# Radiation Oncology/Prostate/Localized Prostate Cancer

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Localized Prostate Cancer

## Definitions

* Historically, clinically localized prostate cancer was primarily determined by stage. Patients with T1-T2 could be offered watchful waiting, surgery, or radiation therapy. Patients with T3-T4 disease were not considered surgical candidates
** Localized: T1-T2
** Locally advanced: T3-T4
* More recently, urologists have been treating some T3a patients using the robotic surgery. Also, NCCN (www.nccn.org) risk stratification includes T3a patients in the localized disease
** Low risk: T1-T2a and PSA <10 and GS 2-6
** Intermediate risk: T2b-T2c or PSA 10-20 or GS 7
** High risk: T3a or PSA >20 or GS 8-10
** Locally advanced: T3b-T4

## Prospective Comparisons

* There are no conclusive randomized trials comparing the 3 primary modalities (EBRT, permanent brachytherapy, radical prostatectomy)
* There have been a number of failed trials in the past, but more recently both the PIVOT trial and the ProtecT trial completed accrual. START trial is ongoing
* Also see:
** Radiation_Oncology/Prostate/Prostatectomy#Prostatectomy vs RT
| Randomized Trial | Dates | Arm 1 | Arm 2 | Arm 3 | Status (2009) |
| NCIC START | 2007- | AS | RP or RT | | Accruing |
| UK ProtecT | 2001-2008 | AS | RP | RT | Published |
| ACOSOG SPIRIT | 2000-2004 | RP | Brachy | | Failed |
| Calgary | 1997-2003 | RT | Cryo | | Published |
| Western Ontario | 1990's - 2000's | RT | Cryo | | Published |
| NCI PIVOT | 1994-2002 | WW | RP | | Published |
| Scandinavian SPCG-10 | 1990's | RP | RT | | Failed |
| UK Christie Hospital | 1990's | RP | RT | | Failed |
| UK MRC PR06 | 1994-1996 | WW | RP | RT | Failed |
| Scandinavian SPCG-7 | 1989-2002 | ADT | RT | | Published |
| Scandinavian SPCG-4 | 1989-1999 | WW | RP | | Published |
| Japanese | 1989-1993 | RP | RT | | Published |
| SWOG 8890 | 1980's | RP | RT | | Failed |
| US Uro-Oncology Group | 1970's | RP | RT | | Published |
| VACURG | 1967-1975 | WW | RP | | Published |

### Systematic Reviews

* Italy; 2014 (1965-2007) PMID 24589471 -- "Radical Prostatectomy or Radiotherapy in High-Risk Prostate Cancer: A Systematic Review and Metaanalysis." (Petrelli F, Clin Genitourin Cancer. 2014 Aug;12(4):215-224.)
** Meta-analysis; high risk pts, treated with RT vs RP (w/ or w/o ADT), no brachy. 17 studies (16 retrospective, 1 randomized); 13,704 pts.
** RP associated with improved OS (OR 0.51), PCSM (OR 0.56), and non-PCSM (OR 0.53). bRFS similar to RT.
** Conclusion: "Overall and cancer-specific mortality rates appear to be better with RP compared with RT in localized, high-risk PC. Surgery is also associated with a 50% decreased risk of non-PCSM compared with RT."
* Amsterdam; 2009 (1980-2007) PMID 19748692 -- "Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review." (Pieters BR, Radiother Oncol. 2009 Nov;93(2):168-73. Epub 2009 Sep 11.)
** Systematic review; EBRT vs EBRT + seed brachytherapy vs EBRT + HDR. 40 studies.
** Outcome: HR for biochemical recurrence EBRT 1.40 vs EB+Seeds 1.37 vs EB+HDR 1.0 (SS); HR for OS EBRT 1.5 vs EB+Seed 2.33 vs EB+HDR 1.0 (SS)
** Conclusion: EBRT with HDR boost results in superior biochemical control and overall survival
* Minnesota; 2008 PMID 18252677 -- "Systematic Review: The Comparative Effectiveness and Harms of Treatments for Clinically Localized Prostate Cancer." (Wilt TJ, Ann Intern Med. 2008 Feb 4 [Epub ahead of print])
** 18 RCTs and 473 observational studies reviewed
** Conclusion: Assessment of comparative effectiveness and harms is difficult because of limitations in the evidence
* Karolinska; 2004 PMID 15303499 -- "A systematic overview of radiation therapy effects in prostate cancer." (Nilsson S, Acta Oncol. 2004;43(4):316-81.)
** 30 RCTs, 55 prospective trials, 210 retrospective studies. Total of 152,614 patients
** Conclusions: There is lack of randomized studies comparing surgery with EBRT or brachytherapy. With advent of prognostic markers (T-stage, PSA, GS), comparisons between modalities can be made in absence of randomized trials and some conclusions can be drawn
* Toronto; 2004 PMID 15003149 -- "A systematic review of randomized trials in localized prostate cancer." (Alibhai SM, Can J Urol. 2004 Feb;11(1):2110-7.)
** 9 publications dealing with 4 RCTs identified (RP vs WW x2, RP vs EBRT x2)
** Conclusion: Further randomized trials are needed
* Oregon; 1993 PMID 8487449 -- "A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team." (Fleming C, JAMA. 1993 May 26;269(20):2650-8.)
** Decision analysis on RP, EBRT or WW using data from review of literature and Medicare claims data
** Outcome: In well-differentiated tumors, treatment offers at best limited benefit in terms of QALY and may result in harm. In moderately/poorly differentiated tumors and age 60-65, RP or EBRT may benefit over WW, but typically <1 QALY. In patients >70, treatment generally appears harmful
** Conclusion: RP and EBRT may benefit select groups, however, in most cases potential benefits are small and choice of therapy is sensitive to patient's preference

