# Radiation Oncology/Prostate/Prostate Overview

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Prostate Cancer Overview

## Anatomy

* Please see the anatomy page

## PSA

* Please see the PSA page

## Gleason score

The Gleason grading system, originally developed in 1966, was modified in 2005 at the International Society of Urological Pathology Consensus Conference. In general, the changes resulted in a more narrow scope of grade 3 and an expanded scope of grade 4, thus shifting a number of previously diagnos
* 1966 PMID 5948714 -- "Classification of prostatic carcinomas." (Gleason DF, Cancer Chemother Rep. 1966 Mar;50(3):125-8.)
* 2005 PMID 16096414 -- "The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma."
* 2006 (Web article, non peer reviewed) PCRI Insights "Gleason Grade Migration: Changes in Prostate Cancer Grade in the Contemporary Era" (August 2006, 9(3))
* 2009 PMID 19886716 Full text -- "Current perspectives on the Gleason grading of prostate cancer."
* 2010 PMID 20157302 -- "Clinical implications of changing definitions within the Gleason grading system.

### Clinical correlates

* Colorado/SEER; 2014 (2004-2006) PMID 25151595 -- "Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer." (Rusthoven CG, Urol Oncol. 2015 Feb;33(2):71.e11-9)
** Retrospective. 26,885 men with Gleason 6-10 PCa, 2004-2006, managed with definitive external beam radiation alone.
** For Gleason 6, 3+4, 4+3, 4+4, 8 with pattern 5 (3+5 or 5+3), 9, and 10 the 7.5-year PCSS rates were 99%, 97%, 95%, 91%, 86%, 81%, and 78% and 7.5-year OS rates were 83%, 76%, 72%, 67%, 66%, 58%, and 54%, respectively.
* CONCLUSION: "In the largest reported survival analysis of Gleason stratifications, biopsy-assigned GS 6, 3+4, 4+3, 4+4, 8 w/P5, 9, and 10 represented sequential prognostic factors for survival in patients managed with definitive EBRT."
* Johns Hopkins; 2013 PMID 23464824 -- "Prognostic Gleason grade grouping: data based on the modified Gleason scoring system" (Pierorazio PM, BJU Int. 2013. May;111(5):753-60)
** Retrospective. 7,869 men with PCa, diagnosed 2004 or later, managed with prostatectomy. Biochemical recurrence-free (BFS) survival evaluated as the primary endpoint.
** 5-year BFS rates for men with Gleason grade ≤ 6, 3 + 4, 4 + 3, 8 and 9-10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P < 0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P < 0.001), based on RP pathology
* Conclusion: "There is a need for a change in (Gleason) reporting to more closely reflect tumour behaviour." Authors propose reporting Gleason score ≤ 6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9-10 (prognostic grade group (V).
* Harvard; 2009 (1984-2004) PMID 19433685 -- "Gleason score and lethal prostate cancer: does 3 + 4 = 4 + 3?" (Stark JR, J Clin Oncol. 2009 Jul 20;27(21):3459-64. Epub 2009 May 11.)
** Retrospective. 812 patients with GS 7 (prostatectomy 693, biopsy 119) on Physicians Health Study and Health Professionals Followup Study. Blinded review by 3 pathologists. Lethal PCA defined as bony mets or PCA death
** Gleason score: Striking upgrading in GS score. Initial GS 2-5 in 25%, on review in <1%
** Outcome: No leathal PCA in GS 2-6; reference 3+4; hazard ratios for lethal cancer GS 4+3 HR 3.1 (SS), GS 8 HR 7.4 (SS), GS 9-10 HR 19 (SS)
* Conclusion: Ignoring pattern 4 in GS 7 may conceal important prognostic information
* MSKCC; 2012 (1989-2011) PMID 23182392 -- "Prognostic Importance of Gleason 7 Disease Among Patients Treated With External Beam Radiation Therapy for Prostate Cancer: Results of a Detailed Biopsy Core Analysis" (Spratt DE, IJROBP. 2012 Nov 20;S0360-3016(12)03663-2)
** Retrospective. 613 patients with GS 7 (all solely with EBRT). Required complete core biopsy information (location of each biopsy core, positive core percentage, individual core involvement, PIN, and PNI). First EBRT study to assess bRFS, DM, and PCSM between GS 3+4 vs 4+3.
** Outcome: The 8-year bRFS rate for pG3 versus pG4 was 77.6% versus 61.3% (P<.0001), DMFS was 96.8% versus 84.3% (P<.0001), and PCSM was 3.7% versus 8.1% (P=.002). On multivariate analysis, pG4 predicted for significantly worse outcome in all parameters. Excellent review of all studies on the subject of GS 3+4 vs 4+3.
** Conclusion: Primary Gleason grade 4 independently predicts for worse bRFS, DMFS, and PCSM among Gleason 7 patients even in the setting of biopsy information.

