onc brain

Secondary margin-width analysis of NRG Oncology/NSABP B-35, a double-blind randomised trial of tamoxifen vs anastrozole that enrolled 3,104 postmenopausal women 2003-2006. Because local recurrence did not differ between the two endocrine arms, the arms were pooled and margin width analysed across the whole population. Margin data were collected prospectively by participating pathologists.

Postmenopausal women with hormone receptor-positive DCIS treated with lumpectomy. Two overlapping analysis cohorts: n=2,707 with margins classifiable as <1mm (close/indefinite) vs ≥1mm, and n=2,546 with the closest margin measured, permitting a <2mm vs ≥2mm cutoff.

All patients received whole-breast irradiation with an optional boost. Dose, fractionation and boost uptake are not reported in the source, so the RT exposure behind these recurrence rates cannot be characterised beyond "whole breast, boost optional".

Primary endpoint of interest: cumulative incidence of ipsilateral breast tumor recurrence at 10 years, analysed at both the 1mm and 2mm cutoffs. A secondary analysis of all breast cancer events, including contralateral disease, was also performed.

The prevailing 2mm threshold rests largely on the SSO/ASTRO/ASCO DCIS consensus, whose meta-analytic base drew heavily on series with variable and often absent adjuvant therapy. This analysis puts the same question to a uniformly irradiated, uniformly endocrine-treated randomised trial population, which is why the residual margin effect looks so much smaller.

Margin width was not randomised, and patients re-excised on trial carry their final margin, so the narrow-margin group is enriched for disease that could not be cleared. Source reports no hazard ratios, confidence intervals or event counts, and no multivariable adjustment for grade, size, age or boost use.

The claim is that a 1.5% to 1.6% absolute 10-year difference does not justify routine reoperation, which is a value judgment about the trade against anxiety, cosmesis and cost rather than a statistical one. The difference was statistically significant at the 1mm cutoff, so the argument turns on clinical meaningfulness, and a patient who weighs local recurrence heavily could reasonably read the same number differently.

Prospectively collected margin data from a large RCT population directly contests the 2mm re-excision threshold, but the margin comparison itself is non-randomised and abstract-only.

ASO Perspectives editorial in Annals of Surgical Oncology, not new trial data. Two radiation oncologists re-read SUPREMO against the PMRT and RNI evidence base. PMRT after neoadjuvant therapy is explicitly out of scope.

The central claim is that SUPREMO tested chest wall alone, not PMRT: RNI was prohibited, supraclavicular nodes were covered in 12% of PMRT-arm pts (n=97), and internal mammary irradiation occurred in fewer than 2% across both arms. Non-UK centres could give RNI in the observation arm, and 12 control pts received supraclavicular RNI.

Only 25% were truly node-negative and would not be offered PMRT under current guidelines; the majority had N1 disease (1-3 nodes). 65% were hormone-receptor positive, TNBC was 10%, and only 14% had SLNB alone with the majority undergoing ALND.

SUPREMO's 10-year chest-wall recurrence fell from 2.5% to 1.1% (HR 0.45) with no gain in overall LRR, DFS or OS. The supplement carries the signal the headline drops: LRR 4.8% to 3.3%, HR 0.51 (95% CI 0.27-0.96) in node-positive pts, not in node-negative.

EBCTCG 2014 found PMRT cut 10-year LRR by 17.9% and 20-year breast cancer mortality by 8% in 1-3 node-positive women, persisting with a single positive node, with no node-negative benefit. MA-20 and EORTC 22922 both showed RNI benefit in 1-3 node-positive disease despite near-universal ALND, and a later EBCTCG RNI meta-analysis showed gains at 15 years including in contemporary systemic-therapy trials.

This is a single-perspective editorial from two radiation oncologists, so the framing selects evidence favouring comprehensive RNI, and the reader gets no independent re-analysis of SUPREMO's data. Its strongest number, the node-positive LRR HR 0.51, comes from a supplementary subgroup the trial did not power for.

