Christi Hughart, D.O.

Prostate Cancer Most common noncutaneous cancer. Second-leading cause of death from cancer in men in US. 234,000 diagnoses and 27,000 deaths/yr. Prevalence increases with age. Autopsy- microscopic foci of prostate cancer in ¼, 1/3, and 3/4 of men

in 4th, 5th, and 9th decades. 1/6 men diagnosed in lifetime. Only 16% of men diagnosed with prostate cancer die of it. Cause of death in 3% of US male population. Screening controversial. 90% now diagnosed at a clinically localized stage. Natural history varies- indolent to highly aggressive. Comparisons of therapies difficult. Overdiagnosis- cancer detected by screening that would not be

detected without screening or would never cause disability or death- 30-50% in older men- should not be generalized to younger men.

Characterization of Primary Tumor DRE, prostate u/s, PSA, PSA velocity, PSA doubling

time, PSA density, free vs complexed- associated with aggressiveness.

Biopsy characteristics- Gleason, # cores, distribution/volume in cores, perineural/ lymphovascular invasion, ductal/ neuroendocrine differentiation- correlate with aggressiveness.

Nomograms, tables, algorithms.

Patient Evaluation

Gleason <7 and PSA <10, Bx not extensive/ aggressive- most say bone scan, CT, MRI not indicated- likelihood of mets low.

If contemplating surgery- consider baseline bone scan/CT.

Conservative Management Active monitoring- delayed primary treatment

if there is evidence of progression (less established in patients with a long life-expectancy).Treatment frequently initiated due to patient fear of

rising PSA and worsening Bx characteristics.Traditionally reserved for men with a life expectancy

of <10 yrs and low grade Gleason score (2-5).Now being considered in younger patients with low-

volume, low- or intermediate-grade tumors.Semiannual or quarterly PSA/DRE and annual or

biennial Bx- intervention if Gleason 4 or 5, >1 Bx core +, or >50% of core involved.

Repeat Bx’s- can be misleading, may cause inflammation which may falsely elevate PSA and make planes difficult in future surgery.

25-50% develop evidence of progression within 5 yrs.

Prospective, randomized trial in Scandinavia- watchful waiting- higher rates of local cancer progression, mets, and death from cancer and shorter cancer-specific and overall survival than those treated initially with radical prostatectomy.

Watchful waiting- monitoring the patient until he develops metastatic disease that requires palliation.

Radical Prostatectomy Gold standard- not all cancer cells can be eradicated

by radiation/other forms of physical energy, hormonal/chemotherapy never curative.

Possibility of cure with minimal collateral damage. Provides a complete pathologic specimen. Treatment failure more readily identified. Reduces local progression/distant mets. If recurrence- can offer salvage with potentially

curative postoperative radiation. Disadvantages- hospitalization, recovery, ED,

incontinence.

Radical Prostatectomy Approaches Perineal- less blood loss, shorter OR time. No access for

LNDx, higher rate of rectal injury, fecal incontinence, more difficult to spare cavernous nerves.

Retropubic- lower risk rectal injury/fecal incontinence, allows pelvic LNDx, preservation of neurovascular bundles, lower risk of positive surgical margins.

Laparoscopic- transperitoneal or extraperitoneal. Shorter hospital stay, less pain. Higher risk for severe complications- bleeding (time to place clips sutures), heat from harmonic/ electrocautery can damage nerves. Comparable incontinence/stricture rates/nerve sparing. Positive margins higher. ? Adequacy of cancer control.

Robotic- early reports favorable but not validated.

Salvage Radical Prostatectomy

Complications far higher- more serious/ difficult to manage.

Prospects for long-term disease-free survival more limited.

Incontinence- 44% (higher after brachy), bladder neck contracture- 22%.

Selection of Patients Ideal- healthy, free of comorbidities- life expectancy 10

yrs +, tumor significant and completely resectable- upper age limit= 75 yrs.

Hormone therapy does not enhance resectability and increases difficulty of performing nerve-sparing surgery.

Feasibility of nerve-sparing questionable- extensive Ca in specimen, palpable extraprostatic extension, PSA >10, Gleason >7, poor-quality erections preop, lack of sexual relationship, comorbidities (DM, HTN, psychiatric disease, neurologic disease, meds that cause ED).

Discuss possible need of postop adjuvant radiotherapy and/or hormone therapy.

Low risk- pelvic lymphadenectomy optional. +/- intraop frozen section of nodes.

Surgery

Avoid injury to external urinary sphincter. Preservation of bladder neck is unnecessary and risks

positive margins if tumor in base. Avoid cautery near NVBs. If must resect NVBs- can do cutaneous nerve graft from

leg/forearm/genitofemoral nerve. Prostatic pedicles suture ligated/clipped and divided

close to gland.

Postop Care

Ambulate with assist on evening of surgery. Remove foley 3-21 days postop (removal before 7days-

15-20% risk of retention. Initiate Kegels after foley DC. PSA should be undetectable in 1 month.

Cancer Control Biochemical recurrence (detectable PSA) precedes

clinical mets by a mean of 8 yrs and cancer-specific mortality by 13 yrs.

