Evolution of Prostate Brachytherapy

REVIEWS
The evolution of brachytherapy for

prostate cancer
Nicholas G. Zaorsky1, Brian J. Davis2, Paul L. Nguyen3, Timothy N. Showalter4,
Peter J. Hoskin5, Yasuo Yoshioka6, Gerard C. Morton7 and Eric M. Horwitz1
Abstract | Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or
high-dose-rate (HDR) temporary source implantation, is an acceptable treatment option for
select patients with prostate cancer of any risk group. The benefits of HDR‑BT over LDR‑BT
include the ability to use the same source for other cancers, lower operator dependence, and —
typically — fewer acute irritative symptoms. By contrast, the benefits of LDR‑BT include more
favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded
room, completion in a single implant, and more robust data from clinical trials. Prospective
reports comparing HDR‑BT and LDR‑BT to each other or to other treatment options (such as
external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5‑year freedom
from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease
are >85%, 69–97%, and 63–80%, respectively. Brachytherapy with EBRT (versus brachytherapy
alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease.
The 10‑year rates of overall survival, distant metastasis, and cancer-specific mortality are >85%,
<10%, and <5%, respectively. Grade 3–4 toxicities associated with HDR‑BT and LDR‑BT are rare,
at <4% in most series, and quality of life is improved in patients who receive brachytherapy
compared with those who undergo surgery.
Prostate cancer is one of the most frequently diagnosed European Association of Urology/European Organisation
cancers diagnosed in the developed world, with 1.4 mil- for Research and Treatment of Cancer (ESTRO/EAU/
lion incident cases and 293,000 deaths in 2013 (REF. 1). EORTC) guidelines10,11. Specifically, LDR‑BT is defined
Local tumour control is associated with improved as ≤2 Gy/h, and consists of the permanent implantation
outcomes in patients with organ-confined (T1 or T2) of sealed sources (seeds) in the prostate8. HDR‑BT is
prostate cancer, even in the presence of high-risk fea- defined as ≥12 Gy/h and consists of insertion of a tem-
tures, which include PSA >20 ng/ml and Gleason score porary source into a target volume (which contains
8–10 (REF. 2). Treatment options for nonmetastatic cancer cells) via a remote afterloader using catheters
prostate cancer typically include active surveil- implanted in the prostate and computer optimization
lance (AS), radical prostatectomy and radiotherapy 3. to optimize dose distribution9. The dose fall-off of both
Radiotherapy can be administered in the form of LDR‑BT and HDR‑BT is rapid, with <10% of dose
external beam radiotherapy (EBRT) using various frac- delivered to tissue >4 cm away from the source (FIG. 1a).
tionation options, and brachytherapy (BT), either high- LDR‑BT and HDR‑BT can be used as monotherapies
dose-rate (HDR‑BT) or low-dose-rate (LDR‑BT), given for some patients with low-risk disease. Furthermore,
alone or combined with EBRT4. The Prostate Testing EBRT combined with brachytherapy, also known as
for Cancer and Treatment (ProtecT) trial suggests that ‘LDR‑BT boost’ or ‘HDR‑BT boost,’ is hypothesized to
1
Department of Radiation radiotherapy offers similar outcomes and improved further improve local control compared with mono-
Oncology, Fox Chase Cancer
toxicity and quality of life over surgery 5–7. therapy, and to improve outcomes in certain patients
Center, 333 Cottman Avenue,
Philadelphia, Pennsylvania Brachytherapy is an excellent treatment option with intermediate-risk or high-risk disease (FIG. 1b).
19111–2497, USA. for patients of all disease groups, according to the Various boost schedules are used (FIG. 1c): in HDR‑BT
Correspondence to: N. G. Z. American Brachytherapy Society (ABS) guidelines8,9, boost, the implantation can be performed after EBRT,
[email protected] the Groupe Européen de Curiethérapie / European interdigitated with EBRT, or before EBRT; by contrast,
doi:10.1038/nrurol.2017.76 Society for Radiotherapy & Oncology (GEC/ESTRO), in LDR‑BT boost, EBRT is usually delivered before the
Published online 30 Jun 2017 and the European Society for Radiotherapy & Oncology / implant is inserted4.
NATURE REVIEWS | UROLOGY VOLUME 14 | JULY 2017 | 415

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Key points cancer and it was thought that local control could not
be obtained without significant toxicity 17.
• Brachytherapy and brachytherapy boost with low-dose-rate brachytherapy (LDR‑BT) At Iowa State University in the 1950s, LDR‑BT was
or high-dose-rate (HDR)-BT can be used as first-line therapies in the management of performed by injecting 198Au colloid solution intra
prostate cancer patients of all National Comprehensive Cancer Network tumorally via open and closed approaches18. In this
(NCCN)-defined risk groups series, the 5‑year survival was 48%, which was similar
• LDR‑BT, consisting of a single implant, typically uses 125I or 103Pd; by contrast, HDR‑BT to other reported techniques at the time18,19. Despite the
consists of 1–3 implants and uses 192Ir encouraging results, brachytherapy was still not accepted
• Benefits of HDR‑BT over LDR‑BT include the ability to use the same source for other for several reasons. Firstly, reports of experience with
cancers, lower operator dependence, and fewer acute irritative symptoms EBRT began to be published in the 1960s, and this tech-
• Benefits of LDR‑BT include more favourable scheduling logistics, lower initial capital nique did not require anaesthesia and also was also asso-
equipment costs, non-requirement of a shielded room, completion in a single implant, ciated with promising results and minimal morbidity 20.
and more robust data from clinical trials Furthermore, 198Au is a relatively high-energy isotope
• Outcomes of HDR‑BT and LDR‑BT are similar to those of other treatment options, and, therefore, challenging radiation safety precautions
including external beam radiotherapy (EBRT) and surgery, and brachytherapy can also were necessary.
be used in combination with EBRT in intermediate-risk and high-risk disease
In the 1970s, Dr Willet F. Whitmore and colleagues
• Severe toxicities of HDR‑BT and LDR‑BT are rare, although the rate of urethral at Memorial Sloan Kettering Cancer Center began to use
stricture is increased when brachytherapy boost is performed; incontinence is not 125
I seeds for prostate cancer implants via an open sur-
associated with any radiotherapy modality
gical procedure that included a bilateral pelvic lymph
adenectomy 21,22. This 125I technique was associated with
several advantages over existing methods for EBRT and
This Review considers the evolution of brachytherapy brachytherapy 14. Firstly, the open procedure permitted
from its inception to contemporary practice, including direct assessment of both the prostate and the lymph
its historical background and the current indications nodes. Secondly, the open approach permitted the pre-
and contraindications of brachytherapy use compared cise placement of radioactive material, thus increasing
with EBRT and surgery. The underlying radiophysics the total tumour dose while minimizing exposure
and technical aspects, including dosimetric quality con- to the rectum and bladder. Thirdly, staging and implan-
straints, radiobiology, cost, clinical outcomes and tox- tation were performed at the same time. Notably, open
icities, and appropriate follow‑up monitoring will also procedures and intraprocedure staging are no longer
be discussed. performed in contemporary practice; by contrast,
novel anatomical and functional imaging methods
Historical background (including CT, MRI, and PET) have replaced invasive
The history of LDR‑BT staging 23 and implantations are now performed via a
Radioactivity was accidentally discovered by Henri transperineal approach.
Becquerel in 1896 (REF. 12) . Radium was discov- Finally, 125I has several benefits in comparison with
ered by Marie and Pierre Curie just 3 years later in 198
Au, which had been used in previous decades 14.
1899, and was used for the treatment of malignant 125
I has a lower energy, requiring less challenging
disease in 1901 — just 5 years after its discovery 13. radioprotection and providing improved dosimetry.
The use of prostatic brachytherapy was first reported 125
I has a low half-dose volume — that is, the volume of
in 1911, when radium was administered temporar- tissue receiving 50% of the minimum tumour dose
ily via a urethral catheter 14,15. In 1917, transperineal — compared with 198Au: 2 cm versus 6 cm (REF. 24).
implantation of radium was performed in New York16. 125
I also has a relatively long half-life of 60 days,
Several cohorts of patients were treated with radium providing extended periods of radiation to the tar-
brachytherapy in the USA during the 1920s; how- get tissue. This extended duration of radiation was
ever, this approach was not favoured because prostate hypothesized to be radiob iologically favourable
cancer was believed to be a relatively radioresistant because of the long doubling time of prostate cancer
cells, and because it would allow for the repair of nor-
mal tissues, thereby minimizing acute genitourinary
Author addresses toxicities21.
In the 1970s and 1980s, patients who were selected
2
Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Charlton Bldg/
for 125I LDR‑BT were anaesthetized, placed in a modi-
Desk R - SL, Rochester, Minnesota 5590,USA.
3
Department of Radiation Oncology, Brigham and Women’s Hospital, fied lithotomy position, and an infraumbilical incision
75 Francis St BWH. Radiation Oncology, Boston, Massachusetts 02115, USA. was made to perform the implantation24–27. A bilateral
4
Department of Radiation Oncology, University of Virginia, 1240 Lee St, pelvic lymph node dissection was performed, and the
Charlottesville, Virginia 22908, USA. prostate was exposed. The prostate gland was mobilized
5
Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, by incising the endopelvic fascia bilaterally. Caliper
Middlesex HA6 2RN, UK. measurements were used to assess the prostate dimen-
6
Department of Radiation Oncology, Cancer Institute Hospital of the Japanese sions: a needle was directed through the gland in the
Foundation for Cancer Research, 3‑8‑31 Ariake, Koto‑ku, Tokyo 135–8550, Japan anteroposterior direction using a needle, with a finger
7
Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health placed in the rectum to prevent rectal perforation. Next,
Sciences Centre, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada.
a nomogram was used to calculate the 3D volume.
416 | JULY 2017 | VOLUME 14 www.nature.com/nrurol

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REVIEWS
a 100 A computer was used to derive the matched peripheral

LDR-BT with 103Pd dose, which was the absorbed dose at the periphery of an
Relative dose (%)
LDR-BT with 125I ellipsoid with the same dimensions. Doses at the centre
HDR-BT with 192Ir
of the gland were typically much higher than those at the
10
periphery. Given the morbidity of incision, the limits of
1/r2 assessing prostate dimensions, and poor dose distribu-
tion and low total dose of 125I, clinical outcomes were
1 poor in many patients28.
0 r (cm) 10
The application of transrectal ultrasonography
b (TRUS) to guide LDR‑BT was successfully introduced
145 Gy (1 implant) in the 1980s29. TRUS guided LDR‑BT was first developed
LDR-BT 103
Pd: 125 Gy in Denmark in the late 1970s, but with disappointing
t1/2 = 17d
early clinical outcomes, likely related to suboptimal
seed placement and dosimetry 30,31. The lack of uniform
Activity
Decay over dosimetry and the use of combination EBRT resulted in

months rectal ulcers30–32.
125
I: 145 Gy As techniques improved, 125I and 103Pd became the
t1/2 = 60 d 145 Gy / most commonly used isotopes in nonrandomized tri-
1 implant, ~2 hours als through the late 1980s33. TRUS-guided LDR‑BT
in a single day 200% 100% became a standard technique in the USA and elsewhere
Time 150% 90% by the late 1990s because of improved associated out-
comes and use of a less-invasive procedure compared
HDR-BT
27 Gy (2 fractions) with laparotomy-based suprapubic approaches34,35. In
the USA, LDR‑BT was subsequently endorsed for treat-
~1–5 days ment of low-risk prostate cancer by numerous organiza-
tions, including the ABS and the American Society for
Radiation Oncology (ASTRO)36.
Although TRUS-guided LDR‑BT is still a standard-
1 2 3 4 5 of‑care treatment option for men with prostate cancer,
Day
1 fraction: potential technical limitations of LDR‑BT exist. Firstly,
~6 – 12 Gy/~2 h/day loose LDR‑BT seeds — particularly those that are not
200% 90% 50%
100% 80% held by a strand (termed ‘stranded’) — can migrate37.
Secondly, permanent implantation of radioactive mat
Conventional fractionation erial in the body, as is carried out for LDR‑BT, means that
EBRT
1
2
Figure 1 | Comparison of LDR‑BT, HDR‑BT, and EBRT.
escalated escalated
Non-dose Dose
3 80 Gy (40 fractions)
a | The dose distribution in water as a function of
4
Week
distance from a point source of three isotopes

5
commonly used for prostate brachytherapy:
6 low-dose-rate brachytherapy (LDR‑BT) with 103Pd (light
7 green), LDR‑BT with 125I (dark green), and high-dose-rate
1 fraction: 8 brachytherapy (HDR‑BT) with 192Ir (blue). The dose has
1.8–2.0 Gy/15 min/day 1 2 3 4 5 been normalized to 100% at a distance of 1.0 cm (note
Day log scale). The high energy 192Ir departs slightly from the
Hypofractionation inverse square law (1/r2), whereas the lower energy
105% 90% 50% isotopes of LDR‑BT have more absorption over a lower
1
100% 80% range. b | Comparison of LDR‑BT, HDR‑BT, and
2
Week
conventional or hypofractionated external beam

