RU2606108C2 - Method of brachytherapy for localised prostate cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, urology, radiology, methods of registration auto fluorescence of tissues for more efficient use of low-dose brachytherapy of localised forms of malignant tumors of the prostate gland. Implantation is carried out at ultrasound control of microcapsules with radionuclide I-125 by trans-perineal access in prostate tumor tissue by template with holes with a pitch of 5 mm. Previously at the beginning of operation through the holes of the template is introduced in prostate tissue a diagnostic catheter for registration of auto fluorescence. Determined amount of centers of auto fluorescence typical for tumor tissue, and their boundaries. According to this data is determined the radiation dose, number of microcapsules and nature of their distribution at implantation.

EFFECT: method allows more precise and specifically explore a whole volume of the body, exclude the possibility of passage of prostate parenchyma sections at its complex anatomical structure or considerable dimensions, as well as use the obtained value for target distribution of micro sources and calculation of necessary doses to avoid bringing excess radiation effect on the surrounding healthy tissues, reduce rate of developing early and late radiation complications.

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Description

The invention relates to oncology, urology, radiology, and in particular to methods for recording autofluorescence of tissues in order to more effectively conduct low-dose brachytherapy of localized forms of malignant neoplasms of the prostate gland.

Prostate cancer is one of the most important problems of oncourology. At the beginning of the XXI century, malignant neoplasms of this localization were among the most common diseases among the male population of most countries of the world. In the structure of oncological diseases of a number of countries, prostate cancer confidently takes 2-3 places after lung and stomach cancer. The prevalence of cancer of this localization in Russia in 2014 amounted to 116.4 per 100 thousand of the population. Due to the development of screening programs and the introduction of tumor markers into everyday practice, tumors began to be detected in the early stages of development. Such formations are characterized by compact localization, lack of spread to surrounding tissues and lesions of the lymph nodes, and they do not have distant metastases (T1-2N0M0). The proportion of patients with stage I-11 prostate cancer with a first-time diagnosis is 52.5%. Mortality of patients during the year since the establishment of this diagnosis in 2014 is 9.7%. These facts (significant morbidity, relatively high detectability of the tumor in the early stages, high mortality) indicate the need to improve treatment methods for the initial stages of prostate cancer.

Currently, surgical treatment of localized prostate cancer (T1-T2) and organ-preserving treatments are alternative. Nevertheless, radical prostatectomy traditionally remains the main form of treatment for these patients. The most commonly used is posadilon prostatectomy, which is associated with the ability to perform pelvic lymphadenectomy from this access before removing the prostate gland, with less difficulty mobilizing the neurovascular bundle and, therefore, maintaining potency in most patients. The stages of surgical intervention are pelvic lymphadenectomy, prostate mobilization, ligation and intersection of the dorsal venous complex, urethral intersection and mobilization of the posterior surface of the prostate gland, excretion of seminal vesicles and ampoules of the vas deferens, excision of the bladder neck. After removal of the drug, consisting of the prostate, seminal vesicles and stumps of the vas deferens, a thorough hemostasis is performed. The neck of the bladder is sutured like a “racket” to a diameter that passes the tip of the index finger. Next, perform the imposition of a vesicourethral anastomosis. (I.G. Rusakov, A.A. Teplov, B.Ya. Alekseev "Surgery for tumors of the genitourinary system", Atlas of oncological operations, edited by V.I. Chissova, Α.X. Trakhtenberg, A.I. Pacesa, M: GEOTAR-Media, 2008, p. 538-545).

The disadvantages of this method are the organ-bearing nature of the treatment, frequent urogenital dysfunction in the postoperative and long-term periods, as well as the risks associated with anesthesia, a long stay of the patient in a hospital.

