# Presentation: 108878

## End points for clinical trials in early prostate cancer:PSA-progression after radical prostatectomy 

- Fernando J. Bianco Jr., Zohar A. Dotan, Michael W. Kattan,
- Paul A. Fearn, Howard I. Scher, James A Eastham and
- Peter T. Scardino
- Departments of Urology and GU Medical Oncology
- Memorial Sloan-Kettering Cancer Center
- New York, NY

## What is the prognostic significance of a rising PSA after RP?

-  What is the probability over time of PSA progression, metastases and death from cancer in men with a rising PSA?
- How can we best predict this risk for individual patients?
-  Is recurrence of cancer local, distant or both?
- What is the response rate to radiation therapy?
-  When is androgen deprivation therapy (ADT) used?
-  What is the duration of response, and can we predict this duration?
-  What is duration of survival after failure of first line ADT (“PSA Castrate” disease state)?

## Study Population –patients treated with radical prostatetomy for clinically localized prostate cancer

- Study Population –patients treated with radical prostatetomy for clinically localized prostate cancer

-  Prospective data collection of all prostate cancer patients from 1983 to 2003 into our SPORE Database
-  4,958 radical prostatectomies
-  Exclusion criteria: Prior therapy for prostate cancer (N=923)
-  Chemotherapy (n=50)
-  Prior radiotherapy (n=135)
-  Neoadjuvant hormonal therapy (n=738)
-  Cohort of 4,035 patients treated with RP alone followed median 6 (range 1-20) years

## Clinicopathological Characteristicsn=4035

- Clinicopathological Characteristicsn=4035

##  Prostate Cancer Disease StatesPrognosis: transition rates between states, quantified by nomograms

- Cancer suspected (PSA, DRE)
-          Localized cancer
- 	        Rising PSA
- 		            Metastases
- 			                Post-castrate mets
- Death, other			                       Death, cancer

- Modified from Scher et al Urology 2000

- Salvage Rx

## Definitions

- Progression “Rising PSA”  (n=639)
- PSA >0.1 ng/ml confirmed by 2 subsequent rises (not necessarily consecutive) (n=438) or initiation of secondary therapy for cancer due to PSA rise (n=55) or an absolute value > 0.4 ng/ml (n=146)

## PSA Progression (BCR) after RP

**Follow-up, median 6 yrs  (range, 1 - 20)**

## Preoperative Nomogram for Prostate Cancer Recurrence

**Biopsy Gleason Grade**

****** ****2+ ******** 2**

**3+3**

****** ****3+******** 4**

****** ****2+3**

****** ****4+******

**Total Points**

** **** ****0**

** ****20**

** ****40**

** ****60**

** ****80**

**100**

**120**

**140**

**160**

**180**

**200**

**60**** ****Month**** ****Rec. Free Prob.**

**.96**

**.93**

**.9**

**.85**

**.8**

**.7**

**.6**

**.5**

**.4**

**.3**

**.2**

**.1**

**.05**

**3+ ******** 2**

**Clinical**** ****Stage**

**T1c**

**T1ab**

**T2a**

**T2c**

**T3a**

**T2b**

**Points**

**PSA**

**0.1**

**1**

**2**

**3**

**6**

**8**

**9**

**10**

**12**

**16**

**30**

**45**

**70**

**110**

**7**

**20**

**4**

_**Instructions for Physician**_**:  **Locate the patient’s PSA on the **PSA** axis.  Draw a line straight upwards to the **Points** axis to determine how many points towards recurrence the patient receives for his PSA.  Repeat this process for the **Clinical Stage **and **Biopsy Gleason Sum **axes, each time drawing straight upward to the **Points** axis.  Sum the points achieved for each predictor and locate this sum on the **Total Points **axis.  Draw a line straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first.
*Note:  This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy.  You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer.*
_**Instruction to Patient**_:  “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”

