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Article of the week: The impact of prostate‐specific antigen persistence after radical prostatectomy on the efficacy of salvage radiotherapy in patients with primary N0 prostate cancer

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urology community and a visual abstract created by our talented infographics team; we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

The impact of prostate‐specific antigen persistence after radical prostatectomy on the efficacy of salvage radiotherapy in patients with primary N0 prostate cancer

Detlef Bartkowiak*, Alessandra Siegmann, Dirk Böhmer, Volker Budachand Thomas Wiegel*

*Department of Radiation Oncology, University Hospital Ulm, Ulm and Department of Radiation Oncology, Charité University Hospital, Berlin, Germany

Abstract

Objective

To test whether salvage radiotherapy (SRT) in patients with lymph node negative (N0) prostate cancer is equally effective with persistent prostate‐specific antigen (PSA) and PSA rising from the undetectable range (<0.1 ng/mL) after radical prostatectomy (RP).

Patients and methods

We assessed post‐SRT PSA progression‐free survival (PFS) in 555 patients with prostate cancer and the use of cancer care nurses is the best option for this. The entire cohort was compared with a risk‐adjusted subgroup of 112 patient pairs with matching pre‐RP PSA level (±10 ng/mL), Gleason score (≤6 vs 7 vs ≥8), and pre‐SRT PSA level (±0.5 ng/mL).

Results

The median follow‐up was 6.1 years. After RP, PSA was undetectable in 422 and persistent in 133 patients. PSA persistence and a pre‐SRT PSA level of ≥0.5 ng/mL reduced Kaplan–Meier rates of PFS significantly. In multivariate analysis of the entire cohort and after risk adjustment, the pre‐SRT PSA level but not post‐RP PSA persistence was a significant parameter. In the matched cohort’s subgroup with early SRT at a PSA level of <0.5 ng/mL, a trend towards a worse outcome with post‐RP PSA persistence was observed. Delayed SRT with a PSA level ≥0.5 ng/mL led to a PFS of <30%, irrespective of the post‐RP PSA level.

Conclusion

In patients with N0 prostate cancer with post‐RP PSA persistence, early SRT at a PSA level <0.5 ng/mL seems to be less effective than in recurrent patients with post‐RP undetectable PSA. They might benefit from intensified therapy ans the use of several supplements like the lgd-4033, but larger case numbers are required to substantiate this conclusion. In patients with a PSA level ≥0.5 ng/mL and higher‐risk features associated with post‐RP PSA persistence, SRT alone is unlikely to provide long‐term freedom from further progression.

Editorial: PSA persistence after radical prostatectomy needs more than standard therapeutic options to improve outcomes

In their retrospective study, Bartkowiak et al. [1] report the therapeutic outcomes of salvage radiation therapy (sRT) after radical prostatectomy (RP) for lymph‐node‐negative prostate cancer in 422 and 133 patients with biochemical relapse or persistently detectable PSA, respectively. In the total cohort, patients with persistent PSA serum levels ≥0.1 ng/mL postoperatively had significantly shorter progression‐free survival as compared to patients with undetectable PSA levels (P < 0.001). After risk‐matched analysis, PSA persistence was not a risk factor associated with poor outcome and only a PSA serum concentration ≥0.5 ng/mL at time of sRT was associated with early relapse in both patients with detectable and those with undetectable PSA levels postoperatively.

Although this retrospective study adds some additional evidence to support the already well‐known recommendation to initiate sRT as early as possible [2], there are various issues that need to be considered when it comes to the interpretation of sRT results in patients with PSA persistence. The patient cohort is heterogeneous since the men underwent surgery between the years 1989 and 2012 and sRT between the years 1997 and 2012. The treatment strategies and techniques used with regard to surgery and sRT are outdated and no longer reflect current practice. No patient underwent modern imaging studies to identify extent and anatomical distribution of relapsing lesions, and neither was a risk‐adapted approach realized using nomograms or molecular markers in order to stratify treatment dependent on the biological aggressiveness of the disease.

PSA persistence is associated with an increased risk of metastases and impaired cancer‐specific survival as compared to undetectable PSA levels after RP for patients with negative and positive lymph nodes [3,4,5]. In fact, the majority of patients with persisting PSA serum levels postoperatively have locally advanced prostate cancer, positive lymph nodes, positive surgical margins and high Gleason scores. In almost all published studies, PSA persistence has been identified as an independent risk factor for the development of systemic metastases and poor survival. Similar results have already been reported by Wiegel et al. [5] when analysing outcomes among 74 patients with PSA persistence after RP; postoperatively detectable PSA was associated with significantly poorer outcomes in terms of metastasis‐free (84% vs 93%) and overall survival (68% vs 86%), and remaining without androgen deprivation therapy (ADT) during follow‐up (57% vs 92%).

