How safe and effective is modern salvage radical prostatectomy? Surgical Treatment for Local Recurrence of Prostate Cancer After Radiotherapy How safe and effective is modern salvage radical prostatectomy? Karim Touijer, MD., James A. Eastham, MD Peter T. Scardino, MD Memorial Sloan-Kettering Cancer Center New York

A Multi-institutional Pooled Analysis of Radiation Therapy For Clinically Localized Prostate Cancer Shipley, JAMA 281:1598, 1999

Without Salvage Therapy Biochemical recurrence distant metastases Post-irradiation patients at high risk of metastases: Rapid PSA doubling time High grade tumors 3 Years

Rationale for Local Salvage Therapy Positive prostate biopsy 2 years or more after EBRT ~ 30% to 50% 32% after EBRT (78 Gy) Zelefsky et al IJROBP 41: 491, 1998 Pollack et al IJROBP 54: 677, 2002 In case of rising PSA after EBRT with negative metastatic evaluation: 60% to 72% local persistence of disease on biopsy Zagars et al IJROBP 33: 23, 1995

Definition of Local Recurrence Cancer in a needle biopsy >2 yr after radiotherapy in a patient with a rising PSA. Caution Difficult to distinguish radiation induced atypia from residual cancer with severe radiation changes. Gleason grading may be inaccurate unless there is abundant viable cancer. PSA “bounce,” a temporary rise in PSA within the first 2-3 years after radiotherapy, may occur in 10-15% of patients. With neoadjuvant androgen deprivation, PSA rise after cessation of hormonal therapy may occur before radiation-induced PSA nadir, resulting in a temporary rise in serum PSA.

Management alternatives for local recurrence after radiotherapy Expectant management (delayed hormonal therapy) Androgen ablation (continuous or intermittent) Salvage radical prostatectomy Cystoprostatectomy with urinary diversion Cryotherapy Investigational techniques: hyperthermia (RITA, HIFU), gene therapy, photodynamic therapy.

Salvage Radical Prostatectomy 10-year PSA progression free probability = 30% - 43%. 10-year cancer specific survival rates = 70% - 77% Fewer than 500 cases reported

Why is salvage radical prostatectomy not widely accepted? High peri-operative morbidity Doubts about long term efficacy

Evaluation of candidates for salvage prostatectomy Is the cancer potentially curable? Is the patient appropriate? Would the operation be safe?

Evaluation for salvage prostatectomy Is the cancer potentially curable? Initial cancer (before radiation) surgically curable: T1-3a N0 M0 Current cancer T1-3a, PSA < 10, no evidence of metastases: bone scan, CT or MRI of abdomen and pelvic LN, Prostascint monoclonal antibody or PET scan

Evaluation for salvage prostatectomy 2. Is the patient appropriate? Good health, life expectancy >10 years Highly motivated, willing to accept risks of salvage surgery

Evaluation for salvage prostatectomy 3. Would the operation be safe? No evidence of radiation cystitis or proctitis

Salvage RP in 100 consecutive patients Between 1984 and 2003, 100 consecutive patients underwent salvage RP with curative intent for biopsy-confirmed, locally recurrent prostate cancer after external-beam radiotherapy or brachytherapy. Disease progression after salvage RP was defined as a PSA level of 0.2 or greater or by the initiation of androgen-deprivation therapy (ADT). Cancer mortality was attributed to patients with active clinical disease progression despite castration at time of death. Cox logistic regression analysis evaluated pre- and postoperative predictors of these endpoints.

Clinical Parameters in 100 Consecutive Patients (1985-2003) Median age at RP (range) 65.4 (44 - 75) Median PSA at RP (range) 6.3 (0.2 - 84) Median time from RT to RP (range), months 48.1 (5 - 155) Pre-RP clinical stage: 1992 TNM T1c 27 T2a 12 T2b 29 T2c 23 T3a 9 Pre-RP biopsy Gleason sum Gleason 2-6 33 Gleason 7 42 Gleason 8-10 16 Radiation treatment effect

Follow up The median follow-up after radiotherapy and salvage RP was 10 years (range, 3 to 24 years) and 5 years (range, 1 to 20 years), respectively The median time between radiation and surgery was 4 years 41 patients had preoperative PSA levels > 10 ng/mL, but the proportion of these patients has decreased significantly since 1993 (56% vs 13%, P=.001) The median preoperative PSA doubling time was 13 months and 22 patients had a PSADT of 6 months or less.

