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Individual patient data meta-analysis from the MARCAP Consortium, 12 eligible trials, 10,853 patients, median follow-up 11.4 years (IQR 9.0-15.0). Three intensification questions analyzed separately: ADT use, neoadjuvant ADT prolongation, adjuvant ADT prolongation.

Localized prostate cancer treated with definitive radiotherapy, stratified by NCCN prognostic risk group. The RT ± ADT comparison ran 2,557 control vs 2,579 experimental (NCCN high 32.6% vs 32.8%, intermediate 47.6% vs 48.7%); the adjuvant-prolongation comparison was high-risk enriched at 71.5% vs 71.1% NCCN high across 1,900 vs 1,874 pts.

Dose was analyzed as a binary ≥74 Gy vs <74 Gy split, with the companion HEAT analysis using 64 to <74 Gy vs ≥74 Gy and escalation up to 79.2 Gy. Brachytherapy boost is discussed as an escalation route alongside external-beam dose.

ADT addition improved MFS HR 0.83 (0.77-0.89) and OS HR 0.86 (0.80-0.92). Adjuvant prolongation improved MFS HR 0.84 (0.78-0.91) and OS HR 0.85 (0.78-0.94); neoadjuvant prolongation did neither (MFS HR 0.95, OS HR 0.95). 10-yr MFS 61% (59-63) with ADT vs 52% (50-54) without; 10-yr OS 65% (63-67) vs 57% (55-59).

The 2022 HEAT network meta-analysis (13 trials, 11,862 pts) found dose escalation improved biochemical RFS but not MFS or OS, and named high-dose RT plus long-term ADT the best strategy. PROG 05/09 and GETUG-18 are invoked to explain the gap: a 21% 5-year biochemical benefit in low risk where metastasis is rare, versus 3% in high risk where it is not.

The pooled trials span 30+ years of practice, so the RT technique behind the <74 Gy stratum is not the technique a reader delivers today. The stated optimal durations (closer to 12 months high risk, 24+ months very high risk) come from DHARMA, accepted but unpublished, so that specific number is not yet auditable.

The framing claim is that dose escalation and ADT are not interchangeable levers: escalation buys biochemical control, ADT buys metastasis-free and overall survival, and the two do not substitute. The dogma that dose escalation obviates ADT is named as widely repeated and never demonstrated.

IPD meta-analysis of randomised trials, large N, long f/u. Reinforces ADT intensification over dose escalation; no new randomisation, and duration guidance rests on unpublished DHARMA.

Multicenter open-label randomized phase III noninferiority trial, 16 hospitals across 11 provinces of China, accrual August 2015 to August 2018, N=599 randomly assigned 1:1 (TNT 302, CRT 297). Stratified by tumor location, clinical stage and MRF status; median follow-up 35.0 months (range 8.3-63.9).

Age 18-70, ECOG 0-1, rectal adenocarcinoma of the distal or middle third (0-10cm from anal verge), cT3-4 and/or node-positive, no distant metastases, no prior anticancer treatment. Arms were balanced: cT4 15.9% v 12.8%, MRF involvement 56.3% v 56.2%, clinical stage III 85.8% v 83.5%.

TNT arm received 25Gy in 5 fractions over one week; CRT arm 50Gy in 25 fractions over 5 weeks with concurrent capecitabine 825mg/m2 twice daily. All patients received IMRT, a departure from RAPIDO, Polish II and PRODIGE 23. CTV covered mesorectum, presacral space, internal iliac, obturator nodes and ischiorectal fossa; superior border at the sacral promontory, inferior 2-3cm distal to the tumor, external iliacs added only for cT4b; CTV-to-PTV expansion 0.5-1.0cm.

TNT arm: 4 cycles CAPOX (oxaliplatin 130mg/m2 day 1, capecitabine 1,000mg/m2 twice daily days 1-14) starting 7-14 days after radiotherapy, then TME, then 2 further cycles. CRT arm: concurrent capecitabine during radiotherapy, then TME, then 6 cycles CAPOX. Total mesorectal excision was scheduled 6-8 weeks after preoperative treatment in both arms; a watch-and-wait pathway was permitted for clinical complete responders.

