# Radiation Oncology/Prostate/Brachytherapy

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Prostate Brachytherapy

## Guidelines

* Please see Prostate Guidelines page

## Isotope

* Seattle (1999 - 2006) -- I-125 vs. Pd-103
** Randomized. 602 patients, Stage T1c-T2a, GS 2-6, PSA 4-10 ng/ml. Arm 1) I-125 at 144 Gy vs. Arm 2) Pd-103 at 125 Gy. Modified peripheral loading pattern. Postimplant CT 2-4 hours later
** Preliminary toxicity; 2002 PMID 11895205 -- "I-125 versus Pd-103 for low-risk prostate cancer: morbidity outcomes from a prospective randomized multicenter trial." (Wallner K, Cancer J. 2002 Jan-Feb;8(1):67-73.) Min F/U 1 year
*** 110 of planned 380 patients
*** Outcome: 6-month AUA score I-125 16 vs. Pd-103 11; 1-year AUA score 13 vs. 12; benefit dependent on baseline AUA score but not on volume or age
*** Toxicity: Generally, trend to higher morbidity with I-125
*** Conclusion: Patients treated with Pd-103 recovered from radiation induced prostatitis faster; patients with minimal pretreatment urinary symptoms benefit most
** Preliminary PSA; 2003 PMID 14630265 -- "125I versus 103Pd for low-risk prostate cancer: preliminary PSA outcomes from a prospective randomized multicenter trial." (Wallner K, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1297-303.)
*** 115 of planned 600 patients. Short neoadjuvant ADT in 20 patients. bPFS defined PSA <= 0.5 ng/ml. Median F/U 2.9 years
*** Outcome: 3-year bPFS I-125 89% vs. Pd-103 91% (NS). If D90 <100% 82% vs. >= 100% 97% (SS). If V100 <90% 87% vs. >=90% 97% (SS). Dosimetric parameters more pronounced for I-125
*** Conclusion: No difference at 3 years
** Morbidity; 2005 PMID 16259869 -- "I-125 versus Pd-103 for low-risk prostate cancer: long-term morbidity outcomes from a prospective randomized multicenter controlled trial." (Herstein A, Cancer J. 2005 Sep-Oct;11(5):385-9.)
*** 352 of planned 600 patients. Use of alpha-blockers at discretion. Minimum F/U 2 years
*** GU: AUA peak at 1 month postimplant. 1-month AUA score I-125 15 vs. Pd-103 19 (SS); 6-months 12 vs. 10 (SS). Use of alpha-blockers similar.
*** GI: Radiation proctitis (persistent bleeding) in 9%, no difference between arms. If R100 <1.0 cc, bleeding in 2%
*** Conclusion: Pd-103 results in more intense symptoms, but faster recovery than I-125
** Dosimetry; 2008 PMID 18376221 -- "There is a wide range of predictive dosimetric factors for I-125 and pd-103 prostate brachytherapy." (Herstein A, Am J Clin Oncol. 2008 Feb;31(1):6-10.)
*** 265 of 602 patients with CT-dosimetry. V50, V75, V100, V150, V200, V300; D50, D75, D90, D200 evaluated
*** Outcome: bPFS I-125 85% vs. Pd-103 89%. Almost all parameters (not just D90 and V100) showed improvement with higher values.
*** D90 and V100 dosimetry: Highly correlated (r=0.7-0.8). V100 (I-125) 3-year bPFS >90% 91% vs. <90% 86% (NS); V100 (Pd-103) 100% vs. 89% (SS); D90 (I-125) >100% 91% vs. <100% 85% (NS); D90 (Pd-103) 100% vs. 87% (SS)
*** Conclusion: Most dosimetric parameters have predictive value, in addition to D90 and V100

## Strand vs loose seeds

* Seattle (2003-2004) -- Stranded seeds vs loose seeds
** Randomized. 62 patients with cT1c-T2a. Brachytherapy, 144 Gy, treatment plan devised prior to randomization. Arm 1) Strand seeds via Mick needles (however, 1/3 of seeds were lose to accommodate standard implant pattern) vs. Arm 2) Loose seeds via Mick applicator. Post-implant dosimetry at day 0 and day 30. Primary outcome seed loss and dosimetric parameters
** 2007 PMID 17434106 -- "A prospective randomized comparison of stranded vs. loose 125I seeds for prostate brachytherapy." (Reed DR, Brachytherapy. 2007 Apr-Jun;6(2):129-34.)
*** Outcome: Seed loss strand 23% vs. loose 47% (p=0.053). Mean seeds lost 0.4 vs. 1.1 (p=0.06). Multiple seed loss in 10% vs. 25% patients. Strand seeds trend to worse V100 and D90
*** Conclusion: Strong trend to lower seed loss with stranded seeds

