RU2420333C2 - Method of treating recurrent nasopharynx cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used for treating patients with recurrent nasopharynx cancer. The method involves administration of chemopreparations and gamma-ray teletherapy; the first therapeutic day involves intravenous drop infusion of an automyelosuspension ex temporae incubated with cisplatin at 50 mg/m² with underlying excessive hydration and forced diuresis; 5-fluorouracil dissolved in normal saline 200 ml is infused the same day at 500 mg/m². After one day of a pause, gamma-ray teletherapy is performed in a hyperfractionation mode taking into account a residual dose 1.5 Gy of single basic dose twice a day every 5 hours to at 5 o'clock to 65 isoGy of total basic dose. After one week of a pause, the second course of automyelochemotherapy with cisplatin at 100 mg/m² with underlying excessive hydration and forced diuresis is performed; 5-fluorouracil 500 mg/m², bleomycine 30 mg/m² and adriamycin 35 mg/m² are infused the same day.

EFFECT: use of the invention allows higher clinical effectiveness ensured by combined anticancer effect of the chemopreparations and additional stimulation of immune cells by the factors contained in the bone marrow.

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Description

The invention relates to medicine, namely to Oncology, and can be used to treat patients with relapse of nasopharyngeal cancer.

A known method of treatment of resistant forms of lymphogranulomatosis (patent for the invention No. 2359683. Bull. No. 18 from 06/27/2009).

The authors developed a method for the treatment of resistant forms of lymphogranulomatosis by administering chemotherapy on a bone marrow suspension taken from the patient’s ilium. The bone marrow suspension is centrifuged for 30 minutes at 1500 rpm, the plasma is removed, divided into two parts and frozen at -40 ° C, the formed elements of the bone marrow suspension are diluted with sterile saline, incubated with chemotherapy in an thermostat at 37 ° C for 30 minutes and reinfused to the patient intravenously drip; then, after 14 and 28 days, the plasma of bone marrow suspension is thawed portionwise, diluted with sterile physiological saline, each portion is incubated with the same chemotherapy in the same doses in a thermostat at 37 ° C for 30 minutes, and the patient is re-infused intravenously, after 2 weeks, repeat the whole complex of medical procedures.

However, this method has not been used to treat patients with recurrent forms of nasopharyngeal cancer.

A known method for the treatment of patients with nasopharyngeal cancer, including chemotherapeutic and radiation treatment (Chuprik-Malinovskaya TP, Aliev BM, Denisov L.E. 5-10-year-old results of various options for radiation and chemoradiotherapy of cancer of the nasopharynx. : Problems of modern oncology. Abstracts of the IV All-Russian Congress of Oncologists. - Rostov-on-Don, 1995. - P.244-245), selected by us as a prototype.

Chemotherapy was carried out in 3 groups of patients with stages III-IV of the disease: 76 people before chemotherapy, 38 patients after irradiation, and 64 patients before and after radiation chemotherapy. Polychemotherapy included platinum preparations; the radiation dose was 60 Gy. The best results were obtained in the last group: 5-year survival was 58% versus 40.06% and 45.7% in the other two groups.

The possibility of additional irradiation of the nasopharynx at a dose of 30 Gy after the end of standard irradiation was studied in 82 patients. For additional exposure, the authors used 3 options for radiation exposure: remote gamma therapy by the rotational method - a field of 5 × 6 cm (32 patients), photonic irradiation of 18 MeV from two hanging fields of 6 × 6 cm (30 patients) and intracavitary radiation on the apparatus Selectron "(20 people). In these groups, 2- and 3-year survival was 87%.

As comparison groups, the results of treatment of patients with the radiation method only are given.

However, as the authors themselves note, a relapse-free course of the disease was noted only in 55% of patients with nasopharyngeal cancer. Treatment failure was observed in 45% of patients, of them: a residual tumor - in 12.6%, local relapses - in 19.4%, distant metastases - in 24% of patients, and in 17% - with a cured primary tumor. Late complications in the form of tissue induction, osteomyelitis of the lower jaw, trismus, etc. were observed in 7% of patients. The authors do not indicate how the patients who completed the primary treatment without effect, as well as those who recurred the disease, were further treated. As you know, it is this contingent of patients that presents the greatest difficulty in terms of treatment.

