2025+循证共识声明：局限性前列腺癌高剂量率近距离放疗联合外照射放射治疗
Introduction
Brachytherapy is a method to deliver high-dose ra-diotherapy directly to the prostate and/or seminal vesi-cles, while sparing surrounding organs-at-risk. The Amer-ican Society of Clinical Oncology(ASCO)/Cancer Care Ontario(CCO) Joint Guideline Update in 2017 stated that for eligible patients with intermediate- and high-risk prostate cancer receiving definitive radiation, a brachyther-apy boost should be routinely offered(1). This recommen-dation is largely based on the seminal ASCENDE-RT trial,which randomized men with intermediate- and high-risk prostate cancer to dose escalated external beam radiother-apy(EBRT)(whole pelvis EBRT: 46Gy in 23 fractions followed by conformal EBRT to prostate: 32Gy in 16 frac-tions; n=200) versus EBRT+brachytherapy boost(whole pelvis EBRT: 46Gy in 23 fractions followed by an I-125 implant to a minimum dose of 115Gy to the prostate;$$n=198).\text{ The}10\text{-year cumulative incidence of biochemi-}$$cal progression was 30% in the DE-EBRT arm and 15% in the EBRT+brachytherapy arm. Multivariable analysis con-firmed brachytherapy boost as an independent predictor of biochemical disease-free survival, with an adjusted hazard ratio of 2.05 for DE-EBRT versus EBRT+brachytherapy for risk of biochemical failure.
In the ASCENDE-RT trial, the brachytherapy was deliv-ered using a permanent seed low-dose-rate(LDR) implant.The study has been criticized for having an unacceptably high rate of grade 3+ genitourinary(GU) toxicities(5-year cumulative incidence 18.4% vs. 5.2%, 5-year prevalence 8.6% vs.2.2%), predominantly urethral stricts, which is thought to be, in part, related to the implantation technique with excessive dose delivered caudally at the genitourinary diaphragm(2). Subsequent studies, also using combined prostate LDR brachytherapy and EBRT, have shown much lower rates of grade 3+ GU toxicities(~2%), stressing the importance of technique on optimal long-term quality of life outcomes(3,4). These and other studies support LDR brachytherapy boost as a proven method of dose escalation with decades of follow-up and endorsement by numerous expert consensus groups(1,5-7).
Another method of brachytherapy is high-dose-rate(HDR) brachytherapy, which has advantageous properties
including temporary implantation of the radioactive source(Ir-192), more consistent dose coverage of the prostate± proximal seminal vesicles, improved dose modulation around the rectum, bladder, and urethra through inverse treatment planning, and a more rapid toxicity resolution(4,8-10). Both LDR and HDR brachytherapy boost are supported by professional guidelines, and the choice be-tween the 2 is often determined by physician, patient,and/or treatment facility resources(1,5,7).
The American Brachytherapy Society(ABS) has previ-ously published guidelines for LDR brachytherapy boost in combination with EBRT in 2021(6). This current con-sensus provides recommendations and accompanying sup-port for the use of HDR brachytherapy in combination with EBRT for patients with unfavorable intermediate- and high-risk prostate cancer.
Methods
In May 2024, the American Brachytherapy Society Board of Directors approved a process to establish con-sensus guidelines regarding the use of HDR brachytherapy in combination with external beam radiotherapy for men with localized prostate cancer. The guidelines were devel-oped utilizing a modified Delphi approach, based on the best available data identified in a formal systematic re-view(11). The guideline panel involved in this process was a collaboration of brachytherapists across the United States and Canada created to review and report the clini-cal and technologic evolution of combination EBRT with HDR brachytherapy. We searched MEDLINE and PubMed between March and October 2024 using a combination of the following terms:“prostate”,“brachytherapy”,“boost”,“high-dose-rate”,“implant”,“combination”. Of the 247 articles that were identified and reviewed, 21 were se-lected for review based on adequate sample size(n>50 in each comparator arm for nonrandomized studies), follow-up time(≥5 years for efficacy endpoints,≥6 months for toxicity endpoints), and relevance to the key questions de-fined below. In total, 22 original studies were selected for this review. The initial screening of abstracts/manuscripts was performed by 1 author(S Patel) followed by review and validation by another author(M Kamrava).
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Table 1
Guideline recommendations for key questions(KQ) based on systematic review.
|Guideline recommendation|Strength of recommendation|Quality of evidence| |---|---|---| |KQ1: How does efficacy compare between EBRT alone versus combination EBRT plus HDR brachytherapy boost?||| |-Biochemical control is improved with the addition of an HDR brachytherapy boost for patients with intermediate- and high-risk disease.|Strong|High| |KQ2: How does efficacy compare with HDR brachytherapy boost compared with LDR brachytherapy boost?||| |-Biochemical control is expected to be similar between HDR versus LDR boosts.|Strong|High| |KQ3: How does toxicity compare with HDR brachytherapy boost compared with LDR brachytherapy boost?||| |-Acute urinary toxicity may be lower with HDR compared with LDR; long-term urinary toxicity is expected to be similar|Strong|Moderate| |-Acute and long-term bowel toxicity may be lower with HDR compared with LDR.|Strong|Moderate| |KQ4: What dose and fractionation schemes are preferred when utilizing an HDR brachytherapy boost?||| |brachytherapy boost?|Strong|Moderate| |-15 Gy xl|Strong|Moderate| |-9.5-11 Gy x 2|Strong|Moderate| |KQ5: What is the role of ADT when using combination EBRT with HDR brachytherapy boost?||| |-Improving disease control outcomes for unfavorable intermediate- and high-risk prostate cancer.|Strong|High| |KQ6: What is the optimal duration of ADT when using combination EBRT with HDR brachytherapy boost for unfavorable intermediate- and high-risk prostate cancer?|Strong|| |-4-6 months (intermediate-risk)|Strong|High| |-6 months (high-risk)|Weak|Moderate| |-12+ months (high-risk)|Strong|High| |KQ7: What are strategies for improving toxicity and quality of life following an HDR implant?|Strong|Moderate| |-Urethra, Rectal, Bladder Dosimetry Constraints -Alpha-blockers|Strong|Moderate| |KQ8: How are HDR brachytherapy boost plans evaluated?|Strong|Low| |-CT|Strong|Low| |-Ultrasound|Strong|Low| |-MRI|Strong|Low| |KQ9: What is the optimal sequencing of HDR brachytherapy with EBRT?|Strong|Moderate| |-HDR brachytherapy can be administered before or after EBRT|Strong|Moderate| |KQ10: What is an appropriate EBRT dose/fractionation regimen to use in combination with HDR brachytherapy boost?||| |-45-50.4 Gy in 1.8-2.0 Gy fractions(prostate/SV+/- pelvic nodes)|Strong|High| |-37 Gy in 2.5 Gy fractions(prostate/SV only)|Strong|Moderate| |-25 Gy in 5 fractions(prostate/SV+/- pelvic nodes)|Weak|Moderate| |KQ11: Which patients are suitable candidates for HDR brachytherapy boost?||| |-Sufficient life expectancy|Strong|Expert Opinion| |-Suitable prostate anatomy/volume|Strong|Expert Opinion| |-Baseline urinary function|Strong|Expert Opinion|
^ KQs not included in the systematic review.
* ADT duration may be individualized based on risk-tier, patient comorbidity, patient quality-of-life priorities.
\# Agreement amongst panel was 69.23%, not meeting consensus threshold of ≥70%.
Key questions that comprehensively addressed disease control, toxicity and patient-reported outcomes, fraction-ation regimens, and ADT use were formulated. A draft of the consensus recommendations was initially reviewed by a smaller panel(S Patel, M Kamrava, J Crook, M Kollmeier, G Morton, D Krauss). Modified recommenda-tions were then disseminated to the full consensus panel,and members rated their level of agreement with each rec-ommendation. Table 1 shows each guideline recommen-
dation for key questions utilized in this statement. Key questions 1 through 7 were derived from systematic re-view, while the remaining questions(addressing techniques for treatment planning/evaluation and patient suitability for HDR brachytherapy boost) were answered via expert opin-ion alone due to the dearth of robust studies around these topics. For each key question, the strength of recommen-dation(weak, strong) and strength of evidence(low, mod-erate, high) were graded based on previously published
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ABS consensus guidelines(6). Final strength of recom-mendations in Table 1 were based on≥70% agreement of the expert panel. Agreement rates for each key question are shown in Supplemental Table.
KQ1: How does treatment efficacy compare be-tween EBRT alone versus combination EBRT plus HDR brachytherapy boost?
Given the accepted understanding of the radiobiology of prostate cancer with a low alpha-beta relative to surround-ing normal tissue, a higher sensitivity to dose-fractionation is expected. The degree of dose escalation achievable with HDR brachytherapy, compared to dose-escalated EBRT alone, is therefore potentially radiobiologically more lethal for prostate cancer cells which could translate into im-proved long-term oncologic outcomes(12,13).
There have been 4 head-to-head studies comparing EBRT alone versus EBRT with HDR brachytherapy boost for patients with localized prostate cancer, as detailed in Table 2. The first, and most robust, report of improved disease outcomes with the addition of HDR brachyther-apy with EBRT came from a prospective, randomized con-trolled trial by Hoskin and colleagues in patients with T1-3N0M0, PSA<50 disease(14). After over 10 years of follow-up, the addition of an HDR brachytherapy boost im-proved 12-year recurrence free survival from 27% to 48%(p=0.008), with a hazard ratio of 0.29(95% CI, 0.11-0.47). The TROG 03.04 RADAR trial(15) was a 2x2 randomization between short- and intermediate-term ADT with or without zoledronic acid, and a posthoc analysis was carried out comparing EBRT alone versus in combination with an HDR brachytherapy boost in patients with clinical T2b or higher, Gleason≥7, and/or PSA≥10 disease. Pa-tients received either 6 or 18 months of ADT. After over 10 years of follow-up, rates of distant metastasis were signif-icantly improved with the addition of HDR brachytherapy(14.9% with HDR boost versus 20.4-22.4% with EBRT alone depending on dose). Compared with men treated with modern dose-escalated EBRT alone of 74Gy, HDR brachytherapy boost trended to provide a distant metasta-sis benefit with a hazard ratio of 0.75(95% CI 0.56-1.01,p=0.06). Finally, 2 large retrospective analyses(16,17)were recently completed, comparing patients with predom-inantly intermediate and high-risk prostate cancer treated with EBRT alone(median dose: 70Gy in 35 fractions)or EBRT(46Gy) with HDR brachytherapy boost(18Gy in 3 fractions or 20Gy in 4 fractions). In the Kent et al. analysis, 5-, 10- and 15-year prostate cancer specific survival(PCSS) was improved with HDR brachytherapy boost and particularly notable in high-risk men(15-year PCSS 85% vs. 69%; p=0.01). In the Tamihardja et al.(17) study, a propensity-scored matched analysis comparing EBRT(mean dose 76.23 Gy) versus EBRT(46Gy) with HDR brachytherapy(18Gy in 2 fractions) showed that 10-year metastasis-free survival was numerically higher with HDR brachytherapy(87.0% vs. 82.9%), but statistical sig-nificance was not reached.
KQ2: How does efficacy compare between HDR brachytherapy boost versus LDR brachytherapy boost?
Key studies comparing HDR versus LDR boost are shown in Table 3. Perhaps the most robust study, per-formed by Crook et al.,(18) was a randomized controlled trial comparing HDR versus LDR brachytherapy boost in combination with EBRT in patients with unfavorable in-termediate or high-risk prostate cancer. 8-year biochemi-cal progression free survival(bPFS) was nearly identical(86% for HDR, 85% for LDR); when using a surgical def-inition of biochemical control of PSA≤0.2, 4-year PSA control was 81% for HDR boost versus 83% for LDR boost(p=0.91). Two retrospective, single institution se-ries(19,20) also compared HDR versus LDR brachytherapy-apy boost. Imai et al.(19) included patients with clinical T1-3aN0 and PSA<100 disease; with a median follow-up of over 6 years in each group, 5-year bPFS was similar between the 2 techniques(86.2% for HDR and 85.6% for LDR,p=0.89). Yamazaki et al.(20) included patients with similar disease characteristics and follow-up time; 5-year bPFS for unfavorable intermediate-risk patients was 97.2%versus 96.2% for HDR boost and LDR boost, respectively(p=0.66); 5-year bPFS for high-risk patients was 95.7%versus 95.5% for HDR boost and LDR boost, respectively(p=0.86). Finally, a large database analysis using the Na-tional Cancer Database(21) found no difference in overall survival outcomes between patients with unfavorable inter-mediate or high-risk prostate cancer treated with an HDR versus LDR brachytherapy boost(5-year survival hazard ratio 1.03, 95% CI, 0.96-1.11). Based on the currently available data, PSA control rates within 5 to 10 years ap-pear to be similar between LDR and HDR boost. Con-tinued follow-up of patients is needed to ensure that this trend continues to hold for patients beyond 10 years after treatment. Details regarding study cohort, ADT use(when available), and outcome measures for each of these studies is detailed in Table 3.
KQ3: How do toxicity outcomes compare between HDR brachytherapy boost versus LDR brachytherapy boost?
