10-27 months.

EFFECT: method makes it possible to predict the progression of cervical cancer in stage IIB patients after complex treatment, including neoadjuvant chemotherapy, by determining the level of expression in the tumor tissue of the tumor stem cell marker CD44, which is an adhesion molecule.

1 cl, 2 tbl, 2 ex

Description

The invention relates to medicine, namely to oncogynecology, and can be used to predict the progression of cervical cancer in stage IIB patients.

Cervical cancer (CC) is one of the most common malignant pathologies in women worldwide (see Khokhlova S.V., Kolomiets L.A., Kravets O.A., Morkhov K.Yu., Nechushkina V.M. ., Tyulandina A. S. et al. Practice Guidelines for the Drug Treatment of Cervical Cancer Malignant Tumors: Practice Guidelines RUSSCO, 2021 (Vol. 11) 13. P. 197-217). According to the International Agency for Research on Cancer, 604 thousand cases of cervical cancer were registered in the world in 2020 (see Sung H., Ferlay J., Siegel R.L. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 10.3322/caac.21660. DOI: 10.3322/caac.21660).

In Russia, the standardized incidence rate of cervical cancer in 2019 was 15.4 per 100 thousand of the population, which corresponds to 17221 cases (see Kaprin A.D., Starinskiy V.V., Shakhzadova A.O. The state of oncological care for the population Russia in 2019. M.: P. A. Herzen Moscow Research Institute of Radiology - branch of the Federal State Budgetary Institution "NMITs Radiology" of the Ministry of Health of Russia, 2020. 239 p.). Over the past decade, an increase in the incidence of cervical cancer in the age group of 20-40 years has almost doubled (41.2% among all age groups) (see Pak R.V. Epidemiological features of cervical cancer in the world // Bulletin of the Kazakh National Medical University, 2019, No. 1, pp. 675-677).

The etiological factor of cervical cancer has now been proven. The persistence of human papillomavirus (HPV) 16/18 types is a trigger factor in cervical carcinogenesis (see Arkhangelskaya P.A., Bakhidze E.V., Berlev I.V., Samsonov R.B., Ivanov M.K., Malek A. V. "MicroRNA, HPV infection and cervical carcinogenesis: molecular aspects and prospects for clinical use // Siberian Journal of Oncology. 2016. Volume 15, No. 4. P. 88-97). In Russia, HPV type 16 is the leader in the frequency of detection among other oncogenic types (see Vinogradova Yu.N., Sokurenko V.P., Neklasova N.Yu., Maslyukova E.A., Chumachenko A.I., Kuznetsov A.D. ., Ilyin N.V. Chemoradiation therapy of virus-associated tumors (on the example of cancer of the head and neck, cervix and anal canal) // Practical Oncology.

In Russia in 2018, locally advanced and advanced forms of cervical cancer were found in 61.5%: stage II of the disease was found in 28.9%, stage III - in 22.8%, IV - in 9.8% (see Malignant neoplasms in Russia in 2018 (morbidity and mortality) Edited by Kaprin A.D., Starinsky V.V., Petrova G.V. National Research Center for Radiology" of the Ministry of Health of Russia, 2019. 250 pp. [Malignant tumors in Russia in 2018(incidence and mortality).

The five-year survival rate in the early stages of cervical cancer is 92%, with locally advanced processes - 56%, in the case of a generalized tumor - only 17% (see Protasova A.E., Lyashchenko V.A. Socio-demographic and clinical- Morphological Features of Common Forms of Invasive Cervical Cancer Tumors of the Female Reproductive System 2021;17(2):93-9 DOI: 10.17650/1994-4098-2021-17-2-93-99).