3
radiotherapy (EBRT). The doses (with respect to the
4 patient) are shown in colour. The dose fractionation of
1 fraction:
2.1 – 3.5 Gy/15 min/day 1 2 3 4 5 LDR‑BT with decay using 103Pd (light green) or 125I (dark
Day green) compared with HDR‑BT (blue fractions) and EBRT
(red fractions) are shown. Brachytherapy requires only
c
1–5 insertions compared with up to 40 fractions of EBRT.
EBRT (41.4–50.4 Gy in 1.8–2.0 Gy fractions) (Wait 1–3 weeks) HDR-BT The isodose distributions of brachytherapy are superior
to that of EBRT, as X‑rays do not pass through the skin.
EBRT (20.7–25.5 Gy in
1.8–2.0 Gy fractions) HDR-BT Resume EBRT c | Brachytherapy boost is defined as the combination of
EBRT with HDR‑BT or LDR‑BT. If EBRT is delivered first,
HDR-BT (Wait 1–6 weeks) EBRT (41.4–50.4 G in 1.8–2.0 Gy fractions) HDR‑BT is typically delivered 1–6 weeks later. A possible
benefit of this method is to use the HDR‑BT to account
EBRT (41.4–50.4 Gy in 1.8–2.0 Gy fractions) (Wait 2–8 weeks) LDR-BT for suboptimal dosimetry of EBRT. Alternatively, EBRT
0 1 2 3 4 5 6 7 can be interdigitated with HDR‑BT. Finally, HDR‑BT can
Time (weeks) be delivered first and EBRT delivered 1–3 weeks later.
Nature Reviews | Urology

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the implant emits a small but detectable dose of radiation boost because with monotherapy the high dose per
for some months after implantation. Additionally, cor- fraction of brachytherapy would not have to be reduced.
rect seed placement is highly operator-dependent, and Furthermore, any extracapsular spread of disease could
cannot be adjusted after deposition. Thus, dosimetry be covered by dose from the needles. In the USA, a trial
might vary among implants. Furthermore, the multiple of HDR‑BT monotherapy was conducted from 1999 to
radioactive seeds required — ~100 seeds might need 2000, and the results were published in 2001 (REF. 61).
to be custom made for a particular date — are costly. Patients with low-intermediate-risk prostate cancer were
By contrast, HDR‑BT procedures use a single, reusable, treated with HDR‑BT, 38 Gy in four fractions of 9.5 Gy
192
Ir source that lasts 3 months. However, relative cost each, delivered twice a day over 2 days. None of the
is debatable, because in certain environments seeds are patients developed severe acute toxic effects.
cheaper than HDR‑BT, particularly if multiple HDR‑BT The use of HDR‑BT addresses some of the issues
fractions are used. Furthermore, LDR‑BT exposes associated with LDR‑BT, but it has its own disadvantages.
staff to radiation, although this exposure is very min- For example, HDR‑BT must be performed in a shielded
imal38. Finally, acute irritative urinary symptoms fre- room instead of an operating room, as in the case with
quently occur as the radioactive sources of LDR‑BT LDR‑BT; thus, considerable start‑up costs are associated
decay (FIG. 1b). The acute toxicity period is more pro- with ensuring an appropriate environment. HDR‑BT
nounced but shorter in duration for 131Cs, which has a is typically performed in 1–3 implants and the cathe-
half-life of 9.7 days; by contrast, the acute toxicity is less ters are left inside the patient to deliver 1–6 fractions
pronounced but longer in duration (by months) for in total. Typically, fractions must be separated by >6 h in
125
I, which has a half-life of 59 days. order to capture cancer cells during the radiosensitive
G2/M phase and allow DNA repair of normal cells. As
History of HDR‑BT an increased number of implants are used, the risk of
In the late 1980s, analysis of CT‑based dosimetry procedure-related events, including infection and bleed-
revealed that dose coverage of LDR‑BT plans was often ing, is also increased58,62,63. Furthermore, as many fraction-
lower than in the preplans. Thus, investigators explored ation options are available for HDR‑BT, no single dose
the use of HDR‑BT with 192Ir to overcome these limita- for HDR‑BT has been standardized, unlike for LDR‑BT.
tions39, theorizing that the higher energy 192Ir HDR‑BT
isotope would enable dose delivery to the periphery Current trends
of the prostate in a highly conformal manner, ensur- The use of brachytherapy to treat patients with local-
ing good tumour coverage and minimizing the dose ized prostate cancer in the USA and western Europe has
to the adjacent bladder and rectum39. Furthermore, been steadily declining since 2003. In the USA, brachy
this approach would enable the dose to be differen- therapy use (either as monotherapy or boost) reached
tially delivered within the peripheral zones of the pros- a peak in 2002, with 17% of all prostate cancer patients
tate where the bulkier portions of carcinoma typically receiving the therapy; in 2010, the rate decreased to
reside40,41; this dose distribution would also limit dose to 8%64 (FIG. 2). For patients with intermediate-risk disease,
the central region that contains the urethra39. use of brachytherapy boost decreased from 33% in 2004
A TRUS-guided remote afterloading system (RALS) to 12% in 2013; and for high-risk disease, use dropped
was first introduced in 1980 to deliver a high radiation from 27% to 11%65.
dose to the prostate while limiting exposure of the sur- The declining use of brachytherapy could be due to
rounding tissues (FIG. 1a) and to address some limitations several reasons. Firstly, according to data from 2015,
of TRUS-guided LDR‑BT, including high dependence 30% of US medical school graduates are not aware of
on the operator for proper seed placement, inability to brachytherapy as a definitive treatment modality for can-
adjust seeds once they are deposited, and variability of cer, and 10% do not believe that radiation therapy alone
dosimetry among implants35. HDR‑BT began to be used can be used to cure cancer 66,67. Additionally, the declin-
as a boost with EBRT in Sweden, Germany, Japan, the ing rate of brachytherapy use in the USA might be due to
UK, and the USA in the 1980s and 1990s35,39,42,43. the low and declining number of prostate brachytherapy
HDR‑BT boost was attempted before HDR‑BT mon- procedures performed by residents68–70. For example, the
otherapy because it was theorized to be an improvement number of LDR‑BT implantations performed in aca-
over LDR‑BT boost. With HDR‑BT boost, staff would demic year 2006–2007 was 1,106 total, with a median of
be completely protected from radiation exposure, and 14 per resident, and a range of 0–129. By academic year
the procedure could be more widely applied, because 2010–2011, the total number increased to 1,990, but the
Remote afterloading system abdominal surgery could be avoided42. Safety and effi- number of residents grew, and the median decreased to
(RALS). Integral to HDR‑BT, a cacy of HDR‑BT boost was subsequently illustrated in just 10 LDR‑BT implantations per resident, with a range
RALS automatically deploys
phase I/II and phase III trials44–56. of 0–122 (REFS 68–70).
and retracts a single small
radioactive source along the By the 1990s, HDR‑BT boost had been evaluated The number of HDR‑BT prostate implantations
implant needle at specific in many studies worldwide. In Osaka, Japan, a trial performed by trainees across the USA as a whole has
positions delivering ≥12 Gy/h. of HDR‑BT monotherapy was initiated after a year of been negligible. In academic year 2006–2007, the total
The RALS enables a physician using HDR‑BT boost, and several reports on HDR‑BT number was 234 (median of 0 per resident; range 0–38);
to control the position where
the HDR source stops for a
monotherapy have been published since 2000 in academic year 2010–2011, the total number of was
predetermined time period (the (REFS 57–60). According to the authors, HDR‑BT mono- 336 (median of 0 per resident, range 0–71)70. Graduates
dwell position and dwell time). therapy was felt to be more advantageous than HDR‑BT are unlikely to develop the necessary skill to do the

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procedures with such few cases, as the associated learn- The NCCN guidelines state that brachyther-
ing curve means that >20 cases are likely necessary apy monotherapy and boost (that is, in combina-
to perform the procedure acceptably without super- tion with EBRT) can be used as first-line therapies
vision71–73. By contrast, the number of Accreditation in the management of men with prostate cancer of
Council for Graduate Medical Education (ACGME)- all risk groups3 (TABLE 1). Monotherapy is an option
accredited radiation oncology residency programmes for those with low-risk disease and favourable
has been growing: from 76 in 2011 to 89 in 2014. These intermediate-risk disease (evidence level 2, compared
data suggest that a growing number of graduating radi- with EBRT). Brachytherapy boost is an option for
ation oncology residents have a declining experience in patients with high-risk or very-high-risk disease. For
brachytherapy for prostate cancer. high-risk patients, brachytherapy boost is preferred
The use of brachytherapy could also be declining to brachytherapy or EBRT monotherapy because
owing to developments in EBRT. EBRT developed in of improved outcomes (evidence level 1), based on
parallel with brachytherapy during the 1990s and 2000s, retrospective evidence88 and prospective studies54,89.
and employed hypofractionated radiation therapy regimens For purposes of this Review, we consider high-risk
that used doses similar to HDR‑BT. In 2001, develop- and very-high-risk disease as a single high-risk cate-
ment of the robotic arm linear accelerator used to deliver gory because the outcomes and toxicities are typically
stereotactic body radiotherapy (SBRT) in dose fractiona- reported without dichotomization.
tion schemes similar to HDR‑BT was reported74,75. SBRT
is a type of EBRT delivered as a single fraction lasting up Contraindications
to 45 minutes per day, for a total of ~5 treatments, each The presence of ataxia telangiectasia or pre-existing
about 6–9 Gy, over ~2 weeks. As of 2017, no randomized rectal fistula are absolute contraindications to any
trials comparing brachytherapy with any form of EBRT, type of radiotherapy. Additionally, TRUS-guided
including SBRT, have been performed76. Importantly, brachytherapy has more contraindications than EBRT,
the dosimetric distribution of brachytherapy provides including absence of a rectum meaning that TRUS
superior conformality and dose concentration to EBRT, guidance cannot be performed. Other relative contra
in part because the X‑rays do not pass through the bowel indications include pubic arch interference, a large
and bladder in order to reach the prostate4,74 (FIG. 1b). prostate or a urethral defect associated with previous
transurethral resection of the prostate (TURP), a low
Indications and contraindications peak urinary flow rate of <10 cm3/s, and a postvoid
All patients require a biopsy to determine tumour Gleason residual volume >100 cm3 (REFS 4,8,9) (TABLE 2). In the
score, pretherapy serum PSA measurement, and clinical past, a gland size of >60 cm3 was generally considered
tumour classification with digital rectal examination and a relative contraindication for LDR‑BT, but LDR‑BT
possible imaging with a CT of the pelvis before initiation can now easily be performed for large prostates using
of any form of treatment, as these prognostic factors deter- 3D planning with CT or ultrasonography (rather than
mine risk classification3,77. Over 80% of prostate cancer the caliper measurements performed in the 1950s)90.
patients do not die of their disease78; thus, maintaining However, a large prostate can be accompanied by
quality of life is key in all patients. All patients should urinary bother symptoms, which would be exacer-
have their urinary and erectile function assessed with val- bated in the postimplant period. Additionally, the
idated questionnaires, including the American Urological patient must be able to tolerate general anaesthesia.
Association (AUA), International Index of Erectile Multiple implantation procedures, typically 1–3 (to
Function (IIEF‑5), and/or Expanded Prostate Cancer deliver 1–6 fractions), can be necessary for HDR‑BT
Index Composite (EPIC), before treatment begins3,79. (FIG. 1b). The procedure is typically performed under
general anaesthesia; thus, a patient would need to be
Indications anaesthetized 1–3 times, and needles might need to
The National Comprehensive Cancer Network (NCCN) be placed through the perineum 1–3 times, although
risk group classification for low-risk disease includes can- one insertion followed by twice daily treatments
cers with Gleason score <6, serum PSA <10 ng/ml, and is common.
clinical tumour classification T1 or T2a. For intermedi- Androgen deprivation therapy (ADT) can be used
Hypofractionated radiation ate-risk disease, patients have Gleason score 7, or PSA with either form of brachytherapy in certain patients
therapy
A type of EBRT that is
≥10 ng/ml ≤20 ng/ml or clinical tumour classification of with intermediate-risk and high-risk disease or as a
delivered as a single T2b or T2c. For high-risk disease, patients have Gleason means of prostate cytoreduction in any patient 91. With
2.1–3.5 Gy fraction lasting score 8–10, serum PSA >20 ng/ml, or clinical tumour respect to risk group, ADT is almost always recom-
15 min per day, 5 days per classification of T3a. Additionally, in more recent ver- mended for patients with high-risk disease because
week, for about 4 weeks.
sions of the NCCN guidelines3 and in studies of HDR‑BT it has been shown to improve overall survival in
Stereotactic body radiation boost45,46,48,50,80–87, a ‘very-high’ risk classification is made. prospective trials of EBRT; ADT is typically recom-
therapy In the NCCN guidelines, this includes patients with T3b– mended in patients with ‘unfavourable’ intermediate-
(SBRT). A type of EBRT T4 disease, primary Gleason score 5, or >4 cores with risk prostate cancer — that is, those with primary
delivered as a single fraction Gleason score 4–5. In studies of HDR‑BT boost45,46,48,50,80– Gleason pattern 4, >50% positive biopsy cores, or mul-
~ 6.0–9.0 Gy lasting up to
45 min per day, for a total of
87
, the definition is more heterogeneous and typically tiple intermediate-risk factors92. However, the effect of
about five treatments over includes patients with multiple high-risk features; for ADT–brachytherapy combination on survival has not
about 2 weeks. example, Gleason 8 and a serum PSA level >20 ng/ml. been confirmed as it has been with EBRT91,93–99.

