RU2547569C1 - Method of treating patients suffering locally advanced cervical cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: first stage of the treatment in the patients with a primary inoperable form of uterine cancer involves a neoadjuvant polychemotherapy combined with a session of therapeutic plasmapheresis. The chemotherapy is preceded with a session of discrete gravity plasmapheresis by means of MCS apparatus + PPP (platelet-poor plasma) Hemonetics. The chemotherapeutic agents are administered on the day following the plasmapheresis session.

EFFECT: method enables overcoming the tumour resistance to cytostatics, reducing the number of the pre-operative chemotherapeutic courses, downsizing the tumour and improving the tumour process respectability, reducing toxic and side chemotherapeutic responses, and reducing cytostatic doses.

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Description

The invention relates to medicine, in particular to oncology, and can be used in gynecology during chemotherapy in patients with locally advanced cervical cancer.

Currently, cervical cancer in most countries of the world continues to be the most common malignant tumor of the female genital organs. Among the diseased, locally advanced cervical cancer occurs in 20-50%, while its growth is noted in young women (3.6). The greatest difficulty for clinicians is the treatment of this particular category of patients, since the regional spread of the tumor leads to rapid lymphogenous metastasis. Traditional chemoradiation treatment makes it possible to achieve a 50-60% survival rate for patients with cervical cancer of the II-III stages. One of the directions in the chemotherapy of cervical cancer is its use as a neoadjuvant (8). The theoretical prerequisites for this are the best delivery of cytostatics to the tumor by vessels intact due to radiation therapy and surgery, the possibility of reducing the tumor in order to increase the effectiveness of subsequent treatment methods, the likelihood of a pathomorphological assessment of the effect, and eradication of micrometastases (1.9).

The data available in the literature indicate that intravenous administration of chemotherapeutic agents makes it possible to transfer cervical cancer to a resectable state in 29.6-89% of patients and perform subsequent surgical intervention (11). Such a wide range of data presented indicates the often emerging resistance of the tumor to the ongoing cytostatic therapy. The use of intra-arterial neoadjuvant chemotherapy allows removal of the tumor in 83.6-93.5% of patients (12), although it is extremely rare due to the technical difficulties of catheterizing the internal iliac or internal hypogastric arteries. A complex treatment method is known for patients with locally advanced cervical cancer, including neoadjuvant chemotherapy with chemoebolization of the uterine arteries with cisplatin and gemcitabine. The radicalism of surgery after this method is 92.9%, however, toxic complications occur in 21.4% of cases, and the development of postembolic syndrome is observed in 65.4% of women (6).

A method of intravenous neoadjuvant chemotherapy (PCT) has been described in patients with stage IIB-IIIB cervical cancer using drugs: cisplatin, bleocin, vincristine, which allows radical surgical treatment to be performed in 80% of cases (8). Moreover, all patients underwent 3 courses of chemotherapy in the preoperative period, which undoubtedly leads to an increase in the cumulative dose of cytostatics in the patient’s body, which cannot but affect the general somatic state of the patients.

According to the protocols of the World Association of Hemapheresis, therapeutic plasmapheresis is currently used in the complex treatment of more than 150 diseases (5). However, despite the obvious feasibility, plasmapheresis has not yet received significant distribution in clinical oncology. The place of therapeutic plasmapheresis as a component of intensive supportive therapy is justified on the basis of the biological effects it produces, such as detoxification, immunocorrection, and re-correction (4.7). In the process of plasmapheresis, catalytic biotransformation of toxic and bioregulatory substances, desorption from the surface of blood cells and transport proteins of ligands of various nature occurs (10). One of the possible mechanisms for increasing the effectiveness of chemotherapy, which can be realized by preliminary plasmapheresis, is to improve the functional state of the liver and other organs and systems of natural detoxification (2). Plasmapheresis can increase the effectiveness of treatment by reducing resistance to chemotherapy, which inevitably develops during treatment, especially in conditions of cancer intoxication (13).

The aim of the present invention is to increase the pathway of chemotherapy to tumor tissues and foci of lymphogenous metastasis, to improve the immediate and long-term results of treatment of patients with locally advanced cervical cancer while reducing the overall adverse reactions of the body, against the background of restoration of the immune system activity in the period most favorable for the antitumor effect.