For half a century, remote radiation therapy of localized prostate cancer has been used as an organ-preserving treatment. The target of radiation exposure is the prostate gland itself, less commonly the seminal vesicles and lymph nodes. An important point in planning is topometric preparation, which is carried out using a simulator, a computer tomograph, which allows you to most accurately determine the boundaries of the organ and the relationship with neighboring structures. Currently, a 4- or 3-pole irradiation technique is used with a total focal dose of at least 65-70 Gy in a period of 6.5-7 weeks. With good technical capabilities in some centers reach a total focal dose of 74-76 Gy. (O. B. Karjakin “Standards in the treatment of various stages of prostate cancer” J. Practicaloncology, 2001, No. 2 (6), pp. 24-25).

The disadvantages of remote radiation therapy for prostate cancer are the duration of treatment (45-60 days), the development of radiation complications (cystitis, prostatitis, rectitis) as a result of a partial dose to healthy tissues.

In the last decade, interstitial radiation therapy (brachytherapy) of localized prostate cancer has become widespread. At the moment, it is customary to distinguish two variants of this method: high-dose (High-Dose-Rate) and low-dose (Low-Dose-Rate) brachytherapy.

High-dose (temporary) prostate cancer brachytherapy is used in patients with locally advanced tumor process in mono mode, as well as in combination with remote radiation therapy. A high-dose preparation of iridium-192 (Ir-192) is used. Indications for the High-Dosc-Rate brachyterpia are aggressive prostate tumors, stages cT2-T3, Gleason's score is 7 and above, PSA is above 10 (group of patients with prostate cancer intermediate prognosis). At the stage of treatment planning, computer programs calculate the effective dose and exposure time, as well as the coordinates of the position of the radiation source in the patient’s body. The radioisotope is located inside special delivery devices (temporary implants, catheter, needles or applicator), which are placed for a certain time in the area of tumor tissue. (A. Challapalli, Ε. Jones, C. Harvey, GO Hellawell, SA Mangar "High dose rate prostate brachytherapy: an overview of the rationale, experience and emerging applications in the treatment of prostate cancer" The British Journal of Radiology, 2012 Nov ; 85 (1): p. 18-27).

Closest to the claimed method (prototype) is Low-Dose-Rate (constant) brachytherapy. The method involves the use of two radionuclides (radioisotopes): iodine-125 (I-125) and palladium-103 (Pd-103), located in a special titanium capsule (microcapsule or "grain" (from the English. Seed - seed)). The average energy released during the decay of I-125 is 0.028 MeV. The half-life of this radionuclide is 60 days. I-125, as a rule, is used in patients with high and medium-grade tumors (Gleason index is from 2 to 6), and with PSA values less than Jung / ml (a group of patients with prostate cancer has a favorable prognosis). In the case of I-125 monotherapy in the prostate, a dose of 140-160 Gy can be achieved (which is 2-3 times higher than with remote radiation therapy). Palladium-103 is more commonly used for low-grade tumors when the Gleason index is 7 or higher. The total dose of monotherapy with its use is 115 Gy, and when combined with remote radiation therapy - 70-90 Gy. The procedure for conducting low-dose brachytherapy takes from 40 minutes to 2 hours, depending on the volume of the prostate gland and the anatomical features of the patient. The method can be applied in inoperable patients with somatic pathology. (S.A. Ivanov, A.D. Kaprin, K.N. Milenin, I.A. Albitsky, K.V. Ivancnko “Results of low-dose brachytherapy as radical treatment of prostate cancer”. 2011, No. 5 (1), pp. 73-76).

However, the disadvantage of this method is the impossibility at the planning stage of an accurate assessment of the boundaries of tumor-modified tissues, which is limited by the sensitivity and specificity of instrumental imaging methods used for this purpose (ultrasound, MPT, KG).

The objective of the present invention is the direct identification of foci of tumor growth in the prostate gland, the exact determination of their actual distribution using autofluorescence diagnostics with the aim of more targeted and effective low-dose interstitial brachytherapy, while reducing radiation exposure to the surrounding unchanged tissue, reducing the cost of treatment.

