RU2707954C1 - Method of treating oncological pain - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and can be used for reduction of oncological pain in cancer patients of various localization with a common process. Method comprises administering to patient T_1-4N_1-3M₁ with different localization of the first allogenic dendritic cell vaccine malignant process paravertebral at level C₇-Th₂ intradermally of 4 points of 0.3 ml, wherein total number of dendritic cells is 5,000,000. 2 weeks after the introduction of the first vaccine, a second allogenic dendritic cell vaccine is administered in a similar way, with a total number of 10,000,000 dendritic cells, thus the number of dendritic cells in total is equal to 15,000,000 in two sessions of vaccine therapy. Two weeks after the second introduction, the third allogenic dendritic cell vaccine is administered by 0.3 ml in a similar way; the total number of dendritic cells is 5,000,000. Two weeks after the third introduction of the dendritic cell vaccine, a fourth allogenic dendritic cell vaccine is administered by 0.3 ml in a total dosage of 10,000,000 cells. Thus, for 3 and 4 sessions of vaccine therapy patient receives 15,000,000 cells, wherein in one course of vaccine therapy patient receives 30,000,000 dendritic cells. Immunotherapy in the above mode is carried out for one year, in the absence of contraindications to the patient in parallel to the immunotherapy, the chemotherapy courses recommended for the given localization of the malignant process are conducted, wherein the first chemotherapy course is started one week before the first dendritic cell vaccine introduction, if there are contraindications to the chemotherapy, the vaccine therapy is performed in an independent mode.

EFFECT: use of the invention enables reducing oncological pain, thereby improving the quality of life of incurable oncological patients.

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Description

The invention relates to medicine, namely to oncology and can be used to stop cancer pain in patients with cancer of various localization with a common process.

It is known that more than 70% of patients with the progression of malignant tumors experience pain, mainly of moderate and severe severity (see van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 1437-1449).

Pain rarely occurs at the onset of the disease and is far from always the first sign of cancer at an early stage. Only 10-20% of tumors appear at the onset of pain symptoms. Constant, localized, untreatable pain is always an alarm .. Pain almost always accompanies advanced stages of the disease, it is often the result of anti-cancer therapy or a sign of relapse, and its relief should be started immediately in order to avoid the transition to the chronic stage (see Original article published on the website of the breast cancer - Russian Medical Journal): https://www.rmj.ru/articles/onkologiya/Problema_boli_v_onkologii/#ixzz5KSFW4iYV Follow us: rusmedjournal on Facebook, by Isakov ME).

The intensity of the pain is often underestimated, and the etiology is unclear. The inability to identify the mechanism of pain is of particular concern in the treatment of patients with neuropathic cancer pain (NCP), when the opioids themselves are often ineffective, and the addition of adjuvant analgesics is essential (see Oldenmenger WH, Sillevis Smitt PA, van Dooren S, Stoter G, van van der Rijt CC. A systematic review on barriers hindering adequate cancer pain management and interventions to reduce them: a critical appraisal. Eur J Cancer 2009; 45: 1370-1380).

NCP is an inevitable cancer problem and accompanies the development of the disease. And sometimes it occurs under the influence of various methods of treating the underlying disease (see Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 2012; 153: 359-365).

NCP is pain caused by direct damage to the elements of the nervous system. The nerve may be infiltrated by the tumor, squeezed by fibrosis of the surrounding tissues (see Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care 2006; 12 (9 Suppl): S256-S262).

As soon as damage to the peripheral nerve occurs, its fibers become hypersensitive, causing spontaneous pain, which intensifies in the spinal cord. Sometimes even a minor irritant, such as touching, can cause pain - allodynia (Yoon So Young, Jeeyoung Oh Neuropathic cancer pain: prevalence, pathophysiology, and management. Korean J Intern Med. 2018; .kjim.2018.162 Publication date (electronic): 2018 June 25 doi: https://doi.org/10.3904/kjim.2018.162).

Pain may persist for several months or years. In such an environment, pain no longer reflects an ongoing trauma, but rather a disturbance in the nervous system. NCP is part of a wider range of neuropathy caused by the disease itself, as well as peripheral neuropathy caused by radio or chemotherapy (Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain Oncologist 2010; 15 Suppl 2: 3-8).

NCP is one of the three main types of cancer pain (others are somatic and visceral pain). There are two main forms of pathophysiology of pain: nociceptive and neuropathic. In the clinical setting of cancer stress, both hypersensitivity and hypersensitivity symptoms often coexist. NCP is often part of a mixed syndrome with other types of pain, including somatic or visceral pain. NCP is a chronic condition and often manifests as constant background pain with exacerbations of intense pain several times a day. Attacks of intense pain often occur spontaneously, but can also be caused by movement, touch, contrast temperature.

In contrast, nociceptive pain is the result of damage to somatic and visceral structures, followed by activation of the nociceptors of the skin, internal organs, muscles and connective tissue. Nociceptive pain can be divided into somatic and visceral pain. Somatic nociceptive pain is sharp, well-localized, throbbing, and assertive. However, visceral nociceptive pain that develops secondary to compression, infiltration, or distention of the abdominal or chest cavity or internal organs is often described as more diffuse, less localized (see Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care 2006 ; 12 (9 Suppl): S256-S262).

In 2012, an extensive meta-analysis of pain was published in more than 10,000 cancer patients. The prevalence of NCP, alone or combined with other types of pain, was approximately 39% (see Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 2012; 153: 359-365). The prevalence rates of pure neuropathic pain, mixed pain, and pure nociceptive pain are approximately 19%, 20%, and 59%, respectively. Sixty-four percent of NCPs were caused by cancer as such and 20% were triggered by chemotherapy, radiation therapy, and surgery.

