Radiation Oncology/Prostate/Randomized

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Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

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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 Cancer: Randomized Evidence


In progress of being cross-linked from the chapter...


Contents

[edit] Watchful Waiting vs. Prostatectomy

  • Scandinavian SPCG-4 (1989-99) - prostatectomy vs watchful waiting
    • Randomized. 695 men, early prostate cancer (T1-T2), biopsy proven. No adjuvant treatment. If symptomatic local progression, treated with orchidectomy or GnRH analog. Clinical follow-up with PSA, exam. Cause of death scored as due to prostate cancer (if progressive distant mets) or due to other causes. 75% had T2 tumors.
    • 8-years; 2005 PMID 15888698 — "Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer" Bill-Axelson A et al. N Engl J Med. 2005 May 12;Volume 352(19):1977-1984.
      • Median 8.2 yrs f/u. Death due to prostate cancer: 14.4% (WW) vs 8.6%, difference of 5.3% at 10 years. Difference in overall survival after 10 years: 5% difference (RR=0.74).
      • Conclusion: Treatment of prostate cancer results in fewer cancer related deaths and fewer overall deaths. May not apply to modern era with PSA screening due to lag time and stage migration.
  • VACURG (1967-1975) -- prostatectomy vs. watchful waiting
    • Randomized. 111/142 patients, prostate cancer Tis-T2, no palpable tumor, no pelvic staging prior to randomization. Arm 1) Radical prostatectomy vs. Arm 2) Placebo
    • 1988 PMID 3187435 -- "Treatment of localized prostatic cancer. Radical prostatectomy versus placebo. A 15-year follow-up." (Madsen PO, Scand J Urol Nephrol Suppl. 1988;110:95-100.)
      • Outcome:
        • Stage I: 5-year OS RP 87% vs. placebo 67%, 10-years 48% vs. 43%, 15-years 23% vs. 13%
        • Stage II: 5-year RP 92% vs. placebo 90% , 10-years 37% vs 55%, 15-years 17% vs. 20%
      • Conclusion: No significant difference in cummulative survival, either by Stage or overall

[edit] Surgery vs Radiation Therapy

  • Japanese Study Group for Locally Advanced Prostate Cancer (1989-1993) -- RP vs EBRT
    • Randomized. 95 patients. T2b-T3N0M0. Arm 1) radical prostatectomy + pelvic LN dissection + endocrine therapy vs. Arm 2) Pelvic RT 40-50 Gy + 20 Gy prostate boost + endocrine therapy. Hormones initiated 8 wks prior to primary therapy (using DES) then continued indefinitely (LHRH agonist +/- antiandrogen, or estrogen).
    • 2006 PMID 17082219 — "A randomized trial comparing radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy for locally advanced prostate cancer: results at median follow-up of 102 months." (Akakura K et al. Jpn J Clin Oncol. 2006 Dec;36(12):789-93.) Median F/U 8.5 years
      • Outcome: 10-year bPFS RP 76% vs. RT 71% (NS); cPFS 83% vs. 66% (p=0.06); DSS 86% vs. 77% (SS); OS 68% vs. 61% (NS)
      • Toxicity: Incontinence worse in surgical arm; erectile dysfunction in almost all patients due to ADT
      • Conclusion: For locally advanced patients, either RP or EBRT demonstrated favorable outcomes. DSS better with surgery. RT dose 60-70 Gy may not be enough
  • Uro-Oncology Research Group -- radical surgery vs. radiation
    • Randomized. 97 patients. cT1-2N0M0. Arm 1) radical prostatectomy vs. Arm 2) megavoltage RT (using Co-60 or betatron) to pelvic field 45-50 Gy + prostate 20 Gy boost. Primary outcome development of metastatic disease by prostatic acid phosphatase, bone scan, and/or pelvic lymphadenectomy
    • 1982 PMID 6811766 -- "Radical surgery versus radiotherapy for adenocarcinoma of the prostate." (Paulson DF, J Urol. 1982 Sep;128(3):502-4.)
      • Outcome: Actuarial development of mets RP 8% vs. RT 31% (SS)
      • Conclusion: Radical surgery more effective than RT

[edit] EBRT Technique

[edit] Para-aortic Field

  • RTOG 75-06 (1976-1983)
    • Randomized. 523 patients with clinical Stage A2-B N+ or Stage C. Arm 1) Pelvic RT 40-45 Gy + prostate boost 20-25 Gy (minimum 65 Gy) vs. Arm 2) Pelvic + PA RT 40-45 Gy + prostate boost (minimum 65 Gy)
    • 1986 PMID 3514555 -- "Extended field (periaortic) irradiation in carcinoma of the prostate--analysis of RTOG 75-06." (Pilepich MV, Int J Radiat Oncol Biol Phys. 1986 Mar;12(3):345-51.). Median F/U 4.2 years
      • Outcome: No difference between arms for DFS, DM, OS
      • Toxicity: Periaortic RT does not increase bowel injury. Prostate doses >70Gy result in increased bowel injury (20% vs 10% rectal bleed) but not bladder injury
      • Conclusion: No benefit to elective peri-aortic irradiation


[edit] Pelvic Field

  • GETUG-01 (French)(1998-2004) -- whole pelvis vs prostate only
    • Randomized. 444 patients, T1b-T3 N0 pNx. Randomized to Arm 1) prostate + pelvis vs. Arm 2) prostate only. RT dose pelvis 46 Gy and prostate 66-70 Gy. Stratified into low (T1-2 and GS <=6 and PSA <=12), intermediate, and high risk (T3 or GS >=7 or PSA >=12 ng/ml; 79%) groups. Short term hormonal therapy (6 mos) allowed only for high risk group.
    • 5-years; 2007 PMID 18048817 — "Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Preliminary Results of GETUG-01." Pommier P et al. J Clin Oncol. 2007 Dec 1;25(34):5366-5373. Median F/U 3.5 years
      • 5-year outcome: PFS 66% vs. 65% (NS); high risk PFS 63% vs. 60% (NS); low risk PFS 75% vs. 84% (NS)
      • Toxicity: Pelvic arm small but nonsignificant late GI toxicity
      • Conclusion: no benefit to pelvic radiotherapy
  • RTOG 94-13 (1995-99) -- whole pelvis vs prostate only, also 2x2 ADT
    • Randomized. 1323 patients. High risk patients with estimated risk of LN involvement of 15% or more by the Roach equation and PSA < 100. Pts with T2c-T4 tumors and Gleason >=6 were allowed regardless of LN risk. 2x2 randomization. Randomized to whole-pelvic (WP) vs prostate-only (PO) RT, and combined neoadjuvant + concurrent hormonal therapy (NCHT) vs adjuvant hormonal therapy (AHT).
    • RT: Dose 70.2 Gy to prostate. For WP RT, 50.4 Gy to pelvis (16x16 field), followed by boost to prostate only. PO RT was to prostate + SV only. Hormones: For NCHT, total of 4 months - 2 months before and 2 months during RT. For AHT, began following RT for total of 4 months.
    • 7-years; 2007 PMID 17531401 -- "An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions." (Lawton CA, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55.) Median F/U for alive patients 7.0 years
      • Outcome: PFS WPRT+NHT 62% vs. PORT+NHT 66% vs. WPRT+AHT 69% vs. PORT+AHT 62% (NS); also no difference in OS. By pairs (as designed), no difference between WPRT and PORT, and no difference between NHT and AHT. No difference in LF or DM
      • Toxicity: No difference in RT Grade 3+ toxicity among the 4 arms
      • Conclusion: No benefit for NHT + WPRT compared with PORT + AHT
  • RTOG 77-06 (1978-1983) - Whole pelvis vs prostate only
    • Randomized. 445 patients. Prostate cancer, Stage A2 (disease on TRUP, poorly differentiated) and Stage B (N0 by lymphangiogram or biopsy). Arm 1) Prostate only 65 Gy vs. Arm 2) Pelvis 45 Gy + prostate boost 20 Gy.
    • 1988 PMID 3058656 -- "Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06." (Asbell SO, Int J Radiat Oncol Biol Phys. 1988 Dec;15(6):1307-16.) Median F/U 7 years
      • Outcome: No difference in terms of LC, DM, DFS, OS.
      • Conclusion: No significant benefit for elective pelvic irradiation
      • Critique: included pts at low risk for LN involvement

