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About · curated by Nick Boehling, MD · @nb2276

    2026-05-21

    digest generated 2026-07-19

    EORTC 22922 at 20yr: IM-MS-RT cut BC mortality (HR 0.82) but excess cardiopulmonary deaths (HR 1.26) erase it, netting flat OS (HR 1.00, p=.967).
    TL;DR
    Regional nodal RT got right-sized from both ends: breast RNI enthusiasm cooled (EORTC 22922 20yr OS flat as cardiopulmonary deaths offset the mortality gain; SWOG S1007 no IDFS benefit in RS≤25 N1), while a first modern IG-IMRT RCT revived adjuvant RT after cystectomy (LRFS HR 0.43). Breast and bladder carried the day.

    Breast

    Two regional-nodal-RT readouts, both tempering enthusiasm: no IDFS gain in RS≤25 N1 (SWOG S1007) and a 20yr OS wash as cardiopulmonary deaths offset the mortality benefit (EORTC 22922).

    Caveats dominate

    SWOG S1007

    ForHR+/HER2− breast, 1-3 nodes, Oncotype RS ≤25

    TL;DR5y LRR 0.55% without RNI vs 0.85% with; IDFS unchanged by RNI (HR 1.03 premenopausal, 0.85 postmenopausal) in RS ≤25 N1 breast.

    Why it mattersRadiation oncology

    The RT read: RNI omission after breast conservation carries low locoregional risk, 5y LRR 0.55% without RNI vs 0.85% with, in RS ≤25 N1 disease. Chemo omission alone is not an RNI indication, so this supports withholding RNI in biologically favorable N1, pending randomized confirmation.

    6 details 3 trials watching
    Design

    Secondary analysis of SWOG S1007 (RxPONDER), a phase 3 RCT of chemo omission by 21-gene recurrence score. RNI receipt was prospectively recorded, not randomized. Median follow-up 6.1y; survival landmarked at 1y.

    Population & inclusion

    HR+/HER2−, Oncotype RS ≤25, 1-3 positive nodes. 4871 had RT forms; 81% received RT, and 59% of those with target data received RNI (targeting ≥ supraclavicular region).

    Radiotherapy

    RNI defined as targeting at least the supraclavicular region. The 59/41 split in RNI use reflects genuine practice equipoise in favorable N1 disease.

    Results

    LRR was low across every locoregional approach; only mastectomy without RT reached 1.7%. IDFS did not differ by RNI in either menopausal group (see tables).

    Locoregional therapy5y cumulative LRR
    BCS + RT + RNI0.85%
    BCS + RT, no RNI0.55%
    Mastectomy + PMRT0.11%
    Mastectomy, no RT1.7%
    Menopausal statusIDFS HR95% CIp
    Premenopausal1.030.74-1.430.87
    Postmenopausal0.850.68-1.070.16
    vs leading data

    Consistent with MA.20 / EORTC 22922, where RNI's benefit was concentrated in higher-risk node-positive disease. TAILOR RT (MA.39) is randomizing RNI in exactly this RS-low N1 population.

    Applies to
    HR+/HER2−, RS ≤25, 1-3 node breast cancer on modern systemic therapy
    Does not represent higher recurrence-score, >3 node, or HER2+/triple-negative disease.
    Limitations

    RNI comparison is non-randomized: confounding by indication (higher-risk pts selected for RNI) can mask a true RNI effect. Landmarking at 1y and diverse-setting RT reporting add noise.

    Rationale

    RNI vs no-RNI comparison is non-randomized within RxPONDER; confounding by indication limits the null IDFS and low-LRR read. Randomized RNI trial (TAILOR RT) pending.

    Monday clinic

    In HR+/HER2− breast with 1-3 positive nodes and Oncotype RS ≤25, this supports omitting regional nodal irradiation given low LRR; it does not extend to higher recurrence-score or >3 node disease.

    Open questions

    Sourced from Jagsi et al.