The standard treatment for locally advanced forms of cervical cancer is chemoradiotherapy (see Mkrtchyan L.S., Kaprin A.D., Ivanov S.A., Kulieva G.K., Krikunova L.I. Effectiveness of treatment of locally advanced cervical cancer depending on prognostic factors // Issues of Oncology, 2019. Vol. 65, No. 4. P. 584-589). Recently, works devoted to the development of new approaches to the complex treatment of cervical cancer with the inclusion of various options for induction chemotherapy have been published more and more often (see Ashrafyan L.A., Aloshikova O.I., Babaeva N.A., Antonova I.B. , Ivashina S.V., Vashakmadze S.L. et al. Evaluation of the results of neoadjuvant chemotherapy of locally advanced cervical cancer stages IIB-IIIB in complex ultrasound diagnostics. Tumors of the female reproductive system. 2015; 11(2): 76-81; see. Smirnova O.A., Bondarev N.E., Ulrikh E.A. et al. Evaluation of the effectiveness of neoadjuvant dose-intensive platinum-containing chemotherapy in the combined treatment of locally advanced cervical cancer Tumors of the female reproductive system 2018;14(4): 56-64 ).

Inclusion in the program of complex treatment of locally advanced forms of cervical cancer of the neoadjuvant stage of treatment can increase the overall survival of patients by 20% compared with standard chemoradiotherapy, bringing this figure to 87.5%, and the cumulative relapse-free survival rate to 79.6% ( see Ovodenko D.L., Khabas G.N., Makarova A.S., Seregin A.A., Golitsyna Yu.S., Ashrafyan L.A. Modern methods of treatment of patients with locally advanced cervical cancer // Obstetrics and Gynecology : opinion news, training, 2019, vol. 7, no. 1, pp. 68-74, doi: 10.24411/2303-9698-2019-11009).

However, even despite the radical removal of the tumor and an integrated approach to treatment, the progression of the disease and the recurrence rate is quite high (35% at all stages) (see Ovodenko D.L., Khabas G.N., Makarova A.S., Seregin A. A., Golitsyna Yu.S., Ashrafyan L.A. Modern methods of treatment of patients with locally advanced cervical cancer // Obstetrics and gynecology: opinion news, training. 2019. V. 7, No. 1. P. 68-74. doi : 10.24411/2303-9698-2019-11009). Most often, relapses occur in the first 2 years after completion of treatment. At the same time, the overall (OS) and event-free survival (OSS) of patients who received similar neoadjuvant treatment after surgery can vary significantly, which is the reason for the search for adequate prognostic tests.

Multivariate analysis by Benedetti-Panici et al. (See Benedetti-Panici P, Greggi S, Scambia G, et al.: UCSC experience on neoadjuvant chemotherapy (NACT) & radical surgery (RS) in locally advanced cervical cancer (LACC): Multivariate analysis of prognostic factors Gynecol Oncol 41: 212, 1994), as well as the results of 2 phase II studies published by Buda A. et al. (2005) and Lissoni A.A. et al. (See Lissoni A.A., Colombo N., Pellegrino A. et al. A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study // Ann Oncol / ESMO 2009 Vol 20 (4) P 660-665) showed that the answer primary tumor to neoadjuvant chemotherapy (NAHT) in patients with cervical cancer may serve as a new independent predictor of survival following clinical stage, tumor size, and parametrial involvement.

The presence of persistent HPV infection has a negative impact on the development of local recurrences in the pelvic cavity, as well as on relapse-free survival of patients already 2 years after completion.

The widespread use of immunohistochemical (IHC) methods suggests their use for this purpose. A meta-analysis of the prognostic significance of the expression of the proliferation marker Ki-67 using IHC revealed that this method allows predicting overall survival in patients with cervical cancer, however, the data on event-free survival (ESS) are considered inconclusive by the authors, although they analyzed more than 300 sources; in addition, they did not consider results obtained in patients after NAC (see Denghua Pan, Kanglai Wei, Yanxin Ling, Shitao Su, Meilin Zhu, and Gang Chen The Prognostic Role of Ki-67/MIB-1 in Cervical Cancer: A Systematic Review with Meta-Analysis // Med Sci Monit 2015 21: 882-889 Published online 2015 Mar 25 doi: 10.12659/MSM.892807).

