RU2185858C1 - Method for treating malignant uterine tumors - Google Patents

Abstract

FIELD: medicine, oncogynecology. SUBSTANCE: the method deals with catheterization of the inner iliac arteries alternately during one angiographic procedure due to access from one femoral artery. Embolization of iliac arteries is carried out. It is conducted the bolus introduction of chemopreparations together with finely reduced hemostatic sponge into each iliac artery. Detoxication therapy is performed during 1.5-2 h after introduction of chemopreparations. Ray therapy is additionally conducted in 2-3 wk after regional bolus chemotherapy. The method enables to decrease traumaticity and intraoperational complications. EFFECT: higher efficiency of therapy. 3 cl, 1 ex

Description

 The invention relates to medicine, more specifically to gynecological oncology, and may find application in the treatment of locally advanced malignant tumors of the cervix and uterine body.

 Malignant tumors of the uterus take fourth, and the cervix is one of the first places among oncological diseases in terms of morbidity and mortality in women. Despite the widespread introduction of early diagnosis methods, at least 30-50% of cases are detected in the III-IV stage, when the effectiveness of all existing treatment methods is significantly reduced. Relapse of the disease is diagnosed during the first two years after the start of treatment in 5-30% of patients with stages III-IV, and 1-year survival is 10-15%. It is for this category of patients that the development of new and improvement of existing methods of treatment is of greatest relevance. This problem is dedicated to the present invention. And although it concerns the treatment of tumors of the cervix and uterine body, our proposed method can equally be used in the treatment of other tumors of the pelvic organs.

 One of the main methods of treating cervical and uterine cancer is radiation therapy. It is carried out by different schemes: remote irradiation of a tumor at a dose of 2 Gy to a total focal dose (SOD) of 40 to 70 Gy or a combination of intracavitary irradiation to the primary focus at a dose of 5-8 Gy 1-2 times a week to SOD 42-56 Gy and remote to the region of regional metastasis at a dose of 2 Gy 4 times a week to SOD 40-44 Gy. However, in the case of significant local spread of the tumor, the use of radiation therapy as an independent treatment option is often insufficient [Romanchishen A.V., Zharinov G.M. "Oncology course", S. Petersburg, 1999, S. 256.].

 The most widely used method for the treatment of locally advanced cervical and uterine tumors is a combination of radiation and systemic chemotherapy. So, with uterine cancer, platinum, doxorubicin and cyclophosphamide are most often used. However, these drugs have high systemic toxicity and can cause myelosuppression, lead to nephro- and neuropathy, as well as toxic lesions of the mucous membranes and renal failure.

 Known methods of regional administration of cytostatics, providing for relatively low general toxicity, the creation in the tumor of a high concentration of a chemotherapeutic drug due to its passage through the circulatory system of the tumor. Direct administration of a chemotherapy drug to the arteries that feed the tumor can reduce systemic toxicity by about half.

Closer to the proposed is a method of treating cervical tumors by combining regional chemotherapy with radiation exposure [Thomas J. Et al., Gynecologic Oncology, 1991, 42, P.54-59]. The method consists in performing bilateral catheterization of the femoral arteries. Catheters are inserted into the anterior portions of the internal iliac arteries (VPA) and 30 mg / m ² bleomycin are administered through them for 24 hours, then 100 mg / m ² cis-platinum, 2 mg vincristine intravenously and 10 mg / m ^{2 of} mitomycin intraarterially. During the entire chemotherapy procedure, the patient is injected intraarterially with 2 L of physiological saline. After removal of the catheters, the patient needs to be in a horizontal position for at least 12 hours. 4-6 weeks after the regional administration of cytostatics, radiation treatment is carried out in the form of photon therapy in total doses of 40-50 Gy or neutron therapy up to 60 Gy. If necessary, regional chemotherapy is repeated after 3-4 weeks.

 This method provides a partial response (reduction of the tumor by more than 50%) in 52%, a complete response (complete disappearance of the tumor) in 24%, stabilization of 24% and tumor progression of 4%. 5-year survival rate was 30%.

 However, a serious drawback of this method is the invasiveness of the procedure and the risk of complications associated with arterial puncture and a catheter in both femoral arteries for a long time, which does not exclude the possibility of thrombosis of the great vessels, bleeding, hematomas or false aneurysms at the puncture site.

