1. 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

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

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

4. 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

5. 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.

6. 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.

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

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

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

10. 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

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

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

13. 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.

14. Clinical Parameters in 100 Consecutive Patients (1985-2003)
Median age at RP (range)
65.4 ( )
Median PSA at RP (range)
6.3 ( )
Median time from RT to RP (range), months
48.1 ( )
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

15. 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.

16. HOSPITALIZATION AND OPERATIVE DATA OF SALVAGE RP
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
<

17. POSTOPERATIVE COMPLICATIONS OF SALVAGE RP
(%)
(%)
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

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

19. 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

20. * 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

21. RECOVERY OF ERECTIONS BY PREOPERATIVE POTENCY STATUS
At Risk

22. 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

23. 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)

24. Pathologic Outcomes after Salvage RP
Overall
N=100
N=48
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

25. 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

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

27. 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

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

29. Cancer Specific Survival after Salvage RP: Preoperative Serum PSA

30. 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.