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About · curated by Nick Boehling, MD · @nb2276

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    ARS Appropriate Use Criteria for Locoregionally Recurrent Rectal Cancer

    TL;DRGuideline update, 116 studies: margin-negative (R0) resection determines survival; preop systemic ± RT/reirradiation enables downsizing, no major practice change.

    Why it mattersRadiation oncology

    Reirradiation and preop (chemo)RT are framed as R0-enabling downsizing tools in the previously-irradiated pelvis, not definitive therapy: the guideline holds that margin-negative resection, not RT dose or intensity, is the survival and local-control lever. Moves the reirradiate-to-downstage-before-salvage-surgery decision.

    8 details 5 trials watching
    Methods
    • 🔍 Systematic review with RAND/UCLA modified Delphi consensus; PICOTS + PRISMA; 116 references, Jan 2013-Jul 2025
    • 🔍 Evidence base skews retrospective (116 refs total)
      • 10 well-designed (phase 2 randomized / phase 3)
      • 29 moderately designed (matched cohort / phase 2)
      • 76 retrospective (design limitations)
      • 1 meta-analysis
    • 💊 Preop systemic therapy, RT, or both facilitate tumor downsizing → improve likelihood of R0 resection
    • 🔍 Five PICO questions: surgery, preop/periop therapy, nonoperative management, RT/reirradiation, systemic therapy
    • 🔍 High-res pelvic MRI preferred to map resectability (sidewall, sacral, nerve involvement)
    • 🔍 FDG-PET/CT separates postoperative fibrosis from active recurrent tumor
    Results
    • 📊 Margin-negative (R0) resection is the ultimate determinant of survival and local control
    Critique
    • ⚠️ Updates 2012 ACR AUC; does not suggest major practice change, reaffirms combined-modality therapy
    Open questions
    📚 Sources · 📄 1 paper
    📄 PAPER Miller, Eric D.; Jethwa, Krishan R.; Dozois, Eric et al. · Cancer (2026-06)
    Executive summary of American Radium Society Appropriate Use Criteria for the treatment of locoregionally recurrent rectal cancer
    doi
    Abstract
    Abstract This literature‐based systematic review and associated guidelines provide evidence‐based paradigms for the management of locoregionally recurrent rectal cancer (LRRC). This multispecialty committee included gastrointestinal radiation and medical oncology, gastroenterology, radiology, and colorectal surgery. As is the standard, the previously described American Radium Society Appropriate Use Criteria methodology for this project was followed rigorously, with the Population, Intervention, Comparator, Outcome, Timing, and Study Design framework and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses methodology to assess the evidence. RAND/University of California Los Angeles consensus methodology (modified Delphi) was used to rate the appropriateness of treatment options. Published between January 1, 2013, and July 16, 2025, 116 peer‐reviewed trials provided the evidence: 10 were well‐designed randomized phase 2/3 trials, 29 were moderately well designed trials that accounted for most common biases (matched cohort and phase 2), 76 trials had design limitations (retrospective), and one was a meta‐analysis. Clinical cases were created as examples to illustrate current acceptable management of LRRC. Treatment and prognosis are influenced by prior therapy and the site(s) and extent of LRRC. The ability to achieve a margin‐negative surgical resection is the ultimate determinant of survival and local control. Preoperative systemic therapy, radiation therapy, or a combination of the two can facilitate tumor downsizing and improve the likelihood of a margin‐negative resection. An individualized multidisciplinary approach is required to ensure the best outcome. Although this review does not suggest a major alteration of current practice, it provides reassuring evidence of the importance of combined‐modality therapy.
    📝 https://doi.org/10.1002/cncr.70464

    Combined Curative Consensus / guideline

    Early signal

    INDIBLADE

    ForStage II/III MIBC, cT2-4aN0-2, bladder-preservation candidates

    TL;DR2yr bladder-intact EFS 78% (67-90%) with induction ipi+nivo before chemoRT; 2yr OS 96% in cT2-4aN0-2 MIBC.

    Why it mattersRadiation oncology

    Cohort spans cT2-4a and clinically node-positive (N1-2), pushing bladder preservation into nodal disease that usually routes to cystectomy. The novel lever is induction ipi+nivo before chemoradiation, not the RT itself; 78% 2yr bladder-intact EFS tests whether induction dual-IO belongs in a trimodality pathway. RT dose and fractionation absent from source, so transferability stays unconfirmed.

    7 details 4 trials watching
    Design

    Single-arm bladder-preservation trial: induction dual checkpoint blockade followed by chemoradiation. N and site count not reported in source. Outcomes reported at 2 years.

    Population & inclusion

    Stage II/III MIBC, cT2-4aN0-2. Notably includes clinically node-positive (N1-2) disease, a group usually routed to radical cystectomy.

    Regimen

    Induction ipilimumab + nivolumab (dual IO) before chemoradiation. Doses, cycles, and radiosensitizing chemotherapy not stated in source.