The addition of a brachytherapy boost with EBRT has been shown to improve long-term biochemical control in the ASCENDE-RT prospective randomized trial, but con cerns have been raised about the potential for increased toxicity suggested from this trial. At 5 years, the cumu-lative incidence of grade 3 GU toxicity was higher in the brachytherapy boost arm(18.4% vs. 5.2%; p<0.001);however, most resolved following intervention. The addi-tional toxicity, namely GU, is thought to be technique-related(e.g. excessive dose deposited at the external uri-nary sphincter), as subsequent LDR boost studies with more stringent preimplant planning have shown lower rates of long-term GU toxicities. For example, in the TRIP trial(3) which investigated ADT duration in a cohort of high-risk prostate cancer patients receiving combination EBRT with LDR brachytherapy, the incidence of grade 3 GU tox-
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Table 2
Comparative outcome studies comparing EBRT alone versus EBRT plus HDR brachytherapy boost in intermediate- or high-risk patients.
|Study|Disease characteristic|Treatment|BED(Gy) $(\alpha/\beta$ 1.5)|N|Age, median (α/β 1.5)|Follow-up time, median|ADT use|Primary outcome| |---|---|---|---|---|---|---|---|---| |Hoskin et al. (14)b|T1-3N0M0 PSA<50 No prior TURP|EBRT+HDRa EBRTb|217.68 160.53|70 (range 47-80)|131 months|76%; Neoadju- variant/concurrent; duration not reported|6-/12-yr RFS: 71%/48% 6-/12-yr RFS: 55%/27%|| |||Randomized|||||P=0.008 HR(EBRT+HDR vs. EBRT): 0.29 (95% CI 0.11-0.47), P=0.001|| |TROG 03.04 RADAR RADham et al. (15)|T2b-4N0M0 Gleason ≥7 PSA ≥10|EBRT+HDRd EBRTc|211.33 154-172.67|237 814|68.7(range 48-85)|10.5 years|100%; 6 or 18 months|DM:14.9% DM:22.4%(66Gy),22.0% (70Gy),20.4%(74Gy)| |Kent et al.(16)|NCCN intermediate and high risk|EBRT+HDR|197.33|215 72.3|12.2 years|||HR(HDR vs. 70Gy) 0.68 (95% CI 0.57-0.80), P<0.0001 HR(HDR vs. 74Gy) 0.75 (95% CI 0.56-1.01), P=0.06| |||EBRTs|163.33|439|68.9|||10-yr PCSM: 93% 15-yr PCSM: 87% 10-yr PCSM: 88% 15-yr PCSM: 79% P<0.037| |Tamihardja et al. (17)sss|NCCN low, intermediate, high risk|EBRT+HDRh risk|233.33 192.28|258 72.3|71.0 53.3 months|95.3 months|51.9%|10-yr MFS: 87.0% 10-yr MFS: 82.9%| |||||1:1- matched||Median duration 20 months|P=0.195||
a EBRT+HDR: 35.75Gy in 13 fractions; HDR 17Gy in 2 fractions over 24 hours.
b EBRT: 55Gy in 20 fractions.
c Randomized controlled trial.
d EBRT+HDR: 46Gy in 23 fractions; HDR 19.5Gy in 3 fractions.
e EBRT: 66, 70, or 74 Gy.
f EBRT+HDR: 46Gy in 23 fractions; HDR median 18Gy in 3 fractions.
g EBRT:70 Gy.
h EBRT+HDR: 46Gy in 23 fractions+HDR 18Gy in 2 fractions.
i EBRT: 76Gy in 33 fractions.
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Table 3
Comparative outcome studies comparing HDR brachytherapy boost versus LDR brachytherapy boost in combination with EBRT.
|Study|Disease characteristic|Treatment|N|Age, median|Follow-up time, median|ADT use|Primary outcome| |---|---|---|---|---|---|---|---| |Crook et al.（18）|NCCN unfavorable intermediate, high risk|EBRT+HDR|108 71|71|74 months|76% overall|4-year PSA ≤0.2:81% 5-year bPFS: 94% 8-year bPFS: 86%| |||EBRT+LDR|87|||4-year PSA ≤0.2:83% 5-year bPFS: 90% 8-year bPFS: 85%|| |||randomized||||P=0.91 (4-year PSA ≤0.2)|| |Imai et al.（19）|cT1-3aN0M0, PSA＜100|EBRT+HDR|252 66|70.5 70.5|98.9 months 77.5 months|94%(mean 29.7 months) 43.9% (69.9% 9.28 months) P=0.89|5-yr bPFS: 86.2% 5-yr bPFS: 85.6% P=0.89| |Yamazaki et al.（20）|cT1-3aN0M0, PSA＜50|EBRT+HDRb <06|924 71|71 70 months|94% 94%|5-yr bPFS: 97.2% (unfav int risk), 95.7% (high risk)|| |||EBRT+LDR|69|69|84 months|80%|| |King et al.（21)a|NCCN unfavorable intermediate, high risk|EBRT+HDR|8526 9877|67.1 66.7|5 years 40.4% 43.1%|OS: adjusted HR(LDR vs. HDR) 1.03 (95% CI 0.96-1.11) P=0.38||
${}^{a}$ HDR boost included 11Gy in 1 fraction, 18-21Gy in 2 fractions, 21Gy in 3 fractions, 25-31.5Gy in 5 fractions.
icity $<1\%$ within 3 years. Patient selection, technique, and implant dosimetry evaluation are important to mitigate tox-icity risks following either LDR or HDR brachytherapy boost.
Nonetheless, there is concern that the improved bio-chemical control with brachytherapy-based dose escala-tion may not be worth the additional toxicity risk, given alternative methods such as partial gland dose escala-tion(i.e., microboosting), which can improve PSA con-trol while remaining isotoxic(22). Due to the slow dose rate of LDR sources, a prolonged inflammatory effect may contribute to the acute and subacute toxicity profile of LDR, which may be improved with an HDR approach.Indeed, a posthoc analysis of the Australian TROG 03.04 RADAR trial, which included patients treated with dose-escalated EBRT to 74Gy or combination EBRT to 46Gy with an HDR brachytherapy boost of 19.5Gy in 3 frac-tions, showed slower recovery of urinary quality-of-life after HDR brachytherapy boost within 1.5 years, yet no long-term differences in urinary quality-of-life beyond 29 months(23).
Notable studies comparing toxicity and patient-reported outcomes between HDR versus LDR brachytherapy boost is shown in Table 4. Most recently, Crook et al.(4) per-formed a prospective randomized trial comparing HDR
versus LDR brachytherapy boost in combination with EBRT in men with unfavorable intermediate or high-risk prostate cancer. Patient-reported outcomes were compared using the Expanded Prostate Index Composite(EPIC-26)and International Prostate Symptom Score(IPSS) question-naires; at 6 months post-treatment completion, both EPIC-26 urinary domain scores and IPSS composite scores were significantly improved with HDR compared with LDR brachytherapy boost. Specifically, EPIC urinary scores de-creased at 1 month for HDR boost patients but recov-ered by 6 months; for LDR boost patients, EPIC uri-nary scores reached a nadir at 3 months with recovery extending out to 18 months post-treatment. Beyond 18 months, urinary quality-of-life was similar between the 2 arms. In terms of bowel toxicity, EPIC bowel domain scores were significantly improved with HDR compared with LDR boost. Specifically, bowel quality-of-life reached a nadir at 12 months for both arms; however, patients re-ceiving HDR recovered near baseline and maintained higher quality-of-life scores extending out to 5 years post-treatment, compared with patients receiving LDR boost.The LDR boost bowel quality-of-life decline was greater than the predefined minimum clinically important differ-ence out to 5 years, while this threshold was not achieved for men receiving HDR boost. These results are con-
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Table 4
Comparative toxicity and quality of life studies between HDR versus LDR brachytherapy boost.
|Study|Treatment|N|Rectal spacer|GU toxicity|GI toxicity|Multivariable analysis| |---|---|---|---|---|---|---| |Crook et al.(4)|HDR boost|108|None|EPIC 84±13 IPSS 8.0 1 G3,7 G2(6.7%)|EPIC 89±12 No G3,5 G2(4.8%)|| |Crook et al.(4)|LDR boost|87||EPIC 77±14 IPSS 11.8 1 G3,2 G2(2.4%)|EPIC 83±16 1 G3,9 G2(10.8%)|| |Crook et al.(4)|Randomized|${}^{b}$||$$P=0.001\text{(EPIC)}$$ P=0.0002(IPSS)|$$P=0.02\text{(EPIC)}$$|| |Crook et al.(4)|Hollmeier et al. (24)b|LDR boost|59 40|73% 18%|G2 5.1% G2 45%|G2 3% R2 5%| |Dhere et al.(25)a|HDR boost|55|None|G2+ 42.9%|G2+ 2.0%|| |Dhere et al.(25)a|LDR boost|51||G2+ 67.5% P<.001|G2+ 2.6%|| |Dhere et al.(25)a||||P<.001|P=0.99|| |Dhere et al.(25)a|Parry et al.(26)c|HDR boost|2,765|None|G2+ 16.6%(95% 15.1-18.2) EPIC 78.9(95% 77.4-80.3) G2+ 15.8%(95% 11.9-20.2) EPIC 72.9(25% 66.9-77.5)|G2+ 16.7%(95% 84.4-87.2) G2+ 32.2%(95% 72.2-82.5)| ||Parry et al.(26)c|||EPIC P<0.001|$$\text{ EPIC} P<0.001$$||
${}^{a}$ 6-month toxicity; EPIC lower scores indicate worse symptoms, IPSS higher scores indicate worse symptoms.
${}^{b}$ 12-month toxicity.
${}^{c}$ 5-year cumulative incidence of toxicity; EPIC(urinary irritation/obstruction, bowel) lower scores indicate worse symptoms.
sistent with that seen in several other large institutional retrospective and population-based studies, as listed in Table 4. Notably, across these studies, physician-reported and patient-reported urinary and/or bowel toxicity was im-proved with HDR boost compared with LDR boost, pre-dominantly within 6 to 12 months after treatment comple-tion.
KQ4: What dose and fractionation schemes are pre-ferred when utilizing an HDR brachytherapy boost?
A wide range of dose and fractionation schedules of HDR brachytherapy in the boost setting have been used(27-34). Table 5 summarizes larger studies that attempted to compare oncologic outcomes and toxicity between var-ious HDR regimens. Notably, there have been no head-to-head randomized trials comparing efficacy and toxicity between the various approaches. The phase II RTOG 0321 trial(27), which prospectively evaluated long-term toxicity and efficacy of combination EBRT 45Gy in 25 fractions with HDR brachytherapy 9.5Gy x 2 in a single implant for unfavorable risk prostate cancer, used a relatively low dose, compared with modern standards, of a BED~238Gy(assuming alpha/beta of 1.5); the 10-year local control rate was 98% and biochemical failure rate was 23%. In 2011,Martinez et al.(35) compared 2 cohorts based on biologi-cal effective dose(BED)>268 versus≤268 Gy achieved;
<EndOfPara>all patients received EBRT 46Gy in 23 fractions. Patients who underwent an HDR brachytherapy boost of 5.5-6.5Gy x 3 or 8.25-10Gy x 2 received a BED ≤268Gy, while those who underwent 10.5-11.5Gy x2 achieved a BED >268Gy. The 10-year biochemical failure rate, defined per Phoenix criteria, was 43.1% versus 18.9% for those treated with BED ≤268 versus >268Gy, respectively (p<0.001); 10-year distant metastasis rate was 12.4% versus 5.7%, respectively (p=0.028). On multivariable analysis,the hazard ratio for 10-year biochemical failure was 0.586(95% CI 0.377-0.910; p=0.017), demonstrating the im-portance of achieving a BED >268 when utilizing combi-nation EBRT with HDR brachytherapy. Notably, grade 3 urinary toxicity was similarly low between dose schedules.
