COMPARATIVE EVALUATION OF RESULTS OF HIGH AND LOW DOSE RATE BRACHYTHERAPY IN THE TREATMENT OF LOCALIZED PROSTATE CANCER

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Introduction. The incidence of prostate cancer is about 14.5% of all cases of cancer in men. In recent decades, there has been a tendency towards an increase in the incidence, its annual increase, which determines the relevance of this health problem [8]. In prostate cancer, advanced forms are often diagnosed (up to 70%), dictating the need to shift the priorities of national health care to early detection of pathology and the search for new methods of effective therapy [1]. When making a diagnosis of localized prostate cancer (lPC), the oncologist faces the task of choosing the tactics of treating the patient, since both surgical and radiation methods are possible. Radical prostatectomy (RP) is a complex, traumatic intervention, often leading to serious urinary problems (13-25%), in severe sexual dysfunction (60-93%). In recent years, as an equal alternative to radical prostatectomy for the treatment of this category of patients, radiation therapy has been used, represented by standard 3D conformal external beam radiation, intensity-modulated methods of external beam radiation therapy, stereotactic radiation therapy and brachytherapy (BT) using sources with low (BT-LMD) ) or high dose rate (BT-HMD) [8]. The distribution of low and high dose rate brachytherapy is based on the definition of the International Commission on Radiation Units & Measurements (ICRU) in accordance with the value of the absorbed dose rate: from 40 to 200 cGy / h - BT-NMD, > 1200 cGy/h – BT-VMD [9]. BT-NMD and BT-AMD are competing treatments for lPCa and have a number of fundamental differences. They differ in dose rate and fractionation, in radiobiological properties, and in the technique of source implantation [5, 12, 14]. BT-NMD has the advantage of one procedure, minimal risk of surgical complications. The results of treatment have been confirmed by long-term follow-up and the presence of a large number of studies, which made it possible to include BT-NMD in the standards for the treatment of prostate cancer [13]. The half-life of I-125 is 59.4 days. The total focal dose (SOD) during BT-NMD is not less than 145 Gy for the prostate gland (PG). The maximum allowable load on the urethra is 140 Gy, the rectum and bladder are 30 Gy. The use of low energies provides a high dose drop gradient. The load on other organs and structures of the small pelvis does not exceed 0.1 Gy [6, 10]. There are a number of factors that negatively affect the accuracy of summing up the planned radiation dose: the possibility of migration of the introduced radioactive grains, differences in the planned and actual location of radiation sources, which can reach 8-13 mm. The reason for the significant variability in the final distribution of the total radiation dose in BT-NMD is the change in the volume of the pancreas at different times after the administration of I-125 due to pronounced edema in the early stages after implantation of radiation sources [4, 9, 15]. BT-AMD is an invasive procedure that requires several consecutive operations at different intervals between each other. In Russia, BT-AMD has been successfully used since 2008; for the first time, this technique was introduced into clinical practice at the Russian Scientific Center for Roentgen Radiology of Rosmedtekhnologii (RSRCR), Moscow [7]. Currently, there are no randomized trials describing the results of treatment (more than 10 years). Physical SOD during BT-AMD is 30 Gy for the pancreas, the biological equivalent dose (BED) is 330 Gy, the isoeffective dose (EQD) is 141.4 Gy, the maximum allowable dose for the urethra is 32 Gy, and the rectum is 22.5 Gy. BT-AMD has an advantage in terms of dosimetric monitoring during the course of irradiation, which cannot be said about BT-LMD, which can cause source migration. From the point of view of radiobiology, BT-AMD is more effective, since it is preferable to use hypofractionation regimens during radiation therapy for prostate cancer. The α/β ratio for pancreatic adenocarcinoma is 1.5 Gy (1.2-3 Gy). If the α/β ratio in the tumor is lower than for normal tissues, increasing the dose per fraction will increase the biologically effective dose for the tumor (at an α/β ratio of 1.5) by a larger amount than for normal tissues (at an α/β ratio 3-10), thereby increasing therapeutic efficacy. [2, 3, 9]. Materials and methods. The study included 226 patients with localized T1-2N0M0 prostate cancer who received contact radiation therapy with sources of various dose rates according to a radical program. All patients were diagnosed with adenocarcinoma of the prostate. With a clarifying diagnosis, it was found that the tumor did not spread to the seminal vesicles, there was no invasion into the paraprostatic tissue, and there were no distant metastases. The study included patients at low or intermediate risk of progression according to the NCCN criteria [11]. According to the treatment, the patients were divided into 2groups. The first group consisted of 88 (39%) patients treated by the BT-AMD method with the Ir-192 source in an independent version (2 fractions of 15 Gy each) on the basis of the Voronezh Regional Clinical Oncological Dispensary for the period from 2015 to 2018 using the GammaMed iX device plus. Biological equivalent dose (BED) 330 Gy, isoeffective dose (EQD) 141.4 Gy. The second group included 138 (61%) patients who received BT-NMD with I-125 source (1 fraction 140-160 Gy) on the basis of the Federal State Budgetary Institution "Russian Scientific Center for Roentgen Radiology" for the period from 2010 to 2016. The study was conducted on the basis of the relevant contract. The median follow-up in both groups was 39.5 months. The characteristics of patients in groups are presented in Table 1. Table 1 General characteristics of patients. Characteristics of BT-VMD BT-NMD N 88 138 Age 64.5±6.2 65.3±6.8 Stage T1a-T2a 58 66% 75 54.3% T2b-T2c 30 34% 63 45.7% Gleason index G1 - Gleason score 5-6 76 86.4% 112 81.1% G2 - Gleason score 7 (3+4) and (4+3) 12 13.6% 26 18.8% Peak PSA level before treatment Less than 10 ng/ml. 69 78.4% 85 61.6% 10-20 ng/ml. 19 21.6% 53 38.4% Androgen Deprivation Therapy None 58 65.9%* 7 5%* Was 30 34.1%* 131 95%* NCCN risk group Low risk 44 50% 59 42.8% Intermediate risk 44 50% 79 57.2% *p < 0.01; BT-HMD, high dose rate brachytherapy; BT-NMD low dose rate brachytherapy; PSA, prostate-specific antigen; NCCN - National Comprehensive Cancer Network. The patient groups were comparable. The groups differed statistically only in terms of androgen deprivation therapy. 