Download Brachytherapy for Clinically Localized Prostate Cancer

8.01.14
Section:
Effective Date:
Therapy
Subsection: Therapy
Subject:
Original Policy Date: September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
Last Review Status/Date:
October 15, 2016
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September 2016
Brachytherapy for Clinically Localized Prostate Cancer Using
Permanently Implanted Seeds
Description
Brachytherapy is a procedure in which a radioactive source (eg, radioisotope "seeds") is permanently
or temporarily implanted to treat localized prostate cancer. The radiation in brachytherapy penetrates
only short distances and is intended to deliver tumoricidal radioactivity directly to the tumor to improve
local control, while sparing surrounding normal tissue. Focal (subtotal) prostate brachytherapy is a
form of organ-preserving therapy for small localized prostate cancers. This policy only reviews
permanent low-dose rate brachytherapy in prostate cancer.
Background
Brachytherapy is a procedure in which a radioactive source (eg, radioisotope "seeds") is used to treat
localized prostate cancer. With brachytherapy, the radiation penetrates only short distances; this
procedure is intended to deliver tumoricidal radioactivity directly to the tumor and improve local
control, while sparing surrounding normal tissue. Local tumor control has been reported to be
associated with lower distant metastasis rates and improved patient survival. Seeds can be
permanently or temporarily implanted. Permanent (low-dose rate, LDR) brachytherapy is generally
used for those with low-risk disease; temporary (high-dose rate, HDR) brachytherapy is typically
reserved for intermediate- or high-risk patients. This policy only reviews permanent LDR
brachytherapy in prostate cancer.
The proposed biologic advantages of brachytherapy compared to external beam radiation therapy
(EBRT) are related to the dose delivered to the target and the dose-delivery rate. The dose rate of
brachytherapy sources is generally in the range of 40-60 centrigray per hour (cGy/h), whereas
conventional fractionated EBRT dose rates exceed 200 cGy/min. Enhanced normal tissue repair
occurs at the LDRs. Repair of tumor cells does not occur as quickly, and these cells continue to die
during continued exposure. Thus, from a radiobiologic perspective, LDRs cause ongoing tumor
destruction in the setting of normal tissue repair. In addition, brachytherapy is performed as a single
procedure in the outpatient setting, which may represent a patient preference issue compared to the
multiple sessions required to deliver EBRT. The total doses of radiotherapy (RT) that can be delivered
may also vary between EBRT and brachytherapy, especially with newer forms of EBRT such as 3D
conformal radiation therapy and intensity-modulated radiation therapy (IMRT).
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
2 of 12
Brachytherapy has not been considered appropriate for patients with a large prostate or those with a
urethral stricture, because the procedure results in short-term swelling of the prostate, which can lead
to urinary obstruction. As with all forms of RT, concerns exist with the long-term risk of treatmentrelated secondary malignancies. Reports have also suggested that the clinician’s level of experience
with brachytherapy correlates with disease recurrence rates.
Studies of permanent brachytherapy have generally used either iodine-125 or palladium-103. Use of
cesium-131 is also being studied. Use of iodine-125 requires more seeds, thus reducing dosimetric
dependence on any single seed. Post-implant dosimetric assessment should be performed to ensure
the quality of the implant and optimal source placement (ie, the targeted tumor areas receive the
predetermined radiation dosages while nearby structures and tissues are preserved).
Permanent brachytherapy may be used alone as monotherapy or may be combined with EBRT
(together known as combined modality therapy [CMT]) as a way to boost the dose of RT delivered to
the tumor; CMT can be performed with permanent or temporary brachytherapy. The brachytherapy
boost is typically done 2 to 6 weeks after completion of EBRT, although the sequence can vary.
Focal or subtotal prostate brachytherapy is a form of more localized, organ-preserving therapy for
small localized prostate cancers. With this approach, brachytherapy “seeds” are placed only in the
areas where the tumor has been identified rather than throughout the whole prostate gland. This is
done in an effort to reduce the occurrence of adverse events that may be associated with
brachytherapy, including urinary, bowel, and sexual dysfunction.
