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APCCC 2019: Local Treatment of the Primary (RT) in the Metastatic Situation

Basel, Switzerland (UroToday.com) Dr. Robert Bristow gave a presentation on the concept of local radiotherapy to the primary tumor in the metastatic prostate cancer setting. He began his talk discussing the concept of oligometastatic disease. This disease concept was originally coined by Hellman and Weichselbaum.1 Oligometastatic disease is limited to specific organs and in limited numbers. Implicit in the concept of oligometastatic disease is the fact that it manifests a potentially less aggressive disease course. A unique subset of patients might benefit (in terms of disease progression and /or overall survival) from aggressive localized therapies. Patients with this type of disease may also have unique biologic characteristics that would differentiate the disease course. They have unique clinical and molecular characteristics allowing for a therapeutic window of treatment with multimodal therapy. 

Dr. Bristow moved on to discuss the rationale for treating the primary tumor in the metastatic setting, which he divided into clinical and biological reasons:
  • Retrospective and level I data suggest possible improvements in survival resulting from this type of treatment
  • Local symptomatic progression may be reduced (rare)
  • Lethal cancer clones may be left in situ despite systemic therapy (unknown)
  • Cytoreductive surgery and radiotherapy is safe in well-selected patients (probably true)

  • May alter secondary polymetastases wave from the primary tumor or oligometastases
  • May alter after immunomodulatory responses or growth factors/cytokines
  • Metastases may be heterogenous

The STAMPEDE trial showed that radiotherapy to low-volume metastatic disease confers a benefit in failure-free survival.2 Bone scanning has been shown to be predictive of response to radiotherapy to the primary site when the bone metastases number is 4 or less (lymph nodes and bone metastases both have overall survival effects from radiotherapy). Novel/modern imaging is unlikely to change the overall result given the profound hazard ratio for low volume disease. More sensitive scans could decrease the proportion of patients amenable to local radiotherapy plus systemic therapy

In a meta-analysis assessing radiotherapy for metastatic hormone-sensitive prostate cancer, 2,126men were included, with 90% of them randomized to radiotherapy+ADT vs. ADT alone3. The results demonstrated that there was a 7% improvement in 3-year survival in men with fewer than five bone metastases who received radiotherapy +ADT.

Next, Dr. Bristow discussed on the future role of metastases-directed therapy in oligometastatic prostate cancer. There have been multiple retrospective studies suggesting that metastases directed therapy may be efficacious. The STOMP randomized phase II trial started to validate the role of this kind of treatment.4 In this study, a total of 62 patients with biochemical recurrence after definitive therapy, with fewer than 3 extracranial metastatic lesions were randomly assigned to surveillance or metastases directed therapy (radiotherapy or surgery). The median ADT free survival for surveillance was 13 months compared with 21 months for the metastases directed therapy arm (HR 0.6).

Three retrospective reviews from the US SEER database and one study from Munich cancer registry have suggested that that metastatic hormone-sensitive prostate cancer (mHSPC) with node-positive disease may benefit from the best systemic therapy plus radical prostatectomy. The 5-and 10-year overall survival rate in the German cohort was 84% and 64%, respectively, following radical prostatectomy and standard of care systemic therapy. In contrast, in patients who did not undergo radical prostatectomy, the 5- and 10-year overall survival rate was 60% and 28%, respectively.5 Currently, radical prostatectomy in this specific setting is being assessed in several trials including the g-RAMPP trial, SWOG-1802, and TRoMbone feasibility study, which has completed accruing in the UK. If these trials are positive, we would need to design a trial to compare radiotherapy to surgery in terms of efficacy and quality of life in this unique setting.

There is some evidence suggesting that radiotherapy to metastases elicits an immune response, providing us with some biologic explanation on why this type of treatment has a beneficial effect on final outcomes (Figure 1).   

Figure 1–The immune response elicited by radiotherapy directed at the metastasis:

Dr. Bristow summarized his talk stating that to date, there is level one evidence that radiotherapy should be added to the standard of care systemic therapy in newly diagnosed low-volume metastatic (M1) prostate cancer. This type of treatment can be considered also in patients with node-positive disease. The question of whether we need to add docetaxel or abiraterone to the systemic standard of care in these patients will need to await the results of the PEACE 1 trial assessing this question specifically. There are ongoing surgical trials attempting to determine if removal of the prostate will give similar results as radiotherapy. From the evidence that is currently available to us, surgery does appear to be well-tolerated, and the continuation of the ongoing trials will be critical to validate these findings. If these trials will be negative, it will support the concept that the translational biology rests solely with radiotherapy.

Dr. Bristow concluded his talk with some speculations regarding the future. Future trials should answer questions regarding the roles of different radiotherapy and surgical volumes, assess which is better–surgery or radiotherapy, and incorporate modern imaging modalities.

Presented by: Robert Bristow, MD, University Professor of Cancer Studies, The University of Manchester, Director, Manchester Cancer Research Centre, Chief Academic Officer, The Christie NHS Foundation Trust, Senior Group Leader, Cancer Research UK Manchester Institute

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA@GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

1. Hellman, Samuel, and Ralph R. Weichselbaum. "Oligometastases." Journal of Clinical Oncology 13, no. 1 (1995): 8-10.

2. Parker CC et al. "Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial, " Lancet Oncology 392, 10162 ( Dec 2018): 2353-2366,  DOI:https://doi.org/10.1016/S0140-6736(18)32486-3

3. Burdett, Sarah, Liselotte M. Boeve, Fiona C. Ingleby, David J. Fisher, Larysa H. Rydzewska, Claire L. Vale, George van Andel et al. "Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: a STOPCAP systematic review and meta-analysis." European urology 76, no. 1 (2019): 115-124.

4. Ost, Piet, Dries Reynders, Karel Decaestecker, Valérie Fonteyne, Nicolaas Lumen, Aurélie De Bruycker, Bieke Lambert et al. "Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial." Journal of Clinical Oncology 36, no. 5 (2017): 446-453.

5. Engel, Jutta, Patrick J. Bastian, Helmut Baur, Volker Beer, Christian Chaussy, Juergen E. Gschwend, Ralph Oberneder, Karl H. Rothenberger, Christian G. Stief, and Dieter Hölzel. "Survival benefit of radical prostatectomy in lymph node–positive patients with prostate cancer." European urology 57, no. 5 (2010): 754-761.

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