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Radiation Oncology/Prostate/Randomized

Prostate Cancer: Randomized Evidence

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

Screening

 * Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial (1993-2001) -- screening vs usual care
 * Randomized. 76,693 men at 10 U.S. centers. Arm 1) Annual PSA screening x6 years and DRE x4 years vs. Arm 2) usual care. Compliance in Arm 1 85% for PSA and 86% for DRE. Rate of control group PSA screening 40-52% and DRE screening 41-46% by year
 * 2009 PMID 19297565 -- "Mortality results from a randomized prostate-cancer screening trial." (Andriole GL, N Engl J Med. 2009 Mar 26;360(13):1310-9. Epub 2009 Mar 18.) Median F/U 7 years
 * Outcome: PCA incidence screening group 116/10,000 vs control group 95/10,000 (RR 1.1, SS). Death from PCA 2/10,000 vs 1.7/10,000 (RR 1.13, NS)
 * Conclusion: After 7 years, rate of death from PCA is very low, and not different between groups
 * 2011 PMID 21041707 -- "Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial." (Crawford ED, J Clin Oncol. 2011 Feb 1;29(4):355-361 .)
 * f/u 10 yrs. 9565 deaths, 164 from PCA. In men with no or minimal comorbidity, the decrease in PCA-specific mortality associated with screening was significant (22 v 38 deaths)(NNTT = 5 pts to prevent 1 death at 10 years). In men with at least 1 significant comorbidity, no decrease in PCSM with screening. (62 v 42 deaths; AHR=1.43; p=0.08).
 * Conclusion: selective use of PSA screening in men with good health appears to reduce the risk of PCSM with minimal overtreatment.

 * European Randomized Study of Screening for Prostate Cancer (ERSPC) (1991-2003) -- screening vs no screening
 * Randomized. 162,387 men, different enrollment strategies in different countries. Arm 1) PSA screening (DRE and other studies per country; interval per country) vs. Arm 2) no screening. Treated with watchful waiting (15%), surgery (28%), RT (17%), RT+ADT (10%), ADT alone (10%)
 * 2009 PMID 19297566 -- "Screening and prostate-cancer mortality in a randomized European study." (Schroder FH, N Engl J Med. 2009 Mar 26;360(13):1320-8. Epub 2009 Mar 18.) Median F/U 9 years
 * Outcome: PCA incidence screening 8% vs control 5%. Death from PCA 3.5/10,000 vs 4.1/10,000 (RR 0.8, SS), rates began to diverge after 8 years. NNS 1410:1, NNT 48:1
 * Conclusion: PSA-based screening reduced PCA death by 20%, but was associated with a high risk of overdiagnosis

 * Quebec LUPCSP (1988) -- Screening vs control
 * Randomized, 2:1. 46,486 men randomized, true screened 7,348 vs true unscreened 14,2341. Arm 1) annual screening (PSA and DRE) vs Arm 2) control
 * 2004 PMID 15042607 -- "Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial." (Labrie F, Prostate, 2004 May 15;59(3):311-8.). Median F/U 7.9 years
 * Outcome: PCA death screened 0.1% vs. unscreened 0.5% (RR 0.4, SS)
 * Conclusion: Screening showed a 62% reduction in cause-specific mortality, but the absolute benefit was small

Prevention

 * REDUCE Trial -- dutasteride vs placebo
 * Randomized. 6729 men, at increased risk for prostate cancer (50-75 years old, PSA 2.5-10.0, one negative biopsy within 6 months). Arm 1) dutasteride 0.5 mg vs Arm 2) placebo. Primary endpoint: PCA on biopsy at 2 and 4 years
 * 2010 PMID 20357281 -- "Effect of dutasteride on the risk of prostate cancer." (Andriole GL,N Engl J Med. 2010 Apr 1;362(13):1192-202.)
 * Outcome: incidence of cancer dutasteride 20% vs placebo 25% (SS, risk reduction 28%). No difference in GS 7-10; less GS 8-10 in dutasteride group
 * Toxicity: dutasteride improved acute urinary retention (2% vs 7%, SS), but had higher cardiac failure (0.7% vs 0.4%, SS)
 * Conclusion: Dutasteride reduced risk of prostate cancer and improved BPH symptoms

Patient Decision-Making

 * US Multi-Institutional -- Patient intervention vs Patient + Support intervention vs Control
 * Randomized, 3 arms. 6 US sites. 256 patients with T1-T2b, GS <10, PSA <20. Arm 1) treatment direct (patient receives intervention) vs. Arm 2) treatment supplemented (patient and primary support person receive intervention) vs. Arm 3) control. Intervention was designed to improve communication strategies when meeting with their physician.
 * 2009 PMID 19819096 -- "Managing uncertainty about treatment decision making in early stage prostate cancer: a randomized clinical trial." (Mishel MH, Patient Educ Couns. 2009 Dec;77(3):349-59. Epub 2009 Oct 9.)
 * Outcome: Improvement in cancer knowledge at 4 weeks and 3 months in both intervention arms; significantly lower rate of decision regret
 * Conclusion: Intervention was effective in preparing patients for uncertainty management in prostate cancer