    Radiotherapy

    Chemoradiation is the definitive local component, but RT dose, fractionation, and target volume are not specified in source, gating whether the result transfers to a given practice.

    Endpoints

    Headline readout is 2yr bladder-intact event-free survival; overall survival reported alongside.

    Applies to
    cT2-4aN0-2 MIBC pursuing bladder preservation, including node-positive disease
    Does not represent cT4b/M1 disease or pts unfit for chemoradiation.
    Limitations

    Single-arm, no comparator vs chemoRT alone or cystectomy; short 2yr follow-up; bladder-intact EFS is a composite surrogate; N and RT details absent from source.

    Rationale

    Single-arm, no comparator vs chemoRT alone or cystectomy; 2yr follow-up; bladder-intact EFS a composite surrogate. Hypothesis-generating induction-IO-plus-CRT signal, not yet mature.

    Monday clinic

    In cT2-4aN0-2 MIBC weighing bladder preservation against radical cystectomy, this signals induction ipi+nivo plus chemoradiation is feasible even with node-positive disease, but single-arm 2yr data do not yet displace cystectomy or chemoRT alone off-protocol.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Phase 2 trial Early signal

    KEYNOTE-689 vs NIVOPOSTOP

    TL;DRRound-up of two positive phase 3 IO trials in resectable LA-HNSCC: perioperative pembro and post-op nivo added to adjuvant CRT.

    Trials discussed

    KEYNOTE-689NIVOPOSTOP

    Why it mattersRadiation oncology

    Neither trial changes the RT prescription: both keep standard adjuvant cisplatin-CRT. What moves for the radonc reader is IO placement around that RT course, neoadjuvant pembro before surgery (KEYNOTE-689) versus nivo added to postop CRT (NIVOPOSTOP, 3-yr DFS ~63% vs 53%). The role is integrating IO into unchanged local therapy, not re-planning it.

    vs leading data
    • KEYNOTE-689 = first positive perioperative IO trial in resectable HNSCC in >2 decades (per source)
    5 details 2 trials watching
    Methods
    • 🔍 Both retain standard adjuvant cisplatin-based (chemo)RT; IO is added, RT dose/fractionation/target volume unchanged
    • 💊 KEYNOTE-689: 2 cycles neoadjuvant pembro → surgery → risk-adapted adjuvant RT/CRT + pembro → maintenance pembro
    Results
    • 📊 KEYNOTE-689 vs NIVOPOSTOP at a glance
      FeatureKEYNOTE-689NIVOPOSTOP
      DrugPembrolizumabNivolumab
      IO timingPerioperative (neoadj + adj)Postoperative only
      PopulationResectable stage III-IVAHigh-risk resected (ENE/margin+)
      Control armSurgery → adj RT + cisplatinPostop cisplatin CRT
      Primary EPEFSDFS
      ResultPositive EFS (no value in source)3-yr DFS ~63% vs 53%
    • 📊 NIVOPOSTOP high-risk criteria for postop CRT + nivo
      • Positive margins
      • Extranodal extension (ENE)
      • ≥4 involved nodes
      • Extensive perineural invasion
    Critique
    • ⚠️ Educational round-up, not primary data; KEYNOTE-689 EFS magnitude not reported in source; NIVOPOSTOP is ASCO 2025 abstract-level
    Monday clinic

    In resectable stage III-IVA LA-HNSCC these inform two settings: perioperative pembro for newly-diagnosed resectable disease (KEYNOTE-689), and nivo on postop cisplatin-CRT for high-risk resected pts with extranodal extension or positive margins (NIVOPOSTOP); the RT backbone is unchanged in both.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative

    Confirmatory

    RADIOSA NCT03940235

    ForMetachronous oligorecurrent HSPC, ≤3 lesions, post-radical local tx

    TL;DRmcPFS 32.2 vs 15.1mo, HR 0.43 (0.26-0.72), p=0.001 adding 6mo ADT to metastasis-directed SBRT in oligorecurrent HSPC.

    Surfaced from a review's discussed trials

    Why it mattersRadiation oncology

    Both arms get ablative SBRT (30 Gy/3fx, BED >100 Gy) to all sites, so the trial isolates the 6-mo ADT add-on, not SBRT's own contribution (no observation arm). The decision it moves: whether to layer short ADT onto metastasis-directed SBRT. SBRT alone still gave 15.1-mo cPFS in selected pts.

    Also covered May 17

    8 details 2 trials watching
    Design

    Single-centre, randomised, open-label phase 2 (European Institute of Oncology, Milan). N=105 randomised 1:1 (52 SBRT alone, 53 SBRT+ADT); modified ITT, 51/arm analysed. Median follow-up 31 mo.

    Population & inclusion

    Metachronous oligorecurrent hormone-sensitive prostate cancer after radical local treatment; ≤3 lesions (pelvic/extra-regional nodal or bone) on PSMA-PET or MRI; ECOG 0-1; median age 70. Stratified by PSMA-DT (≤3 vs >3 mo), site (node vs bone), imaging.

