RU2243766C1 - Method for treating relapses of uterine cervix cancer - Google Patents

Abstract

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1^st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5^th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B₁₂ solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

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Description

The invention relates to medicine, namely to oncology, and can be used for the treatment of patients with cervical cancer with relapses in parametric tissue and the absence of the possibility of radical surgery and the effect of previous radiation therapy.

It is known to treat relapse of cervical cancer using ionizing radiation with previous antitumor chemotherapy or without the latter (Y. V. Bohman "Guide to Oncogynecology. L.," Medicine ", 1989).

As the author himself points out, radiation therapy in full, in the absence of a significant effect in a large number of cases, leads to complications in the form of vaginal and rectal-vaginal fistulas. Patients are exposed to unjustified harmful effects of radiation.

Chemotherapy for cervical cancer during its relapse is not widespread due to the resistance of the tumor to cytostatics and their high toxicity, which is extremely important for this group of patients.

It should be noted that the prognosis in patients with recurrence of cervical cancer is very poor, only 10-15% of patients survive one year after their manifestation. With parametric relapses of cervical cancer, surgery in a radical volume is not technically feasible and biologically justified. When choosing a method of radiation therapy, the features of primary treatment are of most importance. In cases of ineffective radiation treatment carried out earlier in full, a pronounced tumor resistance develops.

Only the use of sufficiently large total absorbed doses supplied to the recurrent node in the parameters can lead to a long-term cure, and this, as a rule, is not possible due to the fact that the dose-tolerant load of healthy tissues, including adjacent organs, is practically exhausted.

There is a method of treating parametric recurrence of cervical cancer (Efimov A.G. "Medical rehabilitation of elderly patients with cervical cancer after combined radiation therapy" Author. Diss .... Ph.D. Medical Sciences., Rostov-on-Don, 2001 ), including intravenous administration of platidiam at a dose of 120 mg / m ² in the form of a one-hour infusion and intramuscular administration of prospidine at a dose of 200 mg every other day to a total dose of 2 g. Platidiam was dissolved in physiological saline and injected against the background of hyperhydration, i.e. after transfusion of two liters of saline for one hour, after which one liter of saline was injected with 30 mg of mannitol for 30 minutes. To improve treatment tolerance, 30 mg of prednisolone and 2 ml of relanium were administered 30 minutes before the infusion of platidimam; two hours after the end of platidiam administration, 10 mg of cerucal, 2 ml of droperidol and 2 ml of relanium were intramuscularly administered. The interval between courses was 4 weeks. The number of courses was determined during chemotherapy, taking into account the effect of the treatment and the condition of the patients.

However, the effectiveness of using this scheme for recurrent cervical cancer according to the author does not exceed 40%, and the percentage of complete regression is 12.5%. Stabilization of the growth of the recurrent lesion was noted in 19% of patients, and the progression of the process during treatment was observed in 44% of patients. The second significant drawback of the use of chemotherapy regimens, including platinum preparations, is their high toxicity. Complications typical of the used doses of cytostatics were observed in 70% of patients. The treatment of these complications is laborious and expensive.

The aim of the present invention is to improve the immediate and long-term results of the treatment of patients with recurrence of cervical cancer in parametric fiber.

The goal was achieved by the fact that on the first day of treatment, 150 ml of blood is taken from the ulnar vein into a sterile standard vial containing the anticoagulant glugycyr. 30 mg of platidiam is added to the same vial and incubated for 1 hour at 37 ° C followed by reinfusion of the contents of the vial with an intravenous drip. On the second, third and fourth days of treatment, patients received daily remote gamma therapy for pelvic organs in a single dose of 2.6 Gy (for three days - 7.8 Gy). On the fifth day of treatment, patients are injected into the sacral space: 60 ml of a 0.5% solution of novocaine; 1 ml of a suspension of hydrocortisone; 2 ml of a 50% solution of dipyrone; 1 ml of 0.01% solution of vitamin B ₁₂ ; 1.6 g of gentamicin; 800 mg cyclophosphamide; 10 mg methotrexate. Therapeutic effects are carried out in the indicated sequence 4 times.