Regulatory Status
A large number of permanently implanted seeds for brachytherapy of prostate cancer have become
available since 1999. The U.S. Food and Drug Administration (FDA) has cleared these devices
through its 510(k) process, including I-Seed® (Theragenics Corp.), Proxcelan™ Cs-131 (IsoRay
Medical), and BrachySource® Brachytherapy Seed Implants (C.R. Bard). The FDA device
classification is: “Source, Brachytherapy Radionuclide.” FDA product code: KXK.
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8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
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Policy
*This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification,
Advanced Benefit Determination, etc.) and/or post-service claims.
Brachytherapy using permanent transperineal implantation of radioactive seeds may be considered
medically necessary in the treatment of localized prostate cancer when used as monotherapy or in
conjunction with external beam radiation therapy (EBRT) (see Policy Guidelines).
Focal prostate brachytherapy is considered investigational in the treatment of prostate cancer.
Policy Guidelines
Permanent brachytherapy using only implanted seeds is generally used in patients whose prostate
cancer is considered low risk. Active surveillance is generally recommended for very low risk prostate
cancer. Permanent brachytherapy combined with EBRT (3-dimensional conformal, radiotherapy [3DCRT], intensity-modulated, or proton) is used, sometimes along with androgen deprivation to treat
higher risk disease. Adequate dose escalation should be achieved with combination permanent
brachytherapy and 3D-CRT. Intensity-modulated radiotherapy [IMRT] should be limited only to cases
in which 3D-CRT planning is not able to meet dose volume constraints for normal tissue tolerance.
Prostate cancer risk is often defined using the following criteria:



Low risk: PSA [prostate-specific antigen] 10 ng/mL or less, Gleason score 6 or less, and clinical
stage T1c (very low risk) or T1-T2a.
Intermediate risk: PSA > 10 but 20 ng/mL or less, or Gleason score 7, or clinical stage T2b-T2c.
High Risk: PSA >20 ng/mL or Gleason score 8–10, or clinical stage T3a for clinically localized
disease and T3b-T4 for locally advanced disease.
Permanent low-dose rate (LDR) brachytherapy, as monotherapy, in the treatment of localized prostate
cancer may be best used in men older than 60 years with small volume cancer of low-risk disease
(Gleason sum, <7; PSA score, <10 mg/mL; stage T1c). (1) Patients in their 50s or younger may not be
considered ideal candidates for brachytherapy based on concerns regarding the durability of treatment
and quality-of-life outcomes. However, favorable outcomes in men 60 years or younger treated with
brachytherapy for localized prostate cancer have been reported. Ideally, the cancer should be within a
prostate with a volume of less than 60 mL. Patients with locally advanced prostate cancer may be
undertreated by permanent brachytherapy alone.
The procedure is usually performed in two stages: a prostate volume study followed at a later date by
the implant itself, which is performed in the operating room with the patient under general or epidural
anesthesia. Iodine or palladium is the typical isotope used; and the selection of isotope is usually
based on physician preference. A CT (computed tomography) scan is usually performed at some
stage after the procedure to determine the quality of the seed placement.
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
4 of 12
Rationale
Evaluating treatment options for clinically localized prostate cancer is difficult because there is minimal
evidence comparing various treatments, including active surveillance, in terms of improving clinically
meaningful patient outcomes. Assuming that an intervention can improve outcomes, the variable and
often indolent natural history of clinically localized prostate cancer would require randomized trials with
follow-up of 10 to 15 years to determine if, eg, brachytherapy is associated with equivalent or superior
long-term outcomes compared to alternative therapies including various types of RT. These data are
not currently available. The lack of randomized controlled trial (RCT) makes it difficult to reach strict
evidence based conclusions regarding the comparative efficacy of brachytherapy with other
treatments for localized prostate cancer.
The framework often used in analyzing treatments of localized prostate cancer, given the lack of
comparative studies and lack of information regarding impact on survival, is to evaluate the effect of
the treatment on surrogate endpoints (eg, biochemical free survival) and treatment-related
complications.
Brachytherapy has become widely accepted among physicians and its speed and convenience
compared to EBRT are appealing to patients. Therefore, given the baseline uncertainty regarding
long-term outcomes associated with any or no treatment of clinically localized prostate cancer,
decisions regarding any treatment option for prostate cancer are frequently reframed as an issue of
patient preference, even while acknowledging that the decision must be made based on incomplete
data.
