Advantages of high-dose rate (HDR) brachytherapy in treatment of prostate cancer

A. A. Molokov, E. A. Vanina, and S. S. Tseluyko

Citation: AIP Conference Proceedings 1882, 020050 (2017); doi: 10.1063/1.5001629

View online: http://dx.doi.org/10.1063/1.5001629
View Table of Contents: http://aip.scitation.org/toc/apc/1882/1
Published by the American Institute of Physics
 Advantages of High-Dose Rate (HDR) Brachytherapy
in Treatment of Prostate Cancer
A. A. Molokov1,a), E. A. Vanina2,b), and S. S. Tseluyko2,c)
1
Regional Public Health Institution “Regional Clinical Center of Oncology”,
Ministry of Health of Khabarovsk Krai, Khabarovsk, 680042 Russia
2
Federal State Budgetary Educational Institution of Higher Education “Amur State Medical Academy”
of Ministry of Healthcare of the Russian Federation, Blagoveshchensk, 675006 Russia
a)
Corresponding author: aleksejmol@rambler.ru
b)
evanina@yandex.ru
c)
agma@nm.ru, Agma1@mail.ru

Abstract. One of the modern methods of preserving organs radiation treatment is brachytherapy. This article analyzes the
results of prostate brachytherapy. These studies of the advantages of high dose brachytherapy lead to the conclusion that
this method of radiation treatment for prostate cancer has a favorable advantage in comparison with remote sensing
methods, and is competitive, preserving organs in comparison to surgical methods of treatment. The use of the method of
polyfocal transperineal biopsy during the brachytherapy session provides information on the volumetric spread of
prostate cancer and adjust the dosimetry plan taking into account the obtained data.
Keywords: prostate cancer, brachytherapy, polyfocal transperineal biopsy

PROSTATE CANCER IN THE STRUCTURE OF CANCER MORBIDITY IN RUSSIA

Prostate cancer (PCa) ranks fourth (6.6%) in the incidence of malignant neoplasms, and in the incidence of
malignant neoplasms of the male population of Russia—the second place (14.4%), after trachea, bronchus, lung
(17.8%). The structure of the incidence of malignant neoplasms of the male population of Russia in 2015 is shown
in Fig. 1.

FIGURE 1. Structure of incidence of malignant neoplasms of the male population of Russia in 2015

Physics of Cancer: Interdisciplinary Problems and Clinical Applications

AIP Conf. Proc. 1882, 020050-1–020050-5; doi: 10.1063/1.5001629
Published by AIP Publishing. 978-0-7354-1562-1/$30.00

020050-1
 FIGURE 2. “Rough” incidence of prostate cancer (per 100 000 male population of Russia)

By increase (“Rough” indicator per 100 thousand male population) prostate cancer, compared with 2014, slightly
decreased (143.88%), but still with a huge margin in the first place, 135.5% and the average annual growth rate for
The last 10 years is the highest, is 7.76% (8.03%—2014) [1]. The dynamics of the incidence of the “rough
indicator” of PCa (per 100 000 male population) is shown in Fig. 2. Thus, the search for new effective approaches in
the treatment and diagnosis of prostate cancer is relevant today.

COMPARISON OF METHODS OF TREATMENT OF PROSTATE CANCER

Traditionally, radical prostatectomy is considered the “gold” standard in the treatment of prostate cancer, but in
recent years, advances in the treatment of prostate cancer using ionizing radiation, visibly shaken the credibility of
the “gold” standard. Kupelian et al. (2004) [2]: a comparison of the treatment results of 2991 patients in Cleveland
Clinic and Memorial Sloan Kettering, who received radical prostatectomy, external radiation therapy <72 Gy,
external radiation therapy >72 Gy, brachytherapy and a combination of brachytherapy and external radiation therapy.
The patients who were prescribed radical prostatectomy were younger, the disease was more favorable; 21% of the
patients were assigned a 6-month course of neoadjuvant hormonal therapy (an advantage to those who received
radiation therapy). Survival without biochemical progression was defined as the PSA content >0.2 after radical
prostatectomy or as three consecutive elevations in all other cases. The highest rates of 5-year survival without
progression were registered in the following groups: radical prostatectomy—81%, external radiation therapy
<72 Gy—51%, external radiation therapy >72 Gy—81%, brachytherapy—83%, brachytherapy + external radiation
Therapy—77%. Predictors of progression-free survival were prostate specific antigen (PSA) before treatment,
Gleason score and duration of treatment (years), but not T stage or hormonal therapy. Thus, the results of the
radiation treatment methods are comparable and even better than surgical methods.