This goal is achieved by the fact that in the preoperative period therapeutic plasmapheresis is performed before chemotherapy is started, a session of gravitational discrete plasmapheresis with the MCS + Hemonetics apparatus is carried out in the PPP protocol mode (production of plasma depleted in leukocytes) with a perfusion rate of 40 ml / min and a blood separation rate V = 4800 rpm, the volume of plasma extraction in this case is 600-800 ml, as plasma-substituting solutions, solutions of hydroxyethyl starch (HES) 10%, albumin 5%, crystalloid solution are injected dropwise the next day after a plasmapheresis session, a course of polychemotherapy is started according to the following scheme: on the first day of chemotherapy, cisplatin is administered at a dose of 50 mg / m ² + bleocin 30 mg iv drip, on the second day 15 mg bleucin iv drip, if necessary the course of chemotherapy is repeated.

The invention "A method for the treatment of patients with locally advanced cervical cancer" is new, since it is not known from the prior art in the field of gynecological oncology for chemotherapy of patients with cervical cancer of the IIA-IIB stages. The novelty of the invention lies in the fact that the patient before a course of chemotherapy conducts a session of hardware-based gravitational discrete plasmapheresis as a modifier that increases the effectiveness of antitumor drug therapy by increasing the sensitivity of tumor cells to chemotherapy and restoring the activity of the immune system in the period most favorable for the antitumor effect. After a plasmapheresis session, the first course of polychemotherapy with cisplatin + bleocin is carried out.

The invention "A method for the treatment of patients with locally advanced cervical cancer" is industrially applicable, as it can be used in healthcare, oncological medical facilities, oncology dispensaries, research institutes, and cancer centers.

A method of treating patients with locally advanced cervical cancer is as follows. Therapeutic plasmapheresis is performed before chemotherapy. A session of gravitational discrete plasmapheresis with the MCS + Hemonetics apparatus is carried out in the PPP protocol mode (obtaining plasma depleted in white blood cells) with a perfusion rate of 40 ml / min and a blood separation rate of V = 4800 rpm The volume of plasma extraction is 600-800 ml. As plasma-substituting solutions, solutions of hydroxyethyl starch (HES) 10%, albumin 5%, crystalloid solution are injected intravenously.

The day after a plasmapheresis session, a course of polychemotherapy is started. On the first day of chemotherapy, cisplatin is administered at a dose of 50 mg / m ² + bleocin 30 mg iv, and on the second day, 15 mg iv bleucin is administered dropwise. Therapeutic plasmapheresis can be used as a modifier that induces the effectiveness of chemotherapy by increasing the sensitivity of tumor cells to chemotherapy and restoring the activity of the immune system in the period most favorable for the antitumor effect. Due to the pronounced detoxification, immunocorrecting and deblocking effects, therapeutic plasmapheresis can be used as an effective component of intensive accompanying therapy before chemotherapy treatment.

An example of a specific implementation of the "Method of treating patients with locally advanced cervical cancer" on the patient.

Patient Apaeva D.A., born in 1981, was admitted to the gynecology department of the RNII on April 19, 2013 with complaints of spotting from the vagina, general weakness.

Anamnesis of the disease: has been sick since October 2012, when the diagnosis was first made: "Cervical erosion." 03/26/2013 in Moscow performed diathermoconization of the cervix. G / a 13857-59: squamous cell moderately differentiated cervical cancer.

The patient independently contacted the RNII. A combined sonographic study and CT scan of the pelvic organs: abdominal cavity and pelvis revealed: cervical infiltration - malignant in structure; retroperitoneal lymph nodes are not enlarged, moderate diffuse changes in the liver, echographic signs of infiltration of parametric fiber on the left, urinary system without pathology.