    Radiotherapy

    SBRT 30 Gy in 3 fractions every other day (EQD2 98.6 Gy at α/β 1.5, BED >100 Gy), or equivalent by site. All oligometastatic sites treated in both arms.

    Regimen

    The SBRT+ADT arm added 6 months of LHRH-analogue ADT starting within 1 week before SBRT.

    Endpoints

    Primary: clinical progression-free survival. OS and time-to-CRPC were not the primary read.

    Results

    Adding short ADT roughly doubled median cPFS; effect sizes in the results table.

    Safety

    Near-absent RT toxicity: 1 G1 GI, 1 G3 GU (left ureter stenosis, SBRT+ADT), no late effects. ADT added 22 G1 AEs, all resolved. No treatment-related deaths.

    vs leading data

    First RCT of adding short ADT to MDT in metachronous oligorecurrent HSPC. STOMP/ORIOLE established MDT vs observation; RADIOSA instead isolates the ADT add-on onto an SBRT backbone.

    Applies to
    metachronous oligorecurrent hormone-sensitive prostate cancer with ≤3 lesions after radical local treatment
    Does not represent synchronous, polymetastatic (>3 lesions), or castration-resistant disease.
    Limitations

    Single-centre, open-label, N=105. Primary endpoint is clinical PFS, a surrogate; ADT's own progression-delaying effect confounds the SBRT+ADT arm. Optimal ADT duration untested.

    Rationale

    Single-centre open-label phase 2, N=105; 1° EP is clinical PFS (surrogate), not OS. Consistent with STOMP/ORIOLE MDT signals; not definitive enough to change practice.

    Monday clinic

    In metachronous oligorecurrent hormone-sensitive prostate cancer with ≤3 lesions on PSMA-PET, this supports adding 6 mo ADT to metastasis-directed SBRT for longer cPFS; it does not address synchronous or polymetastatic disease, and SBRT alone remains reasonable in carefully selected pts.

    Open questions
    📚 Sources · 📄 1 paper
    📄 PAPER Marvaso; Corrao; Zaffaroni et al. · The Lancet. Oncology (2025-03)
    ADT with SBRT versus SBRT alone for hormone-sensitive oligorecurrent prostate cancer (RADIOSA): a randomised, open-label, phase 2 clinical trial.
    PMID 40049196 → doi
    Abstract
    BACKGROUND: Metastasis-directed therapy by stereotactic body radiotherapy (SBRT) has been shown to improve clinical outcomes in the oligometastatic prostate cancer setting. We aimed to investigate whether short-course androgen deprivation therapy (ADT) and SBRT at all oligometastatic sites versus SBRT alone improves clinical progression-free survival in men with metachronous oligorecurrent hormone-sensitive prostate cancer.<br/><br/>METHODS: The RADIOSA study was a single-centre, randomised, open-label, controlled phase 2 trial done in the European Institute of Oncology, IRCCS, Milan, Italy. Key eligibility criteria were histologically proven initial diagnosis of adenocarcinoma of the prostate, biochemical progression after radical local prostate treatment, nodal relapse in the pelvis, extra-regional nodal relapse, bone metastases at next-generation imaging with a maximum of three lesions, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and age 18 years or older. Participants were stratified according to prostate-specific membrane antigen doubling time (&#x2264;3 vs >3 months), metastases localisation (node vs bone), and diagnostic imaging (positron emission tomography vs MRI) and were randomly assigned (1:1) using a computer-generated random number to SBRT alone or SBRT in combination with 6 months of ADT. For SBRT treatment, a schedule of 30 Gy in three fractions every other day (with the equivalent dose in 2 Gy fractions being 98&#xb7;6 Gy, considering &#x3b1;/&#x3b2; ratio of 1&#xb7;5 Gy and biologically effective dose of >100 Gy), or equivalent regimens depending on disease site location, was administered. Patients in the SBRT with ADT group received 6 months of ADT with a luteinising hormone-releasing hormone analogue within 1 week before the start of SBRT. The allocated treatment was not masked. The primary outcome measure was clinical progression-free survival. All analyses followed a modified intention-to-treat principle, consisting of all patients assigned to a treatment group who had available data. The trial is registered at ClinicalTrials.gov, NCT02680587, and is complete.<br/><br/>FINDINGS: Between Aug 1, 2019, and April 30, 2023, 218 patients were assessed for eligibility, 113 were excluded, and 105 were enrolled and randomly assigned to an intervention (52 to SBRT only and 53 to SBRT with ADT). Three patients were lost to follow-up and 51 patients in each group were assessed for the primary outcome. The median age at study enrolment was 70 years (IQR 65-75); data on race and ethnicity were not collected. With a median follow-up of 31 months (IQR 16-36) for both groups, the median clinical progression-free survival was 15&#xb7;1 months (95% CI 12&#xb7;4-22&#xb7;8) for the SBRT group versus 32&#xb7;2 months (22&#xb7;4-not reached) for the SBRT with ADT group (hazard ratio 0&#xb7;43 [95% CI 0&#xb7;26-0&#xb7;72], p=0&#xb7;0010]). One gastrointestinal grade 1 adverse event (SBRT group) and one genitourinary grade 3 adverse event (left ureter stenosis, SBRT with ADT group) were reported, with no late toxicities observed. 22 grade 1 ADT-related adverse events were reported, all of which had resolved at the last follow-up. No treatment-related deaths were recorded.<br/><br/>INTERPRETATION: To our knowledge, the RADIOSA trial represents the first randomised trial in the metachronous oligometastatic hormone-sensitive prostate cancer setting to report improved clinical progression-free survival with the combination of SBRT and a short course of ADT, although carefully selected patients might still benefit from SBRT alone. By demonstrating improved clinical progression-free survival, the RADIOSA trial reinforces the role of metastasis-directed therapy in delaying systemic treatment escalation. Additionally, it underscores the need for further studies to determine the optimal duration of ADT and identify biomarkers predicting response to SBRT alone.<br/><br/>FUNDING: Italian Association of Cancer Research.
    📝 Auto-resolved from a review's discussed trials (RADIOSA).