The aim of the present invention is to improve the immediate and immediate results of the treatment of patients with relapse of nasopharyngeal cancer.

This goal is achieved by the fact that patients with relapse of nasopharyngeal cancer on the first day of treatment exfuse bone marrow suspension from the region of the posterior upper pelvic spine into a vial with heparin, to which cisplatin is added at a rate of 50 mg / m ² , incubated for 30 min at a temperature of 37 ° C and injected into the patient intravenously for 1.5-2 hours with a frequency of 30-40 drops per minute using the regime of hyperhydration and forced diuresis. On the same day, intravenous drip infusion of 5-fluorouracil (500 mg / m ² ) in physiological saline is carried out.

After a break in one day, remote gamma therapy is carried out taking into account the residual dose with a change in the field geometry, in the dose hyperfraction mode - 2 times a day with a break of 5 hours, an irradiation session of 1.5 Gy is carried out to SOD = 65 isoGy.

This is followed by a break in treatment for a week. Then, a second course of automyelochemotherapy with cisplatin (100 mg / m ² ) is carried out against the background of hyperhydration and forced diuresis. On the same day, intravenous drip infusion of chemotherapy is carried out: 5-fluorouracil (500 mg / m ² ), bleomycin (30 mg / m ² ) and adriamycin (35 mg / m ² ).

The invention is new, since it is not known from the level of medicine in the field of oncology in the chemoradiotherapy of patients with relapse of nasopharyngeal cancer. The novelty of the invention lies in the fact that in the treatment of patients with relapses of nasopharyngeal cancer, the stages of radiation treatment are preceded by the introduction of chemotherapeutic agents incubated with autologous bone marrow suspension, in combination with the traditional intravenous administration of chemotherapeutic agents.

The invention has an inventive step, as it is not known to an oncologist in this field and does not explicitly follow from the level of clinical oncology.

Incubation of drugs with autologous bone marrow suspension causes a combination of their specific antitumor activity with additional stimulation of the cells of the immune system by factors contained in the bone marrow, i.e. there is a combination of chemo and autoimmunotherapy.

In accessible sources of information in Russia, the CIS countries and abroad, indications of a similar method for improving the treatment of patients with relapse of nasopharyngeal cancer are not found.

The invention is industrially applicable, as it can be repeatedly reproduced and used in healthcare, in medical institutions with a specialized oncological profile.

The method is as follows.

A bone marrow suspension for automyelochemotherapy (AMXT) is taken from the region of the posterior upper pelvic awns. In order to stabilize the bone marrow suspension (CMS), a solution of heparin is used. The bone marrow suspension obtained by aspiration is transferred to a glass vial. From one bone puncture, 100-150 ml of bone marrow suspension is obtained. Bone marrow exfusion is carried out in accordance with the requirements set forth in the "Instructions for the procurement of autologous bone marrow from patients for clinical use", approved by the Ministry of Health of the USSR on 8.04.80, in compliance with all aseptic and antiseptic rules.

Immediately after the completion of bone marrow puncture, the planned single dose of cisplatin is added to the vial with CMV. Incubation of automyel suspension with chemotherapeutic agents introduced into it is carried out in a thermostat for 30 min at t 37 ° C.

On the 1st day of treatment, patients are given an intravenous drip infusion of an ex temporae automyel suspension, incubated with cisplatin at a rate of 50 mg / m ² through a blood transfusion system for 1.5-2 hours, according to known transfusion rules with a frequency of 30-40 drops per minute using the regime of hyperhydration and forced diuresis. On the same day, 5-fluorouracil is infused at the rate of 500 mg / m ² diluted in 200 ml of 0.9% saline.

The next day, a break, after which a remote gamma therapy is carried out taking into account the residual dose with a change in the field geometry in the hyperfraction mode, an irradiation session of 1.5 Gy is performed 2 times a day with a break of 5 hours, i.e. single focal dose (ROD) is 3 Gy. Irradiation of the primary lesion and regional lymph nodes is carried out according to the standard method to SOD = 65 from Gr (VDF = 107 U).

