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Phase III noninferiority RCT, 17 centers, accrual 2015-2021. ITT cohort n=2,908 (1,444 at 50Gy, 1,464 at 40Gy). Accrual continued until 3-year lymphedema estimates were reported in 1,012 patients.

High-risk breast cancer with an indication for locoregional radiotherapy, the population where nodal coverage has kept 25 fractions standard in Denmark. Median age 57 (range 23-86).

Standard arm 50Gy/25fx, experimental arm 40Gy/15fx, both delivered to the locoregional volume rather than breast or chest wall alone. That target volume is the whole point: it is where the morbidity concern lives.

Primary: arm lymphedema at 3 years, with an assumed 10% incidence under 50Gy/25fx and noninferiority predefined as maximum 5 percentage points excess. Cancer endpoints (locoregional recurrence, distant recurrence, breast cancer mortality, all-cause mortality) were assessed within 8 years.

Lymphedema 8.0% vs 9.4%, OR 0.84 (0.62-1.14), P=.27, comfortably inside the margin. Cancer-outcome HRs are tabulated above and show no difference by random assignment.

The UK hypofractionation programme (START A/B, then FAST-Forward) established 40Gy/15fx and shorter for breast and chest wall, but node-positive patients receiving comprehensive regional coverage were a small fraction, which left the nodal question open. Skagen 1 tests exactly that gap prospectively with morbidity as the primary endpoint.

Median lymphedema follow-up of 4.1 years captures the 3-year endpoint but not the later plateau, and the abstract reports no brachial plexopathy, shoulder, cardiac, or pulmonary late toxicity. The BC mortality HR 1.25 (0.93-1.66) runs the wrong way with a CI that does not exclude harm; the trial was sized for lymphedema, not survival.

The trial removes the specific objection that blocked hypofractionated nodal RT rather than merely adding another positive fractionation result. It does not settle very-long-term arm and shoulder function, nor whether the same holds with a simultaneous integrated boost or in reconstructed chest walls.

Phase III, prespecified noninferiority margin met on the morbidity endpoint that blocked nodal hypofractionation, with 8yr recurrence and mortality HRs showing no difference.

Two open-label phase 3 randomised comparisons within the STAMPEDE MAMS platform, run at 113 UK and Swiss sites, with no overlapping controls, pooled by individual patient data meta-analysis. Recruitment Nov 15, 2011 to March 31, 2016; N=1974; median follow-up 72 months (85 months in the abiraterone trial, 60 months in the abiraterone and enzalutamide trial). The switch of the non-metastatic primary outcome from overall survival to metastasis-free survival was made before any efficacy inspection by randomised group and published as a prespecified declaration.

High-risk non-metastatic prostate adenocarcinoma: node positive, or if node negative, at least two of T3/T4, Gleason 8–10, PSA ≥40 ng/mL; or relapsing with high-risk features (PSA ≥4 with doubling time <6 months, PSA ≥20, or nodal relapse). WHO PS 0–2, no age limit, clinically significant cardiovascular disease excluded. Median age 68 (IQR 63–73), median PSA 34 ng/mL, 774 (39%) node positive, 1563 (79%) of 1968 Gleason 8–10.

ADT for 3 years in all arms, started no more than 12 weeks before randomisation. Combination arms added abiraterone acetate 1000 mg + prednisolone 5 mg daily for 2 years, with enzalutamide 160 mg daily in the second trial only. Median time from randomisation to starting combination therapy 1·4 weeks; when RT was omitted, treatment could continue to progression.

Local RT was mandated for node-negative disease unless contraindicated and encouraged for node-positive disease, per local guidelines at 74 Gy in 37 fractions to prostate and seminal vesicles or a hypofractionated equivalent. Planned RT covered 1684 (85%) of 1974 pts: 99% of newly diagnosed node-negative, 71% of node-positive, and only 7% of previously treated pts.

Primary: metastasis-free survival in the pooled intention-to-treat population, powered for a target HR of 0·75 at 90% power with a one-sided type 1 error of 1·25%, requiring roughly 315 control-group events. Secondary: overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity.

G3+ AEs in the first 24 months were 169 (37%) of 451 vs 130 (29%) of 455 in the abiraterone trial, but 298 (58%) of 513 vs 172 (32%) of 533 once enzalutamide was added. Hypertension (14% vs 5%), fatigue (10% vs 2%) and raised aminotransferases (13% vs 5%) account for most of the gap between the two combination arms. Seven grade 5 events occurred, none in a control group.

Trials of abiraterone combined with enzalutamide or apalutamide in metastatic castration-resistant disease had already shown modest radiographic PFS gains with no overall survival gain, and the interaction HR of 1·02 (0·70–1·50) here reproduces that in the hormone-sensitive non-metastatic setting. The two trials also confirm each other independently, MFS HR 0·54 (0·43–0·68) and 0·53 (0·39–0·71), which is the strongest internal replication available for a result of this size.

