Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response

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.

TPX2 Enhanced the Activation of the HGF/ETS-1 Pathway and Increased the Invasion of Endocrine-Independent Prostate Carcinoma Cells

“…Bone metastasis is the most common type of PC metastasis. The invasion of prostate cancer cells on other organs such as liver, lung, kidney and adrenal glands has also been reported (39). Moreover, although the prognosis of PC has improved in recent years, a large number of PC patients are not responsive enough to androgen deprivation therapy (ADT) and these patients are often considered as endocrine-independent PC.…”

Dosimetric Analysis of the Short-Ranged Particle Emitter 161Tb for Radionuclide Therapy of Metastatic Prostate Cancer

“…The clinical study with [ 131 I]I-PSMA ligand also addressed the bone marrow toxicity as being problematic [ 5 ]. Nevertheless, a Phase II study with [ 131 I]I-MIP-1095 is ongoing and might reveal the clinical potential of using 131 I-based radiopharmaceuticals for aggressive metastatic prostate cancer [ 39 ].…”

“…The required dose increase is more than twofold and it further increases depending on the number of tumors observed, as well as the metastatic dissemination pattern. The first randomized Phase III clinical trial, VISION, has concluded patient inclusion and first results are expected in the near future [ 39 ].…”

“…Despite the responses achieved with actinium-225 in this patient group, it appears that short-ranged particles has its value in the treatment of metastatic prostate cancer. Today, three ongoing Phase I/II clinical trials are exploring the clinical potential of [ 225 Ac]Ac-PSMA-617 and [ 225 Ac]Ac-PSMA-J591 [ 39 ].…”

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

“…For these reasons, α-emitters have been postulated as ideal radionuclides for the treatment of cancer [154][155][156][157]. In particular, the treatment regimen for disseminated and poorly differentiated metastatic disease, e.g., PSMA(+) mCRPC, might highly benefit from targeted α radionuclide therapy (TAT) [158]. Recently, extensive efforts have been made to review in detail α-emitter-based radiotherapeutic approaches for PC [159].…”