RU2143935C1 - Method of retardation of malignant tumor growth - Google Patents

Abstract

FIELD: medicine, particularly, oncology; applicable in treatment of widely spread malignant tumors. SUBSTANCE: method includes adjuvant chemotherapy and additional destruction of healthy tissues. Destruction is prolonged until remission of tumor process. Method ensures extended possibility of patients treatment due to creation of competitive relations between proliferation of tumoral cells and cells of normal tissues. EFFECT: higher efficiency of treatment. 7 ex

Description

 The invention relates to medicine, more specifically to oncology, and may find application in the treatment of common malignant tumors.

 How complex is the problem of treating tumor diseases is well known. Currently, surgical methods are widely used for this purpose, as well as their combination with chemo and / or radiation therapy. Such treatment is effective, as a rule, at stages I – II of the disease, in cases of common forms of cancer its effectiveness is low.

 The present invention relates to precisely such forms of malignant neoplasms. As a prototype, we took a method consisting in carrying out specific treatment using radiation and / or chemotherapy with a palliative purpose, and in some cases in the use of only symptomatic treatment [1]. This somewhat improves the quality of life of patients without changing clinical indicators and their life expectancy, which averages from 2 months to 2 years.

 The technical result of the present invention is to increase the life expectancy of patients with common tumor diseases due to the destructive effect on healthy tissues.

 This result is achieved by the fact that the patient is given adjuvant chemotherapy and additionally carry out the destruction of healthy tissues, prolonging it until remission occurs.

 Recently, the phenomenon of spontaneous remission of the malignant process has been officially recognized [2]. This phenomenon consists in obtaining a good clinical result in patients with a common process in the form of the disappearance or weakening of the signs of the disease, lengthening the life expectancy, etc. in the complete absence of antitumor therapy or its use in a reduced volume with palliative or symptomatic purpose. Spontaneous remission as a whole at different locations is estimated as one case in 60 thousand patients, reaching 4% for individual locations. It should be noted that these statistical guidelines, in all probability, are significantly underestimated, since they are based on passive statistics.

 Given the lack of significant progress in recent years in the effectiveness of treatment with traditional methods, we made an attempt to analyze the essence of the phenomenon of spontaneous remission and, if possible, use the results of this analysis to create a new approach to the treatment of common forms of cancer.

 Having been professionally involved in the treatment of cancer patients with common forms of diseases of various localizations for many years, we analyzed the most documented medical histories of patients undergoing treatment at the Central Research Institute of Radiology, some of which are as follows.

 Medical history N 1194.

 B. Sh., 51, was admitted to the TsNIRRI clinic on 1.07.97 with a diagnosis of cervical cancer.

 From the anamnesis: in April 1997, the patient was treated in the VMA for hypertension against the background of renal failure of the 1st art. During the examination, she was diagnosed with bilateral hydronephrosis as a result of compression of the ureters by a tumor conglomerate found in the small pelvis (squamous cell carcinoma in the biopsy material from the cervix uteri).

When examined at TsNIRRI:
According to a gynecological examination, the uterus is enlarged, its neck is sharply hypertrophied, cyanotic, there are spotting. In the small pelvis, a tumor conglomerate is palpated with the upper border above the bosom, reaching the walls of the pelvis.

 According to echography and nuclear magnetic tomography (NMR), a tumor in the pelvis, metastatic lesion of the pelvic lymph nodes, soft tissues of the pelvis and vagina with tumor invasion into the posterior wall of the bladder, bilateral hydronephrosis.

 With cystoscopy in the region of the bladder triangle, tumor-like growths were detected.

 Biopsy material from the cervix (B-115106-107) - "squamous non-burning cancer (low-grade)."

 According to the results of intravenous urography - a decrease in the concentration and excretory function of the kidneys.

 In biochemical blood tests, a high level of urea (15.7 mmol / L) and creatinine (536 μmol / L) was found.

 As a result of the examination, the diagnosis was established: cervical cancer of the IV stage with metastases to the pelvic and lumbar lymph nodes and germination in the bladder wall. Bilateral hydronephrosis. Renal failure. Secondary hypertension

 Specific antitumor therapy was not possible due to the generalization of the tumor process.

 On 07/14/97 and 07/17/97, the patient, for health reasons, consistently performed percutaneous nephrostomy on the right and left with the installation and removal of permanent catheters on the skin of the lumbar regions.

 1.08.97, the patient was discharged from the clinic under the supervision of an oncologist at the place of residence.

