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Thread: Timing of SRT: increasing evidence for starting at lower PSA values

  1. #1

    Timing of SRT: increasing evidence for starting at lower PSA values

    I just added this paper to the Subforum, but think it is worthy of attention since the question of what PSA level should trigger SRT post-surgery comes up frequently. It looked at 33 reports from 2000 to 2018. All emphasis is mine.

    Optimizing the Timing of Salvage Postprostatectomy Radiotherapy and the Use of Concurrent Hormonal Therapy for Prostate Cancer [2018]

    Full Text: https://euoncology.europeanurology.com/article/S2588-9311(130020-8/fulltext

    Abstract

    Context

    Currently, salvage radiotherapy (SRT) is the only known curative intervention for men with recurrent disease following prostatectomy. Critical issues in the optimal selection and management of men being considered for SRT include the threshold prostate-specific antigen (PSA) value at which to initiate treatment (ie, pre-SRT PSA) and the role of concurrent hormonal therapy (HT).

    Objective
    To review the published evidence pertaining to the optimal timing for SRT and the role of concurrent HT.

    Evidence acquisition
    MEDLINE (via PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, and guideline statements from professional organizations were queried from January 1, 2000 through January 10, 2018.

    Evidence synthesis
    Thirty-three independent reports, including two randomized trials evaluating HT with SRT, were identified. Retrospective data suggest that SRT initiation at lower pre-SRT PSA levels is associated with better clinical outcomes. Prospective data suggest an overall survival benefit with concurrent HT that manifests during long-term follow-up, with the caveat that hypothesis-generating subgroup analyses suggest that this benefit may be limited to patients with higher pre-SRT PSA levels. Patients with adverse risk factors, such as Gleason grade group 4–5 disease, are likely to benefit the most from earlier SRT initiation and/or the use of HT.

    Conclusions
    Given the limitations of the available data, it is imperative that physicians participate in shared decision-making, with the recommendation tailored for each man's desire to maximize oncologic benefit (with a risk of overtreatment) versus potential quality-of-life optimization (with a risk of undertreatment). Within that framework, a significant body of retrospective data supports initiation of SRT at low pre-SRT PSA values, without an arbitrary absolute threshold. Prospective data suggest a benefit of HT, but this benefit may be greatest in patients with a pre-SRT PSA that is higher than the typical level in most patients receiving “early” SRT. Further research is necessary before absolute recommendations can be made.

    Patient summary
    Two ways to potentially improve outcomes following salvage radiotherapy for prostate cancer that recurs after prostatectomy are to start treatment at a lower prostate-specific antigen level and to use concurrent hormonal therapy. Our review suggests that the available evidence is imperfect, but highlights that both measures are likely to improve clinical outcomes in general, but perhaps not uniformly and/or consistently for all patients. Physician-patient shared decision-making and further research are critical.
    It appears that uncertainly and the over-treatment/undertreatment problem will remain until more prospective studies are done. I think it likely that the .06 level will start to trigger more concern, and perhaps the AUA might attach some caveats to its 0.2 mark. As I've mentioned, my doc thinks the BCR demarcation line differs by individual based on factors such as the G score, path report, genomics, pre- and post-RP PSA, rate of increase, time before increase, etc.
    Last edited by DjinTonic; 06-15-2018 at 01:13 PM.
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. biopsies, PCA3 -
    2013 TURP (90→30 g) path. neg. for cancer; then 6-mo. checkups
    6-06-17 DRE: nodule R and PSA rise, on finasteride: 3.6→4.3
    6-28-17 Biopsy #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 5% RLM
    Bone scan, CTs, X-rays: negative
    8-7-17 Open RP, neg. frozen sections, Duke Regional
    SM EPE BNI LVI SVI LNI(16): negative, PNI+, nerves spared
    pT2c pN0 bilat. acinar adenocarcinoma G9 (4+5) 5% of prostate (4.5 x 5 x 4 cm, 64 g)
    11-10-17 Decipher 0.37 Low Risk: 5-yr met risk 2.4%; 10-yr PCa-specific mortality 3.3%
    Dry; ED OK with sildenafil
    9-16-17 (5 weeks) PSA <0.1
    LabCorp uPSA (Roche ECLIA):
    11-28-17 (3 mo. ) 0.010
    02-26-18 (6 mo. ) 0.009
    05-30-18 (9 mo. ) 0.007
    08-27-18 (1 year) 0.018
    09-26-18 (13 mo) 0.013 (checking rise)
    11-26-18 (15 mo) 0.012
    02-25-19 (18 mo) 0.015
    05-22-19 (21 mo) 0.015

