RU2805644C1 - Method of reducing radiation exposure to rectum in treatment of prostate cancer - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: invention can be used to reduce radiation exposure to the rectum in the treatment of prostate cancer (PCa). The method includes the introduction of biodegradable substances (BDS) into fatty tissue located between the wall of the rectum and the prostate gland. Spherogel with a particle diameter of 200–360 μm is used as a BDS, which is injected in a volume of 10 ml before the start of the irradiation procedure under the control of transrectal ultrasound transperineally.

EFFECT: use of the invention makes it possible to increase the distance from the anterior wall of the rectum to the prostate up to 10 mm or more, to reduce the radiation load on the anterior wall of the rectum by 40–60%.

1 cl, 1 tbl, 2 ex, 5 dwg

Description

The invention relates to medicine, namely to radiation oncology, and can be used to reduce radiation exposure to the rectum in the treatment of prostate cancer (PCa).

The topography of the pelvic organs determines the types of radiation toxicity recorded after irradiation of the prostate gland (PG). Early and late complications from the rectum are of greatest importance. For a long time, two methods have been used in clinical practice to improve the safety of radiation therapy, which consisted in choosing the optimal fractionation regimen based on the characteristics of the radiobiology of tumor and normal tissues, as well as the use of radiomodifiers. In recent years, a new way to reduce radiation toxicity has become popular, associated with a mechanical increase in the distance from the irradiated volume to critical organs. This idea is implemented through the introduction of biodegradable substances (BDS) or spacers (English - space) into tissues, causing a temporary change in the spatial relationship between organs. The anatomy of the pancreas allows us to demonstrate the advantages of this approach as much as possible:

1. adherence of the anterior wall of the rectum to the irradiated target (RV), which guarantees its entry into the high-dose zone;

2. the presence of fiber between the Denonvilliers aponeurosis, covering the pancreas and rectum;

3. the possibility of relatively simple administration of BDS through the skin of the perineum.

There is a known method of reducing radiation exposure in the treatment of prostate cancer by perineal injection of hyaluronic acid in case of prostate cancer (Prada P.J., Fernandez J., Martinez A.A. et al. Transperineal injection of hyaluronic acid in anterior perirectal fat to decrease rectal toxicity from radiation delivered with intensity modulated brachytherapy or EBRT for prostate cancer patients. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):95-102. DOI: 10.1016/j.ijrobp.2007.02.034).

The drug “SpaceOAR ^® ” (Boston Scientific (USA)), consisting of polyethylene glycol hydrogel (PEG), has the greatest experience of use as a BDS. At the end of 2020, the first spacer based on hyaluronic acid, Barrigel ^® (Palette Life Sciences (USA)), was registered and introduced into clinical practice in Western European countries.

Currently, in the Russian Federation (RF), none of the listed drugs are approved for clinical use. In addition, the high cost of these BDS ($2,500-3,000) will be a significant limitation for their widespread use in radiotherapeutic practice, even if they are registered in the Russian Federation. There are also no domestic analogues that could successfully replace foreign BDS.

The only current experience of using another common biopolymer, collagen, as a spacer in radiation treatment of prostate cancer was published in 2012. (Noyes WR, Hosford S.S., Schultz SE Human collagen injections to reduce rectal dose during radiotherapy. Int J Radiat Oncol Biol Phys 2012; 82(5): 1918-22. DOI: 10.1016/j.ijrobp.2011.02.034 ). In this work, the authors described the administration method and pharmacokinetics of Cymetra ^® (a crushed form of AlloDerm ^® ) in 11 PCa patients treated with external beam radiation therapy (total focal dose 75.6 Gy). "Cymetra ^® " is an injection material made from the skin of a human corpse, obtained through a special processing technology that ensures antigenic and allergic safety. The main area of application of this drug is otorhinolaryngology, where it performs a volume-forming function, helping to restore the closure of the vocal cords (senile atrophic changes, Parkinson's disease, paresis and paralysis of the vocal cords). In a study by Noyes WR et al. the average value of the distance created between the prostate gland and the anterior wall of the rectum was 12.7 mm (8-19 mm), and the reduction in dose load on the latter was about 50%. The stability of the drug was moderate, which required its administration in a volume of 20 ml per procedure (standard recommended volume of “SpaceOAR ^® ” - 10 ml, “Barrigel ^® ” - 10 ml). The high cost of human collagen, as well as suboptimal spatial stability in tissues, has led to its clinical use as a spacer not being recognized, giving way to more suitable analogues based on PEG and hyaluronic acid.