### Observation vs Radical Prostatectomy

Please see the natural history page
* VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) (1994-2002) -- radical prostatectomy vs observation
** Randomized. 731 men. clinicaltrials.gov entry
** 2017 PMID 28700844 -- "Follow-up of Prostatectomy versus Observation for Early Prostate Cancer." (Wilt TJ, N Engl J Med. 2017 Jul 13;377(2):132-142.)
*** Median f/u 12.7 years. Death in 61.3% (surgery) vs 66.8% (obs)(p=0.06). PC-related mortality in 7.4% vs 11.4% (p=0.06).
*** Disease progression in 40.9% vs 68.4%. Most progression local; regional in 9.1%/14.2%; distant in 10.2%/14.7%. Treatment for disease progression in 33.5% vs 59.7%. Definitive treatment in 20.4% (obs). Use of ADT in 21.7% vs 44.4%.
*** Conclusion: After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression.
** 2012 PMID 22808955 -- "Radical prostatectomy versus observation for localized prostate cancer" (Wilt TJ, N Engl J Med. 2012 Jul 19;367(3):203-13)
*** Median F/U 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation NS. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (SS). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.
** 2009 PMID 18783735 -- "The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer." (Wilt TJ, Contemp Clin Trials. 2009 Jan;30(1):81-7. Epub 2008 Aug 23.)
*** Study overview. 13,022 men screened; 5,023 met eligibility criteria; 731 agreed to participate and were randomized.
*** Description: Mean age 67 years. Median PSA 7.8 ng/ml. Low risk 43%, intermediate risk 36%, high risk 20%. Predominately detected by rising PSA
*** Conclusion: Diverse population representative of men diagnosed with PCA in United States
** 1994 PMID 7523736 -- "The Prostate Cancer Intervention Versus Observation Trial: a randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer" (Wilt TJ, J Urol. 1994 Nov;152(5 Pt 2):1910-4.)
*** Description of the trial
* 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.
** 11-years; 2008 PMID 18695132 -- "Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial." (Bill-Axelson A, J Natl Cancer Inst. 2008 Aug 20;100(16):1144-54. Epub 2008 Aug 11.) Median F/U 10.8 years (3 weeks - 17.2 years)
*** Outcome: 12-year death due to PCA surgery 12% vs. observation 18% (SS); 12-year DM rate 19% vs. 26% (SS). For surgery, if ECE+ PCA death rate 14x higher than if ECE-
*** Conclusion: RP reduces PCA mortality, with little or no further increase in benefit 10+ years after surgery
** Median FU 12.8-years; 2011 PMID 21542742 -- "Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial." (N Engl J Med. 2011 May 5;364(18):1708-17) Median F/U 12.8 years
*** Outcome: 12-year death with surgery 48% vs. observation 57% (SS); Survival benefit confined to <65-years of age ; death from prostate cancer that was 7 times that of men without extracapsular tumor growth -
*** Conclusion: RP reduces mortality
* 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

### Active Surveillance vs Radical Intervention

Please see the natural history page
* Surveillance Therapy Against Radical Treatment (START) -- radical intervention (RP or RT) vs. active surveillance
** See also: Active Surveillance
** Terminated. January 10, 2013 (Not meeting accrual target) Randomized. . NCIC coordinated, enrolling in Canada, US and UK
* Prostate testing for cancer and treatment (ProtecT) -- surgery vs RT vs active surveillance
** Randomized, nested. First ask to randomize to 3 arm trial (surgery vs RT vs active surveillance), if refused, asked to randomize to 2 arm trial (surgery vs RT).
** Active surveillance: consider definitive treatment if PSA increase by 50% in one year. RT: neoadj hormones 3-6 months, 74 Gy. Surgery: post-op RT allowed.
** 2016 PMID 27626136 -- "10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer." (Hamdy FC, N Engl J Med. 2016 Oct 13;375(15):1415-1424.)
*** No difference in PC-related deaths or overall deaths. Higher rate of metastases and disease progression in AS group vs surgery or RT.
*** AS: 54.8% received radical intervention (1/4 of these within 9 months).
*** RP: 18 of 391 (4.6%) with primary treatment failure, including 9 with detectable PSA at 3 months and 9 who received adjuvant RT.
*** RT: 14% had PSA failure (nadir+2)
*** Clinical progression (Met dz, T3 or T4, long term ADT, obstruction, need for catheter): 22.9% per 10 yr (AS) vs 8.9% (RP) vs 9.0% (RT). [i.e. 22.9 per 1000 person-yr = 22.9% of men per 10 yrs]
*** Conclusion: At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring.
** 2002 PMID 12364308 -- "Quality improvement report: Improving design and conduct of randomised trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study. Commentary: presenting unbiased information to patients can be difficult." (Donovan J, BMJ. 2002 Oct 5;325(7367):766-70.)
*** Lessons learned. After changes, all treatments became acceptable, the three arm trial became the preferred design, and randomisation rate increased from 40% to 70%
*** Conclusion: Embedding trial within qualitative research improved recruitment

