Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Immediate radiotherapy versus observation in patients with node-positive prostate cancer after radical prostatectomy

Abstract

Background

The optimal management of node-positive (pN1) prostate cancer following radical prostatectomy (RP) remains uncertain. Despite randomized evidence, utilization of immediate, life-long androgen deprivation therapy (ADT) remains poor, and recent trials of early salvage radiotherapy included only a minority of pN1 patients. We therefore emulated a hypothetical pragmatic trial of adjuvant radiotherapy versus observation in men with pN1 prostate cancer.

Methods

Using the RADICALS-RT trial to inform the design of a hypothetical trial, we identified men aged 50-69 years with pT2-3 Rany pN1 M0, pre-treatment PSA < 50 ng/mL prostate cancer in the NCDB from 2006 to 2015 treated with 60–72 Gy of adjuvant RT (aRT) ± ADT within 26 weeks of RP or observation. After estimating a propensity score for receipt of aRT, we estimated absolute and relative treatment effects using stabilized inverse probability of treatment (sIPW) re-weighting.

Results

In total, 3510 patients were included in the study, of whom 587 (17%) received aRT (73% with concurrent ADT). Median follow-up was 40.0 -months, during which 333 deaths occurred. After sIPW re-weighting, baseline characteristics were well-balanced. Adjusted overall survival (OS) was 93% versus 89% at 5-years and 82% versus 79% at 7-years for aRT versus observation (p = 0.11). In IPW-reweighted Cox regression, aRT was associated with a lower risk of all-cause mortality (ACM) than observation, but this did not reach statistical significance (HR 0.70 p = 0.06). In analyses examining heterogeneity of treatment effects, aRT was associated with improved ACM only for men with Gleason 8–10 disease (HR 0.59, p = 0.01), ≥2 positive LNs (HR 0.49, p = 0.04 for 2 positive LNs; HR 0.42, p = 0.01 for ≥3 positive LNs), or negative surgical margins (HR 0.50, p = 0.02).

Conclusions

In observational analyses designed to emulate a hypothetical target trial of aRT versus observation in pN1 prostate cancer, aRT was associated with improved OS only for men with Gleason 8–10 disease, ≥2 positive LNs, or negative surgical margins.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Adjusted overall survival stratified by treatment group.
Fig. 2: Forest plot of treatment effects stratified by subgroup.

Data availability

The data used herein (NCDB) is provided by the American College of Surgeons through a data request.

References

  1. Pisansky TM, Thompson IM, Valicenti RK, D’Amico AV, Selvarajah S. Adjuvant and salvage radiotherapy after prostatectomy: ASTRO/AUA guideline amendment 2018–2019. J Urol. 2019;202:533–8.

    Article  Google Scholar 

  2. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596–605.

    Article  CAS  Google Scholar 

  3. Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy. In EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam 2022 (EAU Guidelines Office).

  4. Lowrance, W, Breau, R, Chou, R, Crispino, T. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline (2020) - American Urological Association. J Urol. 14–22 (2021).

  5. Abdollah F, Karnes RJ, Suardi N, Cozzarini C, Gandaglia G, Fossati N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol. 2014;32:3939–47.

    Article  Google Scholar 

  6. Abdollah F, Suardi N, Gallina A, Bianchi M, Tutolo M, Passoni N, et al. Extended pelvic lymph node dissection in prostate cancer: a 20-year audit in a single center. Ann Oncol J Eur Soc Med Oncol. 2013;24:1459–66.

    Article  CAS  Google Scholar 

  7. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7:472–9.

    Article  CAS  Google Scholar 

  8. Moschini M, Sharma V, Zattoni F, Quevedo JF, Davis BJ, Kwon E, et al. Natural history of clinical recurrence patterns of lymph node-positive prostate cancer after radical prostatectomy. Eur Urol. 2016;69:135–42.