30.08.97, the patient noticed the cessation of outflow of urine on the right. August 31, 1997 there were severe pains in the lumbar region on the right, the temperature rose to 38 ^o , nausea, vomiting. The patient was urgently hospitalized in hospital No. 18, S. -Pb., Where urine was found to be in the retroperitoneal fiber and, in connection with this, her nephrostomy drainage was removed on her right, and on 2.09.97 she was transferred to TsNIRRI for repeated nephrostomy .

 When examining a patient at the TsNIRRI clinic, compared with the data at its initial admission, there was a slight decrease in tumor conglomerate in the pelvis, a decrease in blood creatinine (235 μmol / L versus 536 mmol / L) with urea 16.4 mmol / L, and the appearance of protein in the urine (99 mg / l) and a large number of white blood cells.

 September 4, 1997, the patient re-performed percutaneous nephrostomy on the right. Her general condition returned to normal. Some stabilization of the tumor process was noted.

 September 26, 1997, she was discharged from the clinic under the supervision of an oncologist.

 November 13, 1997, the patient was again admitted to the TsNIRRI clinic (I / N N 2447) due to a significant improvement in her general condition and the restoration of urine outflow in a natural way to resolve the issue of the possibility of radiation therapy.

 During the examination: the uterus and cervix are slightly enlarged, the mucous membrane of the cervix is not changed, there are no secretions. The uterus with small fibromatous nodules, cysto-uterine and douglas spaces are free. Pelvic lymph nodes are clearly not palpable.

 According to ultrasound, conglomerate is not detected in the pelvis, pelvic lymph nodes are not enlarged. The kidneys are of normal size, the abdominal system is not expanded.

 In the biopsy specimen from the uterus and cervical canal (B-117324) there was a “glandular fibrous polyp of the endometrium”, no tumor cells were found.

 Cytologically, in smears from the surface of the cervix (B-50025), "cells of the squamous epithelium are of the usual type, the endometrium is without atypia."

 With cystoscopy: the mucosa of the bladder without pathological changes.

 Urea and blood creatinine are within normal limits.

 According to the results of the examination, data for the presence of a tumor process in the patient were not found, and therefore there were no indications for radiation therapy. The patient’s condition was regarded as spontaneous remission, the onset of which we associate with the presence of destructive regenerative processes competing with the tumor, associated with surgical intervention for the application of a nephrostomy.

 November 28, 1997, the patient had a spontaneous loss of nephrostomy drainage on the left, and December 3, 1997, the drainage was removed on the right.

 The patient was discharged 12.01.98, under the supervision of a nephrologist.

 April 6, 1998, the patient was again admitted to the TsNIRRI clinic due to impaired urination and right-sided hydronephrosis.

 According to the gynecological examination and ultrasound, an increase in the size of the cervix, infiltration of the posterior wall of the bladder without germination, infiltration of the upper parts of the vagina and an increase in pelvic lymph nodes in the form of conglomerate up to 4.5 cm in diameter were noted.

 In a histological examination of a biopsy sample from the uterus and cervical canal (B-120523) - "no tumor cells were found."

 Blood biochemistry: creatinine ranges from 197 to 176 μmol / L, urea - from 7.5 to 5.4 mmol / L.

 Diagnosis: activation of the tumor process (despite not receiving morphological verification).

 Given the possibility of competition of the destructive process with tumor growth, it was decided to perform a patient repeated nephrostomy.

 04/28/98, performed right-sided drainage of the right kidney.

 05/14/98, the patient was discharged from the clinic for outpatient monitoring in the clinic TsNIRRI.

 From 05/14/98 to 09/16/98 (4 months), the patient again showed improvement: there was no growth of the tumor, metastases, there was no germination in the wall of the bladder, i.e. remission was again noted in the form of stabilization of the tumor process.

 September 16, 1998, the patient was hospitalized due to worsening condition. On the basis of a gynecological examination, ultrasound and NMR data, a relapse of the disease was established in the form of a tumor conglomerate, an increase in the pelvic and right inguinal lymph nodes, and germination of metastases in the bladder wall.

 Conclusion: a patient with stage IV cervical cancer, incurable, not receiving specific antitumor treatment, was in remission for a year (from September 1997 to September 1998) and continues to live at present, while according to statistics, the duration the life of incurable patients is from 2 to 5 months.

 Medical history N 2241.

