HYDRA

Confirmatory

ForLocalised prostate cancer, definitive external-beam RT

TL;DRNo PFS difference for either isodose (HR 0.92) or dose-escalated MHFRT (HR 0.94), but escalation raises late G2+ GI (OR 1.48).

Why it mattersRadiation oncology

The split that matters is isodose vs dose-escalated MHFRT, not hypofractionation itself: escalation adds no PFS (HR 0.94, 0.82-1.09) and costs bowel on both physician grading (OR 1.48) and patient report (OR 1.68). GU was unchanged in both strata. The schedule decision lands on 60 Gy in 20 fractions.

Monday clinic

In a man with localised prostate cancer starting definitive prostate-only EBRT, this supports an isodose moderately hypofractionated schedule over a dose-escalated one; it does not extend to five-fraction ultrahypofractionation, post-prostatectomy salvage, or whole-pelvis treatment.

7 details 5 trials watching

Design

IPD meta-analysis of randomised phase 3 CFRT vs MHFRT trials via the MARCAP consortium. Searches on Dec 15, 2023 and re-run Jan 8, 2025 screened 1696 records down to 7 eligible trials. Three separate analyses: efficacy, physician-scored late toxicity, and patient-reported outcomes.

Population & inclusion

Localised prostate cancer on trials that published patient-level efficacy AND late toxicity data. 3454 pts across three isodose trials, 2426 pts across four dose-escalated trials. Trials whose CFRT arm fell below modern dose were excluded.

Radiotherapy

The intervention split is the whole point: isodose MHFRT (same equivalent dose in fewer fractions, eg 60 Gy in 20 fractions) versus dose-escalated MHFRT. The CFRT comparator had to deliver ≥70 Gy in 2 Gy equivalents.

Endpoints

Primary (efficacy): progression-free survival. Co-primary toxicity endpoints: late grade 2 or higher GU and GI. Co-primary PRO endpoints: clinically-significant decrement in urinary or bowel quality of life.

Safety

The GI signal sits entirely in the dose-escalated stratum and shows up on both physician grading and patient report; the isodose stratum carries neither. GU odds ran above 1 in both comparisons with intervals crossing unity.

vs leading data

CHHiP and PROFIT established 60 Gy in 20 fractions as non-inferior to conventional fractionation. The escalated schedules were built on the premise that a higher equivalent dose in fewer fractions would improve control; pooled here that premise fails on PFS while adding bowel toxicity.

Applies to

localised prostate cancer treated with definitive external-beam RT on randomised trials against modern-dose CFRT

Does not represent five-fraction ultrahypofractionation, post-prostatectomy salvage, or whole-pelvis nodal treatment, none of which were tested.

Limitations

Toxicity scales and PRO instruments were not uniform across the seven trials, and the dose-escalated stratum pools four schedules that are not interchangeable, so the OR describes escalation as a class, not one regimen. Follow-up also differs between strata (5.4 vs 7.1 yrs).

Discussion

With efficacy answered as a null, the schedule decision turns entirely on toxicity, and the toxicity difference runs one way. Escalating per-fraction dose beyond isodose buys no measurable PFS while adding bowel morbidity that pts themselves report, which leaves little argument for an escalated MHFRT schedule in intact localised disease.

Rationale

Pooled IPD from seven randomised phase 3 trials, aligned with existing moderate-hypofractionation practice; refines which regimen rather than establishing a new modality or population.

Open questions

Does the escalation bowel signal extend to five-fraction ultrahypofractionation?

recruiting Comparing Moderately Ultra Hypofractionated Radiation Treatments for Prostate Cancer Phase 2

n=204 · primary completion 2030-11 · randomised 20fx vs 5fx post-op bed +/- pelvis

recruiting Salvage Moderate Hypofractionated Versus Ultrahypofractionated Radiotherapy for Biochemical Recurrence After Radical Prostatectomy in Prostate Cancer Phase 3

n=270 · primary completion 2034-12 · phase 3 moderate vs ultrahypo salvage, toxicity EP
Do rectal spacers and daily IGRT narrow the dose-escalated GI gap?

active Effectiveness of the SpaceOAR Vue System in Subjects With Prostate Cancer Phase NA

n=500 · primary completion 2027-12 · SpaceOAR Vue for late GI toxicity under SBRT

recruiting Barrigel® PPRT (Post-Prostatectomy Radiation Therapy) Trial Phase NA

n=84 · primary completion 2027-12 · Barrigel anterior rectal sparing in post-op RT
Same toxicity read when MHFRT covers whole-pelvis nodal volumes?

active Hypofractionated Accelerated Pelvic Nodal Radiotherapy (GCC 2048) Phase 1

n=18 · primary completion 2026-08 · 20/16/12fx pelvic nodal RT with prostate SIB

📚 Sources · 📄 1 paper

📄 PAPER Kishan; Sun; Tree et al. · The Lancet. Oncology (2025-04)

Hypofractionated radiotherapy for prostate cancer (HYDRA): an individual patient data meta-analysis of randomised trials in the MARCAP consortium.

