## 4 Discussion  
The present study showed that in silico 85% isodose CK treatment plans could generate a higher boost dose to the DIL (PTV-d median D95% = 40.58 Gy and D0.03 cm\({}^{3}\) = 46.66 Gy) while maintaining a lower dose prescription to the prostate volume (PTV-p median D95% = 35.16 Gy and D0.03 cm\({}^{3}\) = 41.63 Gy) with homogeneous dose distribution and respecting all the OARs constraints applied. Technical advances in the field of RT in recent years have enabled the progressive implementation of UH-RT in various scenarios of localized PCa treatment. As a matter of fact, the use of hypoffractionated schedules in PCa has provided sufficient evidence in terms of tumor control results, QoL, toxicity, and reduced treatment time and costs for the patient, and the recent publication of two randomized trials comparing the use of UH-RT versus conventional fractionation (HYPO-RT-PC [14] and PACE-B trials [15]) has been crucial in supporting its use. This in silico planning comparison study showed that UH-RT for localized PCa with a SIB to the macroscopic lesion with CK radiosurgery SBRT-based system, both with 95% and 85% isodose prescriptions is feasible. Dose-volume histograms for the 85% isodose prescription reported better dose coverage up to a maximum of 47 Gy to the DIL PTV while respecting all the OARs constraints previously applied in UH-DWA plans delivered with the VERO system. * Significant \(p\)-value if \(<0.016\) (Bonferroni correction). ** comparison is not possible due to tied values. List of abbreviations: CK = CyberKnife; UH-DWA = ultra-hypoffractionated dynamic wave arc; ns = not significant. \end{table}
Table 4: Comparison of median values of dose-volume histogram parameters for considered OARs. The rationale of the present study is based on the recently published data of [PERSON] et al. [23] in the update at 2 years of the PACE-B trial, which reported lower levels of GU and GI Radiation Therapy Oncology Group (RTOG) toxicity for CK vs. standard linac SBRT treatments (significantly lower for GU: 5.8% vs. 16.5%). Also, in the \"FLAME\" trial, [PERSON] et al. [18] proved that focal boosting the DIL up to 95 Gy in a conventional radiotherapy scheme for 264 patients (vs. 271 patients in the arm without focal boost) improved bDFS and PFS without any relevant additional toxicity. In addition, the preliminary results reported by [PERSON] et al. [20] in the \"GIVE ME FIVE\" trial reported very low acute RTOG GU and GI toxic (G2 4.69% and 1.56%, respectively, and only one patient with GU G3 at 6 months) when a dose escalation to 37.5 Gy in 5 fractions was applied as a SIB to the DIL with the VERO(r) system. In this context, a high focal boost strategy to the DIL with SBRT delivery technique is required to improve tumor control while respecting organ at-risk dose constraints. The pattern of failure analysis by [PERSON] et al. [35] demonstrated that a focal boost to the DIL decreased the rates of local failure (7 vs. 21 events) and the development of regional-distant metastasis (32 vs. 56 events). Similar to our study, [PERSON] et al. [36] confronted two methods of SBRT delivery, CK and VMAT. The dosing scheme applied was a higher prescription dose of 47.5 Gy while maintaining a 36.25 Gy to the whole prostate in five fractions with different PTV margins. Both CK and VMAT planning produced clinically acceptable plans, but certain OARs constraints have not been met for all plans. More violations (43 out of 75) were observed in VMAT planning with larger prostate margins (5 mm). With the experience derived from the above-mentioned planning study, [PERSON] et al. [19] reported in the \"SPARC\" trial the longest follow-up (56 months) of the first eight patients treated with CK SBRT (at 70% isodose prescription) with focal boost for intermediate and high-risk PCa. No biochemical recurrence was detected at the follow-up time, and early results suggest a 2-year bDFS between 95% and 100%, but grade 2+ acute GU and GI toxicities were 37.5%, while grade 2+ late GU and GI toxicities were 12.5% and 0%, respectively.