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Thread: Defining predictors of overall survival for high-risk men after RP

  1. #1

    Defining predictors of overall survival for high-risk men after RP

    Defining the Most Informative Intermediate Clinical Endpoints for Predicting Overall Survival in Patients Treated with Radical Prostatectomy for High-risk Prostate Cancer [2019]

    Abstract

    BACKGROUND:
    Given the prolonged natural history of clinically localized, high-risk prostate cancer, there is a need for the identification of intermediate clinical endpoints (ICEs) to predict long-term overall survival (OS).

    OBJECTIVE:
    To explore the role of novel potential ICEs based on clinical follow-up to predict long-term survival in patients with high-risk prostate cancer.

    DESIGN, SETTING, AND PARTICIPANTS:
    Overall, 3507 patients treated at 12 tertiary referral centers between 1988 and 2016 were evaluated.

    INTERVENTION:
    Radical prostatectomy (RP) with extended pelvic lymph node dissection.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
    The impact of biochemical recurrence (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery on the risk of OS was evaluated in multivariable Cox regression analyses. In patients with BCR, the impact of progression to CR within 6mo and 1, 3, and 5yr on long-term OS was investigated. Discrimination was assessed using Harrell's c index.

    RESULTS AND LIMITATIONS:
    Median follow-up for survivors was 76mo. The 5- and 10-yr OS and cancer-specific survival rates were 94% and 81% versus 98% and 95%, respectively. On a time-varying multivariable analysis, BCR (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 1.00, 1.04) and CR (HR: 1.05; 95% CI: 1.03-1.07) emerged as predictors of OS (p<0.001). The development of CR within 5yr after surgery was the most informative ICE for predicting OS (c index: 0.74). In patients with BCR, progression to CR within 12mo represented the most informative predictor for the subsequent risk of dying from all causes. Patients who developed BCR within 5yr after RP and progressed to CR within 12mo had a 10-yr OS rate of 47%. These results require prospective validation.

    CONCLUSIONS:
    When predicting long-term survival in surgically treated high-risk patients, progression to CR within 5yr of RP confers the highest discrimination with respect to other landmark points. In men experiencing BCR, progression to CR within the subsequent 12mo achieved the highest discrimination. Further studies are needed to validate our findings.

    PATIENT SUMMARY:
    We investigated the most informative intermediate clinical endpoints for predicting overall survival (OS). Occurrence of clinical recurrence within 5yr after radical prostatectomy confers the highest discrimination to a model predicting OS.
    [Emphasis mine]

    A related study:

    Long-term cancer control outcomes in patients with clinically high-risk prostate cancer treated with robot-assisted radical prostatectomy: results from a multi-institutional study of 1100 patients [2015]

    Abstract

    BACKGROUND:
    Long-term cancer control outcomes in clinically high-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP) remain unknown.

    OBJECTIVE:
    To report on long-term biochemical recurrence (BCR)-free survival, clinical recurrence (CR)-free survival, and salvage therapy rates in these patients. Given the heterogeneity of high-risk patients, a second objective was to stratify them according to their BCR risk (using preoperative parameters), in an effort to counsel them better preoperatively regarding their cancer control outcomes.

    DESIGN, SETTING, AND PARTICIPANTS:
    We evaluated 1100 D'Amico high-risk PCa patients who underwent RARP between 2002 and 2013 at three tertiary care centers.

    OUTCOME MEASURES AND STATISTICAL ANALYSES:
    Outcomes consisted of BCR-free survival, CR-free survival, and salvage therapy rates. Regression tree analysis stratified patients into novel risk groups based on preoperative characteristics and corresponding BCR risk. Kaplan-Meier curves estimated BCR-free survival, CR-free survival, and salvage therapy rates in the entire cohort and after stratification according to the novel risk groups (RGs).

    RESULTS AND LIMITATIONS:
    Median age and prostate-specific antigen (PSA) were 63 yr and 6.5 ng/ml, respectively. Biopsy Gleason score (GS) was ≥8 in 57.7%. Mean follow-up was 53 mo (median: 49 mo). At 10 yr, BCR-free survival, CR-free survival, and salvage therapy rates were 50%, 87%, and 37%, respectively. Regression tree analysis stratified patients into five novel RGs): RG1, very low risk (GS ≤6); RG2, low risk (PSA ≤10 ng/ml; GS: 7); RG3, intermediate risk (PSA ≤10 ng/ml; GS ≥8 ); RG4, high risk (PSA >10 ng/ml; GS: 7); RG5, very high risk (PSA >10 ng/ml; GS ≥8 ). In these RGs, the 10-yr BCR-free survival rates were 86%, 70%, 36%, 31%, and 26% (p<0.001), respectively; the 10-yr CR-free survival rates were 99%, 96%, 85%, 67%, and 55% (p<0.001), respectively; and the 10-yr salvage therapy rates were 9.8%, 16%, 42%, 47%, and 64% (p<0.001), respectively.