The authors leave the genuinely open questions to trials in progress: MA.39 (Tailor-RT) for RNI omission at low recurrence score, T-Rex for RNI omission in hormone-sensitive disease with one to two macrometastatic SLNs. They also note the surgical corollary, that ALND should not be chosen to earn a PMRT omission, since ALND is the dominant lymphedema driver.

Editorial, no new data; contests the omission reading of SUPREMO on field design and population grounds, aligning with ASTRO 2025 and NCCN rather than the trial's public messaging.

Nationwide population-based prospective cohort across six Danish RT centres, 2007-14, allocating IMNI by tumour laterality (right yes, left no) under national guideline. N=4541 of 5206 assessed. Median follow-up 13.7 years for OS, 13.2 for distant metastasis; analysis was intention-to-treat by side.

Macrometastatic node-positive breast cancer receiving locoregional RT; median age 59; 68.3% had 1-3 positive nodes. Excluded: prior malignancy, bilateral disease, neoadjuvant systemic therapy, recurrence before RT, non-standard RT. Axillary surgery was always axillary dissection.

Chemotherapy was three cycles EC (epirubicin 900 mg/m2, cyclophosphamide 600 mg/m2) then three cycles docetaxel 100 mg/m2; 96.2% of chemo pts received a taxane. Tamoxifen premenopausal, aromatase inhibitor postmenopausal; trastuzumab concurrent with chemo and RT in HER2+ (13.5% overall).

48 Gy/24 Fx before Jan 2009 (26.2%), 50 Gy/25 Fx after (73.2%), 3D conformal wide tangents in free-breathing. IMN target was intercostal space 1-4; all pts had axilla level II-III plus interpectoral and level IV, with level I added for ≥6 positive nodes or <10 nodes removed. QA showed IMN CTV V90% 94.6% right vs 20.4% left.

Primary: overall survival. Secondary: breast cancer mortality and distant metastasis, both with non-breast-cancer death as a competing event. Cox models adjusted for age, menopausal status, histology, tumour size, and nodal count, stratified by IHC subtype and grade.

The OS point estimate sits on top of the EBCTCG regional-node meta-analysis rate ratio 0.90 (0.84-0.96) and of KROG 08-06's HR 0.87 (0.57-1.31), the only other 3D-based IMNI study, which was underpowered at n=735 and read as negative. It also reproduces DBCG IMN1's absolute OS gain of 4.7%, arguing the taxane/trastuzumab/AI era did not absorb the benefit.

Contamination runs both ways: 10.1% of left-sided pts (n=238) got IMNI and a quarter of right-sided pts had under 64.8% IMN coverage, so the observed gain likely understates a fully delivered one. Cardiac and lung toxicity were captured only as death, with no smoking, comorbidity, or cardiac-event data, and the era predates PET-CT staging and respiratory gating.

The ER-/HER2+ signal (HR 1.49, 0.98-2.25, interaction p=0.021) echoes Kyndi's DBCG 82b&c finding but conflicts with NSABP B-51, and the analysis was explorative without multiplicity correction, so it should not gate treatment. The medial/central plus ≥4 node cell (HR 0.98, 0.79-1.21) is the one group where benefit looks absent, matching IMN1's 0.91 (0.73-1.15).

Prospective nationwide cohort, prespecified primary endpoint, 13.7y follow-up; contradicts guidelines withholding IMNI at 1-3 nodes. Non-randomised laterality allocation keeps it below practice-changing.

Secondary analysis of the randomized SWOG S1007 trial (endocrine therapy alone vs chemotherapy then endocrine therapy). Radiotherapy data were prospectively collected across diverse practice settings, but RNI receipt itself was not randomized. Data analyzed June 2022 to April 2023.

Hormone receptor-positive, ERBB2-negative breast cancer with 1 to 3 involved nodes and Oncotype DX 21-gene Recurrence Score ≤25. 4871 female patients had radiotherapy forms; median age 57 (range 18-87).