The use of this invention in clinical practice will create the conditions for delivering the maximum radiation dose directly to the tumor site, which will achieve an increase in the rates of relapse-free and overall survival of patients with localized forms of prostate cancer, and will also significantly reduce the impact on surrounding healthy tissues, thereby improving quality life of this category of patients.

These therapeutic results in the implementation of the invention are achieved due to the fact that microcapsules with a radionuclide I-125 are implanted in the prostate tumor tissue using a template with holes with a step of 5 mm, using the template with a Low-Dose-Rate brachytherapy.

A feature of the proposed method is that before the implantation of the microcapsules, through the holes in the template, a diagnostic catheter is inserted into the tissue of the prostate gland to register autofluorescence, the boundaries of the tumor-changing tissues are determined, and microcapsules with the radionuclide I-125 are distributed precisely, taking into account the fluorescence navigation data.

The use of this invention will increase the efficiency of low-dose brachytherapy of malignant neoplasms of the prostate gland due to the ability to accurately identify foci of tumor tissue, targeted injection of microcapsules with I-125 radionuclide into these areas, and minimizing the radioactive effects on surrounding normal tissues.

The invention is illustrated by a detailed description of the method and clinical examples.

The method is as follows.

At the planning stage of the procedure, specific radiation diagnostics are carried out in order to obtain a 3D image of the prostate gland (an estimate of the size and shape of the organ). For this, ultrasound, CT or MRI are used.

Before starting low-dose brachytherapy, the colon is prepared for the patient through a cleansing enema.

During the procedure, the patient is in a supine position with raised, bent and divorced fixed legs. A catheter for epidural anesthesia is being performed or general anesthesia is performed. At the same time, an ultrasonic sensor is transrectally inserted and fixed.

A template is installed on the perineum, which is a rigid matrix with holes in increments of 5 mm. Through these openings, a diagnostic catheter recording autofluorescence is inserted into the tissue of the prostate gland and the presence of tumor tissue in the prostate gland is determined. Next, using the same template using the needles, microcapsules with the radionuclide I-125 are installed. The implantation of microcapsules into the prostate is carried out taking into account the planned dosage of radiation, the number of microcapsules, revealed foci of autofluorescence characteristic of tumor tissue. When all the microcapsules are inserted into the prostate tissue, the needles are removed, leaving the microcapsules with the I-125 radionuclide in the prostate gland.

The procedure lasts from 40 minutes to 2 hours, depending on the volume of the prostate gland and the anatomical features of the patient and can be performed both in a hospital and on an outpatient basis.

Clinical examples of implementation.

Clinical example 1.

Patient Α., 71 years old, turned to the Moscow Research Institute of Medicine. P.A. Herzen complaining of an increase in PSA to 12.6 ng / ml. The growth of the tumor marker has been observed over the past 9 months. He appealed to the City Clinical Hospital at the place of residence, where adenocarcinoma was revealed by the results of a multifocal biopsy of the prostate gland.

According to a comprehensive examination: histological examination - adenocarcinoma, 5 points but Glysopu (2 + 3); Ultrasound of the abdominal cavity and pelvis, TRUS - the prostate is enlarged in size 46.8 × 37 × 48.4 mm (volume 44 cm ³ ), with a clear contour, the structure is moderately heterogeneous; a node of hyperplasia with dimensions of 42 × 27.5 × 34.8 mm, a heterogeneous structure; peripheral areas on both sides, more to the right, of a moderately heterogeneous structure with many hypoechoic inclusions up to 6-7 mm; seminal vesicles are symmetrical, not dilated, up to 8 mm in size. An X-ray examination of the chest cavity revealed no focal pathology in the lungs; with scintigraphy of bones of the skeleton - there is no focal pathology. PSA - 15.0 ng / ml. A clinical diagnosis was made: Stage II prostate cancer (cT2 _a N0M0).

Given the localized nature of the tumor lesion, the lack of spread of tumor tissue per capsule of the prostate gland and data for distant metastasis, a consultation plan was developed for the brachytherapy of prostate cancer using the radionuclide iodine-125 with autofluorescence navigation.