 Patient K., born in 1909, was admitted to the TsNIRRI clinic on November 30, 1987, with a diagnosis of stage IV prostate cancer with invasion of the rectum.

 From the anamnesis: March 4, 87, for an acute urinary retention in the urological department of the city hospital, the patient underwent epicystostomy (superposition of the suprapubic urinary fistula).

 According to the results of the examination at TsNIRRI, the diagnosis was established: prostate adenocarcinoma (B-48006 dated 12/17/87) with metastases to the rectum.

 It was decided to conduct transurethral electroresection of a prostate tumor. In view of the perforation of the tumor, when trying to conduct a resectoscope in the bladder on December 23, 87, an unnatural anus was applied and drainage of the abdominal cavity was performed, after which the patient was discharged from the clinic.

 The patient's condition after surgery improved, self-urination appeared, and on 2.02.88, he underwent surgery to close the unnatural anus and bladder fistula.

 03.03.88, the patient was discharged from the hospital in satisfactory condition: the intestines are functioning, the suprapubic urinary fistula is closed, urinating independently. Tumor regression was noted.

 Given the old age of the patient, it is difficult to say anything about his further condition - the patient himself no longer sought help.

 Conclusion: the patient's condition at the time of discharge without specific antitumor treatment for stage IV cancer can be regarded as spontaneous remission.

 Medical history N 1143.

 B. B., born in 1936, was admitted to the TsNIRRI clinic on 06.17.85 with a diagnosis of cancer of the left kidney.

According to the results of the examination at CNIRRI, the specified diagnosis: cancer of the left kidney T ₄ N _x M ₁ (OS) - stage IV.

 1.07.85, the patient underwent chemo-fat embolization of the left kidney with 100 mg of dioxadet.

 On July 4, 855, a left nephrectomy was performed, after which, according to vital indications (the threat of a pathological fracture of the femoral neck), on August 25, 85, the head of the left hip joint was resected and endoprosthetized at the Institute of Prosthetics.

 01/14/86, the patient was admitted for further examination at TsNIRRI. The localization of metastases was clarified - in the roots of the lungs on both sides. For palliative purpose, the patient was prescribed 5 iv injections of 10 mg of vinblastine.

 02/27/87, computed tomography of the mediastinum was performed - the size of the lymph nodes did not change.

 In January 1988 - maintenance therapy in the form of 5 injections of vinblastine.

According to the results of x-ray studies of the chest organs performed
09/12/89, without dynamics,
04/23/90, the picture is the same.

 When the patient went to the clinic on 4.01.91, exudative pleurisy on the right was revealed. Puncture and cytological examination confirmed metastatic lesion; on January 9, 2011, an ultrasound examination revealed hyperplasia of the remaining kidney 16.3 x 4.9 cm in size. Pleurisy was evacuated, 85 mg of dioxadet was administered intrapleurally and 5 injections of 10 mg of vinblastine were administered as maintenance therapy ( 1 time per week) and 45 injections of 3 ml of 12.5% solution of 17-hydroxyprogesterone capronate.

 04/10/91 there was an increase in the amount of pleural exudate on the right. Repeated evacuation of pleural fluid.

 6.06.91, the patient was discharged from the clinic.

 Conclusion: the patient's life expectancy was 6 years, while the average survival of patients with stage IV kidney cancer is 1.5-2 years. It is known that traditional chemo-hormonal treatment regimens used to treat stage IV kidney cancer, including this patient, are used for palliative purposes without increasing life expectancy.

 We classify this result as stabilization of the tumor process (spontaneous remission) and associate it with the presence of a hip joint prosthesis that constantly injures the neck of the thigh and, therefore, distracts the body’s forces, competing with tumor growth.

 Other clinical situations observed by us at the TsNIRRI clinic.

 I. The group of patients with kidney cancer of 28 people who, in accordance with the high degree of prevalence of the malignant process, underwent chemo-fat embolization of the organ affected by cancer, was divided into two subgroups according to the criterion of the effectiveness of the treatment. The first included 15 patients whose average life expectancy was significantly increased on average to 13 months, the second patients, in whom the treatment was ineffective, with an average life expectancy of about 7 months.

 A study of the state of the fraction of rosette-forming lymphocytes in the indicated subgroups of patients, which is responsible for ensuring the process of compensatory hyperplasia in the non-cancerous contralateral kidney, showed that in the first subgroup a positive treatment result was accompanied by compensatory hyperplasia in a healthy paired organ. This pattern served as a prognostic basis for creating a way for us to determine the indications and contraindications for embolization in kidney cancer.