A cross-sectional Dutch study reported that 23% of cancer outpatients (204/892) experienced moderate to severe pain (see Oosterling A, te Boveldt N, Verhagen C, et al. Neuropathic pain components in patients with cancer: prevalence, treatment, and interference with daily activities. Pain Pract 2016; 16: 413-421) and 19% showed neuropathic symptoms (170/892). However, the prevalence of NCP increased to 40% in patients with moderate to severe pain, which more seriously affected activity in everyday life than in patients without neuropathic pain. Even patients with mild neuropathic pain experienced discomfort and decreased quality of life.

Recently, a Korean multicenter intersectoral observational study examined the prevalence and impact of NCP on the quality of life of cancer patients (see Oh SY, Shin SW, Koh SJ, et al. Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients. Support Care Cancer 2017; 25: 3759-3767). The prevalence of NCP with a score of ≥1 on the visual analogue scale (VAS) was 36.0% (722 / 2,003). About 20% of all patients reported moderate to severe pain. It is important to note that those with a VAS≥4 score had a higher prevalence of NCP than patients with mild pain (42.4% versus 27.4%). The prevalence of NCP has been shown to be approximately 40% and has a negative impact on quality of life to a much greater extent than in patients without it (Rayment C, Hjermstad MJ, Aass N, et al. Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerized Symptom Assessment study. Palliat Med 2013; 27: 714-721). Thus, the prevalence of NCP remains high.

Carcinogenesis is a complex and multi-stage process consisting of tumor initiation, progression and spread. The microenvironment in a solid tumor contains various cell populations, such as endothelial, stromal and immune cells of innate immunity, which support tumor progression. In addition, tumors can affect endocrine stress pathways, thereby indirectly modulating neuroimmunology and behavior. Tumors or their treatment can also affect brain function by modifying the innate transfer of immune cells directly to the brain.

Because the pathophysiology of NCP is complex, the long-term management of NCP is a challenge for physicians working with cancer patients. Opioids are the basis for the treatment of cancer patients. Moderate pain treatment requires the use of opioids. When treating with short-acting drugs (for example, codeine, dihydrocodeine and dextropropoxyphene), drugs with mixed effects (tramadol, tapentadol) and partial opioid agonists (transdermal buprenorphine) are recommended if the result with non-opioid analgesics is not satisfactory (see RI, Sant. D, Maranzano E, Berti M, Roila F. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol. 2012; 23 (Suppl 7): vii139-vii154. [PubMed]; Swarm RA, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2013; 11 (8): 992-1022. [PMC free article] [PubMed]).

However, there is disagreement in this approach and there is no convincing evidence that short-acting opioid supplementation is more effective than non-opioid treatment (see Ripamonti CI, Santini D, Maranzano E, Berti M, Roila F. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol. 2012; 23 (Suppl 7): vii139-vii154. [PubMed]).

On the other hand, the use of low doses of strong opioids or low doses of morphine may be more effective than short-acting opioids (see Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence- based recommendations from the EAPC. Lancet Oncol. 2012; 13 (2): e58-e68. [PubMed]: Swarm RA, Abernethy AR, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2013: 11 ( 8): 992-1022. [RMS free article] [PubMed]). Codeine is a prodrug and should be replaced with morphine-6-glucurinide to show its effect. Due to the genetic polymorphism in the metabolism of this drug, it cannot be effective in 10% - 30% of the population (see Lotsch J. Opioid metabolites. J Pain Symptom Manage. 2005; 29 (Suppl 5): S10-S24. [PubMed] ) Strong opioids are used for severe pain alone or in combination with non-opioid analgesics and / or conalgesics. These drugs include morphine, hydromorphone, methadone, and fentanyl. One of the main obstacles to the effective treatment of pain in cancer patients is the fear of drug addiction and / or depressive side effects.

It appears that pro-inflammatory cytokines are important in the pathogenesis of NCP (see Uceyler N, Kafke W, Riediger N, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010; 74 (22): 1806- 1813. [PubMed]). Macrophages are responsible for the participation in the neuro-inflammatory process of axons and neurons of the dorsal root ganglion in NCP. In response to chemotherapy-induced hypoxic damage, macrophages secrete or organize other inflammatory cells to produce cytokines (tumor necrosis factor α, interleukin 1β, IL-6, IL-8), chemokines CCL2, CXC family), growth factors, and inflammatory neurotransmitters such as bradykinin, prostaglandins, serotonin and nitric oxide (see Turabi A, Plunkett AR. The application of genomic and molecular data in the treatment of chronic cancer pain. J Surg Oncol. 2012; 105 (5): 494-501 . [PubMed]; Wang XM, Lehky TJ, Brell JM, Dorsey SG. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine. 2012; 59 (1): 3-9. [PMC free article] [PubMed] ) These small molecules have been investigated both as potential targets for treatment targets and as potential biomarkers for the assessment or early diagnosis of NCP. Further clarification of the underlying mechanisms of NCP may open up new perspectives for targeted therapy of NCP.

Thus, immunotherapy can be one of the directions for the treatment of cancer pain.