Currently, the procedure for perineal introduction of spacers based on PEG and collagen during radiation treatment of prostate cancer is quite standardized and aims to create a space between the prostate gland and the anterior wall of the rectum of ≥1 cm.

The technical result of the invention is to expand the arsenal of domestic means for reducing radiation exposure in the treatment of prostate cancer, increasing the distance from the anterior wall of the rectum to the prostate to 10 mm or more, reducing the radiation exposure to the anterior wall of the rectum by 40% -60%.

The specified technical result is achieved in a method for reducing radiation exposure to the rectum in the treatment of prostate cancer by introducing biodegradable substances (BDS) into the fatty tissue located between the wall of the rectum and the prostate gland, in which “Sfero®GEL” with a particle diameter of 200 is used as a BDS -360 microns, which in a volume of 10 ml is administered transperineally before the start of the irradiation procedure under the control of transrectal ultrasound.

The method is illustrated in Fig. 1-5, where:

In fig. 1 - scheme for introducing a BDS (spacer) based on the drug "Sfero®GEL";

In fig. 2 - topometric MP tomography of patient U. with an inserted paraprostatic spacer (sagittal scan);

In fig. 3 - control MP tomography of patient U., performed two weeks after the introduction of the spacer and the end of radiation treatment (sagittal scan);

In fig. 4 - topometric MP tomography of patient B. with an inserted paraprostatic spacer (sagittal scan);

In fig. 5 - control MP tomography of patient B., performed two weeks after the insertion of the spacer and the end of radiation treatment (axial scan).

As our studies have shown, a biodegradable gel (Sfero®GEL, JSC Biomir Service, Moscow; per. certificate RU No. FSR 2012/13033 dated July 15, 2015) with a particle diameter of 200-360 microns allows you to increase the distance from the front wall rectum to the prostate up to 10 mm or more, and when irradiating the prostate gland, reduce the radiation load on the anterior wall of the rectum by 40%-60%.

The inventive method is based on a study conducted in 2019 to test various domestically produced biopolymers as radiotherapeutic spacers.

The first experience was associated with the use of the drug “Mesogel ^® ” (NPO Lintex, St. Petersburg). The basis of this hydrogel, approved for introduction into human cavities and cellular spaces (registration certificate dated April 27, 2018 No. FSR 2010/08895), is represented by carboxymethylcellulose. About 10 ml of the drug was injected into the paraprostatic space using standard methods. The procedure for introducing Mesogel ^® (7 patients) was not accompanied by any complications. However, MRI of the pelvic organs the very next day after implantation demonstrated almost complete migration of carboxymethylcellulose along the perirectal tissue without creating the recommended (about 1 cm) space between the structures of interest in all 7 observations, which made it impossible to use this drug as a BDS during irradiation of the pancreas.

The experience of using the second domestic drug “Bellarti Lift®” (Grotex LLC, St. Petersburg) (registration certificate RZN 2020/12181 dated 10/07/2020) based on a 1.8% solution of hyaluronic acid in a group of 10 patients also did not allow get satisfactory results. Control MP studies revealed a significant decrease in the volume of the administered drug (10 ml) on days 3-4. The low local stability of Bellarti Lift ^® does not allow providing the necessary spatial topographic anatomy of the prostate and critical structures throughout the course of radiation therapy.

Optimal results were obtained using the domestic drug “Sphero®GEL” (Biomir Service, Moscow) (registration certificate RU No. FSR 2012/13033 dated July 15, 2015). “Sphero ^® GEL” is a heterogeneous composition consisting of microparticles of “cross-linked” collagen of animal origin, placed in a gel identical to the natural extracellular matrix. To date, long-term experience in the clinical use of this drug has been accumulated in the field of traumatology, neurosurgery, surgery, urology, ophthalmology, gynecology and cosmetology.

Depending on the size of the cross-linked Sphero ^® GEL fraction, there are three main versions of this drug (Table 1).

The experience of using Sfero ^® GEL in LIGHT and MEDIUM variants in a group of 12 patients demonstrated insufficient stability in tissues, which was manifested in the rapid migration of injected collagen throughout the entire volume of paraprostatic tissue already on days 1-3 after its administration. The use of the heaviest fraction (10 patients) - LONG with cross-linked particle sizes of 200-360 microns - as a spacer made it possible to achieve the required distance equal to or greater than 1 cm, which was maintained throughout the entire period of radiation treatment (at least 14 days). In all observations, regardless of the form of the drug used, there were no negative local (general) reactions or complications caused by BDS implantation.

