onc brain

Phase 2, open-label, randomised 1:1, investigator-initiated, 21 hospitals across Australia, Belgium, Italy, Norway, Spain and Switzerland. Recruited June 11, 2018 to April 30, 2021; median follow-up 50 months (IQR 42-58). Stratified by PET tracer (choline vs PSMA) and MDT type (sLND vs SBRT); participants and investigators unmasked.

Biochemical relapse after radical prostatectomy, postoperative RT, or definitive RT, with up to five PET-detected pelvic nodes (pelvis defined up to the aortic bifurcation, common iliac included). Bone, visceral, or above-bifurcation nodal disease excluded, as was previous RT overlapping current fields. Median age 70-71, median PSA at inclusion 1·00 vs 0·85 ng/mL, 91% and 86% EAU high-risk BCR, and 55-62% had a single positive node.

MDT arm: SBRT 30 Gy in 3 fractions every other day to 90% of the PTV with a 3 mm margin, or salvage lymph node dissection. ENRT arm: 45 Gy in 25 fractions to the whole pelvis on a modified RTOG 2009 template (upper limit L4-L5) with a simultaneous integrated boost to 65 Gy on PET-positive nodes; IMRT or rotational technique mandatory, with a benchmark-case QA programme. Prostate bed RT (≥66 Gy/33 fx) was advised for pT3-4, Gleason ≥8, or positive margins and given to 25% of MDT and 41% of ENRT pts.

Both groups received 6 months of LHRH agonist or antagonist, started no later than the first fraction (or day 1-10 postoperatively after sLND). Every patient who started intended local therapy plus ADT completed it. Physicians were instructed not to restart ADT absent clinical progression.

Primary: metastasis-free survival (any M1 on PET or death), with local or pelvic nodal relapse explicitly NOT counted as an event. Secondary: biochemical RFS, locoregional RFS, ADT-free survival, and late grade 2+ GU/GI toxicity to 48 months. OS, prostate cancer-specific survival, and time to castration resistance had insufficient events and are deferred.

Grade 2+ GU events above baseline at 4 years were 28% MDT vs 31% ENRT (absolute difference 3%, p=0·73) and grade 2+ GI 7% vs 9% (difference 2%, p=0·93). Most common grade 3 events were urinary incontinence (6% vs 10%) and diarrhoea (1% vs 2%). In post-hoc analysis the driver of toxicity was the prostate bed, not the pelvic volume: GI OR 4·6 (95% CI 1·5-15·8), p=0·0085 and GU OR 1·85 (0·95-3·60), p=0·068 with bed inclusion. No treatment-related deaths.

The single-arm GETUG-P07 OLIGOPELVIS reported 3-year bRFS of 45% for ENRT against 57% at 4 years here, though its median PSA was 3-4 ng/mL and staging was choline-based, so the populations differ. Against the ADT-intensification trials, EMBARK and PRESTO enrolled the PSA-doubling-time population that simulations put at up to 40% pelvic nodal relapse on PET, and this trial's median time off ADT exceeded 48 months in MDT and was not reached in ENRT, versus 13-18 months with RT alone and 16-17 months with ADT alone across earlier series.

No central PET review at baseline or follow-up, so the primary endpoint depends on local reads (authors cite κ 0·74 for pelvic nodes). Curves did not separate in year 1 because of the shared 6 months of ADT, which strains the proportional hazards assumption the HR summarises. The open-label design plausibly biased adverse-event attribution in both directions, and prostate bed RT was left to physician discretion, so a treatment that materially changed both toxicity and local recurrence was not randomised.

The result reads as a field-size question answered on pattern of failure rather than on distant control: relapse after MDT was predominantly locoregional, meaning PSMA PET missed nodal disease in at least half of pts treated to visible targets only. That reframes ENRT less as escalation than as compensation for imaging sensitivity that has not caught up with the treatment paradigm it enabled.

Phase 2 powered at α=0·20; primary MFS p=0·063 would not clear conventional significance, and the authors themselves await a phase 3 (POINTER-PC).