Subsequently, Helow et al.(36) conducted a compara-tive analysis between 2 sequential phase II trials:(1) HDR 15Gy x 1 followed by EBRT 37.5Gy in 15 fractions(cu-mulative BED 265Gy) versus(2) HDR 10Gy x 2 fol-lowed by EBRT 45Gy in 25 fractions(cumulative BED 253Gy). The 5-year biochemical progression free survival,using Phoenix criteria, was 92.7% when using HDR 10Gy x 2 versus 97.4% when using HDR 15Gy x1(p=0.995);the hazard ratio for 10-year biochemical control, defined as PSA nadir<0.4, on multivariable analysis was 1.078(95%CI,0.703-1.652,p=0.729). As such, this study showed no
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Table 5
Comparative outcomes and toxicity between various HDR fractionation schedules.
|Study|BED (Gy)a|HDR dose regimen|N|Primary outcome|Multivariable analysis|Toxicity| |---|---|---|---|---|---|---| |RTOG 0321(27)|238|9.5Gy x 2 (single implant)|129|5-yr bF(Phoenix): 14%||G3 GU:5% G3 GI:4%| |Martinez et al. (35)|≤268|5.5-6.5 Gy x 3, 8.25-8.75x2|167 167|10-yr bF(Phoenix): 14.3% 10-yr LRF:14.3% 10-yr DM:12.4%||G3 dysuria: 2% G3 frequency/urgency: 1% G3 hematuria: 2%| ||>268|9.5-11.5x2|305|10-yr bF(Phoenix): 18.9% 10-yr LRF:2.8% 10-yr DM: 5.7%|HR of 10-yr bF: 0.586(0.377-0.910), P=0.017|G3 dysuria: 1% G3 frequency/urgency: 1% G3 hematuria: 3%| |Helou et al. (36)|253|10Gy x 2|60|5yr bPFS(Phoenix): 92.7%||| ||265|15Gy x 1|123|5-yr bPFS(Phoenix: 97.4% P=0.995|HR(PSA nadir<0.4): 1.078(0.703-1.652) P=0.729|| |Vigneault et al. (37)|<250|6.6-6.5Gy x 3, 9.5Gy x 2|79 79|5-yr bPFS(Phoenix): 97.3% 5-yr PSA <0.2:68.6%|OR of 5-yr PSA ≥0.2: P=0.134|G3+GU:0% G3+ GU:0% acute, 1.7% late| ||250-260|10Gy x 2|497|5-yr bPFS(Phoenix): 94.3% 5-yr PSA <0.2:78.7%|0.639(0.356-1.148), P=0.134|G3+ GU:4.7% acute, 4.9% late| ||>260|15Gy x 1, 10.5Gy x 2|256|5-yr bPFS(Phoenix): 94.9% 5-yr PSA <0.2:86.7%|0.350(0.156-0.782), P=0.011|G3+ GU:4.7% acute, 4.9% late| |||||P(Phoenix).=453||| |||||P(PSA <0.2)=.005|||
External beam radiotherapy(EBRT) doses used:.
- Vigneault et al.: 40Gy in 20 fractions, 44Gy in 22 fractions, 45Gy in 25 fractions, 36Gy in 12 fractions; target volume included prostate and seminal vesicles $\pm$ pelvic nodes.
-Martinez et al.: 46Gy in 23 fractions.
-Helou et al.: 45Gy in 25 fractions with 10Gy x 2 HDR; 37.5Gy in 15 fractions with 15Gy x 1 HDR.
${}^{a}$ BED=biological equivalent dose, calculated assuming an alpha/beta $\sim 1.5$ .
clear differences in outcomes between a single HDR frac-tion of 15Gy versus a 2-fraction approach of 20Gy.
Finally, Vigneault et al.(37) compared 3 BED doses utilizing a range of HDR schedules in combination with 40-45Gy in 20-25 fractions or 36Gy in 12 fractions of EBRT: HDR 6-6.5Gy x 3 or 9.5Gy x 2(BED<250Gy),HDR 10Gy x 2(BED 250-260Gy), and HDR 10.5Gy x 2 or 15Gy x 1(BED>260Gy). The 5-year biochemi-cal progression free survival, defined by Phoenix criteria,did not significantly differ between the 3 groups; however,when defining biochemical control as PSA<0.2, the 5-year biochemical control was significantly improved when achieving a BED>260Gy. Acute grade 3+ genitourinary was modestly higher with BED>260Gy(HDR 10.5Gy x 2 or 15Gy x 1), but rates of toxicity were overall very low.
Current cooperative trials and professional guidelines(38) advocate for either 15Gy x 1 or a range of 9.5-11Gy
$x$ 2 when using HDR brachytherapy in combination with EBRT for intermediate and high risk prostate cancer. Sin-gle fraction of 15Gy may be the preferred approach given BED>260Gy, prospective comparative data showing sim-ilar outcomes as LDR 110Gy boost(18), and the least resource-intensive approach for the clinic and patient with a single implant, plan, and delivery.
KQ5/6: What is the role and duration of ADT with EBRT plus HDR Brachytherapy?
The role of ADT with radiation for prostate cancer has been long-established. In addition to its local cytoreductive effects and potential cytotoxic effect on micrometastatic disease, laboratory data has identified the effect of ADT on the local tumor microenvironment that promotes ra-diosensitization, such as reduction of tumor hypoxia and enhancement of oxidative stress following radiation(39).More recent data suggests that androgen receptor(AR) reg-ulates a transcriptional program of DNA repair genes, and
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with that, AR promotes prostate cancer radioresistance by promoting postradiation DNA repair. As such, inhibiting AR via ADT promotes radiosenitization via inhibition of DNA repair after radiation-induced double-stranded breaks(40).
However, the role of androgen deprivation therapy(ADT) in patients treated with“extreme” dose-escalated radiation, as that achieved with combination EBRT plus brachytherapy, remains poorly studied. The ASCENDE-RT trial(41) supports the use of 12 months of ADT with combination EBRT plus brachytherapy for men with high-risk prostate cancer(which comprised approximately 70% of the trial cohort). In another study(42), a pooled multicenter cohort analysis of over 3000 patients with high-risk prostate cancer receiving definitive radiation and ADT, there was a significant interaction between treatment type(i.e., EBRT alone versus EBRT plus brachytherapy)and ADT duration; specifically, natural cubic spline anal-ysis identified a minimum ADT duration threshold of 12 months for men treated with EBRT plus brachytherapy for optimal effect on distant metastasis free survival(compared with a minimum duration threshold of 26 months for men treated with EBRT alone).
RTOG 0815(43) was a randomized trial comparing radiation alone versus radiation plus 6 months ADT in men with intermediate-risk prostate cancer. In the over-all cohort, after a median follow-up of over 6 years, ad-dition of short-course ADT resulted in small but statisti-cally significant improvements in rates of distant metasta-sis and prostate cancer-specific mortality; no overall sur-vival benefit has been observed. Notably, on subgroup analysis restricted to patients receiving combination EBRT plus brachytherapy(HDR or LDR), the benefit of short-course ADT on distant metastasis remained(98.4% vs 94.9%, p<0.001). Additionally, on multivariable analy-sis, there was a trend toward improved overall survival with 6 months of ADT in patients receiving combination EBRT plus LDR brachytherapy(adjusted HR 0.31, 95%CI, 0.10-1.0, p=0.05). Notably, the number of patients receiving HDR boost was too small for multivariable anal-ysis.
However, use of ADT, even short courses of 4-6 months, can have deleterious effects on quality of life,including physical function/vitality, cognition, and sexual function. Additionally, ADT is associated with metabolic disease, cardiovascular morbidity, and other-cause mortal-ity(44-48); as such, efforts to mitigate the use of ADT in patients with otherwise curable prostate cancer are on-going, such as the NRG GU010 trial, which is randomiz-ing men with unfavorable intermediate-risk prostate cancer and low Decipher genomic classifications core to 6 months ADT versus no ADT with definitive radiation therapy.
The TRIP trial(3) is a multicenter, phase 3 random-ized trial across Japan comparing 6 versus 30 months of ADT with EBRT plus I-125 LDR brachytherapy in patients with high-risk prostate cancer. After a median follow-up
<EndOfPara>of over 9 years, the cumulative incidence of biochemi-cal progression(per Phoenix criteria) at 7 years in the 6-versus 30-month ADT arm was 9.0% versus 8.0%, respec-tively(p=0.65). However, this study was designed as a superiority study, with the hypothesis that 30 months of ADT would improve biochemical control compared with 6 months; given that long-term ADT is the standard of care for men with high-risk prostate cancer, a noninferior-ity study remains warranted to confirm whether truncated duration of ADT in this high-risk cohort is safe.
The duration of ADT with extreme dose-escalated ra-diation has also been scrutinized in the intermediate-risk population. The SHIP0804 trial(49) is a multicenter, phase 3 randomized trial across Japan of men with D'Amico intermediate-risk prostate cancer treated with I-125 LDR brachytherapy 144 Gy, comparing 3 months of neoadju-vant ADT±9 months of adjuvant ADT(i.e., cumulative 3 months ADT versus 12 months ADT). After a median follow-up of over 11 years, the 10-year bPFS was 82.9%with 12 months ADT versus 78.4% with 3 months ADT(p=0.51). These findings persisted even in subgroup anal-ysis based on number of intermediate-risk factors(1,2, or 3).
Notably, these prospective studies exclusively or pre-dominantly utilized LDR brachytherapy. While results would not be expected to differ(18), there have been no head-to-head trials comparing the role of concomitant ADT in men with intermediate and/or high-risk prostate can-cer treated with combination EBRT plus HDR brachyther-apy. There have been single-institution retrospective stud-ies, however, which have had mixed results with respect to the benefit of ADT on oncologic outcomes(50-53).These studies are limited due to imbalances in comparative groups, outdated EBRT and/or HDR brachytherapy dosing regimens, inconsistent ADT durations, and suboptimal se-quencing of ADT with respect to radiation therapy. More recent analysis including more contemporary regimens are detailed in Table 6. Specifically, 1 retrospective study by Ishiyama et al.(54) in 2017 of predominantly high-risk prostate cancer patients compared EBRT plus HDR brachytherapy with versus without ADT(most commonly long course with both neoadjuvant and adjuvant component of ADT). After a median follow-up of 66 months, the ad-justed hazard ratio for disease-free survival was 0.55(95%,CI 0.40-0.76, p<0.0001) and for biochemical control was 0.48(95% CI, 0.36-0.64, p<0.0001). Additionally, per-haps the most robust data indirectly comparing the role of ADT in patients treated with EBRT plus HDR brachyther-apy was the Australian multicenter TROG 03.04 RADAR(55), which was a 2 x 2 factorial randomized trial of men with predominantly high-risk prostate cancer, randomized to receive 6 versus 18 months of ADT as well as ran-domized between 0 versus 18 months of zolendronic acid.Enrolled patients received dose-escalated EBRT or EBRT with HDR brachytherapy. On subgroup analysis confined to men receiving EBRT plus HDR brachytherapy, longer-
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Table 6
Contemporary studies comparing role and duration of ADT with EBRT+HDR brachytherapy boost in men with intermediate- and high-risk prostate cancer.
|Study|Disease characteristic|Treatment|N|Age, median|Follow-up time, median|Primary outcome| |---|---|---|---|---|---|---| |Ishiyama et al.(54)|NCCN risk distribution: 31% intermediate, 49% high, 14% very-high|EBRT+HDR +ADT|2403 69(SD 6.46)|69(SD 6.46)|66 months|${}^{b}$ HR(PSD): 0.55(95% CI 0.40-0.76) ${}^{b}$ HR(PSA control): 0.48(95% CI 0.36-0.64)| |||EBRT+HDR alone|699|||Ref P<0.0001| |TROG 03.04 RADAR, Joseph et al. (55)|T2b-4N0M0, or T2a and GS≥7 and PSA≥10 (66.3% of overall cohort was NCCN high risk; 79.6% was D'Amico high risk)|EBRT+HDR+6 mo ADT ABRT+HDR+18 mo ADT|114 114 69 (range 48-85) 123|69 (range 48-85) 123|10.5 years 10.5 years|Distant Progression, 18mo vs. 6mo: All patients: 0.70(95% CI 0.56-0.87) EBRT+HDR: 0.61(95% CI 0.38-0.97)|
a Median HDR dose was 18 Gy(IQR 18-24), median HDR fractional dose was 9 Gy(IQR 6.4-9.0); median EBRT dose was 39 Gy(IQR 39-45),median EBRT fractional dose was 3 Gy(IQR 2.5-3.0).aMean duration of neoadjuvant and adjuvant ADT was 8.6±7.4 months and 27.9±12.9 months,respectively.
${}^{b}$ Results include patients who received neoadjuvant+adjuvant ADT only.
course ADT of 18 months was associated with significantly improved rates of distant metastasis compared to 6 months of ADT(adjusted hazard ratio 0.61, 95% CI 0.38-0.97). Of note, in the overall cohort analysis, there was no interaction between ADT duration and RT dose(i.e., dose-escalated EBRT versus EBRT plus HDR boost), suggesting that the benefit of long-term ADT in this high-risk cohort was in-dependent of use of an HDR brachytherapy boost or not. A major limitation of this analysis, however, is that the HDR brachytherapy dose utilized in the TROG 03.04 RADAR trial was lower(i.e., BED<260Gy) than optimal contem-porary regimens; whether the oncologic benefit of long-term ADT remains in men treated with optimal“extreme”dose-escalated regimens of EBRT plus HDR brachytherapy remains unclear.
Nonetheless, taking the above studies into consideration,decisions regarding utilization and duration of ADT for men with high-risk prostate cancer should be independent of radiation regimens used. When utilizing extreme dose escalation with combination EBRT plus brachytherapy for high-risk patients, either HDR or LDR, a minimum of 12 months of ADT should be considered. However, emerg-ing data(3) suggests truncated course of 6 months may be safe for select high-risk patients, especially those pref-erentially seeking to avoid sequelae of longer-term ADT.Still, more prospective data is warranted before a 6-month ADT regimen becomes routinely supported for high-risk patients undergoing combination EBRT and brachytherapy.For unfavorable intermediate-risk patients, a standard dura-tion of 4-6 months of ADT is recommended. Ongoing and future studies testing regulerk, a novel oral gonadotropin-releasing hormone antagonist with faster testosterone re-
covery time, in lieu of leuprolide, or intensified regimens of ADT with second-generation androgen signaling in-hibitors may impact future recommendations of ADT dura-tion with extreme dose escalated EBRT plus brachytherapy.
KQ7: What are strategies for improving toxicity and quality of life following HDR implant?
