Medical Reports and Case Studies 2021, Vol.06, Issue S4, 001-004

Review Article

Emergence of Quality Low-Dose-Rate (LDR) Brachytherapy: Ultimate Radiosurgery
for Non-Metastatic Prostate Cancer
Keisei Okamoto*Department of Brachytherapy for Prostate Cancer, Shiga University of Medical Science, Tsukinowa, Seta, Shiga 520-2192, Japan

Corresponding Author*
Keisei Okamoto
Department of Brachytherapy for Prostate Cancer,
Shiga University of Medical Science,
Tsukinowa, Seta,
Shiga 520-2192, Japan
E-mail: keiseiok814@gmail.com
Copyright: © 2021 Okamoto K. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided theoriginal author and source are credited.
Received 06 September 2021; Accepted 20 September 2021; Published 27
September 2021

Abstract
Current advents of new technology in prostate cancer treatment still carries
many problems regarding oncological outcome: Local control remains
elusive, with biochemical failure ultimately occurring in half of the patientsdiagnosed by PSA screening. Failure of the initial treatment imposes manykinds of physical, psychological, and economical burdens on the patients,
such as toxicities caused by salvage hormonal therapy or radiotherapy, riskfor developing Castration-Resistant Prostate Cancer (CRPC), and financial
insecurity after second or third salvage drug therapy.
Considering these potential adverse effects, physicians should conduct
prostate cancer treatment with the utmost care and attention to details. In
order to minimize local recurrence the author has invented a novel technique,called the “Ten-Step Method,” for seed implantation that can disseminate
quality high-dose radiation. In this review, the author summarizes technique,application and oncological outcome of the high-quality high-dose, LowDose-Rate (LDR) branchy therapy that can minimize local recurrence of
prostate cancer.
Keywords: Low-Dose-Rate (LDR) • Brachytherapy • Seed implantation

Introduction
The diagnostic frequency of no metastatic prostate cancer has increased
rapidly after the broad adoption of Prostate-Specific Antigen (PSA) screening[1]. Most of these patients select radical treatments, but those with low-risk
prostate cancer prefer active surveillance. Nguyen, et al. warned that newer
and costlier prostate cancer therapies were rapidly and widely adopted,
causing excess national spending without thorough comparative effectivenessresearch [2]. Ten years later, this trend continues with the advent of robotic
surgery and proton beam radiotherapy [3]. Despite the development of newtechnology, local control remains elusive, with biochemical failure ultimately
occurring in 40% to 60% of the patients [4].
In order to disseminate our rationale and the skills necessary to avoid prostatecancer recurrence, the author has summarized the technique and outcome ofour high-quality, Low-Dose-Rate (LDR) brachytherapy (seed implantation),
which may be the ultimate radiotherapy for patients with intermediate-risk,
high-risk, and super-high-risk prostate cancer, including pelvic lymph nodemetastasis [5-8].

Literature Review
Clinical problems in current prostate cancer treatment
As described in the introduction, many problems exist in the current prostatecancer treatment modalities that can result in treatment failure. The author

describes the reasons for treatment failure after radical prostatectomy
and external beam radiotherapy, which are the most common treatment
modalities at this time. Among the prostate cancer risk categories describedby the NCCN (National Comprehensive Cancer Network), this review excludes
low-risk prostate cancer, because patients with low-risk prostate cancer canbe safely managed by active surveillance [8]. Thus, in this review, the author
focuses on intermediate- and high-risk prostate cancer.

