(UroToday.com) At the European Association of Urology (EAU) Virtual 2020 meeting, Nicolas Mottet, MD, Ph.D., chair of the EAU Guidelines prostate cancer panel, summarized the guidelines for recurrence after radical prostatectomy. Dr. Mottet notes that there is a major difference between prostate-specific antigen (PSA) relapse (any PSA rise following an undetectable level) and a clinically significant PSA rise, which is the best predictor for further metastases (ie. post external beam radiation therapy (EBRT) nadir PSA + 2 ng/mL). The EAU definition after radical prostatectomy is thus a PSA > 0.4 ng/mL and rising, which is a clinically relevant threshold, but is not the threshold to define a relapse and is not the threshold to consider salvage treatment.
Depending on the imaging modality of choice, the PSA level in the biochemical recurrent setting is important:
- A bone scan as a <1% sensitivity when the PSA is <10 ng/mL
- A whole-body magnetic resonance imaging scan (MRI) has a sensitivity of 39% for a PSA <2 ng/mL
- A cholinePositron Emission Tomography- Computed Tomography (PET-CT) scan has a sensitivity of 5-24% for a PSA of <1 ng/mL
- A fluciclovine PET-CT has a sensitivity of <50% for a PSA < 1 ng/mL
In a prostate-specific membrane antigen (PSMA) PET-CT study among 332 patients with biochemically recurrent prostate cancer (97% after radical prostatectomy), Ceci et al.1 found that 68Ga-PSMA-11 PET/CT detection rate for disease was 53.6% (CI 95% 48.1%-59.1%). In a patient-based analysis, disease confined to pelvis (prostate bed and/or lymph-nodes) was detected in 24.7% of cases, and the presence of at least one distant lesion was observed in 28.9% of cases. Furthermore, the detection rate among patients with persisting detectable PSA after radical prostatectomy was 64.5%. Of note, 62.1% of patients were PET negative at a PSA < 0.5 ng/mL. The EAU guidelines2-3 state that in the setting of PSA recurrence after radical prostatectomy a PSMA PET-CT may be obtained if the PSA level is > 0.2 ng/mL and if the results will influence subsequent treatment decisions (level of evidence 2b, strength rating: weak). In cases where PSMA PET-CT is not available, and the PSA level is >= 1 ng/mL, clinicians should perform a fluciclovine PET-CT or choline PET-CT if the results will influence subsequent treatment decisions (strength rating: weak).
Dr. Mottet notes that relapse is important in that it is linked with metastasis free-survival (MFS), disease-specific survival, and overall survival (OS). However, the impact of relapse may be highly variable given that across studies hazard ratios range from 1.03 to 2.32 with regards to survival outcomes. In a systematic review assessing the prognostic value of biochemical recurrence following treatment with curative intent, Van den Broeck et al.4 define the EAU low-risk biochemical recurrence as a PSA-doubling time >1 year and pathologic ISUP grade <4 (whereby salvage treatment should be discussed but may not be needed), and EAU high-risk biochemical recurrence as a PSA-doubling time <= 1 year or pathological ISUP grade 4-5 (whereby salvage treatment is needed). The EAU guideline recommendations for local salvage treatment for biochemical recurrence after radical prostatectomy suggest that clinicians should offer PSA monitoring to patients with biochemical recurrence with low-risk features at relapse who may not benefit from intervention (strength rating: weak). Clinicians should offer salvage radiotherapy to patients with a PSA rise from an undetectable range, and once the decision is made to offer salvage radiotherapy, it should be given (at least 66 Gy) as soon as possible (strength rating: strong). Finally, the guidelines suggest that clinicians should offer hormonal therapy, in addition, to salvage radiotherapy to men with biochemical recurrence (strength rating: weak). Dr. Mottet also added that clinicians should not wait for a positive PET if salvage external beam radiotherapy (EBRT) is planned and that salvage EBRT must be at least 66 Gy and may go up to 72 Gy.