The well-known "Method for the treatment of pain and inflammation in neural tissue using antagonists of IL-31" (see patent RU (11) 2440130 (13) C2. Published: 01/20/2012 Bull. No. 2). The method includes the use of an IL-31 antagonist to inhibit signal transduction of induced IL-31 in the cells of the ganglion of the posterior root. The IL-31 antagonist inhibits the binding of the IL-31 polypeptide, including amino acid residues 27-164 of SEQ ID NO: 2, to its heterodimeric receptor, including IL-31RA and OSMR-beta. The antagonist is a humanized monoclonal antibody or a chimeric antibody. Using the method effectively reduces inflammation, pain and itching.

However, this drug was used in a model with neurogenic pain in animals and was not used to relieve oncological pain in humans.

The known method is “Means for the prophylactic and / or therapeutic treatment of peripheral neuropathic pain caused by an anticancer agent” (see patent RU (11) 2595857 (13) C2. Published: 08/27/2016 Bull. No. 24). The invention relates to a medicament for the prophylactic and / or therapeutic treatment of peripheral neuropathic pain containing thrombomodulin as an active ingredient. The group of inventions also relates to the use of thrombomodulin for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of peripheral neuropathic pain induced by chemotherapy. The group of inventions provides a preventive and / or therapeutic effect against peripheral neuropathic pain induced by chemotherapy, characterized by speed and durability. A prophylactic effect was obtained in relation to peripheral neuropathic pain caused by an anticancer agent in humans, for example, during chemotherapy of 12 courses, each of which consists of two weeks, using FOLFOX6, mFOLFOX6 or the like, in a patient with a malignant tumor, such as colon cancer. TMD123 (e.g., Recomodulin (registered trademark), Asahi Kasei Pharma Corporation) is administered to a patient immediately before, during or immediately after administration of an anticancer agent in each course. After chemotherapy is completed, by examining the chemotherapy dropout rate, the incidence of peripheral neuropathic pain, QOL, changing laboratory coagulation data, the effect on the tumor, etc., the prophylactic effect of the present invention on the peripheral neuropathic pain caused by anti-cancer can be confirmed. a remedy in humans.

However, the authors do not give examples of specific application of the method in cancer patients.

The results of a clinical study similar to our method in the treatment of cancer pain in cancer patients with a common process in the available literature were not found.

The technical result of the proposed method is the relief of cancer by using a donor dendritic cell vaccine.

The technical result of the proposed method is achieved in that for the relief of cancer pain for patients T _1-4 N _1-3 M ₁ with different localization of the process, the first allogeneic dendritic cell vaccine is administered paravertebrally at the level of C ₇ -Th ₂ intradermally from 4 points of 0.3 ml, while the total number of dendritic cells is 5.000.000, 2 weeks after the introduction of the first vaccine, the second vaccine is administered in the same way, with a total of 10.000.000 dendritic cells, thus, for two sessions of vaccine therapy, the number of dendritic cells with mmarno is 15,000,000; two weeks after the second administration, 0.3 ml of the third dendritic cell vaccine is administered in a similar way, with the total number of dendritic cells being 5,000,000, 2 weeks after the third administration of the dendritic cell vaccine, 0.3 ml of the fourth dendritic cell vaccine in a total dosage of 10,000,000 cells, thus, for 3 and 4 sessions of vaccine therapy, the patient receives 15,000,000 cells, while for one course of vaccine therapy the patient receives 30,000,000 dendritic cells; immunotherapy in this mode is carried out for one year every two weeks, alternating dosages, in the absence of contraindications to the patient, in parallel with immunotherapy, chemotherapy courses are recommended for this localization of the malignant process, and the first course of chemotherapy begins one week before the first administration of dendritic cell vaccines, if there are contraindications for chemotherapy, then vaccine therapy is carried out independently.

The developed method has an inventive step, as it obviously does not follow a known level of medical development for a specialist and makes it possible to stop cancer pain in patients with a common process with different tumor localization. In well-known sources of information in Russia, the CIS countries and abroad, a similar method was not found.

The method is as follows.

Donor peripheral venous blood was collected in sterile 50 ml tubes containing an anticoagulant (K3 - EDTA) and diluted with an equal volume of RPMI-1640 growth medium (Paneko, Russia).

Then 10 ml of the resulting suspension was layered on 3 ml of Ficoll-Paque Premium and centrifuged in 15 ml of sterile tubes at 1500 rpm. for 40 min at room temperature (see Boyum A. Separation of leukocytes from blood and bone marrow // Scand.J. Clin. Lab. Investig. - 1968. - Vol. 21 - Suppl. 97. p. 1-9 )

After centrifugation, erythrocytes and granulocytes remained at the bottom of the tube, and mononuclear cells (MNCs) remained at the interface. The transparent layer of the medium located directly above the opalescent layer containing the MNCs was removed, and the MNCs were collected over the entire cross-sectional area of the tube, achieving purification from other cells. A suspension of MNCs was introduced into sterile 15 ml centrifuge tubes, diluted with a 4-fold excess of incomplete RPMI-1640 nutrient medium and carefully resuspended. MNCs were washed in incomplete RPMI-1640 nutrient medium by double centrifugation at 1000 rpm for 10 min.

Then, counting and assessment of the viability of MNCs were carried out using a Goryaev camera and 0.4% trypan blue, 3.5-7 × 106 or more cells were obtained, with a viability of at least 98%.

To obtain DC from peripheral blood MNCs, the latter were placed in incomplete nutrient medium RPMI-1640 (inoculative dose of 1.5 × 106 cells / ml) and 2 flat-bottomed culture bottles of 75 cm ² with vented plugs for growing adhesive cultures. Incubated under conditions of controlled 5% CO ₂ and 98% humidity at 37 ° C for 2 hours.