## Critera for implant

* Volume of the prostate: should be > 20 cc and < 60 cc. Can use androgen ablation to shrink the prostate if it is too large.
* Men with large prostates have significant voiding problems.

## Timing of NSAIDs

* Toronto (2004-2008) -- Meloxicam 1 week prior to implant vs day of implant
** Randomized. 300 patients, treated with brachytherapy. Arm 1) meloxicam 7.5 mg BID started 1 weeks prior to implant x4 weeks vs Arm 2) started day of implant x4 weeks. Primary outcome: MRI prostate volume at 1 month, IPSS at 1 and 3 months, catheterization
** 2010 PMID 20350785 -- "A Phase III Randomized Trial of the Timing of Meloxicam with Iodine-125 Prostate Brachytherapy." (Crook J, Int J Radiat Oncol Biol Phys. 2010 Mar 27. [Epub ahead of print])
*** Outcome: No difference in edema, catheterization (8% vs 6%, NS), or IPSS
*** Conclusion: Starting meloxicam 1 week prior to BT did not impact edema and urinary symptoms

## Erectile function

* PMID 15890585, 2004 - Merrick GS et al.
** Most were Pd-103, 16% were I-125. 37% had implant only; the remainder had EBRT to prostate + seminal vesicles. Hormones used in 23%.
** 3-yr potency preservation of 50.5%. The preimplant erectile score was 29 for those with adequate postimplant function and 25 for those without. Median time to ED was 5.4 months. After brachy, erectile score was 20 in potent patients and 3 in those with ED. On multivariate analysis, the preimplant erectile score and D50 to the proximal crura predicted for ED.

## Comparison to Radical Prostatectomy

* ACOSOG Z0070 - Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT)
** See information at Radiation_Oncology/Prostate/Localized Prostate Cancer#Surgery_vs_RT
** A randomized trial of radical prostatectomy versus brachytherapy for patients with T1c or T2a N0 M0, PSA < 10, G <= 6 prostate cancer.
** Closed early due to non-accrual.

## EBRT and Implant Combinations

* RTOG 00-19 (2000-01) - phase II. Intermediate risk: PSA 10-20 and GS <7, or PSA <20 and GS 7. 45 Gy EBRT followed by 108 Gy I-125 brachytherapy.
** Median f/u 20 mos. Acute grade 3 genitourinary toxicity in 7.6%. No grade 4 or 5. Late grade 3 GU and GI toxicity was 3.3% at 18 mos. No grade 4 or 5.

### Supplemental EBRT dose

* Seattle (2000-2004) -- (EBRT 44 Gy + BT 90 Gy) vs. (EBRT 20 Gy + BT 115 Gy)
** Randomized. Closed prematurely due to slowing accrual. 568 of planned 600 patients, clinical T1c-T2a, Glease 7-10 and/or PSA 10-20 ng/ml. Arm 1) EBRT 44 Gy + Pd-103 implant 90 Gy vs. Arm 2) EBRT 20 Gy + Pd-103 implant 115 Gy
** 2005 PMID 16086912 -- "20 Gy versus 44 Gy supplemental beam radiation with Pd-103 prostate brachytherapy: preliminary biochemical outcomes from a prospective randomized multi-center trial." (Wallner K, Radiother Oncol. 2005 Jun;75(3):307-10.)
*** 165 patients reported
*** Outcome: 3-year bPFS 44 Gy 88% vs. 20 Gy 83% (NS)
*** Conclusion: Likelihood of cure similar with standard or lower dose, in the setting of high prostate coverage by brachytherapy
** Treatment gap; 2008 PMID 18525300 -- "The time gap between Pd-103 prostate brachytherapy and supplemental beam radiation does not impact on rectal morbidity or likelihood of cure." (Bittner N, Am J Clin Oncol. 2008 Jun;31(3):231-6.)
*** Median gap time between completion of EBRT and implant was 3 days (-6 to 40 days). Median F/U 3.2 years
*** Outcome: 3-year bPFS 84%, no significant difference based on gap. Predictors of failure GS, PSA, and D90
*** Rectal toxicity: Overall 7%. Predictors high R100 and EBRT 44 Gy, but not treatment gap
*** Conclusion: Shorter gap between EBRT and BT safe; doesn't improve bPFS but allows timely treatment