  2. #2
    DT, thanks for posting this.
    Diagnosed at age 64 (in November, 2014), PSA 4.3
    Nov 2014 BX 3 of 12 cores positive original pathology G8. Johns Hopkins second opinion, G6
    Surgery with Dr Ash Tewari Jan 6, 2015
    Post surgical pathology, stage T2c, bilateral disease, upstaged to G7(3+4)
    5% of Prostate involved in Tumor. Organ confined, Margins, SV, lymph nodes (9) all negative, PNI positive
    PSA <.02 until (uh-oh), 2/17 .02. Then 5/17-.033, 8/17-.033, 11/17-.046, 4/18-.060, 6/18-.068, 7/18- .082, 8/18-. 078.
    Decipher score low risk, .37
    ADT/Firmagon started August 2018. SRT to start SEPT 2018. Finished SRT November 2018, Finished ADT Feb 2019
    T=7, PSA <.05

  3. #3
    Senior User
    Join Date
    Jun 2017
    Posts
    235
    Question, I think the tests I am taking will round up to .1 if/when it hits .06 according to my doctor and I would jump into gear when I see that happen. I see from the studies cited by Rob Lee that .2 and below is considered very early as far as SR is concerned. Do I have that right?

    I guess I could do an ultra sensitive test and try and catch it before .06.

    I here talk that the standard test is used so as to not cause undo stress watching tiny numbers move around. I think there is anther stress out there. Knowing there is a more sensitive test and wondering if you should be taking it. LOL.
    DOB 1955
    Went for physical on 3/30/17 and had blood work done

    3/31/17 PSA 15.1 Refered to Urologist.
    4/5/17 DRE Negative
    4/7/17 PSA 14.1
    4/19/17 TRUS Negative
    5/1/17 Biopsy 12 cores
    RLB 3+4 30%
    RM 3+3 6%
    RLM 4+3 90%
    RLA 4+3 5%
    Left side negative
    5/26/17 Cat scan Negative
    6/7/17 Full body bone scan, Negative
    Decipher score .62 high risk
    RALP scheduled 6/28/17

    Final pathology report 7/28/17
    Prostatic adenocarcinoma with mucinous differentiation
    Gleason score 4+3 involving both lobes limited to the prostate
    Percentage involved by tumor 5%
    EPE -, SVI -, LVI -, LN -, PNI+, Margins -
    Pathologic stage pT2 N0
    PSA 8/4/2017 <0.1
    PSA 10/27/2017 <0.1
    PSA 1/26/2018 <0.1
    PSA 4/27/2018 <0.1
    PSA 10/25/2018 <0.1
    PSA 2/12/2019 <0.1

  4. #4
    The ultrasensitive PSA test can give you good idea of your PSA level and its stability or upward trend. The problem is how early you want to act on what may or may not increase to 0.2 or higher. But you can always consult RO's for an expert opinion on their latest thinking. 0.2 Is/was considered early, but there is some evidence that starting much earlier might be advantageous, at least in some cases. 0.03 Was shown to be an accurate predictor of BCR in one study. Perhaps those for whom adjuvant RT was considered would be candidates for very early SRT.
    Last edited by DjinTonic; 06-15-2018 at 10:32 AM.
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. biopsies, PCA3 -
    2013 TURP (90→30 g) path. neg. for cancer; then 6-mo. checkups
    6-06-17 DRE: nodule R and PSA rise, on finasteride: 3.6→4.3
    6-28-17 Biopsy #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 5% RLM
    Bone scan, CTs, X-rays: negative
    8-7-17 Open RP, neg. frozen sections, Duke Regional
    SM EPE BNI LVI SVI LNI(16): negative, PNI+, nerves spared
    pT2c pN0 bilat. acinar adenocarcinoma G9 (4+5) 5% of prostate (4.5 x 5 x 4 cm, 64 g)
    11-10-17 Decipher 0.37 Low Risk: 5-yr met risk 2.4%; 10-yr PCa-specific mortality 3.3%
    Dry; ED OK with sildenafil
    9-16-17 (5 weeks) PSA <0.1
    LabCorp uPSA (Roche ECLIA):
    11-28-17 (3 mo. ) 0.010
    02-26-18 (6 mo. ) 0.009
    05-30-18 (9 mo. ) 0.007
    08-27-18 (1 year) 0.018
    09-26-18 (13 mo) 0.013 (checking rise)
    11-26-18 (15 mo) 0.012
    02-25-19 (18 mo) 0.015
    05-22-19 (21 mo) 0.015

