Prostate cancer

Anatomy
Zones of the prostate
Peripheral: most common site of cancer
Transition: source of BPH and the median lobe; cancer rarely presents here
Central: surrounds the ejaculatory duct
Fibromuscular stroma: anterior

Nodal drainage
Obturator/internal iliac/periprostatic/external iliac

Roach formula for nodal risk
% LN involvement = 2/3 PSA + (Gleason score - 6) x 10

Epidemiology
Most common cancer in US men; 230,000 cases per year, 27,000 deaths
More common in black men

Risk factors
Age (most important) - median age of diagnosis is 68 years
Family history
High fat diet
Geographic: incidence high in Scandinavia, low in Asia

Pathology
Adenocarcinoma in the majority of patients (>90%)
Transitional cell, small cell, lymphoma, adenoid cystic, sarcoma are rare histologies

Clinical
Screening
DRE and PSA recommended starting at 50 (45 in black men, men with + family history)

PSA
Free PSA is lower in patients with cancer (usually <20%)
PSA density = serum PSA/prostate volume; higher PSA density is associated with the presence of cancer
PSA velocity = change in PSA over time; increases faster than 0.75ng/ml/year are associated with malignancy; PSA rise more than 2 ng/ml/year in patients with an established diagnosis of prostate cancer is associated with a worse prognosis

Workup
All patients: H&P, rectal exam, PSA, TRUS
Bone scan if PSA higher than 20
CT of abdomen/pelvis/prostate MRI in higher-risk patients

Chemoprevention
Finasteride decreases risk of prostate cancer in a randomized controlled trial
Higher proportion of Gleason 7-10 tumors in the finasteride group

Risk groups
D'Amico
 -Low risk: PSA less than or equal to 10, Gleason 6 or less, T1 - T2a
 -Intermediate risk: PSA 10 - 20 or Gleason 7 or T2b
 -High risk: PSA higher than 20, Gleason 8 - 10, T2c and up

Other prognostic factors
% positive cores: predicts bRFS, OS
PSA velocity: predicts bRFS, OS

Treatment
Low risk - prostate only treatment
1) Prostatectomy
Scandinavian Prostate Cancer Group randomized men to observation vs. prostatectomy
RP improved survival in men under 65

2) Brachytherapy
Candidates for brachy as monotherapy: T1b-T2b, PSA less than 10, Gleason 6 or less
Candidates for brachy boost: T2c, Gleason 7 or higher, PSA 10 - 20
Contraindications: severe urinary obstructive symptoms, TURP defect, large median lobe, pubic arch interference, prostate larger than 60g, positive nodes, seminal vesicle invasion, inflammatory bowel disease (relative)

I-125
Half life 59 days
Rx dose for definitive therapy: 145Gy
Rx dose for boost: 110Gy

Pd-103
Half life 17 days
Rx dose for definitive therapy: 125Gy
Rx dose for boost: 100Gy

Randomized trial did not show any difference in tumor control nor toxicity between the two sources

Post-implant dosimetry
V100 should be greater than 90%
D90 is 140-145Gy for I-125 and 120-125Gy for Pd-103
Mean urethra dose should be less than 150% or V150 of urethra less than 50%
Rectum: V100 should be less than 1cc

3) External beam radiation
Dose escalation tested in multiple RCTs
-Pollak: 70 vs 78Gy to isocenter (3D-CRT technique)
 bRFS improved in the high dose group
 Subgroup analysis confirmed benefit only in patients with PSA greater than 10

-Protons: 70.2 vs. 79.2Gy (protons used for boost phase of treatment only)
 Overall improved bRFS in high dose arm (5-yr bRFS 61 vs 80%)
 Advantage was also seen in low risk pts with PSA less than 10, T2a disease, Gleason 6

-Dutch (Peeters) - 68 vs 78Gy
 bRFS 54 vs 64% at 4 years

High risk
1) Androgen deprivation
GnRH analogues: leuprolide, goserelin; decrease pituitary secretion of LH and FSH; associated with flare of bone pain, hot flashes, decreased libido (acutely); gynecomastia, osteoporosis, muscle wasting, depression with long term use
Testosterone receptor blockers: flutamide, bicalutamide
Suppression of adrenal testosterone: ketoconazole

Trials of hormone therapy
EORTC (Bolla): High grade T1/2, any T3/4 randomized to 70Gy + 3 years ADT vs. 70Gy alone
-ADT improved OS (78 vs 62%) and CSS (94 vs 79%) at 5 years

RTOG 9202: T2c - T4 tumors randomized to 70Gy + 4 months ADT vs. 70Gy + 4 months + 2 years adjuvant ADT
-No benefit seen to prolonged ADT among all patients
-OS was improved in Gleason 8 - 10 patients (ad hoc analysis)

RTOG 8610: T2 - T4 tumors randomized to RT alone vs. RT + ADT
-Trend to improved 10 year OS in ADT group (43 vs 34%); improved CSS and bRFS

D'amico: High risk patients (PSA higher than 10, Gleason 7 or higher, ECE) randomized to 70Gy alone vs 70Gy + 6 months ADT
-Improved 5-year OS in ADT group (88 vs 78%)

RTOG 9413: 4 arm trial, whole pelvis/prostate only; neoadjuvant vs neoadjuvant and concurrent ADT
Best bRFS seen in whole pelvis + neoadjuvant and concurrent group
Benefit thought to be sequence dependent
Trial nearly impossible to interpret

Post-prostatectomy
SWOG: T3/+ margins randomized to RT (60 - 64Gy) vs observation (salvage RT given to 1/3 of the observation group)
-RT improved median OS (15.2 vs 13.3 years) and met-free survival (64 vs 57% at 10 years)
Benefits seen across all subgroups

EORTC: T3/+ margins randomized to 60Gy vs. observation
-5-year PFS improved in RT group (74 vs 53%)