Analysis of known methods for the treatment of recurrence of cervical cancer and developed allows us to state that the proposed method has novelty. The novelty of the method lies in the stimulation of the body's immune system and radiosensitization by the administered complex of drugs.

In available sources of information from Russia, the CIS countries and abroad, no indications of a similar method for improving the immediate results of treatment of parametric relapses of cervical cancer were found.

The invention is industrially applicable, as it can be repeatedly reproduced and repeated in healthcare, in medical institutions of a specialized and therapeutic profile.

The method is as follows.

After conducting a bimanual and ultrasound examination of the pelvic organs, patients with an established diagnosis of cervical cancer recurrence are administered antitumor chemotherapy drugs. From the peripheral vein, 150 ml of the patient’s blood is taken into a vial with 50 ml of glucicir, 30 mg of cisplatin is added, the resulting mixture is incubated at 37 ° C for 1 hour. Then, against the background of standard hyperhydration, the resulting mixture is reinfused. In the second, third and fourth days of treatment, remote gamotherapy is performed on the pelvic organs in a single dose of 2.6 Gy. On the fifth day, 60 ml of a 0.5% solution of novocaine, 1 ml of a suspension of hydrocortisone, 2 ml of a 50% solution of dipyrone, 1 ml of a 0.01% solution of vitamin B ₁₂ , 1.6 g of gentamicin, 800 mg of cyclophosphane and 10 mg methotrexate. All of the listed therapeutic effects are performed in the listed sequence four times.

To prove this, we provide an extract from the medical history confirming the clinical effect of the treatment by the proposed method. An example of clinical application.

1. Patient S., born in 1944 (source of illness No. 6571 / l), is under the supervision of RNII since 05.19.98. Diagnosis: cervical cancer T3NxMo, mixed growth, vaginal-parametric variant. Histoanalysis No. 12977 of 05/19/98 - squamous cell carcinoma with keratinization.

In the period from 05/21/98 to 07/15/98 received combined radiation treatment. Remote gamma therapy on the pelvic area was carried out in a static mode with a single focal dose of 2 Gy to the total dose at point A - 20 Gy, at point B - 42 Gy. Intracavitary Co ⁶⁰ therapy was carried out on AGAT-B with a single dose of 5 Gy with an irradiation rhythm 3 times a week to the total dose at point A 50 Gy and at point B 16.7 Gy. The treatment is completed with a primary clinical recovery. There were no early radiation reactions in the treatment process.

After 10 months of follow-up, at a turnaround 12.05.99 for examination, complaints of drawing pains in the lower abdomen with radiation to the left lower limb, pain in the lumbar region. These complaints worry the patient over the past month. Signs of intoxication syndrome are weakly expressed in the form of subfebrile temperature in the evenings to 37.3 ° C, decreased appetite, weakness.

Local status. The vagina is an adhesive process, normal tissue, clean. The line of adhesion of the walls of the vagina without seals. The cervix is dense, without pathological seals, fixed to the left arch. The uterus is of normal size, dense, painless, limited in mobility. The degree of mobility of the pelvic floor is 0.5 cm. Appendages are not determined. In the parametric space on the right, cicatricial heaviness. On the left, dense fiber infiltration is determined, which performs the parametric space from the uterine rib to the walls of the pelvis, pain on examination. A puncture biopsy of this site was performed.

Cytological examination of punctured parametric space on the left No. 27255-56 of 05/12/99 - erythrocytes, among polymorphic inflammatory cells, single squamous cell cancer cells were found.

Ultrasound of the pelvic organs from 13.05..99 the volume of the cervix is 29.5 cm ³ , the uterus and appendages correspond to standard values. To the left, an enlarged lymph node up to 2.5 cm in diameter is located in the area of the internal iliac artery.

