APCCC 2024: In Patients with BCR and Positive Lesion(s) in the Pelvis – Stereotactic or Whole Pelvis Radiotherapy?

(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the treatment for biochemical recurrence/PSA persistence, and a presentation by Dr. Paul Nguyen discussing whether we should use stereotactic or whole pelvis radiotherapy for patients with biochemical recurrence and a positive lesion in the pelvis. Dr. Nguyen notes that his topic of discussion is focused on one of the APCCC key questions:

Question #49: In the majority of patients with confirmed PSA rise after radical prostatectomy with prior salvage radiotherapy to the prostate bed and PSA doubling time <= 1 year or pathological ISUP grade group 4 or 5 and 1-3 positive lymph nodes in the pelvis alone on PSMA PET. What is your treatment recommendation regarding the radiation therapy?

  • Stereotactic body radiotherapy of positive nodes alone
  • Whole pelvis radiotherapy +/- boost to the positive nodes

Is any local treatment to the nodes justified? According to Dr. Nguyen, the answer is yes. Retrospective data suggests that metastasis-directed therapy (including the nodes) improves cancer specific survival. In a study from Steuber et al.,1 among patients with a PSA relapse following radical prostatectomy plus post-operative radiotherapy, multidisciplinary therapy (salvage lymph node dissection or stereotactic body radiotherapy for N1/M1a disease) versus standard of care (delayed or immediate ADT) was associated with a 3% cancer-specific survival gain at 5-years and a 10% cancer specific survival gain at 10 years:

According to Dr. Nguyen, the following criteria may justify stereotactic body radiotherapy instead of whole body radiotherapy to the pelvis:

  1. If the cancer control is comparable to whole pelvis, and/or
  2. If the toxicity is less than whole pelvis radiotherapy

Is stereotactic body radiotherapy cancer control as good as whole pelvis radiotherapy? According to Dr. Nguyen, the answer is no, particularly extrapolating from surgical series. For example, in a study by Bravi et al.,2 they undertook a multi-institutional approach to assess long-term outcomes, including 189 patients who experienced PSA rise and nodal-only recurrence after radical prostatectomy and underwent salvage lymph node dissection at 11 centers between 2002 and 2011. Recurrences were detected with either 11C-choline or 68Ga PSMA. There were 110 and 163 patients experienced clinical recurrence and biochemical recurrence, respectively, with clinical recurrence-free and biochemical recurrence-free survival at 10 years of 31% and 11%, respectively. After salvage lymph node dissection, a total of 145 patients received ADT, with a median time to ADT of 41 months. Importantly, additional therapy was warranted in >60% of patients within 6 months of salvage lymph node dissection.

De Bleser et al.3 compared outcomes and toxicity between stereotactic body radiotherapy and elective nodal radiotherapy, with a primary endpoint of metastasis-free survival. In this multi-institutional study of 506 men, 309 received stereotactic body radiotherapy and 197 received elective nodal radiotherapy. Elective nodal radiotherapy was associated with fewer nodal recurrences compared with stereotactic body radiotherapy (p < 0.001):

In a multivariable analysis, patients with one lymph node at recurrence had longer adjusted metastasis free survival after elective nodal radiotherapy (HR 0.50, 95% CI 0.30-0.85, p = 0.009).

Is toxicity less with stereotactic body radiotherapy than whole pelvis radiotherapy? According to Dr. Nguyen, the answer is no. Data from the STORM/PEACE V trial was recently presented at EAU 2024. STORM is an international, phase II, open-label, randomized, superiority trial (NCT03569241). Patients diagnosed with PET-detected pelvic nodal oligorecurrence (≤5 nodes) following radical local treatment for prostate cancer, were randomized in a 1:1 ratio between arm A: metastasis directed therapy and 6 months of ADT, or arm B: elective nodal pelvic radiotherapy (25 x 1.8 Gy) with metastasis directed therapy and 6 months of ADT. In case of radiotherapy, SBRT (3 x 10 Gy) was used for arm A, with a simultaneous integrated boost in arm B. The trial design for the STORM trial is as follows:

