Oligometastases in Prostate Cancer: Ablative Treatment

Ablative treatment of metastases in prostate cancer is an emerging therapeutic approach. The aim is to complement, replace or delay the introduction of hormone therapy or other systemic therapies with palliative intent and associated with systemic side effects.

Additionally, metastases ablation can avoid metastases-to-metastases spread¹, source of tumor progression. The different methods of achieving an ablation of metastases and their frequent jointly use have led to these therapies have been grouped under a new concept called MDT (Metastasis-directed therapy), which mainly covers surgical treatment and radiotherapy.

Prostate cancer metastasizes mainly to bone and lymph nodes. Visceral involvement is infrequent. Treatment with an eradicative intention (ablative) in these two main metastatic locations requires a different approach.

In the presence of lymph node oligometastases, both SBRT (stereotactic body radiation therapy) and sLND (salvage lymph node dissection) assume the risk of the existence of subclinical lymph node disease beyond that detected in the PET (positron emission tomography) images^2,3, which is outside its ablative scope.

However, surgical resection is the standard of care (SOC) for lymph node relapse in patients with a controlled primary tumor, provided the disease is amenable to complete resection, with or without androgen deprivation therapy (ADT)⁴.

SBRT by definition covers macroscopic and small tumor volumes without including prophylactic extension and clashes conceptually and technically with including adjacent lymph node stations where experience has shown that the progression of the disease is frequent⁵. The superiority of either SBRT or sLND as MDT in pelvic lymph node oligometastases is being analyzed in the PEACE V (STORM) trial^6,7 as well as the contribution of adding a prophylactic whole pelvic radiation therapy to these two types of ablative therapy and all in the context of a ADT.

SBRT presents more tangible results in relation to bone oligometastases, although it also has gaps in knowledge that require prospective studies for clarification. There is no consensus on the definition of SBRT volumes and the dose or optimal fractionation are unknown.

The schemes are heterogeneous, with a predominance of those using one or three fractions, with a dosing range of 20 Gy/1 fraction to 50 Gy/5 fractions.
Except in situations with measurable tumor spread to soft tissues, the Response Evaluation Criteria In Solid Tumors (RECIST 1.1)⁸ do not offer consistent response criteria and are therefore of little value. Functional imaging and the PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) have also been used, defining local control (LC) as no increase in uptake (11 choline PET, PSMA) or the absence of lesion growth as determined by magnetic resonance imaging.

The response in the case of bone metastases is usually investigator-dependent, which makes it difficult to compare the different therapeutic schemes and thus the efficacy of treatment. These disadvantages in prostate cancer are partially compensated by the PSA kinetics.

In this review the main published MDT series of bone and lymph node oligometastases as well as ongoing studies^9,10 have been compiled. The primary endpoints assessed are LC, toxicity, the imaging method used for diagnosis, ADT-free survival, progression-free survival (PFS), and overall survival (OS) on a point basis. Special emphasis is placed on SBRT as an ablative treatment for bone oligometastatic disease.

The results described allow us to conclude that SBRT is safe and effective¹¹. It has been able to offer excellent LC rates (83-100%), with minimal toxicity^12. It has also been shown to slow disease progression (median 7.3-31.6 mo) and therefore to delay the introduction of ADT (median 15.6-39.7 mo) and its associated side effects^11,13. The impact of these results upon OS in oligometastatic patients is not known. It is obvious that we need phase III trials to answer these questions, or, in their absence, large-scale population registries are required to establish their contribution to the overall survival of oligometastatic patients¹⁴.

However, due to the LC and symptoms control achieved, the convenience of administration, the delaying of side effects of ADT or the delaying of second systemic therapy lines, SBRT has become increasingly widely used in radiation oncology units and should be offered to well-informed patients who request such treatment.

Written by: Amalia Palacios-Eito, MD, PhD and Sonia García-Cabezas, MD, PhD, Department of Radiation Oncology, Reina Sofia University Hospital, Cordoba, Spain

References:
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2.Jilg CA, Drendel V, Rischke HC, et al. Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer. Theranostics. 7(6):1770-1780. doi:10.7150/thno.18421.
3. Siriwardana A, Thompson J, van Leeuwen PJ, et al. Initial multicentre experience of 68gallium-PSMA PET/CT guided robot-assisted salvage lymphadenectomy: acceptable safety profile but oncological benefit appears limited. BJU Int. 2017;120(5):673-681. doi:10.1111/bju.13919.
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10. Khoo V, Hawkins M, Ahmed M, et al. A Randomised Trial of Conventional Care versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases. Clinical Oncology. 2018;30(6):e64. doi:10.1016/j.clon.2018.02.061.
11. Siva S, Bressel M, Murphy DG, et al. Stereotactic Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial. European Urology. 2018;74(4):455-462. doi:10.1016/j.eururo.2018.06.004.
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14. Ost P. It Ain’t Over Till the Fat Lady Sings: The POPSTAR Trial. European Urology. 2018;74(4):463-464. doi:10.1016/j.eururo.2018.06.031.

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