## Workup

* Use of bone scan and CT scan: Use of routine scans in early stage prostate cancer questioned. Bone scan + in <5% and CT scan + in <12% for those with PSA < 20, and <2% and 9% for those with PSA < 20 and Gleason 6 or less. For PSA > 50, positive in 10%; for Gleason 8-10 with PSA >20, positive in 20%. — (SEER data, Prostate Cancer Outcomes Study - Albertsen et al. PMID 10737483 J Urol. 2000 Apr;163(4):1138-43.)
* PMID 15126770 reviews 48 articles and finds
** Bone scan + in 2.3% if PSA < 10, in 5.3% with PSA 10-20 and 16.2% with PSA 20-50.
** Bone scan + in 5.6% if Gleason 7 or less vs 29.9% if Gleason 8-10
** Bone Scan + in 6.4% if stage T2 or less vs 49.5% if T3-4
** CT + in 0% if PSA < 20 and 1.1% if PSA > 20
** CT + in 1.2% Gleason 7 or less vs 12.5% Gleason 8-10
** CT + in 0.7% T2 or less vs 25.8% of T3-4s

## Pattern of spread to lymph nodes

Prostate lymphatic drainage is to hypogastric (primary), obturator (secondary), external iliac (tertiary), and presacral (quarternary). For radical prostatectomy, lymph node dissection includes only the obturator and external iliac LNs, and is recommended for PSA > 10 and Gleason > 6. Heidenreich et al (PMID 11912387) reported that with extended lymphadenectomy (including all four drainage regions), LN mets were detected in 26% vs 12%, and that 2/3 of patients had LN mets outside of the fields of standard lymphadectomy. Recommended extended lymphadenectomy of external and internal iliacs and obturator for pts with PSA > 10 and Gleason 7 or above (only 2% LN+). Do not recommend dissection of presacral region or common iliac.