Toxicity was captured only during the first 2 years of treatment, so late cardiovascular and metabolic effects of a 2-year ARSI on top of 3 years of ADT are not measured here. Data on subsequent therapy at castration resistance are described as unreliable, and the 2-year combination duration was pragmatic (matched to the ADT-with-RT requirement), not compared against shorter or longer schedules.

The result establishes fixed-duration hormone intensification as additive to definitive local therapy, with the effect size holding across nodal status and across planned RT use. What it does not settle is whether MFS at 72 months translates into a durable cure fraction, or which of the enzalutamide-driven toxicities would be acceptable if a future combination did show separation.

Two prospectively randomised phase 3 trials, prespecified pooled primary endpoint hit, 72mo follow-up, and the RT-treated majority carries the same effect as the whole.

International phase 3 randomized trial (BIG 2-04 MRC/EORTC SUPREMO), 125 UK sites plus 27 European and 21 international sites. N=1607 ITT (808 CWI, 799 no CWI), randomized August 2006 to April 2013, database lock June 2024. Median follow-up 9.6 years.

"Intermediate-risk" post-mastectomy disease: pT1N1, pT2N1, pT3N0, or pT2N0 with grade 3 and/or LVI. All had mastectomy, an axillary procedure, and systemic therapy. Baseline systemic exposure: 85% chemotherapy, 79% endocrine, 19% trastuzumab.

Chest wall 40 to 50 Gy in the irradiation arm. Nodal volumes were not part of the randomized question: supraclavicular fossa treated in only 97/808 irradiated patients, internal mammary chain in 12/808. Twelve patients in the no-irradiation arm received SCF treatment.

Primary: overall survival at 10 years. Secondary: chest-wall recurrence, regional recurrence, disease-free survival, distant metastasis-free survival, cause of death, radiation-related adverse events.

The historic case for postmastectomy RT in node-positive disease rests on the EBCTCG overview, where the locoregional-control gain translated into a mortality benefit. SUPREMO tests that inheritance in the 1-3 node and high-risk node-negative band under contemporary systemic therapy and finds the recurrence signal preserved (HR 0.45) but the survival signal absent (HR 1.04).

The chest-wall recurrence benefit rests on 29 events total with a CI upper bound of 0.99, so the point estimate is unstable. Accrual ran 2006-2013, predating routine dual HER2 blockade, extended adjuvant CDK4/6 inhibition, and current genomic risk stratification, all of which lower the baseline recurrence rate this trial was powered against.

A flat OS with a halved chest-wall recurrence is the signature of a locoregional intervention operating below the threshold where local control converts into survival. At 1.1% vs 2.5%, the absolute chest-wall event rate in both arms is low enough that no plausible salvage-to-mortality pathway could move a 10-year OS curve. The result reframes PMRT in this band as a local-control decision to be weighed against RT morbidity, not as a survival decision.

Adequately powered phase 3, prespecified OS primary, 9.6yr median follow-up, modern systemic backbone. Supports omitting PMRT in a population where guidelines still often recommend it.

Prospective randomized phase 3 noninferiority trial, 1:1, 67 hospitals in Sweden, Denmark, Germany, Greece and Italy. 2766 enrolled Jan 2015 to Dec 2021; per-protocol population 2540 (1335 sentinel-node biopsy only, 1205 completion dissection). Median follow-up 46.8 months (range 1.5 to 94.5).

cN0, T1 to T3 breast cancer with one or two sentinel-node macrometastases (>2mm). Preoperative axillary ultrasound was mandatory; suspicious nonpalpable nodes were still eligible even with FNA-confirmed metastasis. Additional micrometastases and extracapsular extension were allowed, and both breast-conserving surgery (63.3% / 64.3%) and mastectomy (36.7% / 35.7%) were eligible. Mean age 61.

RT including nodal target volumes was given to 89.9% (1192/1326) of the sentinel-node-only group and 88.4% (1058/1197) of the dissection group. Whole-breast RT was mandatory after breast-conserving surgery, but the protocol stipulated no specific target volumes or doses, deferring to national guidelines. QA on 1154 plans showed eCRF-to-plan concordance of 99.3% for breast or chest wall and 96.6% for nodal volumes.

Primary: overall survival (switched from breast cancer-specific survival in 2020 on DSMB advice). Prespecified secondary endpoints were recurrence-free survival, breast cancer-specific survival and patient-reported outcomes. Noninferiority required the upper CI bound for recurrence or death below 1.44.