Problems in radical prostatectomy
Radical prostatectomy has been one of the standard treatment modalities fornon-metastatic prostate cancer. Grimm, et al. wrote a large comprehensive
review of the literature comparing risks for patients stratified by treatment
options and with long-term follow-up [9]. According to this literature review,
the Biochemical Failure-Free Survival (BFFS) rates at 8 years after radical
prostatectomy were 70% and 40% in patients with intermediate-risk and highrisk prostate cancer, respectively [9]. The BFFS rate in radical prostatectomy
has not been improved by the advent of robotic surgery [10-13].
The reason for the unsatisfactory BFFS rate in radical prostatectomy isobvious: due to the local anatomy, surgeons cannot secure a sufficient surgicalmargin as compared with surgery for rectal cancer or other types of cancer(Figure 1). As predicted in a nomogram [14-16], preoperative organ-confineddisease has often been diagnosed as non-organ-confined disease after
prostatectomy. Upstaging is commonly observed after radical prostatectomy[17,18]. The upstaging or surgical margin positivity in prostatectomy
specimen may result in insufficient excision of prostate cancer: This situation
exposes the patient to the risk of prostate cancer recurrence. After all, a long
history of outcomes of radical prostatectomy tells us that prostate cancer
should be treated beyond the prostatic capsule: Namely, an optimal treatment
for prostate cancer is a modality that can be applied outside the area of theprostatic capsule.

Problems of external beam radiotherapy
The same type of problems has been observed in External Beam Radiotherapy(EBRT): So-called high-technology EBRT equipment has been widelyadopted, including Intensity-Modulated Radiation Therapy (IMRT), helicaltomotherapy, proton beam radiotherapy and carbon ion radiotherapy. Grimm,
et al. reported BFFS rates at 8 years after EBRT of 70% and 50% in patientswith intermediate-risk and high-risk prostate cancer, respectively [9].
Apart from type of equipment, two key factors are essential to avoid local
recurrence in radiotherapy:
1) A sufficiently high radiation dose and2) Radiation exposure of the entire prostate without cold spots (insufficiently
irradiated areas in the prostate).
Concerning factor (1), the author and others have advocated that the requited
Biologically Effective Dose (BED) (α/β ratio=2) is 200Gy in intermediaterisk prostate cancer and 220Gy in high-risk prostate cancer [5-8,19,20].

Figure 1. Anatomical difference between radical prostatectomy and rectal cancer
surgery.
Sufficient surgical margins exist in rectal cancer surgery (right), but not in radical
Prostatectomy (left). Red oblongs show lesions of prostate cancer or rectal
cancer.
Black lines demonstrate surgical excision lines in radical prostatectomy (left) andrectal cancer surgery (right).
1Medical Reports and Case Studies 2021, Vol.06, Issue S4, 001-004
Stone, et al. have shown that patients with Gleason 8-10 disease receivinga Biologically Effective Dose (BED) ≥ 220Gy by combination therapy with
Low-Dose-Rate (LDR) brachytherapy and EBRT, obtained improvementin Biochemical Failure-Free Survival (BFFS) [19]. Regarding BED, recent
representative BEDs by new EBRT equipment were 157Gy by IMRT [21],156Gy by helical tomotherapy [22], 148Gy by proton beam radiotherapy[23], 161Gy by carbon ion radiotherapy [24]. All of these modalities failed
to achieve the optimal BED proposed by this author and others [5-8,20] .
A second problem, which may result in development of cold spots, arises
because the prostate is an organ in continuous motion during EBRT: This
problem is relevant to the factor (2). Recently, Image-Guided Radiotherapy(IGRT) equipment has been developed: Although clinical implementationof IGRT has improved treatment accuracy and margin reduction in EBRT, it
is still uncertain whether the dosimetry and geometric gains can actually
improve clinical outcomes [25]. As described later, seed implantation is theultimate modality in view of motion tracking. Implanted seeds are moving
with the prostate: That is obviously far better than motion-tracking EBRT.
Thus, there remains a lot of uncertainty regarding radiation dose and cold
spots due to prostate motion, although many institutions have adopted newly
developed EBRT equipment. A final concern regarding the outcome using the
newly developed EBRT equipment is the length of hormonal therapy. NCCN
recommends 4-6 months of Androgen Deprivation Therapy (ADT) for patientswith intermediate-risk prostate cancer and 2-3 years of ADT for patients withhigh-risk prostate cancer in the EBRT protocol. Usage of long-term ADT
should have a strong impact on data analysis of the BFFS rate. Spiegel, etal. made a nomogram of Testosterone Recovery (TR) after cessation of ADT[26]. They reported that the median time for TR after cessation of ADT is 24
months for patients who received two years of ADT. Tomita, et al. reported theoutcome of helical tomotherapy [22]. By applying helical tomotherapy, they
have demonstrated BFFS rates at 5 years of 98.2% and 97.7% in patientswith intermediate- and high-risk cancer, respectively. However, this reportcontains an inherent analytical pitfall. In intermediate-risk patients they used
10 months neoadjuvant and 19 months adjuvant ADT: Median durations of
ADT were 29 months and 30 months in intermediate- and high-risk patients,
respectively. According to Tsumura, et al. [27] more than half of the patients
who received long-term ADT did not experience Testosterone Recovery (TR)at 5 years after cessation of ADT. Moreover, one-fifth of the patients who
received long-term ADT still had castration levels of testosterone at 5 years
after cessation of ADT. The report by Tomita, et al. defined the start date offollow-up as the start of EBRT [27]. This means that after the cessation of
ADT at 5 years the period of follow-up would be only 28 months. Similarly,
Kawamura et al. reported the outcome of carbon ion radiotherapy [24]: By
applying carbon ion radiotherapy, they have demonstrated BFFS rates
at 5 years of 92% in high-risk patients. They administered 5-8 months ofneoadjuvant ADT and 24 months of adjuvant ADT, respectively, before andafter carbon ion radiotherapy. This means that after the cessation of ADT at 5
years the period of follow-up would be only 36 months. Therefore, this study
also may only represent the continuing effect of long-term ADT. Without
using long-term ADT, Abu-Gheida, et al. reported that the IMRT outcome withregard to the BFFS rate was 63% in patients with high-risk prostate cancer

