Abstract
Radiotherapy and surgery are curative treatment options for localized prostate cancer (PCa) with a 5-year survival rate of nearly 100%. Once PCa cells spread into distant organs, such as bone, the overall survival rate of patients drops dramatically. The metastatic cascade and organotropism of PCa cells are regulated by different cellular subtypes, organ microenvironment, and their interactions. This cross-talk leads to pre-metastatic niche formation that releases chemo-attractive factors enforcing the formation of distant metastasis. Biological characteristics of PCa metastasis impacting on metastatic sites, burden, and latency is of clinical relevance. Therefore, the implementation of modern hybrid imaging technologies into clinical routine increased the sensitivity to detect metastases at earlier stages. This enlarged the number of PCa patients diagnosed with a limited number of metastases, summarized as oligometastatic disease. These patients can be treated with androgen deprivation in combination with local-ablative radiotherapy or radiopharmaceuticals directed to metastatic sites. Unfortunately, the number of patients with disease recurrence is high due to the enormous heterogeneity within the oligometastatic patient population and the lack of available biomarkers with predictive potential for metastasis-directed radiotherapy. Another, so far unmet clinical need is the diagnosis of minimal residual disease before onset of clinical manifestation and/or early relapse after initial therapy. Here, monitoring of circulating and disseminating tumor cells in PCa patients during the course of radiotherapy may give us novel insight into how metastatic spread is influenced by radiotherapy and vice versa. In summary, this review critically compares current clinical concepts for metastatic PCa patients and discuss the implementation of recent preclinical findings improving our understanding of metastatic dissemination and radiotherapy resistance into standard of care.
Highlights
Standard of care for metastatic prostate cancer (PCa) patients is systemic therapy, e.g. androgen deprivation therapy (ADT) or docetaxel-based chemotherapy
The results demonstrated in 19% vs. 61% of the patients a metastatic progression favoring the stereotactic body radiation therapy (SBRT) arm
The clinical utility of metastasis-directed radiotherapy in patients with oligometastatic castration resistant prostate cancer (CRPC) was only demonstrated in retrospective studies. These promising results illustrate that PSMAbased imaging can identify oligometastatic disease in up to 75% of patients when applied at low prostate-specific antigen (PSA) values [172]
Summary
Standard of care for metastatic prostate cancer (PCa) patients is systemic therapy, e.g. androgen deprivation therapy (ADT) or docetaxel-based chemotherapy. Inhibition of CXCL12/CXCR4 axis using a CXCR4 antagonist compromised tumor growth by altering the interaction of cancer cells with osteoblast niches [40, 41] This treatment failed to reduce already established metastasis [41, 42], suggesting that CXCL12/CXCR4 axis is relevant during the initial colonization phase, but not at the late stage of the disease. Clonal evolution analysis in metastatic PCa patients based on a deep sequencing technique revealed a branching phylogenetic architecture from primary tumor to distant metastasis with stage-specific mutational signatures [76]. In the randomized proPSMA trial for primary staging of localized high risk prostate cancer, PSMA-based PET imaging showed superior sensitivity and specificity over conventional imaging for accurate diagnosis of nodal and distant metastases {27% (95% CI 23–31) vs 65% [60–69]; p
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