No clinical lymphedema measurements were performed; arm morbidity relies on the LYMPH-ICF, QLQ-C30, QLQ-BR23 and EQ-5D questionnaires at 1, 3, 5 and 10 years. Only 1-year data from a Swedish-Danish subpopulation are published; 3-year data for the whole trial are not yet available.

Consistent with ACOSOG Z0011 and AMAROS, but the authors place SENOMAC alongside AMAROS and OTOASOR rather than Z0011, SINODAR-ONE or POSNOC, because nodal irradiation was routine here. Where the earlier trials enrolled nearly 40% micrometastasis-only pts, one T3 patient between them, and only 248 mastectomies (17.4%) in AMAROS, SENOMAC filled each of those gaps.

Detailed nodal level doses and volumes are not yet reported, so the RT dose actually treating the residual axilla is unquantified. Withdrawal was higher in the dissection arm, reflecting pts' wish to avoid the operation. The ER+/HER2+ subgroup HR of 0.26 (0.07-0.96) rests on 3 versus 10 events among 13 subgroups and should not be read as a real interaction.

The completion dissection arm shows what is being left behind: 34.5% (403/1167) had additional non-sentinel-node metastases, rising to 51.3% with two macrometastases, and 9.9% were upstaged to pN2 with 3.0% pN3. Noninferior recurrence-free survival despite that residual burden is a statement about what systemic therapy plus nodal RT can control, not about the axilla being clean.

Prespecified noninferiority met with wide margin to boundary; enrolls the mastectomy, T3 and ECE subgroups Z0011 and AMAROS excluded, resolving the residual uncertainty.

Randomized, unblinded phase 3 noninferiority trial run by NRG Oncology, 278 sites across North America and 6 other countries, accrual May 2011 to June 2014. 2,354 randomly assigned, 2,255 eligible (sequential 1,118, concurrent 1,137). Median follow-up 7.3 years.

Post-lumpectomy and axillary surgery, selected for higher risk of ipsilateral breast recurrence. Median age 55 (IQR 47-64), 35.6% under 50; 96.8% invasive, 52.7% grade 3, 29.6% ER-negative, 16.7% LVI, 16.7% close (<2 mm) or focally positive margins, 16.3% node-positive, 61.8% received chemotherapy.

Sequential arm: WBI 50 Gy/25F or 42.7 Gy/16F, then boost 12 Gy/6F (84.9%) or 14 Gy/7F. Concurrent arm: WBI 40 Gy/15F with an 8 Gy/15F integrated boost at 0.53 Gy per day. 3DCRT in 1,290 (59%), photons in 1,614 (73.8%). QART scored contours and plans per protocol or acceptable variation in 92.8% and 91.9%.

Primary: IBR as first recurrence, noninferiority margin an HR upper 90% CI limit of 2.12, powered at 80% off an assumed 1.59% 5-year sequential-arm IBR. Secondary: DFS, OS, adverse events, and cosmesis (patient BCTOS, physician global cosmetic score, blinded central digital photo review).

56 IBR events, 24 sequential and 32 concurrent. Cause-specific hazards and Fine-Gray gave the same HR 1.31, and noninferiority held against each sequential WBI fractionation separately. The protocol-specified superiority test was not significant, and post-hoc analyses by stratification variable showed no treatment interactions.

Grade >2 treatment-related toxicity was uncommon with no difference in grade 3-4 events (p=0.81); radiation dermatitis, fatigue, and breast pain were the most prevalent events. Physician-rated excellent/good cosmesis at 3 years was 85.9% sequential vs 82.4% concurrent (p=0.34), photo review 64.2% vs 72.0% (p=0.11).

The boost itself was established by EORTC 22881-10882, where 16 Gy sequential cut IBR but added treatment time and worsened fibrosis. IMPORT HIGH tested integrated boosts on a 40 Gy/15F backbone and found 48 Gy acceptable while its 53 Gy arm carried more induration. NRG 1005 answers the delivery question at scale rather than the dose question.

Cosmetic assessment thinned badly over time: blinded photo review response fell from 79.7% at baseline to 47.1% at 3 years, and physician rating from 90.3% to 50.5%, so the cosmesis conclusions rest on roughly half the cohort with unblinded delivery. The QoL substudy also had imbalances, more stage II sequentially (39.7% vs 32.5%) and more IMRT concurrently (27.1% vs 18.5%).

The point estimate favors sequential (HR 1.31) even as the confidence bound clears the margin, so this is a noninferiority conclusion in the honest sense, not equivalence. With 7-year IBR at 2.2% and 2.6%, the absolute difference is under a percentage point in a deliberately high-risk cohort, which is the frame in which trading 6 to 7 fractions is reasonable.

Adequately powered phase III, prespecified noninferiority margin met at 7.3yr median f/u, with cosmesis and toxicity co-endpoints also noninferior. Removes 6-7 fractions.