Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review

Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, Giorgio Gandaglia, Nicola Fossati, Brian Kelly, Raj Pal, Erik Briers, Philip Cornford, Maria De Santis, Stefano Fanti, Silke Gillessen, Jeremy P. Grummet, Ann M. Henry, Thomas B.L. Lam, Michael Lardas, Matthew Liew, Malcolm D. Mason, Muhammad Imran Omar, Olivier RouvièreIvo G. Schoots, Derya Tilki, Roderick C.N. van den Bergh, Theodorus H. van Der Kwast, Henk G. van Der Poel, Peter Paul M. Willemse, Cathy Y. Yuan, Badrinath Konety, Tanya Dorff, Suneil Jain, Nicolas Mottet, Thomas Wiegel

Research output: Contribution to journalReview articlepeer-review

70 Scopus citations

Abstract

CONTEXT: The optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown.

OBJECTIVE: To perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported.

EVIDENCE ACQUISITION: Medline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4-5 [Gleason score {GS} 8-10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3-4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed.

EVIDENCE SYNTHESIS: Overall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems.

CONCLUSIONS: Based on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment.

PATIENT SUMMARY: We reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.

Original languageEnglish (US)
Pages (from-to)614-627
Number of pages14
JournalEuropean Urology
Volume77
Issue number5
DOIs
StatePublished - May 2020

Bibliographical note

Funding Information:
Financial disclosures: Lisa Moris certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Professor Dr. D. Tilki received speaker honorarium from Astellas and a travel grant from Janssen. Dr. E. Briers has received grant and research support from IPSEN, the European Association of Urology, and Bayer; is an ex officio board member for Europa UOMO; is an ethics committee and advisory group member for REQUITE; is a patient advisory board member for PAGMI; and is a member of SCA and EMA PCWP. Professor Gillessen has served on advisory boards for Orion, Innocrin, Clovis, Bayer, AAA International, Roche, Menarini, Sanofi, and ProteoMedix; receives company speaker honorarium from Janssen; and has served on the IDMC for Janssen. Professor Dr. J.P. Grummet received speaker honorarium from Mundipharma, a travel grant from Astellas, and a research grant from Cancer Australia; and is the owner of MRI PRO Pty Ltd., an online training platform. Professor Dr. A.M. Henry participates in trials by Cancer Research UK and the National Institute of Health Research; her department receives research grants from Cancer research UK, The Medical Research Council, and the National Institute of Health. Professor Dr. M. De Santis is a company consultant for Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Dendreon, Eisai Inc., ESSA, Ferring, GSK, Incyte, IPSEN, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, SeaGen, Shionogi, Synthon, Takeda, Teva, OncoGenex, and Sandoz; receives speaker honoraria from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ferring, GSK, IPSEN, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, Synthon, and Takeda; participates in trials run by the Technical University Munich, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Dendreon, Eisai Inc., Ferring, GSK, IPSEN, Incyte, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, SOTIO, and Cancer Research UK; participates in various trials as a member of the EORTC GU group; and has received research grants from Pierre Fabre Oncologie, and travel grants from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Dendreaon, Ferring, GSK, IPSEN, Incyte, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, SeaGen, Shionogi, Synthon, Takeda, and Teva/OncoGenex. Professor Dr. M.D. Mason is a company consultant for Ellipses Pharma and Oncotherics. Professor Dr. H.G. van der Poel is a company consultant for Intuitive Surgical; has participated in trials for Astellas and Steba Biotech; and has received grant and research support from Astellas. Professor Dr. S. Fanti is a company consultant for Bayer and ANMI; has received speaker honorarium from Bayer, Genzyme, ANMI, and GE Healthcare; and participates in trials by Amgen, Bayer, BMS, Genzyme, Janssen, Merck, and Novartis. Dr. T.B.L. Lam is a company consultant for and has received company speaker honoraria from Pfizer, GSK, Astellas, and IPSEN. Professor Dr. P. Cornford is a company consultant for Astellas, IPSEN, and Ferring; receives company speaker honoraria from Astellas, Janssen, IPSEN, and Pfizer; participates in trials run by Ferring; and receives fellowships and travel grants from Astellas and Janssen. Professor Dr. N. Mottet is a company consultant for Janssen, GE, BMS, Sanofi, and Astellas; has received speaker honoraria from Astellas, Pierre Fabre, Steba, Janssen, and Ferring; and has received fellowships and travel grants from Astellas, IPSEN, Sanofi, Janssen, and Roche. Professor Dr. T. Wiegel is an advisory board member for IPSEN; receives company speaker honoraria from IPSEN and Hexal; is a member of the Janssen Steering Committee; and has participated in the ATLAS/AUO trial. Dr. L. Moris, Dr. M.G. Cumberbatch, Dr. G. Gandaglia, Dr. N. Fossati, Dr. B. Kelly, Dr. R. Pal, Dr. T. Van den Broeck, Dr. R.C.N. van den Bergh, Dr. M.I. Omar, Dr. M. Lardas, Dr. M. Liew, Professor Dr. O. Rouvière, Dr. I.G. Schoots, Professor Dr. T.H. van Der Kwast, Dr. P-P. M. Willemse, Dr. C.Y. Yuan, Professor Dr. B. Konety, Professor Dr. T. Dorff, and Professor Dr. S. Jain have nothing to declare.

Publisher Copyright:
© 2020 European Association of Urology

Keywords

  • Brachytherapy
  • External beam radiotherapy
  • Localized
  • Locally advanced
  • Modality treatment
  • Primary therapy
  • Prostate cancer
  • Radical prostatectomy
  • Systematic review
  • Systemic treatment

PubMed: MeSH publication types

  • Journal Article
  • Systematic Review

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