In color and energy Doppler mapping, the area to the pelvic walls with multiple vascular components of an irregular conglomerate type, characterized by the presence of convoluted vessels with arterio-arterial, arteriovenous anastomoses, is located to the left of the cervix. Dopplerometry of pathological vascular loci records low-resistance arterial blood flow with average resistance index values of 0.51.

With the CG image (05/14/99) on the left, in the projection of the parametry, focal changes of an unevenly chaotic nature in diameter from 0.3 to 0.9 cm are determined. The diffuse component of infiltration, which does not go beyond the limits of fat density (45 units N.), is in contact with the muscular wall of the pelvis.

General blood test from 05/12/99. HB - 98 g / l. Er - 3.9 × 10 ¹² / l, Cp - 0.9; Lake - 6.0 × 10 ⁹ / l, eos. - 2%, fell. - 6%, seg. - 58%, lymph - 26% (abs lymph 1.56 × 10 ⁹ / l), mon - 8% (abs. Mon 0.48 × 10 ⁹ / l), ESR - 24 mm / hour.

In a standard examination, including a chest X-ray, an ultrasound of the liver, kidneys, there were no signs of distant metastasis.

Clinical diagnosis - Cervical cancer TzNxMo, cl. column II. Condition after combined radiation therapy. Relapse of cervical cancer in the left parametrium.

Treatment started. Autohemochemotherapy was carried out once a week: 05/17/99; 05/24/99; 05/31/99 and 06/07/99. Intravenously with a standard hydration regimen, 30 mg of cisplatin was introduced, incubated at 37 ° C for 1 hour with 150 ml of patient’s autologous blood

Presacral injections of 800 mg of cyclophosphamide and 10 mg of methotrexate each in the composition - 0.5% novocaine solution - 60 ml, gentamicin 1.6 g, suspension of hydrocortisone acetate 2.5% - 1.0; cyancobalamin (Vit B ₁₂ ) 0.01% - 1.0 ml, dipyrone 50% - 2.0 ml carried out once a week: 05/21/99; 05/28/99; 06/04/99 and 05/11/99.

On the remaining days, namely (May 18–20, 99; May 25–27, 99; June 1–6, and June 10–99,), remote gamma-therapy was performed in the 2-axis sector rotation mode (fields 7 × 16 cm, distance between rotation axes 6 cm, RIO 75 cm, swing angle 180 °). A single focal dose of 2.6 Gy was administered on the 2nd, 3rd and 4th days of the week, i.e. the day after the course of autohemochemotherapy and before the presacral administration of a mixture of cytostatics during all four weeks of anti-relapse chemoradiation treatment. In total, cytostatics were obtained for the entire treatment cycle: 120 mg of cisplatin, 3200 mg of cyclophosphamide, 40 mg of methotrexate. The total focal dose for both parameters was 31.2 Gy, which corresponds to the biological effect of 34 Gy with standard fractionation of a single dose of 2 Gy.

General toxic manifestations were absent during treatment. General blood test from 06/14/99. HB - 96 g / l, Er - 4.0 × 10 ¹² l, CPU - 0.82; Lake - 4.4 × 10 ⁹ / l, eos. - 1%, fell. - 13%, seg. - 55%, lymph - 26% (abs lymph 1.14 × 10 ⁹ / l), mon - 5% (abs mon 0.22 × 10 ⁹ / l), ESR - 14 mm / hour.

Blood biochemical parameters:

05/14/99 g. 05/31/99 g. June 14, 1999 urea 5.3 mmol / l 7.2 mmol / l 6.1 mmol / l creatinine 95.3 μmol / L 113.1 μmol / L 102.1 μmol / L total protein 63 g / l 67 g / l 63 g / l bilirubin: common 5.7 μmol / L 8.5 μmol / L 8.5 μmol / L free not determined not determined not determined connected 5.7 μmol / L 8.5 μmol / L 8.5 μmol / L ALT-alaninamio-transfrerase 0.4 mmol / l 0.2 mmol / l 0.2 mmol / l medium molecules masses 0.32 units 0.23 units 0.25 units

Local status at checkout. The vagina is an adhesive process, normal tissue, clean. The line of adhesion of the walls of the vagina without seals. Inspection through the rectum. The cervix is dense, without pathological seals. The uterus is of normal size, dense, painless. The degree of mobility of the pelvic floor is 1.4 cm. Appendages are not determined. In parametric spaces on the right and left cicatricial stiffness. There are no signs of fiber infiltration. The study is painless.