Then, RPMI-1640 medium containing non-adherent cells (mainly lymphocytes) was removed and re-washed with 4 ml of RPMI-1640 medium remaining on the cell substrate.

15 ml of CellGroDC medium was added to the culture bottles, growth factors and differentiation factors: GM-CSF (72 ng / ml) and IL-4 (20 ng / ml).

Culture bottles were incubated in a CO ₂ incubator.

On the 3rd and 5th day of cultivation, a fresh portion of GM-CSF (72 ng / ml) and IL-4 (20 ng / ml) were added.

On the 7th day of cultivation, growth factors and differentiation factors GM-CSF (72 ng / ml), IL-4 (20-45 ng / ml) and TNF-α (20 ng / ml), as well as cellular HeLa cell culture lysate at the rate of 3 HeLa culture cells per 1 dendritic cell.

To prepare a lysate containing HeLa culture antigens, cells were cultured in vials in complete DMEM / F12 nutrient medium with 10% calf fetal serum supplemented with glutamine and gentamicin (50 μg / ml) under conditions of controlled 5% CO ₂ and 98% humidity at 37 ° C.

After reaching the confluent monolayer, the cells were reseeded and further cultured for a week.

After receiving a sufficient amount of cell mass, culture medium was taken from the vials, HeLa culture cells were removed from the substrate using a trypsin-Versen solution and resuspended to obtain a homogeneous cell suspension.

Cells were counted in the Goryaev chamber and the percentage of viable cells was determined by staining with 0.4% trypan blue.

To obtain a cell lysate, six consecutive cycles of instant freezing of a suspension of cells in liquid nitrogen and thawing to room temperature in phosphate-buffered saline without cryoprotectant were performed (the quality of cell lysis was controlled using 0.4% trypan blue).

Subsequently, cell detritus was precipitated by centrifugation (10 min, 3000 rpm, 20 ° C) and the supernatant was filtered through a sterile filter (pore diameter 0.2 μm).

The tumor lysate obtained from the HeLa culture was stored at −20 ° C. until use.

48 hours after the addition of the HeLa culture lysate, the culture medium was taken, centrifuged, and the supernatant was removed. 3 ml of trypsin-Versen solution was added to each vial and incubated in a CO ₂ incubator for 5 min.

Then the cells were removed with a scraper, precipitated by centrifugation (10 min, 1000 rpm, 20 ° C), the supernatant was removed. Cells from two vials were combined with the obtained cells from the supernatant by resuspending in incomplete RPMI 1640 medium (final volume 10 ml).

An aliquot of the cell suspension equal to 0.1 ml was taken and the cells were counted in the Goryaev chamber and the percentage of viable cells was determined by staining with 0.4% trypan blue.

Then 200,000 cells were selected to determine the immunophenotype of mature DCs on a flow cytometer, which was performed by isolating MNC-DCs on the population graphs and purifying it from debris and lymphocytes using CD45, CD3, CD4, CD8, CD16 + 56, CD19 tags.

The maturation stage of the mononuclear cells was evaluated using antibodies to CD1a, CD11c, CD14, CD33, CD38, CD83, CD86, HLA-DR.

The required number of dendritic vaccine cells was precipitated by centrifugation, washed with 10 ml of a 0.9% sodium chloride solution containing 10% human albumin, and counted and assessed viability using an automatic cell counter “Countess” and 0.4% trypan blue.

Under the above conditions, cells were obtained with a viability of at least 98% and the immunophenotype of mature DCs (CD14-, CD1alow, CD83high, HLA-DRhigh, CD80high, CD86high, CCR7high).

To administer DC vaccine, 1/2 cells (5 to 10 × 10 ⁶ ) resuspended in 1.5 ml of 0.9% isotonic NaCl solution containing 10% human albumin were transferred to an ampoule and delivered to the clinical unit for administration to the patient.

Another 1/2 DC was cryopreserved and stored in liquid nitrogen until the next vaccination.

For cancer patients T _0-4 N _0-3 M ₁ with different localization of the process, the first dendritic cell vaccine is administered under the conditions of the treatment room, after the skin is treated with an antiseptic solution paravertebrally at the level of C ₇ -Th ₂ intradermally from 4 points of 0.3 ml allogeneic dendritic cell vaccine (a total of 5.000.000 dendritic cells).

Visually, a reaction is observed in the form of papules, slight hyperemia at the injection site. Subfebrile body temperature is noted within two days after the introduction of the vaccine. Allergic reactions, as well as other undesirable side effects, have not been recorded.

Two weeks after the administration of the first dendritic cell vaccine, 0.3 ml of the second dendritic cell vaccine was administered at a dosage of 10,000,000 cells paravertebrally at a level of C ₇ -T _n-2 from 4 points. Visually, a reaction is observed in the form of the formation of papules, slight hyperemia at the injection site. Subfebrile body temperature is noted within two days after the introduction of the vaccine. Allergic reactions, as well as other undesirable side effects, have not been recorded.

In total, 15,000,000 dendritic cells are introduced during the first and second administration.

2 weeks after the administration of the second vaccine, the third dendritic cell vaccine is administered under the conditions of the treatment room, after the skin is treated with an antiseptic solution paravertebrally at the level of C ₇ -T _n-2 from 4 points, 0.3 ml of autologous dendritic cell vaccine (a total of 5,000,000 dendritic cells).

Visually, a reaction is observed in the form of papules, slight hyperemia at the injection site. Subfebrile body temperature is noted within two days after the introduction of the vaccine. Allergic reactions, as well as other undesirable side effects, have not been recorded.