## Predictors of pathologic stage
### Partin tables

* Online tool: Partin tables (Johns Hopkins)
* Original; 1993: PMID 7685418 — "The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer." Partin AW et al. J Urol. 1993 Jul;150(1):110-4.
* Update; 1997: PMID 9145716 — "Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update." Partin AW et al. JAMA. 1997 May 14;277(18):1445-51.
* Update; 2001: PMID 11744442 — "Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium." Partin AW et al. Urology. 2001 Dec;58(6):843-8.
* 2007 (2000-2005) PMID 17572194 -- "Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005." (Makarov DV, Urology. 2007 Jun;69(6):1095-101.)
** Retrospective. 5730 men, prostatectomy, no neoadjuvant therapy. Variables used PSA (80% <10), clinical stage (77% T1c), biopsy Gleason (76% GS 5-6)
** Outcome: Nomogram developed
** Conclusion: Updated "Partin tables" reflect trends in presentation
* 2012 (2006-2011) PMID 22834909 Full text -- "An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011." (Eifler JB, BJU Int. 2012 Jul 26. -- Epub ahead of print)
** 5629 men. Median PSA 4.9; Gleason 6 in 63%; T1c in 78%.
** OC (organ confined) in 73%, EPE 23%, SV+ 3%, LN+ 1.
** Compared to prior cohort (2000-2005), more likely to have PSA <= 4 (30% vs 25%), Gleason score >= 7 on biopsy (37% vs 23%) and prostatectomy (50% vs 36%), but were similar in clinical and pathologic stage.
** Conclusion: "The distribution of pathologic stages did not change at our institution between 2000-2005 and 2006-2011. The updated Partin nomogram takes into account the updated Gleason scoring system and may be more accurate for contemporary patients diagnosed with prostate cancer."
* 2017 (2010-2015) PMID 27367645 -- "Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era." (Tosoian JJ, BJU Int. 2017 May;119(5):676-683. )
** Median PSA 4.9; Gleason 6 in 47%
** OC in 74%, EPE 20%, SV+ 4%, LV+ 2%.
* Caution: The Partin tables assign the "worst-case" pathologic stage for each case; the categories are mutually exclusive. (E.g., those included as "capsular penetration" had to have no seminal vesicle involvement or lymph node involvement, and those included as "positive seminal vesicle" had to have no lymph node involvement. The categories sum to 100%.) This method gives an underestimation of the true rate of extracapsular extension and seminal vesicle involvement.

### Roach equations

* Seminal vesicle involvement - PSA +([Gleason -6] x 10) — PMID 7523343
** Cutoff is 13%. If <13%, risk 7%; if >=13%, risk 37%.
* Lymph node involvement - 2/3 x PSA + ([Gleason-6] x 10) — PMID 7505775
** Cutoff is 15%. If calculated risk is <15%, actual risk 6%; if >=15%, actual risk 40%.
* Extracapsular extension - 1.5 x PSA + ([Gleason-3) x 10) — PMID 10875450
** Approximates actual risk.

### Kattan nomogram

    see also page at Localized Prostate Cancer#Outcome Prediction for other nomograms
* Metagram; 2009 PMID 19544545 -- "Development of a prostate cancer metagram: a solution to the dilemma of which prediction tool to use in patient counseling." (Nguyen CT, Cancer. 2009 Jul 1;115(13 Suppl):3039-45.)
* Preoperative nomogram; 1998 - PMID 9605647 — "A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer." Kattan MW et al. J Natl Cancer Inst. 1998 May 20;90(10):766-71.

### LN involvement

* Harvard; 2009 (2004) PMID 19286330 -- "Predicting the risk of pelvic node involvement among men with prostate cancer in the contemporary era." (Nguyen PL, Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):104-9. Epub 2009 Mar 13.)
** SEER analysis. 9,387 men with cT1c-T4 PCA, surgical LN evaluation, GS and PSA. 98% were cT1c/T2
** Patient characteristics: PSA <4 in 16%, 4-10 in 62%, 10-20 in 14%, >20 in 6%. Gleason <=6 in 39%, 7 in 46%, and 8-10 in 13%. Clinical T1c in 51%, T2 in 46%, T3-T4 in 2.5%. Median 5 LN evaluated.
** Outcome: LN+ in 3.3%. Roach scores overestimated actual rates by 16x if score <10%, by 7x if score 10-20%, and by 2.5x if score >20%. Adjusted expected risk of LN+ is 0.2% for Roach scores <=10%, 2.0% for Roach scores 10-20%, 9.7% (with observed risk 6.5%) for Roach scores 20-30%, and 13.9% for Roach scores 30-40%. Note: adjustment factors should not be applied for T3-T4 disease.
** Provides table of LN risk by clinical T stage, PSA, and Gleason score (similar to Partin table).
** Comment: Synopsis of data from table: >15% risk of +LN for: T1c with G 8-10 and PSA >20; T2 with G 8-10 and PSA >10; T3 overall risk 15%; T4 overall risk 41%.
** Conclusion: Roach formula appears to overestimate contemporary patients with mainly T1c/T2 disease
* Yale formula; 2011 (2004-2006) PMID 20594769 -- "A new formula for prostate cancer lymph node risk." (Yu JB, Int J Radiat Oncol Biol Phys. 2011 May 1;80(1):69-75.)
** Based on SEER database for cT1-T2, PSA < 26. In contrast to Roach equation and Harvard (Nguyen formula), includes T-stage.
** %LN+ risk is [GS - 5] × [PSA/3 + 1.5 × T], where T = 0, 1, and 2 for cT1c, cT2a, and cT2b/cT2c.