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

Androgen Deprivation vs Radiation Therapy + Androgen Deprivation

 * SPCG-7/SFUO-3 (1996-2002) -- ADT +/- RT
 * Randomized. 875 with locally advanced prostate cancer T1b-T2 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
 * Outcome; 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

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

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

Radiation Therapy vs Cryotherapy

 * University of Calgary (1997-2003) -- EBRT vs Cryotherapy
 * Randomized. Trial closed prematurely due to slowing patient accrual. 244 patients of 240 planned, localized prostate cancer (T2-T3N0, PSA <=20 ng/ml, volume <=60 ml), PLND if GS 8+. Excluded clinically bulky patients. Neoadjuvant ADT 3 or 6 months. Arm 1) EBRT (median dose 68 Gy, max 73.5 Gy) using 4F box vs Arm 2) cryoablation using argon/helium and 2 freeze/thaw cycles. Early cryotherapy failures (within 6 months) were not scored as protocol failure, and underwent salvage cryotherapy. QoL assessment. Primary endpoint was failure rate at 3 years
 * 2009 PMID 19937954 -- "A Randomized Trial of External Beam Radiotherapy Versus Cryoablation in Patients With Localized Prostate Cancer" (Donnelly BJ, Cancer. 2010, Epublished) Median F/U of surviving patients 8.3 years
 * Outcome: 3-year failure rate (using nadir+2) cryo 17% vs. EBRT 13% (NS); 5-year rate 25% vs. 25% (NS); 7-year rate 27% vs. 32% (NS); 5-year DSS 96% vs. 96% (NS); 5-year OS 90% vs 88% (NS). Biopsy (+) cryo 8% vs EBRT 29%
 * Toxicity: GI Grade 3-4 cryo 3% vs. EBRT 7%; GU Grade 3-4 cryo 9% vs. EBRT 6%; intercourse 4% vs. 26%
 * Conclusion: Essentially no difference, but with long-term follow up, trend favors cryotherapy
 * 2009 PMID 19691092 -- "A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer: quality of life outcomes." (Robinson JW, Cancer. 2009 Oct 15;115(20):4695-704.)
 * Outcome: Cryotherapy more acute GU dysfunction (SS), no difference in late GU dysfunction. Cryotherapy worse sexual function at 3 months (SS) and 3 years (SS)
 * Conclusion: No long term QoL difference, except worse sexual function after cryoablation

 * University of Western Ontario -- EBRT vs cryotherapy
 * Randomized. Trial stopped prematurely due to slow accrual. 64 of planned 150 patients, cT2c-T3b. Neoadjuvant ADT for 6 months. Arm 1) EBRT vs. Arm 2) cryotherapy
 * 2008 PMID 17579613 -- "Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer." (Chin JL, Prostate Cancer Prostatic Dis. 2008;11(1):40-5. Epub 2007 Jun 19.)
 * Outcome: Treatment failure EBRT 45% vs. cryotherapy 64%. 4-year bPFS 47% vs. 13%. Mean bPFS 41 months vs 28 months. No difference in DSS and OS
 * Toxicity: Serious complications uncommon; EBRT more frequent GI toxicity
 * Conclusion: Low numbers, but cryotherapy is suboptimal primary therapy for locally advanced prostate cancer

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

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

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
 * 10-years; 2010 PMID 20124169 -- "Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09." (Zietman AL, J Clin Oncol. 2010 Mar 1;28(7):1106-11.) Median F/U 8.9 years
 * Outcome: 10-year ASTRO (backdating) bPFS low-dose 68% vs. high-dose 83% (SS). For low-risk disease 72% vs 93% (SS); for intermediate-risk 58% vs. 70% (p=0.06). No difference in OS (78% vs 83%)
 * Toxicity: Late Grade 2+ low-dose 29% vs. high-dose 39% (SS); Grade 3+ 2% in both arms (NS)
 * Conclusion: Long-term advantage for high dose in low/intermediate risk PCA patients, with comparable Grade 3 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
 * 10-years; 2011 PMID 20493642 -- "Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?" (Kuban DA, Int J Radiat Oncol Biol Phys. 2011 Apr 1;79(5):1310-7. Epub 2010 May 20.)
 * 10-year outcome: bDFS of PSA > 10 subset 91% vs. 80% (p=SS).
 * Conclusion: Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up

 * Ontario EBRT/LDR (1992-1997) -- EBRT 66/30 vs. EBRT/LDR 75 (LDR 35 + EBRT 40/20)
 * Randomized. 104 patients, locally advanced T2-T3. All underwent staging pelvic lymphadenectomy. Arm 1) EBRT 66/33 vs. Arm 2) LDR 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