[edit] Dose Escalation

  • MRC RT01 (1998-2002) -- 3D-CRT 64 Gy vs. 74 Gy
    • Randomized. 843 men, T1b-T3a (T3 in <20%), PSA <50 ng/mL. . Neoadjuvant AST 3-6 months, then RT Arm 1) 64/32 Gy vs. 74/37 Gy. GTV = prostate +/- SV (depending on risk). CTV = GTV + 0.5 cm. PTV = CTV + 0.5-1.0 cm
    • 5-years; 2007 PMID 17482880 -- "Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial." (Dearnaley DP, Lancet Oncol. 2007 Jun;8(6):475-87.) Median F/U 5.2 years
      • Outcome: PFS high dose 71% vs. standard dose 60% (SS); clinical PFS 90% vs. 87% (NS)
      • By risk group: low-risk 85% vs. 79%, intermediate-risk 79% vs. 70%, high-risk 57% vs. 43%; benefit across all groups
      • Toxicity: GI Grade 2+ high dose 33% vs. standard dose 24% (SS); GU Grade 2+ 11% vs. 8% (NS); sexual dysfunction prevalent
      • Conclusion: Escalated dose with neoadjuvant AST seems clinically worthwhile, but increased incidence of long-term adverse events
  • Dutch CKVO96-10 (1997-2003) -- 3D-CRT 68 Gy vs. 78 Gy
    • Randomized. 664 patients, T1b-T4, with PSA < 60 (excluded low risk: T1a, T1b-c with GS<5 and PSA <=4; excluded pN+). Arm 1) 68 Gy vs. Arm 2) 78 Gy. CTV = prostate +/- SV (depending on risk group); PTV = 1.0 cm margin to 68 Gy, then 0.5 mm and 0 mm posteriorly. Prescription dose was to the isocenter. Stratified by risk group. Hormonal therapy in 22%
    • Toxicity, 2005 PMID 15752881 — "Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy." (Peeters ST, Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1019-34.)
      • No acute toxicity differences (p=NS)
      • No late GI and GU toxicity difference (p=NS), except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05)
      • Conclusion: Acute and late toxicity higher, but not NS except late rectal bleeding and late nocturia
    • 5-years, 2006 PMID 16648499 — "Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy." (Peeters ST, J Clin Oncol. 2006 May 1;24(13):1990-6.). Median F/U 4.2 years
      • Outcome: 5-year FFS high-dose 64% vs low-dose 54% (SS). Clinical failure both groups 76% (NS), OS 82% vs. 83% (NS)
      • Toxicity: GI Grade 2+ high-dose 32% vs. low-dose 27% (NS), GI Grade 3+ 5% vs. 4% (NS). GU Grade 2+ 39% vs. 41% (NS), GU Grade 3+ 13% vs. 12% (NS).
      • Conclusion: Significantly improved FFS, with comparable toxicity
  • PROG 95-09 (1996-1999) -- Proton/photon 70.2 Gy vs. 79.2 Gy
    • Randomized. 2 institutions (Harvard and Loma Linda). 392 patients, stage T1b-T2b, PSA <15 ng/mL (median PSA 6.3); 75% GS <7. Arm 1) proton boost 19.8/11 GyE followed by photons 50.4/28 vs. Arm 2) proton boost 28.8/16 followed by photons 50.4/28. Proton CTV = prostate + 5 mm margin. PTV = CTV + 7-10 mm. Loma Linda used opposed lateral beams, 250 MeV protons; Harvard used perineal boost, 160 MeV protons. Rectal Lucite probe, inflated with 25-50 mL saline. Photons were 4F plan, photon CTV = prostate/SV + 10 mm margin. No hormones
    • 5-years; 2005 PMID 16160131 -- "Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial." (Zietman AL, JAMA. 2005 Sep 14;294(10):1233-9.) Median F/U 5.5 years
      • Outcome: 5-year bNED 70.2 Gy 61% vs. 79.2 Gy 80% (SS), 50% reduction in risk of failure. LC 48% vs. 67% (SS) No difference in OS 97% vs 96% (NS)
      • Risk stratification: low risk (PSA <10, stage <=T2a, GS <7) 60% vs. 80% (SS); high risk 63% vs. 79% (SS). Contemporary intermediate risk 63% vs. 81% (SS), but contemporary high risk (NS, but small number)
      • Late toxicity: Grade 3+ 70.2 Gy 1% vs. 79.2 2%; GU Grade 2 18% vs. 20% (NS), GI Grade 2 8% vs. 17% (SS). Most GI toxicity by 3 years; GU toxicity continuous
      • Conclusion: Men with intermediate-risk clinically localized PCA have better bNED with high dose, without worse severe toxicity and with only small increase in G2 GI toxicity
  • MD Anderson (1993-1998) -- 4F 70 Gy vs. 3D-CRT 78 Gy
    • Randomized. 301 T1-T3 patients, stratified by PSA <10 (65%), 10-20 (35%), >20 (few). Arm 1) 70 Gy vs. Arm 2) 78 Gy. Technique 4F 46/23, Arm 1) 4F RF 24/12, Arm 2) 3D-CRT 6 fields 32/16. CTV = prostate/SV, margin 1.5 cm anterior/inferior, 1.0 cm posterior/superior. No hormones
    • 8-years; 2008 PMID 17765406 -- "Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer." (Kuban DA, Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):67-74. Epub 2007 Aug 31.) Median F/U 8.7 years
      • 8-year outcome: FFF 78 Gy 78% vs. 70 Gy 59% (SS); if PSA >10 78% vs. 39% (SS), clinical failure 7% vs. 15% (SS); if PSA <10 78% vs. 66% (NS)
      • By risk group: low risk 88% vs. 63% (SS); intermediate risk 86% vs. 76% (NS); high risk 63% vs. 26% (SS). OS 78% vs. 79% (NS)
      • 10-year toxicity: GI Grade 3 7% vs. 1% (SS); GI Grade 2+ 26% vs. 13% (SS); GU Grade 3 5% vs. 4% (NS), GU Grade 2+ 13% vs. 8% (NS)
      • Conclusion: Dose escalation improved PSA and clinical control, particularly if PSA >10 ng/ml
  • Ontario EBRT/HDR (1992-1997) -- EBRT 66/30 vs. EBRT HDR 75 (HDR 35 + EBRT 40/20)
    • Randomized. 104 patients, locally advanced T2-T3. All underwent staging pelvic lymphadenectomy. Arm 1) EBRT 66/33 vs. Arm 2) HDR 35 Gy (delivered via 18 needles over 48 hours) + EBRT 40/20 for total 75 Gy (>80% of prostate received 80 Gy)
    • 5-years; 2005 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, J Clin Oncol. 2005 Feb 20;23(6):1192-9.). Median F/U 8.2 years
      • Outcome: 5-year FFP high dose 71% vs. standard dose 39% (SS); positive biopsy 24% vs. 51% (SS). OS 94% vs. 92% (NS)
      • Conclusion: Higher doses of radiation over shorter duration results in better control
  • Harvard (1982-1992) -- Photon boost 67.2 Gy vs. proton boost 75.6 Gy
    • Randomized. Stage T3-T4N0-2. Standard photons 50.4 Gy four-field, then Arm 1) Conformal protons 25.2 CGE (total 75.6 CGE) vs. Arm 2) Photons 16.8 Gy (total 67.2 Gy). Median F/U 5.1 years
    • 5-years; 1995 PMID 7721636 -- "Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone." (Shipley WU, Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):3-12.)
      • Outcome: 5-year LC photon+proton 92% vs. photons 80% (NS), no difference in OS, DSS, TRFS. GS 4/5 patients 94% vs. 64% (SS)
      • Toxicity: Rectal bleeding photon+proton 32% vs. photons 12% (SS), urethral stricture 19% vs. 8% (p=0.07)
      • Conclusion: Boosting dose with protons increased LC in poorly differentiated tumors, and also worsened late toxicity