Permanent Low-Dose Rate Brachytherapy Alone or Combined With EBRT
Systematic Reviews
In a 2012 comparative effectiveness report from the international Prostate Cancer Results Study
Group (PCRSG), prostate-specific antigen (PSA)-free survival following various prostate cancer
treatments, including brachytherapy, was noted to be difficult to evaluate, because very few studies
that compared results from treatment options were identified. (1) Additionally, variations in methods of
evaluating outcomes and reporting results complicated the analysis. The PCRSG only included
studies on EBRT that used a minimum 72 Gy conformal or intensity-modulated radiation therapy
(IMRT). In low-risk and intermediate-risk prostate cancer, biochemical relapse-free survival (BRFS)
was higher on average with brachytherapy over RP or EBRT. In intermediate-risk patients, outcomes
were similar with brachytherapy with or without EBRT. With high-risk patients, combined
brachytherapy with EBRT with or without androgen deprivation produced better outcomes than
brachytherapy, surgery, or EBRT alone.
A 2009 review was conducted on both brachytherapy (permanent) and proton beam therapy. (2) This
report concluded that brachytherapy was at least comparable to IMRT for localized prostate cancer in
terms of clinical effectiveness. This review also concluded that brachytherapy was a high-value
technology compared with IMRT. Despite identifying 166 studies that met their review criteria for this
report, only 1 study compared these treatments: a single-center evaluation of toxicity rates in 2
different case series of brachytherapy or IMRT. Nearly all other studies were relatively small single-
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
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center case series of a single modality with evidence further limited by variability in population
demographics, disease risk status, and measures of treatment success and treatment-related
complications. In this review, at 5 years after diagnosis, survival estimates ranged from 60% to 90%
for active surveillance and 77% to 97% for brachytherapy. This review also estimated acute and late
radiation toxicities based on studies identified. This analysis of toxicity was based on studies that used
standardized scoring criteria and, in general, involved a level of severity of 2 or more. For acute
gastrointestinal (GI) toxicity, the rate was estimated at 2% for brachytherapy and 18% for IMRT; and
for chronic GI toxicity, these rates were 4% and 7%, respectively. For genitourinary (GU) toxicity,
acute rates were about 30% for both therapies and about 15% for chronic toxicity. Erectile dysfunction
was 32% in the brachytherapy studies. Seed migration is a unique risk with permanent brachytherapy.
It occurs when 1 or more seeds dislodge and travel to nearby organs (eg, bladder, lung). Although
seed migration has been reported in 6% to 55% of patients, reports of harm are limited to individual
case studies.
Permanent Low-Dose Rate Brachytherapy Alone
Systematic ReviewsA 2011 Cochrane review by Peinemann et al evaluated literature on low-dose
brachytherapy for prostate cancer. (3) The review focused on the only identified RCT, Giberti et al. (4)
The Giberti trial compared brachytherapy with RP and was considered to have a high risk of bias.
Peinemann et al also conducted a systematic review of brachytherapy in 2011.5 In this review, the
Giberti RCT and 30 nonrandomized studies were included, all of which were found to also have a high
risk of bias.
Randomized Controlled Trials
The 2009Giberti RCT reported results for 200 low-risk prostate cancer patients randomized to RP or
brachytherapy. (4) Biochemical progression-free survival (BPFS) rates at 5 years were 90% for RP
and 91.7% for brachytherapy. Both treatment groups experienced decreases in quality of life at 6
months and 1 year posttreatment, although brachytherapy patients reported more urinary disorders
but better erectile function than the RP group. At 5-year follow-up, functional outcomes did not differ
between arms.
Crook et al also reported on quality-of-life outcomes at 5 years in 168 patients after RP or
brachytherapy in the SPIRIT (Surgical Prostatectomy Versus Interstitial Radiation Intervention) Trial.
(6) In this study, 34 patients were randomized, and another 134 patients were allowed to select a
treatment group. SPIRIT was closed after 2 years due to poor patient accrual. At a median of 5.2-year
follow-up, the brachytherapy patients scored better in patient satisfaction and urinary and sexual
function than RP patients.