Altered Fractionation

 * Regina Elena NCI Rome, Italy (2003-2007) -- 80/40 (2 Gy/fx) vs 62/20 (3.1 Gy/fx)
 * Randomized. 168 patients, high-risk (GS 8-10, PSA >20 ng/ml, or 2+ of PSA 10-20, T ≥ T2c, GS7), but PSA ≤ 100. All patients neoadjuvant/concurrent/adjuvat ADT x9 months. Arm 1) 3D-CRT 80/40 vs Arm 2) 3D-CRT 62/20, CTV = prostate + SV.
 * 2010 PMID 20047800 -- "A Prospective Phase III Randomized Trial of Hypofractionation Versus Conventional Fractionation in Patients with High-Risk Prostate Cancer." (Arcangeli G, Int J Radiat Oncol Biol Phys. 2010 Jan 2. [Epub ahead of print]). Median F/U 2.7 years
 * Outcome: 3-year bPFS conventional 79% vs hypofx 87% (SS); very high risk subset (GS 8-10, PSA ≥ 20, or ≥ T2c) 76% vs 88% (SS)
 * Toxicity: 3-year late GI G2 conventional 16% vs hypofx 17%, GU G2 11% vs 14%
 * Conclusion: Hypofractionated schedule superior for biochemical control, comparable for late toxicity

 * Vilnius University, Lituania (2004-ongoing) -- 74/37 (2 Gy/fx) vs. 57/17 (3 Gy/fx + 4.5 Gy/fx)
 * Randomized. 91 patients, clinically localized prostate cancer, risk of SV/LN involvement <15%. No neoadjuvant ADT. Arm 1) 74/37 vs. Arm 2) 57/17 (39/13 + 18/4). CTV = prostate + base SV. PTV margin 8-10 mm. 3D-CRT using 5 fields
 * 2009 PMID 19605967 -- "A randomized trial comparing hypofractionated and conventionally fractionated three-dimensional conformal external-beam radiotherapy for localized prostate adenocarcinoma: a report on the first-year biochemical response." (Norkus D, Medicina (Kaunas). 2009;45(6):469-75.)
 * Outcome: 1-year PSA nadir <1.0 HFRT54% vs. CFRT 50% (NS); 1-year PSA nadir <0.5 18% vs. 25% (NS)
 * Conclusion: Preliminary results suggest comparable biochemical response

 * 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
 * 2013 PMID 24101042 --

 * Mount Vernon, UK (1997-2005) -- 55/20 vs 35.75/13 + 17/2
 * Randomized. 220 patients, prostate cancer T1-T3M0 (T3 26%), PSA <50. Arm 1) EBRT 55/20 vs Arm 2) EBRT 35.75/13 + HDR 17/2. ADT 76%.
 * Initial; 2007 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, Radiother Oncol. 2007 Aug;84(2):114-20. Epub 2007 May 24.) Median F/U 1.25
 * Outcome: Mean bRFS combined modality 5.1 years vs EBRT 4.3 years (SS). Improvement seen in all risk groups
 * Toxicity: Acute GI toxicity better in combined group, other acute and late toxicities comparable. QoL FACT-P score better in combined group
 * Conclusion: HDR brachytherapy + EBRT results in improved outcome with less acute toxicity and improved QoL

 * 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

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 abdominal compression. Interfraction motion >3 mm corrected pre-treatment.
 * Outcome: No difference in interfraction or intrafraction motion with or without abdominal compression
 * Conclusion: Addition of abdominal compression didn't influence interfraction or intrafraction prostate motion

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

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. PTV expansion 15 mm. 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
 * 2004 PMID 15465140 -- "Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: observations of a randomized trial." (Koper PC, Radiother Oncol. 2004 Oct;73(1):1-9.) F/U 2 years
 * Toxicity: Grade 2 conventional 10% vs 3D-CRT 7% (NS), Grade 1 47% vs. 40% (NS). Most bothersome symptoms: urgency, soiling, and fecal loss
 * Predictors: Anal/rectal V90% for rectal toxicity. Acute anal/rectal toxicity for late rectal toxicity. Pretreatment urgency for later bladder toxicity
 * Conclusion: Conformal RT at 66 Gy doesn't significantly decrease incidence of rectal, anal, and bladder toxicity compared with conventional RT

 * 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 late proctitis

Contouring Intervention

 * Princess Margaret (2007) -- interactive prostate MRI/CT vs general anatomy CT contouring
 * Randomized. 31 trainees. Pretest contouring of prostate and rectum. Then randomized Arm 1) interactive session on prostate volumes using fused CT/MRI vs Arm 2) interactive session on general contouring using CT. Then retested
 * 2010 PMID 19467804 -- "Effectiveness of educational intervention on the congruence of prostate and rectal contouring as compared with a gold standard in three-dimensional radiotherapy for prostate." (Szumacher E, Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):379-85. Epub 2009 May 19.)
 * Outcome: No difference in score gains between groups. No difference in prostate contour, but improved rectal contour
 * Conclusion: Similar improvement in technical performance; participants in both groups satisfied

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

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 loose 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 standed seeds

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

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

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

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

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

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

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."