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The primary endpoint is metastasis-free survival and the secondary endpoint is late toxicity, defined as worst grade ≥ 2 CTCAE v4.0 gastrointestinal and genitourinary toxicity exceeding baseline within 24 months of treatment. Between June 2018 and April 2021, 196 patients were randomly assigned to metastasis directed therapy or elective nodal pelvic radiotherapy, of which 97 of 99 allocated to metastasis directed therapy and 93 of 97 patients allocated to elective nodal pelvic radiotherapy received per-protocol treatment. Worst late genitourinary toxicity proportions were as follows: grade 2 and 3 events in 18 (19%) and 3 (3.2%) patients in the metastasis directed therapy arm vs 19 (21%) and 5 (5.5%) patients in the elective nodal pelvic radiotherapy arm (p = 0.61):

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Worst late grade ≥ 2 gastrointestinal toxicity was observed in 5.3% of the patients (n = 5, grade 2) in the metastasis directed therapy arm vs 6.6% of the patients (n = 4, grade 2; n = 2, grade 3) in the elective nodal pelvic radiotherapy arm (p = 0.94):

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Dr. Nguyen notes the following conclusions from the PEACE V STORM trial:

  • This is the first randomized trial exploring the best treatment modality for oligorecurrent nodal prostate cancer
  • Worst 24 month grade 2+ toxicities for strategies are acceptable
  • Compared to metastasis directed therapy, elective nodal radiotherapy does not result in a clinically meaningful increase in 24 month GU or GI toxicity
  • The first oncological outcomes at 3 years (biochemical and loco-regional progression free survival) will be presented at ESTRO 2024 in May (Glasgow, UK)

Taking the available evidence together as a whole, Dr. Nguyen suggests that stereotactic body radiotherapy appears to have inferior cancer control and similar toxicity to whole pelvis radiotherapy, therefore whole pelvis radiotherapy should be preferred.

Should we use ADT with nodal radiotherapy? According to Dr. Nguyen, the answer is yes. Data from the RTOG 85-31 trial of radiotherapy +/- ADT showed that ADT improved overall survival for N1 patients getting radiotherapy (HR 1.62, p = 0.03)4:

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Furthermore, based on data from the recently published OLIGOPELVIS trial5 we should be using ADT for >= 6 months. OLIGOPELVIS is a phase 2 trial of 67 patients with <= 6 nodes, with radiotherapy + 6 months of ADT having the following outcomes:

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There are several future randomized trials in this disease space, as highlighted in the following table:

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Dr. Nguyen concluded his presentation discussing whether we should use stereotactic or whole pelvis radiotherapy for patients with biochemical recurrence and a positive lesion in the pelvis by emphasizing what he does for N1 recurrence patients in today’s setting: whole pelvis radiotherapy + boost to the node (no prophylactic PA-node radiotherapy) + 6-24 months of ADT depending on age + clinical factors +/- abiraterone, apalutamide, enzalutamide, or darolutamide depending on age + clinical factors.

Presented by: Paul Nguyen, MD, MBA, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024. 

References:

  1. Steuber T, Jilg C, Tennstedt P, et al. Standard of care versus metastases-directed therapy for PET-detected nodal oligorecurrent prostate cancer following multimodality treatment: A multi-institutional case-control study. Eur Urol Focus 2019 Nov;5(6):1007-1013.
  2. Bravi CA, Fossai N, Gandaglia G, et al. Long-term Outcomes of Salvage Lymph node dissection for nodal recurrence of prostate cancer after radical prostatectomy: Not as Good as Previously Thought. Eur Urol 2020 Nov;78(5):661-669.
  3. De Bleser E, Jereczek-Fossa BA, Pasquier D, et al. Metastasis-directed therapy in treating nodal oligorecurrent prostate cancer: A multi-institutional analysis comparing the outcome and toxicity of stereotactic body radiotherapy and elective nodal radiotherapy. Eur Urol. 2019 Dec;76(6):732-739.
  4. Lawton CA, Winter K, Grignon D, et al. Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: Updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31. J Clin Oncol. 2005 Feb 1;23(4):800-807.
  5. Vaugier L, Morvan C, Pasquier D, et al. Long-term outcomes and patterns of relapse following high-dose elective salvage radiotherapy and hormone therapy in oligorecurrent pelvic nodes in prostate cancer: OLIGOPELVIS (GETUG-P07). Eur Urol. 2024 Mar 14 [Epub ahead of print].