    Combined Phase 2 trial Confirmatory

    Concurrent Systemic Therapy + Radiation Timing (Speers)

    TL;DRTraffic-light framework for what runs concurrent with breast/CW + RNI RT vs hold: continue endocrine + trastuzumab/pertuzumab, caution T-DXd/CDK4/6i, hold cytotoxics/PARPi.

    Trials discussed

    HERANCCTG N9831APHINITYKATHERINEATEMPTDESTINY-Breast05COMBARTKEYNOTE-522

    Why it mattersRadiation oncology

    The actionable RT read: in the DESTINY-Breast05 arm, T-DXd ILD was 10.7% sequential vs 9.6% concurrent, so timing around RT did not change ILD, and concurrency is reasonable with lung-dose limits. The 'do not ignore' signal is T-DM1 plus CNS SRS radionecrosis; hold CDK4/6i for large fields.

    Concurrent Systemic Therapy + Radiation Timing (Speers)
    +1 more figure
    Concurrent Systemic Therapy + Radiation Timing (Speers)
    7 details 3 trials watching
    Design

    ASCO 2026 educational review / Educational Book chapter (Wong, Speers, Schaverien, Table 5). Sorts systemic agents into a continue / caution / hold framework for concurrency with breast/chest-wall + RNI RT. Evidence base is mostly retrospective, post-hoc, or small prospective series.

    Radiotherapy

    Context is adjuvant breast/CW + regional nodal irradiation. Plan features that raise the concurrency stakes: large lung volumes, IMN coverage, bolus, reconstruction, and CNS SRS (T-DM1 radionecrosis, T-DXd ILD).

    Discussion

    Endocrine therapy and trastuzumab/pertuzumab are safe concurrent; T-DXd and CDK4/6i are plan-dependent; cytotoxics, veliparib, and capecitabine sequence. Default outside protocol is PK-based washout, then RT, then resume.

    Results
    Agent classWith RTNotes / evidence
    Endocrine therapyContinueminimal radiosensitization
    Trastuzumab ± pertuzumabContinueconcurrent standard (HERA, NCCTG N9831, APHINITY)
    T-DM1Continueper KATHERINE / ATEMPT; watch dermatitis, pneumonitis, CNS SRS necrosis
    T-DXdCautionILD dominant; sequence/hold for high lung-dose or active pulmonary disease
    PembrolizumabContinue, monitorKEYNOTE-522 concurrent tolerated; pneumonitis vigilance
    CDK4/6i (palbo/ribo/abema)Hold large fieldsmostly retrospective; concurrent only in protocol
    OlaparibSequencecomplete RT 2-12 wks before; RadioPARP suggests concurrent safety
    Veliparib / talazoparibAvoid concurrentveliparib severe acute/late tox (TBCRC 024)
    CapecitabineHold / sequenceadjuvant paradigm sequential (CREATE-X)
    Cytotoxics (anthracycline/taxane/platinum)Holdsequence, do not give concurrently
    MetricValue
    ILD, T-DXd 5.4 mg/kg (PI)~12%; fatal ~0.9%
    DESTINY-Breast05 ILD9.6% T-DXd vs 1.6% T-DM1
    RT timing (T-DXd arm)10.7% seq vs 9.6% concurrent, no effect
    COMBART concurrent RT/SRT40 pts; acute tox 20%
    Monday clinic

    For a HER2+ patient on adjuvant trastuzumab/pertuzumab or T-DM1 needing chest-wall + nodal RT, this supports running HER2 therapy through RT with pneumonitis and CNS-SRS vigilance; it does not extend to concurrent cytotoxics, veliparib, or CDK4/6i in large fields.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative ASCO Annual Meeting 2026

    Challenges SOC

    mRCAT-III NCT06507371

    ForpMMR/MSS LARC, cT3-4N0/+, tumor ≤10cm from verge, no lateral node

    Pathologic complete response surrogate

    61.0% vs 28.6%

    P<0.0001, ITT, blinded central review

    TL;DRpCR 61.0% vs 28.6% (P<0.0001) with node-sparing SCRT + tislelizumab + CAPOX vs conventional SCRT + CAPOX in pMMR LARC.