RT + ADT: Duration of Therapy

 * 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. Endpoint 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

RT + ADT +/- Chemotherapy

 * Nihon University, Japan (2003-2006) -- RT + ADT +/- estramustine
 * Randomized. 39 patients, intermediate/high risk PCA by NCCN guidelines. Arm 1) Neoadjuvant/concurrent LHRH agonist + estramustine x6 months vs Arm 2) NCAHT x 6 months. Both groups 3D-CRT 70/35
 * 2010 PMID 19449118 -- "Neoadjuvant LHRH analog plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: a randomized study." (Hirano D, Int Urol Nephrol. 2010 Mar;42(1):81-8. Epub 2009 May 16.) Median F/U 2.3 years
 * Outcome: 4-year bRFS ADT+EMP 61% vs ADT alone 49% (SS)
 * Toxicity: No severe toxicities
 * Conclusion: ADT + EMP better than ADT alone, but either arm insufficient and dose escalation or adjuvant ADT needed

 * RTOG 99-02 (2000-2004) -- RT + ADT +/- TEE (taxol, estramustine, etoposide)
 * Randomized. Closed early due to thromobembolic events. 397 patients. High risk CaP (PSA 20-100 and GS >=7, or T2+, GS8, PSA <100). Neoadjuvant/concurrent and adjuvant AS + RT (2/2/2 TAA) +/- TEE Chemotherapy (taxol, estramustine, etoposide) x 4 cycles.
 * 2009 PMID 18990504 -- "Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02." (Rosenthal SA, Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. Epub 2008 Nov 5.)
 * Toxicity: AS 37% vs. AS + TEE 715 (SS), for hematological (SS), GI (SS), and trend GU (p=0.07). Three cases of MDS/AML in TEE arm
 * Conclusion: TEE associated with significantly increased toxicity during treatment

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

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

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, amended 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
 * 15 year update; 2009 PMID 19167731 -- "Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial." (Thompson, J Urol 2009)
 * RT improved metastasis free survival (HR 0.71, 93/214 vs. 114/211)
 * RT improved overall survival: HR 0.72, 57% vs 48%, p=0.023. # of Deaths 88/214 vs 110/211.
 * Median f/u of ~12.5y in both arms
 * 70 of 211 pts on observation arm ultimately received RT.
 * For more updated information on the SWOG trial check the Radical Prostatectomy ± Adjuvant RT section

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

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

Exercise

 * Perth, Australia (2007-2008) -- exercise x12 weeks vs control
 * Randomized. 57 patients with CaP, undergoing AST. Arm 1) resistance and aerobic exercise x12 weeks vs. Arm 2) usual care. Primary endpoint lean mass
 * 2010 PMID 19949016 -- "Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial." (Galvao DA, J Clin Oncol. 2010 Jan 10;28(2):340-7. Epub 2009 Nov 30.)
 * Outcome: Patients undergoing exercise improved lean mass (SS), muscle strength (SS), improved walk time (SS), QoL (SS), fatigue (SS), and CRP levels (SS)
 * Conclusion: Relatively brief exposure to exercise significantly improved AST-related adverse effects

 * Rochester -- exercise x4 weeks vs. control
 * Randomized. 38 breast or prostate cancer patients. Arm 1) Home-based aerobic and progressive resistance exercise x4 weeks at start of RT vs. Arm 2) control.
 * 2009 PMID 19831159 -- "A 4-week home-based aerobic and resistance exercise program during radiation therapy: a pilot randomized clinical trial." (Mustian KM, J Support Oncol. 2009 Sep-Oct;7(5):158-67.)
 * Outcome: Good adherence to intervention. At 3 months, significantly more daily steps walked, daily minutes of resistance exercise, number of resistance exercise days. Also significantly higher QoL and significantly lower cancer-related fatigue
 * Conclusion: Exercise during RT may be beneficial for cancer patients

 * Houston VA -- exercise x8 weeks vs. control
 * Randomized. 21 patients with localized PCA, undergoing therapy. Arm 1) RT + aerobic exercise 3x/week x8 weeks vs. Arm 2) RT only
 * 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.)
 * 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

title: Radiation Oncology/Prostate/Randomized


text:
Adventist Youth Honors Answer Book/Knot/Slip

/Transcluded Modules

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


text:
Adventist Youth Honors Answer Book/Knot/Slipped sheet bend

/Transcluded Modules


text: Adventist Youth Honors Answer Book/Knot/Stevedore's


text:
Adventist Youth Honors Answer Book/Knot/Strangle

/Transcluded Modules


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Adventist Youth Honors Answer Book/Knot/Slipped half hitch