Review Article
at 5 years [21]. In conclusion of this section, the BEDs of the current new
EBRT modalities are not high enough to eradicate intermediate- and high-risk
prostate cancer. Use of long-term ADT may produce a good clinical outcome
due to the continuing effect of long-term ADT.

Discussion
What is quality Low-Dose-Rate (LDR) brachytherapy?
Intermediate-risk prostate cancer patients represent the largest of the risk
groups and comprise a heterogeneous population of patients with variable
prognoses [28].
Based on this heterogeneity, a new classification subdividing patientswith intermediate-risk prostate cancer into “favorable” and “unfavorable”
subgroups has been proposed:
1) Favorable Intermediate-Risk (FIR): one IR factor with Gleason score 3+42) Unfavorable Intermediate-Risk (UIR): Gleason 4+3=7 or >1 intermediaterisk factors (cT2b, cT2c, PSA 10-20, Gleason 3+4=7)
A group at Johns Hopkins University reported on BFFS in a cohort of 4,164
intermediate-risk patients [29]. The results showed that 5-year BFFS differedsignificantly between FIR patients and UIR patients. For patients with one
intermediate-risk factor, the 5-year BFFS was 83.0%, compared with 64.3%
for men with two risk factors and 45.9% for those with three risk factors [29] .
Similar differences in BFFS between FIR patients and UIR patients have beenreported for EBRT of 81Gy [30]. In this report, the estimated 8-year BFFS
rates were 86.1% and 71.1% in FIR patients and UIR patients, respectively[30]. The author of this review has shown excellent clinical outcomeswith Low-Dose-Rate (LDR)125I seed implantation-based radiotherapy forintermediate-risk patients, including a substantial number of UIR cases.
BFFS rate of 99.1% at 7 years [6]. In that study, the author concluded that
LDR "125I brachytherapy" (seed implantation) alone with a BED of 200Gy is aneffective treatment in intermediate-risk prostate cancer, including UIR cases,
thus supporting the above-mentioned data from the Mount Sinai group [6].
This unparalleled BFFS rate achieved by LDR monotherapy is based on the“Development of quality high-dose (BED of 200Gy) LDR method”: The detailsof the technique have been published as the “Ten-Step Method,” which
provides implementation specifics for disseminating safe and reproducible
high-dose brachytherapy. As described in the section on problems in radical
prostatectomy, treatment of prostate cancer should include the spaceoutside of the prostatic capsule. Figure 2 shows a representative radiationdose distribution in LDR monotherapy "125I brachytherapy" in intermediaterisk prostate cancer without using ADT by the Ten-Step method (Figure 2).
The two-dimensional dose distribution demonstrates that a dose cloud of
160Gy covers the entire prostate and a significant margin beyond the prostatic
capsule [8]. This exactly fulfils the author’s proposal that prostate cancer
should be treated beyond the prostatic capsule. The method is composed often steps, beginning with the positioning of the ultrasound probe and ending

