(UroToday.com) The 2023 ESMO annual meeting included a session on management of (very) high-risk localized prostate cancer, featuring a presentation by Dr. Derya Tilki discussing the delineation of staging pelvic lymph node dissection before radiotherapy and positioning primary prostatectomy. Dr. Tilki started her presentation by discussing positioning primary radical prostatectomy in patients with high risk prostate cancer. Previous work has noted that not all grade 5 prostate cancer on biopsy is created equal: patients with primary histological Gleason pattern 5 have worse oncological outcomes compared to patients with secondary biopsy Gleason pattern 5 disease.

In the STAMPEDE arm of high-risk localized prostate cancer treated with either abiraterone or enzalutamide, there was a consistent effect with ARPI regardless of metastatic burden.¹ In this study, local radiotherapy was mandated for node negative and encouraged for node positive disease. There were 1,974 patients randomized and over a median follow-up of 72 months (IQR 60–84), metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR NE–NE) than in the control groups (not reached, 97–NE; HR 0.53, 95% CI 0.44–0.64). The 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group:
With regards to surgery for high risk locally advanced prostate cancer, the EAU guidelines suggest that we should offer radical prostatectomy in patients with cN0 disease as part of multi-modal therapy. Additionally, in pN0 patients with ISUP grade group 4-5 and pT3 +/- positive margins, we should offer adjuvant IMRT plus image-guided radiotherapy. As such, Dr. Tilki notes that patients with high-risk prostate cancer are at increased risk of PSA failure, need for secondary therapy, metastatic progression, and death from prostate cancer. Thus, there is no consensus regarding the optimal treatment of men with high-risk prostate cancer.

Based on the ARTISTIC meta-analysis assessing adjuvant versus early salvage radiotherapy after radical prostatectomy, there was no data to show superiority of adjuvant radiotherapy over salvage radiotherapy based on event-free survival.² Furthermore, presented at ESMO 2023, the updated analysis of the RADICALS-RT trial showed that early salvage radiotherapy was as effective as adjuvant radiotherapy for distant metastasis free survival. However, very few men in these trials had very high risk disease, and among men with adverse pathology (pN1 or Gleason 8-10 disease), adjuvant compared with early salvage radiation was associated with a significant reduction in all-cause mortality risk.³

Dr. Tilki notes that taken together, both radical prostatectomy as part of multimodal treatment and external beam radiotherapy + long-term ADT can be recommended as primary treatment in high-risk and locally advanced prostate cancer. If radiation is used, the combination of local with systemic treatment provides the best outcome. Additionally, patients should be fully informed about all available options and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment.

 In 2018, Kishan and colleagues compared radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 disease.⁴ Among 1,809 men across 12 tertiary centers, 639 underwent radical prostatectomy, 734 EBRT, and 436 EBRT + brachytherapy boost. The median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 radical prostatectomy, 186 EBRT, and 90 EBRT + brachytherapy boost patients had died. Adjusted 5-year prostate cancer-specific mortality rates were radical prostatectomy 12% (95% CI, 8%-17%), EBRT 13% (95% CI, 8%-19%), and EBRT + brachytherapy boost 3% (95% CI, 1%-5%). EBRT + brachytherapy boost was associated with significantly lower prostate cancer-specific mortality than either radical prostatectomy or EBRT (cause-specific HRs of 0.38 (95% CI 0.21-0.68) and 0.41 (95% CI, 0.24-0.71)).
Previous work from Dr. Tilki’s group asked the question: Can treatment with radical prostatectomy, adjuvant radiotherapy, and ADT (termed MaxRP) or external beam radiotherapy, brachytherapy, and ADT (termed MaxRT) in men with Gleason score 9-10 prostate cancer provide similar survival outcomes?⁵ Between 1992 and 2013, 80 men were treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were treated with radical prostatectomy and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. In this study, there was no significant difference in the risk of prostate cancer-specific mortality and all-cause mortality when comparing men who underwent MaxRP versus MaxRT.

Currently, the SPCG-15 randomized trial is comparing radical prostatectomy with primary radiotherapy plus ADT in men with locally advanced prostate cancer. This is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1,200 men. Initial results from the SCPG-15 trial showed that randomization between surgery and external beam radiotherapy is feasible, and as of September 2023, 995 patients have been randomized. The primary endpoint is prostate cancer specific mortality and the main secondary endpoints are metastasis free survival and functional outcomes (quality of life).

At the 2022 APCCC conference, the prostate cancer experts were asked “What is your preferred treatment recommendation for the majority of prostate cancer patients with cN0 on conventional imaging but positive pelvic lymph nodes on PSMA PET imaging but not distant lesions (M0)? 58% of respondents selected radiation therapy + ADT + 2 years of abiraterone, 24% responded surgery as the first step of multimodal therapy, and 18% selected radiation therapy + ADT. Thus, even among the experts, there is not consensus in management.