Nonrandomized Studies
In a 1:1 matched-pair design, Pickles et al prospectively followed 278 low- and intermediate-risk,
localized prostate cancer patients treated with brachytherapy or conformal EBRT (139 patients in each
group). (7) The biochemical control (nadir + 2) at 5 years was 95% in the brachytherapy group versus
85% in the EBRT group (p<0.001). This rate was unchanged at 7 years in the brachytherapy group
but decreased to 75% in the EBRT group. Brachytherapy patients experienced more urinary
complaints, whereas EBRT patients had more rectal and bowel issues.
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
6 of 12
Coen et al compared high-dose EBRT (79.2-Gy equivalent) delivered using photons and protons with
permanent LDR in a case-matched analysis of 282 patients (141 matches) with localized, low- and
intermediate-risk prostate cancer. (8) Biochemical failure (nadir + 2) at 8 years was 7.7% in the highdose EBRT group and 16.1% in the brachytherapy group (p=0.42). However, because case-matching
may not account for important patient selection differences, the groups may not be similar.
Nepple et al analyzed data prospectively from 2 centers to compare prostate cancer treatment
mortality outcomes in men without comorbidities. (9) The analysis included 4459 men treated with RP,
972 men treated with brachytherapy, and 1261 men treated with EBRT. After treatment, median
follow-up was 7.2 years. Brachytherapy did not significantly increase prostate cancer mortality
compared with RP using Cox analysis or competing risk analysis; however, EBRT did increase
prostate cancer mortality under Cox analysis. Overall mortality increased with both brachytherapy
(hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.37 to 2.31) and EBRT (HR=1.71; 95% CI,
1.40 to 2.08) compared with RP.
Williams et al compared data from the U.S. Surveillance, Epidemiology, and End Results (SEER)
Medicare-linked data on 10,928 patients with localized prostate cancer treated with primary
cryoablation or brachytherapy. (10) Urinary dysfunction occurred more frequently with cryoablation
(41.4%) than with brachytherapy (22.2%), p<0.001. Erectile dysfunction was also more common after
cryo9ablation34.7%) than brachytherapy (21.0%), p<0.001. In addition, use of androgen deprivation
therapy occurred significantly more often after cryoablation than brachytherapy, suggesting a higher
rate of prostate cancer recurrence after cryoablation (1.4 vs 0.5 per 100 person-years). Bowel
complications, however, occurred significantly more frequently with brachytherapy (19%) than
cryoablation (12.1%).
A 2016 analysis by Pham et al evaluated outcomes of permanent brachytherapy alone in men with
large prostates (>60 mL). (11) The study included 2076 men with prostate cancer from a prospectively
collected database who were treated with iodine-125 brachytherapy without androgen deprivation
therapy. Two hundred sixty-nine (13%) of the 2076 patients had prostate volumes greater than 60 mL
(median volume, 72.5 mL). Men with prostates volumes greater than 60 mL were significantly older
than men with prostates volumes of 60 mL or less, and a significantly larger proportion had Gleason
score of 6 and higher initial PSA levels. Median follow-up was 55 months. The 5-year biochemical
relapse-free survival (BPFS), the primary efficacy outcome, was 96.7% (95% CI, 94.4% to 98.9%) in
men with prostates volumes greater than 60 mL and 92.9% (95% CI, 91.4% to 94.3%) in men with
prostates volumes of 60 mL or less (p=0.02). Men with prostate volumes greater than 60 mL had
significantly higher rates of grade 3 and 4 GU and GI toxicity at 5 years (7.2%) than men with
prostates volumes of 60 mL or less (3.2%; p<0.001). In multivariate analyses, a prostate volume
greater than 60 mL was a statistically significant predictor for better BRFS and for higher rates of late
grade 3 and 4 GU toxicity.
Section Summary: Permanent Low-Dose Rate Brachytherapy Alone
One RCT compared brachytherapy and RP and found similar 5-year BRFS rates, quality of life, and
functional outcomes. A number of observational studies and systematic reviews of the published
literature found similar or better biochemical control rates and similar adverse event rates with
brachytherapy and other treatments (eg, RP, EBRT, cryotherapy).