NAC in various oncological diseases is performed to reduce the volume of the tumor, which is achieved by inhibiting the proliferative activity of its cells, however, tumor stem cells (CSCs) present in the tumor, which are characterized by chemoresistance, are capable of giving rise to relapses and metastases, while having low proliferative activity. They represent a small subpopulation of tumor cells, however, after NAC, which causes the death of normal tumor cells, the percentage of CSCs that are chemoresistant naturally increases, which facilitates their calculation by the IHC method.

CSCs express genes that determine their properties, as well as receptors, including CD44. The biological role of the CD44 adhesion molecule is described in the literature; showed a high self-renewal capacity of CD44 overexpressing cervical cancer cell lines (see Ortiz-Sánchez E, Santiago-López L, Cruz-Domínguez VB, et al. (2016). Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression Oncotarget, 31, 31943-54, see López J, Poitevin A, Mendoza-Martínez V, Pérez-Plasencia C, García-Carrancá A (2012). cell lines exhibit stem-cell markers and increased radioresistance BMC Cancer, 28, 1-14).

High expression of CD44 in some solid tumors is associated with their more aggressive course (see Linge A, Lohaus F, Löck S, et al (2016). HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumor volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: a multicentre retrospective study of the German Cancer Consortium Radiation Radiother Oncol, 121, 1-10).

Known methods for predicting the course of cervical cancer based on the definition of CSC, and studied various markers of these cells. They are summarized in a meta-analysis (see Moh Nailul Fahmi, Inge Nandya Hertapanndika, Fitriyadi Kusuma The Prognostic Value of Cancer Stem Cell Markers in Cervical Cancer: A Systematic Review and Meta-Analysis // Asian Pac J Cancer Prev, 2021. 22 ( 12) 4057-4065), where the most prognostically significant of them are considered.

The authors highlight the significance of overexpression of OCT4, SOX2, and ALDH1 for predicting low event-free survival in patients with cervical cancer. CD44 expression in this study was associated with the prognosis of overall survival only and was studied only in patients with early stages of cervical cancer.

Closest to the claimed method is a study (see Gunawan Rusuldi Dan, Brahmana Askandar Ekspresi CD44 dan ALDH1 (Penanda Sel Punca Kanker) sebagai Prediktor Respons Kemoterapi Neoadjuvant Cisplatin pada Kanker Serviks Uteri Stadium IIB // Indonesian Journal of Cancer Vol. 11, No. 3 July - September 2017 p. 87-95), in which the expression of stem-like markers CD44 and ALDH1 was determined in a biopsy sample of 30 patients with stage IIB cervical cancer before the start of NAC with cisplatin. However, in this study, patients were followed up for 6 months, their OS and EFS were not studied, and the authors conclude that ALDH1 is more important than CD44 for predicting sensitivity to NAC.

The objective of the invention is to assess the risk of recurrence in patients with stage IIB cervical cancer after complex treatment, including neoadjuvant chemotherapy, based on IHC determination of the level of cells expressing CSC markers.

The technical result of this invention is the development of a method for predicting the progression of cervical cancer in stage IIB patients after complex treatment, including neoadjuvant chemotherapy.

The technical result is achieved by the fact that in the tumor tissue, the IHC method determines the expression of CSC markers CD44, at its level of 25% and above, early tumor progression is predicted within 10-27 months after surgery.

The method for predicting the occurrence of relapses in patients with stage IIB cervical cancer after complex treatment, including neoadjuvant chemotherapy, is new, since it is unknown in oncogynecology when predicting the duration of event-free survival (ESV) in patients with cervical cancer after completing complex treatment, including NAPCT. The novelty of the invention lies in the fact that during surgery for CC in patients treated with NAC, the level of expression of CSC with the CD44 marker is determined in the tumor by IHC.

The authors determined the level of expression in the tumor tissue of patients with CC IIB of the CD44 CSC marker in the tissue of the removed tumor after NAC with a combination of cisplatin and bleomycetin preparations, as a result of which the prognostic significance of CD44+ cells in relation to the duration of EFS was found. 2 groups of patients were formed: group 1 (n=6) with the progression of the tumor process in the period from 10 to 27 months (average 16.3±3.0 months) - in the form of locoregional relapses, metastasis in the retroperitoneal lymph collector or distant metastatic foci in the liver and/or lungs, and group 2 (n=14), which was under observation for 60-84 months without progression of the disease (see Table 1).