Rarely, high-grade or neuroendocrine variants can be palpable without elevated PSA (so do DRE).

RRP survival probability 85% for patients with organ-confined disease, 65% for men with extracapsular extension without + surgical margins, 55% for men with extracapsular tumor extension and + margins, 25% for SV invasion, 10% with LN mets.

Patients treated in PSA era have 5% more favorable results within each pathologic category.

Progression-free rates: 5 yr= 85%, 10 yr= 77%, 15 yr= 68%.

Biochemical Recurrence Detectable PSA (>0.1 ng/mL)- usually retained Ca but in

some is retained BPH tissue (PSA increases slowly). When do recurrences appear- 50% within 3 yrs, 80%

within 5 yrs, and 99% within 10 yrs. Rarely >15 yrs. PSA velocity or doubling time, interval to recurrence,

Gleason- reflects rapidity of tumor progression. Only 1/3 with progression develop mets (at 8 yrs in

patients who did not receive immediate XRT- only 34% clinically apparent).

Salvage radiotherapy- initiate before PSA level rises much above 0.5 ng/mL. Most likely to benefit- PSA rise long after Sx, slowly rising PSA, low-grade tumor, no SV invasion/LN mets.

Predictors of progression after radiation Tx- Gleason 8+, pre- rad PSA 2+, neg Sx margins, PSA doubling time of 10 mo or less.

Side Effects Urinary continence-

varies with skill of surgeon- high volume surgeons- 90% recover complete continence.

return associated with patient age- 95% <50 yrs, 85% >70 yrs.

ED- potency after RP- maintain erection sufficient for penetration and intercourse with or without PDE-5 inhibitor. Correlates with patient age, preop function, extent of

nerve-sparing, era of surgery. Normal preop and b/l nerve-sparing- 40 yrs = 95%, 50

yrs= 85%, 60 yrs= 75%, 70 yrs= 50%. Begin with partial erections 3-6 months after surgery and

improve for 3 yrs or more. Encourage to use erectile aids.

Early Complications Overall early= <10%. Hemorrhage, rectal/vascular/ureteral/nerve injury,

urinary leak/fistula, DVT/PE, UTI, lymphocele, wound problems.

Obturator nerve injury- (during lymphadenectomy)- thigh adductor defecit- nerve graft if tension-free primary repair impossible (cutaneous, genitofemoral) vs PT.

Ureteral injury- minor injury/ligation- remove ligature/stent, severe- distal ureter mobilization and ureteroneocystostomy.

Rectal injury- primary multiple-layer repair, if large/history of pelvic radiation/long-term glucocorticoid therapy- diverting colostomy.

Late Complications Strictures- manage initially with dilation- can do DVIU or

injection of glucocorticoids, if persistent/long- transurethral resection of scar tissue cephalad to external sphincter- urethroplasty rarely required.

Urinary continence- varies with skill of surgeon- high volume surgeons- 90% recover

complete continence. return associated with patient age- 95% <50 yrs, 85% >70 yrs. encourage Kegels to bulk external sphincter muscle.

ED- potency after RP- maintain erection sufficient for penetration and intercourse with or without PDE-5 inhibitor. Correlates with patient age, preop function, extent of nerve-sparing, era

of surgery. Normal preop and b/l nerve-sparing- 40 yrs = 95%, 50 yrs= 85%, 60

yrs= 75%, 70 yrs= 50%. Begin with partial erections 3-6 months after surgery and improve for 3

yrs or more. Encourage to use erectile aids.

Radiation Therapy EBR- 3-D conformal radiotherapy- gamma (usually photons). IMRT (intensity-modulated radiation therapy)- most

sophisticated- localizes radiation to geometrically complex fields.

Heavy particle therapy- radiation beam can be stopped within the tissue allowing high dose at localized region.

Disadvantage of focused therapy- prostate movement caused by rectal or bladder filling results in tumor being missed.

Outcomes reported to be comparable but is misleading because endpoints to determine success/failure are different for radiation vs surgery.

Dose escalation improves results. Rectal toxicity limits dose of radiation possible with

brachytherapy.

Radiation Side Effects Injury to microvasculature of bladder, rectum, striated sphincter,

urethra. Proctitis/cystitis- 1/3- usually after the dose exceeds 50 Gy. In

most, the symptoms subside after tx. 5-10% have permanent symptoms- IBS, intermittent rectal

bleeding, bladder irritability, intermittent gross hematuria. EBR causes more rectal toxicity and less urinary toxicity than

brachytherapy. TURP is relative contraindication to brachy and EBR- does not

hold seeds well and increased risk of urethral stricture. Obstructive urinary symptoms- relative contraindication – risk of

acute urinary retention. IBS- relative contraindication. ED- 1/2- injury to vasculature of cavernous nerves and corpora

cavernosa of penis- 1 yr after treatment- should use erectile aids.

Combined EBR and Hormonal Therapy for Locally Advanced Prostate Cancer Randomized clinical trials- high PSA, high Gleason,

large-volume tumor benefit from androgen deprivation therapy in combo with radiotherapy.

28 months of hormonal therapy before, during, and after radiation compared with 4 months before and during- sufficient improvement in all clinical endpoints except overall survival.