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
7 of 12
Permanent Low-Dose Rate Brachytherapy Combined With EBRT
Randomized Controlled Trials
Merrick et al randomized 247 intermediate- to high-risk prostate cancer patients to brachytherapy with
20-Gy or 44-Gy EBRT. (12) At a median follow-up of 9 years, no statistically significant differences
were found in BPFS, cause-specific survival, and overall survival (OS) between the 2 groups of
supplemental EBRT. At 8- and 10-year follow-ups for the entire study population, BPFS was 93.2%,
the cause-specific survival was 97.7% and 96.9%, and OS was 80.8% and 75.4%, respectively.
Nonrandomized Studies
Long-term results from the RTOG 0019 study were published in 2012, with data from 131 patients
followed for a median of 8.3 years. (13) Late GU and/or GI tract toxicity greater than grade 3 was
estimated to be 15%, and most commonly included urinary frequency, dysuria, and proctitis. Grade 3
impotence was reported in 42% of patients. As previously noted, these adverse effects rates with
combined modality therapy (CMT) were higher than often reported for either brachytherapy or EBRT
treatment alone. Estimates of biochemical failure were 18% using the Phoenix definition and 21%
using the American Society for Radiation Oncology’s definition and were similar to either treatment
alone.
Long-term results are also available from large cohorts treated at single institutions. For example,
Sylvester et al reported on results of treatment with 45 Gy of EBRT followed by permanent
brachytherapy. In this series, androgen deprivation therapy was not used. (14) This report was based
on a series of 223 consecutive patients treated between 1987 and 1993; patients had stage T1 to T3
disease. Permanent brachytherapy was performed with radioactive palladium or iodine 4 weeks after
EBRT. Fifteen-year BPFS was 88% in the low-risk group, 80% in the intermediate-risk group, and
53% in the high-risk group. In addition, long-term outcomes were compared with those of 2 institutions
that had results for RP. Results were similar across Gleason score categories (eg, the relapse-free
survival was 25%-30% for those with a Gleason score 7 for the 3 series of patients but varied for other
prognostic factors such as PSA level).
In another single-center report, results were summarized for CMT using 3-dimensional conformal
radiotherapy followed by permanent (palladium) brachytherapy. (15) This study involved 282
intermediate- and high-risk patients. Patients were treated from 1992 to 1996. Fourteen-year freedom
from biochemical progression in the intermediate-risk group was 87% and 72% in the high-risk group.
In a retrospective analysis by Koontz et al, 199 patients with low- to high-risk prostate cancer were
treated with low-dose rate brachytherapy and 46-Gy EBRT from June 1997 through August 2007. (16)
Overall BPFS and PSA control at 5 years were 87% and 92%, respectively. In the high-risk group
(n=66), overall BPFS and PSA control at 5 years were 81% and 86%, respectively.
Section Summary: Permanent Low-Dose Rate Brachytherapy Combined With EBRT
One RCT and a number of observational studies have been published. A 2012 comparative
effectiveness report found that brachytherapy plus EBRT produced similar or better outcomes than
surgery or brachytherapy alone. The RCT evaluated brachytherapy with 1 of 2 doses of EBRT and
found no significant between-group differences in progression or survival outcomes and high rates of
disease-specific survival for the entire study population (eg, 98% at 8 years).
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
8 of 12
Focal Prostate Brachytherapy Alone or Combined With EBRT
Evidence in the published literature on focal prostate brachytherapy is limited. Reports have primarily
focused on methods to delineate and evaluate tumor areas to identify appropriate candidates for focal
prostate therapy and treatment-planning approaches. Original clinical reports on patient outcomes
after focal brachytherapy are limited.
In a 2014 systematic review, Valerio et al reviewed studies on focal prostate cancer therapies. (17)
However, only 1 series by Nguyen et al18 was included in the systematic review reported on focal
brachytherapy. In the Nguyen study, 318 men received brachytherapy only to the peripheral zone. In
low-risk and intermediate-risk cases, freedom from PSA failure (nadir + 2) was 95.1% and 73% at 5
years and 80.4% and 66.4% at 8 years, respectively. Many questions remain including treatment
effectiveness, patient selection criteria, and posttreatment monitoring approaches.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
NCT No.