/Transcluded Modules


text: Adventist Youth Honors Answer Book/Knot/Prusik


text:
Biblical Studies

Front Matter

 * 1) /Introduction/
 * 2) /Authors/

Christianity

 * 1) The Essence of Christianity
 * 2) Christian Theology
 * 3) God the Father
 * 4) Jesus
 * 5) The Holy Spirit
 * 6) Becoming a Christian
 * 7) Living as a Christian
 * 8) Christian texts and writings and the arts
 * 9) The Bible
 * 10) Creeds and catechisms
 * 11) Famous Ancient Christian Texts
 * 12) Famous works of Fiction
 * 13) Famous Works of Non-Fiction
 * 14) Christian Art
 * 15) Christian Music
 * 16) Christian Movies and Television
 * 17) Church history
 * 18) Early Christianity
 * 19) Major events and important movements in church history
 * 20) Bible Characters
 * 21) Authors
 * 22) Famous Christians
 * 23) Evangelists
 * 24) Denominations
 * 25) An introduction to denominations
 * 26) Roman Catholicism
 * 27) Eastern Orthodoxy
 * 28) Protestant churches (1530)
 * 29) Later Christian Movements
 * 30) The Church of Jesus Christ of Latter-day Saints (Mormonism) (1830)
 * 31) Adventism (1863)
 * 32) Bible Students (1868)
 * 33) Christian Science (1879)
 * 34) Jehovah's Witnesses (1931)
 * 35) Christian doctrine and debates
 * 36) The nature of Christ
 * 37) Justification, salvation and grace
 * 38) Other teachings and debates
 * 39) Comparison with other religions
 * 40) Christianity and the world's religions
 * 41) Islam
 * 42) Hinduism
 * 43) Buddhism
 * 44) What is God

Biblical Commentaries

 * /Old Testament Commentaries/
 * /New Testament Commentaries/
 * /Bible Topics/
 * 1599 Geneva Study Bible Study Bible of the version that Shakespeare studied

title: Biblical Studies


text:
User talk:213.42.2.27

Welcome to Wikibooks. We invite everyone to contribute constructively to our collection. Take a look at the welcome page if you would like to learn more about contributing. However, unconstructive edits are considered vandalism, and if you continue in this manner you may be blocked from editing without further warning. Please stop, and consider improving rather than damaging the hard work of others. Thanks. -- Herby talk thyme 11:54, 21 June 2007 (UTC)

title: User talk:213.42.2.27


text:
Adventist Youth Honors Answer Book/Knot/Turn

A turn is a component of a knot. Turns can be made around objects, through rings, or around the standing part of the rope itself. Turns come in various forms, distinguished by the number of passes that the rope makes. A turn or single turn requires one pass. The line makes a U-shape through or around the object, or half a revolution. A round turn requires two passes and makes one and a half revolutions. Two round turns adds another pass and revolution. /Transcluded Modules


text:
Knots/Hitch knots/Round turn

A turn is a component of a knot. Turns can be made around objects, through rings, or around the standing part of the rope itself. Turns come in various forms, distinguished by the number of passes that the rope makes.

A turn or single turn requires one pass. The line makes a U-shape through or around the object, or half a revolution. A round turn requires two passes and makes one and a half revolutions.

Riding turn
A riding turn is a section of rope that passes on top of another section of rope, often parallel or at only a slight angle to the section below. Examples of riding turns can be seen in both the Constrictor knot and the Strangle knot. The second course of wrappings in some seizing knots can be referred to as riding turns. The formation of an unintentional riding turn on a sailing winch can cause it to jam.

title: Knots/Hitch knots/Round turn


text:
User talk:213.166.17.21

Welcome to Wikibooks. We invite everyone to contribute constructively to our collection. Take a look at the welcome page if you would like to learn more about contributing. However, unconstructive edits are considered vandalism, and if you continue in this manner you may be blocked from editing without further warning. Please stop, and consider improving rather than damaging the hard work of others. Thanks. -- Herby talk thyme 13:50, 21 June 2007 (UTC)

title: User talk:213.166.17.21


text:
Talk:X86 Assembly/Bootloaders

Code start
Should the code start at 0x0000 or 0x0100?

 * I'm not quite sure what you're referring to, but MS-DOS .COM files are loaded to address CS:0100h whereas boot loaders are loaded to address 0000:7C00h. AFAIK, all the segment registers are set to 0 by the BIOS, and IP then starts as 7C00h. Telling your assembler that the code will be positioned at 7C00h can ease the calculation of memory offsets. Artelius (talk) 00:51, 19 April 2008 (UTC)

First example
I'm not sure if I understand this code correctly, but in the skip: label, there is a jmp function to print, does this mean it will keep printing "Hello World", indefinitively, and will not stop? 201.216.12.182 (discuss) 04:18, 1 May 2014 (UTC)
 * Well I've just tested it via nasm and VirtualBox myself and it does just that -- it loops "Hello World!" forever. OrangeJacketGuy (discuss • contribs) 07:57, 13 May 2014 (UTC)

title: Talk:X86 Assembly/Bootloaders


text:
Belarusian/Lesson 12

The initial ў
The initial у letter is replaced by the ў if it is preceded by a word with a final vowel.