2 weeks after the third administration of the dendritic cell vaccine, the fourth dendritic cell vaccine is administered at the same points in a total dosage of 10,000,000 dendritic cells. In just 3 and 4 sessions of vaccine therapy, patients receive 15,000,000 cells.

The total total dose of 1 course of DHQ is 30,000,000 dendritic cells. The introduction of DQW to patients is carried out in the specified mode for one year, in total, 24 sessions of vaccine therapy with a total dosage of 180,000,000 dendritic cells are performed.

If there are no contraindications, then the patient is given parallel chemotherapy courses of chemotherapy recommended for this localization of the malignant process. The first course of chemotherapy begins one week before the first injection of DQF.

We give examples of the implementation of the method.

Example No. 1.

Patient Z., born in 1969, is under the supervision of the Federal State Budgetary Institution “RNII” of the Ministry of Health of Russia since January 2017. From the anamnesis: she considers herself a patient since December 2016, when she was diagnosed with cervical cancer at her place of residence.

On January 12, 2017, a nerve-saving extirpation of the uterus with appendages, an upper third of the vagina, and pelvic lymphadenectomy was performed at the RNII.

Histoanalysis 1: moderately differentiated squamous cell carcinoma with ulceration, tumor thrombi in the lumen of blood vessels, invasion up to 1 cm. Histoanalysis 2: no tumor along the resection line, hypoplastic endometrium, adenomyosis. Histoanalysis 3: appendages of the usual structure, in the left ovary there is a smooth-walled cyst. Histoanalysis 4: metastases of squamous cell carcinoma in the lymph nodes on the right. Histoanalysis 5: in the lymph nodes on the left - there is no cancer metastasis.

In February - March 2017, the standard adjuvant combined radiation treatment was performed at the Oncology Center in Taganrog. Conducted 6 courses of APHT according to the scheme: carboplatin, endoxan

10/06/2017, I again applied to the BWW RNII in connection with the growing pain syndrome for further examination. Complaints of pain in the lower abdomen, cramping lower back pain, swelling of the lower extremities, general weakness, decreased performance. The pain syndrome appeared in August 2017 (against the background of ongoing chemotherapy courses), its intensity was constantly increasing, in order to stop the pain syndrome, the patient received NSAIDs (ketorol, ketonal every 4 hours IM) and narcotic analgesics (1% promedol 2 ml for the night).

10/06/2017, examined by an oncogynecologist, revealed infiltration of the anterior wall of the vagina, locoregional recurrence.

St. genitalis: external genitalia without visible pathology. The walls of the vagina in the lower and middle thirds are not visually changed, in the upper third they are circularly narrowed, the mucous membrane is pale pink, with no signs of a tumor. The dome of the vagina is fixed anteriorly and upward (to the posterior wall of the bladder). On palpation, severe infiltration of the anterior wall of the vagina throughout almost to the entrance to the vagina, infiltration involves the posterior wall of the bladder. In the pelvic cavity, a relapsing, dense, motionless tumor is about 6 cm in diameter. Infiltration of the left parametria to the walls of the pelvis, infiltration of the right parametria, not reaching the walls of the pelvis. When viewed through the rectum: at the level reached by the finger, mucosal pathology was not detected. There are traces of feces on the glove.

An ultrasound of the pelvic organs and kidneys was performed on October 6, 2017: recurrent pelvic formation of 68 mm in diameter, deforming the bladder, hydronephrosis on both sides.

Cystoscopy from 10/06/2017: the cystoscopic picture corresponds to either germination in the bladder or a severe postradiation process. An abdominal, pelvic, and chest abdominal CTMS from 10/09/2017: there are few metastatic foci in the lungs on both sides up to 12 mm, metastatic foci up to 22 mm in the right lobe of the liver against fatty hepatosis. Intrathoracic lymph nodes 25 mm, paracaval up to 11 mm, hilar lymph nodes: upper mediastinum up to 11 mm, preaortic 17 mm, bifurcation up to 10 mm. In the pelvic cavity, the tumor node is 50 × 48 mm, closely adjacent to the loops of the intestine. Ureterohydronephrosis on both sides.

MRI of October 13, 2017: condition after complex treatment of cervical cancer, MP picture of tumor recurrence: vaginal germination, bladder walls, urethra, sigmoid colon, left ureter with the development of ureterotectosis, MP signs of metastatic lesion of the right iliac and bifurcation lymph nodes , parietal peritoneum along the right flank.

FCC from 10/20/2017: narrowing of the lumen of the distal sigmoid colon, the endoscopic picture is more characteristic of the adhesive process, taking into account the MRI data, a periprocess is also possible.

Laboratory test results:

KLA from 10.20.2017: hemoglobin = 115 g / l, erythrocytes = 3.79 × 10 ¹² / l, CP = 0.91, white blood cells = 9.67 × 10 ⁹ / l, ESR = 36 mm / hour, stab core = 14%, segmented = 76%, eosinophils = 0%, basophils = 0%, monocytes = 5%, lymphocytes = 7%, platelets = 257 × 10 ⁹ / L.

Biochemical analysis of blood from 10/20/2017: total bilirubin 10.4 mmol / l; ALT = 78.8; AST = 43.2; creatinine = 48 μmol / l; glucose = 10.09 mmol / l, CRP = 48 mg / l, total protein = 72.4 g / l; urea = 10.2 mmol / L.

OAM from 10.20.2017: no pathological changes were detected.

According to the verbal rating scale, pain intensity is defined as severe pain. The physical activity of the patient is moderately reduced (bed rest - less than 50% of the daytime). The quality of night sleep (after injection of promedol) is satisfactory (from 4 to 6 hours).