RNI defined as targeting at least the supraclavicular region. 3947 (81.0%) reported radiotherapy receipt; of 3852 with complete target information, 2274 (59.0%) received RNI. Dose, fractionation, and internal mammary coverage are not reported in source.

Cumulative incidence of locoregional recurrence by locoregional treatment received, plus association between invasive disease-free survival and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery.

Median follow-up 6.1 years. See the LRR and IDFS tables above; IDFS did not differ by RNI receipt in either menopausal stratum.

MA.20 and EORTC 22922 established the regional irradiation question in node-positive disease, both without an overall survival gain, in cohorts assembled before genomic risk stratification. This analysis reads that question in the population those trials could not define, biologically favorable N1, and finds an LRR floor low enough that a relative benefit has little absolute room to operate.

Radiotherapy information was recorded only in the first year after randomization, forcing a 1-year landmark that excludes the earliest events. Target detail stops at supraclavicular coverage, so internal mammary treatment cannot be separated, and the low absolute event count leaves the IDFS confidence intervals wide enough to accommodate a small effect in either direction.

The finding that matters is the floor, not the comparison: with 5yr LRR at or below 1.7% in every locoregional strategy examined, the population has too few events for regional irradiation to demonstrate meaningful absolute benefit. The explicit conclusion is that omission of chemotherapy is not an independent indication for RNI, which addresses a specific compensatory reflex rather than the general RNI question.

Prospectively collected RT data in a large trial cohort, but RNI receipt was not randomized; observational comparison, so an unmeasured-confounding read is unavoidable.

Prospective multicenter randomized phase 3 trial, accrual 1996-2004, 4004 pts, with an RT quality-assurance program built in. The last analysis was planned at 20 years on the assumption that any survival effect of IM-MS-RT would be delayed. Median follow-up 22.2 years.

Women ≤75 yrs, unilateral histologically confirmed breast adenocarcinoma, stage I-III. Gate was tumor location or nodal status: centrally or medially located primary irrespective of axillary involvement, or any quadrant with axillary involvement. Median age 54.

Randomization was to internal mammary and medial supraclavicular (levels 3-4) nodal irradiation or not, layered on standard breast or chest wall treatment. Dose and fractionation are not given in the source excerpt. Planning ran in the two-dimensional and early-conformal era, when IM coverage at least doubled heart dose.

Primary: overall survival. Secondary: disease-free survival, distant metastases-free survival, breast cancer mortality, any breast recurrence.

Lung fibrosis 6.3% vs 3.2%, cardiac fibrosis 2.7% vs 1.7%, cardiac disease 15.2% vs 11.7% with IM-MS-RT. Severe (grade 3-4) events were uncommon and near-equal: cardiac 1.9% vs 1.7%, lung 0.3% vs 0.0%, so the excess sits in lower-grade, chronic morbidity rather than catastrophic events.

MA.20 and DBCG-IMN both read regional nodal RT positively at roughly ten-year horizons, and DBCG-IMN reported an OS gain. This trial covers the same anatomic question at twice that follow-up and shows the disease-specific gain surviving while the survival gain does not, which is the read those trials were too short to produce.

Systemic therapy was left to physician and institutional preference across an eight-year accrual, so the systemic backbone is heterogeneous and predates current regimens. The competing-mortality signal is a cause-of-death attribution over two decades in a population whose baseline cardiovascular risk rises independently, and the source does not report a cardiac-specific mortality breakdown separating RT-attributable from age-attributable death.

The two effects are both real and point opposite ways: HR 0.82 on breast cancer mortality, HR 1.26 on other deaths, netting HR 1.00 on OS. That arithmetic is the finding, and it argues the relevant question is not whether IM-MS coverage works but whether its cost can be engineered down.

Randomised, prespecified 20yr primary analysis, adequate power, endpoint reported honestly. Divergence from the 10yr-era read of nodal RT is internally valid, not a design artifact.