### Surgery vs RT

* CaPSURE -- radical prostatectomy vs RT vs hormonal therapy
** Prospective, non-randomized. 7538 pts. Pts followed uniformly
** 2010 PMID 20690197 -- "Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer." (Cooperberg MR, Cancer. 2010 Aug 5. [Epub ahead of print])
*** Hazard ratio for cancer-specific mortality 2.21 for RT and 3.22 for ADT (relative to prostatectomy). Absolute differences between RP and RT were small for low risk prostate cancer but increased for intermediate and high risk disease.
* ACOSOG Z0070 (SPIRIT) (2002-2004) -- radical prostatectomy vs brachytherapy
** Randomized, North American, patients with T1c or T2a N0 M0 prostate cancer. Permanently closed in 2004 due to non-accrual. 56 patients randomized.
** Princess Margaret; 2006 PMID 16943531 -- "Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial." (Wallace K, J Clin Oncol. 2006 Sep 1;24(25):4158-62.)
*** Development and success of multidisciplinary education session described
*** Conclusion: Men who understand their treatment options are more likely to consent to random assignment
** 2011; HRQOL (Princess Margaret) PMID 21149658 -- "Comparison of Health-Related Quality of Life 5 Years After SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial." (Crook JM, J Clin Oncol. 2011 Feb 1;29(4):362-8.)
*** 190 men eligible for trial seen at Princess Margaret. 34 consented to randomization, 62 chose RP, 94 chose BT. At 5 years after treatment, HRQOL evaluation.
*** Of 168 responders, 102 had BT, 66 had RP. Men treated with BT had better urinary and sexual scores as well as better patient satisfaction; no difference in bowel or hormonal scores.
*** Conclusion: Advantage to BT for urinary and sexual domains and patient satisfaction. (Caution: only 19% were randomized; the others were by choice)
* Scandinavian SPCG-10 -- randomized RT vs. prostatectomy
** Trial abandoned
* Multicenter; 2008 (2003-2006) - radical prostatectomy, brachytherapy, or EBRT.
** Prospective, non-randomized. 1201 pts. Multicenter, 9 hospitals. Treatment with RP, BT, EBRT, +/- hormones. Outcomes surveyed at 2-24 months from the start of treatment.
** 2008 PMID 18354103 -- "Quality of life and satisfaction with outcome among prostate-cancer survivors." (Sanda MG, N Engl J Med. 2008 Mar 20;358(12):1250-61.) -- Median f/u 30 mo
*** Erectile dysfunction: distress related to erectile dysfunction in 44% (RP), 22% (EBRT), 13% (BT).
*** Urinary: moderate or worse distress in 18% (BT), 11% (EBRT), 7% (RP). EBRT: resolved at 12 months and improved over baseline at 24 months. RP: incontinence worst by 2 months and then improved in most; urinary irritative and obstructive symptoms improved over baseline. BT: worse irritation, obstruction, and incontinence compared to baseline; incontinence 4-6% at 1-2 yrs. Large prostate size and hormonal therapy exacerbated urinary irritation after EBRT or BT.
*** GI: bothersome symptoms in 9% of patients (BT or EBRT) at 1 yr. No symptoms in RP patients. BT and EBRT pts had reduced GI QOL early after treatment, lasting 1 yr or more.
* Christie Hospital, UK -- radical prostatectomy vs radical RT
** Randomized. Patients with Stage T1b-T2bN0, GS <=7, PSA <20. Trial closed due to lack of accrual and was converted to a patient-preference study
** 1999 PMID 10356027 -- "Few patients with prostate cancer are willing to be randomised to treatment." (O'Reilly P, BMJ. 1999 Jun 5;318(7197):1556.)
*** Letter to editor. 20 patients evaluated over 12 months, but only 1 agreed to randomization
** 2000 Abstract -- "Trial of Randomisation Between Radical Prostatectomy and Radiotherapy in Early Prostate Cancer" (Livessey JE, Clin Oncol. 2000;12:63)
*** 41 patients counselled, only 1 agreed to be randomized. Reminder chose surgery (55%), RT (42%), or watchful waiting (3%)
** 2002 PMID 12133061 -- "A preliminary report on a patient-preference study to compare treatment options in early prostate cancer." (North West Uro-Oncology Group, BJU Int. 2002 Aug;90(3):253-6.)
*** Prospective. 196 patients recruited (surgery 41%, conformal RT 41%, brachytherapy 15%, watchful waiting #). Similar patient characteristics across groups
*** Conclusion: It should be possible to answer underlying question with this study design
* MRC PR06 (1994-1996) -- Radical prostatectomy vs RT vs watchful waiting
** Randomized. Trial closed early due to non-accrual. 35 men accrued of target 1800.
** 2004 PMID 15610132 -- "Early closure of a randomized controlled trial of three treatment approaches to early localised prostate cancer: the MRC PR06 trial." (PR06 Collaborators, BJU Int. 2004 Dec;94(9):1400-1.)
* 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
** Comment: low RT dose. Small study.
* SWOG 8890 -- randomized RT vs. prostatectomy
** Randomized. Stage A2 and B. Goal 1128 patients. Study closed due to poor accrual (referenced in PMID 7754277, PMID 16018945)
* 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
** 1988 PMID 3360648 -- "More on the Uro-Oncology Research Group report of radical surgery vs. radiotherapy for adenocarcinoma of the prostate." (Hanks GE, Int J Radiat Oncol Biol Phys.)
** Critique: small sample, randomization artifacts (imbalances in health, age, lymph node assessment), worse than usual RT outcomes. Results never widely accepted

### RT 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 endpoing 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

