RU2296564C2 - Method for treatment of relapses in oncogynecological patients - Google Patents

Abstract

FIELD: medicine, oncology, gynecology.

SUBSTANCE: method involves trepanopuncture of flank bone wing, aspiration of bone marrow suspension in the amount 150-200 ml followed by incubation of suspension with chemopreparations cisplatin and cyclophosphan at temperature 37^°C for 40 min in doses above therapeutic ones. Doxorubicin is not incubated with bone marrow suspension and chemopreparations are administrated separately by intravenous route, by drops in indicated order in day when the bone marrow suspension has been taken, and this procedure is repeated with interval for 3-4 weeks but totally 4 times per one treatment course. Proposed method provides attaining the stable anti-tumor effect up to the complete tumor regression in this category of patients showing high tolerance to chemotherapy, and in practical absence of adverse toxic responses. Invention can be used in treatment of patients with relapses of ovary and uterus body cancer in case absence effectiveness of other methods of treatment or in case of their low effectiveness.

EFFECT: improved method of treatment.

2 ex

Description

The invention relates to medicine, namely to oncogynecology, and can be used for the treatment of patients with recurrence of ovarian cancer and uterine cancer, when the possibilities of other methods of treatment have been exhausted or have ineffective results.

Despite the fact that more than 50% of patients with advanced ovarian cancer achieve complete clinical remission after modern complex treatment, most of them develop a relapse within the first three years (A. Urmancheeva. Modern chemotherapy for ovarian cancer. Practical oncology. T3, No. 4, 2002).

There is a method of treating ovarian cancer, as well as relapse of this disease using autohemochemotherapy (AGCT) (Dolmatova OK Autohemochemotherapy of advanced ovarian cancer: Abstract of thesis. Candidate of Medical Sciences. Rostov-on-Don, 1995). The method consists in the fact that in the postoperative period, intravenous drip administration of a combination of 4 cytostatics according to the CMFV scheme, incubated with autoblood is carried out; 1 time per week for 4-5 weeks, that is, 4-5 infusions per course of treatment: vinblastine - 5-10 mg, or vincristine 5-10 mg; cyclophosphamide - 600-800 mg / m ² ; 5-fluorouracil - 500-750 mg / m ² ; methotrexate - 15-25 mg / m ² .

The use of autohemochemotherapy in patients with recurrence of ovarian cancer in a state of generalization of the tumor process, which are considered incurable, made it possible to achieve remission in more than half of the cases (53.3%). Another 1/3 of the patients (33.3%) experienced stabilization of the process. Only 13.3% of patients showed further progression of the disease. At the same time, a significant drawback of the use of AGCT is its high toxicity. So, nausea and vomiting of varying severity were observed in 42.4%, diarrhea, stomatitis, hepatotoxicity, allopecia - in isolated cases. Hematological complications in the form of leukopenia in patients with relapses amounted to 76.6%. The application of the method limits the generalization of the tumor process, improves the condition of patients, but does not prevent relapse even in the near term.

A known method of treating patients with ovarian cancer of the III-IV stage using lymphochemotherapy (Chalabova TG Neoadjuvant lymphochemotherapy in the complex treatment of patients with ovarian cancer of the III-IV stage. Abstract of dissertation for the degree of candidate of medical sciences. Rostov-on-Don, 2002) , including intravenous administration of chemotherapy drugs on autolymph: cisplatin 100 mg / m ² , doxorubicin 40-50 mg / m ² , cyclophosphamide 600-800 mg / m ² . Lymphatic infusion was performed once. Full regression was achieved in 34.2% of patients, partial regression was achieved in 42.4%. Thus, the effectiveness of this method of treating ovarian cancer was 76.7%. At the same time, some drawbacks of the method should be noted: it is not always possible to drain the common thoracic lymphatic duct, the lack of an autolymph volume adequate for autolymphochemotherapy (ALXT), and the patient’s refusal to perform surgery. In addition, the relapse rate was 48% after ALT. Hematological toxicity using lymphochemotherapy was 30%. Dyspeptic disorders appeared in 13.6%. Nephrotoxicity was observed in 2.7%. The method provides tumor regression, but does not prevent further relapse.