Diagnosed with main: (C53.8) ZNO of the cervix pT1вN1M1 gr. 2, the state after surgical treatment, combined radiation therapy and 6 courses of PCT. Locoregional recurrence in the pelvic cavity, sprouting in the vagina, in the bladder, urethra, sigmoid colon (periprocess), metastases in the ileum of the right side, bifurcation, hilar lymph nodes, peritoneal metastases, liver and lungs; generalization of the disease against the background of chemotherapeutic treatment. Complications of the underlying disease: (N13.3) ureterohydronephrosis on both sides; (R 52) chronic pain syndrome. Associated: (E 66) obesity 1 tbsp., Alimentary-constitutional type; (I 42.8) dishormonal myocardial dystrophy, (K 76.0) fatty liver hepatosis, (E 11) type 2 diabetes, first detected.

The RNII Institute of Consolidation, consisting of an oncogynecologist, radiologist and chemotherapist, decided to start a second line of chemotherapy according to the “cisplatin 75 mg / m ² and bleomycetin 60 mg” regimen, alternating with the administration of an allogeneic dendritic cell vaccine to relieve pain.

For the introduction of a new treatment option, permission was obtained from the ethics committee of the RNII. The patient is informed in detail about the method, features and possible complications of the upcoming treatment. The patient received informed voluntary consent for medical intervention.

October 24-27, 2017, the first course of second-line PCT was performed according to the scheme: 75 mg / m ^{2 of} cisplatin, 60 mg of bleocin. There are no complications after the introduction of chemotherapy.

11/03/17, 7 days after PCT, the first series of allogeneic dendritic cell vaccine (DQV) was administered.

In the conditions of the treatment room of the Department of Oncogynecology, after treating the skin with an antiseptic solution, 0.3 ml of allogeneic dendritic-cell (in total 5,000,000 dendritic cells) was injected intradermally at a level of C ₇ -Th ₂ from 4 points. Visually, reactions in the form of a papule, slight hyperemia at the injection site. A transient increase in body temperature to 37.8 ° C was noted within three days after the introduction of the vaccine. Allergic reactions, as well as other undesirable side effects, have not been recorded.

11.17.17 the second series of paravertebral administration of DQW was carried out: 10,000,000 dendritic cells were introduced. The reaction in the form of hyperthermia up to 37.9 ° within 2 days after vaccine therapy.

A total of 15,000,000 dendritic cells were introduced during the first and second administration.

12/01/17, the third paravertebral administration of the dendritic cell vaccine was carried out - 5,000,000 dendritic cells were introduced.

12/15/17, the fourth series of the introduction of 10,000,000 dendritic cells, paravertebral. No serious adverse events were recorded. Short-term hyperthermia was noted (fever up to 38 ° during the day).

The total total dose of DHQ per course was 30,000,000 dendritic cells. Currently, the patient has been given 12 injections of the dendritic cell vaccine - a total of 90,000,000 dendritic cells and 6 courses of PCT have been performed (360 mg of bleocin and 900 mg of cisplatin)

In total, at the indicated intervals, 6 courses of chemotherapy and

The patient subjectively notes changes in the general condition: complete relief of pain, no pain in the lower abdomen and lower back, swelling in the legs, performs all the housework, is socially active. At the same time, after 4 cycles of the dendritic cell vaccine, the patient refused analgesia with narcotic analgesics, the interval between NSAID injections was 8 hours. Before the fifth course of chemotherapy, the patient switched to tableted analgesics (NSAIDs), the interval between doses of tablets is 12 hours. After the completion of 12 cycles of the dendritic cell vaccine and six courses of PCT, she does not receive pain medication.

According to the scale of verbal assessments, the intensity of pain is defined as 0 points - there is no pain. The physical activity of the patient is normal. The quality of night sleep is good (from 6 to 8 hours).

St. genitalis: external genitalia without visible pathology. The walls of the vagina in n / 3 and c / 3 are not visually changed, in the upper third they are circularly narrowed, the mucous membrane is pale pink, without signs of a tumor. The dome of the vagina is fixed anteriorly and upward (to the posterior wall of the bladder). On palpation, infiltration of the anterior wall of the vagina throughout almost to the entrance to the vagina, infiltration involves the posterior wall of the bladder, in the pelvic cavity a recurrent dense tumor about 5 cm in diameter, with clear contours, slight formation mobility appeared, infiltration of the left parametrium “departed” from the wall of the pelvis, decreased infiltration of the right parametrium. When viewed through the rectum: at the level reached by the finger, mucosal pathology was not detected. There are traces of feces on the glove. Infiltration of the parametria on the left. Inguinal lymph nodes are hyperplastic, more to the right.

Ultrasound of the pelvic organs and kidneys of 05/07/2018 was performed: recurrent pelvic formation of 52 mm in diameter, deforming the bladder, hydronephrosis on both sides. Cystoscopy from 05/07/2018: no pathology of the bladder mucosa was detected. MRI from 05/08/2018: condition after complex treatment of cervical cancer, MR picture of tumor recurrence with a moderate decrease in tumor size: vaginal germination, left ureter with the development of ureterotectosis, MP signs of metastatic lesion of the right iliac and bifurcation lymph nodes (with signs the formation of fibrosis in the lymph nodes). MRC of abdominal, pelvic and chest organs from 05/10/2018: in the lungs on both sides there are few metastatic foci up to 9 mm, in the right lobe of the liver against the background of fatty hepatosis metastatic foci up to 15 mm, intranasal lymph nodes 18 mm, paracaval lymph nodes not enlarged, intrathoracic lymph nodes: upper mediastinum up to 8 mm, preaortic 15 mm, bifurcation up to 7 mm. In the pelvic cavity, the tumor node is 48 × 35 mm. Ureterohydronephrosis on both sides (a slight decrease in dynamics), FCC from 05/11/2018: narrowing of the lumen of the distal sigmoid colon, no pathology of the colon mucosa.