In the radiological operating room under spinal anesthesia, at the first stage, ultrasound volumetry of the prostate was performed using an ultrasound transrectal sensor in order to determine the volume, configuration of the organ, and construct a 3D image using the planning system software. Then, a template was installed on the crotch, which is a rigid matrix with holes in increments of 5 mm. Through these openings, a fiber-optic diagnostic catheter of the LESA-01-BIOSPEC spectrometer, which records autofluorescence, was introduced into the tissue of the prostate gland. In the right lobe of the prostate gland 1 lesion of tumor tissue 8 × 23 mm in size was revealed. Under the control of X-ray and ultrasound devices, taking into account the autofluorescence diagnostics data, 11 granules (flow rate - 13 granules) of iodine-125 radionuclide (SSC RF-IPPE, Obninsk) from calculating a dose of 160 Gy on the size of the tumor focus. Source activity on the introduction day of 0.421 mCi; total activity - 18.53 mCi. Intervention suffered satisfactorily.

The postoperative period was uneventful. Urination independent, adequate diuresis. 2 days after the procedure in satisfactory condition, the patient was discharged from the hospital under the supervision of an oncourologist at the place of residence. At the control examination after 3 months - PSA - 5.0 ng / ml; Ultrasound of the abdominal cavity, pelvis, CARGO - radioactive grains are in the prostate gland; with chest x-ray - no evidence of focal pathology.

Clinical example 2.

Patient B., 72 years old, about increasing the PSA level to 8.0 ng / ml, turned to the Moscow Scientific Research Institute named after P.A. Where was Herzen diagnosed with stage II prostate cancer (cT2 _a N0M0). When scintigraphy of the bones of the skeleton and radiography of the pelvic bones - no signs of metastatic lesion were detected. An X-ray examination of the chest cavity from 10.16.07: no focal and infiltrative shadows were detected. With ultrasound of the abdominal cavity and small pelvis, CARGO - the prostate gland is slightly increased in size (volume 32 cm ³ ). The structure of the parenchyma is heterogeneous, a zone of reduced echogenicity of 16 × 14.4 mm is visualized in the peripheral parts of the right lobe, and single calcifications up to 3 mm are visualized in the thickness. The outer contour is smooth, the integrity of the capsule is preserved. Seminal vesicles up to 6 mm. Histological examination - small-acinar adenocarcinoma, 5 points according to Gleason (3 + 2).

At a consultation with surgeons, radiologists, chemotherapists, taking into account the localized nature of the tumor process, it was decided to conduct a low-dose prostate cancer brachytherapy with the radionuclide iodine-125 with autofluorescence navigation for this patient.

In a radiological operating room under conditions of spinal anesthesia, ultrasound volumetry of the prostate was performed using an ultrasound transrectal sensor. A template was installed on the perineum, through the openings of which a fiber-optic diagnostic catheter of the LESA-01-BIOSPEC spectrometer was introduced into the prostate tissue, which recorded autofluorescence. In the right lobe of the prostate, 2 foci of tumor tissue, 10 × 18 mm in size, were detected. Under the control of x-ray and ultrasound devices, taking into account the autofluorescence diagnostics data, 14 granules (flow rate - 50 granules) of iodine-125 radionuclide (SSC RF-IPPE, Obninsk) from calculating a dose of 160 Gy on the size of tumor foci. Source activity on the day of implementation: 0.32 mCi; total activity - 14.10 mCi. The patient suffered a satisfactory intervention.

The postoperative period was uneventful. Urination independent, adequate diuresis. 3 days after the procedure in satisfactory condition, the patient was discharged from the hospital under the supervision of an oncourologist at the place of residence. At the control examination after 3 months - PSA - 3.0 ng / ml; Ultrasound of the organs of the abdominal cavity, pelvis, CARGO - radioactive grains are in the prostate gland, urethritis phenomena of 1 degree; with x-ray of the chest organs - without fresh focal and infiltrative formations.