The well-known "Method for the treatment of cancer of the uterine body" (see patent No. 2195269 from 06/10/02 Bull. No. 26), including ALXT of patients with advanced forms of cancer of the uterus of the III stage. The essence of the method lies in the fact that in the preoperative period, the standard total course dose of cytostatics increased by 2 times, consisting of cyclophosphamide, 5-fluorouracil and methotrexate, is incubated with an autolymph of the patient and administered intravenously, drip for 2 hours, 2 times a week with an interval of 2-3 days, only 4 procedures. The method allows to reduce the size of the tumor and the prevalence of the tumor process, however, the use of this method of treatment in the preoperative period does not affect the further prevention of recurrence of cancer of the uterus.

A known method of treating patients with locally advanced breast cancer using the method of automyelochemotherapy (AMXT), selected by us as a prototype (Nikolaeva N.V. Neoadjuvant autologous chemotherapy in the complex treatment of patients with locally advanced breast cancer. Abstract of dissertation for the degree of candidate honey Ph.D. Rostov-on-Don, 2003), including intravenous administration of chemotherapy on bone marrow suspension according to the scheme: cyclophosphamide 800 mg / m ² on the 1st and 8th days, doxorubicin 40 mg / m ² on the 1st and 8th days treatment, 5-fluorouracil 750 mg / m ² on the 1st and 8th days. Doxorubicin was incubated with a myelous suspension in a volume of 100 ml, cyclophosphamide and 5-fluorouracil were incubated in another vial with the same amount of myelous suspension. Incubation was carried out at a temperature of 37 ° C for 40 minutes, followed by intravenous drip. Efficiency was noted in 81.2% of cases, of which 6.2% - complete tumor regression, partial - in 75%. Analysis of toxic complications showed the absence of reactions caused by AMXT. Leukopenia was observed in 43.7% of cases, anemia was not observed. Neutropenia is noted in 34.3%. Complications such as stomatitis and diarrhea were absent.

The known method of AMXT allows to achieve in the preoperative period, in some cases, complete and often partial regression of the tumor, reduces leukopenia and toxicity of chemotherapy, but has never been used to treat relapse in cancer, especially not used to treat cancer patients in the treatment of relapse of ovarian and body cancer uterus.

The aim of the invention is to improve the immediate and immediate results of the treatment of patients with recurrence of ovarian cancer and cancer of the uterus.

The goal is achieved by the fact that these patients undergo trepanopuncture of the ilium wing, aspirate 150-200 ml of bone marrow suspension, incubate at 37 ° C for 40 minutes with chemotherapeutic agents: cisplatin, cyclophosphamide at doses higher than therapeutic; doxorubicin is not incubated with a bone-marrow suspension, chemotherapy is administered separately in the indicated order intravenously, drip on the day of collection of a bone-marrow suspension, the procedure is repeated with an interval of 3-4 weeks, only 4 times per treatment course.

The invention "A method for the treatment of relapses in gynecological oncology patients" is new, since it is unknown from the level of medicine, namely during chemotherapy of patients with relapses of ovarian cancer and uterine cancer.

The novelty of the invention lies in the fact that patients with relapses of ovarian cancer and endometrial cancer undergo trepanopuncture of the ilium wing, aspirate 150-200 ml of bone marrow suspension, incubate at 37 ° C for 40 minutes with chemotherapeutic agents: cisplatin, cyclophosphamide at doses higher than therapeutic; doxorubicin is not incubated with a bone-marrow suspension, chemotherapy is administered separately in the indicated order intravenously, drip on the day of collection of a bone-marrow suspension, the procedure is repeated with an interval of 3-4 weeks, only 4 times per treatment course. Thus, the novelty of the invention lies in the fact that none of the known methods of treatment for generalized forms of the development of a tumor process with relapses in ovarian cancer and endometrial cancer provides for the treatment of recurrence of ovarian cancer and uterine cancer using automyelochemotherapy. The method provides the ability to conduct a full course of chemotherapy, which is not always possible with conventional methods of chemotherapy, without nephrotoxicity, hematological complications.