95% of patients in the BT-NMD group received androgen deprivation therapy, in the BT-AMD group only 34.1% received hormonal treatment. The groups did not differ in other parameters (p>0.1). After the treatment, patients underwent a follow-up examination after 3,6,9,12 months. The examination included the determination of the level of prostate-specific antigen (PSA), filling out the questionnaires IPSS, IIEF-5, transrectal ultrasound (TRUS). Contrast-enhanced MRI and bone scintigraphy (SPECT-CT) were performed to diagnose local recurrence and/or distant metastasis. The Kaplan-Meier method was used to assess survival. When calculating the reliability of the data, the Log-Rangs criterion was used. PSA-specific survival was assessed based on the Phoenix criteria. A PSA rise of more than 2 ng/mL from nadir was taken as an event. P values ​​< 0.05 were considered statistically significant. At a p value > 0.1, there were no statistically significant differences. To assess significant differences between the distributions of the two samples, the Kolmogorov-Smirnov test was used. Statistical analysis was performed using STATISTICA v.10 software. Assessment of early and late toxicity of radiotherapy was carried out according to the RTOG/EORTC classification. Results. The median follow-up time in both groups was 39.5 months (19-60 months). All patients are alive. Overall survival was 100%. During this time period, 4 patients had a biochemical recurrence, 6 patients had a local recurrence, and 3 patients were diagnosed with distant bone metastases. In the BT-AMD group, 1 case of biochemical recurrence and 1 case with bone metastases were identified. The median follow-up time was 31.5 months (19–44 months). In the BT-NMD group, 3 cases of biochemical recurrence, 6 cases of local and 1 case of metastasis in the skeletal system, 1 case of metastasis to the lymph nodes were found. The median follow-up time in the group was 42 months (24–60 months). Figure 1. PSA - specific survival depending on the type of treatment. (plog-rank=0.067). PSA-specific survival for the presented follow-up time was 96.3% in the BT-AMD group, and 92.7% in the BT-NMD group. The frequency of local relapses, metastases to regional lymph nodes and metastases to the skeletal system is shown in Figure 2. Figure 2. Frequency of local recurrences, metastases to regional lymph nodes, and metastases to the skeletal system. In the BT-AMD group, as in the BT-NMD group, 1 case of bone metastases was observed, which was 1.1% and 0.7%, respectively. There was no statistically significant difference in the spread of the disease in the skeletal system (p>0.1). The incidence of local recurrences and bone metastases in the BT-NMD group was higher than in the BT-AMD group, where these types of progression were absent (p <0.05). When analyzing the reasons for the development of local recurrences in the BT-NMD disease group, it was noted that all patients had an intermediate prognosis and the second stage of the disease (T2b-T2c), in 5 out of 6 patients the initial PSA level was from 10 to 20 ng/ml. However, only one patient with local recurrence in the BT-NMD group had a Gleason index of 7(4+3), while the remaining 5 patients had a Gleason index of 6 (3+3). Convincing data on the relationship between the risk of developing bone metastases and the level of initial PSA, the stage of the disease, the degree of differentiation of the tumor cell, etc.about the Gleason score and the risk of progression was not received. When assessing the quality of life of patients after treatment, good tolerance was noted, the minimum number of toxic reactions in both groups. The majority of patients returned to their normal lifestyle 3-6 months after treatment. After 12 months, 6% of patients reported significant adverse symptoms. When evaluating complaints of frequent urination after treatment, no statistically significant differences were found in both groups. In the BT-AMD group, 53.4±0.5% of patients complained of frequent urination, in the BT-NMD group 42.6±0.5% of patients (p>0.1). One year after treatment, the results of the IPSS urinary disorders questionnaires were analyzed - the number of points ≥ 20, which corresponded to severe urination disorders, in 2.8% and 8.2% in the BT-AMD and BT-NMD groups, respectively. Moderate urinary disorders were noted in 23.8% and 32.8% in the BT-AMD and BT-NMD groups, respectively. The absence of symptoms of urinary disorders and their mild degree in the BT-AMD and BT-NMD groups were noted in 73.4% and 59%, respectively. When evaluating the data, the Kolmogorov-Smirnov criterion was used. No statistically significant differences were obtained (p<0.1). When evaluating the results of patients filling out quality of life (QoL) questionnaires, there were no significant differences in the groups (p>0.1). Most of the patients had good (BT-AMD 31.6%, BT-NMD - 39.3%) and satisfactory (BT-AMD - 41.8%, BT-NMD - 44.3%) quality of life in groups. Unsatisfactory and poor QoL was noted by 26.6% in the BT-AMD group and 16.4% in the BT-NMD group. Assessment of immediate and long-term results will be carried out on the basis of the standard RTOG/EORTC classification scale for adverse effects of radiation treatment. Data on early and late toxic reactions in the BT-AMD and BT-NMD groups are presented in Table 2. table 2 Early and late toxic reactions in the BT-AMD and BT-NMD groups Toxic reactions BT-VMD (%) BT-NMD (%) R Early genitourinary post-radiation complications p<0.001 no 43.2 2.9 I degree 47.7 74.6 II degree 9.1 20.3 III degree 0 2.2 Late genitourinary post-radiation