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a Radium used to Transperineal

treat malignant administration
Radioactivity disease of radium for
Historic discovered by prostate cancer
approaches Henri Becquerel 198
Au
to prostate Radium colloid
brachytherapy administered
Radium discovered via urethral
by Marie and catheter for
Pierre Curie prostate cancer
Year 1890 1900 1910 1920 1930 1940 1950
b Retropubic
placement of
125
I seeds LDR-BT
LDR-BT monotherapy
TRUS
introduced LDR-BT boost
RALS and HDR-BT

introduced
HDR-BT
HDR-BT and HDR-BT and
conventional hypofractionation
fractionation
Radiobiology Hypothesis: high doses

per fraction effective
Conventional LINAC Hypofractionation “Virtual

fractionation 2D brachytherapy”
Intensity
EBRT 3D modulation
conformal Stereotactic
Multileaf body radiation
collimator therapy
Year 1950 1960 1970 1980 1990 2000 2010
c d Brachytherapy alone High-risk

70 30 Intermediate-risk
brachytherapy alone (%)
Low-risk
60 25
Patients receiving
20
50 15
40 10
5
30
Patients receiving
0
initial therapy (%)
2004 2005 2006 2007 2008 2009

20
Brachytherapy boost
10 High-risk
15
brachytherapy boost (%)
Intermediate-risk
0 Low-risk
10
Patients receiving
98
99
00
01
02
03
04
05
06
07
08
09
10
19
19
20
20
20
20
20
20
20
20
20
20
20
Year 5
Brachytherapy Other radiation Hormones

0
Brachytherapy boost Surgery No treatment
2004 2005 2006 2007 2008 2009
Year

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◀ Figure 2 | The evolution of brachytherapy for prostate cancer. a | The use of prostatic imaging. The clinical target volume (CTV) encompasses
brachytherapy was first reported in 1911, when radium was administered temporarily the GTV as well as areas at risk for subclinical cancer
via a urethral catheter14,15. In 1917, a transperineal implantation of radium was involvement. The CTV can include a margin around
performed in New York16. During the 1920s, cohorts of patients were treated with the prostate GTV, and it might include adjacent regions
radium brachytherapy in the USA. b | In the 1950s, low-dose-rate brachytherapy
at risk of having subclinical disease. For example, this
(LDR‑BT) was performed with 198Au (REF. 18), but by the 1970s 125I seeds were used for
prostate cancer implants21. A remote afterloading system (RALS) was developed in the
might include the seminal vesicles and expansion for
1980s and used for high-dose-rate brachytherapy (HDR‑BT). With more advanced forms extraprostatic extension (EPE). For brachytherapy, the
of external beam radiotherapy (EBRT) (for example, 3D conformal radiotherapy and CTV is equivalent to the entire prostate gland, including
then image-modulated radiotherapy)35, EBRT was combined with both forms of the prostate capsule plus any macroscopic extracapsular
brachytherapy to deliver brachytherapy boost56. EBRT developed in parallel over the disease, and a 3D expansion of 3 mm. The CTV is typi-
1990s and 2000s to become increasingly hypofractionated75. In 2001, the development cally constrained anatomically by the anterior rectal wall
of the robotic arm linear accelerator (LINAC), which delivers stereotactic body radiation and bladder base10,11. This definition is similar to that
therapy (SBRT), led investigators to tout it as “virtual brachytherapy”, and they touted used in EBRT planning guidelines101,102.
this treatment to be a superior and more advanced form of brachytherapy, as it could be The planning target volume (PTV) encompasses the
performed without anaesthesia or needles entering the prostate75. As of 2016, no trials
CTV plus an additional margin to account for patient
comparing the two technologies have been performed76, and the dosimetric
distribution of HDR‑BT (FIG. 1b) is superior to any form of EBRT because X‑rays do not
movement, set‑up error, and organ movement (for
pass through the skin of the patient4. c | Trends in the use of brachytherapy compared example, bladder or rectal distention). For prostate can-
with other modalities of therapy in the USA from 1998–2013 show that use has declined cer treated with EBRT, the PTV is typically CTV + 0.5
over the time period. Brachytherapy use reached a high around 2002, when 18% of – 1.0 cm101,102. For brachytherapy, no further PTV expan-
patients received the therapy64. d | Trends in the use of brachytherapy across risk groups. sion is required10,11. In the case of LDR‑BT, once the
The percentage of patients treated with brachytherapy alone by year from 2004 to 2009 needles are deposited, the dose cloud would cover the
stratified by National Comprehensive Cancer Network (NCCN) risk grouping (upper CTV, even if the patient were to move or if there were
panel), and percentage of patients treated with brachytherapy boost by year from 2004 organ movement. In the case of HDR‑BT, the needles
to 2009 stratified by NCCN risk grouping (lower panel)64. Permission obtained from John (typically about 12 in number) anchor the prostate
Wiley & Sons Inc © Martin, J. M. Cancer 120, 2114–2121 (2014).
while the 192Ir source moves to the dwell positions for a
prespecified dwell times to deliver the prescribed dose.
Radiophysics and technical aspects During the dose delivery, there should be no uncertainty
Target delineation regarding the position of the needles.
The GEC/ESTRO guidelines 10,11 provide detailed
instructions for brachytherapy target delineation. LDR‑BT technical aspects
Several differences exist in target volume expansions As of 2017, LDR‑BT is typically performed with 125I
of brachytherapy 100 versus EBRT101,102 (FIG. 3). The gross or 103Pd radioisotopes; few centres use 131Cs, but this
tumour volume (GTV) is the gross demonstrable extent isotope is also an option (TABLE 3) . The American
and location of the malignant growth; it consists of the Brachytherapy Society (ABS) does not recommend the
primary tumour — which for prostate cancer has his- use of one specific radionuclide8. Both 125I and 103Pd
torically been defined as the entire gland as well as any have demonstrated excellent long-term outcomes; 131Cs
visualized extension into surrounding normal tissues — was introduced in 2004 (REF. 103). 125I has the longest
the regional lymph nodes, or distant metastases based on half-life of these three isotopes (59 days); hence, it tends
clinical data (that is, physical examination, anatomical to have a milder toxicity peak, and longer window of
imaging with CT and MRI, and functional and molec- low-grade toxicity over 2–5 months. By contrast, 131Cs
ular imaging)101,102. For both forms of brachytherapy, has the shortest half-life (10 days) and causes more
GTV is typically not contoured, unless gross disease irritative symptoms in the 2–5 weeks following the
— either intraprostatic or extraprostatic — is noted on implantation.
Table 1 | Brachytherapy, external beam radiotherapy and surgery at different treatment stages
Possible indications Treatment option
LDR‑BT or HDR‑BT EBRT Radical prostatectomy
Low-risk disease (Gleason score ≤6, and PSA <10 ng/ Monotherapy Monotherapy Monotherapy
ml, and clinical tumour classification T1, T2a)
Intermediate-risk disease (Gleason score 7, or PSA Boost or monotherapy Monotherapy or boost Monotherapy
10–20 ng/ml or clinical tumour classification of
T2b, T2c)
High-risk disease (Gleason score 8–10, or PSA Boost usually preferred Boost usually preferred over Monotherapy
>20 ng/ml, or clinical tumour classification of T3a) over monotherapy monotherapy
After radical prostatectomy Rarely performed • Adjuvant indications: pT3; positive NA
surgical margins
• Salvage indications: suspected local
recurrence (e.g. rising PSA, findings
on imaging or biopsy)
EBRT, external beam radiotherapy; HDR-BT, high-dose-rate brachytherapy; LDR-BT, low-dose-rate brachytherapy; NA, not applicable.

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Table 2 | Contraindications for brachytherapy, external beam radiotherapy and surgery

Possible contraindication Treatment option
LDR‑BT or HDR‑BT EBRT Radical prostatectomy
Ataxia telangiectasia Contraindicated Contraindicated NA
Pre-existing rectal fistula Contraindicated Contraindicated Possible contraindication
or logistical difficulty
Unacceptable operative risks or medically Contraindicated Possible contraindication or Contraindicated
unsuitable for anaesthesia logistical difficulty *, ‡, §
Distant metastases Contraindicated Possible contraindication or Possible contraindication
logistical difficulty *, ‡, § or logistical difficulty
Absence of rectum such that TRUS guidance is Contraindicated Not a contraindication*, ‡
precluded
Large TURP defects that preclude seed Contraindicated Possible contraindication or Possible contraindication
placement and acceptable radiation dosimetry logistical difficulty *, ‡ or logistical difficulty
History of previous pelvic radiotherapy Possible contraindication or Possible contraindication or Uncommon
logistical difficulty logistical difficulty
Limited life expectancy (<10 years; patient will Possible contraindication or Possible contraindication or Possible contraindication
not realize benefit of radiotherapy in lifetime) logistical difficulty logistical difficulty or logistical difficulty
Moderate-to‑severe urinary symptoms (such as Possible contraindication or Possible contraindication or Not a contraindication
high IPSS score, typically defined as >20) logistical difficulty logistical difficulty; consider
conventional fractionation
Inflammatory bowel disease Possible contraindication or Possible contraindication or Not a contraindication
logistical difficulty logistical difficulty *
Risk of bleeding (from use of anticoagulant Possible contraindication or Not a contraindication Possible contraindication
therapy) logistical difficulty or logistical difficulty
Large median lobes Possible contraindication or Not a contraindication Not a contraindication
logistical difficulty
Pubic arch interference (from previous pelvic Possible contraindication or Not a contraindication Not a contraindication
fracture, irregular pelvic anatomy, or a penile logistical difficulty
prosthesis)
Patient peak flow rate <10 cm3/s and postvoid Possible contraindication or Not a contraindication Not a contraindication
residual volume before brachytherapy >100 cm3 logistical difficulty
Large prostate (e.g. >60 cm3) Possible contraindication or Not a contraindication * Not a contraindication
logistical difficulty; patient might
have accompanying bother
symptoms, but implant is still
technically possible
Concurrent androgen deprivation therapy Not a contraindication Not a contraindication Not a contraindication
EBRT, external beam radiotherapy; HDR-BT, high-dose-rate brachytherapy; IPSS, International Prostate Symptom Score; LDR-BT, low-dose-rate brachytherapy; NA,
not applicable; TRUS, transrectal ultrasonography; TURP, transurethral resection of prostate. *Excluded on clinical trial: Radiation Therapy Oncology Group 0938
or 0534. ‡Placement of fiducials for image-guided radiotherapy might be difficult. §Depends on intraprostatic versus extraprostatic disease burden.
Before implantation, CT or a TRUS planning study in the exact locations modelled by the programme.
can be performed to permit treatment planning as well Thus, the intraoperative dose coverage might not be the
as to calculate prostate volume so that radioactive seeds same as that seen on the preoperative scan. With intra
for the implant can be ordered. Alternatively, an intraoperative planning using TRUS, the seeds are deposited
operative treatment planning approach can be followed, as they would be with a preoperative plan. However,
whereby all radiation treatment planning and delivery use of an intraoperative plan enables adjustment or addi-
Gross tumour volume occurs in real time in a single procedure104. Additionally, tion of seeds if differences in anatomy or dose coverage
(GTV). The demonstrable real-time planning can be performed to overcome the are evaluated by TRUS-based computer planning.
extent and location of the limitations of preimplantation planning 104–106. The standard procedure for implantation of
malignant growth; it consists
With preimplant planning, TRUS is performed a few brachytherapy seeds uses a transperineal approach
of the primary tumour, which
for prostate cancer has weeks before the implantation, and the 3D placement of under TRUS guidance with a template in place. Efforts
historically been defined as seeds, with resultant dose to cover the CTV, is modelled are taken to ensure that patient position and TRUS-
the entire gland as well as any using a computer. However, preimplant dosimetry has probe alignment closely replicates the preimplant plan-
visualized extension into limitations, including quality of the image: distinguish- ning study, if this has been performed. A high-resolution
surrounding normal tissues,
the regional lymph nodes, or
ing the density of the prostate parenchyma from the biplanar ultrasonography system operating at 5–12 MHz
distant metastases based on capsule and some of the pelvic floor musculature can with dedicated prostate brachytherapy software is used.
clinical data. be impossible. Moreover, seeds might not be deposited Fluoroscopy can be used as a complementary imaging

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Clinical target volume a Rectum