Primary: 3-year disease-free survival, noninferiority claimed if the upper bound of the 95% CI of the HR was at or below 1.43 (an 11% absolute margin against an assumed 65% CRT rate). Secondary endpoints were overall survival, metastasis-free survival, locoregional recurrence and surgical complications. Target accrual 600 with at least 194 DFS events for 80% power at one-sided alpha 0.05.

Acute grade III-V toxicity during preoperative treatment was 26.5% with TNT versus 12.6% with CRT (P<.001), driven almost entirely by hematologic events (grade 3-4 15.8% v 2.0%, P<.001) rather than by anything the radiotherapy added. Radiotherapy delivery itself was cleaner in the short-course arm, with no dose reductions at all, and grade III+ surgical complications were comparable (14.0% v 15.7%, P=.625). Grade III-IV toxicity during adjuvant chemotherapy ran lower after TNT (3.3% v 11.8%, P=.003).

STELLAR is the third randomized trial of short-course radiotherapy plus neoadjuvant chemotherapy against long-course CRT, after Polish II and RAPIDO, with PRODIGE 23 addressing the adjacent question of chemotherapy sequencing around long-course CRT. Its 3-year LRR of 8.4% with TNT sits alongside RAPIDO and PRODIGE 23 (4%-8.3%) and well below Polish II (21%-22%), which enrolled a heavier fixed cT3/cT4 population. Unlike RAPIDO and PRODIGE 23, STELLAR showed no reduction in distant metastasis (3-year DM 22.8% v 24.7%), and its OS advantage mirrors the early Polish II signal that later disappeared at 8 years.

The 11% noninferiority margin is wide, and the authors concede in retrospect that a narrower margin or larger sample would have been defensible given how close the arms proved. Distant metastasis, the endpoint short-course TNT was designed to move, did not separate at all (22.8% v 24.7%), which weakens the mechanistic case for the OS difference. Adjuvant chemotherapy completion also differed between arms (60.0% v 48.3%, P=.009), so postoperative treatment intensity is not held constant across the comparison.

The defensible read is the primary endpoint: 25Gy in 5 fractions followed by CAPOX delivers the same 3-year DFS and the same locoregional control as 50Gy in 25 fractions, in one week of radiotherapy instead of five. The 11.4-point OS separation is the number that will be quoted and the one least supported, since neither MFS nor LRR moved and the same pattern in Polish II did not survive longer follow-up. What transfers most reliably is the technique: full elective pelvic coverage with IMRT at 5x5Gy, delivered without a single dose reduction.

Prespecified noninferiority met on 3yr DFS with adequate accrual, but open-label, 35mo follow-up only, and the OS gain is a secondary endpoint unsupported by MFS or LRR.

Multicenter randomized phase III, N=458, accrual June 6, 2017 to December 27, 2023, median follow-up 51 months. Primary endpoint: DFS. Blinding is not reported and the two regimens are not maskable.

Stage II/III LARC aged 18 to 70 with at least one MRI high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with EMVI). Baseline burden was heavy: cT4 47.82%, cN2 75.98%, threatened MRF 70.96%, EMVI 54.80%.

Experimental: one cycle induction CAPOX, LCRT with two cycles concurrent CAPOX, three cycles consolidation CAPOX, then surgery, so all cytotoxic therapy precedes resection. Control: LCRT with concurrent capecitabine, surgery, then six cycles adjuvant CAPOX at 4 to 8 weeks.

Long-course RT in both arms, so RT is the fixed element and the randomized variable is chemotherapy timing plus oxaliplatin exposure. Dose, fractionation, technique and target volume are not reported in the source text, nor is whether concurrent doublet chemotherapy altered RT delivery.

Primary: DFS. Secondary results reported here: MFS, pCR, locoregional failure, overall survival, grade ≥3 adverse events, major postoperative complications.

Primary endpoint met, with MFS moving in step and pCR strongly favoring the experimental arm, while locoregional failure and 3-year OS did not separate. See the efficacy table.

Grade ≥3 toxicity front-loads into the neoadjuvant phase with the doublet, but severe toxicity across the entire treatment course and major postoperative complications were comparable. Total mesorectal excision was performed in approximately 87% (TNT) and 90% (nCRT).

Sits alongside RAPIDO, PRODIGE-23 and STELLAR, the trials that established TNT, but keeps long-course chemoradiation as the RT backbone rather than short-course RT. Unlike RAPIDO's longer follow-up, intensification here did not increase locoregional failure.