RTOG 0321 was a landmark multi-institutional trial es-tablishing the safety and efficacy of combination EBRT 45Gy with HDR brachytherapy 19Gy in 2 fractions(sin-gle implant) for localized prostate cancer. At 10 years the rate of late Grade 3 GI and GU adverse events was 4%and 5%, respectively(27). Notably, this was a prospective cohort that included patients from 14 different institutions,and no single institution was allowed to contribute more than 20 patients. The low toxicity rate provides reassur-ance that adherence to high-quality HDR implants can be generalizable and achieved across multiple institutions.
Genitourinary structures
A dosimetric analysis of RTOG 0321 showed positive correlations with acute grade 2+ GU adverse events with higher urethral dose at multiple levels, most significantly at V120. There was a negative association with acute grade 2+ GU adverse events of and homogeneity index. For late toxicities(median follow-up time of 2.5 years), there were positive correlations with grade 2+ GU adverse events at multiple urethral dose levels, especially V110. There were also positive correlations with PTV high dose volumes(i.e., hot spots) and implanted volume. This work, as well as many others, suggests that the dose-limiting structure in brachytherapy is the urethra(unlike EBRT where it is
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Table 7
Range of HDR brachytherapy boost(15Gy x 1) planning constraints currently in use.
||GEC-ESTRO|Crook J et al|NRG GU 009|ASCENDE|Suggested| |---|---|---|---|---|---| |CTV V100|>95%|≥98%|≥95%|≥90%|>95%| |CTV V100|(14.3Gy)||(14.3Gy)|(13.5Gy)|| |CTV V125||55-65%|||| |CTV V150|≤40%||<35%|≤40%|≤35-40%| ||(6Gy)||(5.25Gy)|(6Gy)|| |CTV V200|||<15%|≤14%|≤15%| ||||(2.25Gy)|(2.1Gy)|| |CTV D90|>100%|||>100%|>100%| ||(15Gy)|||(15Gy)|| |Rectum|D2cc≤10 Gy|D1cc≤9.5|V75%<1 cc|V75%<1 cc|V75%<1 cc| |||Gy|(11.25Gy)|Dmax≤100%|Dmax≤100%| ||||Dmax≤100%|(15Gy)|| |Bladder|||V75%(cc)≤1 cc|Dmax≤100%|V75%<1 cc| ||||(11.25Gy)|(15Gy)|Dmax≤100%| ||||V75%(cc)≤1 cc|(15Gy)|V75%<1 cc| ||||(16.95Gy)|(15Gy)|Dmax≤100%| |Urethra|D10≤17 Gy|Dmax 115%|V125%(cc)≤1 cc|Dmax≤120%(18Gy)|Dmax≤115-120%| ||D30≤15 Gy|(17.25Gy)|(18.75Gy)|D10≤115%(17.25Gy)|D10≤115%| ||||V150%(cc)≤0 cc||| ||||(22.5Gy)|||
the rectum)(56-61). However, it remains unclear what the ideal urethral dose constraint is and whether constraints should be modified for certain patient risk factors, such as high baseline urinary symptoms. The bladder, namely bladder neck which is challenging to define on imaging, is also an organ-at-risk during HDR brachytherapy planning,but a clear correlation between bladder dose and clinical toxicities has not been established. In fact, bladder dosime-try is not routinely evaluated with transrectal ultrasound(US) based planning. In Table 7, commonly used protocol-directed constraints for HDR brachytherapy planning are listed. Two protocols(GEC-ESTRO and Crook et al.(18))- which predominantly utilize US-based planning- do not include a bladder constraint at all.
It is important to note that for LDR brachytherapy, dose to the bladder neck is correlated with incidence of GU tox-icity(62). Yet, this correlation has not been reproduced in patients treated with HDR brachytherapy(63). Similarly,dose to the external urethral sphincter(EUS) has been significantly associated with incidence of GU toxicity in patients receiving LDR brachytherapy(64); however, this association has not been seen with HDR brachytherapy.This does not imply that the bladder shade and/or EUS are not important avoidance structures with HDR brachyther-apy, as robust dosimetric analysis in large datasets in this population is lacking. As such, it is essential that accurate delineation of the prostate base and apex is conducted to avoid excessive dose deposition within the bladder neck and/or external urinary sphincter. For patients undergoing CT-guided planning, prostate fiducial placement at the base and apex, respectively, may help delineate the prostate bor-ders for contouring. Further, brachytherapists are encour-aged to contour these GU substructures, which may facil-itate future analyses to measure any association between
bladder neck and/or EUS dose with GU toxicity following HDR brachytherapy. A recent consensus for delineating GU substructures, including bladder neck and EUS, at the time of prostate treatment planning were recently published and can be used as a guide(65).
Similar challenges are arising with emerging data in nonbrachytherapy cohorts regarding the association of ure-trhal dose and GU toxicity. For example, in the FLAME trial, which utilized intraprostatic microboosting, a urethra planning directive of D0.1 cc of≤80Gy was used, which provided equivalent toxicity outcomes with microboosting compared with standard EBRT(66). Further, data from prostate stereotactic body radiotherapy(SBRT) and hy-pofractionation studies also suggest an association between maximal urethral dose and cumulative incidence of grade 2+ late urinary toxicity, where the risk rises steeply above urethral 75-80Gy EQD2(67). Meanwhile, a typical com-bination regimen of 45 Gy EBRT plus HDR brachytherapy 15Gy x 1 results in a urethral EQD2 of 97Gy(assum-ing an alpha/beta of 3). Whether stricter urethral planning directives, based on patients treated with hypofractionated EBRT or SBRT, should be adapted to HDR brachyther-apy directives is unknown. Additionally, there will soon be longer term toxicity outcomes with“HDR-like” SBRT boost and SBRT monotherapy dosing; whether any asso-ciations between organs-at-risk dose and GU toxicity will be relevant for HDR brachytherapy planning remains to be seen.
Gastrointestinal structures
The incidence of acute and/or late bowel toxicity af-ter HDR brachytherapy boost is very low with existing constraints, as shown in Table 7. For example, in RTOG
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0321, which used 3D-conformal, not IMRT, for the EBRT,there was only 1 grade 3 gastrointestinal late adverse event(proctitis), which resulted in a 10-year cumulative inci-dence of 4%. Whether grade 1-2 rectal toxicities, which cumulatively occurred in 24 of 115 patients in RTOG 0321,could be improved with stricter rectal wall constraints is unclear. Rectal spacers, which have been shown to im-prove early and late grade 1-2 rectal toxicity in patients treated with dose-escalates EBRT alone(68,69), may be utilized for patients treated with combination EBRT and HDR brachytherapy. Caution is advised in patients with larger glands, as the placement of a spacer may intro-duce pubic arch interference that can limit the feasibility of catheter implantation. However, whether rectal spacers significantly improve grade 1-2 bowel toxicity or patient-reported quality of life in patients treated with combina-tion EBRT and HDR brachytherapy remains to be vali-dated. For example, patient-reported bowel quality of life in Crook et al.(18) prospective randomized trial, which in-cluded patients receiving EBRT with brachytherapy with-out rectal spacer, returned to near baseline at 5 years in the HDR boost arm.
Sexual function structures
Ongoing work is being done to determine ways to im-prove sexual function after prostate radiation therapy(70).There are multiple structures that may be implicated at inter-post-treatment sexual function, including the penile bulb,the proximal penile crura, neurovascular bundles, and the internal pudendal arteries. How dose to these structures impacts early and late sexual function following prostate radiation remains under investigation for now. Given that HDR brachytherapy planning can be utilized in real-time with MRI, these structures may be easily delineated during treatment planning and may be important planning direc-tives to improve treatment-related sexual toxicity. However,there are currently no clear dose constraint recommenda-tions for these structures with HDR brachytherapy boost.
Suggestions for brachytherapy dose constraints
The last ABS consensus on HDR brachytherapy boost demonstrated a wide range on institution-specific dose con-straints for various organs at risk. Since the time of that publication, the techniques of HDR have improved, as well as our understanding of various organs at risk and their relationship with post-treatment toxicity. However,there continues to be many unanswered questions regard-ing ideal organ at risk constraints, and the field of prostate brachytherapy is certainly behind the type of work that has been achieved in cervical cancer, such as with the EMBRACE-1 study(71). To provide sufficient guidance for HDR brachytherapy boost treatment planning, Table 7 summarizes the dose constraints that are being used or
recommended from other consensus statements(GEC-ESTRO)(72), recently completed randomized controlled trials(Crook J et al).(4), or ongoing randomized controlled trials(NRG GU009, ASCENDE-SBRT). The most obvi-ous difference between currently used constraints shown in the table is that most are written as a percentage of the prescribed dose and not in terms of an absolute dose(e.g., V75%<1 cc). The exception to this is the GEC-ESTRO recommendations, which do list constraints based on an EQD2: Rectum D2cc≤75Gy EQD2, Urethra D10%≤120Gy EQD2, Urethra D30%≤105Gy EQD2. A sum-mary of the currently used constraints is listed in the ta-ble with absolute doses for an example of a 15Gy single fraction boost. The final column in the table provides sug-gested constraints that 1 can utilize in clinic. Given the variation in what is clinically acceptable, providers should use their judgement in determining which constraints to follow. However, it is recommended that constraints that are within the range of what is listed in the table be uti-lized.
KQ8: How are HDR brachytherapy plans evaluated?
Prostate HDR brachytherapy dose planning requires ac-curate target and organs at risk delineation, as well as op-timal needle reconstructions. Treatment plans are created and evaluated after intraoperative transperineal catheter in-sertion, either with use of transrectal US, pelvic computed tomography(CT), or pelvic magnetic resonance imaging(MRI). Each of these imaging modalities can be appropri-ate with respective advantages/disadvantages of each(Ta-ble 8). The use of 1 versus the other may be determined by the provider and the resources available in the clinic.Notably, treatment planning must be performed on a com-missioned system with source-specific documentation and quality assurance measures, as per recommendations by the American Association of Physicists in Medicine(AAPM)Task Group 53(73). Three-dimensional dose calculations must be performed, and dose-volume analysis of target vol-ume and organs-at-risk should be undertaken for each pa-tient.
Historically, the most utilized imaging techniques for treatment planning are US and CT. US-based planning allows for intraoperative planning and delivery of treat-ment seamlessly while the patient remains under anesthe-sia, which can enhance cost-effectiveness and patient satis-faction(74). Additionally, as US-based planning can occur immediately in the OR after needle implantation, the pa-tient can remain immobile in dorsal lithotomy without the need for transport out of the procedure suite, which min-imizes the risk of needle displacement. This is an impor-tant advantage, as needle migration requires adjustments to be made prior to treatment planning and delivery, which would need to be done while the patient is awake with CT- or MRI-based planning and may require pain medi-cation for needle advancement. However, the challenge of US-based planning is optimal visualization of the prostate gland and inserted needles(especially needle tips), particu-
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Table 8
Comparison of US-, CT- and MRI-based treatment planning for HDR brachytherapy.
||US|CT|MRI| |---|---|---|---| |Workflow Patient transport|***(<2 hours) ***(none)|**(3-4 hours) *(necessary, dependent on distance from OR to CT) **(can be limited if CT in procedure room) **(at risk with patient transport) **(can be limited in CT in procedure room) **(minimal additional costs if CT simulation available)|*(4-5 hours) *(necessary, dependent on distance from OR to MRI) **(can be limited if MRI in procedure room) **(at risk with patient transport) **(can be limited if MRI in procedure room) procedure room) *(MRI access/time, specialized MRI template and needle markers)| |Patient satisfaction|****(±GA throughout procedure and needle/template removal)|*(awake for± needle adjustment, needle/template removal; prolonged immobility with interstitial catheters) ***|*(awake for± needle adjustment, needle/template removal; prolonged immobility with interstitial catheters) **(enhanced with MRI compatible markers) ***| |Identifying needle tip|∗* (**|∗* (star risk with patient transport) **(can be limited in CT in procedure room)|***(enhanced with MRI compatible markers) ***| |Prostate contouring OAR contouring|∗* (**|∗ (star risk with patient transport) **(**|*** (one risk with gate uncertainty(90) procedure room) *(MRI access/time, specialized MRI template and needle markers)|
GA=general anesthesia.
*Measuring needle protrusion distance from the template or relative needle protrusion to a well-visualized needle tip can mitigate uncertainty(90).*Least optimal.
***Optimal.
^ Measuring needle protrusion distance from the template or relative needle protrusion to a well-visualized needle tip can mitigate uncertainty(90).
larly the anterior needles, due to limited US image resolu-tion and ultrasonic shadows from the implanted needles. Of note, contemporary techniques of utilizing needle protru-sion length from the template has been shown to improve needle tip reconstruction (90). Additionally, US-based in-traoperative planning and delivery requires a shielded oper-ating/procedure room, which may be unavailable for many facilities.