Trial Name
Ongoing
NCT00063882
A Phase III Study Comparing Combined External Beam Radiation and
Transperineal Interstitial Permanent Brachytherapy With
Brachytherapy Alone for Selected Patients With Intermediate Risk
Prostatic Carcinoma
NCT00936390 A Phase III Prospective Randomized Trial of Dose-Escalated
Radiotherapy With or Without Short-Term Androgen Deprivation
Therapy for Patients With Intermediate-Risk Prostate Cancer
NCT01368588 Androgen Deprivation Therapy and High Dose Radiotherapy With or
Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or
Favorable High Risk Prostate Cancer: A Phase III Randomized Trial
NCT: national clinical trial.
Planned
Enrollment
Completion
Date
588
Jan 2017
1520
Dec 2020
2580
Jul 2027
Practice Guidelines and Position Statements
National Comprehensive Cancer Network
National Comprehensive Cancer Network guidelines for prostate cancer (v.3.2016) (19) note that LDR
brachytherapy as monotherapy is indicated for patients with low-risk cancers and selected patients
with low-volume immediate-risk cancers. Intermediate-risk cancers may be treated by combining LDR
brachytherapy with EBRT (40-50 Gray [Gy]) and ±4 to 6 months of neoadjuvant/concomitant/adjuvant
androgen deprivation therapy (ADT). Patients with high-risk cancers may be treated with a
combination of EBRT (40-50 Gy) and LDR brachytherapy ±2 to 3 years of
neoadjuvant/concomitant/adjuvant ADT.
The guidelines further state that patients with very large or very small prostates (size cutoffs were not
discussed), symptoms of bladder outlet obstruction, or previous transurethral resection of the prostate
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
9 of 12
are more difficult to implant and may suffer increased risk of adverse effects. In cases of enlarged
prostate, neoadjuvant ADT may be used to shrink the prostate. However, increased toxicity would be
expected and prostate size may not decline.
American Brachytherapy Society
The American Brachytherapy Society (ABS) Prostate Low-Dose Rate Task Group provides the
following patient selection criteria for monotherapy: clinical stage T1b or T2b and Gleason score of 6
or less, and PSA score of 10 or less ng/mL. (20) ABS guidelines also indicate monotherapy may be
used in select higher risk patients and for salvage of select radiotherapy failures. For boost, patient
selection criteria include: clinical stage T2c or greater and/or Gleason score 7 or more and/or PSA
level greater than 10 ng/mL. These guidelines also note inadequate information exists to recommend
supplemental EBRT based on perineural invasion, percent positive biopsies, and/or magnetic
resonance imaging-detected extracapsular penetration.
American College of Radiology and American Society for Radiation Oncology
The American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO)
guidelines on permanent brachytherapy indicate permanent LDR brachytherapy is appropriate in lowto intermediate-risk patients.(21-23) These guidelines also note EBRT may be added to permanent
brachytherapy in high-risk protocols. ACR/ASTRO exclusion criteria for permanent brachytherapy
include: life expectancy less than 5 years; unacceptable operative risk; poor anatomy that prevents a
quality implant; positive lymph nodes by pathology; significant obstructive uropathy, and distant
metastases. ACR and ASTRO also note intensity-modulated radiotherapy is a widely used treatment
option for many indications including prostate tumors.
ACR also developed appropriateness criteria for permanent brachytherapy. ACR found brachytherapy
offers “favorable morbidity profiles and durable biochemical control rates for patients with low-,
intermediate-, and high-risk features.” Favorable outcomes are noted as being dependent on having a
quality implant. The role of EBRT in addition to permanent brachytherapy for higher risk patients is
uncertain.