### ADT vs RT + ADT

* Please see the Primary ADT section for more detail
* 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
* MRC (1980-1985) -- orchiectomy vs RT vs orchiectomy + RT
** Randomized, 3 arms. 277 patients, clinically localized prostate cancer (T2-T4NxM0). Arm 1) RT alone vs Arm 2) orchiectomy alone vs Arm 3) RT + orchiectomy
** 1992 PMID 1422689 -- "Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. Urological Cancer Working Party--Subgroup on Prostatic Cancer." (Fellows GJ, Br J Urol. 1992 Sep;70(3):304-9.)
*** Outcome: Orchiectomy (orchiectomy alone or orchiectomy + RT) superior to RT alone in DMFS. No difference in local control or overall survival
*** Conclusion: Orchiectomy superior to RT alone in metastatic-free survival

## Retrospective Comparisons

Single institution data suggests comparable outcomes between RP and high-dose (>72 Gy) EBRT, but advantage to RP compared with low-dose (<72 Gy) EBRT. In unfavorable tumors, there appears to be some benefit to RT:

### Single Institution

* Washington U; 2012 PMID 22335870 -- "Survival among men with clinically localized prostate cancer treated with radical prostatectomy or radiation therapy in the prostate specific antigen era." (Kibel AS, J Urol. 2012 Apr;187(4):1259-65.)
** Retrospective. 10,429 consecutive pts treated with RP, EBRT, or BT.
** 10-yr OS: favors RP (88.9%) over EBRT (82.6%) or BT (81.7%). Adjusted PCA specific mortality favors RP (1.8%) vs EBRT (2.9%) or BT (2.3%). EBRT is associated with decreased OS and PCSM compared with RP. BT is associated with decreased OS but not PCSM compared with RP.
** Conclusion: "After adjusting for major confounders, radical prostatectomy was associated with a small but statistically significant improvement in overall and cancer specific survival. These survival differences may arise from an imbalance of confounders, differences in treatment related mortality and/or improved cancer control when radical prostatectomy is performed as initial therapy."
* Mayo Clinic - Scottsdale; 2009 PMID 19670452 -- "Radiation dose escalation for localized prostate cancer: intensity-modulated radiotherapy versus permanent transperineal brachytherapy." (Wong WW, Cancer. 2009 Dec 1;115(23):5596-606.)
** Retrospective. 853 pts. Conventional dose 3D-CRT (median 68.4 Gy), high dose IMRT (75.6 Gy), brachytherapy alone (144 Gy I or 120 Gy Pd), EBRT + BT (45 + 110/90). Median f/u 58 mo.
** 5-yr bNED 74% (3D), 87% (IMRT), 94% (BT), 94% (EBRT+BT). For int risk: improved bNED for IMRT, BT, or EBRT+BT vs 3D; no improvement noted for low risk.
** BT caused more GU but less GI tox, EBRT + BT caused more late GU and GI tox than IMRT or 3D.
* British Columbia Cancer Agency; 2009 (1998-2001) PMID 19570619 -- "Brachytherapy or Conformal External Radiotherapy for Prostate Cancer: A Single-Institution Matched-Pair Analysis." (Pickles T, Int J Radiat Oncol Biol Phys. 2009 Jun 29. [Epub ahead of print])
** Retrospective, matched-pair. 601 patients, BCCA database, matched for PSA, GS, T-stage, use/duration of ADT, %positive cores. 278 perfect matches analyzed further. Median BT dose 144 Gy, EBRT dose 68 Gy. Primary endpoint bNED (Phoenix). Median F/U 5.7 years
** Outcome: 5-year bNED BT 95% vs. EBRT 85% (SS), 7-year bNED 95% vs. 75% (SS). Median post-treatment nadir 0.04 ng/ml vs 0.62 ng/ml (SS), which predicted higher EBRT treatment failure rate. Low risk 94% vs 88% (SS); intermediate risk 100% vs. 78%
** Toicity: Late Grade 3 GI/GU at 2 years BT 1% vs. EBRT 6%, at 5 years 5% vs. 2%. Late urinary worse with BT, late rectal/bowel worse with EBRT. Catheterization 15% (42% > 1 month) vs. 0% (SS)
** Conclusion: Brachytherapy for low-risk and selected intermediate-risk exceptional cure rate that will be hard to match for EBRT, even with dose escalation
* Geneva; 2007 (1989-1998) PMID 17923593 -- "Short- and Long-term Mortality With Localized Prostate Cancer." (Merglen A, Arch Intern Med. 2007 Oct 8;167(18):1944-50.)
** Cohort study. All 844 patients with localized PCA diagnosed 1989-1998. Prostatectomy (19%), RT (24%), watchful waiting (45%), hormones (9%), other (4%). Survival curve comparison
** Outcome: 5-year DSS no difference. 10-year DSS: surgery 83% vs. RT 75% vs. watchful waiting 72% (SS). Increased mortality primarily in patients <70 and GS >=7
** Conclusion: Surgery offers best chance of long-term PCA-specific survival
** Critique (PMID 18775078, Full Text): No primary end-point definition, imbalances in PSA and GS, clinical vs pathological staging, no info on RT dose which was likely low in that time period
* University of Virginia; 2006 (1988-2000) PMID 16965872 -- "Case-matched comparison of contemporary radiation therapy to surgery in patients with locally advanced prostate cancer." (Fletcher SG, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1092-9. Epub 2006 Sep 11.)