CT-based planning, on the other hand, allows for rapid needle identification and reconstruction and is readily available in radiation oncology clinics. However, CT im-ages provide suboptimal prostate gland delineation due to poorer soft-tissue contrast, especially at the prostate apex.MRI may provide optimal solutions to both prostate gland delineation and needle visualization(75,76); for example,the spatial resolution of MRI enhances the ability to delin-eate the prostate apex versus the external urethra sphincter,as well as facilitate contouring of a dominant intrapro-static lesion(DIL) for adequate coverage or dose escala-tion. However, this imaging technique is time-, cost- and resource-intensive. Additionally, if direct MRI planning is desired(as opposed to fusion with planning CT), spe-cial MR-compatible equipment(e.g. template) are required.Additionally, catheter tips can be challenging to delineate on MRI, so specialized markers may be needed for catheter reconstruction for treatment planning(77).
KQ9: What is the optimal sequencing of HDR brachytherapy with EBRT?
<BeginOfPara>The HDR brachytherapy boost can be delivered ei-ther before or after EBRT. Further, the sequencing of
HDR brachytherapy and EBRT does not seem to sig-nificantly impact toxicity or patient-reported outcomes.The THEPCA trial(78) was a randomized trial of men with intermediate- and high-risk prostate cancer compar-ing HDR brachytherapy 15Gy in 1 fraction either before(n=50) versus after(n=50) EBRT 46Gy in 23 fractions to the prostate, semial vesicles, and pelvic lymph nodes.With a median follow-up of approximately 5 years, there was no difference in acute or late grade 1-2 genitouri-nary or gastrointestinal toxicities; notably, there was no grade 3+ toxicity. Additionally, there was no difference in patient-reported quality of life between arms. No sta-tistically significant difference in disease free survival has been observed after 5 years.
KQ10: What is an appropriate EBRT dose/fractionation regimen to use in combination with HDR brachytherapy?
There is a range of EBRT dose and fractionation schemes that can be utilized when administered in con-junction with an HDR brachytherapy boost, including the following:
•45-50.4Gy in 1.8-2Gy fractions (prostate $\pm$ seminal vesicles $\pm$ pelvic lymph nodes);
•37.5Gy in 2.5Gy fractions(prostate $\pm$ seminal vesicles only)
When used in combination with HDR brachytherapy of 15Gy x 1 or 10.5-11Gy x 2, each of the above EBRT regi-mens will achieve the recommended overall BED >260Gy.
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Decisions regarding which dose and fractionation to utilize may depend on multiple factors, including target volumes(i.e., prostate/seminal vesicles± pelvic lymph nodes), pa-tient access/amenability to protracted courses, or toxicity concerns with more hypofractionated regimens.
The most widely used EBRT regimen is conventional fractionation of~ 45 Gy in 1.8-2.0 Gy fractions, similar to that utilized in the ASCENDE-RT trial establishing the role of combination EBRT to whole pelvis plus brachytherapy.RTOG 0321 trial, which prospectively established safety(i.e., very low grade 3 toxicity) and efficacy of combination EBRT with HDR brachytherapy for intermediate and high risk prostate cancer, also utilized 45 Gy in 25 fractions.Morton and colleagues conducted a phase II trial to test a more hypofractionated regimen of a single HDR 15 Gy in combination with EBRT 37.5 Gy in 15 fractions target-ing the prostate/seminal vesicles only(34). Late grade 3 toxicity was low at 4%, and clinical efficacy/toxicity were similar as the previously used regimen of EBRT 45 Gy in 25 fractions with an HDR brachytherapy boost of 10Gy x 2. This study established safety and efficacy with this mod-erate hypofractionated EBRT regimen in combination with HDR brachytherapy, when treating the prostate± seminal vesicles only.
The PIVOTALboost trial(79) is an ongoing phase 3 randomized trial for patients with intermediate and high-risk prostate cancer in the UK that is comparing prostate only versus whole pelvis radiation, as well as with ver-sus without HDR brachytherapy. Notably, the whole pelvis treatment regimen is 42Gy in 20 fractions. This trial may support in the future a hypofractionated regimen to use in patients requiring elective pelvic lymph node treatment in combination with a brachytherapy boost.
With advancements in image-guidance, reproducible pa-tient immobilization, and use of rectal spacers, there has been growing interest in ultrahypofractionated EBRT in combination with a brachytherapy boost for intermediate and high-risk prostate cancer. While the use of prostate SBRT alone has become a standard of care, the use of ultrahypofractionation to the prostate/seminal vesicles±pelvic lymph nodes in combination with a brachytherapy boost is still limited, and long-term toxicity associated with this strategy is limited. Gorovets et al.(80) eval-uated a cohort of patients from Memorial Sloan Ketter-ing Cancer Center with localized prostate cancer receiving HDR brachytherapy 15 Gyx 1 followed by EBRT 25 Gy in 5 fractions(to the prostate± seminal vesicles± pelvic lymph nodes). After a median follow-up 24 months, no grade 3+ toxicities were reported. Acute and late grade 2 GI toxicity was only 1%, while acute and late grade 2 GU toxicity was 5.9% and 9.9%, respectively. Inclusion of pelvic lymph nodes and absence of rectal spacer were significantly associated with more frequent grade 1+ GU toxicity.
A phase I/II Canadian trial(81) prospectively enrolled 28 patients with intermediate-risk prostate cancer and
treated EBRT 25 Gy in 5 fractions(to the prostate and proximal 1cm of seminal vesicles using volumetric arc therapy), followed by a single HDR brachytherapy implant of 15 Gy. After a median follow-up of 4 years, toxicity re-sults were compared with historical control groups treated with EBRT 36Gy in 12 fractions or 37.5Gy in 15 frac-tions followed by HDR brachytherapy 15Gy x 1. Patient-reported urinary outcomes(IPSS scores) did not differ sig-nificantly between the treatment regimens. While there was a trend toward greater exacerbation of urinary symptoms with the ultrahypofractionated regimen, this difference was not statistically significant. There were no significant dif-ferences in patient-reported GU and GI toxicity, as mea-sured by EPIC, between ultrahypofractionation and mod-erate hypofractioned. However, sexual toxicity, measured via EPIC, was more impacted with ultrahypofractionation as soon as 6 months and up to 24 months after treatment completion.
The HOPE trial(NCT04197141) is an ongoing Cana-dian phase II randomized trial comparing 45Gy in 25 frac-tions versus 25Gy in 5 fractions whole pelvis EBRT in combination with HDR brachytherapy 15Gy x 1 in pa-tients with unfavorable intermediate- or high-risk prostate cancer, with the primary endpoint of late bowel toxicity and quality of life. Early results after a median follow-up of 1.34 years have shown no significant differences in acute grade 2+ GU or GI toxicity. For GU toxicity, there was a 17.9% versus 9.8% rate of grade 2 toxicity between con-ventional and ultrahypofractionated treatment, respectively;no grade 3 GU toxicity has been reported. For GI toxic-ity, there was a 2.6% versus 4.9% rate of grade 2 toxicity between conventional and ultrahypofractionated treatment,respectively; there was a 4.9% rate of grade 3 GI toxicity in the ultrahypofractionated arm, and no grade 3 events in the conventionally fractionated arm(82). The PCS-XI trial(NCT05820633) is a larger ongoing Canadian phase III,noninferiority randomized trial comparing 25Gy in 5 frac-tions versus 4-5 weeks of fractionated whole pelvis EBRT in combination with HDR brachytherapy 15Gy x 1 in pa-tients with intermediate- or high-risk prostate cancer, with primary endpoint of patient-reported and physician-graded toxicity.
The short-term toxicity profile of ultrahypofractionated EBRT with HDR brachytherapy appears reassuring; more mature toxicity and efficacy data will validate the long-term safety of this regimen, especially when treating the pelvic lymph nodes in patients at higher risk of oc-cult lymph node metastases. Ultrahypofractionated whole pelvis is currently being prospectively evaluated in the phase III NRG GU013 trial, which is randomizing men with high-risk prostate cancer to 5-fraction SBRT ver-sus moderate/conventionally fractionated EBRT. Treatment of the prostate with or without pelvic lymph nodes is at the discretion of the treatment provider; for those pa-tients randomized to SBRT and receiving pelvic lymph node treatment, a dose of 25Gy in 5 fractions is uti-
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Table 9
Target and organ-at-risk constraints with conventional and moderate hypofractionated EBRT regimens in combination with HDR brachytherapy.
||37.5Gy in 15 fractions (Morton et al.[8])|45Gy in 25 fractions*(Emory)| |---|---|---| |CTV|V37.5Gy≥99%|V45 Gy ≥99%| |PTV|V35.6Gy ≥99%|V45 Gy ≥95%| |Rectum|V39.4Gy <1%|| |Rectum|V33 Gy <20%|V45 Gy <10%| |Rectum|V29 Gy <35%|V35 Gy <20%| |Rectum|V24 Gy <50%|V25 Gy <50%| |Rectum|V29 Gy <35%|V45 Gy <15%| |Bladder|V29 Gy <35%|V40 Gy <25%| |Bladder|V24 Gy <5%|V30 Gy <50%| |Bladder|V29 Gy <50%|V25 Gy <10%| |Bladder|Bowel bag|V24 Gy <5%| |Small bowel|Dmax <39.38 Gy|V35 Gy <250 cc| |Large bowel|Dmax <39.38 Gy|| |Penile bulb||V25 Gy <50%|
${}^{a}$ Commonly used constraints but not prospectively validated.
lized. Of note, brachytherapy boost is not allowed in this trial.
While results of these ongoing trials remain to mature,it may be prudent to utilize more protracted EBRT reg-imens, especially when covering the pelvic lymph nodes.Nonetheless, data for 25Gy in 5 fractions is promising, and this regimen mitigates cost and patient travel burden. While this regimen may be appropriate for experienced high-volume centers, long-term follow-up data from prospective trials will be needed for widespread uptake. Suggestions for planning constraints when using standard fractionation to 45Gy or moderate hypofractionated 37.5Gy in 15 frac-tions in combination with HDR brachytherapy are shown in Table 9.
KQ11: Which patients are suitable candidates for HDR brachytherapy boost?
Overall, patients pursuing combination EBRT plus brachytherapy should have a life expectancy such that the biochemical control advantages of a brachytherapy boost will be most likely to translate to significant advan-tages in long-term outcomes(e.g., lower risk of salvage ADT and/or possibly reduced risk of distant metastasis).Suitability criteria for HDR brachytherapy boost mirror that of LDR brachytherapy, with perhaps more flexibility given implantation of hollow catheters and inverse treat-ment planning, which facilitates dose modulation and en-compassing extra-prostatic extension and seminal vesicle invasion, where seed migration concerns with LDR may be relevant. Pubic arch interference, especially for larger prostate glands, can be assessed by transrectal US, CT,and/or MRI volume study. Experienced practitioners may consider brachytherapy for patients with larger prostate glands(>60-80 cc), a limited median lobe, or prior his-tory of transurethral resection of the prostate(TURP).While HDR brachytherapy may be appropriate in these cases, these patients may be at higher risk of acute urinary
retention or acute/late GU toxicity(83,84). If a median lobe resection with a limited TURP is performed prior to brachytherapy, it is suggested to wait approximately 3 months prior to initiating treatment and use preimplant imaging to ensure there is sufficient prostatic tissue remain-ing that will allow appropriate catheter implantation(85).Studies have suggested that the risk of severe toxicity with HDR brachytherapy for patients with large prostate glands>60 cc is relatively low(86).
Additionally, patients pursuing an HDR brachytherapy boost should have nonsevere baseline lower urinary tract symptoms. Patient-ported outcomes, such as the inter-national prostate symptom score(IPSS), should be uti-lized for quantifying baseline urinary function. Addition-ally, postvoid residual volume, which can be easily mea-sured in the clinic, can be used to assess voiding func-tion. Patients with higher baseline IPSS scores, such as$>15-18$ , or elevated postvoid residuals, such as $>100 cc$ ,may be at greater risk of acute urinary issues following implantation $(87,88)$ . However, the risk of significant uri-nary toxicity with HDR brachytherapy for patients with elevated baseline uri-nary symptoms and/or postvoid residual, medications for improving urinary function, such as alpha-blockers or an-timuscarinic agents, should be considered to optimize uri-nary function prior to the starting treatment. A balanced conversation with the patient regarding the risks, benefits,and alternatives to a brachytherapy boost should also be clearly discussed.
Relative contraindications for any prostate brachyther-apy, including HDR, include inability to tolerate general,spinal, or local anesthesia in the dorsal lithotomy posi-tion, absence of a rectum(although, a CT/MRI-guided ap-proach is feasible but technically very challenging), rectal pathology(e.g., active fistula), or unacceptable operative
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659
risks(e.g., anticoagulant dependency, elevated bleeding risk).
Discussion
Intensified radiation therapy with extreme dose esca-lation, which can be safely achieved with combination EBRT plus brachytherapy, can provide benefits in long-term outcomes in patients with intermediate and high-risk prostate cancer. The landmark ASCENDE-RT trial utilized an LDR/permanent seed approach; however, past and emerging data suggest that HDR brachytherapy may have technical and toxicity advantages in this setting. As such, this consensus statement is intended to provide a comprehensive update on the role of HDR brachytherapy in combination with EBRT for localized intermediate and high-risk prostate cancer. Additionally, this review provides guidance on implementing HDR brachytherapy boost into clinical practice, including details on patient suitability, ap-propriate HDR brachytherapy and EBRT dose/fractionation schedules, image guidance options for catheter implanta-tion and treatment planning, role of ADT, and acute/late toxicity risks that may be expected after combination treat-ment.