    CONCLUSIONS:
    Most patients with clinically high-risk PCa treated with RARP alone remain CR free at long term. Nonetheless, almost 37% of the patients at 10 yr require salvage therapy. Our novel tool allows accurate stratification of these heterogeneous patients according to their BCR, CR, and salvage therapy risks. This may help inform patients preoperatively about their cancer control outcomes postoperatively.

    PATIENT SUMMARY:
    Robot-assisted radical prostatectomy confers lasting long-term oncologic control in most high-risk prostate cancer patients. Our novel risk grouping might serve as a useful tool for setting expectations and counseling patients regarding their cancer control outcomes.
    [Emphasis mine]

    Of note in the second study is that pre-RP PSA outweighed GS in the statistically determined risk groups. I am "only" in the intermediate-risk group even with my G9.
    Last edited by DjinTonic; 07-09-2019 at 01:33 PM.

  2. #2
    Experienced User
    Join Date
    Apr 2019
    Posts
    61
    It's frustrating when "intermediate" and "advanced" have different definitions in terms of PSA & Gleason scores. Is it mostly a European vs. US based study issue for those definitions, or a pre/post surgery difference in definitions?

    According to the second study, husband is high risk, with potential to be upgraded to very high risk.
    Wife Posting, Husband D.O.B. 1975
    2/2018 - routine physical PSA 15
    3/2018 - PSA 13
    4/2018 - PSA down to 11.6, free PSA, 18%
    6/2018 - PSA 10, free PSA 20%
    7/2018 - mp- MRI done, prostate volume =22cc, "inflammation consistent with prostititis"
    11/2018 - PSA 14, free PSA 11%,
    3/2019 - PSA 12, free PSA 17%, 2nd opinion on MRI = PI RADs 3 lesion
    4/2019 - Cognitive Fusion Biopsy
    5/12 cores positive
    4 Gleason 3+3
    1 Gleason 3+4 5% (Where PIRADs 3 lesion IDd)
    Decipher Biopsy score: .07 very low risk

    Bone scan negative
    MRI 6/19 said PIRADS 4 lesion, no definite EPE

    RRP 7/19 Final Path: pT3a
    G6 - 75-90%
    G7 (3+4) - 11-25%
    24mm tumor, 30% of prostate
    EPE+, BNI+, SM + (at bladder neck), LVI-, SVI -, PNI-, Nodes -
    Decipher Post RP score: .78, high risk

  3. #3
    Quote Originally Posted by AceVA View Post
    It's frustrating when "intermediate" and "advanced" have different definitions in terms of PSA & Gleason scores. Is it mostly a European vs. US based study issue for those definitions, or a pre/post surgery difference in definitions?

    According to the second study, husband is high risk, with potential to be upgraded to very high risk.
    Hi AceVa. The "high-risk" definition for inclusion in the two studies was the very widely used d'Amico criteria: "Those with a PSA of more than 20, a Gleason score equal or larger than 8, or are in clinical stage T2c-3a" (although there are other definitions).

    The first study is just proposing a reassessment of "high risk" for predicting overall survival (note the very different outcomes for the best and worst risk groups). They clearly state "Further studies are needed to validate our findings." Don't forget, this is after RP, when the final G score has been determined. As you know, up- and down-grading often occur.

    In my case, for example, I'll always be high risk because of my G9. And yet BCBS refused to pay for my post-RP Decipher test with the explanation that I "was no longer high risk" based on my good path report--G score notwithstanding! (I believe my insurance company is alone in believing that! Certainly not my uro/surgeon who tests my PSA every 3 months.) And, as I mentioned, the first paper proposes that I be labeled intermediate risk. The one thing that is clear in this unclear mess is that after treatment, there needs to be a reassessment of risk.

    All the best for the upcoming RP!!!

    Djin
    Last edited by DjinTonic; 07-09-2019 at 01:45 PM.

  4. #4
    Thank you Dj! Great information and risk stratification.