(CTV). This volume
encompasses the GTV as well Bladder
as areas at risk for subclinical
cancer involvement. The CTV
can include a margin around
the prostate GTV and adjacent
regions at risk of having
subclinical disease.
Seminal
vesicle Gross tumour
Planning target volume volume (GTV)
(PTV). This volume
encompasses the CTV plus an Prostate Clinical target
additional margin to account volume (CTV)
for patient movement, setup Planning target
error, and organ movement Urethra
volume (PTV)
Dwell positions
The positions where a 192Ir b
source is located during
HDR‑BT. A combination of
dwell positions in different
needles enables the delivery of
a predetermined dose to the
CTV.
Dwell times
The times that the 192Ir source
spends in a predetermined
dwell position during HDR‑BT.
A longer dwell time in a
position translates to a greater
dose deposited in the volume
around the position. Rectal Patient positioning
distention differences EBRT coverage
Clinical
target
volume
(CTV)
Needles: LDR-BT HDR-BT

Used to deposit sources for LDR-BT A needle deposits 125I seeds with Ir dwell positions and dwell times
192
or used for source dwell of HDR-BT a dose cloud that covers the CTV create a dose cloud to cover the CTV
Figure 3 | Target volume definitions. a | Anteroposterior image of the prostate and seminal vesicles (left). The principal organs
at risk include the urethra, bladder, and rectum. The gross tumour volume (GTV; red) is the gross demonstrable extent and
location of the malignant growth (right). The clinical target volume (CTV; light blue) encompasses the GTV as well as areas at
risk for subclinical cancer involvement. The planning target volume (PTV; purple) encompasses the CTV plus an additional
margin to account for patient movement, set‑up error, and organ movement. b | For prostate cancer treated with external
beam radiotherapy (EBRT), the PTV is typically CTV + 0.5–1.0 cm101,102. The PTV expansion is necessary because the prostate can
move owing to nearby organ changes, such as rectal distention, and because the patient might be positioned differently on the
treatment table. Movements can be translational, rotational, and deformational. Note that the CTV (blue volume) stays inside
of the PTV (purple volume). EBRT (right; red) covers the PTV by passing through the soft tissues of the pelvis.
c | For brachytherapy, the expansion from a CTV to make a PTV can typically be minimized because the set‑up error is almost
nonexistent10,11. In the case of low-dose-rate brachytherapy (LDR‑BT), once the needles are deposited, the dose cloud (green
cloud) would cover the CTV, even if the patient or their organs were to move. In the case of high-dose-rate brachytherapy
(HDR‑BT), the needles (typically ~12) anchor the prostate while the 192Ir source moves to the dwell positions, shown as circles
inside the needles, for prespecified dwell times to deliver the prescribed dose (blue cloud).

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Table 3 | Properties of radionuclides and quality planning constraints

Radionuclide t1/2 Average Prostate (CTV) Urethra Rectum
(days) energy
(keV) D90 V100 V150
125
I 59.4 28.4 >100% of dose >90–95% <50–60% • UV150 ~0 (in volume) • RV100 D2cc <
• UV5 <150% • <1 cc on day 0 and prescribed dose
103
Pd 17.0 20.7 • UV30 <125% <1.3 cc on day 30 and D0.1cc
131
Cs 9.7 30.4 <200 Gy
192
Ir 73.8 380 >90–95% • D0.1 ≤ 120 Gy EQD2 D2cc ≤75 Gy EQD2
of dose • D10 ≤120 Gy EQD2
• D30 ≤105 Gy EQD2
No normal tissue constraints from ABS owing to wide range of
fractionation options9
ABS, American Brachytherapy Society; CTV, clinical target volume; EQD2, equivalent dose in 2 Gy fractions.
Equivalent dose in 2 Gy modality to TRUS, and is typically used to check seed Association of Physicists in Medicine (AAPM)120,121
fractions
deposition. Fluoroscopy can be enhanced by the use of recommend specific postbrachytherapy dosimetric
(EQD2). The “2 Gy‑per-fraction
equivalent dose.” differential concentrations of contrast in the bladder parameters, according to the anatomy. The following
EQD2 = n*d*((d+ α/β)/(2+ and a partially radio-opaque Foley balloon catheter to terminology is used: the D(percent) is the minimum
α/β)). The EQD2 uses a identify the urethra, and gold fiducial markers implanted dose to the hottest percentage of the volume. The
mathematical conversion of at the prostatic base and apex 107. In some centres, V(percent) is the percentage volume receiving a par-
fractions and dose per fraction,
similar to the BED. In this
fluoroscopy is used for intraoperative dose calculation ticular percent of the dose. The D(cc) is the dose to a
formula, n is the number of using image fusion108. However, this approach is not specified cubic centimetres of a volume. The dose for
radiation fractions and d is the considered mandatory for successful LDR‑BT8. any of these parameters can be described as a percent
dose size per fraction. The ABS8 recommends that CT‑based postimplant of the prescribed dose or in the equivalent dose in 2 Gy
dosimetry be performed within 60 days of implant fractions (that is, the EQD2), which is converted using
D90
In prostate cancer ation, in order to achieve good quality assurance109. a radiobiological formula to approximate the dose of
brachytherapy, this is the A planning system generates dose–volume histograms, conventionally fractionated EBRT.
minimum dose in the hottest dose–volume statistics, and 2D and 3D isodose curves The ABS and AAPM recommend reporting dosi
90% of a volume, in Gy. The superimposed on CT and other images, including metric values in the prostate, bladder, and rectum. In the
prostate D90% should be
>100%. This constraint
ultrasonographic and MRI. Careful postimplant assess- prostate D90, the minimum dose to the hottest 90% of
ensures the prostate volume ment provides objective measures of implant quality. the prostate volume in Gy, should be >100%. The pros-
receives adequate dose. Postimplant dosimetry is typically performed on the tate V100, the percentage volume receiving 100% of the
day of LDR‑BT and/or within 30 days after the implant, dose, should be >90–95%. The prostate V150, the volume
V100
once the initial oedema has resolved. If logistically feasi- receiving 150% of the dose, should be <50–60%
In prostate cancer
brachytherapy, this is the ble and consistent with LDR‑BT clinical trials, dosimetry According to the ASTRO, ABS, and AAPM guide-
percentage of a structure performed at 3–4 weeks postimplant is preferred109. lines, the urethra UV150 (REFS 122,123), the percentage of
receiving 100% of the dose. The time required for oedema to resolve and, there- the urethra that receives 150% of the prescription dose,
For example, the V100 for the fore, the optimal time to perform the postimplant scan, should be 0. The UD5, or the average dose to the 5% of
prostate should be >90%,
meaning that 100% of the
depends on the radionuclide used: 16 + 4 days for 103Pd and the hottest urethra volume, should be <150% of the pre-
prostate CTV should receive 30 + 7 days for 125I and seems likely less for 131Cs, though scribed dose. The urethra UD30 or the average dose to
more than 90% of the evidence for the use of 131Cs is limited8,9,110. Reproducibility the 30% of the hottest urethra volume, should be <125%
prescribed dose. of postimplant dosimetry can be improved by using of the prescribed dose. The GEC/ESTRO guidelines10
MR–CT image fusion111,112. The principal benefit of MR– provide similar recommendations with slightly differ-
V150
In prostate cancer CT fusion is improved delineation of soft tissue, including ent terminology. In the prostatic urethra, the D10, or the
brachytherapy, this is the the prostate, seminal vesicles, urethra, rectum, bladder, dose to 10% of the urethra volume, should be <150% of
percentage of a structure and penile bulb23,113–116. Additionally, multiparametric the prescription dose. A secondary parameter, the D30,
receiving 150% of the dose. MRI can help to delineate the GTV, where a focal boost or the dose to 30% of the urethra, should be <130% of
The V150 for the prostate CTV
should be <50–60%, meaning
could be administered117,118. The principal drawback is the prescription dose.
that <50–60% of the CTV that many radiation oncology departments do not own a In the rectum, the RV100, the volume receiving
should receive >150% of the dedicated MRI unit, imaging is expensive (although the 100% of the dose, should be <1 cc on day 0 dosimetry
prescribed dose. overall cost might be the same119), some patients might and <1.3 cc on day 30 dosimetry. According to GEC/
have contraindications to imaging (such as a pacemaker), ESTRO guidelines10, the D2cc, or the dose to hottest
UV150
In prostate cancer and the MRI might not substantially improve tissue de 2 cubic centimetres of the rectum should be less than
brachytherapy, this is the lineation at the prostatic apex, which is blurred by trauma the prescribed dose; and the D0.1cc or Dmax, the hotspot
volume of the urethra receiving after catheter insertion117–119. in the rectum, should be <200 Gy EQD2.
150% of the prescribe dose. No agreement has been reached regarding the crit-
UV150 of the urethra should
be 0%, meaning that 0% of the
LDR‑BT dosimetric quality constraints. Several dosi- ical structures and dose constraints for postimplant
volume should receive 150% metric quality constraints must be achieved (TABLE 3). erectile function, although the internal pudendal
of the prescribed dose. The ABS8, ESTRO/EAU/EORTC10,11, and the American artery, penile bulb, and neurovascular bundles have

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been studied124–126. Gillan et al.124 calculated the dose HDR‑BT has a number of benefits compared with
from LDR‑BT to the internal pudendal arteries. An EBRT and LDR‑BT, some of which are theoretical and
increased dose to these arteries would purportedly not yet validated in the clinic. Firstly, HDR‑BT has the
place patients at higher risk of erectile dysfunction. potential to increase prostate-cancer-cell death and min-
The authors reported that the internal pudendal imize radiation-related toxicity by widening the thera-
arteries can be visualized and receive a low but cal- peutic ratio, depending on the fractionation, α/β ratio,
culable dose from LDR‑BT, but the clinical signifi- and relative biologically equivalent dose (BED)35,63,75,133.
cance of this dose is unknown124. Conversely, Merrick Secondly, dosimetry is improved, as a range of
et al. 125 report that radiation doses to the proximal dwell times can be employed at each dwell position,
penis are predictive of brachytherapy-induced with better dose distribution than EBRT (REFS 134,135)
erectile dysfunction; the authors recommend penile (FIG. 1b). Thirdly, the treatment is completed in a few
bulb D50 and D20 should be maintained <40% and fractions over 1–4 days, which is more convenient for
60%, respectively, of the minimum peripheral dose. the patient than a protracted course of conventional
UV5
In prostate cancer
Buyyounouski et al. 126 recommend the use of MRI EBRT11,35,55,63,136–140.
brachytherapy, this is the for better delineation of erectile tissues but do not Notably, both LDR‑BT and HDR‑BT have excellent
average dose to 5% of the provide dose constraints. dosimetry. Additionally, both forms of brachytherapy
urethral volume receiving the are similarly economically favourable versus EBRT.
highest dose. The UV5 should
LDR‑BT fractionation and sequencing Costs of LDR‑BT and HDR‑BT take into account ini-
receive <150% of the dose.
According to the ABS and GEC/ESTRO guidelines8,10, tial investment cost, including shielding necessary for
UV30 the recommended dose of LDR‑BT monotherapy using HDR‑BT, the cost for each implant, as new sources must
In prostate cancer 125
I is 145 Gy. For LDR‑BT boost, the dose is 108–110 Gy. be used for LDR‑BT, the cost of the number of implants
brachytherapy, this is the The recommended dose of LDR‑BT monotherapy using per patient, and the number of patients treated with the
average dose to 30% of the
urethral volume receiving the
103
Pd is 125 Gy, and that for 131Cs is 120 Gy. For LDR‑BT device, as well as other potential uses for the modality,
highest dose. The UV30 should boost, the dose is 90–100 Gy. The EBRT dose is 41.4– such as gynaecological implants to additionally treat
be <125% of the dose. 50.4 Gy at 1.8–2 Gy fractions per day. Optimal 125I pros- these cancers using HDR‑BT (TABLE 4).
tate implants should deliver a D90 of 140–180 Gy, based
D10
on postimplant dosimetry. Doses of >140 Gy for 125I and HDR‑BT dosimetric quality constraints. During an
The average dose to 10% of a
volume, in Gy. The urethra D10 >125 Gy for 103Pd seem to result in similar outcomes in HDR‑BT procedure, the physician implants the needles,
should be <150% of the retrospective studies127,128. For 125I, doses >180 Gy are and a dosimetrist or physicist prepares a plan. Next, the
prescribed dose. This associated with a slight increase in long-term urinary physician reviews the plan, and the dosimetrist or phys-
constraint limits the dose to symptoms129. icist can make requested changes to the plan. Once the
the urethra.
EBRT is generally performed before LDR‑BT, with plan is optimized, the physician approves the plan, and
D30 a 2–8 week interval between the two therapies8. No the treatment is delivered. The ABS9 and GEC/ESTRO11
The average dose to 30% of a studies have been published investigating either the guidelines state that the CTV V100 should be >90%. The
volume, in Gy. The urethra D30 sequencing of LDR‑BT and EBRT or the time interval ABS does not provide normal tissue constraints given
should be <130% of the
between the modalities. The downside of delivering the heterogeneity in dose fractionation9. The GEC/
prescribed dose. This
constraint limits the dose to LDR‑BT before EBRT is that it exposes tissues to radi- ESTRO11 guidelines provide constraints, with conversion
the urethra. ation simultaneously from both treatments and can into the EQD2 (TABLE 3).
theoretically increase toxic effects on normal tissue. By
RV100 contrast, performing LDR‑BT first enables physician Comparing dosimetry in EBRT, LDR‑BT, and HDR‑BT
In prostate cancer
brachytherapy, this is the
assessment of the dose distribution8 and the seeds can be Both LDR‑BT and HDR‑BT have favourable dosimetry
volume of the rectum receiving used as fiducial markers for daily image guidance during compared with EBRT. The majority of prostate can-
100% of the dose, and should EBRT (FIG. 1c). cers develop in the peripheral zone of the gland, and
be <1 cc. brachytherapy plans can be tailored to deposit the highest
Technical aspects of HDR‑BT dose in this zone40 (FIG. 4a). Furthermore, several caveats to
D2cc
The average dose to 2 cc of a During the HDR‑BT procedure, a RALS automati- dose prescriptions differentiate EBRT from brachytherapy.
volume. cally deploys and retracts a single small radioactive In the 1990s, EBRT was delivered using 3D con-
source of 192Ir along the implant needle at specific formal radiation therapy (3D‑CRT), whereby multiple
D0.1cc or Dmax positions delivering ≥12 Gy/h, compared with beams were centred on the prostate141 (FIG. 4b). With
The average dose to the
hottest point of a volume. The
0.4–2.0 Gy/h with LDR‑BT. The RALS enables a physician 3D‑CRT, the maximal point dose was toward the cen-
term “D0.1cc” is sometimes to control the position where the HDR source stops tre of the prostate, near the urethra; the dose decreased
used because this (the dwell position) for a predetermined time gradually toward the periphery of the prostate. Intensity
approximates the maximum period (the dwell time). The 192Ir used in HDR‑BT is con- modulated radiation therapy (IMRT) was introduced in
dose to the smallest volume
tained within the needles placed in the prostate during this the early 1990s as a further refinement in the delivery
that can be calculated on a
computer. temporary implant; thus, the target does not move dur- of highly-conformal radiation because it increases the
ing radiation, and seed migration, is not possible, as it is dose delivered to the tumour volume and minimizes
Hotspot with LDR‑BT130,131. Moreover, the treating clinicians are the dose delivered to surrounding organs35. IMRT was
A colloquialism used to not exposed to radiation, and source preparation is not made possible by use of a multileaf collimator (MLC), a
describe volume outside the
PTV which receives a dose
required, unlike the case with LDR‑BT132. Furthermore, device made up of individual leaves of a high atomic
>100% of the specified PTV ultrasonography-based planning minimizes catheter numbered material that can move independently in and
dose. displacement 55,56,63. out of the path of a photon beam to contour its shape to