уро́к a lesson

ця́жкi ўро́к a difficult lesson

This rule does not apply to proper names.

старажы́тная Украіна ancient Ukraine

NOTE: In tarashkievitsa, ў is used in such cases (старажытная Ўкраіна).

(However, note that when an adjective or other word is formed from a proper name, if it starts with a small letter in Belarusian, it's still written with ў: гасці́нныя ўкраі́нцы hospitable Ukrainians).

This is also not applied when the preceding word is separated with a dot, a comma or other punctuation sign.

Сусе́дзi Белару́сi - Расiя, Украiна, По́льшча, Лiтва́ i Ла́твiя. The neighbours of Belarus are Russia, Ukraine, Poland, Lithuania and Latvia.

у after vowels
It is not normal for Belarusian that у be preceeded by a vowel. It is usually replaced by ў in such a position. However, there is a number of words in which у after vowels makes a syllable and thus is not replaced by ў. They are all borrowings, most of them having the us or um ending characteristic to Latin.

ра́дыус a radius

Сiрыус Sirius

Іу́да Judah (the betrayer of Christ)

European borrowings having au or ou diphthongs also have vowel+у combinations.

шо́у a show

аудыто́рыя a lecture hall

A number of such words (earlier borrowings), however, use ў rather than у.

а́ўтар an author

Noun Declension Groups
Belarusian nouns are classified into three groups according to endings they get in declension.

The first declension consists of feminine and masculine nouns ending with а or я.

The second declension is made by neuter nouns and masculine nouns ending with a consonant (having a "zero ending").

The third declension, much less numerous, consists of feminine nouns with zero ending.

First Declension
Most first declension nouns have a zero ending in plural Genitive.

рака́ a river - рэк of rivers

каро́ва a cow - каро́ў of cows

скры́ня a box - скры́нь of boxes

саба́ка a dog - саба́к of dogs

Nouns ending with a consonant + ка obtain а before к in plural Genitive (or е if the first consonant is soft).

пту́шка a cat - пту́шак of cats

ка́зка a tale - ка́зак of tails

ля́лька a doll - ля́лек of dolls

ступе́нька a stair - ступе́нек of stairs

 * Exceptions: ба́цька a father - ба́цькаў of fathers

 * дачка́ a daughter - дачо́к (до́чак) of daughters

Nouns ending with a consonant + consonant + а, when the second consonant is not к, have оў (аў when unstressed) ending in plural Genitive.

царква́ a church - цэ́ркваў of churches

Second Declension
Second declension nouns usually have оў (аў when unstessed) for hard basis and ёў (яў when unstressed) for soft basis.

лес a forest - лясо́ў of forests

конь a horse - канёў of horses

го́рад a town - гарадо́ў of towns

вакно́ a window - во́кнаў of windows

по́ле a field - палёў of fields

Third Declension
Third declension nouns usually have эй (ей for soft basis) ending in plural Genitive.

мыш a mouse - мышэ́й of mice

гусь a goose - гусе́й of geese

Some third declension nouns, however, have оў (аў) or ёў (яў) ending in plural Genitive.

рэч a thing - рэ́чаў of things

The Numbers (1 to 10)
Here are the Belarusian numbers from one to ten.

адзiн one

два two

тры three

чаты́ры four

пяць five

шэсць six

сем seven

во́сем eight

дзе́вяць nine

дзе́сяць ten

The word адзiн is deflected by gender and number.

адзiн го́рад one town

адно́ вакно́ one window

адна́ ву́лiца one street

адны́ дзве́ры one door

The plural form адны is used with nouns that have no singular form and are used in plural even when denoting a single object. It also can be used when адзiн means alone or only.

Я тут адзiн. I am here alone.

Мы тут адны́. We are here alone.

Яны́ адны́ до́бра пла́ваюць. = То́лькi яны́ до́бра пла́ваюць. Only they swim well.

The word два has a feminine form дзве.

All other numbers do not deflect.

With адзiн the nouns are used in the Nominative.

With два, тры and чаты́ры the nouns are used in plural Nominative.

With other numbers the nouns are used in plural Genitive.

адзiн год one year - два гады́ two yearts - тры гады́ three years - пяць гадо́ў five years

адно́ ко́ла one wheel - два ко́лы two wheels - чаты́ры ко́лы four wheels - шэсць ко́лаў six wheels

адна́ мыш one mouse - дзве мы́шы two mice - тры мы́шы three mice - пяць мышэ́й five mice

адна́ рака́ one river - дзве ракi two rivers - тры ракi - three rivers - пяць рэк five rivers

Note carefully the last example. The ending of the noun is not shifted as it usually is with feminine nouns having stressed endings.

The question word to ask about quantity is ко́лькi.

'''Ко́лькi тут паве́рхаў? - Тут адзiн паве́рх.''' How many floors are here? - There is one floor here.

'''Ко́лькi там гусе́й? - Там чаты́ры гу́сi.''' How many geese are there? - There are four geese there.