### SV invasion

Seminal vesicle invasion:
* Mayo (1988-93) - PMID 8948342, 1996 — "Correlation of pretherapy prostate cancer characteristics with seminal vesicle invasion in radical prostatectomy specimens." Pisansky TM et al. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):585-91.
** T-stage (T2a or less vs. T2b-c vs. T3a-b), primary Gleason grade (1-2, vs. 3, vs 4+), and PSA predict for SVI on multivariate analysis.

## Definitions of Risk Groups

* NCCN (v1.2011)
** Very low risk: T1c, GS 2- 6, PSA < 10, Fewer than 3 prostate biopsy cores positive, < 50% cancer in each core, PSA density < 0.15 ng/mL/g
** Low risk: T1-T2a and GS 2-6 and PSA <10
** Intermediate risk: T2b-T2c or GS 7 or PSA 10-20
** High risk: T3a or GS 8-10 or PSA >20
** Locally advanced (Very High): T3b-T4
** Metastatic: N1
** Metastatic: M1
* RTOG risk group classification - PMID 10837943 (Roach) - does not include PSA information. Used in RTOG Meta-Analysis
** Group 1 / low risk (T1-2,G<=6)
** Group 2 / int (T1-2,G7; T3 or N1, G<=6)
** Group 3 / high (T1-2,G>=8; T3 or N1, G7)
** Group 4 / very high (T3 or N1, G>=8)
* D'Amico, 1998 (1989-97) - PMID 9749478 — "Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer." D'Amico AV et al. JAMA. 1998 Sep 16;280(11):969-74.
** 1872 pts treated by RP, implant, or EBRT. Defined risk groups:
*** Low risk: T1c-T2a, PSA 10 or less, and Gleason 6 or less - PSA failure risk <25% at 5 years.
*** Intermediate risk: T2b, or PSA >10 and <= 20, or Gleason 7 - 25-50% risk.
*** High risk: T2c or PSA > 20 or Gleason 8 or more - > 50% risk.
** See also update of trial under Comparison of Primary Treatments section (D'Amico, Cancer 2002)
* Shipley (Multi-institutional), 1999 (1988-1995) - PMID 10235152 — "Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis." Shipley WU et al. JAMA. 1999 May 5;281(17):1598-604.
** 1765 pts, T1-2N0M0 with available pretreatment PSA levels were treated with RT alone (median dose 63-79 Gy, 51% 3-D Conformal, various field sizes). Mean pretreatment PSA was 18.9 and median was 10.1 with 74% T2 and ~25% with PSA > 20.
** Median f/u 4.1 years
*** RPA used with pretreatment PSA a continuous variable to find specific risk/cutoff points.
*** Group 1: PSA <~10 bPFS = 81%
*** Group 2: ~10 > PSA < ~20 bPFS = 69%
*** Group 3: PSA > ~20 and Gleason <=6 bPFS = 47%
*** Group 4: PSA > ~20 and Gleason >= 7 bPFS = 29%
** See also: at page Localized Prostate Cancer
* Pisansky (Mayo), 1997 (1987-93) - PMID 9179062 — "An enhanced prognostic system for clinically localized carcinoma of the prostate." Pisansky TM et al. Cancer. 1997 Jun 1;79(11):2154-61.
** 500 pts, T1-4N0M0 treated with RT alone (median dose 64-66 Gy). Elective nodal RT in 30%.
** Median f/u 43 mos.
*** Risk groups (and 5-yr relapse-free survival): Low - 92, Intermediate - 67, High - 24.