Recommendations have been guided by available ran-domized controlled trials or prospective studies. Yet, there remain several clinical questions surrounding combination EBRT plus HDR brachytherapy that need to be addressed with ongoing and future prospective studies. For example,in the era of ultrahyprofractionation, which can enhance cost-effectiveness and patient satisfaction, larger studies with long-term follow-up are needed to establish whether 5-fraction EBRT, delivered to the prostate/seminal vesi-cles alone or with pelvic lymph nodes, is safe and ef-fective, especially in men at high risk of occult lymph node metastases. Additionally, how ultrahyprofractionated SBRT, which achieves a higher biological equivalent dose compared with fractionated EBRT, compares with com-bination EBRT plus brachytherapy is unknown and will be answered via the CCTPR-242 ASCENDE-SBRT trial(NCT06235697). Second, focal intraprostatic boost(i.e.,microboost) has been established as an isotoxic technique that can improve biochemical control in patients with in-termediate and high-risk prostate cancer(22). Utilization of this technique has risen since 2021, but whether onco-logic outcomes with this approach are comparable with combination Betrachy therapy remains unclear and needs to be rigorously evaluated. Additionally, HDR brachytherapy, with inverse planning technique, may local low intraprostatic focal boosting without compromising toxicity. Trials utilizing HDR brachytherapy boost with image-guided intraprostatic boosting would help determine whether clinical outcomes can be further enhanced with this treatment. Third, the role and duration of ADT in the combination EBRT plus brachytherapy setting remains unclear; pooled analyses and recent smaller trials have
suggested that shorter courses of ADT may be appro-priate in this setting. However, larger, noninferiority tri-als are needed to validate the safety of shorter durations of ADT, especially in men with high-risk disease. Fur-thermore, second-generation androgen signaling inhibitors,such as abiraterone acetate or apalutamide, are actively being tested in the localized setting; the optimal duration of intensified ADT, especially if used with combination EBRT plus brachytherapy, will need to be evaluated in fu-ture trials. Finally, in the era of precision medicine with increased utilization of advanced imaging(e.g., PSMA PET/CT, MRI), genomic classifiers and/or histopathologic AI-based biomarkers, improved risk stratification and iden-tification of patients at highest risk of recurrence, who may benefit the most from combination EBRT with a brachytherapy boost, will help improve patient selection and enhance long-term outcomes in this disease. Still, com-bination EBRT with HDR brachytherapy, particularly with high-quality implants using modern imaging and treatment planning techniques, provides a highly effective regimen with excellent quality-of-life outcomes that can be read-ily utilized for patients with intermediate and high-risk prostate cancer.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.brachy.2025.06.005.
References
[1] Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for pa-tients with prostate Cancer: american Society of Clinical Oncol-ogy/Cancer Care Ontario Joint Guideline update. J Clin Oncol 2017;35(15):1737-1743.
[2] Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-RT: an analy-sis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98(2):286-295.
[3] Yorozu A, Namiki M, Saito S, et al. Trimodality therapy with Iodine-125 brachytherapy, external beam radiation therapy, and short- or long-term androgen deprivation therapy for high-risk localized prostate cancer: results of a multicenter, randomized phase 3 trial(TRIP/TRIGU0907). Int J Radiat Oncol Biol Phys 2024;118(2):390-401.
[4] Crook J, Moideen N, Arbour G, et al. A randomized trial com-paring quality of life after low-dose rate or high-dose rate prostate brachytherapy boost with pelvic external beam radiation therapy. Int J Radiat Oncol Biol Phys 2024;120(1):59-68.
[5] Spratt DE, Soni PD, McLaughlin PW, et al. American Brachyther-apy Society Task Group report: combination of brachytherapy and external beam radiation for high-risk prostate cancer. Brachytherapy 2017;16:1-12.
[6] King MT, Keyes M, Frank SJ, et al. Low dose rate brachytherapy for primary treatment of localized prostate cancer: a systemic review and executive summary of an evidence-based consensus statement.Brachytherapy 2021;20(6):1114-1129.
[7] Chang AJ, McBride S, Keyes M, et al. The American Brachytherapy Society and the American Radium Society Appropriate Use Criteria
660
S.A. Patel et al./ Brachytherapy 24(2025) 644-662
genitourary Committee endorse the American Society of Clini-cal Oncology/Cancer Care Ontario Guidelines. J Clinc Oncol 2018 JCO1800626. doi:10.1200/JCO.18.00626.
[8] Mendez LC, Morton GC. High dose-rate brachytherapy in the treat-ment of prostate cancer. Transl Androl Urol 2018;7:357-370.
[9] Wang Y, Sankreacha R, HeiHbsi, et al. Comparative study of dosimetry between high-dose-rate and permanent prostate im-plant brachytherapies in patients with prostate adenocarcinoma.Brachytherapy 2006;5:251-255.
[10] Martinez AA, Demanes J, Vargas C, et al. High-dose-rate prostate brachytherapy: excellent accelerated-hypofrationated treatment for favorable prostate cancer. Am J Clin Oncol 2010;33:481-488.
[11] Lobular DA, Prestrud AA, Somerfield MR, et al. American society of clinical oncology clinical practice guidelines: for-mal systemic review-based consensus methodology. J Clin Oncol 2012;30(25):3136-3140.
[12] King CR. LDR vs. HDR brachytherapy for localized prostate cancer:the view from radiobiologic models. Int J Radiat Oncol Biol Phys 2000;46:165-172.
[13] King CR, DiPetrillo TA, Wazer DE, et al. Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT,and brachytherapy from radiobiologic models. Int J Radiat Oncol Biol Phys 2000;46:165-172.
[14] Hoskin PJ Rojas AM, Ostler PJ, et al. Randomised trial of exter-nal beam radiotherapy alone or with high-dose-rate brachytherapy boost for prostate cancer: mature 12-year results. Radiother Oncol 2021;154:214-219.
[15] Denham JW, Joseph D, Lamb DS, et al. Short-term androgen sup-pression and radiotherapy versus intermediate-term androgen sup-pression and radiotherapy, with or without zolendronic acid, in men with locally advanced prostate cancer(TROG 03.04 RADAR):10-year results from a randomised, phase 3 factorial trial. Lancet Oncol 2019;20(2):267-281.
[16] Kent AR, Mathson B, Millar JL. Improved survival for pa-tients with prostate cancer receiving high-dose-rate brachyther-apy boost to EBRT compared with EBRT alone. Brachytherapy 2019;18(3):313-321.
[17] Tamihardja J, Larenz I, Lutyj P, et al. Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer. Strahlener Onkol 2022;198(8):735-743.
[18] Crook JM, Cheng JC, Arbour G, et al. A randomized comparison of high-dose-rate and low-dose-rate prostate brachytherapy combined with external beam radiation therapy for unfavorable prostate cancer:efficiency results after median follow-up of 74 months. Int J Radiat Oncol Biol Phys 2025 S0360-3016(25)00303-7.
[19] Imai Y, Urabe F, Iuvatani K, et al. Comparison of outcomes in high-risk prostate cancer patients treated with low/high-dose-rate brachytherapy plus external beam radiotherapy. Int J Clin Oncol 2023;28:698-706.
[20] Yamazaki H, Masui K, Suzuki G, et al. High-dose-rate brachytherapy with external beam radiotherapy versus low-dose-rate brachytherapy with or without external beam radiotherapy for clin-ically localized prostate cancer. Sci Rep 2021;111(1):6165.
[21] King MT, Yang DD, Muralidhar V, et al. A comparative analysis of overall survival between high-dose rate and low-dose-rate brachytherapy boosts for unfavorable-risk prostate cancer.Brachytherapy 2019;18(2):186-191.
[22]KermkeijLGW, Groen VH, Pos FJ, et al. Focal boost to the in-traprostatic tumor in external beam radiotherapy for patients with lo-calized prostate cancer: results from the FLAME randomized phase III trial. J Clin Oncol 2021;39(7):787-796.
[23] Ong WL, Nikitas J, Joseph D, et al. Long-term quality-of-life outcomes after prostate radiation with or without high-dose-rate brachytherapy boost: post hoc analysis of TROG 03.04 RADAR.Int J Radiat Oncol Biol Phys 2024;119(3):813-825.
[24] Kollmeier MA, Gorovets D, Flynn J, et al. Combined brachyther-apy and ultra-hypo fractionated radiotherapy for intermediate-risk prostate cancer: comparison of toxicity outcomes using a high-dose-rate(HDR) versus low-dose-rate(LDR) brachytherapy boost.Brachytherapy 2022;21(5):599-604.
[25] Dhere V, Fischer-Valuck BW, Goyal S, et al. Patient-reported outcomes after low-dose-rate versus high-dose-rate brachytherapy boost in combination with external beam radiation for interme-diate and high risk prostate cancer. Brachytherapy 2021;20(6):1130-1138.
[26] Parry MG, Nossiter J, Sujentiran 3, et al. Impact of high-dose-rate and low-dose-rate brachytherapy boost on toxicity, functional and cancer outcomes in patients receiving external beam radiation ther-apy for prostate cancer: a national population-based study. Int J Radiat Oncol Biol Phys 2021;109(5):1219-1229.
[27] Hsu IC, Bae K, Shinohara, et al. Long-term results of NRG oncology/RTOG 0321: a phase II trial of combined high dose rate brachytherapy and external beam radiation therapy for ade-narcinoma of the prostate. Int J Radiat Oncol Biol Phys 2021;110(3):700-707.
[28]Astrom L, Pedersen D, Mercke C, et al. Long-term outcome of high dose rate brachytherapy in radiotherapy of localized prostate cancer.Radiother Ocln 2005;74:157-161.
[29] Kalkner KM, Wahlgren T, Ryberg M, et al. Clinical outcome in patients with prostate cancer treated with external beam radiother-apy and high dose-rate iridium 192 brachytherapy boost: a 6-year follow-up. Acta Oncol 2007;46:909-917.
[30] Kaprealian T, Weinberg V, Speight JL, et al. High-dose-rate brachytherapy boost for prostate cancer: comparison of two different fractionation schemes. Int J Radiat Oncol Biol Phys 2012;82(1):222-227.
[31] Pellizzon AC, Nadalin W, Salvajoli JV, et al. Results of high dose rate afterloading brachytherapy boost to conventional external beam radiation therapy for initial and locally advanced prostate cancer.Radiother Oncol 2003;66:167-172.
[32] Pistis F, Guedae F, Pera J, et al. External beam radiotherapy plus high-dose-rate brachytherapy for treatment of locally advanced prostate cancer: the initial experience of the Catalan Institute of On-cology. Brachytherapy 2019;9:15-22.
[33] Sato M, Mori T, Shirai S, et al. High-dose-rate brachytherapy of a single implant with two fractions combined with external beam radio-theradiotherapy for hormone-naive prostate cancer. Int J Radiat Oncol Biol Phys 2008;72:1002-1009.
[34] Morton GC, Loblaw DA, Sankreacha R, et al. Single-fraction high-dose-rate brachytherapy and hypofractionated external beam radio-therapy for men with intermediate-risk prostate cancer: analysis of short- and median-term toxicity and quality of life. Int J Radiat Oncol Oncol Biol Phys 2010;77:811-817.
[35] Martinez AA, Gonzalez J, Ye H, et al. Dose escalation improves cancer-related events at 10 years for intermediate- and high-risk prostate cancer patients treated with hypofractionated high-dose-rate boost and external beam radiotherapy. Int J Radiat Oncol Biol Phys 2011;79(2):363-370.
[36] Helou J, D'Alimonte L, Lowblaw A, et al. High dose-rate brachytherapy boost for intermediate risk prostate cancer: long-term outcomes of two treatment schedules and early biochemical predic-tors of success. Radiother Oncol 2015;115:84-89.
[75] Vigneault E, Mbodji K, Magnan S, et al. High-dose-rate brachyther-apy boost for prostate cancer treatment: different combinations of hypofractionated regimens and clinical outcomes. Radiother Oncol 2017;124(1):49-55.
[38] NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Version 1.2025. Accessed October 14 2024.NCCN.org.
[39] Milosevic M, Chung P, Parker C, et al. Androgen withdrawal in patients reduces prostate cancer hypoxia: implications for dis-ease progression and radiation response. Cancer Res 2007;67:6022-6025.
S.A. Patel et al./ Brachytherapy 24(2025) 644-662
661
[40] Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor sig-naling regulates DNA repair in prostate cancers. Cancer Discovery 2013;3:1245-1253.
[41] Oh J, Tyldesley S, Pai H, et al. An updated analysis of the sur-vival endpoints of ASCENDE-RT. Int J Radiat Oncol Biol Phys 2023;115(105):1061-1070.
[42] Kishan AU, Steigler A, Denham JW, et al. Interplay between dura-tion of androgen deprivation therapy and external beam radiother-apy with or without a brachytherapy boost for optimal treatment of high-risk prostate cancer: a patient-level data analysis of 3 cohorts.JAMA Oncol 2022(8:3):e216871.
[43] Krauss DJ, Harrison T, Martinez AA, et al. Dose-escalated radiother-apy alone or in combination with short-term androgen deprivation for intermediate-risk prostate cancer: results of a phase III multi-in-stitutional trial. J Clin Oncol 2023;41(17):3203-3216.