**********1997****	****Michael W. Kattan and Peter T. Scardino**

**Kattan MW et al: JNCI 1998; 90:766-771.**

## Preoperative Nomogram for Prostate Cancer Recurrence

**Biopsy Gleason Grade**

****** ****2+ ******** 2**

**3+3**

****** ****3+******** 4**

****** ****2+3**

****** ****4+******

**Total Points**

** **** ****0**

** ****20**

** ****40**

** ****60**

** ****80**

**100**

**120**

**140**

**160**

**180**

**200**

**60**** ****Month**** ****Rec. Free Prob.**

**.96**

**.93**

**.9**

**.85**

**.8**

**.7**

**.6**

**.5**

**.4**

**.3**

**.2**

**.1**

**.05**

**3+ ******** 2**

**Clinical**** ****Stage**

**T1c**

**T1ab**

**T2a**

**T2c**

**T3a**

**T2b**

**Points**

**PSA**

**0.1**

**1**

**2**

**3**

**6**

**8**

**9**

**10**

**12**

**16**

**30**

**45**

**70**

**110**

**7**

**20**

**4**

_**Instructions for Physician**_**:  **Locate the patient’s PSA on the **PSA** axis.  Draw a line straight upwards to the **Points** axis to determine how many points towards recurrence the patient receives for his PSA.  Repeat this process for the **Clinical Stage **and **Biopsy Gleason Sum **axes, each time drawing straight upward to the **Points** axis.  Sum the points achieved for each predictor and locate this sum on the **Total Points **axis.  Draw a line straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first.
*Note:  This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy.  You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer.*
_**Instruction to Patient**_:  “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”

**********1997****	****Michael W. Kattan and Peter T. Scardino**

**Kattan MW et al: JNCI 1998; 90:766-771.**

-  (57)

- (31)

- (47)

- = 135 pts

- 47%

- 135 pts

- Organ confined = 21%

## Palm Pilot nomogram software program: algorithm for prognosis and pathologic stage

- Includes pretreatment and postoperative predictions.
- Uses published nomograms in prostate cancer.

- Available at _[http://www.mskcc.org/prostate/nomograms](http://www.mskcc.org/prostate/nomograms)_

- _[Nomogram](file:///scardinp/Desktop/Prostate.swf)_

**Notes:**
WE DEVELOPED A TOOL FOR THE PALM PILOT.  WRITTEN BY PAUL FEARN, A MEMBER OF OUR GROUP, THIS APPLICATION COMPUTES THE NOMOGRAM PREDICTIONS OF OUR PREOPERATIVE, POSTOPERATIVE, AND PATHOLOGIC STAGING TABLES.  THE USER SELECTS OR WRITES IN VALUES AND PRESSES A BUTTOM TO COMPUTE THE PREDICTIONS, WHICH ARE RETURNED AS CONFIDENCE INTERVALS.  THIS APPLICATION IS IN USE AT SEVERAL ACADEMIC UROLOGIC CENTERS THROUGHOUT THE COUNTRY.  WE PLAN TO ADD OTHER TREATMENT MODALITIES TO IT SOON, SUCH AS BRACHYTHERAPY AND RADIATION THERAPY.

## Carroll et al., UCSF

- Carroll et al., *UCSF*

## Gastric Cancer Disease-Specific Survival Nomogram

- MM

- SM

- MP

- SS

- S2

- S3

- S1

## Predictive Discrimination for Gastric Nomogram

- _Method_			_Concordance Index_
- AJCC Stage			0.77
- Nomogram			0.80
- Although not perfect, nomogram discriminates better (p<0.001).

- Nomogram predictions are jackknifed (leave one out).

## IV(0.08)

- IIIB(0.07)

- IIIA(0.29)

- II(0.42)

- IB(0.78)

- IA(0.87)

- 0(1.0)

- AJCC

## Nomograms vs. Staging/Grouping Systems

| Nomogram | Comparator | AUC (N vs C) |
| --- | --- | --- |
| Preop | L/I/H Risk Groups | 0.67 vs. 0.64 |
| Preop + IL6/TGFβ1 | L/H Risk Groups | 0.84 vs. 0.73 |
| Pre XRT | L/I/H Risk Groups | 0.76 vs. 0.69 |

| Melanoma | AJCC Stage | 0.69 vs. 0.66 |
| --- | --- | --- |
| Pancreatic Ca | AJCC Stage | 0.64 vs. 0.56 |
| Gastric Ca | AJCC Stage | 0.80 vs. 0.77 |
| Breast Ca | NPI Groups | 0.69 vs. 0.64 |
| Sarcoma | CART Groups | 0.77 vs. 0.74 |

## What is the prognostic significance of a rising PSA after RP?

-  What is the probability over time of PSA progression, metastases and _death from cancer _in men with a rising PSA?
- How can we best predict this risk for individual patients?
-  Is recurrence of cancer local, distant or both?
- What is the response rate to radiation therapy?
-  When is androgen deprivation therapy (ADT) usually begun?
-  What is the duration of response?
-  What is duration of survival after failure of first line ADT?