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a tumour, and advanced treatment planning calculation higher doses away from the rectum, rather than a straight
algorithms, which enable inverse optimization of MLC edge through the rectum as seen with 3D‑CRT. IMRT
positioning for complex dose delivery 35. ensures coverage of the entire prostate gland with dose
The dose distribution created by IMRT is character- and minimizes hotspots within the gland. Nonetheless,
ized by a concavity or invagination of the edge of the with IMRT, the prescription dose must be delivered to
Table 4 | Comparison of physician and patient considerations of LDR‑BT and HDR‑BT

Considerations LDR‑BT HDR‑BT
Provider and/or technical aspects
Need to use shielded room No, can be performed in operating room Yes; thus, associated costs to build room
Initial capital equipment costs Relatively low Relatively high
Radioactive source can be used No Yes; most commonly used for gynaecological, breast,
for other cancers advanced head and neck, skin, lung cancers
Recurring cost with each implant Relatively high, to pay for seeds for each implant Relatively low, as source is unchanged
Recurring costs related to source Seeds must be custom made for each implant Same source used for different patients over 3–4 months;
before date of implantation; if 125I implant if implant delayed by 1 week, treatment time relatively
delayed by 1 week, seed activity would unchanged
decrease by 7.8%
Operator dependence Relatively high High, though not as high as LDR‑BT
Planning Preimplant or intraoperative ultrasonography Ultrasonography or CT: inverse planning at the time of implant,
planning then CT postimplant dosimetry checks postimplant dosimetry not necessary
Cost for treatment Relatively low (<$12,000) compared with EBRT Relatively low (<$12,000) compared with EBRT
Dose conformality (versus EBRT) Superior, similar to HDR‑BT Superior, similar to LDR‑BT
Radiation dose to clinician Some, though extremely low None
Use for large prostates (>60 cm3) Technically possible Yes
Use as monotherapy Yes, particularly for patients with low-risk or Yes, particularly for patients with low-risk or select
select intermediate-risk disease intermediate-risk disease
Body of evidence Excellent Good, though not as robust as LDR‑BT
Uniform consensus dose Yes, e.g. 145 Gy for I, 125 Gy for
125
Pd, and
103
Typically no, multiple fractionation options:
120 Gy for 131Cs implants
• HDR-BT monotherapy: 34 Gy in 4 fractions; 36–38 Gy in 4
fractions; 31.5 Gy in 3 fractions; 26 Gy in 2 fractions
• HDR-BT boost: EBRT doses of 45 Gy in 25 fractions over 5
weeks, 46 Gy in 23 fractions over 4.5 weeks, 35.7 Gy in 13
fractions over 2.5 weeks, or 37.5.Gy in 15 fractions over
3 weeks; BT doses of 15 Gy in 3 fractions, 11–22 Gy in 2
fractions, or 12–15 Gy in 1 fraction.
Potential use with EBRT Yes, typically after EBRT Yes, before, interdigitated with, or after EBRT
Potential use to salvage local Yes Yes
recurrence
Patient
Number of implants One Typically 1–3 (to deliver 1–6 fractions); potentially increasing
risk of infection, anaesthesia complications
Convenient for patients who live Yes Yes; however, depending on implantation schedule, might
far from cancer centre require hospitalization for 1–2 days
General anaesthesia used Yes, but can also be performed under spinal or Yes, but can also be performed under spinal or local
local anaesthesia anaesthesia
Incisions, sutures No No
Outcomes: FFBF, DM, PCSS, OS Similar to HDR‑BT, EBRT, surgery (evidence Similar to LDR‑BT, EBRT, surgery (evidence level 1)
level 1)
Acute toxic effects • Overall incidence similar to HDR‑BT • Overall incidence similar to LDR‑BT
• Prolonged duration (2–4 months) compared • Shorter duration (4–6 weeks) compared with LDR‑BT
with HDR‑BT
Chronic toxic effects • Grade 3–4 toxic effects in <5% of patients • Grade 3–4 toxic effects in <5% of patients
• Similar to HDR‑BT, EBRT • Similar to LDR‑BT, EBRT
• <1% risk of incontinence • <1% risk of incontinence
DM, distant metastases; EBRT, external beam radiation therapy; FFBF, freedom from biochemical failure; HDR‑BT, high-dose-rate brachytherapy; LDR‑BT,
low-dose-rate brachytherapy; OS, overall survival; PCSS, prostate-cancer-specific survival.

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a Anterior
Anterior
fibromuscular
layer
Transition zone
Posterior
Anterior
Urethra
Central zone
Ejaculatory duct
Peripheral zone
Posterior Most frequent areas

of adenocarcinoma
b 3D-CRT IMRT SBRT

150% of
Prostate Prostate Prostate
dose
Relative dose
100% of 100% of 85% isodose line

dose dose 100% of 7.25 Gy
Urethra
Urethra
Urethra
Position Position Position
100
Prostate
80 Urethra
Rectum
c
Volume (%)
LDR-BT HDR-BT
60
150% of
Prostate Prostate
dose 40
20 LDR-BT
V150:
Relative dose
0 70 +/– 14%
100% of 0 100 200
dose % of dose p <0.001
100
HDR-BT
80 V150:
Urethra
Urethra
39 +/– 13%
Volume (%)
60
40
Position Position
20 Prostate
Rectum
0
0 200 400 600 800 1,000 1,200 1,400 1,600 1,800
Dose (cGy)
Figure 4 | Dosimetric comparison of LDR‑BT versus HDR‑BT. a | The Nature Reviews

is prescribed to an isodose line to cover the PTV. Furthermore, | Urology
the hotspot is
prostate gland is composed of a peripheral zone, central zone, transitional again in the centre of the prostate toward the urethra; although protocols
zone, and an anterior fibromuscular layer. The majority of prostate cancers include a urethra dose constraint101,102, the increased dose toward the centre
develop in the peripheral zone. b | Relative dose versus position in tissue. With of the gland with SBRT is sometimes unavoidable74,75. c | Both low-dose-rate
3D conformal radiation therapy (3D‑CRT), the maximal point dose is towards brachytherapy (LDR‑BT) and high-dose-rate brachytherapy (HDR‑BT)
the centre of the prostate, near the urethra; the dose decreases gradually provide excellent dosimetric coverage of the prostate, particularly because
toward the periphery of the prostate. Intensity-modulated radiation therapy they provide excellent coverage of the peripheral zone with a low dose to
(IMRT) ensures coverage of the entire prostate gland with dose and minimizes the urethra. HDR‑BT might, in some instances, be superior to LDR‑BT
hotspots within the gland. Nonetheless, with IMRT, the prescription dose must because the hotspots assessed by looking at the V150 (volume receiving
be delivered to the planning target volume (PTV), which expands outside of 150% of the prescribed dose) are typically smaller in a HDR‑BT plan than in
the prostate. With stereotactic body radiation therapy (SBRT), radiotherapy a LDR‑BT plan.

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the PTV, which expands outside of the prostate (FIG. 4b). make the implant technically challenging and worsen
With SBRT (FIG. 4b), radiotherapy is prescribed to an iso- the toxicity of HDR‑BT. Centres are using this method
dose line to cover the PTV. Furthermore, the hotspot is in the USA47,82,152,157–159, Australia152,160–162, Europe50,54,163,164,
in the centre of the prostate toward the urethra; although Japan165–167, and Canada168.
a urethra dose constraint is provided by clinical trials Alternatively, HDR‑BT can be delivered first,
and guidelines101,102, the higher dose toward the centre with EBRT delivered 1–3 weeks later. With this method,
of the gland with SBRT is sometimes unavoidable74,75. EBRT can be used to compensate for suboptimal implant
With LDR‑BT and HDR‑BT, the dose can be dif- dosimetry of HDR‑BT; furthermore, preimplant radia-
ferentially delivered within the peripheral zones of the tion-induced oedema and genitourinary symptoms that
prostate, and the dose towards the centre of the gland typically follow EBRT are minimized169. A disadvantage
can be minimized (FIG. 4c). Furthermore, as the CTV is of this method is the delayed application of radiotherapy
equivalent to the PTV for brachytherapy, the dose is not to pelvic lymph nodes (if these are included in the treat-
prescribed to a large volume outside of the gland. With ment volume). This method is in use in Europe (includ-
HDR‑BT, the hotspots, assessed by looking at the V150 ing the UK)152,170–172, the USA47,52,152,173–176, Australia44,177,178,
(or volume receiving 150% of the prescribed dose), are China179,180, Brazil181, and Canada51.
typically smaller than in LDR‑BT (FIG. 4c); whether this Finally, EBRT can be interdigitated with HDR‑BT.
α/β ratio is an advantage or disadvantage is unclear. This technique combines some of the advantages and
The α/β ratio describes the
disadvantages of the other temporal approaches. EBRT
shape of the cell survival curve
and the gradient of the two HDR‑BT fractionation and sequencing is delivered on days when HDR‑BT is not delivered, thus
components of cell kill, α and β. The standard EBRT dose used in HDR‑BT boost varies minimizing treatment time prolongation and possible
The α/β ratio is used to between institutions9. A particular dose fractionation accelerated repopulation that would be present with a
describe the dose response of schedule has not been recommended by the ABS9 and split course of radiotherapy. Centres are using the inter-
radiation on different tissues.
Prostate cancer cells have a
various options are available according to GEC/ESTRO: digitated method in Europe45,46,80,182–185, the USA45,53,183,186,
relatively low α/β ratio of 1.5, 15 Gy in three fractions at 5 Gy per fraction, 11–22 Gy and Japan166,187.
implying that those cells are in two fractions, at 5.5–11 Gy fractions, or 12–15 Gy in a
more sensitive to doses single fraction11. Currently, 15 Gy in one fraction is the Radiobiology
delivered in larger fraction size.
dose schedule in use in the Radiation Therapy Oncology Fractionation — which refers to dividing a radiation dose
In the radiobiological linear
quadratic equation, it is the Group 0924 phase III trial of dose-escalated radiation into smaller doses given at least 6 h apart — has several
dose at which cell killing due to therapy with or without pelvic nodal irradiation in theoretical radiobiological advantages including repair
the linear and quadratic HDR‑BT monotherapy 63. Thus, for HDR‑BT boost, the of normal tissue damage, redistribution of cancer cells
components are equal. dose is typically delivered in 1–2 implants, using 2–6 into radiosensitive phases of the cycle (G2–M), and re
Biologically equivalent dose
fractions. Each fraction of radiation is 9–15 Gy: a lower oxygenation of the tumour. Thus, fractionation might
(BED). A more conceptually dose-per-fraction is used if more fractions are deliv- increase the efficacy of radiotherapy. As the total fraction
useful measure of biological ered (for example four fractions of 8.5 Gy), or a higher ated radiation dose delivered increases, the number of
damage to cells than physical dose-per-fraction is used if fewer fractions are used surviving cells within the treated volume decreases188.
dose. It takes into account the
(for example a single fraction of 15 Gy)60,142–156. However, the benefits of an increased total dose are offset
α/β ratio, number of radiation
fractions, and fraction size. For HDR‑BT boost 55,56, EBRT is usually delivered by increased toxicity to the surrounding normal tissue.
BED = (nd[1 + d/(α/β)]). In this to a total dose of 36–54 Gy in 1.8–2.0 Gy fractions The α/β ratio is used to describe the dose response of
formula, n is the number of and HDR‑BT is typically delivered to a total dose of radiation on different tissues. The α/β ratio is thought to
radiation fractions and d is the 12–30 Gy in 1–4 fractions. Two HDR‑BT boost frac- be ≥10 Gy for early-responding tissues, including skin,
dose size per fraction.
tionation schedules have evolved most likely because of mucosa, and most malignant tumours, and 3–5 Gy for
Intensity-modulated preference by the physician, centre, and reimbursement late-responding tissues, including connective tissues and
radiation therapy models55,56. A separate procedure for catheter insertion muscles. Clinical radiobiological models suggest that
(IMRT). An advanced form of for each fraction is typically used in European countries. prostate cancer has a low α/β ratio (~1.5), compared with
high-precision radiation that
A single insertion followed by 1–4 fractions delivered most other malignancies189. The α/β ratio is an important
conforms the treatment
volume to the shape of the over 1–2 days is favoured in North American centres51. component of dose equivalent formulae used to convert
tumour. The dose distribution GEC/ESTRO recommends administering 15 Gy in three different fractionation schedules into a common cur-
created by IMRT is fractions, 11–22 Gy in two fractions, or 12–15 Gy in a rency. It includes other assumptions in relation to repair
characterized by a concavity or single fraction11. The separate insertion schedule results and repopulation. A simplified form of the BED formula
invagination of the edge of the
higher doses away from the
in a greater workload of resource-intensive procedures is often used to relate different fractionation schedules,
rectum, rather than a straight and a greater anaesthesia time than the single-insertion where n is the number of radiation fractions and d is
edge through the rectum as procedure, which can require overnight hospital admis- dose size per fraction: BED = (nd[1 + d/(α/β)]).
seen with 3D conformal sion and is associated with risks of interfractional If the α/β ratio for the tumour is lower than that of the
radiation therapy.
catheter displacement62. surrounding tissues, as is hypothesized for prostate can-
Multi-leaf collimator Three temporal approaches for combining EBRT cer, increasing the dose per fraction increases the BED
(MLC). A device made up of and HDR‑BT have been described (FIG. 1c)55,56. If EBRT is more for the tumour than for the normal tissues; that
individual leaves of a high delivered first, HDR‑BT is typically delivered 1–6 weeks is, the BED1.5 increases more than BED10 (REF. 35). The
atomic numbered material that later. One benefit of this method is to dose escalate a par- diverging BED values result in an increase in the thera
can move independently in and
out of the path of an X‑ray
ticular part of the prostate that contains the GTV, though peutic ratio190,191. Radiobiological models approximate
beam to contour its shape to a this approach is still investigational. One disadvantage cell death due to DNA damage from radiation therapy
tumour. of this method is the oedema caused by EBRT, which can using conventional fractionation, that is, 1.8–2.0 Gy per