complications p>0.1 no 72.7 66.8 I degree 23.9 21.7 II degree 3.4 10.1 III degree 0 1.4 Early gastrointestinal post-radiation complications p<0.001 no 93.2 63.1 I degree 5.7 34 II degree 1.1 2.9 III degree 0 0 Late gastrointestinal post-radiation complications p>0.1 no 97.3 97.8 I degree 2.7 2.2 II degree 0 0 III degree 0 0 In the BT-NMD group, toxic reactions from both the urinary tract and the rectum were significantly more common. In the BT-AMD group, early genitourinary toxic reactions were 56.8% versus 97.1% in the BT-NMD group. In the BT-NMD group, 2.2% of severe complications requiring treatment in a specialized hospital were observed. Early gastrointestinal toxic reactions in the BT-AMD group were detected in 6.8% of cases, versus 36.9% in the BT-NMD group With further observation in the groups, toxic reactions decreased and after 6-12 months there was no significant difference. But the number and severity of late toxic reactions in the BT-AMD group were observed less. No grade IV complications were noted in both groups. Erectile function (EF) is one of the most important parameters that determine the level of quality of life of patients after prostate cancer treatment and, often, is the determining factor in the choice of treatment tactics. The IIEF-5 questionnaire was used to assess the retention and quality of EP after treatment in both groups. The study included patients who scored more than 16 points, that is, with good and satisfactory EF. When analyzing the statistical material, it was noted that 12 months after treatment, it was possible to maintain EF in the groups significantly differed and corresponded to 74 and 66.7% in the BT-AMD and BT-NMD groups, respectively (p <0.001). Discussion. The task of brachytherapy is to deliver more bioequivalent radiation doses to the pancreas with a decrease in the dose load on adjacent critical organs and systems of the body, which ensures the achievement of local control over the tumor with minimal loss of the patient's quality of life. In connection with the implementation of screening programs, an increase in life expectancy of the population, prostate cancer is increasingly detected in the early stages of the disease and in younger men who are interested in maintaining a high quality of life and EF. Our study included patients at low and intermediate risk of progression. PSA-specific three-year survival rate was 96.3% in the BT-AMD group, 92.7% in the BT-NMD group, which is undoubtedly a short period of time for assessing the survival of patients with prostate cancer. The main objective of the study was to assess the quality of life after competing treatment methods. When analyzing early toxic reactions, a statistically significant difference was revealed. The advantage of BT-AMD was established both in terms of the quality of urination and the rectum in the early postoperative period (p<0.001). At the control examination after 6-12 months, the difference in the manifestation of adverse eventsand decreased, but the use of BT-AMD in terms of the number of toxic reactions gave better results than BT-NMD (p<0.1). When evaluating sexual function in the BT-AMD group, EF indicators were higher than in the BT-NMD group. When assessing the local control of the tumor, the advantage of BT-AMD was noted. No local recurrences were observed in the BT-AMD group. In the BT-NMD group, 6 cases of local recurrence of prostate cancer were noted. There are a number of factors that negatively affect the accuracy of summing up the radiation dose during BT-NMD. The main factor that negatively reduces the accuracy of summing up the radiation dose is the displacement of I-125 microsources, which leads to differences between the calculated dosimetric plan and the real one. Edema of the pancreas, which develops on the first day after surgery, may be the cause of the distortion of the planned radiation dose. The half-life of I-125 is 59.4 days. During this entire period, the implanted grains of I-125 deliver the planned radiation dose. A change in the architectonics of the pelvic organs due to changes in the volume of the bladder, rectum in the process of human life is an important unfavorable factor that reduces the accuracy of summing up the radiation dose in BT-NMD. The technology of conducting BT-AMD has a more accurate way of summing up the radiation dose to the pancreas. Radiation therapy planning for BT-AMD is carried out in real time. The exposure time, depending on the activity of the Ir-192 source, varies from 10 to 50 minutes, while the prostate is fixed due to intrastats introduced into it. There is no change in the position of the prostatic urethra, bladder, or rectum. Changes in the shape and volume of these organs over a given period of time is minimal. This allows much more accurate delivery of the planned radiation dose to the prostate gland and critical organs in the planned volume, which ultimately affects the results of radiotherapy, including the severity of genitourinary and gastrointestinal toxic reactions. Conclusion. BT-NMD has been the gold standard of brachytherapy in patients at low risk of progression. The effectiveness of BT-NMD has been confirmed by a large number of studies and is characterized as highly effective with a low level of toxicity [12]. Currently, there is growing experience with the use of BT-AMD, which has increased interest in this method in the treatment of lPCa in a stand-alone regimen. BT-VMD ensures high accuracy of radiation dose delivery with minimal dose load on adjacent critical organs. This allows you to achieve high control over the tumor, reduce toxic reactions. The radiobiological features of hypofractionation with the use of ultrahigh doses of radiation creates the most favorable therapeutic ratio between the tumoricidal effect of radiotherapy of tumor cells and the damaging effect on normal tissues [4, 10]. The lack of large randomized trials on the use of BT-AMD, data on the comparison of treatment outcomes depending on treatment regimens, leaves the question of conducting further studies to develop optimal doses and the number of fractions relevant and clinically significant.