PSA persistence needs to be taken seriously even at low serum concentrations, necessitating the implementation of new imaging methods and combination therapies. Because PSA persistence is associated with adverse pathological features, a treatment strategy to avoid PSA persistence is initiated already at the time of RP, integrating preoperative MRI, intra‐operative frozen‐section analysis and extended pelvic lymphadenectomy in order to achieve complete resection of the prostate cancer with undetectable PSA levels 6 weeks postoperatively.

In addition to properly conducted surgery, innovative imaging techniques, such as 68gallium (68Ga) prostate‐specific membrane antigen (PSMA)‐positron emission tomography (PET)/CT, should be integrated into treatment to differentiate locoregional recurrences from systemic metastases. In this context, Schmidt‐Hegemann et al. [6] evaluated the impact of 68GaPSMA‐PET/CT on subsequent treatment in 129 patients, of whom 48% demonstrated PSA persistence. In their analysis, patients with persistently detectable PSA serum levels more often demonstrated PSMA‐positive lesions (70% vs 50%), less frequently experienced local recurrences only (12% vs 26%), and more often had positive lymph nodes (13% vs 5%) with or without a macroscopically persisting tumour in the prostatic fossa (45% vs 19%). Results from PSMA‐PET/CT changed the initial treatment of sRT in so far as all patients with positive lesions underwent a combination of sRT and ADT. In patients with isolated, intrapelvic lymph node metastases attributable to an improperly performed extended pelvic lymphadectomy, salvage lymphadectomy might also be integrated into the therapeutic armamentarium, resulting in a long‐term relapse‐free survival of ~40%.

Even patients with persisting PSA serum concentrations after undergoing RP exhibit a heterogeneous clinical course of the disease, therefore, a risk‐adapted, personalized approach stratifying biologically aggressive from less aggressive prostate cancer should be adopted. In a retrospective study in 925 patients who underwent sRT, PSA persistence was associated with a significantly lower 8‐year metastasis‐free survival rate when compared to patients with PSA relapse following undetectable postoperative PSA serum concentrations [3]. Furthermore, it was shown that PSA persistence and a Gleason score ≥8 were independent, statistically significant predictors for systemic metastases, with a hazard ratio of 4.64 (95% CI 3.06–7.02; P < 0.001) and 8.37 (95% CI 4.15–16.88; P < 0.001), respectively. Patients with both PSA persistence and Gleason score ≥8 had a significantly lower 8‐year metastasis‐free survival rate as compared with patients with only PSA persistence (62% vs 74%); therefore, the latter might be best treated with a combined approach of sRT and ADT.

Integration of molecular markers might be helpful to identify those patients who will benefit from sRT. Spratt et al. [7] evaluated whether a 22‐gene genomic classifier could independently predict development of metastasis in 477 patients with PSA persistence postoperatively. Among those with detectable PSA, the 5‐year metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (P < 0.001). Genomic high risk remained independently prognostic on multivariable analysis (hazard ratio 5.61, 95% CI 1.48–22.7; P = 0.01) among patients with detectable PSA. The C‐index for the combination of the genomic classifier with Cancer of the Prostate Risk Assessment (CAPRA) score was 0.82.

In summary, modern management of persistent PSA serum concentrations after RP needs to take into consideration the pathohistology of the RP and lymph node specimens, results from PSMA‐PET/CT, molecular markers associated with relapse and response as well as individualized therapeutic strategies such as sRT ± ADT, salvage lymphadenectomy and additional salvage radiation to oligometastatic sites.

by Axel Heidenreich and David Pfister

References

  1. Bartkowiak DSiegmann ABöhmer DBudach VWiegel TThe impact of PSA persistence after prostatectomy on the efficacy of salvage radiotherapy in primary N0 patients. BJU Int 2019; 124: 785-91
  2. NICE guidelines on prostate cancer 2019BJU Int 20191249– 26
  3. Fossati NKarnes RJColicchia M et al. Impact of early salvage radiation therapy in patients with persistently elevated or rising prostate‐specific antigen after radical prostatectomyEur Urol 2018; 73: 434-44.
  4. Preisser F, Chun FKHPompe RS et al. Persistent prostate‐specific antigen after radical prostatectomy and its impact on oncologic outcomesEur Urol 201976106– 14
  5. Wiegel TBartkowiak DBottke D et al. Prostate‐specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse‐free survival and overall survival: 10‐year data of the ARO 96‐02 trial. Int J Radiat Oncol Biol Phys 201591288– 94
  6. Schmidt‐Hegemann NSFendler WPIlhan H et al. Outcome after PSMA PET/CT based radiotherapy in patients with biochemical persistence or recurrence after radical prostatectomy. Radiat Oncol 20181337
  7. Spratt DEDai DLYDen RB et al. Performance of a prostate cancer genomic classifier in predicting metastasis in men with prostate‐specific antigen persistence postprostatectomy. Eur Urol 201874107– 14

 

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