Table 1.
Expression of CSC markers CD44 and CD133 in patients with CC with various ESV after NAPCT and surgery Patient groups Index, % CD44+ Progression within 10-27 months 40 (Me)
LQ25 UQ40 p<0.05 No progression 20 (Me)
LQ11.5 UQ30

Patients are evaluated for event-free survival. Statistical data processing was performed using the STATISTICA 13 package (StatSoftInc., USA). The distribution was checked for normality using the Shapiro-Wilk test. Given the absence of a normal distribution, the results were presented as a central trend of the median (Me) and interquartile range - 25th and 75th percentiles (Me [LQ; UQ]). The significance of differences between the samples was assessed using the nonparametric Mann-Whitney test, the differences were considered statistically significant at p<0.05.

The results obtained indicate the presence of statistically significant differences between the groups in terms of CD44 expression (p<0.05).

Characteristics of antibodies are presented in table. 2. The result is expressed as a percentage.

table 2
Antibodies for IHC research Specificity Clone Firm Breeding Antigen Unmasking Buffer CD44 156-3S11 Thermo Scientific 1:2500 Antigen Retrivel Buffer,
(100x Citrate pH= 6.0)

At a CD44 expression level of 25% or more, tumor progression is predicted earlier - within 10-27 months.

A method for predicting the occurrence of relapses in patients with cervical cancer stage IIB, after complex treatment, including neoadjuvant chemotherapy, is performed as follows.

Patients with squamous cell HPV-positive CC stage IIB are treated with NAC as the first stage of treatment according to the "cisplatin and bleomycetin" scheme, then the surgical stage is performed in the volume of Piver III, and combined radiation therapy is performed in the adjuvant mode. Tumor tissue is taken intraoperatively, in which the percentage of cells expressing CSC CD44 markers is determined by IHC, and at a CD44 level of 25% and above, early tumor progression is predicted - within 10-27 months.

This method was calculated prognosis 25 patients.

The invention "Method for predicting the occurrence of relapses in patients with stage IIB cervical cancer after complex treatment, including neoadjuvant chemotherapy" based on the determination of CD44 in the tumor is industrially applicable and can be repeatedly reproduced in healthcare in specialized medical institutions for the treatment of cancer patients with this localization of the malignant process.

The clinical application of the method will allow, already at the stage of surgical intervention, to identify groups of patients with a high risk of disease progression and to form high-risk groups to determine the amount of adjuvant treatment and the timing of dynamic monitoring of patients.

We give examples of clinical observation.

Example #1

Patient Sh., born in 1975, was admitted to the gynecology department on 01/13/2014 with complaints of bloody discharge from the vagina, pain in the lower abdomen.

Anamnesis of the disease: 15.11.2013, she applied to the gynecological department at the place of residence with complaints of menstrual irregularities in the form of menorrhagia for a year and a half, pain in the lower abdomen, contact bleeding from the vagina.

On November 15, 2013, a biopsy of the cervix was performed. Histoanalysis: in the cervix - moderately differentiated squamous cell carcinoma. The patient was consulted by an oncologist. Sent to the Federal State Budgetary Institution "NMIC of Oncology of the Ministry of Health of the Russian Federation", Rostov-on-Don.

Ultrasound of the abdominal cavity and small pelvis from 11/28/2013: infiltration of the cervix - malignant in structure: in the lower third of the cervix there is a hypoechoic area of the infiltrative type, up to 20 mm - with fuzzy contours - with CDI intraperinodular blood flow, with vascular loci in the central sections of the gyrose forms, VMAC 42 cm/s, retroperitoneal lymph nodes are not enlarged, moderate diffuse changes in the liver, echographic signs of parametric fiber infiltration on the left, urinary system without pathology.