Control-arm adjuvant CAPOX delivery and completion are not reported, and a TNT advantage partly reflects therapy planned but not received when postoperative chemotherapy under-delivers. Accrual spanned 2017 to 2023, during which TNT became routine, so control-arm contemporaneity drifted. Age was capped at 70.

The gain is distant, not local: MFS tracks DFS while locoregional failure is flat and low in both arms, which says long-course chemoradiation with a fluoropyrimidine is near its local ceiling in this population and the remaining room is systemic. The pCR tripling is the organ-preservation lever, but pCR is a resection-specimen endpoint and this trial did not test nonoperative management.

Randomized phase III, primary DFS met at 51mo median f/u, but TNT is already established by RAPIDO, PRODIGE-23, STELLAR; this refines regimen rather than the paradigm.

International investigator-initiated phase 3, N=802 from 8 countries, accrued March 2014 to June 2018, median follow-up 8 years. Powered at 80% for an HR 0.67. Primary was changed from OS to MFS during the trial because deaths ran below projection.

High-risk clinically localized or locally-advanced disease suitable for EBRT: 90% Gleason 8-10, 36% PSA >20 ng/ml, 12% cN1 by conventional imaging. 40% planned for pelvic RT and 8% for a brachytherapy boost.

Experimental: enzalutamide 160 mg daily x 24 months plus LHRH agonist x24 months. Control: conventional NSAA x6 months plus LHRH agonist x24 months. The control is an active antiandrogen, not ADT alone.

Prostate to 78Gy, or 46Gy plus brachytherapy boost, starting 16 weeks after hormonal therapy. Pelvic nodal RT required for cN1 (46Gy elective nodes plus boost to gross nodes) and optional for cN0 but declared before randomization. QA was unusually tight: credentialing, benchmarking, real-time review of the first 5 plans per site, then 20% random sampling.

Primary: MFS. Secondary: OS, CSS, PSA PFS, clinical PFS, castration resistance, HRQoL, adverse events, cost-effectiveness. Main effects by unstratified log-rank at alpha=0.05, Cox HRs, all p-values nominal without multiplicity adjustment, five prespecified subgroups tested by interaction.

Primary MFS not met. PFS favored enzalutamide at a nominal p=0.044 and OS was flat; the subgroup detail sits in the table above.

STAMPEDE's abiraterone-based intensification in non-metastatic high-risk disease produced an MFS HR 0.53 against ENZARAD's 0.88, and the ENZARAD cN1 subgroup HR mirrors the STAMPEDE result. The gap plausibly reflects population, not drug: cN1 11% vs 39%, median PSA 14 vs 35 ng/ml, cT3-4 47% vs 92%.

The pelvic-RT subgroup is not a clean randomized comparison of pelvic coverage: it carried 28% N1 and 62% Gleason 9/10 against 0% N1 and 49% Gleason 9/10 in the no-pelvic-RT group, so risk enrichment and biological interaction are entangled. The presenter named both explanations and could separate neither.

Two prespecified subgroups moving together on MFS and OS, with OS HRs tracking MFS HRs as ICECaP surrogacy predicts, is more internally consistent than a lone subgroup blip. It still does not establish that enzalutamide works only when the pelvis is treated.

Adequately powered phase 3 missed its primary MFS endpoint against an active NSAA control; benefit rests on two prespecified subgroups with overlapping risk composition.

Single-centre randomised open-label phase 2 at the European Institute of Oncology, Milan. 105 pts assigned 1:1 between Aug 1, 2019 and April 30, 2023; median follow-up 31 months (IQR 16-36). Modified intention-to-treat analysis, 3 pts lost to follow-up.

Metachronous oligorecurrent hormone-sensitive disease: biochemical progression after radical local treatment with ≤3 lesions (pelvic nodal, extra-regional nodal, or bone) on next-generation imaging, ECOG 0-1. Median age 70 (IQR 65-75). Stratified by doubling time (≤3 vs >3 mo), node vs bone, and PET vs MRI.

30 Gy in 3 fractions every other day to all oligometastatic sites, or equivalent regimens by site. Stated EQD2 98.6 Gy (α/β 1.5 Gy) and BED >100 Gy, an ablative prescription rather than a symptomatic one, which is the dose the control-arm result belongs to.