    In the 2nd Abstract posted, there is a very interesting 10 year observation in this patient population:

    RESULTS AND LIMITATIONS:
    "Median age and prostate-specific antigen (PSA) were 63 yr and 6.5 ng/ml, respectively. Biopsy Gleason score (GS) was ≥8 in 57.7%. Mean follow-up was 53 mo (median: 49 mo). At 10 yr, BCR-free survival, CR-free survival, and salvage therapy rates were 50%, 87%, and 37%, respectively. Regression tree analysis stratified patients into five novel RGs): RG1, very low risk (GS ≤6); RG2, low risk (PSA ≤10 ng/ml; GS: 7); RG3, intermediate risk (PSA ≤10 ng/ml; GS ≥8 ); RG4, high risk (PSA >10 ng/ml; GS: 7); RG5, very high risk (PSA >10 ng/ml; GS ≥8 ). In these RGs, the 10-yr BCR-free survival rates were 86%, 70%, 36%, 31%, and 26% (p<0.001), respectively; the 10-yr CR-free survival rates were 99%, 96%, 85%, 67%, and 55% (p<0.001), respectively; and the 10-yr salvage therapy rates were 9.8%, 16%, 42%, 47%, and 64% (p<0.001), respectively."

    My interpretation is:

    - 50% experienced BCR

    - 13% experienced CR

    Within the time frame of this study in this population of D'Amico High-Risk patients:

    - 50% went on to BCR

    - Only 1 in 4 of the BCR patients went on to CR

    Neither abstract defines BCR (likely 0.1 or 0.2) or CR (likely obvious).

    If this finding is universally accurate and applicable, it supports The Mayo Clinic not using uPSA and suggests that we on The Forum may place too much emphasis on uPSA!

    Regardless, I for one, will continue monitoring via uPSA!!!

    MF
    PSA: Oct '09 = 1.91, Oct '11 = 2.79, Dec '11 = 2.98 (PSA, Free = 0.39ng/ml, % PSA Free = 13%)
    Referred to URO MD
    Jan '12: DRE = Positive: "Left induration"
    Jan '12: Biopsy = 6 of 12 Cores were Positive: 1 = G7 (3+4) and 5 = Gleason 6
    Referred to URO Surgeon
    March '12: Robotic RP: Left: PM + EPE. MD waited in surgery for preliminary Path Report then excised substantial left adjacent tissue(s) down to negative margins and placed 2 Ti clips for SR guidance, if needed in future.
    Pathology: Gleason (3+4) pT3a pNO pMX pRO c tertiary pattern 5 / Prostate Size = 32 grams / Tumor = Bilateral: 20% / PNI: present
    3 month Post Op standard PSA = <0.1 ng/ml
    1st uPSA at 7 months Post Op = 0.018 ng/ml
    uPSA remains "stable" at 84 Months Post Op: Mean = 0.021 (20x uPSAs: Range 0.017 - 0.026) LabCorp: Ultrasensitive PSA: Roche ECLIA
    Continence = Very Good (≥ 99%)
    ED = present

  5. #5
    Quote Originally Posted by Michael F View Post
    Thank you Dj
    - Only 1 in 4 of the BCR patients went on to CR

    If this finding is universally accurate and applicable, it supports The Mayo Clinic not using uPSA and suggests that we on The Forum may place too much emphasis on uPSA!

    Regardless, I for one, will continue monitoring via uPSA!!!

    MF
    Thanks, Michael.

    However, most RP men who encounter BCR get SRT (who wants to risk CR?), so that is keeping the number going on to CR down, right? If so, we return to the question of the best timing for deciding when to start RT, and whether uPSA is advantageous for deciding that question.

    Djin

  6. #6
    OOOPS!!! But of course Dj! Thank you again for the enlightenment!

    Now wish I had thought about it a bit deeper or ran it past you first before posting!!!

    MF

  7. #7
    Quote Originally Posted by Michael F View Post
    OOOPS!!! But of course Dj! Thank you again for the enlightenment!

    Now wish I had thought about it a bit deeper or ran it past you first before posting!!!

    MF
    As the Brits say, Not to worry! I save myself from myself many times only because I'm quick on the draw with the EDIT button. Ha ha.

  8. #8
    Considering the 2nd study - 30-days of my life moved me from Low Risk to High Risk due to my PSA being 9.2 in mid-May and 10.2 in mid-June.

    If my June PSA was just 3% lower (within standard error of PSA test ?) I would have remained Low Risk in their classification.