    📚 Sources · 📄 1 paper
    📄 PAPER Jagsi; Barlow; Woodward et al. · JAMA oncology (2023-08)
    Radiotherapy Use and Incidence of Locoregional Recurrence in Patients With Favorable-Risk, Node-Positive Breast Cancer Enrolled in the SWOG S1007 Trial.
    PMID 37410451 → doi full text (PMC)
    Abstract
    IMPORTANCE: Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments.<br/><br/>OBJECTIVE: To investigate how often patients with low-recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival.<br/><br/>DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX 21-gene Breast Recurrence Score assay result of no more than 25, were randomized to endocrine therapy alone vs chemotherapy then endocrine therapy. Prospectively collected radiotherapy information was collected from 4871 patients treated in diverse settings. Data were analyzed June 2022 to April 2023.<br/><br/>EXPOSURE: Receipt of RNI (targeting at least the supraclavicular region).<br/><br/>MAIN OUTCOME(S) AND MEASURE(S): Cumulative incidence of LRR was calculated by locoregional treatment received. Analyses were assessed for associations between invasive disease-free survival (IDFS) and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery. Radiotherapy information was recorded in the first year after randomization, so survival analyses were landmarked as starting at 1 year among those still at risk.<br/><br/>RESULTS: Of 4871 female patients (median [range] age, 57 [18-87] years) with radiotherapy forms, 3947 (81.0%) reported radiotherapy receipt. Of 3852 patients who received radiotherapy and had complete information on targets, 2274 (59.0%) received RNI. With a median follow-up of 6.1 years, the cumulative incidence of LRR by 5 years was 0.85% among patients who received breast-conserving surgery and radiotherapy with RNI; 0.55% after breast-conserving surgery with radiotherapy without RNI; 0.11% after mastectomy with postmastectomy radiotherapy; and 1.7% after mastectomy without radiotherapy. Similarly low LRR was observed within the group assigned to endocrine therapy without chemotherapy. The rate of IDFS did not differ by RNI receipt (premenopausal: hazard ratio [HR], 1.03; 95% CI, 0.74-1.43; P&#x2009;=&#x2009;.87; postmenopausal: HR, 0.85; 95% CI, 0.68-1.07; P&#x2009;=&#x2009;.16).<br/><br/>CONCLUSIONS AND RELEVANCE: In this secondary analysis of a clinical trial, RNI use was divided in the setting of biologically favorable N1 disease, and rates of LRR were low even in patients who did not receive RNI. Disease-free survival was not associated with RNI receipt; omission of chemotherapy among patients similar to those enrolled in the S1007 trial is not an independent indication for use of RNI.

    Radiation Curative Retrospective Caveats dominate

    Challenges SOC

    EORTC 22922/10925

    ForStage I-III breast, medial/central primary or axillary node-positive

    Overall survival

    HR 1.00

    95% CI 0.90-1.10, p=.967; 20yr OS 61.0% vs 61.8% (ns)

    TL;DR20yr OS 61.0% vs 61.8%, HR 1.00 (p=.967): IM-MS-RT cut breast cancer mortality (HR 0.82) but raised non-BC deaths (HR 1.26).

    Why it mattersRadiation oncology

    The RT read is competing mortality: IM-MS-RT's breast cancer mortality benefit (HR 0.82) is fully offset by excess cardiac and lung deaths (HR 1.26) at 20yr. With 1996-2004 planning the survival case nets to zero, so contemporary heart-sparing (DIBH/IMRT) is the variable that decides whether IM-MS nodal coverage still pays off.

    7 details 5 trials watching
    Design

    Phase 3 multicenter RCT with central RT quality assurance; 4004 women randomized 1996-2004 to added IM-MS nodal RT vs none. Prespecified for final analysis at 20yr on a delayed-benefit hypothesis; median follow-up 22.2yr.

    Population & inclusion

    Stage I-III breast adenocarcinoma, age ≤75. Eligible if central/medial primary (any nodal status) OR any-quadrant primary with axillary node involvement. Surgery was mastectomy or BCS plus ALND; median age 54.

