**12. Evaluation for treatment of oligo-metastatic and poly-metastatic disease**

When a patient presents with a metastatic focus (or foci) after prior definitive treatment, the decision for a biopsy is often not answerable by a straightforward algorithm. The clinical situation as a whole has to be evaluated. Some pertinent questions include:


These questions may be best addressed in a multi-disciplinary setting, such as a Genitourinary Tumor Board. As well, shared decision-making regarding the risks/ benefits and logistics of a biopsy with the patient is important.

Numerous studies have provided insight into the value of treating the primary site and/or metastatic sites for prostate adenocarcinoma. The HORRAD trial from the Netherlands was a multi-center randomized controlled trial to determine whether OS is prolonged by adding prostate EBRT to ADT for patients with metastatic prostate adenocarcinoma [51]. From 2004 to 2014, the study recruited 432 patients with a PSA >20 ng/mL and metastatic prostate adenocarcinoma on bone scan. The patients were then randomized to either ADT with EBRT (radiotherapy group) or ADT alone (control group). OS was the primary endpoint, and PSA progression was the secondary endpoint. In this trial, the median PSA was 142 ng/mL, and 67% of patients had >5 osseous metastases. At a median follow-up of 47 months, the median OS was 45 months in the radiotherapy group and 43 months in the ADT alone group, which was not statistically significant (HR = 0.90, CI = 0.70–1.14, p = 0.4). There was a benefit in time to PSA progression for the radiotherapy group of 15 months versus 12 months (HR = 0.78, CI = 0.63–0.97, p = 0.02).

On a subgroup analysis of 160 patients with <5 bone metastases, an OS benefit started to emerge with HR = 0.68 (CI = 0.42–1.10). However, in this study, the number of bone metastases were categorized as 1–4, 5–15, and > 15; the authors postulated that an upper cut-off of 1–3 metastases may have been statistically significant for the radiotherapy group for OS.

The "Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy" (STAMPEDE) trial studied if local radiotherapy to the prostate would improve OS in men with metastatic prostate adenocarcinoma, with the benefit greatest in men with a low metastatic burden [52]. This study randomized 2061 patients in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Standard of care consisted of lifelong ADT, with up-front docetaxel allowed starting from December 2015. The radiotherapy arm received either 55 Gy/20 fractions over 4 weeks, or 36 Gy/6 fractions over 6 weeks. Overall, radiotherapy to the prostate did not improve OS for unselected patients; however, within the subgroup that had a low metastatic burden (non-regional lymph nodes or ≤ 3 bone metastases without visceral metastases), local radiotherapy to the prostate did confer an OS advantage of 65% vs. 53% at 5 years (HR = 0.64, p < 0.001) [53].

Radiotherapy to the prostate was not recommended for patients with high-volume metastatic disease unless in the context of a clinical trial or for palliative intent. The concern was that this aggressive treatment would increase toxicity, without a meaningful effect on OS. Of note, many experts would argue that the definition of lowvolume disease should not be applied to metastases only detected on Pylarify PET/CT (and not on bone scan/conventional CT), since this imaging modality was not used in the STAMPEDE trial, and will detect smaller metastases.

The "Observation versus Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer" (ORIOLE) phase II randomized trial studied whether SBRT to the oligometastases improves oncologic outcomes for men with oligometastatic prostate adenocarcinoma, and may thereby delay initiation of ADT [54]. The study randomized 54 men with recurrent hormone-sensitive prostate cancer and 1–3 metastases detectable by conventional imaging in a 2:1 ratio to receive SBRT or observation. SBRT improved median progression-free survival (not reached vs. 5.8 months, HR = 0.30, p = 0.02), and the risk of progression at 6 months from 61–19%. There were no acute grade ≥ 3 toxicities.

Data from the ORIOLE trial appeared to indicate that sub-total metastasis-directed therapy (MDT) is not beneficial in extending progression-free survival. In this study, the treating radiation oncologists did not have access to PSMA PET/CT, and treated based upon conventional imaging; therefore, within the SBRT arm (36 patients), 16 patients actually had untreated lesions. The progression-free survival was 63% at 6 months in the sub-total consolidation arm, which was similar to the observation arm (61%). The authors concluded that MDT of all radiotracer-avid disease could potentially provide excellent progression-free survival for oligo-metastatic disease, with limited acute toxicity.

As well, the "Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial" (STOMP) study also analyzed the benefit of MDT in a randomized phase II trial [55]. The trial included patients with asymptomatic prostate cancer with a biochemic recurrence after primary treatment, 1–3 extracranial metastatic lesions, and serum testosterone levels >50 ng/mL (non-castrate level). Sixty-two patients were randomly assigned at 1:1 to either surveillance or MDT of all lesions, with local therapy including

## *Evaluation of Patients for Radiotherapy for Prostate Adenocarcinoma DOI: http://dx.doi.org/10.5772/intechopen.109447*

surgery or SBRT. At a median follow-up time of 3 years, the median ADT-free survival was 13 months for the surveillance group, versus 21 months for the MDT group. Quality-of-life measures were similar between the two arms at baseline, as well as at 3 months and 12 months; there were no grade 2–5 toxicities. The STOMP study also concluded that MDT increases progression-free survival, as well as ADT-free survival.

A recent non-randomized, prospective phase II trial incorporated PSMA PET/CTstaged patients for confirmation of oligometastatic disease after local curative treatment (surgery and/or radiotherapy), and to demonstrate the efficacy and safety of "local ablative radiotherapy" (*authors' designation, though many patients received the non-ablative fractionation of 50 Gy/25 fractions*) [56]. The OLI-P study used gallium-68 PSMA PET/CT to stage patients at two German cancer centers between 2014 and 2018. Patients with ≤5 PSMA PET-positive bone (OSS-MET) or lymph node (LN-MET) metastases without local tumor recurrence or visceral metastases were included in the trial; as well, they must have had no ongoing ADT, PSA <10 ng/mL, and life expectancy ≥5 years. Fractionation schedules were either 30 Gy/3 fractions (stereotactic) or 50 Gy/25 fractions (conventional). The primary endpoint was treatmentrelated toxicity (grade ≥ 2) at 24 months after the start of local ablative radiotherapy; second endpoints included PSA progression-free time (event defined as initial PSA value +20%, or the start of ADT), progression-free survival (event defined as PSA progression, start of ADT, distant progression, or death), and OS.

A total of 72 patients were recruited, with 63 patients receiving local ablative radiotherapy; five patients were later determined to not fulfill the inclusion criteria, and for another four patients, a decision was made during radiotherapy planning not to proceed due to a very significant overlap with prior radiotherapy fields for the primary tumor. The study's median follow-up time was 37.2 months. There were 68 LN-METS and 21 OSS-METS treated; of note, most patients (n = 45, 71%) only had one lesion.

During follow-up, there were no treatment-related grade ≥ 2 adverse events by two years after local ablative radiotherapy. Regarding secondary endpoints, the median time to PSA progression was 13.2 months, progression-free survival was 21.4% at 3 years, and OS was 94.6% at 3 years. The authors concluded that local ablative radiotherapy was a safe and an effective option for selected patients to delay systemic therapy.

In view of the data, the ESTRO-ACROP Delphi consensus published the following four recommendations in *Radiotherapy & Oncology* in October 2022: [57].


Ongoing phase III trials for MDT include the following, in **Table 3** [58–62].


**Table 3.**

*Ongoing prospective trials for metastasis-directed therapy.*