### EBRT + Implant Boost vs. EBRT alone

* ASCENDE-RT
** Randomized. 398 men. Median age 68. High risk disease 69%. Arm 1) ADT + pelvic RT 46 Gy + EBRT boost to 78 Gy, vs Arm 2) ADT + pelvic RT 46 Gy + LDR BT boost.
** 2016 PMID 28262473 -- "Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer" (Morris WJ, Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):275-285. doi: 10.1016/j.ijrobp.2016.11.026. Epub 2016 Nov 24.) Median F/U 6.5 years
*** Outcome: EBRT boost 2x more likely to have biochemical failure. 5-year bPFS EBRT 84% vs 89%; 9-year 83% vs 62% (SS). Benefit in both intermediate- and high-risk groups. No OS difference at 6.5 years
*** Conclusion: LDR brachy boost lower biochemical failure rate
* UK (Mount Vernon), 2007 (1997-2005)
** 220 pts. Stage T1-T3, localized, PSA < 50. Randomized to: 1) EBRT alone: 55 Gy / 20 fx (2.75 Gy/fx), or 2) EBRT + HDR brachy: EBRT 35.75 Gy / 13 fx (2.75/fx) then 8.5 Gy HDR x 2 over 2 days. Majority (76%) received neoadjuvant hormonal therapy (6 months for low/int risk; up to 3 yrs for high risk)
*** Low risk 4%, Int risk 42%, High risk 54%.
** PMID 17531335 — "High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial." Hoskin PJ et al. Radiother Oncol. 2007 Aug;84(2):114-20.
*** Median f/u 30 mo. Mean PSA relapse-free survival (using 1997 ASTRO definition): 5.1 yrs (combined) vs 4.3 yrs (EBRT alone)
** 2012: PMID 22341794 -- "Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer." (Hoskin PJ, Radiother Oncol. 2012 May;103(2):217-22.)
*** Median f/u 7 yrs. Improved RFS: Median time to relapse 74 mo (EBRT) vs 116 mo (EBRT+Brachy). 5-, 7-, and 10-yr RFS 61%, 48% and 39% (EBRT) vs 75%, 66% and 46% (EBRT+Brachy). On multivariate analysis, treatment arm, risk category, and ADT use were significate for risk of relapse. No significant difference in OS
*** Similar rate of severe late urinary and bowel morbidity
*** Conclusion: "EBRT+HDR-BTb resulted in a significant improvement in RFS compared to EBRT alone with a 31% reduction in the risk of recurrence (p=0.01) and similar incidence of severe late urinary and rectal morbidity."
** Comment: relatively low EBRT dose
* McMaster University (Ontario), 2005 (1992-97)
** PMID 15718316 — "Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate." Sathya JR et al. J Clin Oncol. 2005 Feb 20;23(6):1192-9.
** 138 pts. Clinical stage T2-T3,N0, surgically-staged node negative. Randomized to: 1) EBRT alone: 66 Gy four-field box to the prostate + SV + 2cm margin, or 2) EBRT + implant boost: Iridium seed placed at time of lymphadenectomy if frozen section negative. Used Syed's template to guide needle placement of 18 needles; TRUS was not done. Prescribed 35 Gy to entire prostate, 40 Gy to >80%. Two weeks after implant, 40 Gy of EBRT to prostate + SV + 2 cm.
** Median f/u 8.2 yrs. 61% biochemical failure (EBRT) vs 29% (EBRT+brachy)
** Comment: suboptimal EBRT dose

### EBRT Field Size

* Wheeling (WV) (1995-2005)
** Retrospective. 186 pts w/ high risk, treated with 45 Gy EBRT (Whole Pelvis or Mini-Pelvis) and brachytherapy (93% with Pd-103). >75% received hormonal therapy.
** 2010 PMID 19553031 -- "Whole-pelvis radiotherapy in combination with interstitial brachytherapy: does coverage of the pelvic lymph nodes improve treatment outcome in high-risk prostate cancer?" (Bittner N, Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1078-84.)
*** Median f/u 6.7 yrs. 10-yr bPFS 91.7% (WP) vs 84.4% (MP). Nonsignificant trend toward improved bPFS, CSS, and OS with WPRT. Improved OS for WPRT for pts who did not receive hormones.
*** Limited by retrospective nature. Pts treated with WP had higher risk features and were more likely to be treated with a longer course of hormonal therapy (69% receiving >6 months vs 38%).

