Harnessing the potential of multimodal radiotherapy in prostate cancer

Abstract

Radiotherapy in combination with androgen deprivation therapy (ADT) is a standard treatment option for men with localized and locally advanced prostate cancer. However, emerging clinical evidence suggests that radiotherapy can be incorporated into multimodality therapy regimens beyond ADT, in combinations that include chemotherapy, radiosensitizing agents, immunotherapy and surgery for the treatment of men with localized and locally advanced prostate cancer, and those with oligometastatic disease, in whom the low metastatic burden in particular might be treatable with these combinations. This multimodal approach is increasingly recognized as offering considerable clinical benefit, such as increased antitumour effects and improved survival. Thus, radiotherapy is becoming a key component of multimodal therapy for many stages of prostate cancer, particularly oligometastatic disease.

Key points

  • Radiotherapy combined with androgen deprivation therapy (ADT) is a common treatment option for men with prostate cancer.

  • In many patients, the use of radiotherapy is hindered by tumour resistance and a reduction in quality of life caused by toxic effects to normal tissue, which limits the radiation dose that can be delivered safely.

  • Tumour control could be improved by using radiotherapy in combination with other treatments beyond ADT, including chemotherapy, radiosensitizing agents, immunotherapy and surgery.

  • This multimodality approach could be beneficial in men with many stages of prostate cancer, including oligometastatic disease.

  • A survival benefit from using a multimodality therapy approach seems to be achievable in the context of the low metastatic burden of oligometastatic prostate cancer.

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Fig. 1: Direct and indirect effects of ionizing radiation on DNA.
Fig. 2: Immunogenic cell death and immunogenic modulation of tumour cells by radiotherapy.
Fig. 3: Molecularly targeted agents as potential radiosensitizers.

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Acknowledgements

Research in the laboratory of R.J.B. is funded by a Cancer Research UK/Royal College of Surgeons of England Clinician Scientist Fellowship (reference C39297/A22748), and research grants from the Urology Foundation (to Y.P.), and the Oxford-based charity Urology Cancer Research and Education (UCARE; to R.J.B.). Research in the laboratory of A.D.L. is funded by a Cancer Research UK Clinician Scientist Fellowship (reference C57899/A25812).

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Nature Reviews Urology thanks B. Koontz and the other, anonymous, reviewer(s) for their help with the peer review of this manuscript.

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Y.P. and R.J.B researched data for the article, made substantial contributions to discussions of content, and wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Richard J. Bryant.

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Glossary

External beam radiotherapy

(EBRT). External delivery of irradiation using several types of energy (for example photons, electrons or heavy particles).

Brachytherapy

Internalized radiotherapy using implanted iodine-125, palladium-103 or caesium-131 radioisotope seeds.

Oligometastatic prostate cancer

Prostate cancer with relatively few (three to five) small-volume distant disease foci.

5Rs of radiation biology

Repair, reassortment, repopulation, reoxygenation and radiosensitivity. Each of these terms describes a cellular mechanism by which to understand the success or failure of localized radiotherapy.

Mitotic catastrophe

A mechanism of delayed mitosis-linked cell death. It describes a sequence of events resulting from premature or inappropriate entry of cells into mitosis, caused by chemical or physical stresses.

Immunogenic cell death

Immune-mediated cell killing secondary to radiation-induced generation of mutated tumour antigens, which subsequently stimulate the immune system.

Stereotactic body radiotherapy

(SBRT). Delivery of external beam radiotherapy for treatment of prostate cancer, with target localization using image guidance and five to seven fractions of 6–10 Gy per fraction to the prostate gland.

Bragg peak

The peak on the Bragg curve, which plots the energy loss of ionizing radiation (protons, α-rays and other ion rays) as they travel through matter. The peak occurs immediately before the particles come to rest.

Salvage radiotherapy

Delivery of radiotherapy with curative intent to patients with biochemical recurrence (defined as a postoperative serum PSA level ≥0.2 ng/ml, without evidence of distant metastases).

Immunomodulation

Regulation of the immune system, whereby the immune responses are induced, amplified, reduced or prevented according to the therapeutic goal.

Tumour-associated antigen

An antigenic peptide produced in tumour cells that can trigger an immune response. It could potentially be used as a tumour marker and/or a therapeutic target.

Calreticulin

An endoplasmic reticulum-associated chaperone protein, which is exposed in the outer leaflet of the plasma membrane of stressed or dying cells, where it functions as a potent phagocytosis signal.

HMGB1

High mobility group box 1 protein is encoded by the HMGB1 gene and functions to organize DNA and regulate transcription.

CTLA4

Cytotoxic T lymphocyte associated protein 4 is a protein receptor that functions as an immune checkpoint and downregulates immune responses.

Abscopal effect

A systemic antitumour immune response induced by local irradiation, with regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation.

PD1

Programmed cell death protein 1 is a cell surface protein that downregulates the immune system’s response by suppressing T cell inflammatory activity.

PDL1

Programmed cell death 1 ligand 1 is a trans-membrane protein that suppresses the adaptive immune system.

FAK

Focal adhesion kinase is a protein involved in cell–cell adhesion and migration, and which can promote malignant cellular invasion and metastasis.

HSP90

Heat shock protein 90 is a chaperone protein that promotes protein folding and stabilization against heat stress, thereby potentially promoting tumour growth.

HIF1α

Hypoxia-inducible factor 1α is a subunit of the heterodimeric hypoxia-inducible factor 1 (HIF1) transcription factor encoded by the HIF1A gene.

VEGFA

Vascular endothelial growth factor A is a peptide encoded by the VEGFA gene and acts on endothelial cells to increase vascular permeability, induce angiogenesis, vasculogenesis and endothelial cell growth, to promote cellular migration and to inhibit apoptosis.

VEGFR1

Vascular endothelial growth factor receptor 1 is a protein with tyrosine protein kinase activity that regulates cellular proliferation and differentiation.

Tumour vessel normalization

A spectrum of biological changes to the tumour vasculature including increased pericyte coverage, improved perfusion, reduced vascular permeability and reduced hypoxia.

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Philippou, Y., Sjoberg, H., Lamb, A.D. et al. Harnessing the potential of multimodal radiotherapy in prostate cancer. Nat Rev Urol 17, 321–338 (2020). https://doi.org/10.1038/s41585-020-0310-3

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