    Radiotherapy

    Intervention added internal-mammary + medial-supraclavicular (levels 3-4) nodal irradiation on top of standard breast/chest-wall RT. 1996-2004 planning era (2D/3D, pre-DIBH/IMRT); dose and fractionation not specified in source text.

    Endpoints

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

    Results

    Primary OS was flatly null; the significant efficacy signals (lower breast cancer mortality, fewer breast recurrences) were offset in OS terms by excess non-breast-cancer deaths. Per-endpoint numbers in the table.

    Endpoint (20yr)IM-MS-RTControlHR (95% CI), p
    Overall survival61.0%61.8%1.00 (0.90-1.10), p=.967
    Disease-free survival48.2%49.0%0.97 (0.89-1.06), p=.515
    Distant metastasis-free58.9%59.8%0.97 (0.88-1.08), p=.578
    Breast cancer mortality18.6%22.4%0.82 (0.72-0.95), p=.006
    Non-BC/unknown deaths20.4%15.8%1.26, p=.002
    Late morbidityIM-MS-RTNo IM-MS-RT
    Lung fibrosis6.3%3.2%
    Cardiac fibrosis2.7%1.7%
    Cardiac disease15.2%11.7%
    Severe cardiac (G3-4)1.9%1.7%
    Severe lung (G3-4)0.3%0.0%
    Safety

    Excess late lung fibrosis, cardiac fibrosis, and cardiac disease with IM-MS-RT is the mechanism behind the competing non-breast-cancer mortality; severe grade 3-4 cardiac and lung events stayed rare in both arms (table).

    vs leading data

    Aligns with the 10-yr EORTC 22922 report (Poortmans, NEJM 2015) and MA.20 in showing regional nodal RT improves disease control more than OS. The new 20yr signal: late cardiopulmonary deaths neutralize the breast cancer mortality gain.

    Applies to
    stage I-III breast cancer with medial/central primaries or axillary node involvement treated with 1996-2004 RT technique
    Does not represent pts treated with contemporary heart-sparing delivery (DIBH, IMRT, protons), where cardiac dose is materially lower.
    Limitations

    1996-2004 planning predates modern cardiac-sparing, so the non-breast-cancer-death penalty likely overstates contemporary risk. Systemic therapy followed era standards (tamoxifen era), not current regimens. OS as primary is a high bar a single nodal-RT field rarely clears.

    Rationale

    Large randomized phase 3, OS-primary, 22yr f/u: internally valid to contest the IM-MS-RT survival rationale, which the mortality-toxicity tradeoff nullifies. Divergence is the headline.

    Monday clinic

    In a woman with a medial/central or node-positive stage I-III breast tumor, this tempers the survival rationale for adding the internal-mammary + medial-supraclavicular field specifically; it does not change breast/chest-wall or axillary RT indications.

    Open questions

    Sourced from Kaidar‐Person, Orit et al.