Objective status: general condition is relatively satisfactory (according to the Karnowski scale of 80 points), clear consciousness, skin integument of pale pink color, dry. Height = 160 cm, weight = 76 kg (body surface area 1.8 m ² ). No swelling. Varicose expansion of the saphenous veins of the lower extremities was not detected. The mammary glands are without features. HELL 120/80 mm Hg, pulse 72 min, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. The vesicular breathing, no wheezing. The tongue is wet, clean. The abdomen is soft, painless. The liver is not enlarged, the gall bladder is not palpable, the spleen is not palpable. The chair is decorated once a day. Adequate diuresis, free urination, painless.

Status genitalis: external genitalia without pathology. In the mirrors: abundant bloody discharge with clots in the vagina, the cervix is hypertrophied, the ectocervix is completely affected by an exophytic, spontaneously bleeding, tuberous tumor 6 cm in diameter, with a transition to the left lateral vaginal fornix. The body of the uterus is slightly enlarged, the usual consistency is relatively mobile, the appendages are not enlarged, the parametrium on the left is infiltrated (not to the pelvic wall).

Laboratory data.

1. General blood test from 04/23/2013: hemoglobin - 120 g / l; erythrocytes - 4.01 * 10 ² / l: white blood cells - 5.8 * 10 ⁹ / l; platelets - 234 * 10 ⁹ / l; ESR - 6 mm / hour; p / poison - 6%; s / venom - 62%, monocytes - 4%; eosinophils 1%, lymphocytes - 25%. 2. Biochemical analysis of blood from 04/23/2013: glucose - 5.32 mmol / l; total protein 79.9 g / l; total bilirubin - 8.5 mmol / l; ALT 12.8 IU / L; ACT 13.3 IU / L; blood amylase 95.5 U / L; CRP 1.47 mg / ml, urea 2.81 mmol / L, creatinine 57 μmol / L.

Ultrasound of the abdominal and pelvic organs from 04/19/2013: cervical infiltration is malignant in structure: malignant in the lower third of the cervix, hypoechoic infiltrative type, up to 16 mm with fuzzy contours - with intraperinodular blood flow, with vascular loci in the central sections of the convoluted forms, VMAC 12.9 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.

After the examination, the diagnosis was made: cervical cancer T _2B N _x M _o gr 2, exophytic form, laginal-parameter variant.

Given the primary unresectable status of a tumor, the council of the gynecology department No. 1 recommended that treatment be started with neoadjuvant chemotherapy according to the “cisplatin + bleocin” regimen with the inclusion of a preliminary session of therapeutic gravitational plasmapheresis into the treatment program, to which the patient received consent and approval of the ethics committee of RNIIII.

04/23/2013 a session of gravitational discrete plasmapheresis was performed with the MCS + Gemonetics apparatus in the PPP protocol mode (production of plasma depleted in leukocytes) with a perfusion rate of 40 ml / min and a blood separation rate of V = 4800 rpm. The volume of plasma extraction was 607 ml. Netoches 10% - 500 ml, albumin 5% - 200 ml, tetrospan 800 ml were intravenously dripped as replacement solutions.

April 24, 2013, the first course of PCT was started in the neoadjuvant mode: 100 mg of cisplatin and 30 mg of bleocin were administered.

04/25/2013 in / drip 15 mg of bleocin are entered. The patient underwent satisfactory administration of chemotherapy.

No gastrointestinal, hematological, neurological, skin, nephrological toxicity was noted.

04/25/2013 the patient was discharged from the hospital with relevant recommendations. Appearance after 3 weeks to address further treatment tactics.

05/15/2013, the patient was admitted to the gynecology department of RNII. No complaints. There are no spotting from the vagina.

Objective status: general condition is relatively satisfactory (on the Karnovsky scale of 90 points), clear consciousness, skin integument of pale pink color, dry. Height = 160 cm, weight = 76 kg. No swelling. Varicose expansion of the saphenous veins of the lower extremities was not detected. The mammary glands are without features. HELL 120/80 mm Hg, pulse 72 min, rhythmic. Heart sounds are clear, rhythmic. CDC 16 per minute, no shortness of breath. The vesicular breathing, no wheezing. The tongue is wet, clean. The abdomen is soft, painless. The liver is not enlarged, the gall bladder is not palpable, the spleen is not palpable. The chair is decorated once a day. Adequate diuresis, free urination, painless.

