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Long-term outcomes of salvage lymph node dissection for nodal recurrence of prostate cancer after radical prostatectomy: Not as good as previously thought

  • Carlo A. Bravi,
  • Nicola Fossati,
  • Giorgio Gandaglia,
  • Nazareno Suardi,
  • Elio Mazzone,
  • Daniele Robesti,
  • Daniar Osmonov,
  • Klaus-Peter Juenemann,
  • Luca Boeri,
  • R. Jeffrey Karnes,
  • Alexander Kretschmer,
  • Alexander Buchner,
  • Christian Stief,
  • Andreas Hiester,
  • Alessandro Nini,
  • Peter Albers,
  • Gaëtan Devos,
  • Steven Joniau,
  • Hendrik Van Poppel,
  • Shahrokh F. Shariat,
  • Axel Heidenreich,
  • David Pfister,
  • Derya Tilki,
  • Markus Graefen,
  • Inderbir S. Gill,
  • Alexander Mottrie,
  • Pierre I. Karakiewicz,
  • Francesco Montorsi,
  • Alberto Briganti

Background

Long-term outcomes of patients treated with salvage lymph node dissection (sLND) for nodal recurrence of prostate cancer (PCa) remain unknown.

Objective

To investigate long-term oncological outcomes after sLND in a large multi-institutional series.

Design, setting, and participants

The study included 189 patients who experienced prostate-specific antigen (PSA) rise and nodal-only recurrence after radical prostatectomy (RP) and underwent sLND at 11 tertiary referral centers between 2002 and 2011. Lymph node recurrence was documented by positron emission tomography/computed tomography (PET/CT) scan using either 11C-choline or 68Ga prostate-specific membrane antigen ligand.

Outcome measurements and statistical analysis

The primary outcome of the study was cancer-specific mortality (CSM). The secondary outcomes were overall mortality, clinical recurrence (CR), biochemical recurrence (BCR), and androgen deprivation therapy (ADT)-free survival after sLND. The probability of freedom from each outcome was calculated using Kaplan-Meier analyses. Cox regression analysis was used to predict the risk of prostate CSM after accounting for several parameters, including the use of additional treatments after sLND.

Results and limitations

At long term, 110 and 163 patients experienced CR and BCR, respectively, with CR-free and BCR-free survival at 10 yr of 31% and 11%, respectively. After sLND, a total of 145 patients received ADT, with a median time to ADT of 41 mo. At a median (interquartile range) follow-up for survivors of 87 (51, 104) mo, 48 patients died. Of them, 45 died from PCa. The probabilities of freedom from cancer-specific and all-cause death at 10 yr were 66% and 64%, respectively. Similar results were obtained in sensitivity analyses in patients with pelvic-only positive PET/CT scan, as well as after excluding men on ADT at PET/CT scan and patients with PSA level at sLND higher than the 75th percentile. At multivariable analyses, patients who had PSA response after sLND (hazard ratio [HR]: 0.45; p = 0.001), and those receiving ADT within 6 mo from sLND (HR: 0.51; p = 0.010) had lower risk of death from PCa.

Conclusions

A third of men treated with sLND for PET-detected nodal recurrence of PCa died at long term, with PCa being the main cause of death. Salvage LND alone was associated with durable long-term outcomes in a minority of men who significantly benefited from additional treatments after surgery. Taken together, all these data argue against the use of metastasis-directed therapy alone for patients with node-only recurrent PCa. These men should instead be considered at high risk of systemic dissemination already at the time of sLND.

Commented by Prof. Igor Tsaur

Bravi et al. present a retrospective multicenter assessment of long-term outcomes of males with prostate cancer who experienced a lymph node (LN)-only (pelvic and/or retroperitoneal) recurrence after radical prostatectomy (RPE) and were treated with salvage lymph node dissection (sLND). 189 men from 11 centers were included in the final analysis. Recurrence was confirmed by PET/CT scan using 11C-choline or 68Ga prostate-specific membrane antigen ligand. The primary outcome was cancer-specific mortality, secondary outcomes included overall mortality, clinical or biochemical recurrence as well as androgen deprivation (ADT)-free survival after sLND.

At a median follow-up of 87 mos. for survivors, 45 out of 48 deaths were tumor-specific. 145 males received ADT after 41 mos. At 10 years, BCR-free survival, freedom from tumor-specific and overall mortality were estimated at 11%, 66% and 64%. PSA response defined as PSA < 0.2 ng/ml as well as ADT start during the first 6 mos. after sLND were independent predictors of a lower risk of death from PCa. In 86% of patients, primary LND was performed earlier during RPE. The median number of lymph nodes at sLND was 19, while LN metastasis was not histologically confirmed in 21% of cases.  In 63% of men, no PSA response could be achieved.

The findings of the study appear discouraging, since previous reports pointed to promising outcomes of some patients treated with metastasis-directed approaches upon progression in up to 3 lesions. The strength of the current analysis is undoubtedly its large sample size and long-term follow-up providing a robust survival estimation. However, it is noteworthy that one out of five patients had no histologic confirmation of PCa in resected lymph nodes putting the completeness of the surgical resection of recurrent disease or the imaging quality into question. More specific lymph node imaging-guided navigation during surgery could have impacted results. Moreover, in 81% of cases choline tracer was used allowing for a putative underestimation of the true extent of disease compared to PSMA. Importantly, STOMP and ORIOLE trials (PMID:  32215577; Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): Five-year results of a randomized phase II trial.Piet Ost, Dries Reynders, Karel Decaestecker, Valerie Fonteyne, Nicolaas Lumen, Aurélie De Bruycker, Bieke Lambert, Louke Delrue, Renée Bultijnck, Els Goetghebeur, Geert Villeirs, Kathia De Man, Filip Ameye, Ignace Billiet, Steven Joniau, Friedl Vanhaverbeke, and Gert de Meerleer Journal of Clinical Oncology 2020 38:6_suppl, 10-10) provided favorable outcomes in patients progressing in up to 3 lesions after initial treatment, while in the current study 52% of males revealed ≥ 3 positive nodes.The question is if the cohort investigated in the current analysis truly represents PCa patients with limited tumor spread who might benefit from eradication of visualizable metastasis not only in terms of ADT-free but cancer-specific survival. If not and the proportion of extended disease is high, it is not surprising that the number of positive nodes was not a predictor for cancer-specific mortality in the multivariate cox regression. Taken together, further marker-driven prospective research is warranted in order to better identify truly oligometastatic males with PCa who might benefit most from metastasis-directed therapy.