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Para-Aortic Radiation Therapy for Oligorecurrent Prostate Cancer - Beyond the Abstract

The treatment for oligometastatic prostate cancer has been evolving over the last several years. Oligorecurrent prostate cancer represents a subset of men with oligometastatic prostate cancer, specifically those who responded to initial definitive treatment but had the disease return in 5 or fewer metastatic sites.1 Several trials have explored using metastasis-directed therapy (MDT) for prostate cancer patients with oligorecurrent cancer. The phase II STOMP trial randomized patients with oligorecurrent (in this trial, limited to three metastases) prostate cancer to surveillance versus MDT consisting of metastectomy or stereotactic body radiation therapy (SBRT) to all visible metastases.2 Androgen deprivation therapy (ADT)-free survival was nearly a third longer in the MDT group. The phase II ORIOLE trial randomized men with oligorecurrent hormone-sensitive prostate cancer to SBRT versus observation.3 Patients who received SBRT based on conventional imaging had a significantly longer progression-free survival (PFS) with minimal added treatment toxicity. A third phase II trial, SABR-COMET, included patients with oligorecurrent cancer of different histologies (16% with prostate cancer) and randomized them 2:1 to SBRT versus observation.4 There was an overall survival advantage for patients on the SBRT arm.

Advances in imaging techniques (e.g., prostate-specific membrane antigen [PSMA] or fluciclovine positron-emission tomography [PET]) have made it feasible to identify oligorecurrent prostate cancer at a low prostate specific antigen (PSA) to guide potential therapy. In many of these patients, disease is confined to the pelvic or subdiaphragmatic lymph para-aortic lymph nodes. In the OLIGOPELVIS GETUG P07 phase II trial of patients with oligorecurrent prostate cancer limited to ≤5 pelvic nodal relapses, Supiot et al. reported a median PFS of 45.3 months with whole pelvic radiation therapy and short-term ADT.5 Based on these results, the PEACE V-STORM trial is randomizing patients with oligorecurrent pelvic nodal prostate cancer to metastasis directed therapy with or without elective pelvic nodal irradiation.

While the optimal treatment for oligorecurrent prostate cancer limited to the pelvic lymph nodes remains to be determined, we know that these patients are likely to recur in the sub-diaphragmatic lymph nodes.6 Thus, one limitation of MDT, whether with SBRT or metastectomy, is the failure to treat subclinical disease harbored in neighboring lymph nodes. This limitation of MDT may lead to higher failure rates. A recent analysis of patients with recurrent pelvic nodal disease treated with salvage radiation therapy found that the most common site of distant failure found with PSMA PET was the in the subdiaphragmatic para-aortic lymph nodes (42.5% of patients with distant failure).7 Therefore, patients with oligorecurrent prostate cancer limited to the subdiaphragmatic para-aortic lymph nodes likely represent the natural progression of disease from the pelvic lymph nodes. Furthermore, given that the disease has not manifested osseous or visceral spread, it may represent a more favorable oligorecurrent state.

Based on this, our institution has been offering men with oligorecurrent prostate limited to the subdiaphragmatic para-aortic lymph nodes conventionally-fractionated radiation therapy to the para-aortic lymph nodes (PA-RT). PA-RT consists of 45-50 Gy in 25 fractions electively to the para-aortic lymph nodes with a simultaneous integrated boost of 60-65 Gy to the involved nodes. Radiation therapy is delivered with intensity modulated radiation therapy (IMRT) with photons or proton beam radiotherapy with modulated scanning (IMPT). Historically, this radiation treatment has been shown to be safe and effective in patients with cervical cancer receiving prophylactic extended field radiation therapy,8 but this has not been traditionally used in prostate cancer patients. Although the type and duration of androgen suppression are not well defined for patients with oligorecurrent prostate cancer limited to the subdiaphragmatic para-aortic lymph nodes, nearly all patients received ADT and a majority had additional systemic therapy such as abiraterone.