Discharged from hospital with clinical recovery. With a turnout 1 month after treatment, there are no complaints. Surveyed.

Ultrasound of the pelvic organs from 12.07.99 (a month after completion of treatment) the volume of the cervix is 27.5 cm ³ , the uterus and appendages correspond to standard values. Signs of damage to the retroperitoneal lymph nodes were not detected.

With color and energy Doppler mapping, positive dynamics were noted. The hypovascular type of blood flow is determined, single color loci and arteriovenous shunts are preserved. The architectonics of the vessels is preserved, without structural changes. In the spectral assessment of blood flow, the resistance index is 0.82. With a CT image (07/14/99) of the parametric space, the same type of cluster-like focal-like structures are determined with a vascular version of the structure.

With a clinical diagnosis - Cervical Cancer TzNxMo, class. column III. Condition after combined radiation therapy in 1998. Chemotherapy for the treatment of parametric cervical cancer recurrence in 1999. It is observed until January 2003, i.e. within 42 months, without signs of relapse and metastases.

The proposed method was carried out the treatment of 45 patients with recurrence of cervical cancer in the parametric tissue. Before and after treatment, all patients underwent examination in the mirrors, rectovaginal examination, general and biochemical blood tests, chest x-ray and excretory urography, radioisotope examination of kidney function, ultrasound examination and computer homogram of the pelvic organs, pelvic and para-aortic lymphatic system departments, puncture biopsy with cytological examination.

The effectiveness of the proposed treatment method was 70%, of which in 56% of cases there was a complete regression and in 14% a partial regression of the recurrent tumor. Process stabilization is recorded at 30%. The progression of the process was not detected in any case. The survival rate of 16 patients was 40-45 months.

The improvement of treatment results seems to us to be a combination of various positive factors consisting in an increase in the local concentration of chemotherapeutic agents, against the background of objectively reduced indicators of their general toxic effect, the sensitizing effect of small doses of platidiam in relation to ionizing radiation, and the activation of immunocompetent cells of the body under the action of small doses of methotrexate . An additional positive effect occurs due to the termination of the conduction of impulses along sensitive nerve fibers under the action of novocaine, which, without significantly changing the resting potential of nerve fibers, inhibits the generation and distribution of the action potential, which causes a kind of membrane stabilization associated with the ability of local anesthetics to penetrate the lipid layer cell membranes. Stabilization of cell membranes in turn leads to local deposition of cytostatics in the zone of recurrent growth. This occurs against the background of anti-inflammatory therapy and analgesic effect, which is also extremely important for such a contingent of patients.

Technical and economic efficiency of the “Method for the treatment of recurrence of cervical cancer” is that:

- the duration increases and the quality of life of patients improves;

- reduced radiation exposure and toxic side effects of antitumor therapy;

- A large percentage of tumor regression is achieved.

Claims (1)

A method for treating cervical cancer relapses, including the use of chemotherapeutic agents combined with autologous blood and external radiation, characterized in that 30 mg of platidiam, incubated for 1 hour at 37 ° C with 150 ml of autologous blood, is intravenously administered on the first day of treatment, and the next three days are carried out external irradiation of 2.6 Gy; on the fifth day, the composition is injected into the sacral space: 60 ml of a 0.5% solution of novocaine, 1 ml of a suspension of hydrocortisone, 2 ml of a 50% solution of dipyrone, 1 ml of 0.01% a solution of vitamin B ₁₂ , 1.6 g of gentamicin, 800 mg of cyclophosphamide, 10 mg m etotrexate, therapeutic effects are repeated four times in the indicated sequence.