 Closest to the proposed is the "Method of regional bolus chemotherapy for uterine cancer" (Yu.V. Suvorova et al. Materials of the scientific-practical conference "Modern radiation diagnostics and radiation therapy", 1997, pp. 149-151, Chelyabinsk) taken by us as a prototype.

The method consists in the fact that the patient performs pelvic arteriography, the degree of vascularization and the sources of blood supply to the tumor are assessed on angiograms. Then, access from one femoral artery catheterizes the internal iliac arteries (VPA) in turn. After installing a catheter at the mouth of a tumor-feeding vessel, chemotherapy is administered for 10 minutes under the control of fluoroscopy. Depending on the histological picture of the tumor, cis-platinum (75-120 mg), doxorubicin (25-60 mg), cyclophosphamide (400-600 mg) are used, while the dose of the chemotherapy administered depends on the hematological parameters. With the hypervascular nature of the tumor, the front portions of the VPA are embolized with particles of polyvinyl alcohol (ayvalon) or a finely chopped hemostatic sponge. If it is not possible to selectively catheterize the visceral branches of the VPA, metal spirals are inserted before the administration of chemotherapeutic agents and small particles of the embolizate into the obturator and superior gluteal arteries. After the procedure, which takes an average of 1.5 hours, the catheter is removed. Over the next 2-3 days, patients have minor dyspeptic disorders in the form of nausea and vomiting, pulling pains in the lower abdomen and a rise in temperature to 38 ^o C.

 Compared with the foregoing method, the prototype is significantly less traumatic due to access from one femoral artery and bolus administration of chemotherapeutic agents, which reduces the procedure time by 2–3 times. However, the massive introduction of chemotherapy, despite the embolization of the iliac arteries, causes a general toxic effect, while the severity of toxic manifestations is associated with the dose of the chemotherapy administered. In addition, the implementation of one chemotherapeutic treatment in the prototype method, especially in the advanced stages of the disease, has an insufficient antitumor effect and often leads to a relapse of the disease.

 The technical result of the present invention is to enhance the antitumor and reduce the toxic effects due to the additional conduct of radiation and detoxification therapy.

 This result is achieved by the fact that in the known method for treating malignant uterine tumors, including catheterization of the internal iliac arteries alternately during one angiographic procedure by access from one femoral artery, subsequent embolization of the iliac arteries and bolus administration of chemotherapy drugs into each of them mixed with a finely chopped hemostatic sponge , according to the invention, detoxification therapy is carried out within 1-2 hours before and 1.5-2 hours after the administration of chemotherapy, and 2-3 weeks after reg onary bolus chemotherapy additionally carry out radiation therapy.

 It is advisable to carry out radiation therapy by combining intracavitary irradiation of the primary lesion at a dose of 7 Gy once a week to a total focal dose of 42-49 Gy and remote therapy to the region of regional lymph nodes at a dose of 2 Gy 4 times a week to a total dose of 40-44 Gy.

It is also advisable to use 100-150 mg of cis-platinum, 1 g of cyclophosphamide and 40-60 mg of doxorubicin with the addition of 0.25-0.5 cm ^{3 of} finely chopped hemostatic sponge per 100 ml of chemotherapeutic solution as chemotherapeutic agents.

 Conducting detoxification therapy within 1-2 hours before and additionally within 1.5-2 hours after the bolus administration of chemotherapy reduces their possible toxic effect on the patient's body, excluding the dilution of chemotherapy drugs at the time of their bolus administration, taken to increase and prolongation of antitumor activity.

 Additional radiation therapy certainly enhances the antitumor effect, and its implementation 2-3 weeks after a course of regional chemotherapy due to the time of restoration of blood counts. As we have shown in the treatment of patients, 2-3 weeks are the best time to start it without the risk of serious complications from the blood. Later radiation therapy, as a rule, reduces the effectiveness of treatment.

 Performing various traditional radiation treatment regimens, we give preference to combined radiation therapy, which includes intracavitary irradiation of the primary focus 1 time per week at a dose of 7 Gy to a total focal dose (SOD) of 42-49 Gy and remote from two opposite fields 4 times a week in a dose of 2 Gy to SOD 40-44 Gy.

 The use of cis-platinum, cyclophosphamide and doxorubicin as recommended chemotherapy in the recommended doses is due to the highest sensitivity of cervical and uterine tumors to them.