Laboratory test results:

KLA from 05/07/2018: hemoglobin = 104 g / l, red blood cells = 3, 50 × 10 ¹² / l, CP = 0.89, white blood cells = 5.21 × 10 ⁹ / l, ESR = 28 mm / hour, band stab = 10%, segmented = 65%, eosinophils = 0%, basophils = 0%, monocytes = 10%, lymphocytes = 15%, platelets = 279 × 10 ⁹ / L.

Biochemical analysis of blood from 05/07/2018: total bilirubin 14.2 mmol / l; ALT = 26.78; AST = 27.68; creatinine = 98 μmol / L; glucose = 4.96 mmol / l, CRP = 12.7 mg / l, total protein = 83.1 g / l; urea = 6.49 mmol / L.

In OAM dated 05/07/2018, no pathological changes were detected.

Diagnosed with:

- Before treatment: main: (C53.8) ZNO of the cervix pT1eN1M0 gr 2, condition after surgical treatment, combined radiation therapy and 5 courses of PCT. Locoregional recurrence in the pelvic cavity, sprouting in the vagina, in the bladder, urethra, sigmoid colon (periprocess), metastases in the ileum of the right side, bifurcation, hilar lymph nodes, peritoneal metastases, liver and lungs; generalization of the disease against the background of chemotherapeutic treatment. Complications of the underlying disease: (N13.3) ureterohydronephrosis on both sides; (R 52) chronic pain syndrome.

- after 12 series of specific immunotherapy and 6 courses of second-line PCT: (C53.8) cervical cancer pT1eN1M0 gr 2, condition after surgical treatment, combined radiation therapy and 6 courses of PCT. Locoregional recurrence in the pelvic cavity, sprouting in the vagina, in the bladder, urethra, sigmoid colon (periprocess), metastases in the ileum of the right side, bifurcation, hilar lymph nodes, peritoneal metastases, liver and lungs; generalization of the disease against the background of the first line of chemotherapy; complication of underlying disease: (N13.3) ureterohydronephrosis on both sides.

The condition after 12 cycles of vaccine therapy and 6 courses of second-line PCT and - complete relief of the pain syndrome, stabilization of the tumor process (reduction in the size of recurrent and metastatic tumors by less than 50%).

Currently receiving vaccine therapy sessions with an interval of 2 weeks with alternating doses of the dendritic-cell vaccine administered from 5,000,000 to 10,000,000 cells.

Example No. 2

Patient S., born on 08/18/1965 is under observation at the RNII since May 28, 2015

Clinical diagnosis: (C50.8). Cancer of the right breast, edematous-infiltrative form, luminal type A, Her-2, neo-positive, CT4N1M0, pT4N0M0, st III century. Condition after complex treatment. Generalization of the process in May 2017 with metastasis along the pleura on the left, to the liver, osteolytic metastases in the bones of the skeleton of C. gr. 2.

05/28/2015, at the RNII during the examination, a trepan biopsy of the mammary gland was performed

GA # 1: infiltrating carcinoma

IHC No. 1 - Expression of estrogen receptors - 3%, progesterone - 3% - Expression Ki67 - 3-5% of nuclei, Her2 / Neu expression (C-erbB-2) at the level of 3+.

05/28/2015, SKRK of the neck, OGK, OBP - severe infiltration, swelling of the right breast, tumor nodes up to 3.3 cm in it, axillary lymph nodes to the right up to 2.4 cm.

06/01/2015, 9 courses of neoadjuvant polychemotherapy were carried out. Of these, 2 courses according to the FAC scheme (without clinical effect) and 7 courses of herceptin + paclitaxel, carboplatin (with moderate clinical effect)

12/04/2015, a radical mastectomy on the right was performed on Madden.

GA No. 2 - invasive lobular cancer with severe sclerosis and dystrophic changes in tumor cells. GA number 3 in the lymph nodes - no metastases.

From 01/19/15 to 02/05/16, adjuvant radiation therapy was performed on the postoperative scar and all areas of regional metastasis.

Then, standard courses of herceptin were administered in adjuvant mode.

Examination in connection with increasing pain, shortness of breath and weakness. The intensity of pain on a scale of verbal assessments is recorded as - "strong". The physical activity of the patient is moderately reduced (bed rest - less than 50% of the daytime).

As an anesthetic, ketone injections of 2.0 ml (50 mg / ml) are used 3-4 times a day.

SRKT OGK, OBP and bone structures from 05.16.2017, in the pleural cavities, the fluid on the right is up to 100.0 ml, on the left is up to 200.0 ml.

On the pleura on the left, metastatic nodes up to 1.3 cm. In the right lobe of the liver, few metastatic lesions up to 2.9 cm. Appendages on the right with a solid structure up to 5 cm. In C1 - L5 and pelvic bones, multiple osteolytic metastatic lesions.

MRI OBP from 05.17.2017: metastatic lesions in the liver S5 - to differentiate between metastases with pathomorphosis and local fibrosis.