## Optimal dose

* BED equation for low dose-rate implants:
** BED = (R$_0$/λ)*{1+(R$_0$/(μ+λ)*(α/β))}
** R$_0$ = initial dose rate of implant = D90 * λ
** λ = radioactive decay constant = ln2/T$_{1/2}$
** T$_{1/2}$ = isotope half-life
** μ = repair rate constant = 0.693/t$_{1/2}$
** t$_{1/2}$ = tissue repair half time
** Based on PMID 16242258: t$_{1/2}$ = 1h, T$_{1/2}$ = 60 days for I-125 or 17 days for Pd-103
* Stock and Stone, Mount Sinai, 1998 - PMID 9588923 — "A dose-response study for I-125 prostate implants." Stock RG, Stone NN et al. Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):101-8.
** Retrospective. 134 pts, T1-T2, G <= 6. I-125 seeds. No EBRT or hormonal therapy. CT scan for post implant dosimetry performed at one month on all pts. Used TG43 guidelines. Biochemical failure defined as two consecutive PSA rises or nadir > 1. Biopsies routinely performed at 2 yrs.
** Median f/u 32 months. Improved freedom from biochemical failure (FFBF) with increasing D90. 4-yr FFBF 68% (D90 < 140 Gy) vs 92% (>= 140 Gy). Negative prostate biopsies at 2 yr in 70% vs 83%.
** Conclusions: Dose was most significant predictor of biochemical failure. Dose response is more pronounced in pts with PSA > 10, with 51% vs 100% FFBF.

## Outcomes

Disease-specific survival:
* Mount Sinai, 2006 (1990-2004) - PMID 16309852 — "Disease-specific survival following the brachytherapy management of prostate cancer." Stock RG et al.
** Retrospective. 1561 pts. Treated with various techniques including brachy alone, brachy + hormones, or brachy + EBRT. Death from prostate cancer was counted if a pt died with the presence of metastatic disease. Pts who had rising PSA at the time of death or who were receiving systemic treatment at the time of death were not necessarily counted as prostate cancer related deaths.
** 10-yr DSS 96% and OS 74%. Gleason score significantly affected DSS, 98% (6 or less), 91% (7), 92% (8+). PSA after treatment had most significant effect on DSS: 100% for no PSA failure, 52% for doubling time < 10 m, and 98% for doubling time > 10 m.
** Comment: first brachytherapy series to report DSS>

## Implant Quality Assessment

HDR + EBRT Combination:
* Hospital A C Camargo (Brazil) (1997-2005)
** 2008 PMID 18566673 -- "The relationship between the biochemical control outcomes and the quality of planning of high-dose rate brachytherapy as a boost to external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO Phoenix definition. "(Pellizzon AC, Int J Med Sci. 2008 Jun 4;5(3):113-20.)
*** Retrospective. 209 patients, low/intermediate/high risk. HDR 16-24Gy/4 + EBRT 45 Gy. Median F/U 5.3 years
*** Outcome:Overall survival (OS) and disease specific survival rates at 3.3 years were 97.8% and 98.4%, respectively. On univariate analysis the prognostic factors related bC were GR (p= 0.040), GS ≤ 6 (p= 0.002), total dose of HDR-BT ≥ 20 Gy (p< 0.001), 3DHDR (p< 0.001), BED-HDR ≥ 99 Gy1.5 (p<0.001) and BED-TT ≥ 185 (p<0.001). On multivariate analysis the statistical significant predictive factors related to bC were RG (p< 0.001), HDR-BT ≥ 20 Gy (p=0.008) and 3DHDR (p<0.001).
** 2008 PMID 18601759 -- "Updated results of high-dose rate brachytherapy and external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO Phoenix definition." (Pellizzon AC, Int Braz J Urol. 2008 May-Jun;34(3):293-301.)
*** On multivariate analysis the only statistical significant predictive factor for biochemical control (bNED) was the risk group.
*** Conclusion: "Although the radiation dose administered to the prostate is an important factor related to bNED, this could not be established with statistical significance in this group of patients. "