** Retrospective, matched cohort. 409 men with high-risk PCA (Stage >= T2b or PSA >=10 or GS 7-10). Treated with RP, brachytherapy alone, or EBRT+BT boost + ADT. 208 matched
** Outcome: 4-year bPFS EBRT+BT 72% vs. brachy 25% vs. RP 53% (SS). RR of relapse for EBRT+BT 0.56, RP 1.0, and brachy alone 0.44 (SS)
** Conclusion: High risk PCA patients receiving multimodality therapy display superior outcome to surgery or brachytherapy alone
* Columbia 2005 ASCO Abstract -- Intermediate-Risk Localized Prostate Cancer in the PSA Era:Radiotherapeutic Alternatives and the Effects of Biochemical Failure Definition and Year of Treatment on Outcome (Ennis RD, ASCO)
** 347 patients with intermediate cancer treated 8/89-6/01 with standard EBRT (SD-EBRT), high dose >72 Gy EBRT (HD-EBRT), brachytherapy, or brachytherapy+EBRT. AST analyzed also. Median follow-up 36 months
** All treatments were comparable to each other except brachytherapy-based vs. SD-EBRT (p=0.0003)
** AS+SD-EBRT better than SD-EBRT (p=0.0001) only if failure definition PSA > 1.5 is used
** Conclusion: "For intermediate-risk prostate cancer patients, brachytherapy-based treatment results in an excellent outcome that is significantly better than SD-EBRT. AD+SD-EBRT may also result in improve outcome compared to SD-EBRT, but this conclusion is dependent on the definition of biochemical failure. Year of treatment is an important prognostic factor in patients with intermediate-risk prostate cancer treated in the PSA era."
* Cleveland Clinic, 2002 (1990-98) PMID 12177097 Full Article -- "Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy." (Kupelian PA, J Clin Oncol.)
** Retrospective, single-institution. 1682 pts with clinical stage T1-T2, treated during the PSA era. Treated with prostatectomy (n=1,054) or RT (n=628) to 68-78 Gy (median 70.2 Gy). Excluded pts with adjuvant androgen deprivation. Allowed neoadjuvant androgen deprivation if less than 6 months (19%). End-point was biochemical relapse free survival. Used ASTRO definition for PSA failure after RT. For RP failure was two consecutive PSA > 0.2; defined failure at time of first detectable level. Median follow-up 51 months
** 8-year overall PSA-DFS: RP 72% vs. RT 70% (p=0.01) but RP patients significantly more favorable profile
** 8-year PSA-DFS for favorable tumors (T1-T2a, GS<=6, PSA<=10): RP 86% vs. RT 90% (NS)
** 8-year PSA-DFS for unfavorable tumors: RP 62% vs. RT 59% (NS) but dose dependent:
*** 8-year PSA-DFS for unfavorable tumors at RT <72Gy: RP 70% vs. RT 50% (p<0.001)
*** 8-year PSA-DFS for unfavorable tumors at RT >72Gy: RP 70% vs. RT 82% (p=0.004)
* Harvard/UPenn PMID 12124827 Full Article -- Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. (2002 D'Amico, Cancer)
** A retrospective study of 2635 men treated with RP (n = 2254) or conventional-dose RT (n = 381) between 1988-2000. ASTRO definition for both RP and RT. Median follow-up 48 months)
** 8-year PSA-DFS for low risk (T1c-T2a and PSA <=10 and GS <=6): RP 88% vs RT 78% (p<0.01)
** 8-year PSA-DFS for intermediate-risk (T2b or GS=7 or PSA 10-20) with <34% positive bx: RP 79% vs. RT 65% (p=0.05)
** 8-year PSA-DFS in intermediate-risk with >34% positive bx: RP 36% vs RT 35% (p=NS)
** 8-year PSA-DFS in high risk (T2c or PSA>20 or GS 8-10): RP 33% vs RT 40% (p=NS)
** Original paper, 1998 - PMID 9749478 - see above under section Definitions of Risk Groups
* M. D. Anderson Cancer Center Orlando, 2004 (1990-98) - PMID 14697417 — "Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer." Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):25-33 Kupelian et al.
** Retrospective. Comparison of biochemical relapse-free survival (bRFS) for various methods.
** CONCLUSION: The biochemical failure rates were similar among PI, high-dose (> or =72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (<72 Gy) EBRT.
* Memorial Sloan Kettering Cancer Center at Mercy Medical Center, 2004 (1992-98) - PMID 15066293 — "Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation" Radiother Oncol. 2004 Apr;71(1):29-33 Potters L et Al.
** Retrospective. 1819 pts, clinical stage T1-T2 (AJCC 1997). Compared freedom from biochemical recurrence (FBR) for various methods. EBRT dose was >= 70 Gy. All received monotherapy without adjuvant therapy.
** 7-year FBR for PPB vs EBRT vs RP were 74, 77, and 79%, respectively. Multivariate analysis identified iPSA and bGS as prognostic factors of relapse. Treatment modality, age, clinical T-stage, and race were not independent predictors of failure.
** CONCLUSIONS: Pretreatment PSA levels, and biopsy Gleason score determined outcome in this study cohort. Biochemical failure rates in this study cohort are similar between PPB, RT, and RP as monotherapy for clinically localized prostate cancer.
* Wake Forest; 2001 (1998-1999) PMID 11597800 -- "A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy." (Lee WR, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):614-23.)
** Prospective. 90 men with T1-T2, treated with curative intent. Brachytherapy (50%), EBRT (25%), RP (25%). Completed QoL questionnaire prior and at 1 month, 3 months, and 12 months
** Outcome: Scores not significantly different at 12 months amongh the 3 groups
** Conclusion: Health-related QoL is treatment-specific

### Review

* Harvard; 2009 PMID 19417179 -- "A 64-year-old man with low-risk prostate cancer: review of prostate cancer treatment." (Sanda MG, JAMA. 2009 May 27;301(20):2141-51. Epub 2009 May 5.)