    Why it mattersRadiation oncology

    The RT read is a confound, not a green light for nodal omission: the experimental arm changed two things at once, tumor-bed-only targeting AND added tislelizumab, so node-sparing's own contribution to the pCR doubling (61.0% vs 28.6%) can't be isolated. Node-sparing plausibly drove the lower severe-GI toxicity, but this doesn't yet license dropping elective nodal RT.

    mRCAT-III
    EndpointExperimentalControlP
    pCR (ITT)61.0% (47/77)28.6% (22/77)<0.0001
    MPR (TRG0+1)77.9% (60/77)50.6% (39/77)<0.0001
    +1 more figure
    mRCAT-III
    6 details 5 trials watching
    Design

    Open-label, multicenter phase 3 RCT across 17 China hospitals; randomized 1:1, 77 pts per arm, stratified by clinical N stage (cN0 vs cN+). Primary pCR read by blinded independent central review.

    Population & inclusion

    pMMR/MSS rectal adenocarcinoma, cT3-4N0/+M0, tumor lower edge ≤10cm from the anal verge, ECOG 0-1, age 18-75, no positive lateral pelvic node.

    Regimen

    Both arms CAPOX (oxaliplatin 130mg/m² d1, capecitabine 1000mg/m² d1-14). Experimental adds tislelizumab 200mg d1; control is chemo + RT only.

    Radiotherapy

    Both arms short-course 5Gy×5. Experimental is node-sparing (tumor bed only, spares tumor-draining nodes); control is conventional elective-nodal coverage. This target-volume contrast is the RT question.

    Endpoints

    Primary: pCR (ITT). Secondary: MPR, TRG, organ-preservation rate, EFS, OS, AEs.

    Results

    Primary pCR and secondary MPR both favored the experimental arm (see figure); EFS, OS, organ-preservation not reported in source.

    Safety

    Experimental arm reported fewer severe GI AEs (author takeaway), plausibly from the smaller node-sparing volume; numeric AE rates not in source.

    vs leading data

    Control pCR 28.6% matches short-course RT + consolidation chemo benchmarks (RAPIDO ~28%). The novelty is a PD-1 benefit in an MSS population usually IO-refractory, with nodal-RT omission as the immunologic rationale.

    Applies to
    pMMR/MSS cT3-4 LARC with tumor ≤10cm from the anal verge and no positive lateral node
    Does not represent dMMR/MSI-H disease, upper-rectal or colon primaries, or patients needing lateral pelvic nodal treatment.
    Limitations

    Open-label; pCR is a surrogate with EFS/OS immature; the experimental arm confounds node-sparing target volume with added tislelizumab, so the RT-attributable effect can't be isolated; N=154, single country.

    Rationale

    Divergent MSS-rectal result from a randomized P3 with blinded-review primary; kept off practice-changing because pCR is a surrogate (EFS/OS immature) and node-sparing is confounded with added tislelizumab.

    Monday clinic

    In pMMR/MSS LARC (cT3-4, tumor ≤10cm from verge), this is a trial-stage signal that neoadjuvant PD-1 may help an IO-resistant group; it does not extend to dMMR disease and does not yet displace conventional elective-nodal short-course RT off-protocol.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Phase 3 RCT Challenges SOC ASCO Annual Meeting 2026

    Confirmatory

    CAN-2409 NCT01436968

    ForIntermediate or high-risk localised prostate cancer, EBRT candidates

    TL;DRDFS HR 0.70 (0.52-0.94, p=0.016) adding intraprostatic CAN-2409 to EBRT in intermediate/high-risk localised prostate; OS and PCSM immature.

    Why it mattersRadiation oncology

    The RT read is local control: 2yr biopsy positivity fell 36.4% to 19.6% (p=0.0015), comparable to adding ADT (RTOG 9408) but on standard 78Gy without a brachy or SIB boost. Whether it adds over modern dose-intensification plus ADT is the open integration question, since ADT was optional and no boost was used.

    CAN-2409
    EndpointCAN-2409PlaceboHR / p
    DFS medianNR86.1 moHR 0.7 (0.52-0.94), p=0.0155
    2yr biopsy pCR80.4%63.6%n/a
    2yr local recurrence19.6%36.4%p=0.0015
    +1 more figure
    CAN-2409
    TrialIntensifierLocal endpoint: control → intensified
    RTOG 9408+4mo ADT2yr biopsy+ 40% → 20%
    ASCENDE-RTLDR brachy boost10y local failure 7.1% → 1.5%
    FLAMESIB 95GyCrude local failure 7.7% → 2.7%
    CAN-2409+CAN-24092yr biopsy+ 36.4% → 19.6%
    8 details
    Design

    Phase 3, double-blind, placebo-controlled RCT, 2:1 randomisation, N=745 across 51 US and Puerto Rico centres. Median follow-up 50.3 mo.