According to the SRCT of the OGK, OBP dated 11/15/2013: data for damage to the abdominal organs and chest were not revealed. OMT MRI of 11/14/2013: cervical tumor with infiltration of parametric spaces, pelvic lymph nodes are not enlarged. Cystoscopy and sigmoidoscopy revealed no invasion into the bladder and rectum. PCR for PVI - identified 16 type.

Diagnosed with cervical cancer T _2v N _x M ₀ gr.2, parametric variant, exophytic form. Taking into account the locally advanced tumor process, the council of doctors of the KDO National Medical Research Center of Oncology decided to start treatment with neoadjuvant courses of NAPCT. Conducted 3 courses of NAPHT according to the scheme of cisplatin, bleomycetin in combination with antiviral therapy with an interferon inducer. After 2 courses of NAPCT, a partial regression of the tumor was stated: according to MRI of the OMT and ultrasound of the OMT, a decrease in the volume of the tumor of the cervix by more than 30%, pelvic lymph nodes without features.

A decision was made to carry out the surgical stage of treatment.

Objective status: general condition is satisfactory, consciousness is clear, skin is pale pink, dry. There are no edema. Slight varicose veins of the lower extremities. Mammary glands without features. BP 120/75 mm Hg, pulse 84 per minute, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. Breathing is vesicular, no wheezing. The tongue is moist and clean. The abdomen is soft and painless. The liver is not enlarged, the gallbladder is not palpable, the spleen is not palpable. The chair is decorated, 1 time per day. Diuresis is adequate, urination is free, painless.

Status genitalis: External genitalia without pathology. In the mirrors: there are no pathological discharges in the vagina, the cervix is reduced in size, no more than 4 cm in diameter, cylindrical in shape, the ectocervix is completely epithelized, around the external pharynx there is a “residual” tumor with undermined edges about 1 cm in diameter, spontaneously and does not bleed on contact . The body of the uterus is slightly enlarged, of the usual consistency, movable, the appendages are not enlarged, the parameters are free, the vaults are free from the tumor.

Laboratory data: 1. Complete blood count dated 01/14/2014: hemoglobin - 105 g/l; erythrocytes - 4.1 * 10 ² / l; leukocytes - 6.62 * 10 ⁹ / l; platelets - 278*10 ⁹ /l; ESR - 12 mm/hour; p / poison - 6%; s / poison - 64%, monocytes - 6%; eosinophils 1%, lymphocytes - 23%. 2. Biochemical blood test dated 01/14/2014: glucose - 5.57 mmol/l; total protein - 67.4 g/l; bilirubin total - 8.5 mmol / l; ALT 12.4 IU/L; AST 13.1 IU/l; blood amylase 82.3 U/l; CRP 1.45 mg/ml, urea 2.71 mmol/l, creatinine 68 µmol/l. Ultrasound data from 01/13/2014: cervical tumor (cervical structure without nodules, with DG without signs of atypical blood flow), condition after CT treatment, submucosal uterine myoma, diffuse changes in the pancreas, chronic cholecystitis. SRCT of OGK and OBP dated 01/15/2014: data for the pathology of the chest and abdominal organs were not revealed.

After the examination, the following diagnosis was made: cervical cancer T _2b N _x M ₀ gr 2, exophytic form, parametric variant, condition after 3 courses of NAPHT, partial regression of the tumor.

On January 30, 2013, extended extirpation of the uterus with appendages with the upper third of the vagina and pelvic lymphadenectomy (Piver III operation) was performed.

An IHC study of the tumor revealed a CD44 expression level of 10%.

The result of histological analysis: on the ectocervix in a limited area of about 5 mm, moderately differentiated squamous cell carcinoma with pronounced signs of drug-induced pathomorphosis (grade III), the rest of the cystic expansion of the lumen of the glands; integumentary stratified squamous epithelium has a normal structure, no signs of tumor growth are determined; endometrium of the proliferation phase of the menstrual cycle, the resection line has a normal structure; leiomyoma, submucosal leiomyoma; fallopian tubes and ovaries have a normal structure; in the lymph nodes - sinus histiocytosis, focal lipomatosis, deposition of homogeneous eosinophilic masses (total number of removed lymph nodes - 22).