 As our clinical observations have shown, to date, in 43 patients with cervical and uterine body cancer, the combination of radiation therapy with bolus chemotherapy and detoxification therapy in the regimes we proposed allowed us to achieve for the first time a partial and complete response to treatment in 80% of patients III-IV Art. tumor process and two-year survival of such patients in 58%, which distinguishes the proposed method from the known.

 If continued tumor growth is detected, it is advisable to repeat the intervention procedure after 3-4 weeks, which increases the reliability of treatment.

 The essence of the method is as follows.

A patient with a verified diagnosis of cervical and / or uterine body cancer is rehydrated by intravenous administration of Ringer, glucose and sodium chloride solutions for 1-2 hours and regional bolus chemotherapy is performed in the angiography room, for which access from one femoral artery (for example, the right one) Seldinger catheterizes the aorta. On a series of angiograms, the site of hypervascularization in the projection of the organ to be affected is noted. After the diagnostic phase of the study, the catheter is replaced with another and set it in the front portion of the left VPA. Over the next 5-7 minutes, 50-75 mg of cis-platinum, 0.5 g of cyclophosphamide and 20-30 mg of doxorubicin in 50 ml of physiological saline are added with the addition of 0.25 cm ³ finely chopped hemostatic sponge, after which the VPA is embolized the same sponge. After that, the same catheter is moved to the front portion of the right VPA, the same chemotherapy drugs are injected in the same volume and the VPA is also embolized. At the end of the procedure, the catheter is removed and after hemostasis, an aseptic pressure dressing is applied to the puncture area. After the patient is transferred to the clinical department, she is post-hydrated for 1.5-2 hours by intravenous administration of solutions of Ringer, sodium chloride and mannitol.

 After 2-3 weeks, the patient is given combined radiation therapy, and 3-4 weeks after it, if necessary, repeat regional chemotherapy in the same modes.

 The essence of the method is illustrated by example.

 Patient B., 62 years old, was admitted to the gynecology department of the TsNIRRI clinic on 09/07/99 with complaints of aching pain in the lower abdomen, lower back and spotting from the genital tract over the past year.

 When viewed in the mirrors: the neck is destroyed by a tumor and bleeds profusely.

 During vaginal and rectal examination: the cervix is hypertrophied, the fundus of the uterus is not palpable, the parameters on the right are somewhat infiltrated, and on the left, the infiltration reaches the walls of the pelvis.

 According to the results of a histological examination from 09.09.99 - moderately differentiated adenocarcinoma.

 September 22, 1999, magnetic resonance imaging (MRI) was performed - the uterus was enlarged to 120 mm in length, the body across - 60 mm, the cervix was expanded to 50x49 mm. The uterine cavity is dilated, the wall is filtered by a tumor, the thickness of the myometrium is 10 mm. The cervical canal is occluded. On the left is a conglomerate of lymph nodes 30x25 mm, on the right (near the walls of the pelvis) - 20x20 mm.

Based on the data of an objective examination of the patient, the diagnosis was established: a cervical tumor with a transition to the body lll st (T ₃ N _X M ₀ ). Moderately differentiated adenocarcinoma of the endometrium and cervix.

Despite the presence of chronic bleeding on September 27, 1999, her hemoglobin index was 117 g / l, the number of red blood cells was 3.9 • 10 ¹² / l, the number of leukocytes was 5.6 • 10 ⁹ / l, and the platelet count was 273 • 10%, which allowed her to start a specific treatment. September 28, 1999 the patient underwent regional chemotherapy. For this, 2 hours before the angiographic procedure, the patient was injected intravenously with 200.0 ml of 5% glucose solution, 400 ml of Ringer's solution, 500 ml of 0.9% sodium chloride solution within 1 hour. In the angiography room, access from the right femoral artery by Seldinger performed aortic catheterization. On a series of angiograms, a site of hypervascularization was noted in the projection of the uterus, which supplies blood from the branches of the front portions of the VPA. After that, the catheter was replaced with another and installed in the front portion of the left VPA. Over the next 5 minutes, 50 mg of cis-platinum, 0.5 g of cyclophosphamide and 30 mg of doxorubicin were injected into 50 ml of physiological saline mixed with 0.25 cm ^{3 of} finely chopped hemostatic sponge soaked in 96 ^o ethanol, after which the same catheter was transferred to the front portion of the right VPA and introduced the same solution with a sponge and in the same volume. At the end of the administration of chemotherapy, the catheter was removed and after hemostasis, an aseptic pressure bandage was applied to the area of the right groin. In the patient’s department, 400 ml of Ringer's solution were injected intravenously, 400 ml of 0.9% sodium chloride and 400 ml of mannitol for 1.5 hours. In the next day, the patient was bothered by moderate pain in the pelvic area and nausea, there were no bloody discharge from the genital tract.