Known methods of chemotherapy in gynecological oncology - autohemochemotherapy, autolymphochemotherapy - are usually used in the preoperative period of treatment and are not aimed at ensuring the effectiveness of treatment of recurrence of ovarian cancer and endometrial cancer, therefore our method differs significantly from the known treatment methods and goals.

The invention "A method for the treatment of relapses in gynecological oncology patients" is industrially applicable, as it can be repeatedly repeated and used in the treatment of relapses of ovarian cancer and endometrial cancer and reproduced in various medical institutions, especially oncology: oncology dispensaries, cancer research institutes.

“A method for the treatment of relapses in gynecological oncology patients” is performed as follows: after antiseptic treatment of the skin of the lumbosacral region, under local anesthesia with a 0.5% solution of novocaine, trepanopuncture of the ilium is performed and 150-200 ml of bone marrow suspension are aspirated. The resulting suspension is placed in a vial with glyugitsir. Bone marrow suspension is incubated with cisplatin at a dose of 150-200 mg / m ² and cyclophosphamide at a dose of 600-800 mg / m ² at a temperature of 37 ° C for 40 minutes, after which the patient is administered intravenously, drop by drop, against the background of hyperhydration and forced diuresis. Doxorubicin is not subject to incubation and is administered intravenously, dropwise at a dose of 60-70 mg / m ² . Polychemotherapy is carried out on the day of the collection of bone marrow suspension with an interval of 3-4 weeks.

An example of a specific implementation of the method can serve as extracts from medical records.

1. Patient Schepeleva G.M., born in 1960, was admitted to the gynecology department of the RNII on January 27, 2004 with complaints of periodically occurring pains in the lower abdomen.

From the anamnesis: sick since the end of 2001, when there were pains in the right hypochondrium, weight loss. In September 2002, the patient turned to the RNII, where during the examination the diagnosis of ovarian cancer was suspected. 09/10/2002, an operation was performed in the amount of supravaginal amputation of the uterus with appendages, omentectomy. The abdominal cavity is drained by microirrigators. Histological analysis No. 662080-81, 83-84: low-grade serous papillary cystadenocarcinoma, in the greater omentum - cancer metastasis of the above structure. In the postoperative period, from September 2002 to January 2003, the patient received 6 courses of intraperitoneal chemotherapy with platinum preparations and taxanes: cisplatin 150 mg / m ² , paclitaxel 210 mg / m ² . Until January 2004, I felt quite satisfactory. At the end of the month there were pains in the lower abdomen, the patient turned to the RNII.

On admission: general condition is relatively satisfactory. Height - 158 cm, weight - 85 kg. The skin is pale pink, dry. Peripheral lymph nodes, palpations available, not enlarged. Hemodynamics is stable. In the lungs, vesicular breathing. The abdomen is moderately painful in the lower sections, physiological functions are normal.

Status genitalis: external genitalia without features. In the mirrors: the cervix stump is clean, moderately mobile. PV: in the pelvis, at the site of the removed uterus and appendages, a dense, tuberous, inactive formation of 6.0 × 5.0 cm is palpated. The vaults are free.

Laboratory data: 1. General blood test dated January 28, 2004: Hemoglobin - 142 g / l, Red blood cells - 4.8 × 10 ¹² / l, White blood cells - 6.1 × 10 ⁹ / l, ESR - 16 mm / h, P ./poison. - 3.5%, C. / poison. - 59%, Eosinophils - 7.5%, Monocytes - 5%, Lymphocytes - 25%. 2. Biochemical analysis of blood from 01/28/2004: Glucose - 4.4 mmol / l; Urea - 4.7 mmol / l; Total protein - 73 g / l; Creatinine - 113.8 μmol / L; Alkaline phosphatase - 47.0 U / L. 3. Analysis of CA-125 from 01.20.2004: CA-125 = 160.0 U / ml. 4. Ultrasound of the organs of the abdominal cavity, pelvis from 01/20/2004, conclusion: postoperative, local recurrence of ovarian cancer 6.1 × 5.36 cm; diffuse changes in the liver, kidneys; chronic cholecystopancreatitis.

After the examination, the diagnosis was made: n / a ovarian cancer, St.IIIC, gr. 2, the state after complex treatment (operation + 6 XT courses). Local relapse. T _3c N ₁ M ₀ .