[edit] Altered Fractionation

  • Fox Chase -- 76/38 (2 Gy/fx) vs. 70.2/26 (2.7 Gy/fx)
    • Randomized. First 100 men reported. Intermediate-high risk. Neoadjuvant ADH x4 months permitted. Arm 1) conventional 76/38 (@ 2 Gy/fx) vs. Arm 2) hypofractionated 70.2/26 @ 2.7 Gy/fx)
    • 2006 PMID 16242256 -- "Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial." (Pollack A, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):518-26. Epub 2005 Oct 19.)
      • Toxicity: Slight increase in acute GI toxicity, no difference in GU toxicity
      • Conclusion: Hypofractionation well tolerated acutely
  • Adelaide (Australia)(1996-2003) -- 64/32 (2 Gy/fx) vs. 55/20 (2.75 Gy/fx)
    • Randomized. 217 patients, T1-2N0 PCA. No ADT. Arm 1) conventional 64/32 vs. Arm 2) hypofractionated 55/20.
    • 4-years; 2006 PMID 16965866 -- "Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: updated results of a phase III randomized trial. (Yeoh EE, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1072-83. Epub 2006 Sep 11.) Median F/U 4 years
      • Outcome: 5-year biochemical/clinical PFS conventional 55% vs. hypofractionated 57% (NS), OS 84% vs 86% (NS)
      • Toxicity: GI urgency worse with hypofractionation, otherwise (NS). GU significantly worse with hypofractionation
      • Conclusion: Hypofractionated schedule equivalent in efficacy, toxicity somewhat worse
  • NCI Canada (1995-1998) -- 66/33 (2 Gy/fx) vs. 52.5/20 (2.62 Gy/fx)
    • Randomized. 936 men, T1-T2, PSA <40, no AST. Technique 3D-CRT
    • 5-years; 2005 PMID 16135479 -- "Randomized trial comparing two fractionation schedules for patients with localized prostate cancer." (Lukka H, J Clin Oncol. 2005 Sep 1;23(25):6132-8.). Median F/U 5.7 years
      • Outcome: 5-year FFP standard 47% vs. hypofractionated 40% (NS); no difference in post-RT biopsy rate or OS
      • Toxicity: Grade 3 late toxicity 3.2% both arms (NS)
      • Conclusion: Current hypofractionated regimen may be inferior to standard fractionation

[edit] Prostate Localization

  • Princess Margaret; 2008 PMID 18279985 -- "A randomized comparison of interfraction and intrafraction prostate motion with and without abdominal compression." (Rosewall T, Radiother Oncol. 2008 Feb 13 [Epub ahead of print])
    • Randomized. 32 patients. Arm 1) VacLok immobilization vs. Arm 2) BodyFix adbominal compression. Interfraction motion >3 mm corrected pre-treatment.
    • Outcome: No difference in interfraction or intrafraction motion with or without adominal compression
    • Conclusion: Addition of abdominal compression didn't influence interfraction or intrafraction prostate motion

[edit] Endorectal balloon

  • Nijmegen, The Netherlands -- 3D-CRT +/- endorectal balloon
    • Randomized. 48 patients, treated with 3D-CRT to 67.5 Gy. Arm 1) No endorectal balloon (ERB-) vs. Arm 2) with endorectal balloon (ERB+). Rectosigmoidoscopy at 3 months, 6 months, 1 year, 2 years. 146 endoscopies and 2,336 mucosal areas analyzed
    • 2007 PMID 17161552 -- "Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy." (van Lin EN, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):799-811. Epub 2006 Dec 8.) Median F/U 2.5 years
      • Outcome: ERB group significantly lower rectal wall volume exposed to high doses. Late rectal toxicity G1: ERB- 58% vs. ERB+ 21%; G2 4% vs. 0%; G3 4% vs. 0%. Overall G1+ rectal toxicity 67% vs. 21% (SS)
      • Endoscopy: Telangiectasia ERB- vs ERB+ @ 6 months 16% vs. 24%; 1 year 45% vs. 28%; 2 years 39% vs. 24% (SS). High grade telangiectasia @ 1 years 20% vs. 10%; 2 years 19% vs. 9% (SS). Significantly less high grade telangiectasia at lateral and posterior part of Rwall
      • Conclusion: ERB reduced rectal wall volume exposed to >40 Gy, resulting in reduction of late mucosal changes and reduced late rectal toxicity

[edit] 2D RT vs 3D-CRT

  • Rotterdam, Netherlands (1994-1996) -- conformal RT vs conventional RT
    • Randomized. 266 patients, prostate cancer Stage T1-4N0. RT 66/33. Arm 1) conventional RT (rectangular, open fields) vs. Arm 2) conformal RT (conformally shaped fields with MLC). PTV = GTV + 1.5 cm
    • 1999 PMID 10098427 -- "Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study." (Koper PC, Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):727-34.)
      • Outcome: Acute GI Grade 2 conventional 32% vs. conformal 19% (SS); Acute GU Grade 2 in 17% vs. 18% (NS). Further GI analysis: rectal symptoms 18% vs. 14% (NS) but anal symptoms 16% vs. 8% (SS)
      • Conclusion: Significant reduction in GI toxicity, driven by anal symptoms. No difference between rectum/sigmoid and bladder toxicity
  • Royal Marsden (1988-1995) -- conformal RT vs conventional RT
    • Randomized. 225 men with prostate CA, T1-T4N0. NACHT in 68%. RT 64/31. Arm 1) conformal RT vs. Arm 2) conventional RT
    • 1999 PMID 9929018 -- "Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial." (Dearnaley DP, Lancet. 1999 Jan 23;353(9149):267-72.) Median F/U 3.6 years
      • Outcome: Radiation-induced proctitis G1+ conformal RT 37% vs. conventional RT 56% (SS), G2+ 5% vs. 15% (SS). No difference in bladder toxicity. No difference in bPFS (78% vs 83%, NS)
      • Conclusion: Conformal RT significantly reduced risk of later proctitis