Status genitalis: external genitalia without pathology. In the mirrors: there are no pathological discharge in the vagina, the cervix is reduced in size, partially epithelized, on the ectocervix an exophytic tumor 3 cm in diameter, spontaneously and contactlessly not bleeding, tuberous. The body of the uterus is slightly enlarged, the usual consistency is relatively mobile, the appendages are not enlarged, slight infiltration of the parametrium on the left is preserved, the arches are freed from the tumor.

Laboratory data.

1. General blood test from 05.16.2013: hemoglobin - 111 g / l; erythrocytes - 3.87 * 10 ² / l: white blood cells - 6.2 * 10 ⁹ / l; platelets - 205 * 10%; ESR - 6 mm / hour; p / poison - 5%; s / poison - 65%, monocytes - 5%; eosinophils 1%, lymphocytes - 24%.

2. Biochemical analysis of blood from 05.16.2013: glucose - 5.24 mmol / l; total protein - 74.4 g / l; total bilirubin - 11.4 mmol / l; creatinine - 55 μmol / l; ALT 45.0 IU / L; ACT 20.8 IU / L; blood amylase 88.7 U / L; CRP 7.43 mg / ml, urea 3.04 mmol / L.

3. Ultrasound of the abdominal cavity and pelvic organs from 05.16.2013: cervical infiltration - malignant in structure: in the lower third of the cervix uterine hypoechoic infiltrative type, up to 12 mm - with fuzzy contours - with CDC weak intraperinodular blood flow, with single vascular loci in the central sections of the convoluted form, VMAC 6.1 cm / s, retroperitoneal lymph nodes are not enlarged, moderate diffuse changes in the liver, echographic signs of residual infiltration of parametric tissue on the left (positive dynamics compared to the data ultrasound from 04/19/2013).

After the examination, the diagnosis was made: cervical cancer T _2B N _x M _o gr 2, exophytic form, vaginal-parametric variant, condition after the neoadjuvant course of PCT with the inclusion of plasmapheresis in the treatment program, partial tumor regression.

Given the persistent slight infiltration in the left parametrium, the council of the gynecology department No. 1 recommended a second neoadjuvant course of polychemotherapy according to the scheme: “cisplatin + bleocin”.

May 16-17, 2013, the second course of PCT was carried out in the neoadjuvant mode: 100 mg of cisplatin, 30 mg of bleocin were administered on the first day, and 30 mg of bleocin on the second day. The patient underwent satisfactory administration of chemotherapy. Gastrointestinal toxicity of the 1st degree was noted, hematological, neurological, skin, nephrological toxicity was noted.

05/17/2013 the patient was discharged from the hospital with relevant recommendations. Appearance after 3 weeks to address further treatment tactics.

06/13/2013, the patient was admitted to the gynecology department of RNII. No complaints. There are no spotting from the vagina.

Objective status: general condition is relatively satisfactory (on the Karnovsky scale of 90 points), clear consciousness, skin integument of pale pink color, dry. No swelling. Varicose expansion of the saphenous veins of the lower extremities was not detected. The mammary glands are without features. HELL 120/80 mm Hg, pulse 72 min, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. The vesicular breathing, no wheezing. The tongue is wet, clean. The abdomen is soft, painless. The liver is not enlarged, the gall bladder is not palpable, the spleen is not palpable. The chair is decorated once a day. Adequate diuresis, free urination, painless. Status genitalis: external genitalia without pathology. In the mirrors: there are no pathological discharge in the vagina, the cervix is reduced in size, epithelized, does not bleed spontaneously and contact, 3-4 small tumor defects are visually detected on the ectocervix, the uterine body is slightly enlarged, the usual consistency is mobile, the appendages are not enlarged, the parameters are free , arches are free.

Laboratory data.

1. General blood test from 06/14/2013: hemoglobin - 123 g / l; erythrocytes - 4.19 * 10 ² / l; white blood cells - 6.2 * 10 ⁹ / l; platelets - 245 * 10 ⁹ / l; ESR - 11 mm / hour; p / poison - 10%; s / venom - 53%, monocytes - 5%; eosinophils 2%, lymphocytes - 30%.