Figure 2. Radiation dose distribution in the Ten-Step method.
A representative intraoperative two-dimensional (2D) dose distribution in an LDR monotherapy case is shown: D90=194Gy, V100=100%, UD30=191Gy, R100=0.6cc,
prostate volume=50 ml. The entire prostate target is covered with 160Gy (orange), and the high-dose band (240Gy, pink) is intentionally made peripheral and does notinvade the urethra and rectum. Note that the space beyond the prostatic capsule is sufficiently treated by the dose area of 160Gy. D90: The minimal dose (Gy) is received
by 90% of the prostate. V100: The percentage prostate volume receiving 100% of the prescribed minimal peripheral dose; UD30: Minimal dose (Gy) received by 30% of theurethra; R100: Rectal volume (cm3) receiving 100% of the prescribed dose.
2

Medical Reports and Case Studies 2021, Vol.06, Issue S4, 001-004
with the last seed placement at the midline of the apex between the urethra
and rectum. The final step is a confirmation of the dose cloud and dosimetry.
The Ten-Step method is based on the following rationale. First of all, placing
a sufficient number of seeds in the peripheral region away from the urethra
and rectum insures a good treatment margin beyond the prostate capsule andachieves the following four goals.
1. The entire prostate should be covered by the prescription dose cloud with asufficient margin (5-7 mm) from the capsule in all directions except for thoseanterior to the rectal wall, thus achieving high D90 (D90>190Gy) and V100
(V100>99%) values by the "125I seed implantation".
2. A high-dose cloud (240Gy) should not approach the urethra or rectum.
3. In order to achieve goals (1) and (2), it is necessary to make the high-dosecloud intentionally along the periphery (bilateral wall to anterior wall) awayfrom the urethra and rectum.
4. In order to achieve goal (3), seeds at the periphery, except those anterior
to the rectal wall, should be placed just 1 mm inside the capsule. The
above-mentioned rationale is shown in Figure 3 [8]. By using high dose LDR
monotherapy with a BED of 200Gy, patients with intermediate-risk cancer,
including UIR, have demonstrated a biochemical failure rate of only 1%. The
advantage of this method is the cost-effectiveness for the patients. The
patients can omit supplemental EBRT. This can reduce the length of treatment
and eliminate the cost of supplemental EBRT. Furthermore, the method does
not require hormonal therapy in most cases because the implant quality anddose are consistently high even in cases with large prostates [8].

Quality LDR brachytherapy for high-risk and super-high-risk
prostate cancer including pelvic lymph node metastasis
The author has shown good clinical outcomes by escalating the radiationdose for high-risk and very-high-risk prostate cancer patients including fivepelvic lymph node metastasis cases with a BFFS rate of 95.2% at five years
by tri-modality therapy of BED>220Gy (a combination of LDR brachytherapy,
EBRT, and Androgen Deprivation Therapy (ADT) [5]. In this report, 63% of thecases analyzed were T3a, T3b or T4. In this study, we used short-term ADT(six months ADT before and after LDR brachytherapy). The author has also
shown that T4 prostate cancer with pelvic lymph node metastasis can be
cured in the same way [7]. In the above-mentioned reports, duration of followup started from the end of EBRT. This means that during the 5 years of followup, the period of ADT was only three months: In the studies, representative
patients demonstrated that TR decreased to normal range at 9-12 months
after cessation of ADT [5,7]. Therefore, the effect of ADT in the reports is
negligible. In concluding this section, the studies by the author have shownthat patients having locally advanced prostate cancer with pelvic lymph nodemetastasis can be cured by the author’s strategy using tri-modality with BED
of 220Gy.