[edit] Brachytherapy

[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
    • 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] Hialuronic acid injection

  • Oviedo, Spain -- transperineal perirectal HA injection vs. nothing
    • 2009 (2005-2006) PMID 19213607 -- "Transperineal injection of hyaluronic acid in the anterior perirectal fat to decrease rectal toxicity from radiation delivered with low-dose-rate brachytherapy for prostate cancer patients." (Prada PJ, Brachytherapy. 2009 Apr-Jun;8(2):210-7. Epub 2009 Feb 12.)
      • Randomized. 69 patients with low/intermediate PCA, treated with I-125 brachytherapy to 145 Gy. Median prostate volume 35 cc. Arm 1) control vs Arm 2) transperineal perirectal fat injection. Endoscopic follow up. Median F/U 1.5 years
      • Outcome: Endoscopic mucosal damage control 36% vs. HA injection 5% (SS), rectal bleeding 12% vs 0% (SS)
      • Conclusion: Increased distance resulted in smaller rectal dose, less mucosal damage, and no rectal bleeding

[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

[edit] Androgen Deprivation Therapy

[edit] Primary ADT

  • EORTC 30891 (1990-1999) -- Immediate ADT vs. Deferred ADT
    • Randomized. 985 with clinical T0-4 N0-2 M0, refused or were not suitable for local definitive treatment. Excluded if <80 years, pain from prostate, ureteric obstruction. Arm 1) Immediate androgen deprivation vs. Arm 2) Deferred androgen deprivation at symptomatic progression.
    • 2006 PMID 16622261 -- "Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891." (Studer UE, J Clin Oncol. 2006 Apr 20;24(12):1868-76.) Median F/U 7.8 years
      • Outcome: Median OS immediate ADT 7.4 years vs deferred ADT 6.5 years (HR 1.25, SS). Most deaths due to prostate cancer (36%) or cardiovascular disease (34%). No difference in prostate cancer-specific deaths. Median time-to-start deferred ADT 7 years; 44% of patients who died never needed ADT
      • Conclusion: Immediate ADT provides modest but statistically significant increase in overall survival, but no difference prostate cancer survival

[edit] Primary ADT +/- RT

  • SPCG-7/SFUO-3 (1996-2002) -- ADT +/- RT
    • Randomized. 875 with locally advanced prostate cancer T1b G2-G3 or T3 (78%) and PSA <70 and N0 (if PSA >11, then PLND). Arm 1) ADT (total androgen blockade x3 months, then continuous flutamide 250 mg) vs. Arm 2) Same ADT + RT 70 Gy to prostate/SV. Breast RT in 80% to prevent gynecomastia
    • 7-years; 2008 PMID 19091394 -- "Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial." (Widmark A, Lancet. 2008 Dec 15. [Epub ahead of print]). Median F/U 7.6 years
      • Outcome: 10-year CSS ADT 76% vs. ADT + RT 88% (SS); 10-year OS 61% vs. 70% (SS); 10-year bPFS 25% vs. 74% (SS)
      • Toxicity: Urethral stricture ADT 0% vs. ADT + RT 2% (SS), urgency 8% vs 14% (SS), urinary incontinence 3% vs. 7% (SS), erectile dysfunction 81% vs. 89% (SS)
      • Conclusion: In patients with high risk or locally advance PCA, addition of RT to ADT improved survival, with acceptable side effects

[edit] RT +/- Long-Term ADT

  • Casodex Early Prostate Cancer Program (EPC) (1995-1998) -- Casodex vs. placebo
    • Randomized, double blind, placebo. 8113 patients. Comprised of 3 separate trials: North America (Trial 23), Europe (Trial 24), and Scandinavia (SPCG-6, Trial 25). Pts with non-metastatic disease on bone scan, stages T1-4. Primary treatment with RT, surgery, or watchful waiting. Randomized to +/- adjuvant bicalutamide (Casodex) 150 mg. For 2 yrs (North America) or until progression (other 2 trials). Localized defined as clinical or pathological T1-T2N0-Nx, locally advanced defined as T3-T4 any N or any TN+. Surgical procedures, RT techniques, and dose-fractionation schedules not specified. Neoadjuvant hormonal therapy permitted in Trials 23-24
    • RT 7-years; 2006 PMID 16896884 -- "The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer." (See WA, J Cancer Res Clin Oncol. 2006 Aug;132 Suppl 1:S7-16.) Median F/U 7.2 years
      • RT subset (n=1370); locally advanced 22%, localized 78%. EBRT 93%, EBRT + BT 6%. Median EBRT dose 64 Gy
      • Outcome: Overall events bPFS 57% vs. 47% (SS), cPFS 67% vs. 61% (SS), OS 74% vs. 69% (NS)
        • Locally advanced: bicalutamide improved bPFS by 59% (SS), cPFS by 44% (SS), DSS by 24% (SS), and OS by 35% (SS).
        • Localized: no difference in cPFS or OS, benefit for bPFS 59% vs 53% (SS)
      • Conclusion: In patients with locally advanced disease, survival benefit for adjuvant Casodex, but no benefit in localized prostate cancer
  • EORTC 22863 (1987-1995) -- RT +/- concurrent/adjuvant ADT
    • Randomized. 415 patients with T1-2 WHO grade 3 or T3-4 any grade, N0-1. RT alone vs RT + concurrent/adjuvant goserelin. Goserelin monthly starting on first day of RT, total of 3 years. RT pelvis 50/25 + boost 20/10
    • 5-years; 2002 PMID 12126818 — "Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial." Bolla M et al. Lancet. 2002 Jul 13;360(9327):103-6. Median F/U 5.5 years
      • Outcome: 5-yr OS RT+ADT 78% vs RT alone 62% (SS), disease-specific survival 94% vs 79%, DFS 74% vs 40% (SS).
      • Conclusion: AST during and 3 years after EBRT improves DFS and OS
  • RTOG 85-31 "High Risk Non-Bulky Trial" (1987-92) - long term (indefinite) hormones
    • Randomized. 977 patients. Scheme: XRT alone vs XRT + long-term adjuvant goserelin (Zoladex). Eligibility: cT3 or pT3 (after prostatectomy) or N+ regional nodes (including common iliac or paraaortics). Bulky patients (primary tumor volume > 25 cm by product of two dimensions) not allowed unless they had +LN outside of the pelvis (i.e. common iliac or paraaortic). (Bulky pts were enrolled on parallel study 86-10.) Hormones: Goserelin started during last week of XRT and continued monthly until progression. Radiation technique: For patients with LN+ disease within the pelvis: upper border at L5/S1 interspace, lower border 5-6 cm below pubic symphysis, lateral borders for AP/PA 2cm lateral to pelvic brim. For positive common iliac nodes, extended up to L2/L3 interspace to include paraaortic nodes. For positive periaortic LN, extend to body of T11. Dose: 65-70 Gy definitive. 60 Gy for post-op. 44-46 Gy to pelvic field followed by boost.
    • 10-years; 2005 PMID 15817329 — "Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31." (Pilepich MV, Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90.). Median F/U 7.6 years (11 for living patients)
      • 10-year outcome: OS 49% vs. 39% (SS); LF 23% vs. 38% (SS); DM 24% vs. 39% (SS); disease-specific mortality 16% vs. 22% (SS)
      • Conclusion: In unfavorable prognosis patients, long-term adjuvant AST improves survival