## SALVAGE RADIOTHERAPY FOR RISING PSA AFTER RADICAL PROSTATECTOMY:

- IMPLICATIONS FOR LOCAL RECURRENCE

- Andrew J. Stephenson, Michael J. Zelefsky, Michael W. Kattan, Eric A. Klein, Patrick A. Kupelian, Claus G. Roehrborn, Steven A. Leibel, Kevin M. Slawin and Peter T. Scardino
- Memorial Sloan-Kettering Cancer Center
- The Cleveland Clinic
- University of Texas-Southwestern Medical Center
- University of Florida  Baylor College of Medicine
- JAMA, March, 2003

## FREEDOM FROM PSA PROGRESSIONPSA Response to Salvage RT

- FREEDOM FROM PSA PROGRESSIONPSA Response to Salvage RT

- PSA  0.1 (CR)67 % of patients

-  50% PSA Decline (PR)

- < 50% PSA Decline (NR)

- CR vs PR: *P < *0.0001
- PR vs NR: *P < *0.0001

## FREEDOM FROM PROGRESSION AFTER SALVAGE RT

- Mets and/or
- Salvage ADT

- PSA Recurrence

## What is the prognostic significance of a rising PSA after RP?

-  What is the probability over time of PSA progression, _metastases and death from cancer _in men with a rising PSA?
- How can we best predict this risk for individual patients?
-  Is recurrence of cancer local, distant or both?
- What is the response rate to radiation therapy?
-  When is androgen deprivation therapy (ADT) usually begun?
-  What is the duration of response?
-  What is duration of survival after failure of first line ADT?

## Survival Competing Risk Analysis after PSA Progression

**Progression**
**N=639**

**Follow-up from Surgery, mean 8-yrs  (1-20)**
**Follow-up from BCR, ****mean 6-yrs  (1-17)**

- 639               314                101                   12

- Death of other causes (DOC)
- Death from Prostate Cancer DOD)

- 18%

- 14%

- 36%

- 32%

## Clinical progression after initial PSA rise 

- Clinical progression after initial PSA rise
- Positive Bone Scan, MRI, CT Scan or PSA rise after first line hormonal therapy

- 80%

- 66%

- 36%

## Metastatic progression for BCR patients multivariate analysis

| Predictors  | Odds Ratio (95%CI)  | p value |
| --- | --- | --- |
| Pre-operative PSA | 0.99 | 0.13 |
| Surgical margin | 0.84 | 0.43 |
| Extracapsular extension | 0.8 | 0.38 |
| Seminal vesicle invasion | 1.98 | 0.005 |
| LN metastases | 1 | 0.98 |
| Pathology Gleason score | 1.67 | <0.001 |
| PSA doubling time |  --- | <0.001 |
| PSA value at time of BCR | 1.07 | <0.001 |

## Concordance Index 0.89

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- 45

- 50

- Total Points

- 70

- 94

- 119

- 143

- 167

- 191

- 216

- 240

**8-Yr. Probability of **
**Freedom from **
**Metastases**

- 0.01

- 0.05

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

- 0.6

- 0.7

- 0.8

- 0.9

- 0.95

## What is the prognostic significance of a rising PSA after RP?

-  What is the probability over time of PSA progression, _metastases and death from cancer _in men with a rising PSA?
- How can we best predict this risk for individual patients?
-  Is recurrence of cancer local, distant or both?
- What is the response rate to radiation therapy?
-  When is androgen deprivation therapy (ADT) usually begun?
-  What is the duration of response?
-  What is duration of survival after failure of first line ADT?

## Actuarial probability of ADT implementation after PSA progression  median time from PSA progression 4.3 (3.4-5.2) years328 patients received ADT

##  Prostate Cancer Disease StatesA new “state”: Castrate PSA, for those patients who receive ADT for a rising PSA before developing mets

- Cancer suspected (PSA, DRE)
-          Localized cancer
- 	        Rising PSA
- 		            Metastases
- 			                Post-castrate mets
- Death, other			                       Death, cancer

- Modified from Scher et al Urology 2000

- Salvage Rx

- Castrate PSA

- HT

- Indolent

## Duration of response to primary ADT (n=328) Median 10.9 (10-11.7) years until “PSACastrate” state

## Cox regression analysis model evaluating factors influencing  duration of primary ADT response (time until PSACastrate State)

## Median survival from PSACastrate State was 26.4 (22.2-30.8) months

## Cox regression analysis model evaluating factors influencing  survival after PSACastrate State

## Conclusions

- ADT use is common in men with a rising PSA after radical prostatectomy, and most patients receive ADT before clinical metastasis.
- The response to ADT  is prolonged (10.9 years).
- The long-term side effects and QOL of these men treated with ADT are not well documented.
- For men with a rising PSA after primary ADT (PSACastrate), the median time to metastases was 9.5 mo. and survival only 2 years. No factors predict duration of survival in this state.
- The PSACastrate disease state is a candidate surrogate for clinical trials of men with a rising PSA.