01/29/2004 1 course of automyelochemotherapy was carried out. For 150 ml of bone marrow suspension, 150 ml of cisplatin, 800 mg of cyclophosphamide were dripped. 60 mg of doxorubicin was administered intravenously. The patient underwent satisfactory administration of chemotherapy. 01/30/2004 nausea, single vomiting was noted. Detoxification therapy was carried out. 02.02.2004 the patient was discharged with appropriate recommendations. Appearance in RNII after 3 weeks for the 2nd course of AMHT.

02/19/2004 the patient arrived for the next course of chemotherapy. Complaints of minor weakness.

Objectively: the general condition is relatively satisfactory. Height - 158 cm, weight - 81 kg (weight loss of 4 kg is noted). The skin is pale pink, dry. Peripheral lymph nodes, palpations available, not enlarged.

Status genitalis: external genitalia - without features. The stump of the cervix in the mirrors is clean. PV: behind a stump of the cervix, a dense tuberous formation is determined about 4.0 cm in diameter. In the arches - freely.

Laboratory data: 1. General blood test dated February 19, 2004: Hemoglobin - 138.6 g / l; Red blood cells - 4.4 × 10 ¹² / l; White blood cells-4.5 × 10 ⁹ / l; ESR - 15 mm / h; P. / poison. - 10%; C. / poison. - 58%; Eosinophils - 1%; Basophils - 1%; Monocytes - 9%; Lymphocytes - 21%. 2. Blood biochemistry from 02/19/2004: Glucose - 4.4 mmol / l; Urea - 5.2 mmol / L; Total protein - 85 g / l; Creatinine - 95.3 μmol / L. 3. Analysis of CA-125 of 02.19.2004: CA-125 = 20.5 U / ml. 4. Ultrasound of the abdominal cavity, pelvis of 02/19/2004, conclusion: recurrence of p / o ovarian cancer - a hypoechogenic formation with uneven, fuzzy contours up to 4.0 cm in diameter is located posterior to the cervical stump.

After the examination, the diagnosis was made: n / a ovarian cancer, St.IIIC, gr. 2, the state after complex treatment. Local relapse, condition after 1 course of AMXT of the ^2nd line T _3c N ₁ M ₀ . Partial tumor regression.

2. Patient Kramarenko LS, born in 1950, was admitted to the Department of Gynecology, RNII on 01.01.2004 with complaints of pain in the lower abdomen, spotting from the genital tract, pain in the lumbar region on the left, fever up to 38 C. From anamnesis: has been sick since 2000, when pain first appeared in the lower abdomen, weakness. Since January 2002 - heavy periods. Surveyed at the Oncology Center of Mariupol, where on May 29, 2002, an operation was performed in the amount of panhisterectomy for cancer of the uterus. Histological analysis No. 12552: moderately differentiated adenocarcinoma. In the n / a period, combined radiation treatment was performed. Until January 2003, the patient felt satisfactory, then there were spotting from the genital tract, pain in the lower abdomen. A repeated course of intracavitary Co-therapy was carried out in the area of the scar scar (SOD = 60 Gy). Treatment without effect. The patient herself came to the RNII for treatment.

Objectively: the general condition is relatively satisfactory. Height - 165 cm, weight - 95 kg. The skin is of normal color, moist. Peripheral lymph nodes, palpations available, not enlarged. Hemodynamics is stable. In the lungs, vesicular breathing. The abdomen is soft, painful on palpation in the lower sections. Stool, diuresis is normal.

Status genitalis: external genitalia without features. The vagina ends with a "blind sac", from the genital tract moderate spotting. PV: the vaginal stump is fixed, sharply painful, tuberous. In place of the removed uterus - relapse of 7.0 × 3.0 cm. Infiltration of the parameters is pronounced, on the left - almost to the walls of the pelvis.