    Population & inclusion

    Intermediate or high-risk localised prostate cancer, ECOG 0-2, planned for EBRT. Stratified by risk category and ADT use. 79% White, 16% Black.

    Radiotherapy

    EBRT 78 Gy/2 Gy, or hypofractionated 60 Gy/3 Gy or 70 Gy/2.5 Gy. ADT optional. No dose-escalation or brachytherapy boost mandated.

    Regimen

    Three intraprostatic aglatimagene injections (5×10^11 viral particles) plus valacyclovir prodrug, versus placebo plus valacyclovir.

    Endpoints

    Primary: disease-free survival (recurrence or death, ITT). Secondary/exploratory: OS, PCSM, 2-year post-RT biopsy pathologic response.

    Results

    Primary met: DFS favoured aglatimagene; OS and PCSM immature, not significantly different. Arm-by-endpoint values in the results figure.

    Event (G3+)AglatimagenePlacebo
    Any TEAE8% (40/479)7% (17/232)
    Acute kidney injury2% (9/479)2% (4/232)
    Serious AEs6% (28/479)7% (17/232)
    Safety

    Grade 3+ TEAEs 8% vs 7%; most common acute kidney injury (2% both arms). Serious AEs 6% vs 7%. No treatment-related deaths.

    vs leading data

    Discussant benchmarked the biopsy-positivity gain against ADT (RTOG 9408), brachytherapy boost (ASCENDE-RT), and SIB (FLAME) as established local-control intensifiers.

    Applies to
    intermediate or high-risk localised prostate cancer treated with definitive EBRT
    Does not represent post-prostatectomy, salvage, or metastatic disease.
    Limitations

    DFS is a composite surrogate; OS and PCSM immature. ADT optional, no boost mandated, confounding added value over modern intensification. Accrual (2012-2021) predates PSMA staging.

    Rationale

    Positive phase 3 primary (DFS) but on a surrogate/composite; OS and PCSM immature (1 event/arm). Additive benefit over modern dose-intensification plus ADT unproven.

    Monday clinic

    In intermediate or high-risk localised prostate cancer planned for definitive EBRT, this informs whether an added intraprostatic biologic could improve local control; it does not extend to post-prostatectomy, salvage, or metastatic settings.

    Open questions
    • Does the local-control gain add over modern dose-escalation and ADT?
    • Do DFS and pCR gains translate to overall or cancer-specific survival?
    • Optimal ADT and RT-intensification pairing with intraprostatic CAN-2409
    📚 Sources · 🐦 1 tweet · 📄 1 paper
    📄 PAPER DeWeese, Theodore L; Manzanera, Andrea; Sylvester, John et al. · The Lancet Oncology (2026-06)
    Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial
    doi
    Abstract
    Background About 30% of men with localised prostate cancer undergoing radiotherapy with curative intent have disease recurrence associated with progression-related symptoms and substantial toxicity of salvage therapies. Previous studies with aglatimagene besadenovec (CAN-2409, hereafter referred to as aglatimagene) showed synergy with radiation and immune-mediated cytotoxicity in patients with prostate cancer. We aimed to assess whether addition of aglatimagene plus prodrug (valacyclovir) to standard-of-care external beam radiation therapy (EBRT) could improve disease-free survival in this population. Methods We conducted a phase 3, randomised, double-blind, placebo-controlled trial at 51 medical centres (26 community and 25 institutional or military) across the USA and Puerto Rico in patients with intermediate or high-risk prostate cancer. Patients aged at least 18 years who were planning to undergo EBRT and with an Eastern Cooperative Oncology Group score of 0-2 were eligible. Patients were randomly assigned (2:1) via central block-randomisation to receive either three courses of intraprostatic aglatimagene (5 × 10 11 viral particles) plus valacyclovir or placebo plus valacyclovir, with randomisation stratified by risk category and androgen deprivation therapy (ADT) use. Patients received standard-of-care EBRT (78 Gy in 2 Gy fractions) or hypofractionated EBRT (60 Gy in 3 Gy fractions or 70 Gy in 2·5 Gy fractions) with optional ADT. The primary endpoint was disease-free survival, defined as time-from-randomisation to prostate cancer recurrence or death in the intent-to-treat population (all randomly assigned patients). Safety was assessed in all individuals who received at least one injection. The trial is registered at ClinicalTrials.gov, NCT01436968, and long-term follow-up is ongoing. Findings Between Feb 21, 2012, and Sept 9, 2021, 745 men (591 [79%] White, 121 [16%] Black) were randomly assigned to receive aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249). After a median follow-up of 50·3 months (IQR 35·2-63·3), median disease-free survival was not reached (95% CI 121·78 to not reached) in the aglatimagene plus valacyclovir group versus 86·1 (IQR 29·7-143·0) months in the placebo plus valacyclovir group (hazard ratio 0·70, 95% CI 0·52-0·94; p=0·016). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 40 (8%) of 479 patients in the aglatimagene group and 17 (7%)of 232 patients in the placebo group. The most common TEAE of grade 3 or worse was acute kidney injury in both the aglatimagene group (nine [2%] of 479 patients) and the placebo group (four [2%] of 232 patients). Serious adverse events occurred in 28 (6%) of 479 patients in the aglatimagene group and 17 (7%) of 232 in the placebo group. Treatment-related serious adverse events occurred in eight (2%) patients in the aglatimagene group (four acute kidney injury, two pyrexia, and one each influenza-like symptoms and urinary retention) and five (2%) in the placebo group (four acute kidney injury, and one each increased creatinine levels and skin rash; one patient reported two serious adverse events). No treatment-related deaths were reported. Interpretation Aglatimagene plus valacyclovir was associated with longer disease-free survival than placebo plus valacyclovir when added to standard of radiotherapy for the treatment of localised prostate cancer, offering a meaningful benefit without increasing clinically significant toxicity. Funding Candel Therapeutics and US National Institutes of Health.
    📝 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(26)00071-9/fulltext

