Surgical Treatment for Local Recurrence of Prostate Cancer After Radiotherapy

How safe and effective is modern salvage How safe and effective is modern salvage radical prostatectomy?radical prostatectomy?

Karim Touijer, MD., James A. Eastham, MD

Peter T. Scardino, MD

Memorial Sloan-Kettering Cancer Center

New York

Shipley, JAMA 281:1598, 1999Shipley, JAMA 281:1598, 1999

A Multi-institutional Pooled Analysis of Radiation Therapy A Multi-institutional Pooled Analysis of Radiation Therapy For Clinically Localized Prostate Cancer For Clinically Localized Prostate Cancer

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 TherapyRationale 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

Zelefsky et al IJROBP 41: 491, 1998 Zagars et al IJROBP 33: 23, 1995

Definition of Local Recurrence

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.

Cancer in a needle biopsy >2 yr after radiotherapyCancer in a needle biopsy >2 yr after radiotherapyin a patient with a rising PSA.in a patient with a rising PSA.

Management alternatives for local Management alternatives for local recurrence after radiotherapyrecurrence 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 Why is salvage radical prostatectomy not widely accepted?not widely accepted?

• High peri-operative morbidity

• Doubts about long term efficacy

Evaluation of candidates Evaluation of candidates for salvage prostatectomyfor salvage prostatectomy

1.1. Is the cancer potentially curable?Is the cancer potentially curable?

2.2. Is the patient appropriate?Is the patient appropriate?

3.3. Would the operation be safe?Would the operation be safe?

Evaluation for salvage prostatectomy

1.1. Is the cancer potentially curable?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?2. Is the patient appropriate?

– Good health, life expectancy >10 yearsGood health, life expectancy >10 years

– Highly motivated, willing to accept risks of salvage Highly motivated, willing to accept risks of salvage surgerysurgery

Evaluation for salvage prostatectomy

• 3. Would the operation be safe?3. Would the operation be safe?

– No evidence of radiation cystitis or proctitisNo 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 9

Follow upFollow 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.

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 3.7 < 0.0001

HOSPITALIZATION AND OPERATIVE DATA OF HOSPITALIZATION AND OPERATIVE DATA OF SALVAGE RPSALVAGE RP

1984-92 (%)1984-92 (%) 1993-03 (%)1993-03 (%) P-P-valuevalue

Major Postoperative ComplicationsMajor Postoperative Complications 13 (33)13 (33) 8 (13)8 (13) 0.020.02

Rectal InjuryRectal Injury 6 (15)6 (15) 1 (2)1 (2) 0.010.01

Ureteric Transection/StrictureUreteric Transection/Stricture 22 33

Postoperative HemorrhagePostoperative Hemorrhage 22 00

LymphoceleLymphocele 00 22

Vesicocutaneous FistulaVesicocutaneous Fistula 11 11

Postoperative SepsisPostoperative Sepsis 11 00

ThromboembolismThromboembolism 11 00

Obturator Nerve InjuryObturator Nerve Injury 00 11

ReoperationReoperation 4 (10)4 (10) 2 (3)2 (3) 0.170.17

Anastomotic StrictureAnastomotic Stricture 11 (28)11 (28) 19 (32)19 (32) 0.660.66

POSTOPERATIVE COMPLICATIONS OF SALVAGE RPPOSTOPERATIVE COMPLICATIONS OF SALVAGE RP

RECOVERY OF CONTINENCE BY YEARRECOVERY OF CONTINENCE BY YEAR

Months from Prostatectomy

60544842363024181260

Pro

po

rtio

n R

eco

veri

ng

Co

ntin

en

ce

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

1993-20031993-2003

1984-19921984-1992

P = P = .33.33

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

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

Bilateral 8 (12)

Unilateral 10 (15)

* Defined as erections * Defined as erections satisfactory for intercoursesatisfactory for intercourse

+/- sildenafil+/- sildenafil

5-yr Recovery: 16% (4-28%) 5-yr Recovery: 16% (4-28%)

67 49 38 35 29 21

Months from Prostatectomy

60483624120

Pro

port

ion R

ecove

ring E

rections

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Pre-RP Potency 1-2

Pre-RP Potency 3-5

At Risk 24 18 13 12 7 4 40 30 24 22 20 16

RECOVERY OF ERECTIONS BY PREOPERATIVE POTENCY STATUSRECOVERY OF ERECTIONS BY PREOPERATIVE POTENCY STATUS

P < P < 0.00010.0001

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) afterSalvage Radical Prostatectomy

Years from Surgery

20151050

PS

A P

rogre

ssio

n-F

ree

1.0

.8

.6

.4

.2

0.0Follow-up, median 9-yrs (1-19)

Median Time to PSA Failure after Surgery 6.1 Years

5-year PFP: 57%5-year PFP: 57%10-year PFP: 38%10-year PFP: 38%15-year-PFP: 29%15-year-PFP: 29%

None received adjuvant treatment before relapseNone received adjuvant treatment before relapse

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 5-year 10-year

Organ Confined 94.9% 92.2% 86.0% 86.0%

ECE 76.3% 71.4% 61.6% 41.0%

SVI 37.4% 37.4% 47.6% 32.6%

LN + 18.5% 7.4% 60.0% -

N=1,000 N=100

**Hull et al. Hull et al. J. UrolJ. Urol, 167: 528, 2002, 167: 528, 2002

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

prostatectomyprostatectomy

Risk Factor PSA Progression HR (95% CI)p value

Serum PSA 0.01 4 to 10 vs. < 4 ng/ml 0.02 3.25 (1.2 -8.9) 10 vs. < 4 ng/ml 0.01 5.79 (2.1-15.4) Organ Confined 0.84 Extracapsular Extention 0.73 Seminal Vesicle Invasion 0.01 3.31 (1.3-8.0) Lymph Node Metastasis 0.04 2.39 (1.0-5.9)

Positive Surgical Margins 0.32 Specimen Gleason Score 0.22

Log-Rank Test:

1 vs. 2: p= 0.02

1 vs. 3: p= 0.014

2 vs. 3: p= 0.79

Progression by Preoperative PSA levelProgression by Preoperative PSA level<4 vs. <4 vs. >>4 and <10 vs. 4 and <10 vs. >>10 ng/mL10 ng/mL

Time (years)

151050

Pro

gre

ssio

n-f

ree

Pro

ba

bili

ty (

%)

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

N=32N=30N=26

3. PSA >10 ng/mL

1. PSA <4 ng/mL

2. PSA >4 & <10

ng/mL

N=9N=3N=13

N=5N=2N=6

Time from Salvage RP (years)

20151050

Can

cer

Spe

cifi

c S

urvi

val

1.0

.8

.6

.4

.2

0.0

73%

60%

At Risk100 51 21 9

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

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

Time from Salvage RP

151050

Can

cer

Spe

cifi

c S

urvi

val

1.0

.8

.6

.4

.2

0.0

100%22

95.4%18

95.4%7

56.5%7

PSA < 10

PSA > 10

PSA < 10At risk

PSA > 10At risk

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.