RADIOBIOLOGICAL ADVANTAGE OF HIGH DOSE RATE BRACHYTHERAPY

Gryls et al. (2004): the results of the treatment of 65 patients who received radiotherapy with a high dose rate (Ir
192, 9.5 Gy 2 times a day for 2 days) and 84 patients who received brachytherapy with low dose rate (Pd1103,
120 Gy) at William Beaumont Hospital. In the majority of the patients with T1c-2a, Gleason score ”6 and PSA
content <10.36% of the patients received neoadjuvant hormonal therapy. Three-year biochemical control (as
determined by ASTRO) in 98% of the patients treated with high-dose doses and 97% with low-dose doses. The
appointment of high-power doses was associated with a mild frequency of acute reactions of level 1-3, such as
dysuria, imperative, frequent urination for urination and pain in the direct kink, as well as late complications [3].
According to the formalism of the linearly quadratic model [4], the biologically equivalent dose is defined as:
D1/D2 = (d2 + Į/ȕ)/(d1 + Į/ȕ), (1)
where D1 is the total dose at a single dose d1 Gy, D2 is the total equivalent dose for a single dose d2 Gy, Į—
characterizes the initial slope of the survival curve and corresponds to one-and one-shot cell death, ȕ—characterizes
sublethal cell damage.

020050-2
 FIGURE 3. Dose distribution for HDR brachytherapy for prostate cancer Co60

The function of survivors after irradiation of cells was introduced by Chadwick, Leenhouts and Kellere, Rossi
(1971–1973) [5]:
C(d) = exp(–Įd – ȕd2), (2)
where C(d) is the fraction of surviving cells after irradiation with a dose of d.
The ratio Į/ȕ has the dimension Gy and is numerically equal to the dose at which the linear function Įd is equal
to the quadratic ȕd2.
Radiobiologists in the experiments on the animal cultures and radiotherapists in a retrospective analysis of the
clinical data have established that the Į/ȕ ratio is characterized by an irradiation response and has a definite value for
each type of the tissue included in the irradiation volume.
For prostate cancer, Į/ȕ, according to various studies [6], is very low and varies from 0.4 to 6.0 Gy. If we take
Į/ȕ = 1.1 Gy, then obviously the radiobiological advantage in the treatment with high doses, so at a total dose of
D1 = 20 Gy (Brachyterapy) for two fractions (d1 = 10 Gy per fraction), the biologically equivalent dose (BED) for
classical fractionation (d2 = 2 Gy per fraction): BED1.1 = 20/((2 + 1.1)/(10 + 1.1)) = 71.43 Gy, and at 28 Gy for two
fractions: BED1.1 = 28/((2 + 1.1)/(14 + 1.1)) = 133.33 Gy. Obviously, no methods of the External beam radiotherapy
(EBRT) will give such an equivalent dose. At classical fractionation of external remote irradiation of EBRT 37
fractions of 2 Gy total dose of 74 Gy. With radiosurgery, 5 fractions of 7.25 Gy BED1.1 = 36.25/((2 + 1.1)/(7.25 +
1.1)) = 97.76 Gy.
Advantages of HDR technology:
– The highest biological equivalent dose (BED of the order of 130–140 Gy) in comparison with other radiation
methods of the treatment of prostate cancer.
– The localization of the dose (in comparison with EBRT order of 10% per 1 mm, when brachytherapy is of the
order of 20% per 1 mm) Fig. 3.
– The volume of irradiation is less than 2–5 times. There is no bias in the amount of irradiation during the
session.
– Thanks to the technology of sequential automatic introduction of the source: any dose at the standpoint, the
possibility of adjusting the position of the needles during the session (in comparison with LDR I125). The target
volume does not change during the session (with LDR and EBRT changes).
– The long-term use of the Co60 source (in comparison with the LDR I125 and HDR Ir192).
– The cost of the procedure is 8 times lower than the LDR I125.

RESULTS OF TREATMENT
The needle applicators were placed under spinal anesthesia, the position was monitored using a biplane rectal
ultrasound probe, which had a specialized application for brachytherapy of prostate cancer. The required number of
needle applicators was determined in real time, depending on the coverage of the target volume at the HDRplus
special dosimetry planning station, with the subsequent creation of a dosimetry plan for the irradiation session.