Overall survival benefit of longer hormonal therapy seen in patients with Gleason 8-10.

Radiation Therapy for Localized Prostate Cancer

Locally advanced or localized high-risk- PSA >20, Gleason 8-10- should add long-term concurrent hormonal therapy.

Intermediate-risk/localized disease- PSA 10-10, Gleason 7, T2b- 6 months of androgen deprivation therapy (beginning 2 months before) improves PSA outcomes.

Endpoints for Treatment PSA gradually decreases for 2-3 yrs after the completion

of radiotherapy (cancer cells not killed immediately- have lethal DNA damage but do not die until they attempt to enter cell division)- monitor Q6 months until nadir.

Transient PSA elevations can occur due to inflammation (bounce)- occurs during first 2 yrs- more common with brachy than EBR.

ASTRO definition of progression after EBR- three consecutive PSA increases measured 6 mo apart and back-dates progression to halfway between the PSA nadir and first rise in PSA.

Phoenix definition of progression after EBR- PSA rise by 2 ng/mL.

Cannot compare outcomes of radiation vs radical prostatectomy due to differences in endpoints (ASTRO vs undetectable).

Treatment Results for Localized Prostate Cancer

EBR- 10 yr cancer cure rates- 50%. 3D-CRT dose escalation- higher than 50%. XRT + 2-3 yrs androgen deprivation- 5 yr progression-

free probabilities- 70-85%.

Brachytherapy Radioactive sources (needles or seeds)- attempt to spare bladder/rectum.

General or regional anesthesia. Iodine- 125 (145 Gy), Palladium-103 (125 Gy)(theoretically higher radiation dose rate – better for poorly diff tumors with shorter cell cycles- no sig advantage in practice).

After placed- CT to check post-implant dosimetry (affected poorly by poor placement/migration).

Many- PSA undetectable (destroys more of prostate than EBR). Seldom used in treatment of high-volume, high-risk (do 3D-CRT). Often pre-treat with androgen deprivation if large gland. TRUS currently used- future MRI. ASTRO- 5 and 7 yr progression-free survival- 85% and 80%. PSA nadir suggested for Brachy/EBR combo= 0.2 ng/mL (if fail to reach by 60

mo, persistent disease). Side-effects-

Urinary symptoms more common than with EBR (esp if BPH)- alpha blockers and hormone therapy prior to help avoid these.○ Urinary retention- 22%.○ TURP required after brachy- 10% (20-40% risk of incontinence if standard TURP).

Proctitis/rectal injury- less common than with EBR. Rectourethral fistula. ED- preservation of function in 62-86%, ED rates higher than with EBR.

Adjuvant Radiotherapy after RP Patients with adverse findings on path may benefit but no

improvement in long-term survival. Wait 3-4 mo (healing and return of continence). Bed of prostate- 60-64 Gy. Or- can watch and perform if PSA rise. Retrospective studies- reduces recurrence rates if stage T3 and

positive margins (also extracapsular extension)- but randomized prospective studies showed this compared to observation.

SV invasion/lymph node mets- ? Benefit. Patients with highly unfavorable prognostic factors (high

likelihood of failure with distant mets)- more likely to benefit from androgen deprivation therapy.

If high risk and opt for postop radiation ?able benefit from combo with androgen deprivation (studies under way). Known improved survival with LN mets.

Primary Hormone Therapy May be appropriate for older men with signif

comorbidities precluding curative therapy or those who do not wish to undergo it.

Never curative, long-term remissions possible. Bilateral orchiectomy and estrogen administration

have been replaced largely by LHRH analogs and antiandrogens (less sexual dysfunction and osteoporosis but higher risk of CV complications).

Cryoablation Argon gas thru hollow needles to freeze prostate

and helium gas to warm the urethra. Primary treatment for salvage after RP or

radiotherapy. Recurrence-free outcomes difficult- no clear

definition of recurrence. Minimally invasive, repeated treatment possible,

cavernous nerve warming (not validated). Long-term biochemical control/QOL not yet

available.

Radiofrequency Interstitial Tumor Ablation

Hyperthermia is claimed to kill cancer cells selectively vs nonselectively at high temperatures.

Office procedure, can be repeated. Long-term data not available.

High-Intensity Focused Ultrasound Generates heat in prostate to ablate focal lesions or the entire

gland by coagulation necrosis. Days to months are required for necrosis and cavitation to occur.

General or spinal anesthesia. 1-4 hrs for glands up to 40 mL. Rectal mucosa cooled, TURP/BNI often performed at beginning

of procedure to limit retention. Urethral/SP cath several days. Side effects- AUR 20%, fistula, incontinence, stricture, perineal

pain, ED (27-61%). 23 month progression-free survival= 70%. Progression criteria- any positive Bx, PSA rise >0.4 ng/mL. Has been used to treat radiation failures. Salvage HIFU- rectourethral fistula 6%, severe incontinence 7%,

bladder neck stenosis 17%. Insufficient evidence to recommend as standard therapy.

Recommendations for Treatment by Patient Risk Groups

See Campbell’s Tables 95-1 and 95-2.