2. Biochemical analysis of blood from 06/14/2013: glucose - 5.0 mmol / l; total protein - 75.0 g / l; total bilirubin - 11.4 mmol / l; creatinine 58 μmol / L.

3. Ultrasound data dated 06/14/2013: moderate cervical infiltration with positive dynamics (malignant in structure): in the lower third of the cervix, hypoechoic infiltrate up to 8 mm — with fuzzy contours — avascular; moderate diffuse changes in the liver, retroperitoneal lymph nodes are not enlarged,

After the examination, the diagnosis was made: cervical cancer T _2B N _x Mo gr 2, exophytic form, vaginal-parametric variant, condition after 2 neoadjuvant courses of PCT including plasmapheresis in the treatment program, partial tumor regression.

The council of the gynecology department No. 1 recommended surgical treatment.

06/19/2013, the extended hysterectomy with appendages was performed (operation Piver III).

The result of histological analysis: No. 35585-586 / 13: moderately differentiated cancer with an invasion of 4 mm, endocervicosis, healing according to I and II variant, therapeutic pathomorphosis of the III degree; No. 35587-588 / 13: endometrial glands in the proliferation phase, there is no tumor along the resection line; No. 35589-592 / 13: appendages of a conventional structure; No. 35593-602 / 13: in the lymph nodes and fiber - no cancer metastasis.

In the postoperative period, combined radiation therapy was performed on the pelvic area.

At the control turnout on October 14, 2013, the patient was in satisfactory condition (100 points on the Karnowski scale), the patient did not make complaints. Height = 160 cm, weight = 74 kg. The consciousness is clear, the skin is pale pink, dry. No swelling. Varicose expansion of the saphenous veins of the lower extremities was not detected. The mammary glands are without features. HELL 120/80 mm Hg, pulse 72 min, rhythmic. Heart sounds are clear, rhythmic. NPV 16 per minute, no shortness of breath. The vesicular breathing, no wheezing. The tongue is wet, clean. The abdomen is soft, painless. The liver is not enlarged, the gall bladder is not palpable, the spleen is not palpable. The chair is decorated once a day. Adequate diuresis, free urination, painless.

Status genitalis: external genitalia without pathology. In the mirrors: the vaginal stump is formed, completely epithelized, smooth, macroscopically without signs of relapse. Smears from the rumen of the vagina (c / a No. 16432-16433: atypical cells were not found). With a bimanual examination in the pelvic cavity, pathological formations are not determined.

Ultrasound data from 10/14/2013: in the pelvis, pathological formations are not located; retroperitoneal lymph nodes are not enlarged; moderate diffuse changes in the liver, urinary system without features.

After the examination, the diagnosis was made: cervical cancer pT _2B NoMo, exophytic form, vaginal-parametric variant, condition after complex treatment, clinical group 3, which corresponds to the complete response according to the RECIST scale.

The technical and economic efficiency of the “Method of treating patients with locally advanced cervical cancer” is that the use of gravitational discrete plasmapheresis in combination with the subsequent conduct of neoadjuvant chemotherapy can overcome the resistance of the tumor to cytostatics, reduce the number of courses of preoperative chemotherapy, reduce the mass of the tumor, increase the resectability of the tumor reduce the frequency of metastasis to the lymph nodes.

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Claims (1)

A method of treating patients with locally advanced cervical cancer, including a combination of plasmapheresis with neoadjuvant chemotherapy, characterized in that in the preoperative period, therapeutic plasmapheresis is performed before chemotherapy is started, a gravitational discrete plasmapheresis session with MCS + Gemonetics is carried out in PPP protocol (receiving plasma, lunch ) with a perfusion rate of 40 ml / min and a blood separation rate of V = 4800 rpm, the volume of plasma extraction in this case is 600-800 ml, as a plasma substitute solutions of hydroxyethyl starch (HES) 10%, albumin 5%, crystalloid solution are injected dropwise, the next day after the plasmapheresis session, a chemotherapy course is started according to the following scheme: on the first day of the chemotherapy course, cisplatin is administered at a dose of 50 mg / m ² + bleocin 30 mg iv drip, on the second day 15 mg of bleocin iv drip is administered, if necessary, repeat the course of polychemotherapy.