[edit] RT +/- Short-Term ADT

  • Harvard (1995-2001) - 6 months vs. no AST
    • Randomized. 206 men. Intermediate/High Risk: T1b-T2b (1992 staging), PSA >= 10, Gleason >= 7, radiographic ECE, or low risk pts with T3 based on endorectal MRI. Arm 1) 70 Gy 3D XRT (did not treat the pelvis) vs. Arm 2) 6 months androgen suppression (leuprolide/goserelin + flutamide) beginning 2 months prior to RT.
    • 5-years; 2004 PMID 15315996 — "6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial." (D'Amico et al. JAMA. 2004 Aug 18;292(7):821-7.) Median F/U 4.5 years
      • Outcome: 5-year OS RT+AST 88% vs RT alone 78% (SS). 5-year survival free of salvage androgen suppression 82% vs 57% (SS). Decreased cancer-specific mortality.
      • Conclusion: Addition of 6 months of AST confers survival benefit
    • 8-years; 2008 PMID 18212313 -- "Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial." (D'Amico AV, JAMA. 2008 Jan 23;299(3):289-95.)
      • Postrandomization evaluation of comorbidity impact via ACE-27. Comorbidity none 66%, minimal 11%, moderate 22%, severe 12%. Median F/U 7.6 years
      • Outcome: 8-year OS RT+AST 74% vs. RT alone 61% (SS); PCA-specific mortality significantly better (HR 4.1)
      • Comorbidity: None/minimal OS 90% vs. 64% (SS); moderate/severe OS 25% vs. 54% (NS)
      • Conclusion: Addition of 6 months AST increases OS, though possibly only in men with no/minimal comorbidities
    • Comment: Showed a survival benefit after only 6 months of hormones, so long-term AST may not be needed. However, trend to worse survival in men with significant comorbidities
  • Quebec L-101 (1991-94) -- no ADT vs 3 months neoadjuvant vs. neoadjuvant/concurrent/adjuvant 10 months
    • Randomized. 120 patients. T2a-T4. Arm 1) RT 64/32 alone, 2) 3 months neoadjuvant combination hormonal therapy (flutamide + LHRH agonist) + RT, or 3) hormonal therapy 3 months before, during, and 6 months after RT. Endpoint: Biopsy recurrence at 1 year and 2 years. 1-year biopsy compliance 77%, 2-year 57%
    • 2004 PMID 14767287 — "The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer." (Laverdiere J et al. J Urol. 2004 Mar;171(3):1137-40.) Median F/U 5 years
      • Outcome: 7-year bNED RT 42% vs. RT + 3 months 66% (SS) vs. RT + 10 months 69% (SS, NS)
      • Conclusion: Adding short course (6 months) of adjuvant ADT after neoadjuvant/concurrent ADT provided no further advantage
  • RTOG 86-10 "Bulky Trial" (1987-91) - short term androgen deprivation in addition to RT
    • Randomized. 471 patients. Bulky primary tumors (T2-T4), palpable tumor 25 cm (by product of two dimensions). Allowed LN+ if below common iliac. Allowed bulky disease (unlike 85-31). Randomized to goserelin + flutamide 2 months before and 2 months during XRT, versus no AD. XRT to 45 Gy to pelvis, with boost to 65-70 Gy. RT fields to L5/S1 level if LN- but extend to L2-L3 if LN+.
    • 8-years; 2001 PMID 11483335 — "Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate." Pilepich MV et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52.
      • 8-year LC 42% vs 30% (p=0.02), DM 34% vs 45% (p=0.04), DFS 33% vs 21% (p=0.004), bDFS 24% vs 10% (p<0.0001), cause-specific mortality 23% vs 31% (p=0.05), overall survival 53% vs 44% (p=0.10)
      • Conclusion: Beneficial effect in Gleason 2-6, with improved overall survival 70% vs 52% (p=0.015); For Gleason 7-10, no improvement in LRC or OS.
    • 10-years; 2008 PMID 18172188 — "Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610." Roach M et al. J Clin Oncol 2008 (ahead of print).
      • Outcome: 10-yr OS AST 43% vs control 34% (NS), median OS 8.7 vs 7.3 yrs (NS, p=0.12). Improved DSM (23% vs 36%, SS), DM (35% vs 47%, SS), DFS (11% vs 3%, SS), and BF (65% vs 80%, SS). No difference in fatal cardiac events.
      • Conclusion: "The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease, with no statistically significant impact on the risk of fatal cardiac events."

