Background
PCa is the second most common cancer among men in the world (1.1 million new cases estimated) and death PCa related (estimated in over 300,000 deaths annually) correlates with metastatic state [
1].
The advent of novel imaging techniques, such as Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET) and Whole-Body Magnetic Resonance Imaging (WB MRI), allows an increasing an early detection and diagnosis of metastases after primary curative treatment. In clinical practice the possibility to identify a few number of lesions is called “oligometastatic state” and it is considered an intermediate phase of tumor spread with limited metastatic capacity [
2]. This state consists of low-volume disease, typically defined as the presence of up to 3–5 metastases [
3] treatable with a local approach (such as surgery or radiotherapy) either with or without systemic therapy.
Patients with low-volume or oligometastatic disease have improved survival compared with those with high-volume metastases or a disseminated metastatic cancer [
4]. While chemo-hormonal therapy is the standard of care for men with high-volume metastatic castration-sensitive PCa [
5], in the low-volume metastatic PCa additional chemo-therapy did not demonstrate survival benefit [
6], so SBRT is emerging as a promising low-toxicity treatment option for oligometastases both at diagnosis and recurrence [
7]. Small-volume high-dose SBRT limited to metastatic site might potentially eliminate all macroscopic cancer foci prolonging the progression-free interval and postponing ADT. The aim of SBRT in this setting is to achieve local control and delay progression, and thereby postpone the need for further treatment.
Moreover, an open question in this framework is the patient QoL, to be evaluated in the balance of oligometastatic disease diagnosis, less treatment option and additional ADT-induced side effects. A deeper understanding of the predictive role of biomarkers is desirable for a targeted treatment selection and proper surveillance programs. The limitation associated with the use of the prostate-specific antigen (PSA) as diagnostic and follow-up marker stimulated significant investigations of several novel biological markers, such as blood-based parameters, microRNAs and cell-free DNA [
8,
9]. However, this new approach requires a large amount of coherently collected data to give reliable and univocal results.
A further research frontier is the role of imaging in this setting of patients. Recently, the role of WB MRI has been proposed as a suitable solution for tumor detection and therapy evaluation in this setting of patients with performance at least comparable with the Choline positron emission tomography/computed tomography Ch-PET/CT [
10].
Overall, clear-cut data and tools to guide a consensus about the optimal therapeutic choice for the individual clinical situation are not validated and the standard of care to recurrent PCa remains ADT, with significant side effect and deterioration of QoL [
11].
Discussion
Recently, the concept of ADT-free survival, intended as the time to the delayed start of ADT, in order to spare the related negative side effect, such as the increased occurrence of cardiovascular events and metabolic syndrome, that significantly affect the QoL [
7]. The aim of SBRT in this setting is to achieve local control and delay progression, and thereby postpone the need for further treatments.
From the clinical standpoint, the emergence of castration resistance is usually a nearby antecedent of widespread disease progression, visceral involvement and death from PCa. Therefore, preservation of the responsiveness to ADT is crucial in the long-term management of patients with metastatic PCa.
Also, from socio-economic point of view, 12 months without ADT can be considered a consistent gain for the National Health System, especially considering the relevant costs of the new and spreading anti-androgens like Abiraterone and Enzalutamide [
5].
Current knowledge is mainly based on retrospective and non-randomized studies, thus suffering from heterogeneous population (i.e., due to biased patient selection) and inappropriate sample power [
18].
It is evident that also in the setting of metastatic PCa, prostatic definitive radiotherapy could find a place. First data derived from retrospective trials by Löppenberg et al. and Rusthoven et al. demonstrated an improvement in OS for patients who underwent radiation therapy targeting the prostate in comparison to those who received only hormonal treatment [
19,
20].
The oligometastatic concept has been developed in the last years and recent trials show interesting results on adding local treatments (LCT) (such as radiotherapy or surgery) at standard therapy. Particularly, it is important to mention the results achieved by Gomez and Palma. Gomez et al., that conducted a randomized phase II trial on oligometastatic NSCLC, reporting a significant PFS benefit with LCT (both radiotherapy or surgery) vs maintenance systemic therapy (14.4 months vs 4.4 months respectively) [
18]. In another randomized phase II trial, named SABR-COMET, a benefit in OS in the SBRT arm for the oligometastatic setting compared to palliative treatment was demonstrated (41 months vs 28 months) [
21].
The HORRAD study is a multi-centric prospective study, randomized controlled trial recruiting bone metastatic PCa patients. The objective was to compare irradiation of primary prostatic tumor with external beam radiation therapy with ADT versus ADT only. The trial revealed no significant difference in OS. However, subgroup analysis suggests that radiotherapy to the prostate actually improves OS in patients with a low metastatic burden (< 5 bone lesions) [
22].
More recently, subgroup analysis of patients with a low metastatic burden from STAMPEDE (a phase 3 randomized controlled trial) showed that OS was improved with radiotherapy, giving a three-year survival of 81% in these men, compared to 73% in the standard treatment group [
5].
For Murphy et al., the approach to metastatic PCa “catching ‘em all”, or “pokemet”, must be considered experimental [
23]. Also, in this setting, data from retrospective studies suggest that cancer specific and OS is improved with Metastasis-directed therapy (MDT) compared to the standard of care. MDT treatment regimens vary with different radiotherapy techniques, doses, and volumes [
3]. Among prospective studies, STOMP and ORIOLE trials are worth mentioning [
24,
25].
However, despite encouraging data, some authors remain skeptical that MDT will delay the use of ADT. Moreover, this argument is a weak endpoint compared to PFS or OS especially given that timing for using hormonotherapy remains controversial.
Whereas the use of systemic therapy was largely investigated by several large clinical trials, currently, limited studies focus on metastasis-directed SBRT. These studies, despite short follow-up that limited the evaluation of OS and cancer-specific survival, showed that metastasis-directed SBRT is a safe treatment, reaching a high local control (about 95%) with low-grade toxicity, generally limited to gastro-intestinal effects [
3,
26‐
29].
So, new biomarkers are mandatory to help determining the natural history of the disease and to select the patients who could actually benefit from MDT. The discovery of miRNA seems to give a start of answers to many questions that arise.
Recent studies have demonstrated that miRNAs influence many stages of carcinogenesis and can effectively modulate tumor radiosensitivity at different levels, by affecting targets involved in DNA damage repair, cell cycle checkpoint, apoptosis, signal transduction pathways and tumor microenvironment. Thus, the identification of miRNA involved in DNA damage radiation response is not excluded and might lead to the use of Poly (ADP-ribose) polymerase (PARP) inhibitors in the near future [
26].
In a recent published study by Pitroda PS et al., a molecular basis (such as mi-RNA profiling) for oligometastatic state in colorectal liver metastasis was identified in order to predict clinical outcome and establish clinical risk factors associated with long-term survival following hepatic resection [
30].
According to Formosa et al. a series of miRNAs called oligomers would be typical of oligometastatic diseases, and thus have a role in the developmentof the oligometastatic state and the transition from an oligometastatic state to a polymetastatic disease [
31].
Overall, data and tools to guide an optimal therapeutic choice in this setting are not validated and the standard of care to recurrent PCa remains ADT, with significant side effects and deterioration of QoL [
10]. To address a larger consensus on oligorecurrent PCa management, randomized clinical trials selecting homogeneous patient population are needed.
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