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Box 1 | The ideal patient for definitive brachytherapy with the delivery of each fraction136. Thus, changing to
a hypofractionated schedule or brachytherapy could
Patients should have the following characteristics decrease the number of work-hours and overall cost of
• For brachytherapy monotherapy: Low-risk disease (Gleason score <6, and PSA treating each patient75. By contrast, brachytherapy treat-
<10 ng/ml, and clinical tumour classification T1, T2a), or favourable intermediate-risk ment is substantially more efficient — based on American
disease (Gleason score 7, or PSA 10–20 ng/ml or clinical tumour classification of T2b, Medicare reimbursements, per-patient costs of conven-
T2c) with primary Gleason score 3 + 4, <50% positive biopsy cores, and only a single tionally fractionated EBRT with intensity modulation,
intermediate-risk feature.
LDR‑BT, and HDR‑BT with four fractions, are estimated
• For brachytherapy boost: High-risk disease (Gleason score 8–10, or PSA >20 ng/ml, or at $29,356, $9,938, and $17,514 respectively 137. LDR‑BT
clinical tumour classification of T3a), or unfavourable intermediate-risk disease
might have a lower initial capital expense requirement
(Gleason score 7, or PSA 10–20 ng/ml or clinical tumour classification of T2b, T2c)
with primary Gleason score 4 + 3, ≥50% positive biopsy cores, and multiple
than HDR‑BT, in part because the kV energy isotopes
intermediate-risk features. used for LDR‑BT do not require use of a shielded room
and the procedure can be performed in an operating
Patients should have none of the following
room, unlike that of mV energy 192Ir used for HDR‑BT,
• Ataxia telangiectasia which requires a special vault. Nonetheless, both forms
• Pre-existing rectal fistula of brachytherapy are relatively inexpensive.
• Unacceptable operative risks or medically unsuitable for anaesthesia
• Distant metastases Clinical outcomes and toxicities
• Absence of rectum such that TRUS guidance is precluded Level 2 evidence regarding outcomes for HDR‑BT
• Large TURP defects that preclude seed placement and acceptable radiation dosimetry and LDR‑BT suggests they are similar in patients with
low-risk and favourable intermediate-risk disease4.
Patients should preferably not have the following
Furthermore, level 1 evidence shows improved quality of
• History of previous pelvic radiotherapy
life with brachytherapy over prostatectomy, based on the
• Limited life expectancy (<10 years) results of the Surgical Prostatectomy Versus Interstitial
• Moderate-to‑severe urinary symptoms (for example, high IPSS score, typically Radiation Intervention Trial (SPIRIT)200. For both types
defined as >20) of brachytherapy, the 5‑year freedom from biochemical
• Inflammatory bowel disease failure (FFBF) outcomes for patients with low-risk, inter-
• Increased risk of bleeding mediate-risk, and high-risk disease are >85%, 69–97%,
• Large median lobes and 63–80%, respectively 4,56.
• Pubic arch interference Brachytherapy plus EBRT (as opposed to brachy
• Patient peak urinary flow rate <10 cm3/s and postvoid residual volume before therapy alone) is an appropriate approach in select patients
brachytherapy >100 cm3 with intermediate-risk and high-risk disease (evidence
• Large prostate (>60 cm3) level 1)4 using either LDR-BT89 or HDR‑BT54,201 (BOX 1;
TABLE 1). Briefly, patients who benefit from brachytherapy
boost are typically those with unfavourable-intermediate
fraction. However, the models do not account for cell risk and high-risk disease. Patients receiving boost should
death due to other mechanisms (as seen with >5 Gy per have no absolute contraindications to the treatment,
fraction), including lipid membrane phosphorylation, including ataxia telangiectasia, a pre-existing rectal fistula,
necroptosis, or immune-mediated death192–195, but, they unacceptable operative risks, distant metastases, absence
do account for vasculogenesis secondary to mesen- of a rectum such that TRUS guidance is precluded, or large
chymal stem cell infiltration196. Thus, the higher BED TURP defect that would result in unacceptable dosimetry.
of hypofractionated approaches suggests a theoretical Other factors, including history of previous pelvic radio-
benefit of HDR‑BT versus conventionally fractionated therapy, limited life expectancy, and moderate-to‑severe
EBRT. Similar estimates for the BED of LDR‑BT show urinary symptoms are relative contraindications.
that optimal 125I prostate implants should deliver a
D90 of 140–180 Gy, based on postimplant dosimetry. LDR‑BT
Doses of <140 Gy are associated with increased bio- LDR‑BT monotherapy for low-risk disease. Patients with
chemical failure rates and doses >180 Gy with a slight low-risk features deemed suitable candidates for LDR‑BT
increase in long-term urinary symptoms129,197. can be appropriately treated with LDR‑BT monotherapy.
Published studies demonstrate that excellent long-term
Cost outcomes can be expected when optimal dosimetric
Brachytherapy is typically much more efficient, in terms parameters are achieved202–204. According to a review
of the resources it consumes198, than EBRT35. For radio published by the Prostate Cancer Results Study Group,
therapy, calculation models show that wage costs out- the 10‑year rates of FFBF for patients with low-risk
weigh the cost of machines, owing to the labour-intensive disease receiving LDR‑BT monotherapy have been esti-
nature of radiotherapy planning and delivery 139,140. For mated at >86%205. Rates of prostate cancer distant meta
treatment of a patient with prostate cancer using 40 frac- stasis, prostate-cancer-specific mortality (PCSM), and
tions of EBRT, staffing of radiotherapy facilities accounts overall survival (OS) in these patients are estimated to be
for an estimated 50% of the cost199. Additionally, although <10%, <5%, and >85%, respectively, at 10 years after treat-
IMRT treatment planning is complex, the planning is ment205, and grade 3–4 toxicities occur in <4% of patients
only done at the beginning of therapy, while cost builds (TABLE 5).

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Table 5 | Percentage of late grade 3–4 toxic effects associated with HDR‑BT, LDR‑BT, and EBRT
Brachytherapy Boost External beam radiotherapy (with intensity modulation)
Low-dose- High-dose-rate Brachytherapy + Conventional Hypofractionation Stereotactic body
rate conventional fractionation radiotherapy
fractionation
Quality of Early Late Early Late Early Late Early Late Early Late Early Late
life domain
Sexual 1–5% 1–5% 1–5% Inconclusive 1–5% >5% 1–5% 1–5% 1–5% 1–5% 1–5% Inconclusive
Urinary 1–5% <1% 1–5% <1% 1–5% <1% <1% <1% <1% <1% <1% Inconclusive
incontinence
Urinary >5% 1–5% <1% Inconclusive >5% 1–5% 1–5% <1% 1–5% <1% 1–5% Inconclusive
irritative
and/or
obstructive
Bowel and/ 1–5% <1% <1% Inconclusive 1–5% 1–5% 1–5% 1–5% 1–5% 1–5% <1% Inconclusive
or rectal
LDR‑BT monotherapy or boost for intermediate-risk LDR‑BT boost for high-risk disease. LDR‑BT boost is an
disease. For patients with intermediate-risk disease, the accepted treatment modality for patients with high-risk
appropriateness of LDR‑BT monotherapy depends on disease8,9. Outcomes and toxicities of LDR‑BT boost have
many factors including the required margin of treatment. been reported from Radiation Therapy Oncology Group
In pathological series of whole-mount radical prostat (RTOG) 0019 (REF. 213), Cancer, Leukaemia Group B
ectomy specimens of <pT3 disease defined as being (CALGB) 99809 (REF. 214), and the Androgen Suppression
organ-confined206–209, the radial extraprostatic extension Combined with Elective Nodal and Dose Escalated
(EPE) rarely extends >5 mm; the posterolateral region, Radiation Therapy (ASCENDE‑RT; NCT00175396)89. In
which is near the seminal vesicles, is at highest risk of ASCENDE‑RT, LDR‑BT boost was shown to be superior
EPE209. Many intermediate-risk tumours have equivalent to EBRT in terms of FFBF, bodily pain, general health,
or even lower risk of adverse pathological features such sexual function, and urinary function89. Additionally, in
as EPE, seminal vesicle invasion, or lymph node involve- a retrospective cohort of 245 patients receiving LDR‑BT
ment. Thus, they can be treated with LDR‑BT mono- (with or without a boost) rates of Grade ≥2 and ≥3 rectal
therapy 210. A recommended margin of 3 mm around the toxicities were estimated to be 7% and 3%, respectively215.
prostate is used as the planning target volume in all direc- The risk of Grade ≥2 rectal toxicity was 2.8‑fold higher
tions, except posteriorly because this would expose the in patients receiving supplemental EBRT compared
rectum to high doses of radiation. This expansion usually with LDR‑BT alone, and the risk of Grade ≥3 rectal
encompasses all EPE in intermediate-risk disease8. toxicity was 11.9‑fold higher 215 (TABLE 5). Toxic effects
In the RTOG 0232 study, which ran from 2003 to are likely to be due, in part, to patient comorbidities,
2012, patients with intermediate-risk prostate cancer including increased BMI and hyperglycaemia or hyper
were randomized to receive LDR‑BT alone (with either insulinaemia216,217. Incontinence is not a common toxic
103
Pd or 125I) or EBRT (45 Gy, partial pelvis, 1.8 Gy/ effect after brachytherapy.
fraction), followed by LDR‑BT. Based on the report ADT in combination with EBRT (in the neoadjuvant,
released in 2016, the addition of EBRT to LDR‑BT did concurrent, and adjuvant settings) has been shown to
not result in superior FFBF (80% at 5 years for LDR‑BT improve patient outcomes over the use EBRT alone in
and LDR‑BT + EBRT), overall survival, distant meta multiple clinical trials91,93–99,218–220. However, the data
stasis rate, or PCSM211. Additionally, participants in the regarding the addition of ADT to LDR‑BT patients is less
LDR‑BT‑alone arm experienced fewer late events than robust than for results regarding EBRT. Merrick et al.221
the EBRT group: 53% versus 37% for any late Grade 2+ reported that 10‑year FFBF was improved with the
effects and 12% versus 7% for any late Grade 3+ effects. addition of ADT, but overall survival and PCSM were
The 10‑year rates of FFBF for patients with not. In addition, a multi-institutional series reported
intermediate-risk disease receiving LDR‑BT mono by Stone et al.222 showed that patients with Gleason
therapy is estimated to be >65%, with most reports score 8–10 tumours had improved overall survival and
around 90%205. In a multi-institutional analysis of about freedom from distant metastasis with higher doses
3,000 patients with prostate cancer, including 960 men (BED10 >220 Gy) of LDR‑BT.
with intermediate-risk disease, the 8‑year FFBF rate
was 70%204. Notably, the majority of these patients were HDR‑BT
treated before 1999 and fewer than 25% had formal HDR‑BT monotherapy for low-risk and intermediate-
postimplantation quality assurance109. A survey of 18 risk disease. HDR‑BT monotherapy can be used
brachytherapy practitioners who treated over 10,000 in select (BOX 1; TABLE 1) patients with low-risk and
patients with LDR‑BT suggested that practitioners intermediate-risk disease4,63. The ABS and GEC/ESTRO
employ monotherapy carefully, on a case‑by‑case basis212. guidelines recommend monotherapy for patients with