[edit] RT + Short-Term ADT vs. Long-Term ADT

  • EORTC 22961 (1997-2002) -- AST 6 months vs. AST 3 years
    • Randomized. 970 men. Locally advanced prostate cancer (T1c-T2b pN1-N2 M0 or cT2c-T4 N0-N2 M0), PSA up to 40x normal, Hb >10. 3D-CRT pelvis + prostate boost 70 Gy. AST 6 months (complete androgen blockade) initiated 1st day of RT. If no progression, Arm 1) observation vs Arm 2) AST 2.5 years (LHRH triptorelin). 72% completed full 3 years. Median F/U 6.4 year
    • 2009 PMID 19516032 -- "Duration of Androgen Suppression in the Treatment of Prostate Cancer" (Bolla M, N Engl J Med. 2009 Jun 11;360(24):2516-2517.)
      • Outcome: 5-year OS 6-months 81% vs. 3-years 85% (HR 1.4, SS); 5-year CSS 95% vs. 97% (HR 1.7, SS).
      • Toxicity: 6 month AST hot flashes 29%, gynecomastia 7%, incontinence 10%. 3 year AST hot flashes 39%, gynecomastia 18%. Quality of life comparable between arms. No difference in fatal cardiac events (4% vs. 3%)
      • Conclusion: Combination of RT + 3 years AST provides superior survival to 6 month AST in locally advanced cancer
  • TROG 96.01 (Australia)(1996-2000) -- ADT None vs 3 months vs 6 months
    • Randomized. 802 men with locally advanced PCA (T2b-T4N0). Treatetd with 1) RT alone 66/33 vs. RT + 3 month AST (goserelin+flutamide starting 2 months prior to RT) vs. RT + 6 months AST (starting 5 months prior to RT).
    • 2005 PMID 16257791 -- "Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial." (Denham JW, Lancet Oncol. 2005 Nov;6(11):841-50.) Median F/U 5.9 years
      • 5-year outcomes: bF 0 mo 14% vs. 3 mo 20% (SS) vs. 6 mo 21% (SS, NS) Local failure: 10% vs. 6% (SS) vs. 4% (SS, NS); distant failure 7% vs. 8% (NS) vs. 5% (SS, SS); PCA-specific survival: 34% vs. 35% (NS) vs. 35% (NS)
      • Conclusion: 6 months AST before/during improves outlook of patients with locally advanced PCA. 3 months and 6 months comparable with local control, 6 months benefit for distant mets and freedom from salvage
  • Canada multicenter (1995-2001) -- ADT 3 vs 8 months prior to RT
    • Randomized. 378 patients. Clinically localized cT1-T4 (low 26%, intermediate 43%, high risk 31%). Median PSA 9.7 ng/ml Arm 1) Flutamide + goserelin x3 months vs. Arm 2) Same x8 months. Subsequently prostate RT 66 Gy. If LN+ risk >10-15%, treated pelvis. No concurrent ADT
    • 2009 PMID 18707821 -- "Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer." (Crook J, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):327-33. Epub 2008 Aug 15.) Median F/U 6.6 years
      • Outcome: 5-year bPFS 3 months 72% vs. 8 months 75% (NS); OS 81% vs. 79% (NS). Improved DFS for high-risk patients with 8 months (71% vs. 42%, SS)
      • Conclusion: Longer neoadjuvant HT before standard RT didn't alter patterns of failure
  • Quebec L-200 (1994-1999) -- Neoadjuvant/concurrent (5 months) vs neoadjuvant/concurrent/adjuvant (10 months) ADT
    • Randomized. 325 patients, cT2-T3 prostate cancer. Arm 1) RT + eoadjuvant/concurrent ADT (5 months) using LHRH agonist + antiandrogen vs. Arm 2) RT + neoadjuvant/concurrent/adjuvant (10 months) ADT. Endpoing bNED by Vancouver definition
    • 2004 PMID 14767287 — "The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer." (Laverdiere J et al. J Urol. 2004 Mar;171(3):1137-40.)
      • Outcome: 4-year bNED 65%, no difference between arms
      • Conclusion: Adding short course (5 months) of adjuvant ADT after neoadjuvant/concurrent ADT provided no further advantage
  • RTOG 92-02 (1992-95) -- 4 months versus 2 years ADT
    • Randomized. 1554 patients with locally advanced PCA. T2c-T4 (T2 45%, T3 50%); PSA <150 (PSA <=30 in 67%), allowed N+ (N+ 4%, Nx 87%) but excluded LN+ at common iliac or higher chains. Goserelin 3.6 mg SC qM + flutamide 250 mg TID for 2 months before and 2 months during XRT. Then Arm 1) observation (ST-ADT) vs. Arm 2) 2 years of goserelin (LT-ADT). XRT pelvis 45 Gy, followed by a boost to 65-70 Gy.
    • 10-years; 2008 PMID 18413638 -- "Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer." (Horwitz EM, J Clin Oncol. 2008 Apr 14 [Epub ahead of print]). Median F/U 11.3 years
      • Outcome: 10-year DFS ST-ADT 13% vs. LT-ADT 22% (SS), DSS 84% vs. 89% (SS), LR 22% vs. 12% (SS); OS 52% vs. 54% (NS)
      • Subset analysis (GS 8-10): OS ST-AST 32% vs. LT-AST 45%; all other points also SS
      • Conclusion: LT-ADT is superior to ST-ADT; no impact on survival but trial not powered for it. On subgroup analysis, GS 8-10 gains survival advantage

[edit] Lipid Profile

  • Toremifene Trial (2003-2005)
    • Randomized. 1389 men, prostate cancer, receiving long-term ADT (>6 months, or intermittently for >12 months, or bilateral orchiectomy). Arm 1) Toremifene 80 mg/d (second generation SERM) vs. Arm 2) placebo
    • Lipid effect; 2008 PMID 18398147 -- "Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study." (Smith MR< J Clin Oncol. 2008 Apr 10;26(11):1824-9.)
      • Interim analysis of 188 patients. Fasting serum lipids compared at baseline and 1 year later
      • Outcome: total cholesterol toremifene -8% vs. placebo -1% (SS); LDL -8% vs. +1% (SS); HDL +0.5% vs. -5% (SS); triglycirides -13% vs. +7% (SS)
      • Conclusion: Tofemifene significantly improved lipid profile

[edit] Gynecomastia

  • Italy (2002-2004) -- observation vs. tamoxifen vs RT
    • Randomized, 3 arms. 5 centers. 151 patients with prostate cancer, any TN, M0, no gynecomastia/breast pain. Arm 1) bicalutamide 150 mg alone vs. Arm 2) bicalutamide 150 mg + tamoxifen 10 mg x24 weeks vs. Arm 3) bicalutamide 150 mg + RT 12/1. RT given as electrons to 5cm diameter of tissue around each nipple, 6-12 MeV to deliver 90% between skin and chest wall. In observation patients who developed gynecomastia (35/50), subsequently randomized to TAM or RT
    • 2005 PMID 15863377 -- "Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial." (Perdona S, Lancet Oncol. 2005 May;6(5):295-300.)
      • Outcome: Gynecomastia observation 69% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain observation 57% vs. TAM 6% (SS) vs. RT 30% (SS). In observation patients randomized secondarily, gynecomastia TAM 12% vs. RT 56% (SS)
      • Toxicity: both TAM and RT well tolerated
      • Conclusion: Antiestrogen treatment with TAM appears superior to RT
  • Italy (2002-2004) -- observation vs. tamoxifen vs RT
    • Randomized. 102 patients, treated with RP for localized or locally advanced PCA. Treated with adjuvant bicalutamide and Arm 1) observation vs. Arm 2) tamoxifen 10 mg vs. Arm 3) RT. Arm 1 failures subsequently randomized to TAM vs. RT
    • 2005 PMID 16280763 -- "Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy." (DiLorenzo G, J Urol. 2005 Dec;174(6):2197-203.)
      • Outcome: Gynecomastia observation 67% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain 58% vs. 7% vs. 30%
      • Toxicity: No difference in QoL between TAM and RT
      • Conclusion: Gynecomastia and breast pain induced by bicalutamide after RP can be prevented. Tamoxifen more effective than RT
  • Italy (2000-2002) -- observation vs. tamoxifen vs. anastrozole
    • Randomized. 114 patients with localized, locally advanced, or recurrent prostate cancer. Treated with bicalutamide 150 mg. Arm 1) placebo vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x 48 weeks
    • 2005 PMID 15681525 -- "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer." (Boccardo F, J Clin Oncol. 2005 Feb 1;23(4):808-15.)
      • Outcome: Gynecomastia observation 73% vs TAM 10% vs. anastrozole 51% (SS). Breast pain 39% vs. 6% vs. 27% (SS).
      • Toxicity: No difference in PSA response. Adverse events 37% vs. 35% vs. 69% (SS). No difference in sexual function
      • Conclusion: Tamoxifen was effective, no significant benefit for anastrozole
  • US Multi-institutional -- placebo vs. tamoxifen vs. anastrozole
    • Randomized, 3 arms. 107 patients with prostate cancer, T1-4 any NM0 (T2-3 in 92%), on bicalutamide 150 mg/d. Arm 1) observation vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x3 months. Excluded if gynecomastia >2cm or breast discomfort
    • 2005 PMID 15685254 -- "Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole." (Saltzstein D, Prostate Cancer Prostatic Dis. 2005;8(1):75-83.)
      • Outcome: 3-month gynecomastia TAM 12% (SS) vs. anastrozole 64% (NS) vs. placebo 69%
      • Toxicity: PSA decreased in all groups
      • Conclusion: Incidence of gynecomastia reduced by tamoxifen; anastrozole 1mg/d not a viable option
  • European (1999-2001) -- RT 10/1 vs. sham
    • Randomized. 106 patients, prostate cancer (T1b-T4NxM0), Casodex 150 mg/d x1 year. Arm 1) RT 10/1 electrons vs. Arm 2) sham RT.
    • 2004 PMID 15380582 -- "Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia." (Tyrrell CJ, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):476-83.)
      • Outcome: Gynecomastia RT 52% vs. sham 85% (SS), fewer were >5 cm (11% vs. 50%) and fewer were moderate/severe (21% vs 48%). Breast pain 83% vs. 91% (NS)
      • Conclusion: Prophylactic breast RT is effective and well tolerated for prevention of gynecomastia

