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Cytoreductive treatment strategies for de novo metastatic prostate cancer

Abstract

In the past decade, a revolution in the treatment of metastatic prostate cancer has occurred with the advent of novel hormonal agents and life-prolonging chemotherapy regimens in combination with standard androgen-deprivation therapy. Notwithstanding, the use of systemic therapy alone can result in a castrate-resistant state; therefore, increasing focus is being placed on the additional survival benefits that could potentially be achieved with local cytoreductive and/or metastasis-directed therapies. Local treatment of the primary tumour with the established modalities of radiotherapy and radical prostatectomy has been explored in this context, and the use of novel minimally invasive ablative therapies has been proposed. In addition, evidence of the potential clinical benefits of metastasis-directed therapy with ionizing radiation (primarily stereotactic ablative radiotherapy) is accumulating. Herein, we summarize the pathobiological rationale for local cytoreduction and the potentially systemic immunological responses to radiotherapy and ablative therapies in patients with metastatic prostate cancer. We also discuss the current evidence base for a cytoreductive strategy, including metastasis-directed therapy, in the current era of sequential multimodal therapy incorporating novel treatments. Finally, we outline further research questions relating to this complex and evolving treatment landscape.

Key points

  • The treatment of de novo, synchronous castration-sensitive metastatic prostate cancer has undergone a revolution with the advent of novel hormone therapies and life-prolonging chemotherapy for use in combination with androgen-deprivation therapy.

  • Men with low-burden metastatic (oligometastatic) prostate cancer can have localized disease control and substantial delays in disease progression with local cytoreductive treatment of the primary tumour (with radiotherapy, surgery or minimally invasive ablative therapies) in combination with metastasis-directed therapies (typically with stereotactic ablative radiotherapy).

  • Local cytoreduction of a primary prostate cancer (and/or metastases thereof) has various effects on tumour-derived factors that are likely to translate into survival benefits for patients.

  • Prostate tumour ablation and/or metastasis-directed therapy offers an exciting new minimally invasive approach; however, evidence supporting the inclusion of this approach in current treatment algorithms is currently limited, warranting further prospective investigation.

  • Accumulating high-level evidence now supports progression-free survival and overall survival benefits of cytoreductive prostate radiotherapy, in combination with systemic therapy, in men with de novo oligometastatic prostate cancer.

  • Cytoreductive prostatectomy might provide similar survival benefits, although confirmatory randomized controlled trials are required.

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Fig. 1: Mechanisms underlying the potential clinical benefits of local cytoreductive treatment and metastasis-directed therapy of prostate cancer.

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Acknowledgements

M.J.C. and H.U.A. acknowledge grant funding from the Wellcome Trust and University College London Hospitals (UCLH) charity. H.U.A. also acknowledges grant funding from the UK Medical Research Council, the UK National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Prostate Cancer UK, the Urology Foundation and Imperial Healthcare Charity.

Review criteria

All original studies relating to local cytoreductive and metastasis-directed therapy concepts for prostate cancer were selected during an extensive literature search of Medline, Embase and Cochrane databases and ClinicalTrials.gov, inclusive of basic science original articles that evaluated the pathobiology and biological mechanisms underlying these concepts. The search was completed on the 1st August 2019, without date limitation. Search terms included (“prostate” OR “prostatic”) AND (“cancer” OR “carcinoma” OR “adenocarcinoma” OR “tumour” OR “tumour” OR “neoplasm”) AND (“metastatic” OR “metastasis” OR “lymph node” or “nodal”) AND (“metastasis directed therapy” OR “SABR” OR “ablation” OR “cryotherapy” OR “local therapy” OR “cytoreductive” OR “cytoreduction” OR “surgery” OR “prostatectomy” OR “radiation therapy” OR “radiotherapy” OR “external beam radiotherapy”). All selected articles were further searched to identify additional relevant articles. In addition, the reference lists of relevant articles were search for other relevant articles.

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M.J.C. and H.U.A. researched data for article. M.J.C., M.W. and H.U.A made substantial contributions to discussion of content. M.J.C., T.T.S. and H.U.A. wrote the manuscript. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Martin J. Connor.

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H.U.A. has received research grants and personal fees from SonaCare Medical and Sophiris Bio, and grant funding from Trod Medical. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks the three anonymous reviewers for their contribution to the peer review of this work.

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Connor, M.J., Shah, T.T., Horan, G. et al. Cytoreductive treatment strategies for de novo metastatic prostate cancer. Nat Rev Clin Oncol 17, 168–182 (2020). https://doi.org/10.1038/s41571-019-0284-3

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