This is followed by a week-long break followed by a 2nd course of automyelochemotherapy with cisplatin at a dosage of 100 mg / m ² against the background of water load and forced diuresis. On the same day, the infusion of chemotherapy is carried out: 5-fluorouracil - 500 mg / m ² , bleomycin 30 mg / m ² and adriamycin 35 mg / m ² .

For evidence, we provide an extract from case histories confirming the clinical effect of treatment by the proposed method.

Case Study Example

Patient G., born 1984 (source. Bol. No. 19267 / c) has been under the supervision of the RNII since September 18, 2007. about relapse of nasopharyngeal cancer.

In the CODE of Krasnodar from 10/31/05 to 12/14/05 after diagnosis - nasopharyngeal cancer T ₂ N ₁ M _{0, the} patient underwent a course of remote gamma therapy according to the standard method for the primary lesion and cervical lymphatic collector in SOD 60 from Gr with full effect . No signs of recurrence and metastasis were observed dynamically for two years. In August 2007, nasal congestion and enlarged l / nodes of the neck appeared. When examined at the RNIIII on September 18, 07, enlarged lymph nodes up to 5.5 cm in size are found in the upper third of the neck on both sides, dense, fused with the surrounding tissues, the skin above them is not changed. When posterior rhinoscopy in the lumen of the nasopharynx is predominantly on the left, a tumor infiltrate of 4 × 5 cm is determined, a cartilaginous consistency, the surface of which is tuberous, covered with purulent-bloody discharge, bleeds upon contact.

09/18/07 with fibroepipharyngoscopy - The mucous membrane of the nasopharynx is infiltrated, swells into the lumen in the form of polypoid, exophytic formations. The surface of the infiltrate is tuberous with necrotic-ulcerative overlay, easily bleeds upon contact. Infiltration dimensions of 4 cm × 5 involves a set nasopharynx, preferably the left half of it, blocking the _^3/4 left nasal passages. Conclusion: relapse of nasopharyngeal cancer. The result of histological examination No. 969451-453 of 09/26/07: undifferentiated nasopharyngeal s-r.

09/19/07 with head and neck SRCT - a 6.5 × 4 cm nasopharyngeal tumor with a predominant lesion on the left with spreading to the Eustachian tubes, parapharyngeal tissue, enlarged lymph nodes on both sides of the neck in the upper third to 5.8 cm.

09/19/07, an ultrasound scan with a CDC and an EDC of the cervical lymph nodes - in the upper third of the neck, pronounced pathological arterial and venous blood flow is recorded on both sides of the lymph nodes. The sizes of the lymph nodes are from 5.6 to 5.8 cm in diameter.

Clinical diagnosis: Relapse of nasopharyngeal cancer T ₂ N ₃ M ₀ , CL 2.

10/01/07, the patient was hospitalized in the department of radiation treatment of RNII.

10/08/07 a course of automyelochemotherapy was carried out: after trepanopuncture of the left iliac bone, 120 ml of automyel suspension was obtained, after incubation of which at 37 ° C for 30 minutes with 100 mg of cisplatin (at a rate of 50 mg / m ² ) was administered iv drip against the background of hyperhydration and forced diuresis. 1000 mg of 5-fluorouracil (based on 500 mg / m ² ) was added to physiological saline.

From 10/10/07 to 10/19/07, taking into account the residual dose of 36 isoGy (VDF = 59 U), a course of DHT was carried out on an AGAT-S apparatus to the area of the primary focus from three fields: 2 opposite cheek-cheekbones with a size of 7x8 cm and one anterior nasal field size 6 × 8 cm. Irradiation was carried out twice a day with an interval between fractions of 5 hours (1.5 Gy + 1.5 Gy). At a total focal dose equal to 65.0 isoGy (VDF = 107 U). From 10/20/07 to 10/26/07 a planned break was made.