 20 hours after regional therapy (09/29/99), the pressure bandage applied after removal of the catheter was removed. In the area of the puncture, the pulsation of the femoral artery is distinct, the color of the skin is not changed, pathological formations in the projection of the punctured vessel are not noted.

Pain in the pelvic area went away on its own over the next two days. 6 days after the procedure (10/04/99), a slight decrease in hemoglobin to 104 g / l, the number of red blood cells - 3.5 • 10 ¹² / l, white blood cells - 2.7 • 10 ⁹ / l, platelets - 210 • 10 ⁹ / l After normalizing the blood picture on 10/11/99, on the 13th day after the regional therapy (hemoglobin - 115 g / l, the number of red blood cells - 3.9 • 10 ¹² / l, white blood cells - 4.1 • 10 ⁹ / l, platelets - 259 • 10 ⁹ / l) combined radiation therapy has been started. 6 sessions of intracavitary irradiation were performed on the zone of the primary focus of 7 Gy 1 time per week to a total dose of 42 Gy. And 20 sessions of remote irradiation from two opposite fields to the zone of regional lymph nodes, 2 Gy 4 times a week to a total dose of 40 Gy.

 According to MRI (13.10.99), a decrease in the size of the uterus to 100 mm was noted (body across 50 mm, cervix 40x43 mm). The cervical canal is visualized with a length of 30 mm.

 On 10.28.99 (a month after the course of regional therapy), histological examination of aspirate from the uterine cavity revealed single tumor cells, and in the scraping from the cervix uteri, single dystrophic bare nuclei were noted among leukocytes. When viewed in the mirrors: the cervix is formed, elastic, not hyperemic.

 Repeated histological examination on 11/19/99 revealed atypical cells suspicious of tumor cells among white blood cells and red blood cells.

 12/02/99 when viewed in the mirrors: the cervix with mild symptoms of radiation epithelitis, the vaginal mucosa is easily vulnerable, with vaginal and rectal examination: the cervix is elastic, up to 1.5 cm long, the uterine body is slightly enlarged, limited, displaced. On the right, the parameter is free. On the left, infiltration persists to the walls of the pelvis. Histological examination 03.12.99 no tumor elements were found. The patient was discharged in satisfactory condition 03.12.99. The result of treatment is regarded as the primary clinical cure.

 During a follow-up examination in November 2000, data for a relapse of the disease were not obtained.

 To date, the above method has been treated 43 patients with cancer of the cervix and uterine body of III-IV art. with a positive result. Postembolization complications were not noted. A partial and complete response to treatment was noted in 80% of patients, and two-year survival rate was 58%.

 The proposed method in comparison with the known has several advantages, the main of which is a significant reduction in the overall toxic effect due to additional detoxification therapy. In addition, the combination of radiation therapy with bolus administration of chemotherapy provides the most effective antitumor effect.

 The proposed method was developed in the Department of Angiography TsNIRRI MH RF and underwent clinical testing in 43 patients with a positive result.

Claims (3)

 1. A method for the treatment of malignant tumors of the uterus, including catheterization of the internal iliac arteries alternately during one angiographic procedure by access from one femoral artery, subsequent embolization of the iliac arteries and bolus administration of chemotherapy drugs into each of them mixed with a finely chopped hemostatic sponge, characterized in that for 1-2 hours before and 1.5-2 hours after the administration of chemotherapy, detoxification therapy is carried out, and 2-3 weeks after regional bolus chemotherapy, an additional by radiation therapy.  2. The method according to p. 1, characterized in that radiation therapy is carried out by intracavitary irradiation of the primary tumor focus at a dose of 7 Gy once a week to a total focal dose of 42-49 Gy and remote gamma-therapy to the region of regional lymph nodes at a dose of 2 Gy 4 times a week to a total focal dose of 40-44 Gy. 3. The method according to p. 1, characterized in that 100-150 mg of cis-plate, 1 g of cyclophosphamide and 40-60 mg of doxorubicin with the addition of 0.25-0.5 cm ³ finely chopped hemostatic sponge per 100 are used as chemotherapeutic agents ml of a solution of chemotherapy.