6 months of ADT with an LHRH analogue in the combination arm, begun within 1 week before SBRT; no ADT in the control arm. The RT backbone is fixed across arms, so the randomised variable is the short systemic course alone.

Primary: clinical progression-free survival, assessed in 51 pts per group. No overall survival, ADT-free survival, or castration-resistance readout is reported in source.

Radiation contributed one G1 GI event; the only G3 was a left ureter stenosis in the combination arm, with no late toxicity in either group. The 22 G1 events were ADT-attributed and had resolved by last follow-up, so the harm ledger sits with the systemic course, not the RT.

STOMP and ORIOLE established MDT against observation in metachronous oligorecurrence, partly on the strength of keeping men off systemic therapy. EXTEND tested the mirror-image addition, MDT layered onto hormone therapy. This is the first randomised trial in this setting to report improved cPFS for the combination.

Progression was assessed unmasked, and PSA suppression from the randomised ADT gates the restaging that defines the event. Median follow-up sits below the combination arm's median cPFS of 32.2 mo, so the tail after testosterone recovery is thin. No biomarker separates the pts who would do well on SBRT alone.

Local and systemic therapy read as additive here rather than redundant, but the trade is priced in cPFS only. Whether 6 months is the right duration, and for whom SBRT alone suffices, is exactly what the investigators leave to future biomarker work.

Randomised, prespecified primary cPFS hit (HR 0.43). Single-centre, N=105, surrogate composite endpoint, so it supports adding short ADT to MDT rather than establishing it.

Randomized phase III SWOG/NRG cooperative-group trial, accrual 8/13/20 to 9/6/24, 417 randomized / 403 eligible (201 SBRT alone, 202 atezolizumab + SBRT) against an accrual goal of 432. Closed at the first interim analysis for futility on both OS and PFS. Median follow-up in living pts was 12 months (range 0.03-49).

T1-3N0M0 NSCLC ≤7 cm, medically inoperable or declined surgery, with ≥1 recurrence risk factor: tumor diameter ≥2 cm, ≥6.2 (SUV), or moderately/poorly/undifferentiated histology. Median age 73 (41-91), 89% ECOG 0-1, median tumor diameter 2.3 cm. Stratified by location (central vs peripheral), size (<4 vs ≥4 cm) and PS.

SBRT in 3-8 fractions to a BED ≥100 Gy in both arms, i.e. standard definitive dosing rather than a de-escalated backbone. In the experimental arm SBRT began with cycle 3, so radiation was delivered after two neoadjuvant atezolizumab cycles and concurrently with the third.

Atezolizumab 1200 mg IV Q3W for 8 cycles, given neoadjuvantly, concurrently and adjuvantly around SBRT. No protocol treatment was received by 6 pts on S and 8 on AS.

Primary: overall survival, compared by 1-sided stratified log-rank at the 2.5% level. Secondary: PFS, failure patterns, toxicity, QoL.

Neither OS nor PFS favored the IO arm, and local failure ran higher with atezolizumab. See the failure-pattern table and primary endpoint above.

G≥3 AEs 12% on AS vs 2% on S (21 G3, 1 G4, and 1 G5 respiratory failure with atezolizumab; 3 G3 and 1 G4 with SBRT alone). A six-fold excess of high-grade toxicity with no efficacy return is the safety read.

The prior randomized phase II (PMID 37478883) suggested benefit from adding immunotherapy to SBRT; this larger phase III does not reproduce it. It also sits against PACIFIC-era logic, where consolidation IO helps after chemoRT for stage III, and shows that result does not port down to node-negative disease treated with ablative SBRT.

Follow-up is short (median 12 mo alive) and central review of local recurrence events is not complete, so the local-failure imbalance is provisional. The smoker subgroup harm signal was not multiplicity-controlled, and PD-L1 status, QoL and correlative blood/tissue analyses are all still pending.

A negative primary endpoint with a directionally worse PFS, worse local control and six-fold more high-grade toxicity is stronger than a null result: it argues against the abscopal/radiosensitization rationale in this setting. It does not exclude benefit in a biomarker-selected subset, which the pending PD-L1 analysis will test.

Phase III, primary OS endpoint not met, closed at interim for futility. Reaffirms SBRT alone as SoC and refutes the earlier phase II IO signal.