We recently published our institution's preliminary results with PA-RT in the Red Journal.9 This was a carefully selected group of prostate cancer patients: all patients had been previously treated with radiation therapy to the pelvis in the definitive setting or after prostatectomy. They had no history of osseous or visceral disease, and all had 5 or fewer positive pelvic lymph nodes at time of PA-RT. A total of 34 patients were included with a median PSA of 3.1 ng/mL at time of PA-RT. The patients were treated at a median time of 5.7 years after initial prostate cancer diagnosis. With a median follow-up of 21.5 months, the PFS was 83.4%. The estimated 2-year biochemical failure-free survival and overall survival were 90.4% and 100% respectively.

Importantly, the PA-RT treatment was safe with minimal toxicity. In the cohort of 34 patients, there were 10 (29.4%) grade 2 acute toxicities and no grade 3 acute toxicities. There were 4 (11.8%) chronic grade 2 toxicities and two (5.9%) grade 3 chronic toxicities. The grade 3 toxicities consisted of an exacerbation of hemorrhagic cystitis requiring hospitalization and a small bowel obstruction several months after PA-RT possibly related to treatment that resolved with non-operative management.

We also collected creatinine and blood counts to assess for a decline in renal or hematological function. This was of particular interest because it might have an impact on the ability to receive further systemic therapy. There was no significant rise in creatinine levels at any time point following PA-RT. Hemoglobin was significantly lower at all time points compared to baseline, with a nadir at 6 months out from PA-RT (median 12.85 mg/dL). There were a statistically significant decline one month out from PA-RT in white blood cell count (-1.06 103/µL) and platelets (-21.6 109/L) before recovering. It is possible that restarting ADT explains the decline in hemoglobin.

It should be cautioned that this study is based on a retrospective cohort with limited follow-up time for prostate cancer and further work is necessary to make PA-RT part of the standard of care for patients with oligorecurrent prostate cancer limited to the subdiaphragmatic para-aortic lymph nodes. However, these results are exciting because PA-RT appears to have limited toxicity with good early disease control. PA-RT may offer patients with oligorecurrent prostate cancer limited to the subdiaphragmatic para-aortic lymph nodes a safe opportunity to control their disease, possibly without the lifelong side effects of ADT.

Urotodayfigure.jpg
Figure 1: Representative patient in cohort with oligorecurrent prostate cancer to the para-aortic lymph nodes receiving PA-RT. Left: PSMA PET scan illustrating PET-avid left para-aortic lymph node. Right: Proton beam therapy plan with intensity modulated proton therapy (IMPT) delivering 50 Gy in 25 fractions to the elective para-aortic lymph nodes with a simultaneous integrated boost (SIB) of 62.5 Gy.

Written by: Benjamin Rich, MD & Alan Dal Pra, MD, Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine

References:

  1. Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21(1):e18-e28.
  2. Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol. 2018;36(5):446-453.
  3. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-659.
  4. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838.
  5. Supiot S, Vaugier L, Pasquier D, et al. OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer. Eur Urol. 2021;80(4):405-414.
  6. Ost P, Jereczek-Fossa BA, Van As N, et al. Pattern of Progression after Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Nodal Recurrences. Clin Oncol (R Coll Radiol). 2016;28(9):e115-120.
  7. Zamboglou C, Strouthos I, Sahlmann J, et al. Metastasis-free survival and patterns of distant metastatic disease after PSMA-PET-guided salvage radiotherapy in recurrent or persistent prostate cancer after prostatectomy. Int J Radiat Oncol Biol Phys. 2022.
  8. Rotman M, Choi K, Guse C, Marcial V, Hornback N, John M. Prophylactic irradiation of the para-aortic lymph node chain in stage IIB and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 7920. Int J Radiat Oncol Biol Phys. 1990;19(3):513-521.
  9. Rich BJ, Montoya C, Jin WH, et al. Para-Aortic Radiation Therapy for Oligorecurrent Prostate Cancer. Int J Radiat Oncol Biol Phys. 2022.

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