2025-00547. Supplemental Evidence and Data Request on Primary Hypofractionated Radiation Therapy for Localized Prostate Cancer: A Systematic Review

PICOTS (Populations, Interventions, Comparators, Outcomes, Timing, and Setting)

	Inclusion criteria	Exclusion criteria
Preliminary PICOTS criteria
Population	KQs 1-5. Adult aged ≥18 years with localized prostate cancer (stages T1 to T4N0M0) who have elected to receive EBRT as their primary treatment regardless of pretreatment characteristics KQs 1a, 2a: Consider patient characteristics ( e.g., age, race and ethnicity), pretreatment characteristics ( e.g., prostate cancer risk group, prostate gland volume, presence of lower urinary tract symptoms), use of adjunctive therapies ( e.g., androgen deprivation therapy)	Individuals aged <18 years, those with non-localized stage of prostate cancer at enrollment.
Interventions	All KQs. Radiation therapy administered as a primary treatment KQ 1. MHF (2.4 to 3.4 Gy per fraction). KQ 2. UHF (≥5.0 Gy per fraction). KQ 3. Various dose-fractionation regimens (MHF, UHF). KQ 4. Various target volumes (MHF, UHF) ( e.g., prostate, seminal, vesicles, pelvic lymph nodes, focal intraprostatic boosts). KQ 5. Various treatment planning and delivery techniques. • Advanced imaging for target delineation (any pretreatment imaging, i.e., CT, MRI, MR-linac, PET, urethral contrast). • Dose-volume criteria for OARs (urethra). • Image-guidance techniques ( i.e., cone-beam CT, intraprostatic fiducial markers, MRI, electromagnetic tracking). • Delivery techniques ( i.e., IMRT, VMAT [term ARCS] protons [IMPT, passive scatter], SBPT, SBRT/SABR, 3D CRT). • Rectal-sparing technologies ( e.g., rectal spacers). • Online adaptive radiotherapy (treatment planning software). • Patient preparation for treatment planning and daily treatment ( e.g., daily enemas, full bladder, empty rectum).	Other treatments and techniques. Salvage radiation therapy; adjuvant or neoadjuvant radiation therapy.
Comparators	KQ 1. CF (1.8 to 2.0 Gy per fraction) KQ 2. CF, MHF. KQ 3. Dose-fractionation regimens compared to each other. KQ 4. Target volumes compared to each other [all grouped by type of hypofractionation (MHF and UHF). KQ 5. Treatment planning and delivery techniques compared to each other	Other comparators.
Outcomes	KQ 1—KQ 5. Overall and prostate cancer-specific survival, local recurrence, metastases, biochemical recurrence-free survival, acute and late gastrointestinal toxicity, acute and late genitourinary toxicity, patient reported outcomes ( i.e., GI, GU, ED) and quality of life	Other outcomes.
Timing	Any followup duration	NA
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Setting	KQ 1—KQ 5. All clinical settings	NA
Study Design	KQs 1, 2. Randomized controlled trials KQs 3-5. Randomized controlled trials. Comparative cohort studies with concurrent control groups, conducted within the same clinical setting. Other observational studies with concurrent control groups, that control for confounders. Studies conducted in countries rated as very high on the Human Development Index.a	KQs 1, 2: Other designs. KQs 3-5: Uncontrolled cohort studies, case-control studies, case reports, case series, cost-effectiveness and other modeling studies. Studies using nonconcurrent comparators ( e.g., historical controls). Studies comparing methods across different settings/clinics. Observational studies that do not control for confounders.
Abbreviations: CF = conventionally fractionated external beam radiation therapy; CT = computed tomography; CRT = conventional radiotherapy; EBRT = external beam radiation therapy; ED = erectile dysfunction; GI = gastrointestinal issues; GU = genitourinary issues; Gy = gray; IMPT = intensity modulated proton therapy; KQ = key question; MHF = moderately hypofractionated radiation therapy; MRI = magnetic resonance imaging; MR-linac = MRI-guided linear accelerator; NA = not applicable; OARs = organs at risk; PET = positron emission tomography; PICOTS = population, interventions, comparators, outcomes, timing, and setting; SABR = stereotactic ablative radiotherapy; SBPT = stereotactic body proton therapy; SBRT = stereotactic body radiation therapy; UHF = ultra-hypofractionated radiation therapy; VMAT = volumetric modulated arc therapy.
a  United Nations Development Programme. Human Development Index. Retrieved from https://hdr.undp.org/​data-center/​human-development-index#/​indicies/​HDI.