  5. #5
    Djin: thank u for the study, makes me feel good about my treatment path. Equally as important, thank u for your endless devotion to the forum, it is much appreciated. Best to u, MM

  6. #6
    Here is a study (abstract) that further stratifies men in an attempt to segment those who should treat early...apologies if it was previously posted and I missed it...but relevant to this conversation....

    https://www.jurology.com/article/S00...620-9/fulltext

    And an article that synthesizes many other studies....

    https://prostatecancerinfolink.net/2...ation-therapy/

    It sure does seem that over the last 5 years or so, the thinking has changed toward early treatment ����
    Diagnosed at age 64 (in November, 2014), PSA 4.3
    Nov 2014 BX 3 of 12 cores positive original pathology G8. Johns Hopkins second opinion, G6
    Surgery with Dr Ash Tewari Jan 6, 2015
    Post surgical pathology, stage T2c, bilateral disease, upstaged to G7(3+4)
    5% of Prostate involved in Tumor. Organ confined, Margins, SV, lymph nodes (9) all negative, PNI positive
    PSA <.02 until (uh-oh), 2/17 .02. Then 5/17-.033, 8/17-.033, 11/17-.046, 4/18-.060, 6/18-.068, 7/18- .082, 8/18-. 078.
    Decipher score low risk, .37
    ADT/Firmagon started August 2018. SRT to start SEPT 2018. Finished SRT November 2018, Finished ADT Feb 2019
    T=7, PSA <.05

  7. #7
    Thanks, Pratoman, I recently added the 2nd article (flagged by RobLee) to the Subforum.

  8. #8
    TY Dj! This is a retrospective review meta analysis of 'pre-existing(!)' published clinical data. The authors are all affiliated with the Apical PCa Programs in the U.S., UK & France.

    Not surprisingly, Early Intervention is associated with a better PCSM. However, THE Question I was hoping would be answered is: "At What Post RP PSA should SRT be initiated?"

    Apparently there is no exact or magical #. IMO, Reason is due to the heterogeneous nature of PCa and the myriad combinations of identified risk factors make it impossible to determine a single universal PSA level at which to initiate SRT.

    Key Takeaways:

    - PSADT:

    PSADT following BCR may be an important factor with regard to the use of HT with SRT. As briefly mentioned in the context of pre-SRT PSA, PSADT is associated with poor prognosis following RP and SRT [14–18]. In general, patients with shorter PSADTs are likely to have more aggressive disease (whether local or systemic), and in fact SRT may be more likely to provide a PCSM benefit in patients with shorter PSADTs, even if the overall prognosis for such patients is inferior to that for men with longer PSADTs

    - PSA Level:

    If maximizing oncologic benefit is the primary goal, we recommend strongly considering SRT when two consecutive rising PSA values have been identified, and recommend against delaying SRT until PSA has exceeded an arbitrary absolute threshold. However, we submit that certain factors, such as the kinetics of the PSA rise, the possibility of persistent benign tissue, the patient’s life expectancy, and, most importantly, the patient’s preferences, must be incorporated into any final treatment recommendation. We suggest that there a spectrum of benefit probably exists, with SRT offering better outcomes if delivered at PSA values <0.2 ng/ml than if performed when PSA is between 0.2 and 0.5 ng/ml. The absolute benefit of such an intervention is likely to be highly dependent on other disease factors [28]. For example, in a patient with GG 1–2 disease and a positive margin, SRT could be reasonably delayed despite a rising pre-SRT PSA above 0.2 ng/ml to aid in functional recovery. However, in patients with multiple high-risk features, such as negative margins and/or GG 4–5 disease, SRT should be considered for consecutive rising PSA values, regardless of the absolute value of the pre-SRT PSA. It should be acknowledged that in this latter scenario, the competing risk of synchronous out-of-field disease is higher than in the former, which might limit the benefit of SRT.