Laboratory data: 1. General blood test dated 12.01.2004: Hemoglobin - 124 g / l; Red blood cells - 4.1 × 10 ¹² / l; White blood cells - 5.0 × 10 ⁹ / l; Platelets - 221.4 × 10 ⁹ / L (54 ‰); P. / poison. - 60%; C. / poison. - 9%; Eosinophils - 3%; Monocytes - 9.5%; Lymphocytes - 18.5%. 2. Blood biochemistry from 01/12/2004: Glucose - 5.2 mmol / l; Urea - 3.2 mmol / L; Total protein - 73 g / l; Creatinine - 118 μmol / L; Alkaline phosphatase - 16.2 U / L. 3. Ultrasound of the abdominal cavity, pelvis of 01/14/2004, conclusion: recurrence of cancer of the uterine body 3.78 × 4.2 × 7.0 cm, hydronephrosis on the left, hepatomegaly, diffuse changes in the liver, chronic cholecystopancreatitis.

After the examination, the diagnosis was made: n / a cancer of the uterus of the uterus St.IIIA, column 2, condition after complex treatment. Local relapse. T _3a N ₀ M ₀

01/27/2004 1 course of AMHT. For 200 ml of bone marrow suspension introduced: 200 mg of cisplatin; 800 mg cyclophosphamide. 70 mg of doxorubicin was administered intravenously. The patient endured the introduction of drugs satisfactorily. In the next three days, nausea, vomiting was not observed in the patient, the general condition was assessed as quite satisfactory. Significantly decreased bleeding from the genital tract, decreased pain. On 2.02.2004, the patient was discharged in satisfactory condition with the following recommendations: oncologist's supervision at the place of residence, monitoring of the level of white blood cells once a week. Appearance in RNII after 3 weeks for the 2nd course of AMHT.

02/26/2002 the patient was hospitalized in the Department of Gynecology for 2 courses AMHT. Complaints of scanty, sacred nature, discharge from the genital tract, minor pain in the lumbar region on the left. In general, the patient notes a significant improvement in well-being (absence of pain during urination, reduction of pain in the lower abdomen).

Laboratory data: 1. General blood test dated February 26, 2004: Hemoglobin - 110.4 g / l; Red blood cells - 3.9 × 10 ¹² / l; White blood cells - 3.0 × 10 ⁹ / l; Platelets - 245.7 × 10 ⁹ / L (63 ‰); ESR-25 mm / h; P. / poison. - 14.5%; C. / poison. - 58%; Eosinophils - 0.5%; Monocytes - 9.0%; Lymphocytes - 17.5%. 2. Blood biochemistry from 02.26.2004: Glucose - 4.4 mmol / l; Urea - 3.7 mmol / L; Total protein - 73 g / l; Alkaline phosphatase - 32.3 U / L. 3. Ultrasound of the organs of the abdominal cavity, pelvis from 03/01/2004, conclusion: relapse of cancer of the uterine body 3.47 × 4.55 × 4.62 cm, hydronephrosis on the left, chronic cholecystopancreatitis.

After the examination, the diagnosis was made: n / a endometrial cancer, St.IIIA, column 2, condition after complex treatment. Local relapse, condition after 1 course of AMXT. T _3a N ₀ M ₀ . Partial tumor regression.

The proposed method treated 11 patients with relapse of ovarian cancer, 2 patients with relapse of endometrial cancer. At the same time, gastroenterological complications occurred - nausea, vomiting in 5 patients, which amounted to 38.4%. In no case was nephrotoxicity observed. Hematological complications in the form of mild leukopenia were noted in 2 patients (15.3%). In all cases, treatment was effective - partial tumor regression was noted in 9 patients (69.2%); complete regression - in 4 patients (30.8%). The progression of the disease was not observed in any case.

The technical and economic effectiveness of the “Method for the treatment of relapses in cancer patients” lies in the possibility of treating patients of this category in the absence of the effect of previously used chemotherapy methods; significantly reduce toxic adverse reactions.

Claims (1)

A method of treating relapse in gynecological oncological patients, including chemotherapy, characterized in that the patients undergo trepanopuncture of the ilium wing, are aspirated with 150-200 ml of bone marrow suspension, incubated at 37 ° C for 40 min with chemotherapy drugs: cisplatin, cyclophosphamide at doses higher than therapeutic ; doxorubicin is not incubated with a bone-marrow suspension, chemotherapy is administered separately in the indicated order intravenously, drip on the day of collection of a bone-marrow suspension, the procedure is repeated with an interval of 3-4 weeks, only 4 times per treatment course.