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high-risk disease only in a clinical trial or in case‑by‑case combines the benefits of conventionally fractionated
circumstances9,11. In a systematic review of HDR‑BT EBRT or hypofractionated EBRT monotherapy to cover
monotherapy, FFBF rates for patients with low-risk, extraprostatic disease with the high radiation dose
intermediate-risk, and high-risk disease are ≥85% at delivered to the CTV by HDR‑BT56,224. Thus, the BED
up to 5 years60,142–156. OS, PCSM, local recurrence, and achieved with HDR‑BT boost is typically much higher
distant metastasis rates are typically >95%, <4%, <4%, than can be achieved with EBRT alone; at an α/β ratio
and <4%, respectively 63. The highest rate of distant meta of 1.5, the BEDs are 200–300 for HDR‑BT boost versus
stasis was reported by Yoshioka and colleagues153,154 but ~187 for EBRT monotherapy of 80 Gy in 2.0 Gy fractions
was secondary to their inclusion of a greater number of (REFS 56,225) (FIG. 5).
patients with high-risk disease than other studies. Based Hoskin et al.54 published one of the few randomized
on a systematic review, grade 3–4 gastrointestinal or trials performed, including 220 patients randomized
genitourinary toxicity occurs in <5% of patients63. to HDR‑BT boost versus EBRT alone. After a median
In one of the largest series of HDR‑BT mono follow‑up duration of 85 months, a noticeable improve-
therapy from the University of California, Los Angeles ment in was observed in recurrence-free survival for
(UCLA)223, the authors reported encouraging outcomes patients who received HDR‑BT boost, with a median time
with 6.5 years of follow‑up monitoring, which was some to relapse of 116 months compared with 74 months for
of the longest follow‑up available at that time, but likely EBRT alone. The 5‑year, 7‑year and 10‑year estimates of
not long enough to draw long-term outcome conclu- FFBF were 75%, 66% and 46%, respectively, for HDR‑BT
sions. Similar to LDR‑BT, HDR‑BT monotherapy is boost, compared with 61%, 48% and 39%, respectively,
associated with excellent and comparable rates of bio- for EBRT alone (log rank P = 0.04). T3 disease was pres-
chemical control, patient survival, treatment toxicity, ent in 27% of their population and Gleason score ≥7
and erectile preservation63. in 58%. The 5‑year and 7‑year incidences for patients
with any severe urinary symptoms were 26% and 31%,
HDR‑BT boost for intermediate-risk and high-risk respectively, for those treated with HDR‑BT boost com-
disease. HDR‑BT boost beneficial in patients with pared with 26% and 30%, respectively, for those given
intermediate-r isk and high-risk disease because it EBRT alone (log rank P = 0.5). The authors concluded
(Total Gy) / (number of fractions) / (Gy per fraction)

320 HDR-BT monotherapy or SBRT
300 34.5 / 3 / 11.5 Dose-escalated conventionally
fractionated EBRT
280 38 / 4 / 9.5
54 / 9 / 6
260
240 42 / 6 / 7
30 / 3 / 10
Biologically equivalent dose (Gy)
220
200
180 78 / 39 / 2
160
140
120
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10
α/β (Gy)
Prostate cancer, per Late-responding Early-responding
hypothetical reports tissues (i.e. for late tissues (i.e. for early
as of 2001 toxicity) toxicity)
Figure 5 | BED versus α/β curves for fractionated radiotherapy for prostate cancer. Biologically equivalent doses
(BEDs) for several major studies of high-dose-rate brachytherapy (HDR‑BT) are shown compared with theReviews
Nature regimen| of
Urology
dose-escalated conventionally fractionated external beam radiotherapy (EBRT) monotherapy. The use of higher doses per
fraction (for example with HDR‑BT versus conventionally fractionated EBRT) results in a higher BED at α/β of 1.5
(for prostate cancer) than at α/β of 3.0 (for late toxicity), thereby increasing the therapeutic ratio.

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that HDR‑BT boost could have an important role in <5%55,56,62 (TABLE 5). By contrast, Grade 3–4 toxicities,
the treatment of patients with intermediate-risk and including stricture, occur in <3% of patients receiving
high-risk disease. EBRT alone4,56,227. LDR‑BT boost RTOG Grade 3–4
A number of other prospective studies have been genitourinary toxicities, including stricture, from two
performed using HDR‑BT boost 44–46,48,51,53,54,161,174,175,183. phase II studies were observed in 13%213 and 3%214 of
In a systematic review of these studies56, the reported patients, and gastrointestinal toxicities were seen in 3%213
5‑year PCSM, OS, local recurrence rates, and distant and 0%214 of patients. Besides dosimetric quality con-
metastasis rates were 99–100%, 85–100%, 0–8%, and straints, characteristics predicting late toxicity include
0–12%, respectively. These outcomes are similar to initial presence of symptoms157, ADT use157,180, older age
those of LDR‑BT, EBRT, and LDR‑BT boost 55,56 and bet- (> ~65 years)157,181, high-risk status180, previous trans
ter than EBRT alone, as reported in ASCENDE‑RT54. urethral resection of the prostate152,171, hypertension152,
Studies reporting outcomes outside of these ranges and diabetes217. Based on these data, HDT‑BT is not
typically include patients with high-risk and locally an ideal treatment modality for all patients with high-
advanced disease or exclude patients who have received risk prostate cancer, and clinicians might choose to use
ADT45,48,49,53,183. another modality, for example EBRT alone, in elderly
Based on systematic reviews55,56, the rates of Grade patients with comorbidities (TABLE 2).
3–4 genitourinary and gastrointestinal toxicities are In summary, HDR‑BT boost is now a well-
0–12% and 0–8%, respectively, in phase I/II studies established treatment modality for patients with inter-
with ≥4‑year median follow‑up duration 44,46,48,52,53. mediate-risk and high-risk prostate cancer, particularly
Furthermore, among studies that compare HDR‑BT those without contraindications (BOX 1) . Similarly,
boost with EBRT alone, the rate of stricture occurrence HDR‑BT monotherapy is associated with excellent
is considerably higher in the boost arm54,160,162. RTOG outcomes and toxicity profiles in men with low-risk
032147, the first multi-institutional prospective trial using and favourable intermediate-risk disease. HDR‑BT
HDR‑BT boost in the USA, provided detailed reports of monotherapy studies tend to have a shorter follow‑up
toxicity and stricture occurrence. With a median follow‑ time and include fewer patients than studies of LDR‑BT
up period of 2.5 years, RTOG 0321 reported a rate of and EBRT; thus, studies with >10–15 years of follow‑up
2.6% for Grade 3–4 toxic effects, and a rate of urinary duration that report efficacy and toxicity will not be
stricture of 0.7%47. published until the 2020s.
The outcomes of HDR‑BT boost are encourag-
ing, particularly for high-risk prostate cancer. One Salvage for local recurrence after EBRT
of the most important factors associated with out- Brachytherapy with either LDR‑BT or HDR‑BT mono
come analyses is the role of ADT, which is associated therapy are possible treatments for local recurrence
with improved rates of FFBF, distant metastasis-free after EBRT or LDR‑BT228–232. Salvage brachytherapy is
survival, and prostate-cancer-specific survival91,226. a promising option, particularly for patients who are
However, the role of ADT is often overlooked and in not deemed fit for salvage prostatectomy. The NCCN
the systematic reviews of published studies, no mul- guidelines include few recommendations regarding the
tivariate analysis is performed to evaluate the effect approach3; thus, referral to a specialty centre with salvage
of ADT on outcomes 55,56. In the prospective study experience is recommended.
by Hoskin and colleagues 54, treatment arm, risk Nguyen et al.233 published a prospective phase II
category, and ADT use were significant covariates for study of MRI-guided salvage brachytherapy for 24 men
biochemical recurrence. with a rising serum PSA and biopsy-proven, intrapros-
The toxic effects associated with of HDR‑BT boost tatic cancer >2 years after initial radiotherapy (EBRT
are similarly encouraging, and in systematic reviews of or brachytherapy), who had favourable clinical features:
prospective studies, the late Grade 3–4 toxicity rate is Gleason score <8, serum PSA <10 ng/ml, and negative pel-
vic and bone imaging studies. They achieved biochemical
control in 70% of patients at 4 years after the salvage pro-
Box 2 | The ideal patient for salvage brachytherapy cedure. The 4‑year estimate of grade 3+ gastrointestinal or
genitourinary toxicity was 30% and 13 patients required a
• Local-only recurrence colostomy and/or urostomy to repair a fistula.
-- PSA nadir after initial therapy that did not rise
The ideal salvage brachytherapy patient 233–236 (BOX 2)
-- PSA doubling time >1–2 years
-- Recurrent PSA <10 ng/ml
should have biopsy-proven local-only recurrence, pref-
-- No Gleason 8–10 disease, which has a higher erably with no evidence of widely metastatic disease,
propensity to disseminate or none that cannot be controlled with focal therapy
• Biopsy-proven disease at other sites (for example, SBRT for oligometastatic
recurrence) 237,238. Factors that suggest a local-only
• No or minimal morbidity from prior radiotherapy
recurrence are the presence of a nadir after initial ther-
• >4.5 years since prior radiotherapy
apy, PSA doubling time >1–2 years, recurrent serum
• Ability to tolerate MRI, which would be used for PSA measurements <10 ng/mL, and no Gleason 8–10
brachytherapy planning
disease, which is more likely to disseminate239. For
• Possible insertion of a rectal spacer to minimize dose to patients with widely metastatic disease, the excessive
the rectum
morbidity of local therapy and likely lack of a survival

