Focal Micro-boost Strategy in Patients With Intermediate- to High-risk Prostate Cancer (IR-HR PCa) Undergoing Hypofractionated Radiotherapy (62SPECIAL)

HYPO62 SPECIAL is a no-profit, single-centre, prospective observational cohort study promoted by IFO-IRE, Istituto Nazionale Tumore Regina Elena, IRCCS, Rome, Italy. The study is entitled "Moderately Hypofractionated Micro-Boost Radiotherapy for Localized Prostate Cancer (62SPECIAL): an Observational Study" and is coordinated by the Department of Radiation Oncology of IFO-IRE. The study focuses on patients with localized intermediate to high-risk prostate cancer who are eligible for moderately hypofractionated radiotherapy. The aim is to evaluate the oncological efficacy and safety of a radiotherapy strategy combining whole-gland moderately hypofractionated irradiation with a focal simultaneous integrated micro-boost to dominant intraprostatic lesions identified by multiparametric magnetic resonance imaging. Definitive radiotherapy is an established treatment option for localized prostate cancer. Over the last decades, radiotherapy techniques have progressively evolved from three-dimensional conformal radiotherapy to intensity modulated radiotherapy and image-guided approaches. These technical advances have allowed dose escalation to the prostate while improving sparing of adjacent organs at risk. However, whole-gland dose escalation is limited by the proximity of critical normal structures, particularly the rectum, bladder and urethra, and may increase late gastrointestinal or genitourinary toxicity. A key biological and clinical rationale for focal dose escalation is that most local prostate cancer recurrences occur within the original dominant tumour region. The availability of multiparametric MRI has made it possible to identify clinically significant intraprostatic lesions, commonly referred to as dominant intraprostatic lesions or DILs. These lesions are classified according to the Prostate Imaging Reporting and Data System, PIRADS. The protocol considers MRI-visible PI-RADS 4 or 5 lesions eligible for boosting, while PIRADS 3 lesions require pathological confirmation. The rationale of the study is supported by previous clinical evidence, particularly the FLAME and DELINEATE studies. The FLAME randomized phase III trial investigated focal boosting of macroscopic intraprostatic tumour areas in addition to whole-gland radiotherapy and demonstrated a significant improvement in biochemical control without a relevant increase in toxicity when organ at risk constraints were prioritized. The DELINEATE phase II study further supported the feasibility of delivering a selective boost to MRI-visible intraprostatic lesions within a 20-fraction moderately hypofractionated schedule. Based on these data, current guidelines allow a micro-boost strategy in selected patients with intermediate and high-risk localized prostate cancer. At the IRCCS Regina Elena National Cancer Institute, the standard moderately hypofractionated radiotherapy schedule consists of 62 Gy in 20 fractions to the prostate. In the HYPO62 SPECIAL study, the dominant intraprostatic lesion is planned to receive a focal micro-boost up to 71.3 Gy, corresponding to a dose escalation of approximately 15% over the whole gland dose. Seminal vesicles, when clinically indicated according to risk of involvement, are prescribed 56 Gy. This strategy aims to increase the biological dose delivered to the tumour focus while maintaining an isotoxic approach, meaning that organ-at-risk tolerance is prioritized over boost target coverage. The study is observational and does not introduce experimental treatments outside clinical practice. Patients will receive standard-of-care radiotherapy according to institutional practice. Clinical, radiological, dosimetric, toxicity and follow-up data will be prospectively collected and analysed.

Study Design HYPO62 SPECIAL is a prospective, observational, cohort, single centre study. The study will enrol consecutive patients treated at IFO-IRE who meet the predefined inclusion and exclusion criteria. Since the treatment is delivered according to routine clinical practice, the study is designed to evaluate outcomes in a real-world clinical setting while using a standardized data collection framework. The planned recruitment and data collection period is 36 months.

Treatment and Procedures All enrolled patients will undergo standard of care treatment consisting of moderately hypofractionated radiotherapy delivered in 20 fractions, five sessions per week. Patients will also undergo routine clinical follow-up according to institutional practice. Treatment planning includes a planning computed tomography scan and a pretreatment multiparametric MRI examination. The MRI protocol includes T2 weighted sequences, diffusion-weighted imaging and dynamic contrast enhanced sequences. The prostate gland is delineated on T2 weighted MRI. The clinical target volume includes the prostate gland and, depending on clinical risk, the seminal vesicles. Any tumour tissue visible within the clinical target volume on multiparametric MRI is contoured as the gross tumour volume, corresponding to the dominant intraprostatic lesion. After registration of MRI with planning CT, target volumes and organs at risk are delineated. The planning target volume is generated from the clinical target volume using margins ranging from 4 to 8 mm, depending on the treatment technique and image guidance strategy. No additional margin is applied to the dominant intraprostatic lesion. The prostate planning target volume is prescribed 62 Gy, while seminal vesicles, when included, are prescribed 56 Gy. The dominant intraprostatic lesion receives a simultaneous integrated focal micro-boost to 71.3 Gy, with an allowed variation of ±5%. Organ at risk constraints take priority over full coverage of the boosted lesion. If required to respect organ at risk tolerance, planning target volume coverage may be reduced, with V95% considered acceptable down to 90%. Radiotherapy may be delivered using VMAT or CyberKnife, according to clinical and technical indications. In case of CyberKnife treatment, margins may vary depending on fiducial tracking, with smaller margins when three fiducials are available and larger margins when only one or two fiducials are present.