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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.

Online ahead of print. * Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic

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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:

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