    Combined Curative Phase 3 RCT Confirmatory

    Early signal

    MIRACLE-2

    For1L unresectable MSS rectal cancer, synchronous liver/lung mets

    TL;DR68% ORR, mOS 23.2mo, 18% NED with RT-primed chemo + tislelizumab in MSS unresectable met rectal ca.

    Why it mattersRadiation oncology

    The RT-relevant read is technique: HFRT to the primary plus HFRT/SBRT to mets, delivered first to prime immunity, but no dose or fractionation in source, so it doesn't transfer to practice yet. 18% (9/50) converted to NED via resection or watch-and-wait. Near-universal lymphopenia (95.9% all-grade, 36.7% G3/4) undercuts a strategy premised on RT-driven T-cell activation.

    MIRACLE-2
    Metricn (%)95% CI
    CR1 (2.0%)
    PR33 (66.0%)
    SD10 (20.0%)
    PD6 (12.0%)
    ORR34 (68.0%)53.6-80.0%
    DCR44 (88.0%)76.0-95.2%
    ETS38 (76.0%)62.4-86.8%
    9 details 2 trials watching
    Design

    Prospective single-arm phase I, N=50, Fudan University Shanghai Cancer Center. Data cutoff Dec 31 2025; median follow-up 19.9 mo (95% CI 16.4-23.4).

    Population & inclusion

    MSS rectal cancer, primary ≤10cm from anal verge, synchronous unresectable mets. 76% male, median age 57; 52% liver, 8% lung, 40% both; RAS/BRAF-mut 56%.

    Radiotherapy

    RT delivered first as an immune primer: HFRT to the primary, HFRT or SBRT to metastases. Dose, fractionation, and target volumes not reported in source.

    Regimen

    Post-RT, biomarker-gated: FOLFOX-bevacizumab-tislelizumab (RAS/BRAF-mut) or FOLFIRI-cetuximab-tislelizumab (WT); tislelizumab 200mg Q2W. Resection/metastasectomy if converted, watch-and-wait if primary cCR.

    Endpoints

    Primary: ETS rate (≥20% target shrinkage at 8wk). Secondary: DCR, DOR, OS, PFS, safety.

    Results

    ETS 76.0%, ORR 68.0%, DCR 88.0%; 18% (9/50) reached NED. Median OS 23.2mo, PFS 9.3mo, DOR 8.0mo (endpoints in table).

    EndpointMedian95% CI1-yr rate
    OS23.2 mo15.1-31.393.3%
    PFS9.3 mo7.1-11.533.4%
    DOR (n=34)8.0 mo5.2-10.820%
    Applies to
    treatment-naive MSS rectal cancer with synchronous unresectable liver/lung metastases
    Does not represent MSI-H tumors, resectable disease, or non-rectal colorectal primaries.
    Limitations

    Single-arm phase I, N=50, no comparator to isolate RT's contribution. Surrogate primary (ETS at 8wk), short median DOR (8mo), and near-universal lymphopenia (95.9%).

    Rationale

    Single-arm phase I, N=50; surrogate primary (ETS at 8wk); no comparator to isolate RT's contribution to the immune-priming effect.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Phase 1 Early signal

    Caveats dominate

    OCEANUS

    ForAdvanced/refractory NSCLC on immunoradiotherapy, median age 64, 74% male

    TL;DRSequential iRT beat concurrent for real-world OS in newly-dx advanced NSCLC: median 20.3 vs 16.0 mo, HR 0.68 (0.47-0.99), P=.045.