### Subclassification

Subclassification of Intermediate Risk into Unfavorable and Favorable:
* Zumsteg; 2013 (1992-2007) PMID 23541457 Full text -- "A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy."
** Based on pts treated with EBRT to ≥ 81 Gy +/- ADT. Using NCCN risk classification.
** Unfavorable intermediate risk: primary Gleason 4 (G 4+3) pattern, percentage of positive biopsies (ppb) ≥ 50%, or ≥ 2 intermediate-risk factors (using NCCN, i.e. T2b-T2c, PSA 10-20, Gleason 7).
** Favorable intermediate risk: a single NCCN intermediate risk factor, Gleason ≤ 3+4=7, and < 50% positive biopsy cores.

### Other prognostic factors

* Percent positive prostate cores: D'Amico 2004 (1988-2002) - retrospective
** PMID 15365069 — "Impact of the percentage of positive prostate cores on prostate cancer-specific mortality for patients with low or favorable intermediate-risk disease." D'Amico AV et al. J Clin Oncol. 2004 Sep 15;22(18):3726-32.
** 421 pts, low or "favorable intermediate risk", treated with RT alone.
** Median f/u 4.5 yrs. Percentage of positive prostate cores (>=50 vs <50%) was the only significant predictor of disease-specific mortality, with a RR between 6 and 12.

## Utilization

* Please also see Radiation_Oncology/Prostate/Protons for Proton Therapy utilization
* Center for Disease Control (CDC), Atlanta; 2007 PMID 17469027 -- "Use of additional treatment for prostate cancer after radical prostatectomy, radiation therapy, androgen deprivation, or watchful waiting." (Berge V, Scand J Urol Nephrol. 2007;41(3):198-203.)
** SEER + Medicare claims data. 12,711 patients. Initial RP 31%, initial RT 31%, initial ADT 9%, initial WW 28%
** Outcome: Initial RP: 8% additional RT, 12% additional ADT. Initial RT: 23% additional ADT. Initial WW: 22% additional ADT
** Conclusion: If initially treated with RT or observation, more likely to receive ADT as follow-up treatment than if initially treated with RP
* American College of Radiology; 2002 (1992-1993) PMID 12065564 -- "Comparing the costs of radiation therapy and radical prostatectomy for the initial treatment of early-stage prostate cancer." (Burkhardt JH, J Clin Oncol. 2002 Jun 15;20(12):2869-75.)
** Linked SEER-Medicare analysis.
** Outcome: Costs RT $14,048 vs. RP $17,226 (SS)
** Conclusion: For early-stage PCA, average costs were at least 23% greater for RP
* UCLA; 2000 (1993-1996) PMID 11042575 -- "A nationwide charge comparison of the principal treatments for early stage prostate carcinoma." (Brandeis J, Cancer. 2000 Oct 15;89(8):1792-9.)
** HCFA claims data for inpatient, outpatient and Part B claims. 10,107 men with initial diagnosis of prostate cancer, treatment, +6 months of follow-up. RT 58%, brachy 7%, RP 35%. During the 4 years, RT decreased by 20%, brachy increased by 21%
** Cost: RP + adjuvant RT $31,329 vs. RT + brachy boost $24,407 vs. RP $19,019 vs RT $15,937 vs brachy $15,301 (SS). Utilization varied with age, race, and geographic region
** Outcome: Without clear survival advantage, costs, QoL and patient preference take on paramount importance

## Other Resources

* eContouring Webinar - Prostate Cancer with Michael Zelefsky, M.D.
* ASTRO/ARRO Journal Club Webinar 2012 - "Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials" with Anthony D'Amico, MD, PhD, FASTRO
* ASTRO/ARRO Journal Club Webinar 2011 - "Radiotherapy and short-term androgen deprivation for localized prostate cancer" with Anthony Zietman, MD