Dr. Tilki concluded this part of her presentation discussing positioning primary radical prostatectomy with the following take-home points:

• There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. Randomized controlled trials are only available for primary radiotherapy
• Experts cannot define the most optimal treatment option for locally-advanced prostate cancer
• Up front surgery can be performed with anticipation of postoperative radiotherapy
• SPCG-15 will compare radical prostatectomy with primary radiotherapy + ADT in men with locally advanced prostate cancer

Dr. Tilki then discussed delineating staging pelvic lymph node dissection before radiotherapy. The rationale for this approach is that it is potentially more accurate in identifying men who harbor nodal metastases to guide therapy decisions (ie. to select pelvic radiotherapy or intensified systemic treatment). Furthermore, there is previous experience with this approach in the past, as this was used in randomized trials to determine pathological lymph node status before randomization (ie. GETUG12 randomization from 2002-2006), and SPCG-7 (randomization from 1996-2002). Thus, the question is: can we rely on PSMA PET/CT findings or should pelvic lymph node dissection be performed before deciding on intensity of radiotherapy and systemic treatment?

De Barros and colleagues looked at sentinel node procedure to select clinically localized prostate cancer patients with occult nodal metastases for whole pelvis radiotherapy.⁶ Among 528 cN0 patients, 267 patients were directly treated with prostate only radiotherapy, and 261 patients underwent sentinel lymph node biopsy prior to radiotherapy. pN1 patients were offered whole pelvis radiotherapy. This study found that sentinel lymph node biopsy based selection of pN1 patients with whole pelvis radiotherapy was associated with favorable oncological outcomes as compared with imaging based prostate-only radiotherapy in cN0 prostate cancer patients: 7 year biochemical recurrence free survival rates were 81% for the sentinel node group and 49% in the non-sentinel node group (HR 0.42, 95% CI 0.27-0.66):

Importantly, only 7.5% of patients in this study had a PSMA PET/CT for staging.

To date, there is no outcome data available for sentinel node based radiotherapy field adjustments in patients with miN0 prostate cancer. With regards to PSMA PET/CT, we do know that the per patient sensitivity and specificity in the detection of lymph node metastases >=3 mm were 61.5% and 98.8%, respectively for PSMA PET/CT. Additionally, we know that in high risk men with lymph node metastases, 47.7% will have metastatic deposits outcomes of the pelvic lymph node dissection template. What about extended pelvic lymphadenectomy? We also know that this comes with a cost of morbidity in that up to 14% will have lower limb lymphedema following radical prostatectomy and extended pelvic lymph node dissection. Dr. Tilki notes that the lack of a uniform definition and standardized diagnostic criteria for lower limb and genital lymphedema hampers the accurate estimation of their true prevalence.

Dr. Tilki concluded this part of her presentation discussing the delineation of staging pelvic lymph node dissection before radiotherapy with the following take-home points:

• Pelvic lymph node dissection is associated with significant complications
• PSMA PET/CT provides more accurate staging than conventional imaging
• Both PSMA PET/CT and extended pelvic lymph node dissection miss micro-metastatic pelvic lymph node metastasis
• Whether lymphadenectomy-based treatment adjustment of radiotherapy field or systemic treatment in miN0 patients is associated with better outcomes remains unclear
• Optimal management of pN1 remains unknown, and pre- and postoperative PSMA PET/CT may help direct appropriate management

Presented by: Derya Tilki, MD, Martini-Klinik, Hamburg, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.

References:

1. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: A meta-analysis of primary results from two randomized controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022 Jan 29;399(10323):447-460.
2. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
3. Tilki D, Chen MH, Wu J, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and risk of death. J Clin Oncol. 2021 Jul 10;39(20):2284-2293.
4. Kishan AU, Cook RR, Ciezki JP, et al. Radical prostatectomy, external beam radiotherapy, or External Beam Radiotherapy with Brachytherapy Boost and Disease Progression and Mortality in Patients with Gleason Score 9-10 Prostate Cancer. JAMA 2018 Mar 6;319(9):896-905.
5. Tilki D, Chen MH, Wu J, et al. Surgery vs Radiotherapy in Management of Biopsy Gleason Score 9-10 Prostate Cancer and the Risk of Mortality. JAMA Oncol. 2019 Feb 1;5(2):213-220.
6. De Barros HA, Duin JJ, Mulder D, et al. Sentina Node Procedure to Select Clinically Localized Prostate Cancer Patients with Occult Nodal Metastases for Whole Pelvis Radiotherapy. Eur Urol Open Sci. 2023 Jan 30:49:80-89.