Strategy for high-risk and very-high-risk prostate cancer patients
including pelvic lymph node metastasis cases
In order to achieve a BED of 220Gy in high-risk and very-high-risk prostate

Review Article
cancer patients, including pelvic lymph node metastasis cases, the author
also applies the Ten-Step method in seed implantation. Dose distributions of
240Gy, 160Gy, and 144Gy by LDR monotherapy correspond to 160Gy, 130Gy
and 110Gy by LDR in combination with EBRT. Seeds should be implanted in
the same way by the Ten-Step method. When the author treats cases withsuper high risk, including pelvic lymph node metastasis or PSA ≧ 40 ng/ml,
the target area for EBRT is expanded to include the Whole Pelvis (WP) [5,7].
The radiation dose to the WP should be set at 45Gy in order to minimize GI
toxicity (Usually 1.8Gy/fraction × 25 times). In order to secure a radiationdose of 45Gy to WP, D90 of LDR should be ranged from 130Gy to 138Gyon the dosimetry schedule at one month after seed implantation. In orderto achieve a BED of 220Gy on the prostate, one or two fractions of EBRT to
prostate and seminal vesicles only may be added after calculation of BED by
LDR. In the other high-risk cases, the target of EBRT is designed to include
prostate and seminal vesicles only. In those cases, D90 of LDR should be
ranged from 135Gy to 145Gy at one month after seed implantation. Fractionsof EBRT can be reduced according to the D90 of LDR at one month after seed
implantation and calculation of BED by LDR.

Importance of seminal vesicle seed implantation
In order to conduct quality seed implantation in combination with EBRT in
high-risk and very-high-risk prostate cancer patients, the author commonly
applies seminal vesicle implantation. Stock, et al. published clear evidence
that dose from implanted seeds from the prostate contributes little to theseminal vesicle. Therefore, they proclaimed necessity of seminal vesicle
seed implantation for some of the high-risk prostate cancer patients [31].
The author and others have already described the method for seminal vesicle
seed implantation [7,32]. A representative dose distribution with seminal
vesicle implantation in high-risk or super-high-risk prostate cancer is shownin Figure 4.
Seminal vesicle implantation has two benefits:
1) Treating seminal vesicle invasion.
2) In cases of small-volume prostate, by using neoadjuvant ADT a highD90 is achievable by seminal vesicle seed implantation, which canFigure 3. Rationale for the Ten-Step method.
A high-dose band (240Gy, pink) should be made intentionally along the bilateralcorners and the lateral and anterior walls of the largest transverse prostate image.
The rationale for this step is making a high-dose band (pink area) at peripheral
areas at a sufficient distance from the urethra (U) and rectal wall (R) (Right).

Figure 4. Radiation dose distribution with seminal vesicle implantation in high-risk or super-high-risk prostate cancer.
A representative intraoperative two-dimensional (2D) dose distribution of LDR in combination with EBRT in a T3b case is shown. A high-dose band (160Gy, yellow) should
be made intentionally along the bilateral corners and the lateral and anterior walls of the largest transverse prostate image. Note that seed implantation in seminal vesicles
should be placed on the anterior wall of the vesicle.
3Medical Reports and Case Studies 2021, Vol.06, Issue S4, 001-004
help in obtaining a high D90 of 130-140Gy without increasing urethraland rectal doses.
In concluding this section, the technique of seminal vesicle implantation isessential for conducting quality seed implantation in combination with EBRT
in high-risk and very-high-risk prostate cancer patients.

Conclusion
The author raised the problems associated with current treatments of prostatecancer using newer and costlier modalities. Quality seed implantation by
the Ten-Step method can be the ultimate radiosurgery for non-metastatic
prostate cancer including very-high-risk prostate cancer with pelvic lymph
node metastasis.

Disclosure
Keisei Okamoto was associated with the Department of Brachytherapy for
Prostate Cancer endowed by Nihon Medi-Physics Co.,Ltd. The present
affiliation of Keisei Okamoto is Uji Hospital, Department of Urology, Kyoto,
Japan.

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Cite this article: Okamoto K. Emergence of Quality Low-Dose-Rate (LDR) Brachytherapy: Ultimate Radiosurgery for Non-Metastatic
Prostate Cancer. Med Rep Case Stud, 2021, 06(S4), 001-004
4