## PSA kinetics

Brachytherapy alone:
* Princess Margaret, 2007 (1999-2003) PMID 17869662 — "PSA kinetics and PSA bounce following permanent seed prostate brachytherapy." (Crook J, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):426-33.)
** 292 pts treated with I-125 brachytherapy without EBRT or hormones. All have >30 months of PSA followup.
** Resolved PSA bounces (>=0.2) seen in 40%, median onset 15 months with median magnitude 0.76. Magnitude >2 (i.e. biochemical failure by Phoenix definition) seen in 15%. Younger age is predictive of bounce.
** Conclusions: The PSA bounce does not predict subsequent failure. Caution is advised in interpreting an early increasing PSA level in the first 30 months after 125I brachytherapy in favorable-risk patients.
With hormonal thearpy:
* Germany, 2007 PMID 17270634 — "Prostate-specific antigen kinetics after brachytherapy or external beam radiotherapy and neoadjuvant hormonal therapy." (Pinkawa M, Urology. 2007 Jan;69(1):129-33.)
** 75 pts treated with neoadj hormones (median 4 mo). RT was implant alone (29 pts), EBRT + implant boost (21), or EBRT only (25). Minimum 24 mo f/u.
** Trend: initial nadir - PSA 0.1 at 3 months after RT. Rising PSA levels noted in 83%. Subsequent PSA rises/bounces noted (one time-23%, two-21%, or more-17%) to median 0.6 at 16 months. New nadir of 0.1 reached by 35 mo.
** Conclusion: Temporarily rising PSA levels can be expected for most patients after primary RT and NHT following a first nadir.
Mixed (pts with and without hormones)
* Cleveland Clinic, 2007 PMID 16213667 — "PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time." (Ciezki JP, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):512-7.)
** 162 pts, brachytherapy +/- hormones (in 38%).
** PSA bounce (>=0.2) in 46%.
** Conclusions: "Patients experiencing a PSA bounce are more likely to be younger and will have a better bRFS. The PSADT cannot differentiate a PSA bounce from bF. The time to the initial PSA rise after nadir is an excellent discriminator of bF from PSA bounce. The time of the PSA rise after nadir occurs far sooner for a PSA bounce than for bF. This factor should be considered when assessing a patient with a rising PSA level after PI before a patient is administered salvage therapy."

### PSA bounce

* Cleveland Clinic (1996-2005)
** 1261 pts, predominantly low-int risk, T1-T2, treated with I-125 brachy alone. 3 yrs minimum follow-up. Androgen deprivation given in 22%.
** 2011 PMID 20646846 -- "PSA Bounce and Biochemical Failure After Brachytherapy for Prostate Cancer: A Study of 820 Patients With a Minimum of 3 Years of Follow-Up." (Caloglu M, Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):735-41.)
*** Median f/u 58 m. PSA bounce ≥0.2 above nadir in 30%. Median time to first PSA rise was 17.4 months vs 34.35 months for bF.
*** The use of PSA bounce definitions other than 0.2 did not provide additional prognostic benefit. Patients with PSA bounce had superior bRFS rates to those without PSA bounce. The time to first rise in PSA is an important discriminator between a PSA bounce and bF; a bounce usually occurs much earlier than a rise that corresponds to bF.
*** Conclusion: A bounce definition of a rise ≥0.2 ng/mL is a reliable definition among several other definitions. The time to first PSA rise is the most valuable factor for distinguishing between a bounce and biochemical failure.
* Institut Curie, 2006 (1999-2001) - PMID 16644467 — "PSA bounce after permanent implant prostate brachytherapy may mimic a biochemical failure: a study of 295 patients with a minimum 3-year followup." (Toledano A, Brachytherapy. 2006 Apr-Jun;5(2):122-6.)
** 295 pts. I-125.
** 55% showed a bounce of at least 0.1 ng/ml. Mean bounce 0.8 at mean time to bounce 19 months. 11% of pts had 3 consecutive rises (met ASTRO criteria for biochemical failure), among which 56% had complete normalization of PSA. D90 > 200 Gy predicted PSA bounce of > 0.4.