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benefit obviate the need for salvage brachytherapy. Next, Other QOL metrics available include the AUA
the patient should have minimal, and preferably no, International Prostate Symptom Score (I‑PSS) and
morbidity from previous radiotherapy, and that treat- the Sexual Health Inventory for Men (SHIM)248. The
ment should have been performed >4.5 years before the IPSS is intended to evaluate men with benign prostatic
date of salvage brachytherapy 233. Patients with ongoing hypertrophy, whereas the SHIM was designed by indus-
toxic sequelae, such as a nonhealing ulcer, are unlikely to try to evaluate therapies for erectile dysfunction249,250
benefit from salvage brachytherapy and are more likely Although these are sometimes used for QOL com-
to develop further toxic effects, including infection, parison, they are not preferred as they do not capture
bleeding, pain, necrosis, and blood clots. Additionally, such a wide range of data as is collected in the EPIC,
the patient should have no contraindications to prevent UCLA-PCI, or EORTC QLQ‑C30 (REF. 251). For exam-
use of pelvic MRI, which is used to delineate the region ple, the IPSS score does not collect information about
of recurrence and for brachytherapy planning 233. Finally, incontinence.
the use of a rectal spacer can be considered to minimize PSA kinetics should be monitored after brachy
radiation dose to the rectum236. therapy (FIG. 6). Biochemical failure can be defined in
a number of ways: the ABS and ASTRO favour the
Ongoing trials use of the Phoenix definition (PSA nadir + 2 ng/ml)
Several studies are currently in progress to directly following treatment. After LDR‑BT, PSA decreases
compare LDR‑BT with HDR‑BT (TABLE 6). Additionally, to <0.3 ng/ml in most men with localized disease252.
several studies are evaluating the efficacy of HDR‑BT Patients should also be monitored for biochemical
for local recurrence. The use of brachytherapy as a focal failure, keeping in mind that the features of benign
boost to treat part of the prostate in the area identified to PSA bounces and biochemical failure overlap sub-
have the cancer focus, either with biopsy or novel imag- stantially, although benign bounce is uncommon after
ing, is also under investigation. 36 months253.
Focal therapy aims to minimize the volume of nor- PSA bounce can occur after any form of radiotherapy,
mal tissue irradiated (rectum, bladder, urethra) and and the clinician must appreciate that PSA bounces are
maximize the dose to tumour, which is typically iden- common, do not automatically represent cancer recur-
tified using imaging studies. In a systematic review of rence, and are associated with various patient, cancer,
focal therapy in the management of localized prostate and dosimetric factors (for example, the urethra D90)254.
cancer that included 2,350 patients across 30 studies, A routine biopsy is not usually recommended; however,
brachytherapy was used in only two of these stud- before any treatment is recommended or initiated, can-
ies, and one was in the setting of recurrent disease233. cer recurrence needs to be documented by biopsy or
Thus, the ideal patient and dose for focal therapy are imaging 23,239. If a rising serum PSA is noted and pros-
not well established; the meta-analysis states that focal tate biopsy is performed, the biopsy should be done
therapy was mainly delivered to men with low-risk and ≥30 months after completion of LDR‑BT, or it might be
intermediate-risk disease240. uninterpretable, and a false positive result can be mis-
takenly determined when actually a benign PSA bounce
Follow‑up monitoring is likely 255.
After brachytherapy, close follow‑up monitoring with PSA bounces >1.0 ng/ml are rare after LDR‑BT
serum PSA measurements at regular intervals is rec- with or without neoadjuvant ADT, occurring in <10%
ommended, as well as a digital rectal examination of patients 256. However, as PSA bounce amplitude
(DRE). The optimal surveillance frequency following increases, the biochemical failure rate also increases256.
brachytherapy has not been established. According By contrast, patients with Gleason score 6 disease are
to the NCCN and ABS guidelines, an interval of more likely to experience a PSA bounce and have
every 6–12 months is appropriate for most patients, improved FFBF 257. An increased prostatic urethra
but those with high-risk disease should be monitored D90 seems to correlate with the likelihood of having
more frequently 3,8. Quality of life (QOL) measure a PSA bounce, and PSA levels typically take 2–3 years
ments can include the Short Form‑36 (SF‑36), to reach the nadir 254.
the Client Satisfaction Questionnaire‑8 (CSQ‑8), the The PSA nadir is typically a very low after
Functional Assessment of Cancer Therapy-General HDR‑BT, <0.05 ng/ml (REF. 258) . The rate of PSA
(FACT‑G), the European Organization for Research bounce seems to be more frequent in patients treated
and Treatment of Cancer (EORTC) Quality of Life with LDR‑BT than those who received HDR‑BT or
Questionnaire (QLQ)–C30 (EORTC QLQ–C30), the EBRT, at 42%, 23%, and 20%, respectively 259. In a
University of California, Los Angeles Prostate Cancer series of 114 men treated with HDR‑BT boost with
Index (UCLA-PCI), and the Expanded Prostate hypofractionated EBRT, PSA bounce occurred in 39%
Cancer Index Composite (EPIC)79. All of these forms of patients after a median of 16 months. The median
capture the recommended quality-of‑life components: magnitude of bounce was 0.45 ng/ml and biochemical
Phoenix definition urinary incontinence, urinary obstruction and irrita- failure occurred in 11% of patients who experienced
Used for measuring tion, bowel-related symptoms, sexual dysfunction, a bounce260. In a separate series of 67 patients, 43%
biochemical failure after
radiotherapy for prostate
and hormonal symptoms241. Among the various met- experienced a PSA bounce; among all patients treated
cancer, defined as the PSA rics, the EPIC, UCLA-PCI, and EORTC are the most with HDR‑BT monotherapy, 28% of patients have a
nadir value plus 2 ng/ml. frequently used and are preferred241–247. bounce <1 ng/ml and 15% have a bounce >1 ng/ml

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(REF. 261) .
Patients who experienced a PSA bounce Conclusions
typically had a lower Gleason score tumour than Brachytherapy and brachytherapy boost are excellent first-
those who did not experience a bounce and were aged line therapies in the management of men with prostate
<55 years261. The authors provided several hypotheses cancer. LDR‑BT monotherapy is acknowledged as a stand-
for these findings, including more frequent sexual ard option in low-risk prostate cancer by health organiza-
activity among younger patients. tions internationally. HDR‑BT monotherapy can be used
Table 6 | Ongoing studies evaluating brachytherapy for prostate cancer

Study identifier Location Phase Study arms Outcomes
NCT02628041 (REF. 262) Université de Montréal, 1–2 • Active comparator: LDR‑BT with 125I Quality of life
Sunnybrook Health Sciences • Experimental: HDR‑BT
Centre, Quebec, Canada
NCT02346253 (REF. 263) Stanford University, Palo Alto, 1 Experimental: Treatment (HDR‑BT, ADT and Acute toxicities
California, USA LHRH agonist therapy)
NCT02258087 (REF. 264) National Institute of 1–2 • Active Comparator: LDR‑BT with 125I Acute and chronic toxicities
Oncology, Hungary • Experimental: HDR‑BT
NCT02560181 (REF. 265) Sunnybrook Health Sciences 1–2 Experimental: HDR‑BT for recurrent prostate Acute toxicities
Centre, Quebec, Canada cancer
NCT02322931 (REF. 266) British Columbia Cancer 2 Experimental: Imaging interventions. Patients Feasibility of replacing
Agency, Vancouver, British are randomized to one of four arms with day 0 CT with intraoperative
Columbia, Canada different imaging procedures for LDR‑BT 3D C‑arm imaging
NCT02225925 (REF. 267) Johns Hopkins University, 2 Experimental: Dynamic dosimetry with Procedure time
Baltimore, Maryland, USA intraoperative LDR‑BT
NCT00450411 (REF. 230) British Columbia Cancer 1–2 Experimental: US‑guided LDR‑BT for prostate Acute toxicities
Agency, Canada and USA cancer local recurrence after EBRT
NCT02632669 (REF. 268) Royal Surrey County Hospital 1 Experimental: Hemigland focal LDR‑BT Acute toxicities
NHS Foundation Trust, UK using permanent 125I seed implantation
NCT02290366 (REF. 269) University of Pittsburgh, 2 Experimental: Hemigland focal LDR‑BT Biochemical outcomes at
Pittsburgh, Pennsylvania, USA using permanent 131Cs seed implantation 5 years
NCT00913939 (REF. 270) Princess Margaret Hospital, 2 • Experimental arm 1: MRI-guided HDR‑BT as Favourable measures of
Toronto, Canada salvage after EBRT technical performance
• Experimental arm 2: MRI-guided HDR‑BT as
boost to EBRT
NCT01936883 (REF. 271) British Columbia Cancer 3 • Active comparator: LDT‑BT with 125I Acute toxicities, quality of
Agency, Vancouver, British • Experimental: HDR‑BT life, biochemical outcomes
Columbia, Canada
NCT01909388 (REF. 272) Alfonso Gomez-Iturriaga, 1–2 Active comparator: MRI–TRUS-fusion-guided Feasibility based on
Hospital de Cruces, Bizkaia, real-time HDR‑BT dosimetry
Spain
NCT02790216 (REF. 273) Sheba Medical Center, Tel 2 Experimental: Deformable registration Feasibility, based on absence
Hashomer, Israel of multiparametric MRI to intraoperative of tumour outside of
transrectal ultrasound for LDR‑BT with 125I brachytherapy volume (from
biopsy)
NCT02652000 (REF. 274) University of Zurich, 3 LDR‑BT with 125I Acute toxicities, quality of life
Switzerland
NCT02597894 (REF. 275) University of California Los 1 Experimental: Targeted biopsies in determining Feasibility of obtaining
Angeles, California, USA response to ADT and HDR‑BT adequate biopsies from
intraprostatic index lesion
before ADT and then at time
of HDR‑BT
NCT02805894 (REF. 276) Brigham and Women’s 1 • Experimental: NBTXR3 (a radiosensitizing Maximum tolerated dose
Hospital, Boston, nanoparticle) activated by IMRT and early dose limiting
Massachusetts, USA • Experimental: NBTXR3 activated by toxicities
brachytherapy and IMRT
NCT01437085 (REF. 277) Cross Cancer Institute, NA Experimental: Observational study quantifying NA
Alberta, Canada needle deflection and tissue deformation in
prostate brachytherapy
NCT02623933 (REF. 278) Sunnybrook Health Sciences 1 Experimental: MRI-assisted focal boost with Acute toxicities
Centre, Ontario, Canada HDR‑BT monotherapy
ADT, androgen deprivation therapy; EBRT, external beam radiation therapy; HDR‑BT, high dose rate brachytherapy; IMRT, intensity-modulated radiation therapy;
LDR‑BT, low dose rate brachytherapy; NA, not available.

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10 as a first-line treatment option in patients with low-risk

HDR-BT and intermediate-risk prostate cancer, whereas HDR‑BT
EBRT boost is a well-established treatment modality for certain
LDR-BT intermediate-risk and high-risk prostate cancers. ADT can
The Phoenix definition
Radical of biochemical failure
prostatectomy be used in conjunction with either form of brachytherapy.
(nadir + 2 ng/ml)
The outcomes from either form of brachytherapy are
PSA generally excellent and superior to EBRT, and the risk
PSA (ng/ml)
bounces of grade 3–4 toxicities is <5% according to most studies.

1 Patients should be followed up every 6–12 months with
serum PSA measurement and DRE. Several QOL ques-
tionnaires can be used to gauge urinary incontinence,
urinary obstruction and irritation, bowel-related
symptoms, sexual dysfunction, and hormonal symptoms.
The ideal brachytherapy patient should have no abso-
lute contraindications to the therapy, including ataxia
0.1
telangiectasia, pre-existing rectal fistula, comorbidity
precluding anaesthesia, distant metastases, absence of a
1 6 12 24 36 48 60
rectum, or large TURP defects. Clinicians considering
Time after therapy (months) LDR‑BT versus HDR‑BT should consider the need for a
shielded room, initial capital equipment and recurring
Checking PSA q3 – 6 months
costs, and operator dependence.
Checking PSA q12 months Salvage brachytherapy can be used to treat local
recurrence after prior radiation therapy. The ideal
Figure 6 | Characteristic PSA curves after treatment. Different radiotherapy modalities patient for salvage therapy has biopsy-proven local-only
are associated with different trends in post-treatment PSA4. The Phoenix definition
recurrence with no morbidity from prior radiotherapy.
(PSA nadir + 2 ng/ml, circled on the right) following treatment (in this case, external beam
radiotherapy (EBRT)) is the preferred protocol to define biochemical failure. EBRT typically
Salvage brachytherapy is best if performed >4.5 years
induces a gradual and inconsistent decrease in PSA to levels that are still detectable. after prior radiation treatment, with the use of advanced
After low-dose-rate brachytherapy (LDR‑BT), PSA has been noted to decrease to <0.3 ng/ image guidance, and with a rectal spacer.
ml in most men with localized disease, although a much lower decrease is possible. Overall, brachytherapy offers an excellent treatment
After high-dose-rate brachytherapy (HDR‑BT), PSA nadir is usually very low (<0.05 ng/ml). option for definitive and salvage treatment of pros-
All radiotherapy modalities can induce a PSA bounce — a temporary elevation in PSA tate cancer; its continued evolution provides excellent
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oligometastases. Lancet Oncol. 14, e28–e37 (2013). (2015). The Cancer Genome Atlas: http://cancergenome.nih.gov
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ALL LINKS ARE ACTIVE IN THE ONLINE PDF
Foroudi, F. Advances in local and ablative treatment of CyberKnife SBRT for localized prostatic carcinoma:

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Evolution of Prostate Brachytherapy

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REVIEWS

The evolution of brachytherapy for

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a 100 A computer was used to derive the matched peripheral

Decay over dosimetry and the use of combination EBRT resulted in

distance from a point source of three isotopes

conventional or hypofractionated external beam

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a Radium used to Transperineal

Year 1890 1900 1910 1920 1930 1940 1950

RALS and HDR-BT

Radiobiology Hypothesis: high doses

Conventional LINAC Hypofractionation “Virtual

Year 1950 1960 1970 1980 1990 2000 2010

c d Brachytherapy alone High-risk

2004 2005 2006 2007 2008 2009

Brachytherapy Other radiation Hormones

Nature Reviews | Urology

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Table 2 | Contraindications for brachytherapy, external beam radiotherapy and surgery

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Clinical target volume a Rectum

Needles: LDR-BT HDR-BT

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Table 3 | Properties of radionuclides and quality planning constraints

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Table 4 | Comparison of physician and patient considerations of LDR‑BT and HDR‑BT

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Posterior Most frequent areas

b 3D-CRT IMRT SBRT

100% of 100% of 85% isodose line

Figure 4 | Dosimetric comparison of LDR‑BT versus HDR‑BT. a | The Nature Reviews

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(Total Gy) / (number of fractions) / (Gy per fraction)

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Table 6 | Ongoing studies evaluating brachytherapy for prostate cancer

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10 as a first-line treatment option in patients with low-risk

bounces of grade 3–4 toxicities is <5% according to most studies.

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