About the authors

Ivan Petrovich Moshurov

FSBE HE «N.N. Burdenko Voronezh State Medical University» of the Ministry of Healthcare of the Russian Federation, Voronezh. Russia.

Email: moshurov@vokod.vrn.ru
ORCID iD: 0000-0003-1333-5638
SPIN-code: 3883-6042

M.D., prof., Head of Department of Oncology N.N. Burdenko Voronezh State Medical University

Russian Federation, г. Voronezh, 4 Vaitsekhovsky St.

Natalia Viktorovna Korotkikh

FSBE HE «N.N. Burdenko Voronezh State Medical University» of the Ministry of Healthcare of the Russian Federation, Voronezh. Russia.

Email: kornat78@mail.ru
ORCID iD: 0000-0002-0308-513X
SPIN-code: 2212-6667

Candidate of Medical Sciences, Assistant, Department of Oncology

Russian Federation, г. Voronezh, 4 Vaitsekhovsky St.

Dmitry Kamenev

FSBE HE «N.N. Burdenko Voronezh State Medical University» of the Ministry of Healthcare of the Russian Federation, Voronezh. Russia.

Email: kamenev_dmitrii@mail.ru
ORCID iD: 0000-0001-9774-9496
SPIN-code: 2478-7289

Candidate of Medical Sciences, Assistant, Department of Oncology

 

Russian Federation, г. Voronezh, 4 Vaitsekhovsky St.

Sergey Povarkov

Voronezh Regional Clinical Oncological Clinic, Voronezh, Russian Federation
Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russian Federation

Author for correspondence.
Email: Sergey-povarkov13@yandex.ru
ORCID iD: 0000-0002-7040-0929

Врач-онколог онкологического отделения №2

Аспирант кафедры онкологии ВГМУ им.Н.Н. Бурденко

Russian Federation

References

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