### Point-Counterpoint

* Journal of Urology 2009
** AS PMID 19836767 -- "Active surveillance for favorable risk prostate cancer. Pro." (Klotz L, J Urol. 2009 Dec;182(6):2565-6. Epub 2009 Oct 17.)
** AS risks PMID 19836809 -- "Active surveillance for favorable risk prostate cancer. Beware the risks." (Parekh DJ., J Urol. 2009 Dec;182(6):2566-8. Epub 2009 Oct 17.)
* Oncology 2009
** RP PMID 19839427 -- "Radical prostatectomy reigns supreme." (Rayala HJ, Oncology (Williston Park). 2009 Sep;23(10):863-7.)
** RT PMID 19839425 -- "Radical radiotherapy for prostate cancer is the 'only way to go'." (Sandler HM, Oncology (Williston Park). 2009 Sep;23(10):840-3.)
* Urology 2008
** EBRT PMID 19022492 -- "Why External Beam Radiotherapy Is Treatment of Choice for Most Men With Early-stage Nonmetastatic Prostate Cancer." (Horwitz EM, Urology. 2008 Nov 19. [Epub ahead of print])
** Brachytherapy PMID 19038423 -- "Brachytherapy for Localized Prostate Cancer." (Ciezki JP, Urology. 2008 Nov 25. [Epub ahead of print])
* Urological Oncology 2008
** Active treatment PMID 18774465 -- "Screen detected, low volume prostate cancer: the case for active treatment." (Montie JE., Urol Oncol. 2008 Sep-Oct;26(5):511-5.)
** Observation PMID 18774462 -- "What is the best approach for screen-detected low volume cancers?--The case for observation." (Klotz L, Urol Oncol. 2008 Sep-Oct;26(5):495-9.)

### 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
* UCSF; 2009 PMID 19841280 -- "Patient decision aids for prostate cancer treatment: a systematic review of the literature." (Lin GA, CA Cancer J Clin. 2009 Nov-Dec;59(6):379-90. Epub 2009 Oct 19.)
** Systematic review. 13 studies of decision aids for patients with low-risk prostate cancer
** Outcome: Use of DA's can improve knowledge, encourage active patient involvement, and decrease anxiety. Impact on treatment choice less clear
* Fred Hutchinson
** 2009 PMID 19589564 -- "Access to information sources and treatment considerations among men with local stage prostate cancer." (Ramsey SD, Urology. 2009 Sep;74(3):509-15. Epub 2009 Jul 9.)
*** Prospective survey of men with local prostate cancer, prior to starting therapy
*** Outcome: On average, ~5 sources of info consulted. Physician (97%), lay literature (76%), other health professionals (71%), friends with PCA (67%), internet (58%)
*** Conclusion: Men consult wide range of information sources
** 2006 PMID 16568450 -- "Why do men choose one treatment over another?: a review of patient decision making for localized prostate cancer." (Zeliadt SB, Cancer. 2006 May 1;106(9):1865-74.)
*** Literature review.
*** Outcome: Conflicting evidence on how men make decisions

## Incidentally detected prostate cancer (T1a-b)

* U.New Mexico, 1988 - PMID 3193495 - "Incidental carcinoma of the prostate: an analysis of the predictors of progression." Lowe BA et al. J Urol. 1988 Dec;140(6):1340-4.
** Constructed probability tables for progression based on Gleason score and volume of disease.
* Cantrell, 1981 - PMID 7218450 — "Pathological factors that influence prognosis in stage A prostatic cancer: the influence of extent versus grade." Cantrell BB et al. J Urol. 1981 Apr;125(4):516-20.
** 117 pts. No pt with Gleason 2-4 had progression. Only 2% with Stage T1a (<5% cancer) had progression. Of Stage T1b (>5% cancer), 32% had progression, and for Gleason 5 and above, 17% progressed.
** No additional treatment needed for Stage T1a with Gleason 2-4.

## Organ-confined (T1-T2) cancers
### EBRT

* Conventional (2D) RT can safely deliver maximum 65-70 Gy before causing significant GI and GU toxicity. Some subpopulations of tumor clonogens appear resistant to this dose.
* 3D-CRT allows delivery of significantly higher doses, and is currently the standard of care
* IMRT permits further dose escalation while providing lower GI toxicity. Its role is under evaluation