## HDR Boost

* RTOG 0321; 2010 PMID 20207506 -- "Phase II Trial of Combined High-Dose-Rate Brachytherapy and External Beam Radiotherapy for Adenocarcinoma of the Prostate: Preliminary Results of RTOG 0321." (Hsu IC, Int J Radiat Oncol Biol Phys. 2010 Mar 5. [Epub ahead of print])
** Phase II. 112/125 patients, T1c-T3b (T3 9%) prostate cancer. EBRT 45/25 + HDR 19/2. Median F/U 2.5 years
** Toxicity: Acute G3 GU/GI 3%, Late G3+ GU/GI 3%
** Conclusion: Acceptable level of adverse events
* Geneva; 2009 (2000-2004) PMID 19250768 -- "Hypofractionated boost with high-dose-rate brachytherapy and open magnetic resonance imaging-guided implants for locally aggressive prostate cancer: a sequential dose-escalation pilot study." (Ares C, Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):656-63. Epub 2009 Feb 26.)
** Phase I. 77 patients with locally aggressive PCA (perineural invasion, GS 8-10). Conventional 3D-CRT 64-64.4, followed by MRI-guided HDR boost Ir-192 given 12/2 -> 14/2 -> 16/2. ADT 81%
** Outcome: 3-year bDFS 87%, DSS 100%
** Toxicity: 3-year late GI Grade 2+ 6%, GU Grade 2+ 9%
** Conclusion: Boosting partial volume with HDR brachytherapy is feasible, preliminary control is encouraging
** Comment: See PMID 19910135 for SBRT boost from same group
* William Beaumont/Kiel
** 2006 PMID 16520907 -- "Hypofractionated conformal HDR brachytherapy in hormone naive men with localized prostate cancer. Is escalation to very high biologically equivalent dose beneficial in all prognostic risk groups?" (Galalae RM, Strahlenther Onkol. 2006 Mar;182(3):135-41.)
*** Retrospective. 378 patients at WBH, 201 patients at Kiel. Localized PCA, hormone-naive, high risk features (>=T2b or GS >=7 or PSA >=10). Mean F/U 5.3 years
*** bNED: 80%, dose >94Gy 85% vs. <94Gy 59% (SS)
*** By risk group: no difference if only 1 risk factor, benefit with 2 RFs (p=0.02) and 3 RFs (p<0.001)
*** Conclusion: Dose escalation >94 Gy results in improved long-term outcomes, especially if 2-3 risk factors
* William Beaumont
** 2002 PMID 12023135 -- "Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer." (Martinez AA, Int J Radiat Oncol Biol Phys. 2002 Jun 1;53(2):316-27.)
** Dose escalation. 207 patients (PSA>10, or GS>=7, or >=cT2b) treated with pelvic EBRT 46 Gy + HDR (5.5 - 11.5 Gy/fx x2-3). 58 patients low-dose (<93 Gy), 149 patients high-dose (>93 Gy). Mean F/U 4.4 years
** 5-year bNED: 74% (low-dose 52% vs. high-dose 87%)
** Toxicity: GI/GU Grade III 0.5%-9%
** Conclusion: Effective for unfavorable PCA. Incremental benefit for bNED and CSS