PMID 40112848 → doi

Abstract

BACKGROUND: Trials comparing moderately hypofractionated radiotherapy (MHFRT) to conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs superiority) and MHFRT dose. We compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT. METHODS: This was an individual patient data meta-analysis that identified randomised phase 3 trials of CFRT versus MHFRT that had published individual patient-level data on efficacy and late toxicity. A systematic literature search using MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was initially conducted on Dec 15, 2023, and was re-conducted on Jan 8, 2025. Trials that did not publish efficacy data, did not publish late toxicity data, or did not use modern dose radiotherapy (≥70 Gy in 2 Gy equivalents) in the CFRT group were excluded. Individual patient data were provided to MARCAP by study investigators. Three separate meta-analyses were designed to compare efficacy (primary endpoint was progression-free survival), physician-scored late toxicity (co-primary endpoints were late grade 2 or higher genitourinary and late grade 2 or higher gastrointestinal toxic effects), and patient-reported outcomes (co-primary endpoints were clinically-significant decrements in patient-reported urinary or bowel quality of life) between patients receiving CFRT versus MHFRT. FINDINGS: We identified 1696 records for review. Seven phase 3 trials comparing MHFRT with CFRT were eligible for inclusion in our analysis. Individual patient data were obtained from these seven studies (3454 patients from three trials comparing CFRT with isodose MHFRT and 2426 patients from four trials comparing CFRT with dose-escalated MHFRT). At a median follow-up of 5·4 years (IQR 4·6-7·2) for isodose MHFRT and 7·1 years (5·7-8·4) for dose-escalated MHFRT, no differences in progression-free survival were detected (hazard ratio 0·92, 95% CI 0·81-1·05; p=0·21 and 0·94, 0·82-1·09; p=0·43 respectively). No increased odds of grade 2 or higher genitourinary toxic effects were identified for either isodose (odds ratio [OR] 1·16, 95 CI% 0·86-1·57; p=0·32) or dose-escalated MHFRT (1·20, 0·95-1·51; p=0·13). The odds of grade 2 or higher gastrointestinal toxic effects were significantly higher with dose-escalated (OR 1·48, 95% CI 1·14-1·92; p=0·0035) but not isodose MHFRT (1·30, 0·59-2·87; p=0·51). Isodose MHFRT was not found to show different odds of urinary quality-of-life decrement (OR 1·03, 95% CI 0·51-2·09; p=0·93) or bowel quality-of-life decrement (0·76, 0·40-1·43; p=0·39). Dose-escalated MHFRT was associated with greater odds of bowel quality-of-life decrement (OR 1·68, 95% CI 1·07-2·61; p=0·023), but no evidence of greater urinary quality-of-life decrement was found (1·57, 0·87-2·85; p=0·13). INTERPRETATION: Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel toxicity. Isodose regimens, eg, 60 Gy in 20 fractions, should be the standard MHFRT regimen for localised prostate cancer. FUNDING: None.

Radiation Curative Meta-analysis Confirmatory ASTRO Annual Meeting 2024

The longer read

The clinical question is no longer whether to hypofractionate, which the non-inferiority trials settled a decade ago, but which hypofractionated schedule, and this analysis answers it by separating two things the literature has been conflating. Isodose schedules asked whether the same biologically equivalent dose delivered in fewer fractions preserves control. Dose-escalated schedules asked whether the low α/β of prostate cancer lets a higher equivalent dose in fewer fractions improve it. Pooling both into one moderate-hypofractionation bucket blurs a real distinction. Split apart, the escalation premise does not hold: PFS hazard ratios are 0.92 (0.81-1.05) and 0.94 (0.82-1.09), and the point estimates sit essentially on top of each other. Escalation bought nothing visible in progression-free survival at a median 7.1 years of follow-up.

The toxicity result is where the analysis earns its keep. Late grade 2 or higher GI toxicity was raised only in the dose-escalated stratum (OR 1.48, 1.14-1.92, p=0.0035), and the patient-reported bowel decrement moves with it (OR 1.68, 1.07-2.61, p=0.023). Concordance between a physician-scored endpoint and an independently collected patient-reported one is what should move confidence here: CTCAE grading in unblinded RT trials under-captures bowel symptoms, and PRO instruments are noisy, so agreement between the two is harder to dismiss as a scoring artefact than either alone. The isodose stratum shows neither signal, with a bowel QoL point estimate below 1 (0.76, 0.40-1.43). GU differs in shape: both comparisons put the odds ratio above 1 with intervals crossing unity, which is what a small underpowered effect looks like rather than evidence of no effect.

A skeptic would point out that this is an IPD pool across trials differing in intent, target volume, image-guidance era and toxicity instrument, and that the dose-escalated stratum draws on 2426 pts from four trials whose schedules are not interchangeable. The pooled GI odds ratio therefore describes escalation as a class, not the risk attaching to any single regimen. A null PFS result is also not equivalence: upper bounds of 1.05 and 1.09 leave room for a modest efficacy loss that would matter to a man with long life expectancy, although the one-sided toxicity finding makes the trade unambiguous regardless.

What it does not settle is the comparison the field has actually moved toward. Five-fraction ultrahypofractionation is absent from this dataset, as are salvage and whole-pelvis volumes, where rectal and bladder dose are the constraining variables and an escalated per-fraction schedule would be tested under different geometry. Nor does it address whether contemporary technique narrows the gap: the escalated trials accrued before hydrogel spacing and daily fiducial or MR guidance were routine, and a bowel signal driven by rectal dose is the kind better conformality could plausibly shrink. For a reader picking a schedule for intact localised disease treated to prostate-only volumes, though, the read is narrow and firm: isodose, 60 Gy in 20 fractions, not an escalated variant.