The Numbers
Use these words with the numbers given in parentheses.

(1) (one, two, seven) book(s)

(2) (one, three, five) mirror(s)

(3) (one, two, four, six) goat(s)

(4) (one, three, eight, ten) oak(s)

(5) (one, two, three, seven) village(s)

(6) (one, two, three, nine) land(s)

Clue: (1) адна кнiга; дзве кнiгi; сем кнiг (2) адно люстра; тры люстры; пяць люстраў (3) адна каза; дзве казы; чатыры казы; шэсць коз (4) адзiн дуб; тры дубы; восем дубоў; дзесяць дубоў (5) адна вёска; дзве вёскi; тры вёскi; сем вёсак (6) адна зямля; дзве зямлi; тры зямлi; дзевяць земляў.

Translation
Translate into Belarusian.

(1) There are six wolves here.

(2) How many students are unwell? Three students are unwell.

(3) How many trees are there? There are seven trees there.

(4) How many jars of honey are here? There are two jars of honey here.

(5) How many students paint well? Only she paints well.

(6) Are we here alone? No, two women are here.

Clue: (1) Тут шэсць ваўкоў. (2) Колькi студэнтаў хварэюць? Тры [студэнты хварэюць]. (3) Колькi там дрэваў? Там сем дрэваў. (4) Колькi тут слоiкаў мёду? Тут два слоiкi мёду. (5) Колькi студэнтаў добра малююць? Яна адна добра малюе. (6) Мы тут адны? Не, тут дзве жанчыны.

title: Belarusian/Lesson 12


text:
Change Issues in Curriculum and Instruction/Final Assignment Links/Peter Baker

Here's my list.

Context rather than Content is of primary importance.
In an era of accountability, content is being emphasized more than ever before. Students are being forced to learn concrete facts at the expense of abstract thought strategies. Likewise, teachers are forced to master the content of their specialty(ies) to such a degree that their other strengths are left out. Teachers don't get to hone their various skills, and students don't get the benefit of linking the diverse knowledge most teachers could offer in a better system.

The world is changing, (duh), and there is no way for us to predict with any level of certainty how the world will look when our students are fully-fledged members of the working world. Nonetheless, the system continues to force-feed its students arbitrarily determined content whose value is impossible to understand. The current focus on content reminds me of a "blind" wager in some gambling game.

The number one change issue in my book is context rather than content. As teachers, our first responsibility is to prepare our students for the world they will encounter after they leave our classroom. It seems to me that, since describing this future-world is impossible, teaching the students how to think and how to find information—rather than exactly what information to know—makes much more sense.

Recursive Learning: Learning does not always happen in linear fashion.
Today's education system, as we all know, very closely mirrors the education system of the distant past. Our society's scientific knowledge, on the other hand, does not. We are lucky enough to have vast knowledge of the human brain at our disposal. Likewise, our educational scholars have researched learning patterns and other pertinent areas of educational psychology and instructional methods to the point where best practices are no longer a matter of conjecture; educators know the right way to teach. Just the same, an object at rest tends to stay at rest, and our educational system has followed this rule.

While many specific things need to change, one irrefutable fact stands above them all. This is my number two change issue—learning is not linear. Learners need to progress at their own paces. A system which employs annual promotion or retention is irresponsible to our students, given all the knowledge the educational community has at its disposal. Another analogy, (since we all liked the last one so well): the current practices of the education system that ignore the fact that learning is recursive are a lot like, (but perhaps not quite as extreme as), principals handing their students cigarettes on the way into the building every morning!

If education leaders put the community's knowledge in practice once and for all, individualized learning programs would no longer be novelties but would be par for the course. Students could learn at their own pace. Specific reforms that come to mind are, as I mentioned before, a departure from the current model of annual promotion or retention, a modularized approach to knowledge mastery and a more flexible model of staffing and administering the schools. Learning theory has proved that learning takes place at different rates for different students. Once the community recognizes this fact, schools can begin to responsibly serve their students.

Digital Divide: How long do we wait to implement these new technologies without waiting too long?
Let me start by saying that I have no idea how to answer the question posed by my number three change issue. The digital divide is very very real, and I have no idea how to negotiate with it. I don't feel bad making this confession, because I get the distinct impression that nobody else knows how to deal with the digital divide either. We all know, to one degree or another, that it exists, but we rarely take the digital divide into consideration when it comes to decisions of technology implementation. In my work here at ODU, I've been guilty of the same negligence. Generally speaking, when educators get a bright idea for technology integration into curriculum, we do it without consideration of who may be disenfranchised by the implementation. The result has been that technology has not been used to its utmost potential in any educational setting. Likewise, students on the overwhelmingly rural, poor and non-white side of the digital divide go without the technologies the rest of us take for granted.