HOSPITALIZATION AND OPERATIVE DATA OF SALVAGE RP 1984-92 1993-03 P-value Mean Operative Time, hours 4.4 3.7 0.001 Mean Estimated Blood Loss, mL 910 1035 0.19 Mean Length of Stay, days 9.6 < 0.0001

POSTOPERATIVE COMPLICATIONS OF SALVAGE RP 1984-92 (%) 1993-03 (%) P-value Major Postoperative Complications 13 (33) 8 (13) 0.02 Rectal Injury 6 (15) 1 (2) 0.01 Ureteric Transection/Stricture 2 3 Postoperative Hemorrhage Lymphocele Vesicocutaneous Fistula 1 Postoperative Sepsis Thromboembolism Obturator Nerve Injury Reoperation 4 (10) 2 (3) 0.17 Anastomotic Stricture 11 (28) 19 (32) 0.66

RECOVERY OF CONTINENCE BY YEAR P = .33 1993-2003 1984-1992 5-yr Recovery 1993-2003 67% (49-84) 1984-1992 45% (26-64)

SEVERE URINARY CONTINENCE 23 patients required insertion of artificial urinary sphincter for severe incontinence Sphincter insertion rate did not improve over time (P= .92) Good outcome after sphincter placement, only one patient required revision procedure

* Defined as erections satisfactory for intercourse RECOVERY OF POTENCY* Patients Evaluated 66 Median age, years 65.8 Potent preoperatively 24 (36) NVB preservation Bilateral 7 (11) Unilateral 17 (25) Nerve grafts 8 (12) 10 (15) 5-yr Recovery: 16% (4-28%) * Defined as erections satisfactory for intercourse +/- sildenafil 67 49 38 35 29 21

RECOVERY OF ERECTIONS BY PREOPERATIVE POTENCY STATUS At Risk 24 18 13 12 7 4 40 30 24 22 20 16

RECOVERY OF POTENCY 5-Year Potency (95% CI) Overall (n=66) 16% (4-28%) Bilateral (n=7) or Unilateral NVB (n= 17) Preservation 28% (2-54%) Potent Preoperatively (n=24) 45% (16-75%) 5 of 7 patients (71%) who had bilateral nerve-sparing salvage RP are potent Nerve grafting (n=18) was not associated with recovery of potency

Progression Free Probability (PFP) after Salvage Radical Prostatectomy Median Time to PSA Failure after Surgery 6.1 Years None received adjuvant treatment before relapse 5-year PFP: 57% 10-year PFP: 38% 15-year-PFP: 29% Follow-up, median 9-yrs (1-19)

Pathologic Outcomes after Salvage RP Overall N=100 1984-94 N=48 1995-2003 N=52 P-value Organ-confined 32% 17% 46% 0.002 Extraprostatic extension 45% 67% 25% 0.005 Seminal vesicle invasion 38% 50% 27% 0.03 Positive surgical margin 29% 31% 8% 0.004 Positive lymph nodes 9% 4% 14% 0.02

Long term cancer control: Standard versus salvage RP Standard RRP* Salvage RRP PFP: 5-year 10-year Organ Confined 94.9% 92.2% 86.0% ECE 76.3% 71.4% 61.6% 41.0% SVI 37.4% 47.6% 32.6% LN + 18.5% 7.4% 60.0% - N=1,000 N=100 *Hull et al. J. Urol, 167: 528, 2002

Cox logistic-regression (multivariable) analysis risk of risk factors for PSA progression after salvage radical prostatectomy

Progression by Preoperative PSA level <4 vs. >4 and <10 vs Progression by Preoperative PSA level <4 vs. >4 and <10 vs. >10 ng/mL Log-Rank Test: 1 vs. 2: p= 0.02 1 vs. 3: p= 0.014 2 vs. 3: p= 0.79 1. PSA <4 ng/mL 3. PSA >10 ng/mL 2. PSA >4 & <10 ng/mL N=32 N=30 N=26 N=9 N=3 N=13 N=5 N=2 N=6

Cancer Specific Survival Median follow up from surgery 5 years (1 – 20)

Cancer Specific Survival after Salvage RP: Preoperative Serum PSA

Lessons Learned Modern salvage radical prostatectomy is safe and major complications are much less common. Long-term progression-free probability, by pathologic stage, is comparable to standard RP. Continuing challenges: High rate of incontinence, strictures Long lag time between radiotherapy and salvage RP leads to high recurrence rate despite restricting surgical candidates to those with PSA <10 ng/mL.