Radiation Oncology/Prostate/Brachytherapy

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Prostate: Main Page | Prostate Overview | Screening and Prevention | Workup | Natural History | External Beam RT | IMRT | Androgen Suppression Therapy | Brachytherapy | Protons | Prostatectomy | Adjuvant RT after Prostatectomy | Salvage RT | Chemotherapy | Localized prostate cancer | Node Positive | Advanced disease | Recurrence after RT | Cryotherapy | RTOG Prostate Trials | Randomized Evidence


Prostate Brachytherapy


Contents

[edit] Guidelines

[edit] 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

[edit] 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 accomodate 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 standed seeds

[edit] 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.

[edit] 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.

[edit] Comparison to Radical Prostatectomy

  • ACOSOG Z0070 - Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT)
    • 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.

[edit] 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.

[edit] 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

[edit] EBRT + Implant Boost vs. EBRT alone

  • UK (Mount Vernon), 2007 (1997-2005)
    • 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.
    • 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.
    • Median f/u 30 mo. Mean PSA relapse-free survival (using 1997 ASTRO definition): 5.1 yrs (combined) vs 4.3 yrs (EBRT alone)
    • 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

[edit] Optimal dose

  • 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.

[edit] 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>

[edit] 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."


[edit] PSA bounce

  • 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.

[edit] HDR Boost

  • 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


[edit] Hypofractionated HDR

  • 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
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