    Article  Google Scholar 

  9. Touijer KA, Mazzola CR, Sjoberg DD, Scardino PT, Eastham JA. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol. 2014;65:20–25.

    Article  Google Scholar 

  10. Kawakami, J, Cowan, JE, Elkin, EP, Latini, DM, Duchane, J, Carroll, PR. Androgen-Deprivation Therapy as Primary Treatment for Localized Prostate Cancer Data from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). (2006) https://doi.org/10.1002/cncr.21799.

  11. Jang JW, Hwang W-T, Guzzo TJ, Wein AJ, Haas NB, Both S, et al. Upfront androgen deprivation therapy with salvage radiation may improve biochemical outcomes in prostate cancer patients with post-prostatectomy rising PSA radiation oncology. Int J Radiat Oncol Biol Phys. 2012;83:1493–9.

    Article  CAS  Google Scholar 

  12. Touijer KA, Karnes RJ, Passoni N, Sjoberg DD, Assel M, Fossati N, et al. Survival outcomes of men with lymph node-positive prostate cancer after radical prostatectomy: a comparative analysis of different postoperative management strategies. Eur Urol. 2018;73:890–6.

    Article  Google Scholar 

  13. Jegadeesh N, Liu Y, Zhang C, Zhong J, Cassidy RJ, Gillespie T, et al. The role of adjuvant radiotherapy in pathologically lymph node-positive prostate cancer. Cancer. 2017;123:512–20.

    Article  CAS  Google Scholar 

  14. Rusthoven CG, Carlson JA, Waxweiler TV, Raben D, Dewitt PE, David Crawford E, et al. The impact of definitive local therapy for lymph nodeepositive prostate cancer: a population-based study radiation oncology. Int J Radiat Oncol Biol Phys. 2014;88:1064–73.

    Article  Google Scholar 

  15. Bolla, M, Van Poppel, H, Tombal, B, Vekemans, K, Da Pozzo, L, De Reijke, TM, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). www.thelancet.com 380, 2018-45 (2018).

  16. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathologic t3n0m0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956.

    Article  Google Scholar 

  17. Wiegel T, Bartkowiak D, Bottke D, Bronner C, Steiner U, Siegmann A, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243–50.

    Article  Google Scholar 

  18. Wiegel, T, Bottke, D, Steiner, U, Siegmann, A, Golz, R, Störkel, S, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pt3 prostate cancer with postoperative undetectable prostate-specific antigen. J Clin Oncol. 27, 2924–30.

  19. Kneebone A, Fraser-Browne C, Duchesne GM, Fisher R, Frydenberg M, Herschtal A, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21:1331–40.

    Article  CAS  Google Scholar 

  20. Parker CC, Clarke NW, Cook AD, Kynaston HG, Petersen PM, Catton C, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;396:1413–21.

    Article  CAS  Google Scholar 

  21. Sargos P, Chabaud S, Latorzeff I, Magné N, Benyoucef A, Supiot S, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020;21:1341–52.

    Article  CAS  Google Scholar 

  22. Vale CL, Fisher D, Kneebone A, Parker C, Pearse M, Richaud P, et al. Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet. 2020;396:1422–31.

    Article  CAS  Google Scholar 

  23. Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183:758–64.

    Article  Google Scholar 

  24. D’Agostino RJ. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;15:2265–81.

    Article  Google Scholar 

  25. Harrell, Frank E. J. Regression Modeling Strategies: With Applications To Linear Models, Logistic And Ordinal Regression, And Survival Analysis (Springer Series In Statistics). (Springer International Publishing, 2015).

  26. Abdollah F, Dalela D, Sood A, Keeley J, Alanee S, Briganti A, et al. Impact of adjuvant radiotherapy in node-positive prostate cancer patients: the importance of patient selection. Eur Urol. 2018;74:253–6.

    Article  Google Scholar 

  27. Gershman B, Guo DP, Dahabreh IJ. Using observational data for personalized medicine when clinical trial evidence is limited. Fertil Steril 2018;109:946–51.

