ASCO GU 2020: Optimal Integration of Systemic and Localized Treatment for High-Risk Localized Prostate Cancer: Radiation Oncologist

San Francisco, CA ( Dr. Juanita Crook from the University of British Columbia presented the radiation oncologist’s perspective regarding the optimal integration of systemic and localized treatment for high-risk prostate cancer. According to Dr. Crook, it is important to define standard high-risk vs very high-risk localized prostate cancer. Very high-risk patients are those that have clinical stage T3b/T4 disease, primary pattern 5, >=50% of cores or those with >=2 high-risk features. Among 2,248 patients undergoing dose-escalated EBRT, patients with very high-risk prostate cancer had significantly worse PSA-RFS (p < 0.001), DMFS (p < 0.001), and PCSM (p = 0.001) compared with patients with standard high-risk prostate cancer.1 

Certainly, these high-risk patients require a multi-modality approach. For those undergoing primary surgery, additional treatment is based on pathology, which may include radiation and/or androgen deprivation therapy. For those undergoing radiation as their primary treatment, Dr. Crook notes that this may be regarded as an “all-cards-on-the-table” approach, including ADT in the initial phase. Dose-escalated radiation therapy includes spatial cooperation from external beam (nodal coverage) and brachytherapy (optimal dose for ablation of the primary). Large phase 3 trials have shown us that radiation plus hormones is better than hormones alone, with improved OS at 7 years and decreased PCSM. This has also been shown to improve biochemical, cause specific, and reduced local and distant failure. We’ve also learned that a higher radiation dose is better in that there is improved biochemical and cause specific survival and reduced local and distant failure. As follows is a summary of randomized trials of hormones + radiation for high-risk disease:

ASCO GU 2020 hormones plus radiation randomized trials

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.2 Among 1809 men across 12 tertiary centers, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. The median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP 12% (95% CI, 8%-17%); EBRT 13% (95% CI, 8%-19%); and EBRT+BT 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 (95% CI 0.21-0.68) and 0.41 (95% CI, 0.24-0.71)).

The Canadian ASCENDE-RT trial provided level 1 evidence for the benefit of brachytherapy in high-risk patients.3 In this phase 3 trial, 398 patients were randomized to 12 months ADT + 78 Gy versus 46 Gy + LDR brachytherapy – patients receiving brachytherapy had a better 9-year PSA RFS compared to standard dose-escalation EBRT (78% vs 58%, p=0.05). Although biochemical failure was associated with increased mortality and randomization to dose escalation-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (HR 1.13; p = 0.62).

According to Dr. Crook it is crucial to identify at risk patients that are likely to fail primary therapy. In a 2018 study, 5,783 patients with intermediate-risk or high-risk localized prostate cancer who were diagnosed between 2000 and 2015 and treated with radiation therapy and androgen deprivation therapy were identified from Veterans Affairs data.4 Patients were divided into groups based on 3-month post-RT PSA values: <0.10 ng/mL, 0.10 to 0.49 ng/mL, and ≥0.50 ng/mL. A higher 3-month PSA level was found to be strongly associated with each outcome compared with patients in the group with a 3-month PSA value <0.10 ng/mL: bPFS, PCSS, and OS. As such, PSA level 3 months after RT may be a clinical biomarker for identifying particularly high-risk men that may need additional systemic therapy.

Dr. Crook concluded with several important take home messages from her talk discussing radiation therapy for high-risk prostate cancer:

  • Effective treatment of the prostate is important in high-risk cancer, whether by surgical removal or sufficient radiation to the primary disease through dose escalation/addition of brachytherapy
  • It is important to identify those that are likely to fail for intensification of treatment through the addition of advanced hormonal agents/docetaxel

1. Zumsteg ZS, Zelefsky MJ, Woo KM, et al. Unification of favourable intermediate-, unfavourable intermediate-, and very high-risk stratification criteria for prostate cancer. BJU Int 2017 Nov;120(5B):E87-E95.
2. 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.
3. Morris WJ, Tyldesley S, Rodda S, et al. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer. Int J Radiat Oncol Biol Phys 2017 Jun 1;98(2):275-285.
4. Bryant AK, D’Amico AV, Nguyen PL, et al. Three-month post-treatment prostate-specific antigen level as a biomarker of treatment response in patients with intermediate-risk or high-risk prostate cancer treated with androgen deprivation and radiotherapy. Cancer 2018 Jul 15;124(14):2939-2947.

Presented by: Juanita Crook, MD, FRCPC, University of British Columbia, Vancouver, BC, Canada

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California