U.S. Preventive Services Task Force Recommendations
Not applicable
Summary of Evidence
The evidence for permanent LDR brachytherapy alone or in combination with external beam
Radiotherapy (EBRT) in patients who have localized prostate cancer consists of 2 randomized
controlled trials and nonrandomized comparative or observational studies. Clinical outcomes of
importance are overall survival (OS) and treatment-related morbidity. High-quality studies that
differentiate superiority of any type of radiation technique are not available. In general, however, the
RCT results suggest LDR brachytherapy is at least similar to either surgery (radical prostatectomy
[RP]) or EBRT in terms of biochemical recurrence-free survival and functional outcomes; indirect
comparison of some observational studies suggests OS rates with LDR brachytherapy are similar to
those achieved with alternatives including RP and EBRT. Limitations of the evidence include patient
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
10 of 12
heterogeneity; variability in treatment protocols; short follow-up periods; inconsistency in reporting
important health outcomes (eg, survival vs biochemical progression-free survival rates), and
inconsistency in reporting or collecting outcomes. These limitations notwithstanding, the body of
evidence on permanent LDR brachytherapy, used as monotherapy or in conjunction with EBRT to
treat localized prostate cancer, is sufficient to demonstrate improvements in health outcomes.
The evidence for permanent LDR brachytherapy alone or in combination with EBRT for focal
treatment in patients who have localized prostate cancer consists of few observational studies. Clinical
outcomes of importance are OS and treatment-related morbidity. The body of evidence on permanent
LDR brachytherapy, used as focal monotherapy or in conjunction with EBRT to treat localized prostate
cancer, is insufficient to demonstrate improvements in health outcomes.
Medicare National Coverage
Brachytherapy sources and services for administration and delivery of brachytherapy are covered by
Medicare.
References
1. Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes
for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the
Prostate Cancer Results Study Group. BJU Int. Feb 2012;109 Suppl 1:22-29. PMID 22239226
2. Institute for Clinical and Economic Review (ICER). Brachytherapy/proton beam therapy for clinically localized,
low-risk prostate cancer. http://www.icer-review.org/bt-pbt/. Accessed June 27, 2016.
3. Peinemann F, Grouven U, Hemkens LG, et al. Low-dose rate brachytherapy for men with localized prostate
cancer. Cochrane Database Syst Rev. 2011(7):CD008871. PMID 21735436
4. Giberti C, Chiono L, Gallo F, et al. Radical retropubic prostatectomy versus brachytherapy for low-risk
prostatic cancer: a prospective study. World J Urol. Oct 2009;27(5):607-612. PMID 19455340
5. Peinemann F, Grouven U, Bartel C, et al. Permanent interstitial low-dose-rate brachytherapy for patients with
localised prostate cancer: a systematic review of randomised and nonrandomised controlled clinical trials. Eur
Urol. Nov 2011;60(5):881-893. PMID 21763066
6. Crook JM, Gomez-Iturriaga A, Wallace K, et al. Comparison of health-related quality of life 5 years after
SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol. Feb 1
2011;29(4):362-368. PMID 21149658
7. Pickles T, Keyes M, Morris WJ. Brachytherapy or conformal external radiotherapy for prostate cancer: a
single-institution matched-pair analysis. Int J Radiat Oncol Biol Phys. Jan 1 2010;76(1):43-49. PMID
19570619
8. Coen JJ, Zietman AL, Rossi CJ, et al. Comparison of high-dose proton radiotherapy and brachytherapy in
localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. Jan 1 2012;82(1):e25-31.
PMID 21470787
9. Nepple KG, Stephenson AJ, Kallogjeri D, et al. Mortality after prostate cancer treatment with radical
prostatectomy, external-beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol. Sep
2013;64(3):372-378. PMID 23506834
10. Williams SB, Lei Y, Nguyen PL, et al. Comparative effectiveness of cryotherapy vs brachytherapy for localised
prostate cancer. BJU Int. Jul 2012;110(2 Pt 2):E92-98. PMID 22192688
11. Pham YD, Kittel JA, Reddy CA, et al. Outcomes for prostate glands >60 cc treated with low-dose-rate
brachytherapy. Brachytherapy. Mar-Apr 2016;15(2):163-168. PMID 26796717
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
11 of 12
12. Merrick GS, Wallner KE, Butler WM, et al. 20 Gy versus 44 Gy of supplemental external beam radiotherapy
with palladium-103 for patients with greater risk disease: results of a prospective randomized trial. Int J Radiat
Oncol Biol Phys. Mar 1 2012;82(3):e449-455. PMID 22196131
13. Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG Phase II Trial (00-19) of external-beam
radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized
adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys. Apr 1 2012;82(5):e795-801. PMID 22330999
14. Sylvester JE, Grimm PD, Blasko JC, et al. 15-Year biochemical relapse free survival in clinical Stage T1-T3
prostate cancer following combined external beam radiotherapy and brachytherapy; Seattle experience. Int J
Radiat Oncol Biol Phys. Jan 1 2007;67(1):57-64. PMID 17084544
15. Dattoli M, Wallner K, True L, et al. Long-term outcomes after treatment with brachytherapy and supplemental
conformal radiation for prostate cancer patients having intermediate and high-risk features. Cancer. Aug 1
2007;110(3):551-555. PMID 17577217
16. Koontz BF, Chino J, Lee WR, et al. Morbidity and prostate-specific antigen control of external beam radiation
therapy plus low-dose-rate brachytherapy boost for low, intermediate, and high-risk prostate cancer.