    Article  Google Scholar 

  28. Bravi CA, Tin A, Vertosick E, Mazzone E, Bandini M, Dell’Oglio P, et al. Androgen deprivation therapy in men with node-positive prostate cancer treated with postoperative radiotherapy. Urol Oncol Semin Orig Investig. 2020;38:204–9.

    CAS  Google Scholar 

  29. Johnstone PAS, Assikis V, Goodman M, Ward KC, Riffenburgh RH, Master V. Lack of survival benefit of post-operative radiation therapy in prostate cancer patients with positive lymph nodes. Prostate Cancer Prostatic Dis. 2007;10:185–8.

    Article  CAS  Google Scholar 

  30. Marra G, Valerio M, Heidegger I, Tsaur I, Mathieu R, Ceci F, et al. Management of patients with node-positive prostate cancer at radical prostatectomy and pelvic lymph node dissection: a systematic review. Eur Urol Oncol. 2020;3:565–81.

    Article  Google Scholar 

  31. Tilki D, Preisser F, Tennstedt P, Tober P, Mandel P, Schlomm T, et al. Adjuvant radiation therapy is associated with better oncological outcome compared with salvage radiation therapy in patients with pN1 prostate cancer treated with radical prostatectomy. BJU Int. 2017;119:717–23.

    Article  CAS  Google Scholar 

  32. Tilki D, Chen MH, Wu J, Huland H, Graefen M, Wiegel T, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol. 2021;39:2284–93.

    Article  CAS  Google Scholar 

  33. Morgan TM, Hawken SR, Ghani KR, Miller DC, Feng FY, Linsell SM, et al. Variation in the use of postoperative radiotherapy among high-risk patients following radical prostatectomy. Prostate Cancer Prostatic Dis. 2016;19:216–21.

    Article  CAS  Google Scholar 

  34. Hawken SR, Spratt DE, Qi J, Linsell SM, Cher ML, Ghani KR, et al. Clinical investigation utilization of salvage radiation therapy for biochemical recurrence after radical prostatectomy radiation oncology. Int J Radiat Oncol Biol Phys. 2019;104:1030–4.

    Article  Google Scholar 

  35. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014;2014:MR000034.

  36. Soni PD, Hartman HE, Dess RT, Abugharib A, Allen SG, Feng FY, et al. Comparison of population-based observational studies with randomized trials in oncology. J Clin Oncol 2019;37:1209–16.

    Article  CAS  Google Scholar 

  37. Mendez LC, Arifin AJ, Bauman GS, Velker VM, Ahmad B, Lock M, et al. Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial. BMC Cancer. 2020;20:978.

Download references

Author information

Authors and Affiliations

Authors

Contributions

CS: study conception/design, interpretation of results, drafting manuscript, revision of manuscript. SK: study conception/design, interpretation of results, drafting manuscript, revision of manuscript. AF: study conception/design, interpretation of results, drafting manuscript, revision of manuscript. RK: study conception/design, interpretation of results, revision of manuscript. PC: study conception/design, interpretation of results, revision of manuscript. AW: study conception/design, interpretation of results, revision of manuscript. SK: study conception/design, interpretation of results, revision of manuscript. JB: study conception/design, interpretation of results, revision of manuscript. IK: study conception/design, interpretation of results, revision of manuscript. AO: study conception/design, interpretation of results, revision of manuscript. BG: study conception/design, interpretation of results, drafting manuscript, revision of manuscript; supervision.

Corresponding author

Correspondence to Boris Gershman.

Ethics declarations

Competing interests

The authors have no conflicts of interest to disclose. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.

Ethics approval and consent to participate

The study was exempt from ethics or Institutional Review Board approval. It was performed in accordance with the Declaration of Helsinki.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schaufler, C., Kaul, S., Fleishman, 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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41391-022-00619-1

This article is cited by

Search

Quick links