Radiotherapy in patients with node-positive prostate cancer after radical prostatectomy

Radiotherapy in patients with node-positive prostate cancer after radical prostatectomy


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In most solid cancers, the presence of clinical or pathological lymph node involvement is an indication for radiotherapy, if not chemoradiotherapy. Infact, bi- and tri-modality therapy is


the standard of care for most cancers. However, despite prostate cancer being common, >75% of the randomized trials in non-metastatic prostate cancer have utilized radical radiotherapy as


the backbone of treatment. Few phase III trials have been conducted using radical prostatectomy (RP), and those that have primarily focused on the use of adjuvant (ART) or early salvage


radiotherapy (SRT). Thus, there remain large voids of high-level evidence to support the optimal treatment of men with locally advanced prostate cancer with RP. Recently, the results of the


ARTISTIC meta-analysis demonstrated early SRT to have similar biochemical recurrence rates to ART. However, only ~40% of patients in this cohort recurred by 5-year post-RP and almost no


patients had multiple high-risk features or pN1 disease. It is estimated that >90% of men will recur post-RP who have pN1 disease, and thus it remains unclear if ART may be superior in


this population. To investigate this, Schaufler et al. [1]. present a hypothetical pragmatic trial based on RADICALS-RT trial design of immediate ART versus observation in patients with pN1


disease who were treated between years 2006 and 2015 identified through the National Cancer Database (NCDB). This retrospective analysis showed that reduction in all-cause mortality by


immediate RT compared to observation did not reach statistical significance in all patients, but was significant in patients with Gleason 8–10 disease (HR 0.59, _p_ = 0.01), ≥2 positive


lymph nodes (HR 0.49, _p_ = 0.04), or negative surgical margins (HR 0.5, _p_ = 0.02). As the authors indicate, there are numerous limitations with the study methodology and they were not


able to capture the use and duration of ADT or timing of salvage therapy in the observation arm. Given the known low utilization of early SRT in the real-world, it is probable that this


analysis did not test ART versus early SRT. The optimal management of pN1 disease is controversial. The small <100 patient ECOG 3886 trial demonstrated superiority of life-long ADT vs


deferred ADT [2]. Additionally, Granfors et al. reported the results of a small randomized trial showing that overall survival was improved with RT plus ADT vs RT alone in pN1 disease [3].


In a cohort analysis from STAMPEDE in men with clinical node involvement (cN1), RT was associated with improved failure-free survival (HR 0.48, 95% CI 0.29–0.79) [4]. Accordingly, a rational


approach would be to utilize RT in the pN1 setting. Currently, NRG Oncology has an open trial (NRG GU008) in men with pN1 disease and PSA > 0.01 ng/mL, where the control arm is RT plus 2


years of ADT. A trial comparing ADT vs RT plus ADT was proposed, but there lacked equipoise to use ADT alone given its non-curative potential. Thus, the current functional standard of care


is RT plus long-term ADT despite the gaps in evidence. The NRG GU008 trial will determine if the addition of apalutamide improves outcomes further. Given the increased utilization of PSMA


PET/CT imaging, the detection of cN1 disease will increase. NCCN guidelines remain clear that only highly selected patients with known cN1 prior to surgery should undergo RP, and thus the


incidence of pN1 will decrease with time as these patients will be managed with definitive radiotherapy plus ADT and abiraterone. While ART should not be pursued for most patients post-RP


with pN0 disease, it remains unclear if there would be any difference in outcomes between ART and early SRT in the setting of pN1 disease. A systematic review of SRT notes a 2.6% decline in


biochemical control with every 0.1 increase in PSA after prostatectomy [5], and given >90% of men with pN1 disease will recur, at the very minimum a lower threshold of 0.05 ng/mL may be


more appropriate to trigger early SRT. If the PSA becomes detectable prior to complete urinary healing post-RP, ADT can be initiated to delay the start of SRT until 6 months post-RP. In


summary, Schaufler et al. ask an important question in a population space without level 1 evidence. However, given the high probability of recurrence in patients with pN1 disease and a


potential window for cure, we believe very early SRT with ADT should be strongly considered. REFERENCES * Schaufler C, Kaul S, Fleishman A, Korets R, Chang P, Wagner A, et al. Immediate


radiotherapy versus observation in patients with node-positive prostate cancer after radical prostatectomy. _Prostate Cancer Prostatic Dis._ 2022. https://doi.org/10.1038/s41391-022-00619-1.


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Google Scholar  * James ND, Spears MR, Clarke NW, Dearnaley DP, Mason MD, Parker CC, et al. Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate


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after radical prostatectomy: a systematic review. Int J Radiat Oncol Biol Phys. 2012;84:104–11. Article  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND


AFFILIATIONS * Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA Angela Y. Jia & Daniel E. Spratt Authors


* Angela Y. Jia View author publications You can also search for this author inPubMed Google Scholar * Daniel E. Spratt View author publications You can also search for this author inPubMed 


Google Scholar CONTRIBUTIONS The authors confirm their contribution to the paper as follows—study conception, design, draft manuscript preparation: AYJ, DES. All authors reviewed and


approved the final version of the manuscript. CORRESPONDING AUTHOR Correspondence to Angela Y. Jia. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests.


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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jia, A.Y., Spratt, D.E. Radiotherapy in patients with node-positive prostate cancer after radical prostatectomy. _Prostate Cancer


Prostatic Dis_ 27, 1–2 (2024). https://doi.org/10.1038/s41391-022-00631-5 Download citation * Received: 28 November 2022 * Revised: 30 November 2022 * Accepted: 05 December 2022 * Published:


16 December 2022 * Issue Date: March 2024 * DOI: https://doi.org/10.1038/s41391-022-00631-5 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:


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