Ch. 95 Definitive Therapy for Localized Prostate Cancer- An Overview

1. Christi Hughart, D.O. Ch. 95 Definitive Therapy for Localized Prostate Cancer- An Overview

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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/ electrocauterycan damage nerves. Comparable incontinence/stricture rates/nerve sparing. Positive margins higher. ? Adequacy of cancer control. • Robotic- early reports favorable but not validated.

9. 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%.

10. 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.

11. 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.

12. 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.

13. 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%.

14. 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+, negSx margins, PSA doubling time of 10 mo or less.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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).

23. 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%.

24. 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.

25. 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.

26. 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).

27. 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.

28. 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.

29. 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.

30. Recommendations for Treatment by Patient Risk Groups • See Campbell’s Tables 95-1 and 95-2.