Salvage lymph node dissection may also be an option for these patients. In a systematic review, Ploussard et al.5 found that over a mean follow-up of 29.4 months, complete biochemical response after salvage lymph node dissection was achieved in 13-79.5% of cases (mean 44.3%). Furthermore, the 2- and 5-year biochemical progression-free survival rates ranged from 23% to 64% and from 6% to 31%, respectively.
Citing data presented at Advanced Prostate Cancer Consensus Conference (APCCC) 2019, Dr. Mottet notes that there is no consensus regarding the definition of oligometastatic disease.6 When panelists were polled to define “oligo”:
- 46% of participants said it was a limited number of synchronous or metachronous metastases in bone or lymph nodes but not visceral organs
- 8% of participants said it was a limited number of metachronous metastases in bone or lymph nodes but not visceral organs
- 33% of participants said it was a limited number of synchronous or metachronous metastases, including visceral organs
- 4% of participants said it was a number of metachronous metastases, including visceral organs
- 9% of participants said they did not believe that oligometastatic prostate cancer exists as a clinically meaningful entity
Furthermore, there was additional debate as to the number of metastases that should define “oligo”: (i) 48% said <= 3 metastases, (ii) 41% said <= 5 metastases, and (iii) 11% said that there should be no defined cut-off. Treatment in this setting is also unclear, as there is only one randomized controlled trial available assessing targeted treatment of oligometastatic disease.7 Among 62 patients randomized, at a median follow-up time of 3 years (IQR 2.3-3.75 years), the median androgen deprivation therapy (ADT)-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the metastasis directed therapy group (HR 0.60, 95% CI 0.31-1.13, log-rank p = 0.11):
With regards to relapse beyond the prostatic bed, the EAU guidelines suggest that the real efficacy of salvage lymph node dissection remains unproven, given the unknown impact on survival. Furthermore, in the setting of systemic relapse, patients should not be offered ADT in the M0 setting if the PSA-doubling time is > 12 months (strength rating: strong). Dr. Mottet notes that in the M1 setting there is plenty of level 1 data to treat these patients, based on the CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN studies. In this setting, the EAU guidelines suggest that patients should be offered ADT in combination with chemotherapy (docetaxel) for those that first present with M1 disease and who are fit to receive docetaxel (strength rating: strong). Furthermore, patients should be offered ADT in combination with abiraterone acetate plus prednisone or apalutamide or enzalutamide to patients who first present with M1 disease and who are fit enough for the regimen (strength rating: strong).
Dr. Mottet concluded that with regards to systematic treatment, there is significant overtreatment that treating a PSA value is irrelevant. We must offer treatment that has a clinical impact.
Presented by: Nicolas Mottet, MD, Ph.D., University Hospital Nord, Saint Etienne, France
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, twitter: @zklaassen_md at the 35th Annual EAU Congress, 2020 Virtual Program #EAU20, July 17-19, 2020.
- Ceci F, Castellucci P, Graziani T, et al. 68-Ga-PSMA-11 PET/CT in recurrent prostate cancer: Efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med Mol Imaging 2019 Jan;46(1):31-39.
- Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol 2017;71(4):630-642.
- Cornford P, Grummet J, Fanti S, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Scans Before Curative Treatment: Ready for Prime Time? Eur Urol. 2020 Jul 2;S0302-2838(20)30451-6.
- Van Den Broeck T, van den Bergh RCN, Arfi N, et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. Eur Urol 2019 Jun;75(6):967-987.
- Ploussard G, Gandaglia G, Borgmann H, et al. Salvage Lymph Node Dissection for Nodal Recurrent Prostate Cancer: A Systematic Review. Eur Urol 2019 Oct;76(4):493-504.
- Gillessen S, Attard G, Beer TM, et al. Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol 2020 Apr;77(4):508-547.
- Ost P, Reynders D, Decaestecker K, et al. Surveillance of Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol 2018 Feb 10;36(5):446-453