The following diagnosis was made: cervical cancer pT _2v N ₀ M ₀ gr 2, exophytic form, parametric variant, condition after 3 courses of NAPHT, partial regression of the tumor, condition after surgical treatment.

The consultation of doctors of the KDO National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation recommended adjuvant radiation therapy (taking into account the primary status of the tumor).

In the postoperative period, combined radiation therapy was performed on the pelvic area. The treatment was completed in March 2013. Dynamic follow-up with an oncologist in the OD at the place of residence was recommended once every 3 months for 2 years, then once every six months up to 5 years. Regularly observed by an oncologist at the place of residence.

At the follow-up visit on January 12, 2022, the patient's condition was satisfactory (according to the Karnovsky scale, 100 points), the patient did not complain. Consciousness is clear, the skin is pale pink, dry. There are no edema. Slightly pronounced varicose veins of the saphenous veins of the lower extremities were not detected. Mammary glands without features. BP 120/80 mm Hg, pulse 72 per minute, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. Breathing is vesicular, no wheezing. The tongue is moist and clean. The abdomen is soft and painless. The liver is not enlarged, the gallbladder is not palpable, the spleen is not palpable. The chair is decorated, 1 time per day. Diuresis is adequate, urination is free, painless.

Status genitalis: external genitalia without pathology. In the mirrors: the vaginal stump is formed, completely epithelialized, smooth, macroscopically without signs of recurrence. Smears from the vaginal scar (histoanalysis: no atypical cells were found). Bimanual examination in the cavity of the small pelvis does not reveal pathological formations.

Ultrasound data from 01/12/2022: pathological formations are not located in the small pelvis; retroperitoneal lymph nodes are not enlarged; moderate diffuse changes in the liver, urinary system without features.

SRCT of OGK and OBP dated 01/12/2022: pathological formations in the chest and abdominal cavity were not detected. OMT MRI on 01/13/2022: no evidence of recurrence in the pelvic cavity was found.

After the examination, the following diagnosis was made: cervical cancer pT _2v N ₀ M ₀ , exophytic form, parametric variant, condition after complex treatment, incl., courses of NAPHT, surgical treatment and combined radiation therapy, gr. 3. Complete clinical remission.

The total duration of clinical remission at the moment is 92 months (8 years and 2 months).

Example #2.

Patient B., born in 1987, was admitted to the gynecology department on January 28, 2013 with complaints of pain in the lower abdomen, contact and spontaneous blood smears from the vagina.

Anamnesis of the disease: considers himself ill since September 2012, when contact spotting and bleeding from the vagina first appeared. The patient turned to the gynecologist at the place of residence, where a smear was taken from the surface of the tumor: c/a - carcinoma. On November 13, 2012, the patient independently applied to the KDO FGBI "NMRC of Oncology" of the Ministry of Health of the Russian Federation in Rostov-on-Don. Examined at the level of the clinic: 1) taken a biopsy of the cervix - g/a: G 3 carcinoma; 2) Ultrasound of 11/12/2012: bend, moderate adenomatous changes in the body of the uterus, echographically tr of the cervix with the transition of the process beyond the external os. OMT MRI dated 11/12/2012: cervical tumor involving parametrical and paracervical tissue. SRCT of OGK and OBP dated 11/13/2012: data for MTS lesions of the abdominal cavity and small pelvis organs were not revealed, retroperitoneal lymph nodes were not enlarged. Cystoscopy and sigmoidoscopy revealed no invasion into the bladder and rectum. PCR for PVI - identified 16 type. Diagnosed with cervical cancer T _2v N _x M ₀ gr.2, vaginal parametric variant, exophytic form. Taking into account the locally advanced tumor process, the council of doctors of the KDO National Medical Research Center of Oncology decided to start treatment with neoadjuvant courses of NAPCT. Conducted 3 courses of NAPHT according to the scheme of cisplatin, bleomycetin in combination with antiviral therapy with an interferon inducer. After 3 courses of NAPCT, a partial regression of the tumor was noted: according to MRI of the OMT and ultrasound of the OMT, a decrease in the volume of the cervical tumor by more than 30%, pelvic lymph nodes without features. A decision was made to carry out the surgical stage of treatment.

