Stereotactic Radiotherapy for Localised Prostate Cancer: Time to Clarify the Possible Impact of Concurrent Androgen Deprivation Therapy

Surgical treatment and prostate irradiation are the primary methods used to treat localised prostate cancer (PCa). The results of the ProtecT trial have demonstrated that surgery and radiotherapy (RT) have comparable oncological outcomes in terms of prostate cancer-specific survival and biochemical disease free survival (bDFS). Urinary incontinence and erectile dysfunction are more frequent after surgery, whereas gastrointestinal (GI) toxicity and urethral stricture are associated with increased risk after RT. RT is delivered either with external beam RT (EBRT) or via implanted radioactive seeds (brachytherapy). Traditional EBRT exploits high-energy X-ray photons, and standard schedules consist of conventional fractionation (e.g. 74–78 Gy in 37–39 fractions; 1.8–2 Gy fraction) or moderate hypofractionated RT (e.g. 60–70 Gy in 20–28 fractions; 2.5–3.1 Gy fraction). “Unfavourable intermediate risk” or “high risk” localised PCa, is managed with the concurrent administration of androgen deprivation therapy (ADT) for 4–6 months (short term) or 18–36 months (long term), respectively. This combination reduces the risk of local failure and metastasis and increases bDFS and overall survival. At least five mechanisms explain the biological synergy of RT and ADT. First, RT grants local disease control, and ADT eliminates undetected micro-metastases, establishing a “spatial cooperation”. Androgen receptor signalling increases the expression of DNA repair genes (classical non-homologous end joining) and promotes the proliferation of prostate cancer by accelerating the repair of RT-induced DNA damage. Thus, ADT can prevent these radio-resistance mechanisms through cytotoxic enhancement. Additionally, ADT enhances oxygenation in androgen-deprived tumour microenvironments, thus facilitating the perfusion of gland tissues and increasing the sensitivity of PCa to RT. Lastly, ADT-related prostate and tumor cytoreduction, if managed within a neoadjuvant period before RT, enhances the coverage of the tumour target while reducing the dose to the rectum and bladder and thus results in temporal modulation and normal tissue protection.