Novel Insights into the Management of Oligometastatic Prostate Cancer: A Comprehensive Review

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Abstract

Context

The current standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) plus either docetaxel or abiraterone. Growing evidence suggests that metastasis-directed therapy (MDT) and/or local therapy targeted to the primary tumour (ie, prostate) may be of benefit in the setting of oligometastatic disease. Several prospective studies are underway; however, until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with oligometastases.

Objective

This comprehensive review aims to collate the available evidence to date for a role of MDT and/or prostate-targeted therapy in the setting of oligometastatic PCa, as well as discuss ongoing trials in this setting.

Evidence acquisition

We searched PubMed for the combination of “prostate cancer” and “oligometastatic”, “oligometastases”, “oligometastasis”, “solitary metastases”, “stereotactic body radiotherapy”, “SBRT”, “stereotactic ablative radiotherapy”, “SABR”, “salvage lymphadenectomy”, or “metastasectomy” in publications over the last 20 yr. We also searched ClinicalTrials.gov to identify relevant ongoing trials.

Evidence synthesis

The studies were divided according to the timing of metastasis into synchronous (ie, detected at the time of primary PCa diagnosis) and metachronous (ie, detected after treatment of the primary tumour), and according to treatment modality into MDT (including salvage lymph node dissection [sLND]) and prostate-targeted treatment. For MDT of synchronous/metachronous metastases, we included 16 completed studies and 11 ongoing prospective studies. In the case of sLND for nodal-only recurrence after primary treatment with curative intent, we included 11 completed studies. Finally, for prostate-targeted treatment of synchronous metastatic PCa, we included 25 completed studies and 11 ongoing prospective studies. In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions (surgery or radiotherapy) appears to be a feasible strategy and may delay the use of systemic therapies. MDT is a promising option in oligometastatic PCa patients, but more robust data are needed. In the setting of synchronous oligometastatic disease, aggressive cytoreductive treatment needs further data to confirm the benefits.

Conclusions

In this review, we provide a comprehensive overview of the current literature on the treatment of patients with oligometastatic PCa. The data suggest that although ADT plus either docetaxel or abiraterone remains the mainstay of treatment for mPCa, in oligometastatic PCa, improved outcomes may be achieved with metastasis- and prostate-targeted therapies. The studies included in this review are mainly retrospective in nature, limiting the strength of the evidence they provide. Prospective studies are ongoing, and their results are eagerly awaited.

Patient summary

We reviewed the treatment of patients with prostate cancer that has spread to five sites or fewer. We conclude that while androgen deprivation plus either docetaxel or abiraterone should remain the standard of care, there is evidence that treatment targeted at the metastases and the primary tumour may improve the outcome for the patient and potentially delay the use of systemic treatment.

Introduction

Patients with metastatic prostate cancer (mPCa) are currently best treated with palliative treatments such as androgen deprivation therapy (ADT) plus either docetaxel or abiraterone [1]. However, we hypothesise that oligometastatic PCa is a different clinical entity to widely disseminated mPCa and presents an interesting opportunity to explore novel treatment approaches. The term “oligometastasis” refers to an intermediate cancer state between locally confined and widely disseminated disease [2], in which patients develop only a limited number of metastatic lesions (defined as 1–5 lesions in most studies) [3]. For example, multiple studies have shown that, in mPCa, an increasing number of metastatic lesions are associated with poorer outcomes [2], [3], [4], [5]. Within the subgroup of patients exhibiting oligometastatic disease, different oligometastatic entities (summarised in the Supplementary material) have different prognoses, which justifies considering these disease states as separate entities that are likely to require different therapeutic approaches [6]. In addition, some studies have provided more insight into the molecular underpinnings of oligometastatic PCa. Lussier and colleagues [7] studied micro-RNA profiles of primary tumour and metastatic sites in patients with oligometastatic cancer, treated with stereotactic body radiation therapy (SBRT). Patients who failed to develop polymetastases during follow-up were characterised by unique features in the microRNA-200 family. More recently, the same group demonstrated that patients with metastatic colorectal cancer who have metastases exhibiting MSI-independent immune activation, experience the most favourable survival [8].

The main prognostic factor in oligometastatic PCa is the status of the primary lesion; active primary lesions (as in the case of synchronous oligometastases) confer a worse prognosis than controlled primary lesions (as in oligorecurrent PCa) [9]. This is not surprising given the complex patterns of metastatic seeding involving crosstalk between the primary tumour and metastatic sites. Moreover, PCa metastases can be seeded not only from the primary tumour, but also from other metastatic sites [10]. It is therefore reasonable to hypothesise that metastasis-directed therapy (MDT) or treatment of the primary tumour in oligometastatic disease might break the vicious cycle of tumour seeding.

Ablation of limited metastases using surgery or SBRT may slow disease progression, delay or avoid the need for systemic therapy, and improve survival [11]. Although this paradigm shift in treatment is not accepted by all, such MDT could theoretically lead to cure. In addition to MDT, ablation of the primary tumour may have a role in slowing disease progression in patients with synchronous oligometastatic PCa [12].

Despite the emerging data described, there is absence of high-level evidence to direct oligometastatic PCa management. Until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with PCa oligometastases. The aim of this review was to collate the available evidence on the role of MDT (including salvage lymph node dissection [sLND]) and/or prostate-targeted therapy in the setting of oligometastatic PCa, and to outline ongoing trials in this setting.

Section snippets

Evidence acquisition

We searched PubMed for the combination of “prostate cancer” and “oligometastatic”, “oligometastases”, “oligometastasis”, “solitary metastases”, “stereotactic body radiotherapy”, “SBRT”, “stereotactic ablative radiotherapy”, “SABR”, “salvage lymphadenectomy”, or “metastasectomy” until January 2018. To complete the picture about oligometastatic PCa, we also searched ClinicalTrials.gov for “prostate cancer” and “oligometastatic” for the most relevant ongoing trials.

Evidence analysis

The studies were categorised into synchronous and metachronous according to the timing of metastasis, and into prostate-targeted treatment or MDT (including sLND) according to treatment modality. For MDT of synchronous/metachronous metastases, we included 14 completed studies (Table 1). For sLND for nodal recurrence after primary treatment with curative intent, we included 11 completed studies (Table 2). For MDT of synchronous/metachronous metastases, we included 11 ongoing prospective studies (

Conclusions

In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions with surgery or RT appear to be a feasible strategy. However, current evidence supporting a role for MDT in oligometastatic PCa largely derives from retrospective case series [11]. In general, absence of control groups, selection bias, and use of adjuvant ADT at different time periods hinder the ability to draw firm conclusions from these studies [31]. Although many patients achieve

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