[44] Voog JC, Paulus R, Shipley WU, et al. Cardiovascular mortal-ity following short-term androgen deprivation therapy in clinically localized prostate cancer: an analysis of RTOG 94-08. Eur Urol 2016;69:204-210.
[45] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and sat-isfaction with outcome among prostate cancer survivors. N Engl J Med 2008;358:1250-1261.
[46] Green HJ, Pakenham KI, Headley BC, et al. Altered cognitive func-tion in men treated for prostate cancer with luteinizing hormone-re-leasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 2002;90:427-432.
[47] Beyer DC, McKeough T, Thomas T. Impact of short course hor-monal therapy on overall and cancer specific survival after per-manent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;61:1299-1305.
[48] Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during anrogen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448-4456.
[49] Water F, Miki K, Aoki M, et al. Ten-year outcomes of a phase III, multicenter, randomized controlled trial(SHIP0804) with three-month neoadjuvant anrogen deprivation prior to 1251-seed superneilrate prostate brachytherapy followed by nil versus nine-month adjuvant hormonal therapy inients with intermedi-ate-risk prostate cancer. Int Radiat Oncol Biol Phys 2024:15 S0360-3016(24)03584-3.
[50] Krauss D, Kestin L, Ye H, et al. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer. Int J Radiat Oncol Biol Pays 2011;80:1064-1071.
[51] Schiffmann J, Lesmana H, Tennstedt P, et al. Additional andro-gen deprivation makes the difference: biochemical recurrence-free survival in prostate cancer patients after HDR brachytherapy and external beam radiotherapy. Strahlentber Onol 2015;191:330-337.
[52] Demanes DJ, Brandt D, Scour L, et al. Excellent results from high dose rate brachytherapy and external beam for prostate can-cer are not improved by endrogen deprivation. Am J Clin Oncol 2009;32:342-347.
[53] Galalae RM, Martinez A, Mate T, et al. Long-term outcome by risk factors using conformal high-dose-rate brachytherapy(HDR-BT) boost with or without neoadjuvant androgen suppres-sion for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:1048-1055.
[54] Ishiyama H, Kamitani N, Kawamura H, et al. Nationwide multi-institutional retrospective analysis of high-dose-rate brachytherapy combined with external beam radiotherapy for localized prostate cancer: an Asian Prostate HDR-BT Consortium. Brachytherapy 2017;16(3):503-510.
[55] Joseph D, Denham JW, Steigler A, et al. Radiation dose esca-lation or longer androgen suppression to prevent distant progres-sion in men with locally advanced prostate cancer: 10-year data
from the TROG 03.04 RADAR trial. Int J Radiat Oncol Biol Phys 2020;106(4):693-702.
[56] Ghadjar P, Keller T, Rentsch CA, et al. Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy. Brachytherapy 2009;8(1):45-51.
[57] Ghadjar P, Matzinger O, Isaak B, et al. Association of urethral tox-icity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer. Radiother Oncol 2009;91(2):237-242.
[8] Ishiyama H, Kitano M, Satoh T, et al. Genitourinary toxicity af-ter high-dose-rate(HDR) brachytherapy combined with Hypofrac-tionated external beam radiotherapy for localized prostate cancer:an analysis to determine the correlation between dose-volume his-togram parameters in HDR brachytherapy and severity of toxicity.Int J Radiat Oncol Biol Phys 2009;75(1):23-28.
[59] Sullivan L, Williams SG, Tai KH, et al. Urethral stricture following high dose rate brachytherapy for prostate cancer. Radiother Oncol 2009;91(2):232-236.
[60] Ghadjar P, Rentsch CA, Isaak B, et al. Urethral toxicity vs.cancer control- lessons to be learned from high-dose rate brachytherapy combined with intensity-modulated radiation ther-apy in intermediate- and high-risk prostate cancer. Brachytherapy 2011;10(4):286-294.
[61]Hindson BR, Millar JL, Matheson B. Urethral strictures following high-dose-rate brachytherapy for prostate cancer: analysis of risk factors. Brachytherapy 2013;12(1):50-55.
[62] Hathout L, Folkert MR, Kollmeier MA, et al. Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: implications for establishing new dose constricts for treatment planning. Int J Radiat Oncol Biol Phys 2014;90(2):312-319.
[63] Aichi IB, Hathout L, Carignan D, et al. Dose to the blad-der neck is not correlated with urinary toxicity in patients with prostate cancer treated with HDR brachytherapy boost. Brachyther-apy 2020;19(5):584-588.
[64] Boyce-Fappiano D, Bathala TK, Ye R, et al. Predictors of urinary toxicity with MRI-assisted radiosurgery for low-dose-rate prostate brachytherapy. Brachytherapy 2020;19(5):574-583.
[65] Le Guevelou J, Zilli T, Ferretti L, et al. Urinary organs at risk for prostate cancer external beam radiation therapy: contouring guide-lines on behalf of the francophone group of urological radiation therapy. Pract Radiat Oncol 2024;14(6):541-554.
[66] Groen VH, van Schie M, Zuithoff N, et al. Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial. Radiother Oncol 2022;167-127-132.
[67] Zilli T, Achard V, Le Guevelou J. Intraprostatic urethra: the new kid on the block for prostate cancer radiation therapy? Int J Radiat Oncol Biol Phys 2022;113(1):92-95.
[68] Hamstra DA, Mariadas D, Sylvester J, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys 2017;97(5):976-985.
[69] Mariados NF, Orio PF, Schiffman Z, et al. Hyaluronic acid spacer for hypofractionated prostate radiation therapy: a randomized clinical trial. JAMA Oncol 2023;9(4):511-518.
[70] Le Guevelou J, Sargos P, Ferretti L, et al. Sexual structure sparing for prostate cancer radiotherapy: a systematic review. Eur Uro Oncol 2024;7(3):332-343.
[71] Potter R, Tanderup K, Scmid MP, et al. MRI-guided adap-tive bracytherapy in locally advanced cervical cancer(EM-BRACE-1): a multicentre prospective cohort study. Lancet Oncol 2021;22(4):538-547.
[72] Henry A, Pieters BR, Siebert FA, et al. GEC-ESTRO ACROP prostate brachytherapy guidelines. Radiother Oncol 2022;167:244-251.
662
S.A. Patel et al./ Brachytherapy 24(2025) 644-662
[73] American Association of Physicists in Medicine Radiation Therapy Committee Task Group 53. Quality assurance for clinical radiother-apy treatment planning. Med Phys 1998;25:1773.
[74] Batchelar DL, Chung HT, Loblaw A, et al. Intraoperative ultra-sound-based planning can effectively replace postoperative CT-based planning for high-dose-rate brachytherapy for prostate cancer.Brachytherapy 2016;15(4):399-405.
[75] Villeirs GM. DeMeerleer GO. Magnetic resonance imaging(MRI)anatomy of the prostate and application of MRI in radiotherapy planning. Eur J Radiol 2007;63:361-368.
[76] Rylander S, Buus S, Pedersen EM, et al. Dosimetric impact of con-touring and needle reconstruction uncertainties in US-, CT-, and MRI-based high-dose-rate prostate brachytherapy treatment plan-ning. Radiothose Oncol 2017;123(1):125-132.
[77] Ning MS, Vedam S, Ma J, et al. Clinical utility and value contribu-tion of an MRI-positive line marker for image-guided brachyther-apy in gynecologic malignancies. Brachytherapy 2020;19(3):305-315.
[78] Choudhury M, Shibu S, Cain, A et. Timing of high-dose-rate brachytherapy with external beam radiation therapy in patients with intermediate- and high-risk localized prostate cancer and its ef-fects on toxicity and quality of life: a randomized controlled trial(THEPCA). Int J Radiat Oncol Biol Phys 2024;119(1):90-99.
[79] Syndikus I, Cruickshank C, Staffurth J, et al. PIVOTALboost: a phase III randomised controlled trial of prostate of pelvis ver-sus prostate alone radiotherapy with or without prostate boost(CRUK/16/018). Clin Transl Radiat Oncol 2020;25:22-28.
[80] Gorovets D, Hopkins M. Kollmeier M. et al. Early outcomes of high-dose-rate brachytherapy combined with ultra-hypofrac-tionated radiation in higher-risk prostate cancer. Brachytherapy 2021;20(6):1099-1106.
[81] Beaudry MM, Carignan D, Foster W, et al. Comparison of four-year toxicities and local control of ultra-hypofractionated vs moder-ate-hypofractionated image guided prostate radiation with HDR
brachytherapy boost: a phase I-II single institution trial. Clin Transl Radiat Oncol 2023;8(40):100593.
[82] Mendez LC, Crook J, Martell K, et al. Is ultrahypofractionated whole pelvis radiation therapy(WPRT) as well tolerated as con-ventionally fractionated WPRT in patients with prostate cancer?Early results from the HOPE trial. Int J Radiat Oncol Biol Phys 2024;119(3):803-812.
[83] Crook J, McLean M. Catton C, et al. Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol 2002;52(2):453-460.
[84] Keyes M, Miller S, Moravan V, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy:long-term outcome in 712 consecutive patients. Int J Radiat On-col Biol Phys 2009;79(3):1023-1032.
[85] Hao LL, Fang FM, Chuang YC, et al. Previous transurethral re-section of the prostate is not a contraindication to high-dose rate brachytherapy for prostate cancer. BJU Int 2009;104(11):1620-1623.
[86] Press RH, Morgan TM, Cutrell PK, et al. Patient-reported health-re-lated quality of life outcomes after HDR brachytherapy between small(<60 cc) and large(>60 cc) prostate glands. Brachytherapy 2019;18(1):13-21.
[87] Bucci J, Morris WJ, Keyes M, et al. Predictive factors of uri-nary retention following prostate brachytherapy. Int J Radiat Oncol 2002;53(1):91-98.
[88] Beekman M, Merrick GS, Butler WM, et al. Selecting patients with pretreatment postvoid residual urinary volume less than 100 mL may favorably influence brachytherapy-related urinary morbidity. Urology 2005;66(6):1266-1270.
[89] Morgan TM, Rossi PJ, Cutrell PK, et al. High-dose-rate brachyther-apy appears safe in patients with high baseline International Prostate Symptom scores. Brachytherapy 2019;18(6):793-799.
[90] Batchelar D, Gaztanaga M, Schmid M, et al. Validation study of ul-trasound-based high-dose-rate prostate brachytherapy planning com-pared with CT-based planning. Brachytherapy 2014;13(1):75-79.