    📚 Sources · 📄 1 paper
    📄 PAPER Kaidar‐Person, Orit; Weltens, Caroline G.; Fortpied, Catherine et al. · CA: A Cancer Journal for Clinicians (2026-05)
    Twenty‐year results of the randomized European Organization for Research and Treatment of Cancer trial 22922/10925 evaluating internal mammary chain and medial supraclavicular lymph node irradiation in stage I–III breast cancer
    doi
    Abstract
    Abstract European Organization for Research and Treatment of Cancer trial EORTC 22922/10925 evaluated internal mammary and medial supraclavicular (IM‐MS) lymph node irradiation (IM‐MS‐RT) in patients with stage I–III breast cancer. Eligible patients had involved axillary nodes and/or centrally/medially located tumors regardless of nodal involvement. The primary end point was overall survival, secondary end points were disease‐free survival, distant metastases‐free survival, breast cancer mortality, and any breast recurrence. Between 1996 and 2004, 4004 patients were randomized. The median patient age was 54 years. At a median follow‐up of 22.2 years, 1550 (38.7%) patients died, of whom 796 (51.4%) died from breast cancer. At 20 years, the overall survival rate was 61.8% in the control group versus 61.0% in the IM‐MS‐RT group (hazard ratio [HR], 1.00; p = .967); the disease‐free survival rate was 49.0% versus 48.2%, respectively (HR, 0.97; p = .515); and the distant metastases‐free survival rate was 59.8% versus 58.9%, respectively (HR, 0.97; p = .578). The breast cancer mortality rate was 22.4% in the control group and 18.6% in the IM‐MS‐RT group (HR, 0.82; p = .006), whereas the rate of deaths not from breast cancer or from unknown causes was 15.8% versus 20.4%, respectively (HR, 1.26; p = .002). Lung fibrosis, cardiac fibrosis, and cardiac diseases were more frequent after IM‐MS‐RT versus no IM‐MS‐RT (6.3% vs. 3.2%, 2.7% vs. 1.7%. and 15.2% vs. 11.7%, respectively); and the rates of severe cardiac and lung morbidities (scores of 3 or 4) were 1.9% versus 1.7% and 0.3% versus 0.0%, respectively. Breast cancer mortality at 20 years was statistically significantly lower after IM‐MS‐RT, but deaths not from breast cancer increased after 15 years, resulting in no long‐term benefit of IM‐MS‐RT on overall survival. Therefore, the authors strongly call for very long‐term follow‐up of treatments for prognostically favorable cancers such as breast cancer.

    Radiation Curative Phase 3 RCT Challenges SOC

    Bladder

    First modern IG-IMRT RCT revives adjuvant RT after cystectomy on locoregional control, though DFS/BCSS/OS stay non-significant.

    Challenges SOC

    Bladder Adjuvant Radiotherapy Trial

    ForHigh-risk MIBC post-cystectomy (pT3-4, N+, or margin+), chemo-treated

    2-year locoregional recurrence-free survival local control

    HR 0.43

    2y LRFS 87.1% vs 76.0%; 95% CI 0.20-0.96, P=.04

    TL;DR2y LRFS 87.1% vs 76.0%, HR 0.43 (0.20-0.96) P=.04 favoring adjuvant pelvic IMRT after cystectomy; DFS/BCSS/OS all NS.

    Why it mattersRadiation oncology

    Locoregional control is the RT read: 2y LRFS 87.1% vs 76.0% (HR 0.43) with stoma-sparing IG-IMRT 50.4Gy/28fx to the cystectomy bed plus pelvic nodes, no added severe toxicity. DFS, BCSS, and OS all trended toward RT but none significant at N=153, reopening adjuvant pelvic RT for high-risk MIBC without settling survival benefit.

    8 details 3 trials watching
    Design

    Phase 3 multicenter RCT, 1:1, N=153 (RT=77 vs Obs=76); stratified by nodal involvement and chemotherapy timing (neoadjuvant/adjuvant/none). Median follow-up 47 mo.

    Population & inclusion

    High-risk nonmetastatic urothelial MIBC after radical cystectomy: any of pT3-4, N1-3, margin-positive, or ≤10 nodes dissected. Enrolled 62% pT3-4, 41% pN+.

    Radiotherapy

    Stoma-sparing IG-IMRT, 50.4Gy in 28 fractions to the cystectomy bed and pelvic nodes.

    Regimen

    Over 90% received perioperative chemotherapy (71% neoadjuvant, 20% adjuvant). None received immunotherapy.

    Endpoints

    Primary: 2-year locoregional recurrence-free survival. Secondary: disease-free survival, bladder-cancer-specific survival, overall survival.

    Results

    Primary LRFS met (HR 0.43, P=.04); DFS, BCSS, and OS all favored RT but none reached significance (see table).