[edit] Surgery +/- RT

  • German ARO 96-02 / AUO AP 09/95 (1997-2004) -- Adjuvant RT vs. observation
    • Randomized. 385 men, radical prostatectomy pT3 pN0, undetectable post-op PSA (80%). Arm 1) RT 60/30 Gy vs Arm 2) observation. RT 3D plan prostatic fossa + SV + 1cm. Start 8-12 weeks after RP. Primary endpoint PSA control (PSA relapse defined as undetectable to detectable, followed by another increase). Patients not reaching undetectable PSA (20%) treated with 66.6 Gy. Arm 1 21% patients didn't receive RT
    • 2009 PMID 19433689 -- "Phase III Postoperative Adjuvant Radiotherapy After Radical Prostatectomy Compared With Radical Prostatectomy Alone in pT3 Prostate Cancer With Postoperative Undetectable Prostate-Specific Antigen: ARO 96-02/AUO AP 09/95." (Wiegel T, J Clin Oncol. 2009 May 26.) Median F/U 4.5 years
      • Outcome: 5-year bPFS observation 54% vs. RT 72% (HR 0.53, SS). DM 3% vs. 2%. Negative predictors preop PSA >10, stage pT3c
      • Toxicity: No Grade 4, 1 patient with Grade 3 bladder, Grade 2 in 3%
      • Conclusion: Patients with pT3 PCA who achieve undetectable PSA after surgery benefit from adjuvant RT
  • EORTC 22911 (1992-2001) Protocol -- Adjuvant RT vs. observation
    • Randomized. 1005 patients. Radical prostatectomy pT2-3N0, ilio-obturator LND, with extracapsular disease (ECE, SV+, SM+). Arm 1) observation vs. Arm 2) RT 60/30, start within 16 weeks of RP. RT technique conventional (non-3D), 50/25 + 10/5 boost with smaller margins. Borders surgical limits SV to apex. No Gleason scoring (used WHO grade). Biochemical failure increase of 0.2 from postop nadir measured on 3 occasions at least 2 weeks apart and is dated from first day of rise. After biochemical or clinical failure, could get salvage RT. By risk: 43% had one RF only, 43% had two RFs, 12% had all three RFs. Primary endpoint clinical PFS, ammended to bNED in 2003
    • 5-years; 2005 PMID 16099293, 2005 — "Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)." (Bolla M, Lancet. 2005 Aug 13-19;366(9485):572-8.) Median F/U 5 years
      • Outcome: 5-year bNED RT 74% vs observation 53% (SS), regardless of risk factors. Most failures loco-regional. Clinical PFS 85% vs. 78% (SS). OS 91-92% (NS).
      • Late toxicity: Grade 3 RT 4% vs. observation 3% (p=0.07)
      • Conclusion: Post-operative radiotherapy results in improved biochemical and clinical PFS, but its benefit should be weighed against the risk of increased toxicity.
    • Subset analysis; 2007 PMID 17878474 -- "Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911." (Van der Kwast TH, J Clin Oncol. 2007 Sep 20;25(27):4178-86.)
      • Pathology data review. 552 patients
      • Surgical margin impact: if SM+, RT prevents 291 events/1000 patients (SS); need to treat 3 patients to prevent 1 recurrence. If SM-, RT prevents 88 events/1000 patients (NS).
      • Conclusion: After careful central path review, RT beneficial only for patients with positive margins (this effect was not seen when using the local pathology data), no benefit if negative margins
  • SWOG-8794 / RTOG 90-19 / INT-0086 (1988-95) -- prostatic fossa RT vs. observation
    • Randomized. 473 patients, radical prostatectomy with extraprostatic disease (ECE, SV+, or SM+). Pelvic LND required until 1995, when very low risk patients (T1a or T2a GS2-6 PSA <10, T1b-c GS2-5 PSA <10, T2b GS2-6 PSA <6, T2c GS2-6 PSA <4) were exempt. Arm 1) Prostatic fossa RT 60-64 Gy vs Arm 2) observation, within 18 weeks from RP. No concurrent hormones . RT field non-3D, 4-field, 9x9 or 10x10 cm. Primary endpoint mets-free survival
    • 10-years; 2006 PMID 17105795 — "Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial." (Thompson IM Jr, JAMA. 2006 Nov 15;296(19):2329-35.) Median F/U 10.6 years
      • Outcome: Mets-free survival RT 65% vs. observation 57% (p=0.06), median 14.7 years vs. 13.2 years. However, 33% of observation group received salvage RT for disease relapse instead of observation alone. PSA relapse (defined as >0.4) RT 36% vs. 65% (SS), median 10.3 yrs vs observation 3.1 yrs (SS). Recurrence free survival 61% vs. 47% (SS). Hormones initiated in 10% vs 21%. No difference in OS.
      • Rectal complications 3% vs 0%, urethral strictures 18% vs 9%, total urinary incontinence 6% vs 3%.
      • Conclusion: Adjuvant RT significantly decreases PSA and clinical recurrence

[edit] Surgery +/- Chemotherapy

  • SWOG 9921 / Intergroup (2000-2007) -- ADT vs. ADT + mitoxantrone
    • Randomized. Closed prematurely after AML toxicity. 983 patients patients, radical prostatectomy, high risk features (GS >=8, or pT3b-T4, or N1, or GS 7 and SM+, or PSA >15 ng/ml. Had to have undetectable post-op PSA). Arm 1) ADT x2 years (bicalutamide 50mg QD + goserelin 10.8 mg SC q3 months) vs. Arm 2) ADT x2 years + mitoxantrone 12 mg/m2 q3W x6 cycles
    • 2008 PMID 18349405 -- "Randomization reveals unexpected acute leukemias in Southwest Oncology Group prostate cancer trial." (Flaig TW, J Clin Oncol. 2008 Mar 20;26(9):1532-6.)
      • Outcome: 3 cases of AML reported in 487 patients in mitoxantrone arm. Time-to-detection 13, 48, and 72 months. Trial stopped
      • Conclusion: Highlights importantce of controlled trials to define safety and efficacy