Some scholars claim that the digital divide is getting smaller. After all, more people have internet access today than they did five years ago. However, technological advances are outstripping these gains. New technologies are creating an equally intimidating new digital divide—not between those with internet access and those without, but between those who can efficiently use technology and those who cannot. This is the divide which needs to be explored and traversed. As educators, we need to focus much of our resources on training young, newly "arrived" digital immigrants in the most effective ways possible. The world of the future is uncertain, but it is extremely likely that technology will play a very important role in this world. In order to give our students access to the opportunities they need and deserve, we cannot simply avoid technology. Rather, we must find ways to educate our students in and grant them access to sophisticated technology that is, at present, reserved for the wealthy.

My proposition is a common one. Many people make it, and no one has successfully made it work. We need to find a way to share our society's wealth. Welfare, as it currently stands, is not the answer. If society realized the degree to which the digital divide would shape the futures of its young people, more emphasis would be placed on this issue. My hope is that digital divide consciousness will bring about significant and wide-sweeping social change that our world has craved for centuries.

Who's Responsible? Who should be held accountable for making change happen? and Professionalizing the Teaching Profession: Teacher and Administrator Accountability and Effective Motivation
My number four change issue (like all my others) may as well be my number one. Accountability, even as it gains popularity as a buzzword, remains dangerously uncertain in the educational community today. It is unclear who is responsible for what, and as NCLB approaches its zenith, it's easy to predict some serious finger-pointing among some of the community's most powerful people.

As an individualistic American, I hate bureaucracy as much as the next guy, but I think that the educational community is in need of some. However, NCLB has proven that extrinsic regulation is not the answer. The answer seems clear. An organization of educational high-ups needs to be formed to develop some accountability system within the community. Teachers can no longer be blamed for bigger problems, and until an attempt is made to meet accountability head-on, such problems will be unavoidable.

On a more positive note, were accountability finally wrestled down, change could really happen. Passing the buck would no longer be tolerated, and real reforms could come to fruition rather than hanging in the vapor and eventually disappearing completely.

How School Policy Should be Influenced by Social Software
As social software becomes a larger part of our world (and that of our students), it becomes apparent that regulations will need to be adopted to ensure the safety of our students and to ensure the quality of their educational experiences.

Child pornography, digital bullying and identity theft pose real risks to all of us, especially our digital immigrants and children. These issues are being handled, but not quickly enough to effectively protect everyone at risk. Some major resources need to be geared toward figuring this issue out. On the other hand, schools have already limited student's access to various social software-type sites, and this censorship is creating a forbidden fruit mystique which may prove counter-productive. Rather than this type of reform, it seems to me that more thoughtful safeguards need to be devised. A spirit of shared responsibility between the society and the schools would be a good starting point, but it goes without saying that we are far from such a starting point, at least for now.

On the other side of the coin, social software presents us with many new educational opportunities. The wikis we've used here at ODU are prime examples. In an attempt to convert the nay-sayers (to cite yet another change issue), and in order to guarantee the quality of these new opportunities, research needs to be undertaken to address issues such as credibility and intellectual property rights. Without this research, social software will always be scorned by the conservative academics, and the potential benefits of social software can never be realized.


text:
Logic for Computer Scientists/Predicate Logic/Strategies for Resolution/A Prolog-like Implementation

A Prolog-like Implementation
gprove(true,_). gprove((G & H),A):- gprove(G,A), gprove(H,A). gprove(G,A):- member(G,A). gprove(G,A):- (G <- B), neg(G,NG), gprove(B,[NG|A]).

p(a,X) <- ~p(b,Y) & q(X,Y). p(b,Y) <- ~p(a,X) & q(X,Y). ~q(X,Y) <- ~p(a,X) & ~p(b,Y). p(Z,Z) <- true. q(b,a) <- true. yes   <- p(U,V). ~p(U,V) <- ~yes.


text:
User:Whiteknight/Wikibooks Categories

I would like to redo the category system in order to make it more coherent and easier to navigate. --Whiteknight (Page) (Talk) 19:23, 21 June 2007 (UTC)

The Plan

 * Category:Categories (new root category)
 * Category:Wikibooks
 * Category:Discussion Pages
 * Category:Policy and Guidelines
 * Category:Message Templates (for site-wide nessage templates templates)
 * Category:Main Page (for the main page, it's subpages, etc)
 * Category:Wikijunior (category for wikijunior meta-data pages)
 * Category:Books (root node for all books)
 * Category:Boolshelves (category for each bookshelf)
 * Category:Wikibooks bookshelves (redirected to the previous category, for consistency)
 * Category:Alphabetical
 * Category:Dewey (Dewey decimal classifications)
 * Category:Library of Congress
 * Category:Books by Audience
 * Category:Children's Books (contains wikijunior books)
 * Category:Books for School Students
 * Category:Books for University Students
 * Category:Books for Graduate Students
 * Category:Books for Professionals
 * Category:Books for Hobbyists
 * Category:Books by Curriculum
 * Category:Help
 * Category:Users
 * Category:Projects
 * Category:Curriculum (used for pages related to curricula)

title: User:Whiteknight/Wikibooks Categories