    EndpointRTObsHR (95% CI)
    2y LRFS (1°)87.1%76.0%0.43 (0.20-0.96), P=.04
    DFS71.6%58.7%0.62 (0.36-1.05)
    BCSS79.6%65.0%0.59 (0.33-1.10)
    OS70.4%57.4%0.78 (0.49-1.26)
    Safety

    No additional severe toxicity reported with adjuvant pelvic IMRT versus observation.

    vs leading data

    Reopens the adjuvant-RT-after-cystectomy question that prior Egyptian NCI trials raised for local control; first randomized test in the modern IG-IMRT era.

    Applies to
    high-risk post-cystectomy MIBC (pT3-4, N+, or margin-positive) treated with perioperative chemotherapy
    Does not represent organ-confined, node-negative low-risk disease, nor immunotherapy-treated patients.
    Limitations

    Small (N=153); primary endpoint is a locoregional-control surrogate, and survival endpoints were underpowered and nonsignificant. No immunotherapy-era comparator.

    Rationale

    Randomised phase III hit prespecified primary LRFS endpoint favoring adjuvant RT (non-standard); but N=153 and DFS/BCSS/OS all NS. Field reopened, not settled.

    Monday clinic

    In high-risk post-cystectomy MIBC (pT3-4, N+, or margin+) after perioperative chemo, this supports adjuvant pelvic IMRT as a locoregional-control option but not a proven survival gain; it does not extend to organ-confined, node-negative low-risk disease.

    Open questions

    Sourced from Murthy et al.

    📚 Sources · 📄 1 paper
    📄 PAPER Murthy; Maitre; Pal et al. · Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2026-05)
    Bladder Adjuvant Radiotherapy: Phase III Multicenter Randomized Controlled Trial of Adjuvant Radiotherapy or Observation for Postcystectomy Muscle-Invasive Bladder Cancer.
    PMID 42166701 → doi
    Abstract
    PURPOSE: To report the primary analysis of a multicenter, phase III randomized trial of adjuvant radiotherapy (RT) after chemotherapy and radical cystectomy (RC) in patients with high-risk muscle-invasive bladder cancer (MIBC).<br/><br/>METHODS: Patients with nonmetastatic urothelial MIBC at high risk after RC (any one of: T3-4, N1-3, margin positive, &#x2264;10 nodes dissected) were randomly assigned 1:1 to adjuvant RT or observation (Obs), stratified by nodal involvement (yes/no) and chemotherapy (neoadjuvant/adjuvant/none). Stoma-sparing IG-IMRT 50.4Gy in 28 fractions was prescribed to the cystectomy bed and pelvic nodes. The primary end point was 2-year locoregional recurrence-free survival (LRFS), and the secondary end points were disease-free survival (DFS), bladder cancer-specific survival (BCSS), and overall survival (OS).<br/><br/>RESULTS: From June 2016 to May 2024, 153 patients were randomly assigned (Obs = 76, RT = 77), with 62% and 41% of patients having pT3-T4 and pN+ stages, respectively. Over 90% of the patients received systemic chemotherapy (71% neoadjuvant and 20% adjuvant), and none received immunotherapy. After a median follow-up of 47 months, the 2-year LRFS was significantly higher with adjuvant RT versus observation (87.1% v 76.0%, hazard ratio [HR], 0.43 [95% CI, 0.20 to 0.96], P = .04). The DFS was 71.6% versus 58.7% (HR, 0.62 [95% CI, 0.36 to 1.05]), BCSS was 79.6% versus 65.0% (HR, 0.59 [95% CI, 0.33 to 1.10]), and OS was 70.4% versus 57.4% (HR, 0.78 [95% CI, 0.49 to 1.26]) for RT and Obs, respectively.<br/><br/>CONCLUSION: Adjuvant pelvic IMRT after radical cystectomy and perioperative chemotherapy suggests an improvement in locoregional control in patients with high risk urothelial MIBC with no additional severe toxicity.

    Radiation Curative Phase 3 RCT Challenges SOC