## Primary HDR

* William Beaumont/California Endocurietherapy; 2009 (1993-2004) PMID 19952715 -- "High-Dose-Rate Prostate Brachytherapy: An Excellent Accelerated-Hypofractionated Treatment for Favorable Prostate Cancer (Martinez AA, Am J Clin Oncol. 2009 Nov 30. [Epub ahead of print])
** Retrospective. 454 patients (HDR 55%, LDR-Pd 45%). WBH-HDR dose 38/4 BID, CET-HDR dose 42/6 in 2 implants one week apart, WBH-LDR 120 Gy. Median F/U 4.8 years
** Outcome: 5-year bPFS WBH-HDR 91% vs. CET-HDR 88% vs WBH-LDR 89%
** Toxicity: HDR better Grade 1-3 dysuria, urinary frequency/urgency, and rectal pain (SS). No difference in impotence rate
** Conclusion: Comparable control, better toxicity with HDR monotherapy
* Mount Vernon, UK; 2008 (2003-2006) PMID 18249501 -- "A Phase II study of high-dose-rate afterloading brachytherapy as monotherapy for the treatment of localized prostate cancer." (Corner C, Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):441-6. Epub 2008 Feb 4.)
** Phase II. 110 patients, locally advanced PCA. Dose escalation: 34/4 (n=30), 36/4 (n=25), 31.5/3 (n=55). Mean F/U (30, 18, 12 months)
** Outcome: No PSA failures
** Toxicity: No difference between groups; urethral cath rate 6%. Late G3 GU toxicity 2%; Late G3 GI toxicity 0%
** Conclusion: Excellent biochemical response with no difference in toxicity
* University of Bern
** Gold markers; 2009 (2003-2006) PMID 19899006 -- "Use of gold markers for setup in image-guided fractionated high-dose-rate brachytherapy as a monotherapy for prostate cancer." (Ghadjar P, Strahlenther Onkol. 2009 Nov;185(11):731-5. Epub 2009 Nov 10.)
*** Retrospective. 35 patients. HDR monotherapy 38/4. Review of gold markers for position verification. Median F/U 3 years
*** Outcome: Change of applicator position compared to plan: fraction #1 1.4 mm, fraction #2 13.1 mm, fraction #3 4.1 mm, and fraction #4 2.6 mm. Readjustment required in 51% patients
*** Toxicity: No difference between patients who required readjustment vs none
*** Conclusion: Shifts up to 36 mm were observed; gold markers ensure setup accuracy
** Initial; 2009 (2003-2005) PMID 19038584 --- "Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy." (Ghadjar P, Brachytherapy. 2009 Jan-Mar;8(1):45-51. Epub 2008 Nov 26.)
*** Retrospective. 36 patients (low risk 78%, intermediate risk 22%). HDR 38/4 BID. ADT 13%. Median F/U 3 years
*** Outcome: 3-year bPFS 100%
*** Toxicity: Acute G3 GU toxicity 3%; late G3 GU toxicity 11%. No G3 GI toxicity. Sexual preservation 75%. Late G3 GU toxicity associated with urethral and PTV doses
*** Conclusion: Decrease of irradiated urethral volume may reduce GU toxicity and improve therapeutic ratio
* William Beaumont
** 2004 (1999-2001) PMID 14767279 -- "High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds." (Grills IS, J Urol. 2004 Mar;171(3):1098-104.)
*** Retrospective. 149 patients with early stage low-risk PCA, treated with HDR (44%) or LDR (56%) Pd-103 implant. HDR 38/4 BID; LDR 120 Gy. Neoadjuvant ADT in 36% for gland volume optimization. Median F/U 2.9 years
*** Outcome: bPFS (ASTRO) HDR 98% vs LDR 97%
*** Toxicity: Acute dysuria HDR 36% vs LDR 67% (SS), acute urinary frequency/urgency 54% vs 92% (SS), acute rectal pain 6% vs 20% (SS). Late urinary frequency/urgency 23% vs 56% (SS), urethral stricture (NS). 3-year impotence HDR 16% vs LDR 45%
*** Conclusion: HDR and LDR have comparable control, but HDR better toxicity profile
** 2001 (1999-2000) PMID 11163498 -- "Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report." (Martinez AA, Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):61-9.)
*** Phase II. 41 patients, favorable risk PCA, prostate 15-60cc (mean 31 cc). HDR monotherapy 38/4 BID (estimated equivalent to 76.4 Gy)
*** Outcome: Dosimetric outcomes reported
*** Conclusion: HDR protocol feasible
* Osaka University