 These results illustrate the mechanism of distraction of the proliferative potential of the body to compensatory regeneration of the contralateral kidney after performing total occlusion of the paired organ affected by cancer. We believe that the relationship of patients' life expectancy with the number of circulating undifferentiated lymphocytes indicates the decisive role of healthy kidney parenchyma regeneration in obtaining a positive clinical result, since this particular subpopulation is responsible for this process [3].

 II. A group of patients of 30 people with small-cell locally advanced lung cancer of the II-III stage underwent radiation treatment in 2 versions. A common course for them was local radiation therapy in fractions of 2 Gy to a total dose of 45 Gy. A distinctive feature of one of the two groups was additional whole-body irradiation (STOT) in a non-tumoricidal total dose of 1 Gy of 0.1 Gy fractions, which were used between local radiation fractions with the aim of not deep radiation damage not only to the tumor, but also to large volumes of normal tissues. A distinctive feature of the second group was the conduct of one course of CMF chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) after completion of the course of local radiation therapy. The results of treatment in both groups of patients turned out to be comparable, which indicates an independent therapeutic significance of the course of total exposure in group I patients.

 These data indicate that irradiation of patients, carried out in obviously non-tumoricidal doses, creates, as we have established, over the long term extensive, but not deep damage to normal tissues, the destruction of which requires regeneration and thereby distracts a significant part of the proliferative potential of the body, competing for him with a tumor.

 Thus, as follows from the above, far from single observations and literature data [2], the revealed spontaneous remissions in the form of the disappearance or stabilization of the tumor process, as a rule, were accompanied by certain surgical situations (long-healing postoperative wounds, fistulas in the area of permanent catheters, places anastomoses) or radiation damage to normal tissues, which caused a long-running regenerative process.

 The totality of these data allowed us to conclude that it is possible to use a destructive effect on normal tissues with prolonged subsequent healing as an element of treatment of common malignant tumors in order to stabilize the tumor process on a competitive basis.

 We give examples of the implementation of the proposed method in experiments and in the clinic.

Example 1. In an experiment in 20 mice (C 57 Bl ₆ • CBA) • F ₁ with grafted adenocarcinoma of the bronchus RL-67 in the soft tissues of the foot of the hind paw on the 7th and 9th day, a partial skin flap operation was performed on the back. The control (without separation of the skin flap) and experimental mice were used to measure the size of the tumor using a special micrometric device throughout the experiment. The data obtained showed the suspension of tumor growth during the engraftment of the flap (for 4 days) and the resumption of growth at the end of the period of intensive regeneration.

 Example 2. Twenty RL-67 grafted tumor-bearing mice were exposed to radiation at a dose of 5.5 Gy once with the exception of the tumor itself by shielding it with lead. Then, during the entire period of life of the animals, the size of the tumor was measured as in Example 1. In the postradiation period, the tumor growth was slowed down by 8 days compared with control animals in which only the tumor was exposed to radiation.

 Example 3. In an experiment on 100 rats, growth of foci of Walker sarcoma in the liver was initiated by introducing tumor cells into the venous system of the organ. The animals were then divided into 2 groups - control and experimental. In the liver of animals of the experimental group, parenchyma micronecrosis was additionally caused by introducing majodil oil solution into the portal system 4 times with an interval of 4 days. Micronecrosis caused subsequent regeneration of parenchymal liver cells. The regimen of administration of majodil ensured in animals repeated cycles of micronecrtization-regeneration practically throughout the entire lifetime of tumor carriers. In control animals, the development of the tumor process occurred naturally.

 Comparison of animal deaths in the experimental and control groups showed that in the experimental group of animals with increased life expectancy was 3 times more than in the control. This is explained by the fact that the slowdown in the death of animals in the experimental group occurred against the background of the intensification of the regenerative process in the liver tissue by majodil, which, according to estimates made by taking into account mitotic activity in normal hepatocytes, reached a maximum of 100-fold (up to the value of the mitotic index 7.088 ± 1.155 on the second day after the introduction of majodil compared with the norm of 0.0475 ± 0.0320). Increased regeneration was accompanied by an increase in infiltration of the liver tissue by lymphocytes. Thus, an increase in the regeneration process in the liver tissue of experimental animals was directly related to an increase in their lifespan due to stabilization of the tumor process.