The method is carried out, for example, as follows:

two hours before the procedure, a cleansing enema and preparation of the surgical field are performed (shaving the skin of the perineum);

- 30 minutes before the procedure, antibacterial prophylaxis is carried out with a single parenteral administration of a broad-spectrum antibiotic;

- the patient is placed in the lithotomy position for perineal manipulation;

- after inserting the endorectal sensor into the rectum, attached to the stepper, the skin of the surgical field is treated with an antiseptic solution;

- standard installation of three radiopaque markers is carried out in different lobes of the prostate gland;

- through local infiltration anesthesia with a 1% lidocaine solution, anesthesia is performed at the skin point of insertion of the introducer needle and paraprostatic tissues;

- to introduce a sufficiently dense substance, introducer needles with a diameter of 14-16 CH are used;

- insertion of the introducer needle is carried out strictly along the midline 1-1.5 cm above the anal verge;

- advancement of the introducer needle is carried out under ultrasound control in the sagittal scanning plane into the space between the aponeurosis; Denonvilliers and the prostate (top) and the anterior wall of the rectum (mesorectal fascia) below (Fig. 1);

- when the introducer needle reaches the level corresponding to the middle of the prostate gland, hydrodissection is carried out with a 1% lidocaine solution in a volume of 2-3 ml to create a primary space and orientation in the tissue layers to prevent damage to the anterior wall of the rectum by the needle;

- the implanted drug is administered in a volume of 10 ml, followed by removal of the introducer needle;

- apply an aseptic bandage to the skin of the perineum.

The method is illustrated by clinical examples.

Example 1 (Fig. 2, 3). Patient U., born in 1969 Clinical diagnosis: prostate cancer cT2aN0M0G2. PSA level - 8.7 ng/ml (intermediate risk group according to NCCN). Indications for stereotactic radiation therapy were formulated (5 fractions of 7.25 Gy to a total focal dose of 36.25 Gy, an isoeffective dose equivalent to the dose with a fractionation regimen of 2 Gy (EQD ₂ ) (α/β - 1.5 Gy) - 90 , 6 Gy). Before carrying out topometric studies (CT and MRI), 10 ml of spherogel (spacer) - “Sphero®GEL” LONG with cross-linked particle sizes of 200-360 µm (Fig. 2) was introduced according to the standard method.

A preliminary (before the introduction of the spacer) calculation of the dosimetric plan demonstrated a high dose load on the rectal area: the D _2cc value (dose delivered to 2 cm ³ of the rectum) was 35 Gy (EQD ₂ (α/β 3 Gy) = 70 Gy eq. ), which is quite close to the recommended limit for this indicator - 75 Gy eq. The introduction of a spacer made it possible to reduce the calculated value of D _2cc by 40% - 42 Gy eq.

Example 2 (Fig. 4, 5). Patient B., born in 1970 Clinical diagnosis: prostate cancer cT2cN0M0G2. PSA level - 7.3 ng/ml (intermediate risk group according to NCCN). Radiation treatment was planned in the form of stereotactic radiation therapy (5 fractions of 7.25 Gy). Before planning radiation therapy, a spherogel (spacer) - “Sphero®GEL” LONG with cross-linked particle sizes of 200-360 microns was introduced in a volume of 10 ml (Fig. 3).

The dosimetric benefit from using a spacer relative to the load on the rectum was 57%.

In all ten clinical cases, a reduction in radiation exposure to the anterior wall of the rectum by 40%-60% was achieved.

Thus, the proposed method expands the arsenal of domestic means for reducing radiation exposure in the treatment of prostate cancer, allows increasing the distance from the anterior wall of the rectum to the prostate to 10 mm or more, and reducing radiation exposure to the anterior wall of the rectum by 40% -60%.

Claims (1)

A method for reducing radiation exposure to the rectum in the treatment of prostate cancer (PCa) by introducing biodegradable substances (BDS) into the fatty tissue located between the wall of the rectum and the prostate gland, characterized in that a spherogel with a particle diameter of 200-360 is used as a BDS micron, which in a volume of 10 ml is administered transperineally before the start of the irradiation procedure under the control of transrectal ultrasound.