    Makes one wonder about the utility of the stratification IF such a small change in a single test score can make such a dramatic change in prognostication.
    DOB: July 1947
    PSA: 2.0/2004 4.0/2010 5.8/2010 4.5/2012 5.6/2013 ALL Normal DRE
    5/18 PSA: 9.2
    6/18 PSA: 10.2 & 8.4% Free
    6/28 3T mpMRI PIRADS 3
    18 cc gland=PSD 0.57 ng/cc
    0.32 cc lesion in apical PZ with subtle T2 signal hypointensity
    mild restricted diffusion of contrast into lesion prostate unremarkable intact capsule
    7/18 4KScore 34% Probability Gleason =>7

    8/03/18 Bx: Adenocarcinoma 6 of 13 cores ONLY L lobe
    T1c / Grade II / unfavorable intermediate
    extent of G3-G4 tissue far greater than indicated by MRI
    G6 (3+3) 70% LL Base 50% L Lateral Mid 20% L Base
    G7 (3 +4) 100% LL Apex 20% L Mid 60% L Apex
    8/15/18 Clear CT scan and Bone Scan
    RALP 8/23/18 pT3a, G7 (3+4), 20% involvement, SM+ (Focal 2mm G6), EPE(Focal G6)+, PNI+, LNI-, SVI-, LVI-
    7g Tumor 20x size in MRI & biopsy report & in BOTH lobes not just L as biopsy reported

    PSA Post Surgery
    10/3/18 0.021
    01/4/19 0.018
    04/03/19 0.022
    06/26/19 0.028

  9. #9
    Quote Originally Posted by OldTiredSailor View Post
    Considering the 2nd study - 30-days of my life moved me from Low Risk to High Risk due to my PSA being 9.2 in mid-May and 10.2 in mid-June.

    If my June PSA was just 3% lower (within standard error of PSA test ?) I would have remained Low Risk in their classification.

    Makes one wonder about the utility of the stratification IF such a small change in a single test score can make such a dramatic change in prognostication.
    OTS, I fear there will always be cases like that -- even nomograms have discrete values hard-wired in behind the scenes. Some, in fact, have a y/n question about PSA above/below 10 (or above/below 20). In fact, hard PSA values are in D'Amico's risk criteria as well.

    However, I think you can take that into account if you like, and either interpolate the two different resulting values, or just be an optimist and say that with all the error/variability sources, your 10.2 might really have been a 9.9

    On the more serious side, if one's values are indeed going up, say 7.7, 8.8, 9.9, (10.2), then you can make a case that the pre-op PSA is definitely trending up, and if surgery were postponed, or the PSA rise caught later, you would unequivocally be in the >10 group (even without the 10.2 with my hypothetical numbers).

    Djin

  10. #10
    DT - I am not trying to sneak down the stairs to the Low Risk level - everything in my pathology report, and as you mention, the trend/velocity of the PSA change (it had gone up to 10.4 at the time of the surgery) puts me squarely in a High Risk group.

    But, for someone with a PSA hovering (for some length of time) in the upper 9.x and lower 10.x range it might be quite disconcerting. Many nomograms and predictors have an inflection point at PSA=10.0.

    I spent several decades building predictive models, based on many types of multiple regression on enormous datasets, and always worried about single variables with sharp inflection points. But, never really figured out what to do.
    DOB: July 1947
    PSA: 2.0/2004 4.0/2010 5.8/2010 4.5/2012 5.6/2013 ALL Normal DRE
    5/18 PSA: 9.2
    6/18 PSA: 10.2 & 8.4% Free
    6/28 3T mpMRI PIRADS 3
    18 cc gland=PSD 0.57 ng/cc
    0.32 cc lesion in apical PZ with subtle T2 signal hypointensity
    mild restricted diffusion of contrast into lesion prostate unremarkable intact capsule
    7/18 4KScore 34% Probability Gleason =>7

    8/03/18 Bx: Adenocarcinoma 6 of 13 cores ONLY L lobe
    T1c / Grade II / unfavorable intermediate
    extent of G3-G4 tissue far greater than indicated by MRI
    G6 (3+3) 70% LL Base 50% L Lateral Mid 20% L Base
    G7 (3 +4) 100% LL Apex 20% L Mid 60% L Apex
    8/15/18 Clear CT scan and Bone Scan
    RALP 8/23/18 pT3a, G7 (3+4), 20% involvement, SM+ (Focal 2mm G6), EPE(Focal G6)+, PNI+, LNI-, SVI-, LVI-
    7g Tumor 20x size in MRI & biopsy report & in BOTH lobes not just L as biopsy reported

    PSA Post Surgery
    10/3/18 0.021
    01/4/19 0.018
    04/03/19 0.022
    06/26/19 0.028

 

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