| Guideline recommendation | Strength of recommendation | Quality of evidence |
|---|---|---|
| KQ1: How does efficacy compare between EBRT alone versus combination EBRT plus HDR brachytherapy boost? | ||
| -Biochemical control is improved with the addition of an HDR brachytherapy boost for patients with intermediate- and high-risk disease. | Strong | High |
| KQ2: How does efficacy compare with HDR brachytherapy boost compared with LDR brachytherapy boost? | ||
| -Biochemical control is expected to be similar between HDR versus LDR boosts. | Strong | High |
| KQ3: How does toxicity compare with HDR brachytherapy boost compared with LDR brachytherapy boost? | ||
| -Acute urinary toxicity may be lower with HDR compared with LDR; long-term urinary toxicity is expected to be similar | Strong | Moderate |
| -Acute and long-term bowel toxicity may be lower with HDR compared with LDR. | Strong | Moderate |
| KQ4: What dose and fractionation schemes are preferred when utilizing an HDR brachytherapy boost? | ||
| brachytherapy boost? | Strong | Moderate |
| -15 Gy xl | Strong | Moderate |
| -9.5-11 Gy x 2 | Strong | Moderate |
| KQ5: What is the role of ADT when using combination EBRT with HDR brachytherapy boost? | ||
| -Improving disease control outcomes for unfavorable intermediate- and high-risk prostate cancer. | Strong | High |
| KQ6: What is the optimal duration of ADT when using combination EBRT with HDR brachytherapy boost for unfavorable intermediate- and high-risk prostate cancer? | Strong | |
| -4-6 months (intermediate-risk) | Strong | High |
| -6 months (high-risk) | Weak | Moderate |
| -12+ months (high-risk) | Strong | High |
| KQ7: What are strategies for improving toxicity and quality of life following an HDR implant? | Strong | Moderate |
| -Urethra, Rectal, Bladder Dosimetry Constraints -Alpha-blockers | Strong | Moderate |
| KQ8: How are HDR brachytherapy boost plans evaluated? | Strong | Low |
| -CT | Strong | Low |
| -Ultrasound | Strong | Low |
| -MRI | Strong | Low |
| KQ9: What is the optimal sequencing of HDR brachytherapy with EBRT? | Strong | Moderate |
| -HDR brachytherapy can be administered before or after EBRT | Strong | Moderate |
| KQ10: What is an appropriate EBRT dose/fractionation regimen to use in combination with HDR brachytherapy boost? | ||
| -45-50.4 Gy in 1.8-2.0 Gy fractions(prostate/SV+/- pelvic nodes) | Strong | High |
| -37 Gy in 2.5 Gy fractions(prostate/SV only) | Strong | Moderate |
| -25 Gy in 5 fractions(prostate/SV+/- pelvic nodes) | Weak | Moderate |
| KQ11: Which patients are suitable candidates for HDR brachytherapy boost? | ||
| -Sufficient life expectancy | Strong | Expert Opinion |
| -Suitable prostate anatomy/volume | Strong | Expert Opinion |
| -Baseline urinary function | Strong | Expert Opinion |
| Study | Disease characteristic | Treatment | BED(Gy) $(\alpha/\beta$ 1.5) | N | Age, median (α/β 1.5) | Follow-up time, median | ADT use | Primary outcome |
|---|---|---|---|---|---|---|---|---|
| Hoskin et al. (14)b | T1-3N0M0 PSA<50 No prior TURP | EBRT+HDRa EBRTb | 217.68 160.53 | 70 (range 47-80) | 131 months | 76%; Neoadju- variant/concurrent; duration not reported | 6-/12-yr RFS: 71%/48% 6-/12-yr RFS: 55%/27% | |
| Randomized | P=0.008 HR(EBRT+HDR vs. EBRT): 0.29 (95% CI 0.11-0.47), P=0.001 | |||||||
| TROG 03.04 RADAR RADham et al. (15) | T2b-4N0M0 Gleason ≥7 PSA ≥10 | EBRT+HDRd EBRTc | 211.33 154-172.67 | 237 814 | 68.7(range 48-85) | 10.5 years | 100%; 6 or 18 months | DM:14.9% DM:22.4%(66Gy),22.0% (70Gy),20.4%(74Gy) |
| Kent et al.(16) | NCCN intermediate and high risk | EBRT+HDR | 197.33 | 215 72.3 | 12.2 years | HR(HDR vs. 70Gy) 0.68 (95% CI 0.57-0.80), P<0.0001 HR(HDR vs. 74Gy) 0.75 (95% CI 0.56-1.01), P=0.06 | ||
| EBRTs | 163.33 | 439 | 68.9 | 10-yr PCSM: 93% 15-yr PCSM: 87% 10-yr PCSM: 88% 15-yr PCSM: 79% P<0.037 | ||||
| Tamihardja et al. (17)sss | NCCN low, intermediate, high risk | EBRT+HDRh risk | 233.33 192.28 | 258 72.3 | 71.0 53.3 months | 95.3 months | 51.9% | 10-yr MFS: 87.0% 10-yr MFS: 82.9% |
| 1:1- matched | Median duration 20 months | P=0.195 |
| Study | Disease characteristic | Treatment | N | Age, median | Follow-up time, median | ADT use | Primary outcome |
|---|---|---|---|---|---|---|---|
| Crook et al.（18） | NCCN unfavorable intermediate, high risk | EBRT+HDR | 108 71 | 71 | 74 months | 76% overall | 4-year PSA ≤0.2:81% 5-year bPFS: 94% 8-year bPFS: 86% |
| EBRT+LDR | 87 | 4-year PSA ≤0.2:83% 5-year bPFS: 90% 8-year bPFS: 85% | |||||
| randomized | P=0.91 (4-year PSA ≤0.2) | ||||||
| Imai et al.（19） | cT1-3aN0M0, PSA＜100 | EBRT+HDR | 252 66 | 70.5 70.5 | 98.9 months 77.5 months | 94%(mean 29.7 months) 43.9% (69.9% 9.28 months) P=0.89 | 5-yr bPFS: 86.2% 5-yr bPFS: 85.6% P=0.89 |
| Yamazaki et al.（20） | cT1-3aN0M0, PSA＜50 | EBRT+HDRb <06 | 924 71 | 71 70 months | 94% 94% | 5-yr bPFS: 97.2% (unfav int risk), 95.7% (high risk) | |
| EBRT+LDR | 69 | 69 | 84 months | 80% | |||
| King et al.（21)a | NCCN unfavorable intermediate, high risk | EBRT+HDR | 8526 9877 | 67.1 66.7 | 5 years 40.4% 43.1% | OS: adjusted HR(LDR vs. HDR) 1.03 (95% CI 0.96-1.11) P=0.38 |
| Study | Treatment | N | Rectal spacer | GU toxicity | GI toxicity | Multivariable analysis |
|---|---|---|---|---|---|---|
| Crook et al.(4) | HDR boost | 108 | None | EPIC 84±13 IPSS 8.0 1 G3,7 G2(6.7%) | EPIC 89±12 No G3,5 G2(4.8%) | |
| Crook et al.(4) | LDR boost | 87 | EPIC 77±14 IPSS 11.8 1 G3,2 G2(2.4%) | EPIC 83±16 1 G3,9 G2(10.8%) | ||
| Crook et al.(4) | Randomized | ${}^{b}$ | $$P=0.001\text{(EPIC)}$$ P=0.0002(IPSS) | $$P=0.02\text{(EPIC)}$$ | ||
| Crook et al.(4) | Hollmeier et al. (24)b | LDR boost | 59 40 | 73% 18% | G2 5.1% G2 45% | G2 3% R2 5% |
| Dhere et al.(25)a | HDR boost | 55 | None | G2+ 42.9% | G2+ 2.0% | |
| Dhere et al.(25)a | LDR boost | 51 | G2+ 67.5% P<.001 | G2+ 2.6% | ||
| Dhere et al.(25)a | P<.001 | P=0.99 | ||||
| Dhere et al.(25)a | Parry et al.(26)c | HDR boost | 2,765 | None | G2+ 16.6%(95% 15.1-18.2) EPIC 78.9(95% 77.4-80.3) G2+ 15.8%(95% 11.9-20.2) EPIC 72.9(25% 66.9-77.5) | G2+ 16.7%(95% 84.4-87.2) G2+ 32.2%(95% 72.2-82.5) |
| Parry et al.(26)c | EPIC P<0.001 | $$\text{ EPIC} P<0.001$$ |
| Study | BED (Gy)a | HDR dose regimen | N | Primary outcome | Multivariable analysis | Toxicity |
|---|---|---|---|---|---|---|
| RTOG 0321(27) | 238 | 9.5Gy x 2 (single implant) | 129 | 5-yr bF(Phoenix): 14% | G3 GU:5% G3 GI:4% | |
| Martinez et al. (35) | ≤268 | 5.5-6.5 Gy x 3, 8.25-8.75x2 | 167 167 | 10-yr bF(Phoenix): 14.3% 10-yr LRF:14.3% 10-yr DM:12.4% | G3 dysuria: 2% G3 frequency/urgency: 1% G3 hematuria: 2% | |
| >268 | 9.5-11.5x2 | 305 | 10-yr bF(Phoenix): 18.9% 10-yr LRF:2.8% 10-yr DM: 5.7% | HR of 10-yr bF: 0.586(0.377-0.910), P=0.017 | G3 dysuria: 1% G3 frequency/urgency: 1% G3 hematuria: 3% | |
| Helou et al. (36) | 253 | 10Gy x 2 | 60 | 5yr bPFS(Phoenix): 92.7% | ||
| 265 | 15Gy x 1 | 123 | 5-yr bPFS(Phoenix: 97.4% P=0.995 | HR(PSA nadir<0.4): 1.078(0.703-1.652) P=0.729 | ||
| Vigneault et al. (37) | <250 | 6.6-6.5Gy x 3, 9.5Gy x 2 | 79 79 | 5-yr bPFS(Phoenix): 97.3% 5-yr PSA <0.2:68.6% | OR of 5-yr PSA ≥0.2: P=0.134 | G3+GU:0% G3+ GU:0% acute, 1.7% late |
| 250-260 | 10Gy x 2 | 497 | 5-yr bPFS(Phoenix): 94.3% 5-yr PSA <0.2:78.7% | 0.639(0.356-1.148), P=0.134 | G3+ GU:4.7% acute, 4.9% late | |
| >260 | 15Gy x 1, 10.5Gy x 2 | 256 | 5-yr bPFS(Phoenix): 94.9% 5-yr PSA <0.2:86.7% | 0.350(0.156-0.782), P=0.011 | G3+ GU:4.7% acute, 4.9% late | |
| P(Phoenix).=453 | ||||||
| P(PSA <0.2)=.005 |
| Study | Disease characteristic | Treatment | N | Age, median | Follow-up time, median | Primary outcome |
|---|---|---|---|---|---|---|
| Ishiyama et al.(54) | NCCN risk distribution: 31% intermediate, 49% high, 14% very-high | EBRT+HDR +ADT | 2403 69(SD 6.46) | 69(SD 6.46) | 66 months | ${}^{b}$ HR(PSD): 0.55(95% CI 0.40-0.76) ${}^{b}$ HR(PSA control): 0.48(95% CI 0.36-0.64) |
| EBRT+HDR alone | 699 | Ref P<0.0001 | ||||
| TROG 03.04 RADAR, Joseph et al. (55) | T2b-4N0M0, or T2a and GS≥7 and PSA≥10 (66.3% of overall cohort was NCCN high risk; 79.6% was D'Amico high risk) | EBRT+HDR+6 mo ADT ABRT+HDR+18 mo ADT | 114 114 69 (range 48-85) 123 | 69 (range 48-85) 123 | 10.5 years 10.5 years | Distant Progression, 18mo vs. 6mo: All patients: 0.70(95% CI 0.56-0.87) EBRT+HDR: 0.61(95% CI 0.38-0.97) |
| GEC-ESTRO | Crook J et al | NRG GU 009 | ASCENDE | Suggested | |
|---|---|---|---|---|---|
| CTV V100 | >95% | ≥98% | ≥95% | ≥90% | >95% |
| CTV V100 | (14.3Gy) | (14.3Gy) | (13.5Gy) | ||
| CTV V125 | 55-65% | ||||
| CTV V150 | ≤40% | <35% | ≤40% | ≤35-40% | |
| (6Gy) | (5.25Gy) | (6Gy) | |||
| CTV V200 | <15% | ≤14% | ≤15% | ||
| (2.25Gy) | (2.1Gy) | ||||
| CTV D90 | >100% | >100% | >100% | ||
| (15Gy) | (15Gy) | ||||
| Rectum | D2cc≤10 Gy | D1cc≤9.5 | V75%<1 cc | V75%<1 cc | V75%<1 cc |
| Gy | (11.25Gy) | Dmax≤100% | Dmax≤100% | ||
| Dmax≤100% | (15Gy) | ||||
| Bladder | V75%(cc)≤1 cc | Dmax≤100% | V75%<1 cc | ||
| (11.25Gy) | (15Gy) | Dmax≤100% | |||
| V75%(cc)≤1 cc | (15Gy) | V75%<1 cc | |||
| (16.95Gy) | (15Gy) | Dmax≤100% | |||
| Urethra | D10≤17 Gy | Dmax 115% | V125%(cc)≤1 cc | Dmax≤120%(18Gy) | Dmax≤115-120% |
| D30≤15 Gy | (17.25Gy) | (18.75Gy) | D10≤115%(17.25Gy) | D10≤115% | |
| V150%(cc)≤0 cc | |||||
| (22.5Gy) |
| US | CT | MRI | |
|---|---|---|---|
| Workflow Patient transport | ***(<2 hours) ***(none) | **(3-4 hours) *(necessary, dependent on distance from OR to CT) **(can be limited if CT in procedure room) **(at risk with patient transport) **(can be limited in CT in procedure room) **(minimal additional costs if CT simulation available) | *(4-5 hours) *(necessary, dependent on distance from OR to MRI) **(can be limited if MRI in procedure room) **(at risk with patient transport) **(can be limited if MRI in procedure room) procedure room) *(MRI access/time, specialized MRI template and needle markers) |
| Patient satisfaction | ****(±GA throughout procedure and needle/template removal) | *(awake for± needle adjustment, needle/template removal; prolonged immobility with interstitial catheters) *** | *(awake for± needle adjustment, needle/template removal; prolonged immobility with interstitial catheters) **(enhanced with MRI compatible markers) *** |
| Identifying needle tip | ∗* (** | ∗* (star risk with patient transport) **(can be limited in CT in procedure room) | ***(enhanced with MRI compatible markers) *** |
| Prostate contouring OAR contouring | ∗* (** | ∗ (star risk with patient transport) **(** | *** (one risk with gate uncertainty(90) procedure room) *(MRI access/time, specialized MRI template and needle markers) |
| 37.5Gy in 15 fractions (Morton et al.[8]) | 45Gy in 25 fractions*(Emory) | |
|---|---|---|
| CTV | V37.5Gy≥99% | V45 Gy ≥99% |
| PTV | V35.6Gy ≥99% | V45 Gy ≥95% |
| Rectum | V39.4Gy <1% | |
| Rectum | V33 Gy <20% | V45 Gy <10% |
| Rectum | V29 Gy <35% | V35 Gy <20% |
| Rectum | V24 Gy <50% | V25 Gy <50% |
| Rectum | V29 Gy <35% | V45 Gy <15% |
| Bladder | V29 Gy <35% | V40 Gy <25% |
| Bladder | V24 Gy <5% | V30 Gy <50% |
| Bladder | V29 Gy <50% | V25 Gy <10% |
| Bladder | Bowel bag | V24 Gy <5% |
| Small bowel | Dmax <39.38 Gy | V35 Gy <250 cc |
| Large bowel | Dmax <39.38 Gy | |
| Penile bulb | V25 Gy <50% |
引用 / 出处
2025+循证共识声明：局限性前列腺癌高剂量率近距离放疗联合外照射放射治疗. 2025.