Transcript Ch. 95 Definitive Therapy for Localized Prostate Cancer

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 death30-50% 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 differentiationcorrelate with aggressiveness.
Nomograms, tables, algorithms.
Patient Evaluation


Gleason <7 and PSA <10, Bx not extensive/ aggressivemost 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 lifeexpectancy).
 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 lowvolume, 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 Scandinaviawatchful 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 7days15-20% 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 organconfined 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 sphincterurethroplasty 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 duringsufficient 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 progressionfree 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.