020050-3
 TABLE 1. Comparison of the results of treatment.
Research
Remote radiation therapy Brachytherapy with
Radical prostatectom, Brachytherapy with
50.4 Gy + Bust-irradiation a high dose rate of
D’Amico, low dose rate I125,
with protons 28.8 Gy, Co60, RCCO,
Risk groups (HUP)(B&W) [7] RSOC, Moscow
Zietman et al. [8] Khabarovsk
5-year survival rate
5 year old without Survival without biochemical
without biochemical
recurrence rate, % recurrence, %
recurrence, %
Low 85.0 98.0 96.4 93.1
Intermediate 65.0 91.0 90.5 93.6
High 32.0 – 83.3 80.0
The brachytherapy session itself was performed on a gamma-therapeutic device for contact radiation therapy
“MultiSource® HDR” from BEBIG (Germany) with a source of ionizing radiation Co60, and from 2015 on the
Russian complex for brachytherapy “Nukletrim”. Brachytherapy technologies, which are used at the Russian
complex “NUKLETRIM” are identical to the “MultiSource® HDR” device and do not require adaptation, allow
using the entire range of the applicators manufactured by Eckert & Ziegler BEBIG, Germany.
From 2011 to 2016, 218 sessions of brachytherapy for prostate cancer in 128 patients were performed at the
"Regional Clinical Oncology Center".
The age of the patients was 44 to 78 years. Distribution by age: up to 50 years—1 person (0.8%), 50–59 years—
32 people (25%), 60–69 years—74 people (57.8%), 70 and more years—21 people (16.4%). Observation period: 6
to 60 months. Median follow-up is 33 months.
To assess the risk group, as well as the likelihood of disease progression after the radical treatment
(radiotherapy), the most frequently used in clinical practice is the classification of D’Amico et al. [7].
This classification is important in planning treatment tactics and evaluating the results of treatment. According to
this classification, the patients who received brachytherapy can be distributed as follows:
– Low risk group of 29 patients (23.4%).
– Group of intermediate risk patients 31 people (24.2%).
– A group of high-risk patients 65 people (50.8%).
– “Saving” RT after radical prostatectomy—2 people (1.6%).
At the same time, the distribution according to the clinical stages is as follows:
– I stage—2 people (1.6%),
– II stage—82 people (64.0%),
– III stage—42 people (32.8%),
– IV stage—2 people (1.6%).
The primary maximum PSA ranged from 3.5 to 171 ng/ml.
Three cases of complications after brachytherapy were recorded: two cases of tamponade bladder (cropped with
abundant washing bladder), one case of long-term catheterisation of the bladder (within 4 days after the treatment).
These complications refer to the procedure of brachytherapy and are not associated with the radiation exposure.
With a median follow-up of 33 months, in the low-risk group, after treatment, there were two cases of biochemical
recurrence of 6.9%. In the intermediate risk group, two cases of biochemical recurrence are 6.4%. In the high-risk
group, 13 cases of biochemical recurrence are 20%. Thus, without recurrent survival (without biochemical
recurrence) during the follow-up period in the low-risk group was 93.1%, in the middle-risk group 93.6% and in the
high-risk group 80%. Local control, at the same time, was 100%, i.e. all detected cases of biochemical relapses were
caused by the presence of metastases.
Comparison of the results of the treatment with prostatectomy, remote radiation therapy 50.4 Gy with proton
28.8 Gy, brachytherapy of low power I125, brachytherapy of high dose rate Co60 from Table1.

DISCUSSION
The brachytherapy session is performed under spinal anesthesia, so it is possible to perform a polyfocal
transperineal biopsy without additional trauma to the patient. Purpose of the polyfocal biopsy:

020050-4
 FIGURE 4. Areas of positive biopsy from the results of a
polyfocal biopsy during the first brachytherapy sess

FIGURE 5. Adjustment of the dosimetry plan on the second

seance of brachytherapy, taking into account the data
of polyfocal biopsy at the first session
1. Obtaining information on the volume distribution of PCa. On the basis of the information received, an increase
in the volumetric dose distribution is possible in order to increase the effectiveness of the treatment (Fig. 4).
2. Determination of individual sensitivity to radiation. Based on the data obtained, the degree of radiation
therapy pathomorphosis, it is possible to determine the required dose of RT to achieve the best therapeutic effect,
with minimal complications (Fig. 5).
When investigating a biopsy material, we are trying to determine the individual radiation sensitivity. Based on
the data obtained, it is possible to correct the dose of brachytherapy to obtain the maximum therapeutic effect. Our
research should answer the questions:
– Is it possible to use the data of transperineal polyfocal biopsy to increase the dose in the area of positive
biopsies?
– Is it possible to determine the individual radiation sensitivity to the administered dose from a biopsy material
and, on the basis of this, adjust the dose during the second brachytherapy session?
CONCLUSIONS
After 218 sessions of brachytherapy, there were no significant radiation complications G2-3. The patients
underwent brachytherapy much more easily than EBRT at the doses above 74 Gy. At the moment, it can be
concluded unambiguously that brachytherapy with a high dose rate is a modern organ-preserving treatment for
prostate cancer.

REFERENCES
1. “Malignant neoplasms in Russia in 2015”, edited by A. D. Caprin, V. V. Starinskiy, and G. V. Petrova (MNIOI
named after P.A. Herzen, branch of the FGBU “NMIRC” of the Ministry of Health of the Russian Federation,
Moscow, 2017), pp. 4–99.
2. P. A. Kupelian, L. Potters, D. Khuntia, et al., Int. J. Radiat. Oncol. Biol. Phys. 58, 25–33 (2004).
3. I. S. Grills, A. A. Martinez, M. Hollander, et al., J. Urol. 171, 1098–1104 (2004).
4. Basic Clinical Radiobiology, edited by G. Gordon Steel (Oxford University Press, New York, 2002), p. 136.
5. T. E. Wheldon, J. Kirk, and J. S. Orr, Brit. J. Radiology 50, 681–682 (1977).
6. S. M. Oliveira, et al., Med. Phys. 39(6), 3189–3198 (2012).
7. A. V. D’Amico, R. Whittington, S. B. Malkowicz, et al., J. Clin. Oncol. 18, 1164–1172 (2000).
8. A. L. Zietman, M. DeSilvio, J. D. Slater, et al., JAMA 294, 1233–1239 (2005).

020050-5