05/18/2017 osteoscintigram - signs of multiple osteodestructive changes in the bones of the skeleton: in the projection of the sternum, pelvic bones C1 - L5, the upper third of the right femur.

Consultation of RNIII: given the manifest generalization of the process (bone metastases, pleura, liver), the continuation of chemotherapy courses is recommended: beiodime (pertuzumab + trastuzumab) + docetaxel 1 time in 3 weeks, zoledronic acid 4 mg intravenously 1 time per month (other drugs)

It is advisable to alternate chemotherapy courses with the introduction of allogeneic dendritic-cell suspension (DKV) for the relief of pain.

The clinical use of allogeneic dendritic-cell suspension obtained the permission of the ethics committee of RNII. The patient is informed about this treatment option, its rationale and possible reactions.

On May 24, 2017, a venous port was installed in the right internal jugular vein.

05/25/2017, 1 course of recommended drug therapy was carried out.

On June 1, 2017, 1 week after the administration of chemotherapeutic agents, 0.3 ml of DHQ was administered paravertebrally intradermally at 4 points, which amounted to 5,000,000 dendritic cells.

Visually - a slight hyperemia in place of the resulting papule.

06/05/2017, 14 days after the first injection, similarly repeated paravertebral administration of the vaccine (10,000,000. Dendritic cells) was carried out.

The total dose of DHQ was 15,000,000 cells.

According to the patient, no subjective negative toxic reactions were noted in the form of temperature, chills, nausea, or weakness. At the same time, the intensity of the pain syndrome decreased markedly. The patient drew attention to this, since she did not require the introduction of ketonal in the middle of the day.

2 weeks after the second vaccine therapy session, the third DHA was introduced paravertebrally - 0.3 ml each, for a total of 5.000.000.

2 weeks after the introduction of the third vaccine, the fourth DHQ was paravertebrally administered - 0.3 ml each, totaling 10,000,000.

The total for the third and fourth introduction is 15,000,000.

The total dose for 1 course of DHQ was 30,000,000 cells.

A positive point noted by the patient was the rejection of injectable analgesics. At night, the patient, because of fear of the pain that tormented her, drank 1 tablet of analginum or used a rectal suppository with ketonal.

In total, up to September 13, 17, the patient underwent 6 courses of APCT beiodime + docetaxel. Moreover, every two weeks, allogeneic dendritic-cell suspension was introduced. In total, over a half-year period of treatment (until December 2017), 90,000,000 dendritic cells were introduced.

12/14/2017 IBS: in TN1-S1, pelvic bones, multiple osteoblastic metastatic foci.

The patient is invited to continue courses of chemotherapy. However, the patient refused to implement them, citing the fact that she has no pain and she feels quite satisfactory.

In the period from 09/13/2017 to 07/13/2018, every 2 weeks, the patient is administered at 5.000.000 DKV and 10.000.000 DKV. In total, 180,000,000 DKVs have been introduced, taking into account previous courses.

According to the OGC of the OGC and OBP dated April 18, 2018, there are multiple osteoblastic metastatic foci in the bone window in the thoracic vertebrae, ribs, sternum, lumbar vertebrae, and pelvic bones. The multiple deforming growths of the vertebral bodies of the thoracic spine are visualized in the form of “hooks”, “spikes” and “staples” of small size. Conclusion: metastatic damage to bone structures.

The patient does not complain of bone pain. The intensity of pain on a scale of verbal assessments is defined as zero (0). The physical activity of the patient is normal. Full self-service. Sleep quality is good - from 6 to 8 hours

She still refuses chemotherapy courses.

In this way, 37 cancer patients T _1-4 N _1-3 M ₁ were treated. Of these, there were 20 people with cervical cancer, 3 cancer of the stomach, 3 colon cancer, 8 breast cancer, 3 lung cancer. Objective effect - the intensity of pain, defined on the scale of verbal ratings as zero, occurred in 36 patients. The pain did not stop in only one patient with cervical cancer.

The invention is industrially applicable, as it can be repeatedly reproduced in medical institutions of oncological profile, providing high-tech assistance and having laboratories of molecular oncology and cell culture.

The application of the method allows to stop oncological pain, thereby improving the quality of life of incurable oncological patients.

Claims (1)

A method of treating cancer pain, characterized in that for patients of T _1-4 N _1-3 M ₁ with different locations of the malignant process, the first allogeneic dendritic cell vaccine is administered paravertebrally at the level of C ₇ -Th ₂ intradermally from 4 points of 0.3 ml, the total number of dendritic cells is 5,000,000, 2 weeks after the first vaccine is administered, the second allogeneic dendritic cell vaccine is administered in a similar way, with a total of 10,000,000 dendritic cells, thus, in two sessions of vaccine therapy, the number of dendritic glue Approx total of 15,000,000; two weeks after the second administration, in a similar manner, 0.3 ml of the third allogeneic dendritic cell vaccine is administered, the total number of dendritic cells being 5,000,000, 2 weeks after the third administration of the dendritic cell vaccine, 0.3 ml is administered in the same way the fourth allogeneic dendritic cell vaccine in a total dosage of 10,000,000 cells, thus, for 3 and 4 sessions of vaccine therapy, the patient receives 15,000,000 cells, while the patient receives 30,000,000 dendritic cells for one course of vaccine therapy; immunotherapy in this mode is carried out for one year, in the absence of contraindications to the patient, in parallel with immunotherapy, chemotherapy courses are recommended for this localization of the malignant process, and the first course of chemotherapy begins one week before the first administration of the dendritic cell vaccine, if there are contraindications to chemotherapy, then vaccine therapy is carried out independently.