Clinical example 3.

Patient V., 59 years old. During a routine examination at the City Clinical Hospital, an increase in PSA to 15.0 mg / ml was revealed. A prostate biopsy was performed, morphologically - an adenocarcinoma. For further examination and development of treatment tactics, he turned to the Moscow Scientific Research Institute of Medical Sciences. P.A. Herzen. Clinical diagnosis made: Stage II prostate cancer (cT2 _c N0M0). Hormone therapy was started in the MAB mode for 3 months, then the administration of androcur continued. During the follow-up examination: ultrasound, TRUS - the prostate is not enlarged (volume 13 cm3), with a clear even contour, the structure is diffusely changed in both lobes with a decrease in echogenicity, the vesicles are not expanded, symmetrical, the paraprostatic tissue is not changed, the bladder is not filled adequately, the wall is not thickened, homogeneous anechoic content. An X-ray examination of the chest cavity revealed no focal pathology in the lungs. When scintigraphy of the bones of the skeleton - signs of focal lesions of the bones are not detected. PSA was 1.2 ng / ml. The histological conclusion is small-acinar adenocarcinoma, 6 points according to Gleason.

Given the localized location of the tumor, the intactness of the capsule of the prostate gland, as well as the lack of data for distant metastasis, the council developed a treatment plan: brachytherapy of prostate cancer with the radionuclide iodine-125 with autofluorescence navigation.

In the radiological operating room under spinal anesthesia, at the first stage, ultrasound volumetry of the prostate was performed using an ultrasound transrectal sensor in order to determine the volume, configuration of the organ, and construct a 3D image using the planning system software. Then, a template was installed on the crotch, which is a rigid matrix with holes in increments of 5 mm. Through these openings, a fiber-optic diagnostic catheter of the LFSA-01-BIOSPEC spectrometer was introduced into the prostate tissue, which recorded autofluorescence. In both lobes of the prostate gland, up to 8 foci of tumor tissue 8-20 mm in size were detected. Under the control of X-ray and ultrasound devices, taking into account the autofluorescence diagnostics data, 73 granules (flow rate - 73 granules) of iodine-125 radionuclide (JSC SSC RF-IPPE, Obninsk) from calculating a dose of 160 Gy on the size of tumor foci. Source activity on introduction day: 0.405 mCi. Total activity: 8.51 mCi. Intervention suffered satisfactorily.

The postoperative period was uneventful. Urination independent, adequate diuresis. 2 days after the procedure in satisfactory condition, the patient was discharged from the hospital under the supervision of an oncourologist at the place of residence.

At the control examination after 3 months - PSA - 0.2 ng / ml; Ultrasound of the abdominal cavity, pelvis, TRUS - radioactive grains are located in the prostate gland; with chest x-ray - no evidence of focal pathology.

Using the proposed method in clinical practice has shown that due to the detection of tumor tissue in the prostate gland by the method of autofluorescence control with low-dose brachytherapy, a more rational distribution of radionuclides in the gland tissue occurs and thereby reduces the risk of radiation complications (cystitis, prostatitis, rectitis), which significantly affect on the quality of life of this contingent of patients and require additional medical prescriptions. In addition to social and medical applications, the invention has an economic effect, since the rational use of radionuclides allows you to reduce the cost of expensive treatment. The proposed method uses radionuclides 1-125 of domestic production, which also reduces the cost of treatment and solves a number of tasks for import substitution in our country.

Claims (1)

A method for brachytherapy of localized prostate cancer, including ultrasound-controlled implantation of microcapsules with I-125 radionuclide via transient access to the prostate tumor tissue using a template with 5 mm increments, characterized in that, at the beginning of the operation, they are inserted into the prostate tissue through the holes of the template glands diagnostic catheter for recording autofluorescence, determine the number of foci of autofluorescence characteristic of tumor tissue, and their boundaries, with Using these data, the radiation dose, the number of microcapsules for implantation and the nature of their distribution during implantation are determined.