Objective status: the general condition is relatively satisfactory, consciousness is clear, the skin is pale, dry. The nutritional status is satisfactory. There are no edema. Peripheral lymph nodes accessible for palpation are not enlarged. Moderate varicose veins of the lower extremities. Mammary glands without features. BP 120/80 mm Hg, pulse 68 per minute, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. Breathing is vesicular, no wheezing. The tongue is moist and clean. The abdomen is soft and painless. The liver is not enlarged, the gallbladder is not palpable, the spleen is not palpable. The chair is decorated, 1 time per day.

Status genitalis: external genitalia without pathology. In the mirrors: the cervix has decreased in size up to 4 cm in diameter, on the ectocervix the residual exophytic tumor is about 3 cm in maximum dimension, it bleeds in contact (before NAPCT courses: the cervix is hypertrophied, affected by an exophytic contact bleeding tumor up to 6 cm in diameter). The body of the uterus in retroflexio, normal size, dense consistency, mobile. The vaults and parameters are free, freed from tumor infiltration. Laboratory data: 1. Complete blood count dated January 29, 2013: hemoglobin - 113 g/l; erythrocytes - 4.59 * 10 ² / l; leukocytes - 7.76 * 10 ⁹ / l; platelets - 234*10 ⁹ /l; ESR - 34 mm/h; p / poison - 17%; s / poison - 42%, monocytes - 9%; eosinophils 1%, lymphocytes - 32%. 2. Biochemical blood test dated January 29, 2013: glucose - 6.26 mmol/l; total protein - 73.6 g/l; total bilirubin - 3.1 mmol/l; ALT 13.8 IU/l; AST 14.3 IU/l; blood amylase 75.5 U/l; CRP 3.47 mg/ml, urea 3.81 mmol/l 3, creatinine 50 µmol/l. OMT ultrasound from 01/25/2012: moderate infiltration of the cervix with positive dynamics (malignant in structure): in the lower third of the cervix, hypoechoic infiltrate up to 10 mm - with fuzzy contours - avascular; moderate diffuse changes in the liver, retroperitoneal lymph nodes are not enlarged.

After the examination, the following diagnosis was made: cervical cancer T _2v N _x M ₀ gr 2, exophytic form, vaginal parametric variant, condition after 3 courses of NAPHT, partial regression of the tumor.

On January 30, 2013, extended extirpation of the uterus with appendages with the upper third of the vagina and pelvic lymphadenectomy (Piver III operation) was performed.

An IHC study of the tumor revealed a CD44 expression level of 60%.

The result of histological analysis: moderately differentiated squamous cell carcinoma with an invasion of more than 1 cm; there is no tumor along the resection line; endometrial glands in the proliferation phase, leiomyoma; appendages of the usual structure; there is no cancer metastasis in the removed pelvic lymph nodes (the total number of removed lymph nodes is 20).

The following diagnosis was made: cervical cancer pT _2v N ₀ M ₀ gr 2, exophytic form, vaginal-parametric variant, condition after 3 courses of NAPHT, partial regression of the tumor, condition after surgical treatment.

The consultation of doctors of the KDO National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation recommended adjuvant radiation therapy (taking into account the primary status of the tumor).

In the postoperative period, combined radiation therapy was performed on the pelvic area. The treatment was completed in March 2013. Dynamic follow-up with an oncologist at the oncology dispensary at the place of residence was recommended once every 3 months for 2 years, then once every six months up to 5 years. Regularly observed by an oncologist at the place of residence. In January 2014, a metastatic lesion of the para-aortic lymph nodes was detected.