    - Importance of HT:

    Multiple randomized studies have shown an OS benefit for concomitant HT with RT in definitive treatment of localized PCa [38]. While the precise pathophysiological basis of this benefit remains an active area of study, recent data have identified a direct radiosensitizing action of HT [39,40], raising the possibility that concurrent HT has both local control benefits and benefits in terms of controlling micrometastatic disease. Adjuvant HT may also be important to suppress the induction of androgen receptor–mediated signaling by RT [41]. However, HT is associated with multiple effects, including bone loss, altered metabolism, diminished muscle mass, gynecomastia, hot flashes, possibly increased cardiovascular events, renal events, and cognitive-psychological disorders [42–45]. Emerging data do suggest an additive, rather than redundant, negative functional impact of RT and HT in the postoperative setting

    For the full paper, follow DjinTonic's link and then click on The PDF Icon (located to the right)

    As with all issues in life and in the world: Timing is important!

    MF
    Last edited by Michael F; 06-15-2018 at 03:07 PM.
    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 = Gleason 7 (3+4) and 5 = Gleason 6
    Referred to URO Surgeon
    March '12: Robotic RP: Left Positive Margins + EPEs. 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 / Prostate Size = 32 grams; Tumor = Bilateral; 20% / Perineural invasion: 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

  9. #9
    Thanks, Michael. Yes, it is a retrospective study -- which is why I said more prospective studies are needed. While it may well turn out in the end that there is no "universal" PSA number for BCR, what would be nice is the development of some formula or algorithm to come up with an individual PSA number based on all the factors currently in discussion (or an individualized PSA range--the authors speak of a "spectrum of benefits"). Something similar to the nomograms that are currently used to predict BCR risk.

    I think uro's are comfortable with what to do, and when, with patients in the 0.2 to 0.5 range; I'm not so sure about their recommending SRT below 0.2 in those cases where it may be beneficial. It seems wise to take into consideration the experience one's uro has with his/her patient base and SRT. But there is no harm in bringing to their attention recent studies that indicate much lower PSA levels may be reliable indicators that BCR is at hand, or consulting an RO if you begin to get nervous about a low, but definitely rising PSA, but your uro isn't concerned yet (the authors emphasize patient preference).
    _________________________
    BTW, I get an "article not found" error with your full-text link-- I think there is "emoticon interference". I've changed the link above and in the Subforum from the Abstract to the full text:

    https://euoncology.europeanurology.com/article/S2588-9311(130020-8/fulltext

    (When there is an 8 followed by a close parentheses sign, you need to use the URL tag for a link. If you just paste in the link you get the smiley interference.)
    Last edited by DjinTonic; 06-15-2018 at 01:31 PM.
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. biopsies, PCA3 -
    2013 TURP (90→30 g) path. neg. for cancer; then 6-mo. checkups
    6-06-17 DRE: nodule R and PSA rise, on finasteride: 3.6→4.3
    6-28-17 Biopsy #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 5% RLM
    Bone scan, CTs, X-rays: negative
    8-7-17 Open RP, neg. frozen sections, Duke Regional
    SM EPE BNI LVI SVI LNI(16): negative, PNI+, nerves spared
    pT2c pN0 bilat. acinar adenocarcinoma G9 (4+5) 5% of prostate (4.5 x 5 x 4 cm, 64 g)
    11-10-17 Decipher 0.37 Low Risk: 5-yr met risk 2.4%; 10-yr PCa-specific mortality 3.3%
    Dry; ED OK with sildenafil
    9-16-17 (5 weeks) PSA <0.1
    LabCorp uPSA (Roche ECLIA):
    11-28-17 (3 mo. ) 0.010
    02-26-18 (6 mo. ) 0.009
    05-30-18 (9 mo. ) 0.007
    08-27-18 (1 year) 0.018
    09-26-18 (13 mo) 0.013 (checking rise)
    11-26-18 (15 mo) 0.012
    02-25-19 (18 mo) 0.015
    05-22-19 (21 mo) 0.015

  10. #10
    Jared! 4 Items:

    1. That Damn "#8" Emoticon!!! I will edit to: "click on The PDF Icon" after following your original link.

    2. IMO, uPSA is currently the only way to identify early progressing PCa following RP

    3. Every PCa case is 100% unique. Thus it is not surprising that there is not a single universal absolute PSA level that triggers SRT.

    4. A topic for future investigation/clarification is: "What are the roles of 1) Micrometastases and 2) CTCs? / How & When do they occur? / When are they clinically significant? / How and When to Treat Them?"

    I've started to collect info.

    MF

 

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