** Initial; 2000 (1995-1998) PMID 11020563 -- "High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial." (Yoshioka Y, Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):675-81.)
*** Prospective. 22 patients with localized PCA (T1-T4). HDR 48/8 BID or 54/9 BID. ADT in 86%. Median F/U 2.6 years
*** Outcome: 4-year bPFS 55%, 4-year cPFS 95%.
*** Toxicity: No acute G3+ toxicity
*** Conclusion: Acute toxicity acceptable; continued patient accrual
** Toxicity; 2003 (1995-2001) PMID 12694841 -- "High-dose-rate brachytherapy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity." (Yoshioka Y, Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):213-20.)
*** Retrospective. 43 patients, localized PCA (T1-T4). Median PSA 19.3. HDR 54/9 BID (except first 7 cases 48/8 BID). ADT in 88%. Median F/U 2 years
*** Outcome: 3-year bPFS 55%, local control 100%, OS 94%. Low risk 100% (5/5), intermediate risk 80% (8/10), high risk 61% (17/28)
*** Toxicity: Acute G4 in 2%, no Grade 3. No Late G3-4 toxicity; late G1-2 toxicity in 12% (rectal bleeding and rectal ulcer)
*** Conclusion: HDR as monotherapy feasible and well tolerated
** Technique; 2006 PMID 17041799 -- "New ambulatory implant technique of high-dose-rate interstitial brachytherapy for prostate cancer." (Yoshida K, Radiat Med. 2006 Oct;24(8):595-9.)
*** Technique. New removable template described, to allow ambulatory implant
** ADT; 2006 (1995-2002) PMID 16715663 -- "High-dose-rate brachytherapy combined with long-term hormonal therapy for high-risk prostate cancer: results of a retrospective analysis." (Oh RJ, Radiat Med. 2006 Jan;24(1):58-64.)
*** Retrospective. 35 patients, high risk PCA (>=T2b or Grade 3 or PSA >= 20). HDR 54/9. Median neoadjuvant ADT 7 months, median adjuvant ADT 3.3 years. Median F/U 4.7 years
*** Outcome: 5-year bPFS 62%, local control 96%, DFS 76%, CSS 89%, OS 87%
*** Conclusion: HDR plus long-term ADT is at least as effective as EBRT plus ADT
** Outcomes; 2006 (1995-2004) PMID 16870289 -- "High-dose-rate brachytherapy without external beam irradiation for locally advanced prostate cancer." (Yoshioka Y, Radiother Oncol. 2006 Jul;80(1):62-8. Epub 2006 Jul 25.)
*** Retrospective. 111 patients, localized PCA (low risk 13%, intermediate 25%, high risk 61%). HDR dose 48/8 BID or 54/9 BID. Median F/U 2.2 years
*** Outcome: 3-year bPFS 83%; 5-year bPFS 70%. Local control 100% and 97%.
*** Toxicity: Late G3 toxicity 1%
*** Conclusion: Feasible and acceptable toxicity
** Late toxicity; 2009 (2001-2005) PMID 19345517 -- "Correlation between dosimetric parameters and late rectal and urinary toxicities in patients treated with high-dose-rate brachytherapy used as monotherapy for prostate cancer." (Konishi K, Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1003-7. Epub 2009 Apr 3.)
*** Retrospective. 83 patients, T1-T4 (low risk 17%, intermediate risk 23%, high risk 59%). HDR 54/9 BID. Median F/U 3 years
*** Toxicity: Grade 3 toxicity 1/83 patients (urethrorectal fistula). Grade 2 GI toxicity 5%, Grade 2 GU toxicity 6%
*** Predictors for rectal bleeding: Rectal V40 <8cc, D5cc <27 Gy
*** Conclusion: Dosimetric parameters predicting for rectal bleeding identified
* Offenbach, Germany; 2004 (2002-2003) PMID 15057433 -- "3-D conformal HDR brachytherapy as monotherapy for localized prostate cancer. A pilot study." (Martin T, Strahlenther Onkol. 2004 Apr;180(4):225-32.)
** Retrospective. 52 patients, low/intermediate risk. HDR 38/4. Median F/U 8 months
** Outcome: Acute G3 GU toxicity 4%; no G2+ GI toxicity
** Conclusion: HDR as monotherapy is feasible, with minimal acute toxicity
Dose Comparisons
* Ohio State; 2000 PMID 10661360 -- "A simple method of obtaining equivalent doses for use in HDR brachytherapy." (Nag S, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):507-13.)
** Microsoft Excel based program that applies the LQ formula to calculate BED for various fractionation schemes, and reconverts it to "standard" (2 Gy/fx) fractionation
** Comment (PMID 11183737): impact of a/b on prostate hypofractionated regimens. Consider 5 x 6.7 Gy equivalent to 78 Gy as a good dose vs. 5 x 8.0 Gy proposed equivalent to 60 Gy proposed by Nag