On January 14, 2014, she applied again to the KDO National Medical Research Center of Oncology. The patient's condition was 80 points according to the Karnovsky scale, complaints of back pain. Consciousness is clear, the skin is pale pink, dry. There are no edema. Varicose veins of the saphenous veins of the lower extremities were not detected. Mammary glands without features. BP 120/80 mm Hg, pulse 72 per minute, rhythmic. Heart sounds are clear, rhythmic. NPV 14 per minute, no shortness of breath. Breathing is vesicular, no wheezing. The tongue is moist and clean. The abdomen is soft and painless. The liver is not enlarged, the gallbladder is not palpable, the spleen is not palpable. The chair is decorated, 1 time per day. Diuresis is adequate, urination is free, painless.

Status genitalis: external genitalia without pathology. In the mirrors: the vaginal stump is formed, completely epithelialized, smooth, macroscopically without signs of recurrence. Smears from the vaginal scar (c/a: atypical cells were not detected). Bimanual examination in the cavity of the small pelvis does not reveal pathological formations.

Data from CT scan of the chest, MRI of the OMT and OBP from 01/14/2014: lung fields without focal and infiltrative changes, intrathoracic lymph nodes are not enlarged, para-aortic lymph nodes are about 2 cm, paracaval lymph nodes are 1.4 cm; moderate diffuse changes in the liver, urinary system without features; in the small pelvis, pathological formations are not located.

After the examination, the following diagnosis was made: cervical cancer pT _2c N ₀ M ₀ gr 2, exophytic form, vaginal parametric variant, condition after 3 courses of NAPHT, partial regression of the tumor, condition after surgical treatment and combined radiation therapy (2012-2013) . Progression of the disease: mts defeat of the retroperitoneal para-aortic lymph nodes.

The council of doctors of the KDO National Medical Research Center of Oncology recommended conducting courses of PCT according to the scheme: carboplatin, paclitaxel.

Conducted 6 courses of second-line PCT according to the scheme carboplatin, paclitaxel. The treatment was completed in June 2014. According to the CT scan of the OBP dated June 18, 2014, the stabilization of the tumor process: mts of the affected paraaortic lymph nodes remain up to 2 cm in size.

In September 2014, severe pain syndrome, weakness. SRCT of OGK, OBP and OMT from 09/10/2014: multiple mts foci up to 16 mm in the lung tissue, a few mts foci up to 22 mm in the right lobe of the liver, para-aortic lymph nodes up to 32 mm, paracaval - up to 17 mm, iliac on both sides up to 16 mm with calcifications, intrapelvic on both sides up to 20 mm, under the legs of the diaphragm up to 22 mm, bodies of Th12, L1, L5 vertebrae sprout on the right, preaortic and upper mediastinal lymph nodes up to 26 mm, supraclavicular lymph nodes on the left up to 28 mm, pathological formations in the small cavity the pelvis was not identified. The following diagnosis was made: cervical cancer pT _2c N ₀ M ₀ gr 2, exophytic form, vaginal parametric variant, condition after 3 courses of NAPCT, partial regression of the tumor, condition after surgical treatment and combined radiation therapy (2012-2013). Progression of the disease: mts defeat of the retroperitoneal para-aortic lymph nodes in January 2014, condition after 6 courses of second-line chemotherapy. Mts to lungs, liver, supraclavicular, paracaval, paraaortic lymph nodes, to mediastinal lymph nodes (September 2014).

The third line of PCT was started according to the scheme: gemcitabine 1000 mg/m ² on days 1,8,15. In January 2015, the patient died. Time without progression: 14 months.

The presented clinical examples demonstrate the possibility of predicting event-free survival after complex treatment, including NAPCT, in patients with stage IIB cervical cancer and, as a result, the need for a personalized approach to their management when performing an adjuvant treatment regimen.

The technical and economic efficiency of the method based on determining the level of expression of the CSC marker CD44 lies in the fact that the level of CD44+ expression determined by the IHC method can be a prognostic criterion for tumor progression and low ESF in such patients and, with a personalized approach to their management, reduce the economic costs of treatment.

Claims (1)

A method for predicting the progression of cervical cancer in stage IIB patients, which consists in the fact that after neoadjuvant chemotherapy, the level of CD44 expression is determined intraoperatively in the tumor tissue by immunohistochemical method, and at its level above 25%, the development of disease progression is predicted within 10-27 months.