Brachytherapy. Apr-Jun 2009;8(2):191-196. PMID 19433320
17. Valerio M, Ahmed HU, Emberton M, et al. The role of focal therapy in the management of localised prostate
cancer: a systematic review. Eur Urol. Oct 2014;66(4):732-751. PMID 23769825
18. Nguyen PL, Chen MH, Zhang Y, et al. Updated results of magnetic resonance imaging guided partial prostate
brachytherapy for favorable risk prostate cancer: implications for focal therapy. J Urol. Oct 2012;188(4):11511156. PMID 22901567
19. National Comprehensive Cancer Network. Prostate cancer. Clinical Practice Guidelines in Oncology,
v.3.2016. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed June 27, 2016.
20. American Brachytherapy Society, Prostate Low-Dose Rate Task Group, Merrick GS, et al. Prostate Low-Dose
Rate Task Group: Patient Selection Criteria for Monotherapy Clinical Stage T1b-T2b and Gleason Score of 6
or Less. n.d. https://www.americanbrachytherapy.org/guidelines/prostate_low-doseratetaskgroup.pdf.
Accessed June 27, 2016.
21. Frank SJ, Arterbery VE, Hsu IC, et al. American College of Radiology Appropriateness Criteria permanent
source brachytherapy for prostate cancer. Brachytherapy. Sep-Oct 2011, amended 2014;10(5):357-362.
PMID 21497562
22. ACR-ASTRO. Practice Guideline for Intensity Modulated Radiation Therapy (IMRT). 2011, amended 2014;
http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/IMRT.pdf. Accessed June 27, 2016.
23. Rosenthal SA, Bittner NH, Beyer DC, et al. American Society for Radiation Oncology (ASTRO) and American
College of Radiology (ACR) practice guideline for the transperineal permanent brachytherapy of prostate
cancer. Int J Radiat Oncol Biol Phys. Feb 1 2011;79(2):335-341. PMID 21106306
8.01.14
Section:
Therapy
Subsection: Therapy
Subject:
Effective Date:
October 15, 2016
Original Policy Date:
September 9, 2011
Brachytherapy for Clinically Localized Prostate Page:
Cancer Using Permanently Implanted Seeds
12 of 12
Policy History
Date
Action
September 2011
New Policy
Reason
December 2012
Update Policy
Policy updated with literature review; investigational policy
statement added on focal or subtotal prostate brachytherapy.
Information on use of IMRT added to Policy guidelines.
References updated
September 2013
Update Policy
Policy updated with literature review; policy statements
unchanged. References updated, 13, 15, 16 added.
September 2014
Update Policy
September 2015
Update Policy
Policy updated with literature review, policy statements
unchanged. References 1 and 25-26 added.
Policy updated with literature review, reference added. Policy
statements added. Policy statements unchanged.
September 2016
Update Policy
Policy updated with literature review through June 7, 2016;
reference 11 added. Policy statements unchanged.
Keywords
Brachytherapy for Prostate Cancer
Prostate Cancer, Brachytherapy
Radioactive Seeds
This policy was approved by the FEP® Pharmacy and Medical Policy Committee on
September 16, 2016 and is effective October 15, 2016.
Signature on file
Deborah M. Smith, MD, MPH