Subjectively, after the 1st stage of treatment, a significant improvement in the general condition was noted: hearing improved, nosebleeds stopped, nasal breathing recovered, headaches stopped.

10.27.07 a repeated course of automyelochemotherapy was conducted with the introduction of 200 mg of cisplatin against the background of water load and forced diuresis. 5-fluorouracil was infused - 1000 mg, bleomycin 60 mg and adriamycin 70 mg.

The chemoradiation treatment satisfactorily, the signs of early radiation reactions - islet epithelitis.

Hemograms of patient G. in the dynamics of chemoradiotherapy are presented in the table.

Indicators of the peripheral blood of the patient at the stages of chemoradiotherapy Hematological indicator date of 01.10 - before treatment 17.10 - after stage I of chemoradiation treatment 24.10 - before the second course of automyelochemotherapy 26.10 - at the end of complex treatment Red blood cells × 10 ¹² / L 4,51 4.80 4.81 490 Hemoglobin, g / l 155 132 156 155 Color indicator 1,0 0.98 0.97 1,0 White blood cells × 10 ⁹ / L 4.4 3.6 4.4 4.7 Eosinophils 3 one 2 one Stab 7 7 5 6 Segmented 72 fifty 60 60 Lymphocytes,% 13 19.1 29th eighteen Monocytes,% 5 3,5 four 4,5 ESR, mm / h eighteen 16 fifteen 12

Diagnosis at discharge: Relapse of nasopharyngeal cancer, T ₂ N ₃ M ₀ , class 3.

1 month after completion of complex treatment, the patient was examined.

11/26/07 with fibroepipharyngoscopy - No evidence of tumor and relapse. Pronounced positive dynamics after radiation therapy. Hyperemia and swelling of the mucosa, signs of islet epithelitis in the nasopharynx are determined.

11/26/07 on the head and neck CT scan - in the nasopharynx the tumor tissue is not visualized, thickening of the mucosa. In the alveolar bay of the left maxillary sinus, thickening of the mucosa. In the fiber of the neck there are areas of infiltration, lymph nodes on both sides (submandibular) with dimensions of 0.5 × 0.7 cm. Positive radiological dynamics from 09/19/07.

11/26/07 on an ultrasound scan with a CDK and an EDK of the cervical lymphatic cells, pathological blood flow in the submandibular and other groups of lymph nodes is not visualized. The size of the lymph nodes is from 0.4 to 0.7 cm in diameter.

The patient is observed in RNII until July 2009 with no signs of recurrence and metastasis.

The improvement of treatment results seems to us to be a combination of various positive factors, which include an increase in the antitumor activity of chemotherapy drugs after their preliminary incubation with automyel suspension, nonspecific stimulation of the patient’s immunity, and stimulation of hematopoiesis by colony-stimulating bone marrow factors.

The technical and economic effect of the use of the “Method for the treatment of relapse of nasopharyngeal cancer” consists in the ability to improve the immediate and immediate results of treatment of patients, to establish natural nasal breathing, to avoid hematological toxicity, to conduct a radical course of chemotherapeutic and radiation treatment, to improve the quality of life due to auto myelochemotherapy in combination with traditional polychemotherapy and remote gamma therapy.

Claims (1)

A method for treating relapse of nasopharyngeal cancer, including the introduction of chemotherapy and remote gamma therapy, characterized in that on the first day of treatment, patients are given intravenous drip infusion of an ex temporae automyel suspension incubated with cisplatin at a rate of 50 mg / m ² against the background of hyperhydration and forced diuresis, on the same day, 5-fluorouracil is infused at the rate of 500 mg / m ² diluted in 200 ml of 0.9% saline, after a break of one day, remote gamma-therapy is carried out in hyperfraction mode, taking into account the residual dose of ROD = 1.5 Gy twice a day with a break between sessions of 5 hours until SOD = 65 isoGy, after a week-long break, a second course of automyelochemotherapy with cisplatin is performed at a rate of 100 mg / m ² against the background of overhydration and forced diuresis, in 5-fluorouracil 500 mg / m ² , bleomycin 30 mg / m ² and adriamycin 35 mg / m ² are infused on the same day.