[edit] Metastatic

  • Atrasentan - endothelin-A receptor antagonist
    • Randomized. 809 men with HRPC. Arm 1) atrasentan 10 mg vs. Arm 2) placebo. Endpoint TTP
    • 2007 PMID 17886253 -- "A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer." (Carducci MA, Cancer. 2007 Nov 1;110(9):1959-66.)
      • Outcome: No difference in time-to-progression; most progressed radiographically within 12 weeks; no difference in PSA progression
      • Toxicity: Well tolerated
      • Conclusion: No difference in delay of disease progression
  • TAX 327 (2000-2002) -- Docetaxel + prednisone vs. mitoxantrone + prednisone
    • Randomized. 1006 patients with HRPC. Arm 1) docetaxel q3 weeks + prednisone (D3P) vs. Arm 2) docetaxel q1 week + prednisone (D1P) vs. Arm 3) mitoxantrone + prednisone (MP).
    • 2004 PMID 15470213 -- "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer." (Tannock IF, N Engl J Med. 2004 Oct 7;351(15):1502-12.)
      • Outcome: median OS D3P 18.9 months vs. D1P 17.4 months vs. MP 16.5 months (SS). Improved QoL: 23% vs. 22% vs. 13% (SS)
      • Conclusion: Docetaxel q3 weeks + prednisone led to improved survival and quality of life
    • 2008 PMID 18182665 -- "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study." (Berthold DR, J Clin Oncol. 2008 Jan 10;26(2):242-5.)
      • Outcome: median OS: D3P 19.2 months vs. D1P 17.8 months vs. MP 16.3 months (SS); 3-year OS 18.6% vs. 16.6% vs. 13.5%. Similar outcome regardless of age, pain, or baseline PSA
      • Conclusion: Survival longer after docetaxel q3 weeks with prednisone
  • SWOG 9916 (1999-2003) -- Docetaxel + estramustine + dexamethasone vs. mitoxantrone + prednisone
    • Randomized. 674 men with HRPC. Arm 1) docetaxel + estramustine + dexamethasone q3 weeks vs. Arm 2) mitoxantrone + prednisone q3 weeks
    • 2004 PMID 15470214 -- "Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer." (Petrylak DP, N Engl J Med. 2004 Oct 7;351(15):1513-20.)
      • Outcome: median OS DED 17.5 months vs. MP 15.6 months (SS). Median TTP 6.3 months vs. 3.2 months (SS). Pain relief comparable
      • Toxicity: Grade 3-4 neutropenic fever, N/V, and CV events more common in docetaxel group
      • Outcome: Improved median survival with docetaxel + estramustine
  • CALGB 9182 -- Mitoxantrone + hydrocortisone vs. hydrocortisone alone
    • Randomized. 242 patients with HRPC. Arm 1) mitoxantrone + hydrocortisone (MH) vs. Arm 2) hydrocortisone alone (H).
    • 1999 PMID 10561316 -- "Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study." (Kantoff PW, J Clin Oncol. 1999 Aug;17(8):2506-13.)
      • Outcome: MH better in TTTF, response rate, pain control, and QoL. No difference in survival (12.3 months vs. 12.6 months, NS)
      • Conclusion: Mitoxantrone with hydrocortisone had more frequent response, delay to progression, and pain control than hydrocortisone alone
  • Scandinavian SPCG-5 (1992-1997) -- parenteral estrogen vs. total androgen blockade
    • Randomized. 910 patients, metastatic prostate cancer. Arm 1) parenteral estrogen 240 mg/month vs. Arm 2) flutamide 250 mg TID + triptorelin 3.75 mg or bilateral orchidectomy
    • 2008 PMID 18432528 -- "Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5." (Hedlund PO, Scand J Urol Nephrol. 2008;42(3):220-9.
      • Outcome: No difference in bPFS, cPFS, DSS, or OS
      • Toxicity: No difference in CV mortality, but increased cardiovascular events in parenteral estrogen arm. Increased skeletal events/osteoporosis in androgen arm
      • Conclusion: No difference in outcome. Toxicity profiles different
  • CALGB 9181 (1992-1994) -- low-dose vs. high-dose Megace
    • Randomized. 149 ment with HRPC, with progressive metastatic or LN carcinoma; only 1 prior hormonal therapy allowed. Arm 1) oral megestrol acetate 160 mg/day (low dose) vs. Arm 2) oral megestrol acetate 640 mg/day (high dose). Primary endpoint tumor response
    • 2000 PMID 10679652 -- "A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma: cancer and leukemia group B study 9181." (Dawson NA, Cancer. 2000 Feb 15;88(4):825-34.)
      • Outcome: Tumor response comparable. Median OS low dose 11.2 months vs. high dose 12.1 months (NS). Most (91%) died of prostate cancer
      • Toxicity: comparable, but 7% had acute pain flare
      • Conclusion: Megestrol acetate has limited activity in HRPC; there is no apparent dose-response correlation
  • Canada -- Mitoxantrone + prednisone vs. prednisone alone
    • Randomized. 161 HRPC with pain. Arm 1) mitoxantrone + prednisone vs. Arm 2) prednisone alone. Primary end point palliative response (1/3 pain decrease)
    • 1996 PMID 8656243 -- "Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points." (Tannock IF, J Clin Oncol. 1996 Jun;14(6):1756-64.)
      • Outcome: Palliative response MP 29% vs. P 12% (SS). Duration of palliation MP 9.9 months vs. P 4.1 months (SS)
      • Conclusion: Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic HRPC
  • Scandinavian SPCG-2 (1984-1989) -- bilateral orchiectomy +/- cyproterone
    • Randomized. 294 patients, metastatic PCA, Grade 1-2. Arm 1) bilateral orchiectomy vs. Arm 2) bilateral orchiectomy + cyproterone
    • 1993 PMID 8287887 -- "Total androgen suppression: experience from the Scandinavian Prostatic Cancer Group Study No. 2." (Jorgensen T, Eur Urol. 1993;24(4):466-70.)
      • Outcome: No difference in disease progression, or overall survival
      • Conclusion: Total androgen blockade with cyproterone not superior to orchiectomy
  • Scandinavian SPCG-1 (1984-1989) -- DES vs. estramustine
    • Randomized. 197 patients with high grade metastatic PCA (M1, G2-3). Arm 1) estramustine 560 mg vs Arm 2) diethylstilbestrol (DES) 3 mg
    • 1997 PMID 9165581 -- "Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group." (Hedlund PO, Scand J Urol Nephrol. 1997 Apr;31(2):167-72.)
      • Outcome: DES better for time-to-progression (p=0.05), treatment failure (SS), CSS (p=0.07), and OS (SS)
      • Conclusion: Treatment with DES had relatively good effect

[edit] Exercise

  • Houston VA; 2007 PMID 17964881 -- "Exercise prevents fatigue and improves quality of life in prostate cancer patients undergoing radiotherapy." (Monga U, Arch Phys Med Rehabil. 2007 Nov;88(11):1416-22.)
    • Randomized. 21 patients with localized PCA, undergoing therapy. Arm 1) RT + aerobic exercise 3x/week x8 weeks vs. Arm 2) RT only
    • Outcome: Significant benefit in fatigue, cardiac fitness, strength, flexibility, FACT-P, physical well-being, social well-being, and functional well-being
    • Conclusion: 8-week cardiovascular program during RT improves fatigues, well-being, and fitness
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