Management of pN1 Prostate Cancer (Including Systemic Therapy) APCCC 2022 Presentation - Derya Tilki

August 14, 2022

At the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting, Derya Tilki presents on the management of pN1 prostate cancer (including systemic therapy).


Derya Tilki, MD, Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

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Neha Vapiwala: And I'd like to invite for our final talk of the session, Dr. Derya Tilki, a urologist from Hamburg will speak to us about the management of pathologic node, positive disease.

Derya Tilki: Thank you very much.

Aurelius Omlin: And briefly, I see a lot of question on Twitter. So if you, because we've got now, what, 25 screen here, so if you could put your question and the APCC application, that would be easier for us. Thank you.

Silke Gillessen: And there's also microphones in the room. So afterwards, when we have the question of answer, you can also use these. Thanks, Derya.

Derya Tilki: Thank you. And thank you to Silke and Aurelius for inviting me to speak about management of pN1 disease. I have disease disclosures. I will talk about trends in prostate cancer, stage migration, about natural history of pN1 disease, management options in pN1 disease and current guidelines.

We have shown last year that rates of patients with positive lymph nodes at radical prostatectomy increased from 3.7% to 10.5% in 2000 to 2012, compared to 2013 to 2020. This is a study by Zareba and colleagues using the national cancer database, looking at distribution of post RP management strategies for pN1 one disease. And as you see on the left, there's mostly used observation and ADT alone. Men with higher grade tumors where more likely to be treated with ADT alone than observation radiotherapy alone, or combination therapy. Men with highest stage tumors were more likely to receive any treatment than undergo observation and men with a higher positive lymph node count were more likely to receive ADT alone.

With regards to ADT alone, lymph node metastases at the time of radical prostatectomy have traditionally been sought to be a manifestation of widely disseminated disease and consequently poor prognosis. And this paradigm was the basis for the randomized Messing trial, which showed higher overall survival among men who received immediate as opposed to delayed ADT. However, recent retrospective studies have shown the heterogeneity of pN1 disease where not all known positive patients may be affected by systemic disease and this suggests that immediate ADT represents overtreatment in a lot of men and that further treatment must be individualized based on risk factors.

In this study, we looked at 209 pN1 patients with one or two positive histologically proven positive lymph nodes without adjuvant treatment and what we saw is that a substantial subset of patients here, 27%, stay free of biochemical recurrence during follow up. This is another study by Touijer and colleagues from MSKCC, who also looked at the natural history of pathological lymph node, positive disease and have shown similar numbers. 28% of the pN1 patients in this study remained free from biochemical recurrence at 10 years. For patients with recurrence, most recurrences or occurred within the first five years after surgery. Higher pathological Gleason score, and three or more positive lymph nodes were significantly associated with increased risk of biochemical recurrence and metastasis and the 10 year probability of freedom from distant metastasis was 65%.

Multiple multicenter studies looked at the question of adjuvant radiation at additional benefit to ADT in pN1 disease. On the left, you see is study by Briganti and colleagues who did show that adjuvant radiation plus ADT did lead to better cancer specific survival compared to adjuvant ADT alone in a propensity score matched analysis. And similar data were shown again by Touijer and colleagues from MSKCC who also showed that higher risk patients benefited more from adjuvant radiotherapy.

Given the worst prognosis with the increasing number of positive lymph nodes, whether the association of a reduction in mortality risk applies irrespective of the number of positive lymph nodes when using adjuvant radiotherapy was explored after adjusting for the time dependent use and duration of ADT, we looked here at more than 1,600 patients with positive lymph nodes. At radical prostatectomy, adjuvant radio therapy use was associated with a significant reduction and all cause mortality risk compared with early salvage radiation therapy. The magnitude of this reduction increased by 8% with each additional positive lymph node. Men with four or more lymph nodes appeared to benefit the most from the use of adjuvant radiotherapy.

There's no randomized data on the question if adjuvant radiotherapy should be used with or without ADT in pN1 disease so far, but there are differing data from retrospective studies. For example, on the left side, a studied by Bravi and colleagues who used a single center experience from San Raffaele in Italy, and did not show any difference in overall survival when comparing radiotherapy to radiotherapy plus ADT. In contrast on the right side is study by Wong and colleagues from the National Cancer database, who did show difference in over all survival, better overall survival for patients with radiation plus ADT compared to radiation alone.

We may get some insight on this question from the RADICALS-HD study on hormone duration. The study randomized patients to radiotherapy alone, radiotherapy plus six months hormone therapy or radiotherapy plus two years hormone therapy and we will hear about the pN1 subset probably end of this year at [inaudible 00:06:35].

Ahlgren and colleagues looked at chemotherapy in high risk patients. This is the SPCG-12 study randomized 459 patients, including 12% pN1 patients after prostatectomy to six cycles of docetaxel or surveillance. Median follow up was 57 months, no improvement in biochemical recurrence free survival, which was defined as rising PSA above .5 was demonstrated and the lack of combination of docetaxel to ADT in this trial and the inclusion of patients not classically considered as very high risk for relapse may explain these negative findings.

While we just heard about data on new hormonal agents in the cN1 setting, we don't have data on that yet for the pN1 setting. There's a DASL-HICAP trial and the 1801, which is currently recruiting a randomized international trial of adding darolutamide to ADT and definitive or salvage radiation in very high risk prostate cancer and this study will include a stratification on clinical or pathological pelvic lymph node involvement.

Furthermore, in this setting, there's the NRG-GU008 innovate study. What's unique about the study is it is focusing on only pN1 disease, pathologically node, positive prostate cancer patients at the time of radical prostatectomy and currently having a detectable PSAR randomized to radiotherapy plus ADT two years versus radiotherapy plus ADT plus apalutamide for two years.

I would like to summarize using this systematic review on management of pN1 patients, which we performed within the EAU [inaudible 00:08:34] prostate cancer working group. It includes 26 studies with more than 12,500 men. 10 year biochemical recurrence free survival ranged from 28% to 56% and cancer specific survival from 72 to 98%. While the majority of men with pN1 disease experienced biochemical recurrence after surgery, long term disease free survival has been reported in selected patients. We saw that the use of adjuvant radiotherapy with, or without ADT was shown to improve survival in men with locally advanced disease and a higher number of positive lymph nodes. Risk stratification, according to pathological Gleason score, number of positive nodes and pathological stage is key for selection of the optimal postoperative therapy. The uncertainty regarding the optimal management of pN1 disease is reflected in the guidelines as seen here for the EAU guidelines, which list observation, adjuvant ADT and radiotherapy plus ADT as management options with the strengths rating of weak. Thank you.

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