 The above experiments once again convincingly showed that the creation of a regeneration focus in normal tissues leads to a weakening of proliferative activity in the tumor on a competitive basis for mechanisms to ensure regeneration in the host body. We believe that, provided that the competitive relationship between the tumor and the artificially created focus of damage to healthy tissues is maintained for a long time, it is possible to control tumor growth on a fundamentally new basis.

 To date, medicine has almost the only method of controlled damage and healing of normal tissues in the form of the apparatus and methodology of Professor Ilizarov. However, in view of the rather high traumatism of this method, the implementation of such an option for the destruction of healthy tissues with their subsequent long-term regeneration for social and ethical reasons is unacceptable in clinical practice.

 In this regard, we present the following clinical examples that we have carried out.

Example 4. Patient X., born in 1959, and / b N 1794/93, was first admitted to the gynecological department of TsNIRRI on 10/13/93 with a diagnosis of ovarian cancer of the third century. T ₃ N _x M ₀ .

 On 28.10.93, the patient underwent an operation in the amount of: removal of the uterine appendages, leaving the tumor sites on the right-side and posterior walls of the pelvis 7 x 4 cm and 5 x 4 cm, with a large omentum resection. During the audit during the operation, in addition to ovarian tumors and metastases in the Douglas space, small tumors were found on the parietal and visceral peritoneum of the abdominal cavity, on the surface of the liver and diaphragm, in the greater omentum. According to the histological study N 0-91103-08 "serous ovarian cystadenocarcinoma".

 From 12.11 to 12.12.93, the patient underwent subtotal irradiation of the lower half of the body on a Rocus-M gamma-ray apparatus in a regimen of 0.1 Gy 2 times a week to a total dose of 1 Gy in order to create for a sufficiently long time (1 month ) extensive, but not deep damage to normal tissues to distract the proliferative potential of the body to their regeneration.

 In the process of subtotal irradiation, the residual tumor on the right pelvic wall practically disappeared, and in the douglas space it remained only in the form of a cord without clear contours. The result is marked as the onset of remission.

 Then, in January, March and May 1994, the patient underwent 3 courses of adjuvant chemotherapy according to the CMF scheme against remission with palpable tumor residues in the Douglas space.

 In the future, the patient abstained from chemotherapy.

 To date, i.e. 5 years from the start of treatment, is in remission, is actively working.

 It should be noted that in the traditional chemosurgical treatment, according to the clinics of the Central Research Institute of Radiology and Oncology Research Institute named after prof. N.N. Petrova, the average life expectancy of patients with stages III-IV of the disease is 14.6 months. (± 0.5), and the five-year survival rate of 6.8% (± 1.3).

 To date, 71 patients with advanced ovarian cancer have been treated in this way after non-radical, cytoreductive surgery. Subtotal irradiation of the body was carried out in non-tumoricidal doses of 0.1 Gy 2 times a week to a total dose of 1 Gy (followed by adjuvant chemotherapy). The introduction of STOT in the treatment regimen for this difficult group of patients allowed us to increase the frequency of remissions in primary patients with stages III-IV compared with the results of traditional chemosurgical treatment by more than 16%, in patients with relapses - by 22.6%, while increasing the average the duration of remissions is 3 times. The indicators of 3- and 5-year survival at stages III-IV increased 4 times (28.5% versus 6.8% lived for 5 years), and in the treatment of relapses, 3-year survival from zero values increased to 13 months.

The proposed method in comparison with the known has the following advantages:
1. The method is based on the competitive relationship between proliferation in a tumor and proliferation in normal tissues caused by their preliminary damage, which is a fundamentally new approach to slowing tumor growth and achieving remission.

 2. The method is not associated with the aggressive effects of chemo- and radiation therapy, which are carried out only in gentle modes.

 3. The method expands the possibilities of treating patients with common forms of malignant neoplasms.

 The method was developed at TsNIRRI MH of Russia on the basis of long-term observations of treatment results and has been tested in experimental animals and is currently in the clinic for patients with stage III-IV ovarian cancer.

Used Books
1. Gershanovich M. L., Paykin M. D. Symptomatic treatment of patients with malignant neoplasms in advanced stages. - M .: Medicine, 1980.

 2. Kappauf N. at al. Annals of Oncology. 1997, 8, 1031-39.

 3. Babaeva A.G. et al. Archive of pathology. 1993, N 1, 63-65.

Claims (1)

 A method of slowing the growth of malignant tumors, including adjuvant chemotherapy, characterized in that they additionally carry out the destruction of healthy tissues, prolonging it until remission occurs.