### EBRT Outcomes

* Multi-institutional PMID 15667961 -- Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: the combined experience of nine institutions in patients treated in 1994 and 1995. (2005 Kupelian P, Int J Radiat Oncol Biol Phys. 2005 Feb)
** 1325 patients with T1-T2 treated in 1994 and 1995; 1061 were treated with <72 Gy (median dose 68.4 Gy, median follow-up 5.8 years) and 264 with > or =72 Gy (median dose 75.6 Gy, median follow-up 5.7 years).
** PSA-DFS estimates were 64% at 5-years and 62% at 8-years.
** The 5-year PSA-DFS estimates for <72 Gy vs. > or =72 Gy were 63% vs. 69% (p = 0.046).
* Multi-institutional PMID 14575822 -- Long-term multi-institutional analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA era. (2003 Kuban DA, Int J Radiat Oncol Biol Phys. 2003)
** 4839 patients with T1b, T1c, and T2; no hormones; median follow-up 6.3 years
** PSA-DFS was 59% at 5 years and 53% at 8 years after treatment
** Of the 4839 patients, 1582 (33%) had PSA failure, 416 (9%) had local failure, and 329 (7%) had distant failure.
* Multi-institutional PMID 10235152 -- Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. (1999 Shipley WU, JAMA. 1999)
** Retrospective, nonrandomized, multi-institutional pooled analysis of patients treated with EBRT alone between 1988 and 1995 at 6 US medical centers. Conventional + 3D-CRT techniques
** 1765 men with stage T1b, T1c, and T2 tumors
** 5-year OS 85%, DFS 95%, bNED 66%
** for more info: see at page Prostate Overview
* MGH PMID 7751173 -- The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. (1995 Zietman AL, Int J Radiat Oncol Biol Phys. 1995)
** Retrospective, single institution (MGH) review. PSA failure defined >4ng/ml
** 1044 total patients, 504 with T1/T2;median follow-up 49 months
** 5-year bNED: 60%
** 10-year bNED: 40%
* RTOG PMID 8270458 -- Patterns of Care and RTOG [75-06 and RTOG 77-06] studies in prostate cancer: long-term survival, hazard rate observations, and possibilities of cure. (1994 Hanks GE, Int J Radiat Oncol Biol Phys. 1994)
** 10-year clinical DFS: 85-96%
* Stanford PMID 3173503 -- Status of radiation treatment of prostate cancer at Stanford University. (1988 Bagshaw MA, NCI Monogr. 1988;(7):47-60.)
** 900 patients (T0-T4) treated in 30-year Stanford review
** 15-year OS: T0 was 45%, T1 was 35%, and T2 was 33%
** 15-year clinical DFS: T0 was 85%, T1 was 64%, and T2 was 45%

## Dose escalation vs ADT

* See also: Adjuvant ADT
* See also: Dose Escalation (Dose Escalation and ADT)
* UCSF; 2007 PMID 18167004 -- "Dose escalated external beam radiotherapy versus neoadjuvant androgen deprivation therapy and conventional dose external beam radiotherapy for clinically localized prostate cancer: do we need both?" (Roach M 3rd, Strahlenther Onkol. 2007 Dec;183 Spec No 2:26-8.)
** Review. 4 RCT comparing EBRT +/- short-term neoadjuvant ADT. 4 RCTs comparing dose escalation to 74-79 Gy
** Conclusion: Quality of evidence supporting NADT with EBRT is stronger than evidence supporting dose escalation. However, with low cure rates, higher dose EBRT combined with NADT and whole pelvic RT may be indicated
* PMID 16007687 -- "Optimal treatment of intermediate-risk prostate carcinoma with radiotherapy." (Nichol AM, Cancer. 2005 Jul 8;104(5):891-905)
** There is Level I evidence that patients with intermediate-risk prostate carcinoma benefit from dose-escalated EBRT or AD plus conventional-dose EBRT. However, clinical evidence is lacking to support the uniform use of AD plus dose-escalated EBRT.

## Locally advanced or higher-risk cancer (T3, select T1/2)

Please also see the Hormones section for in-depth discussion
* Oslo; 2007 (Norway)(1989-1996) PMID 17703896 -- "10-year survival and quality of life in patients with high-risk (p)n(0) prostate cancer following definitive radiotherapy." (Berg A, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1074-83. Epub 2007 Aug 20.)
** Retrospective. 164/203 patients with T3-4N0 or GS>=7B, treated with 3D-CRT to 65-70 Gy and no hormones
** Outcome: 10-year OS 52%, CSS 66%, cPFS 39%
** Conclusion: RT <=70 Gy as monotherapy insufficient to control T3-4N0 or GS >=7B
* EORTC trial PMID 20933466 -- External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. (2010 Bolla M, Lancet Oncol. 2010 Nov;11(9327):1066-73.)
** Randomised PIII trial of 415 patients (90% T3-4, 10% T1-2 G3) to EBRT alone (50Gy pelvis + 20Gy boost) vs. EBRT + AST x 3 years; median follow-up 9.1 years
** 10-year OS: 39·8% in patients receiving radiotherapy alone and 58·1% for combined treatment (p=0.0004)
** 10-year clinical DFS: 22·7% in the radiotherapy-alone group and 47·7% in the combined treatment group (p<0.0001)
** Conclusion: "The combination of radiotherapy and 3 years of androgen suppression improved long-term overall survival, without increasing late cardiovascular mortality, and should be regarded as standard of care for treatment of men with prostate cancer who are at high metastatic risk, with a WHO performance status of 0–2, and who have no contraindicating coexisting conditions."
* MDACC PMID 10386637 -- Conventional external-beam radiation therapy alone or with androgen ablation for clinical stage III (T3, NX/N0, M0) adenocarcinoma of the prostate. (1999 Zagars, Int J Radiat Oncol Biol Phys 1999; 44:809-19.)
** Retrospective review; 344 men with T3 N0/Nx who received RT alone (260; median follow-up 68 months) or with androgen ablation (84; median follow-up 44 months)
** RT (<68Gy) alone: bNED <50%
** RT (68-70Gy) alone: PSA >10 had 6-year bNED <50%; PSA <10 had 6-year bNED 76%
** RT + AST: 6-year bNED 78%
** Conclusion: "Conventional radiation alone has little curative potential for Stage III disease. Doses < 68 Gy are particularly ineffective. Patients with PSA < or = 10 ng/ml may be candidates for conventional radiation to a dose of 70 Gy. Other patients are probably best served by combined radiation-androgen ablation or high-dose conformal radiation."
* Stanford PMID 3173503 -- Status of radiation treatment of prostate cancer at Stanford University. (1988 Bagshaw MA, NCI Monogr. 1988;(7):47-60.)
** 900 patients (T0-T4) treated in 30-year Stanford review
** 15-year OS was 20% for T3 and 10% for T4 (lymph node status was unknown).
** 15-year DFS was 33% for T3 and 15% for T4 for same patients

## Bone Marrow Status

* Oslo; 2007 PMID 17230512 -- "Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy." (Berg A, Int J Cancer. 2007 Apr 15;120(8):1603-9.)
** Prospective. 131/272 patients with cT1-4pN0 disease with bone marrow aspirates with 1+ unfavorable feature (cT3-4, GS >=7B, PSA >=10). Definitive treatment with RT 66-72 Gy +/- hormones
** Disseminated tumor cells in 18% (with pN0)
** Outcome: 7-year risk of DM: BM- 6% vs. BM+ 21% (p=0.07); if no AST 9% vs. 28% (SS). No difference if GS <7B, or if long-term AST
** Conclusion: Presence of tumor cells in bone marrow increases risk of DM after RT

## Outcome Prediction

* MSKCC Nomogram
Outcome: Disease-specific mortality
* Harvard, 2005 (1989-2002) - PMID 16046650 — "Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy." D'Amico AV et al. JAMA. 2005 Jul 27;294(4):440-7.
** 358 men treated with RT alone
** PSA velocity >2 ng/mL/year (i.e. more than 2 pts per yr) associated with increased all-cause and cancer-related mortality. 7-yr cancer-specific mortality for velocity >2 vs velocity < 2 is 19% vs 0% for low risk, and 24% vs 4% for high risk pts.
** Conclusion: pts with high PSA velocity before treatment may need more aggressive treatment (i.e. should be treated like high risk pts)
Outcome: Distant Metastases
* UT Southwestern, 2007 PMID 17264329 -- "Association of the circulating levels of the urokinase system of plasminogen activation with the presence of prostate cancer and invasion, progression, and metastasis." (Shariat SF, J Clin Oncol. 2007 Feb 1;25(4):349-55.)
** Prospective. Measured plasma levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), in patients s/p RP for localized CaP (429 preop, 76 postop), in patients with LN+ (19) and with DM (10)
** Conclusion: elevation associated with biologically aggressive CaP, disease progression, and DM
* MSKCC/Cleveland Clinic, 2003 PMID 14673043 -- Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. (Kattan MW, J Clin Oncol.)
** Retrospective, nonrandomized analysis of 1,677 patients with stage T1c-T3 treated with 3D-CRT at MSKCC to develop the nomogram, validated with 1,626 patients at the Cleveland Clinic; median follow-up 38 months
** At 5 years, 11% of patients experienced DM
** Nomogram was developed, and is available at MSKCC's web site. Concordance was 0.81
** Conclusion: "A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 years after three-dimensional CRT."
Outcome: Biochemical Failure
* MSKCC, 2000 (1988-98) PMID 11013275 -- "Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer." (Kattan MW, J Clin Oncol. 2000 Oct 1;18(19):3352-9.)
** Retrospective, 1042 pts.
* Multi-institutional, 1999 PMID 10235152 -- Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. (Shipley WU, JAMA)
** Retrospective, nonrandomized, multi-institutional pooled analysis of 1765 men with stage T1b, T1c, and T2
** At 5-years OS was 85%, DFS was 95%, and PSA-DFS was 66%
** Risk groups were established by RPA with 5-year PSA-DFS:
*** (1) PSA <10: 81%
*** (2) PSA 10-20: 69%
*** (3) PSA 20+ and GS 2-6: 47%
*** (4) PSA 20+ and GS 7-10: 29%
** Conclusion: "These rates indicate the probability of success for subsets of patients with tumors of several prognostic category groupings. These results represent a multi-institutional benchmark for evidence-based counseling of prostate cancer patients about radiation treatment."
* Mayo, 1997 PMID 9179062 -- An enhanced prognostic system for clinically localized carcinoma of the prostate. (Pisansky TM, Cancer)
** 500 patients with stage T1-4, NO or NX, MO
** Risk score = (1.07 x tumor stage risk) + (1.21 x Gleason Score risk) + (1.2 x ln PSA)
** Tumor risk (T1-2=0, T3-T4=1), GS risk (2-6=0, 7-10=1),
** Risk groups with 5-year PSA-DFS:
*** (low) risk score <3.1: 92%
*** (intermediate) risk score 3.1-4.9: 67%
*** (high) risk score >4.9: 24%

## Quality of life

* Please see the Erectile dysfunction page for further information

### Evaluation Scales

* EPIC

### 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

### Quality of Life

Prostate Cancer Outcomes Study (1994-95)
* NCI Prostate Cancer Outcomes Study website. Main publication: PMID 10528021 Free full text
* Project of the NCI, based on the SEER population. 3500 men. All men were diagnosed from 1994-95 with positive biopsies. 88% had clinically localized disease. 42% treated with prostatectomy, 24 with RT, 13 with hormonal therapy, and 22 were not treated.