    Why it mattersRadiation oncology

    Sequential iRT (ICI and RT not overlapping) beat concurrent for real-world OS in newly-dx advanced NSCLC, HR 0.68 (0.47-0.99), P=.045, favoring temporal separation of RT from ICI. RT dose, fractionation, and target volume aren't in the source, so the signal can't yet transfer to a specific plan. The refractory RT+ICI-maintenance read was NS (P=.20).

    7 details 1 trial watching
    Design

    Territory-wide real-world cohort (OCEANUS, Hong Kong CDARS, >90% population coverage); NSCLC diagnosed 2010-2021 who received iRT. Overlap-weighting propensity score primary, IPTW sensitivity; landmark-based OS with weighted Kaplan-Meier and Cox (restricted mean survival time where PH violated).

    Population & inclusion

    335 of 3522 ICI-treated pts received RT: 155 newly-dx advanced, 180 refractory. Median age 64 (34-90), 73.7% male. Refractory analysis required survival ≥90 days (landmark).

    Radiotherapy

    RT dose, fractionation, modality, and target volume not reported in source. The variable studied is timing of RT relative to ICI (sequential vs concurrent), not technique.

    Results

    Both comparisons favored the sequential / ICI-maintenance arm (magnitudes in table). Chemotherapy was associated with longer OS in newly-dx pts only; not significant in refractory disease.

    Setting / comparisonExperimental OSControl OSHR / P value
    Newly-dx advanced, sequential vs concurrent iRT20.3 mo (95% CI 13.3-NR)16.0 mo (95% CI 8.3-30.0)HR 0.68 (0.47-0.99), P=.045
    Refractory, RT + ICI maintenance vs RT alone11.2 mo (95% CI 7.9-20.6)6.7 mo (95% CI 4.4-17.4)P=.20 (ns)
    vs leading data

    Randomized data on iRT sequencing in advanced NSCLC are limited (stated by authors). RT-before-ICI direction is consistent with the PACIFIC consolidation paradigm, but PACIFIC treated curative-intent unresectable stage III with concurrent chemoRT, a different population.

    Applies to
    advanced or refractory NSCLC receiving immunoradiotherapy, predominantly male, median age 64
    Does not represent curative-intent stage III chemoRT, oligometastatic, or ICI-treated patients who did not receive RT.
    Limitations

    Observational: sequential vs concurrent not randomized, residual confounding by indication despite weighting. Small subgroups (155 newly-dx). Refractory comparison non-significant (P=.20).

    Rationale

    Observational real-world cohort; sequential-vs-concurrent not randomized, confounding by indication despite propensity weighting. Small subgroups (155 newly-dx). Authors label it hypothesis-generating.

    Monday clinic

    In newly-diagnosed advanced NSCLC starting immunoradiotherapy, this real-world signal supports separating RT from ICI in time rather than delivering them concurrently; it does not extend to refractory disease, where the RT-plus-ICI-maintenance benefit was not significant.

    Open questions
    📚 Sources · 📄 1 paper
    📄 PAPER Zhou; Wang; Lee et al. · JAMA oncology (2026-05)
    Combination of Radiotherapy and Immunotherapy in Advanced Non-Small Cell Lung Cancer.
    PMID 41885834 → doi full text (PMC)
    Abstract
    IMPORTANCE: The optimal sequencing of radiotherapy (RT) combined with immunotherapy (iRT) and the value of chemotherapy remain undefined for advanced non-small cell lung cancer (NSCLC), where randomized data are limited.<br/><br/>OBJECTIVE: To compare real-world overall survival (OS) between sequential and concurrent iRT in newly diagnosed advanced NSCLC, assess the effect of immune checkpoint inhibitor (ICI) maintenance after RT in refractory disease, and evaluate the association of chemotherapy with survival.<br/><br/>DESIGN, SETTING, AND PARTICIPANTS: This is a territory-wide study (OCEANUS) based on the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (more than 90% population coverage). Patients with NSCLC diagnosed from January 1, 2010, to December 31, 2021, who subsequently received iRT for advanced or refractory disease were included. Overlap weighting was the primary propensity score-weighted method, with inverse probability of treatment weighting used for sensitivity analysis. Data were analyzed from December 2024 to April 2025.<br/><br/>EXPOSURES: Sequential vs concurrent iRT for newly diagnosed advanced NSCLC; RT with vs without ICI maintenance for refractory NSCLC; receipt of chemotherapy.<br/><br/>MAIN OUTCOMES AND MEASURES: The primary outcome was real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. When proportional hazards were violated (per Schoenfeld residuals), treatment effects were summarized using restricted mean survival time.<br/><br/>RESULTS: Of 3522 patients who received ICIs, 335 received RT, including 155 with newly diagnosed advanced and 180 with refractory NSCLC. Of these, 247 (73.7%) were male, and the median (range) age was 64 (34-90) years. In newly diagnosed NSCLC, patients treated with sequential iRT had significant longer real-world OS than those treated with concurrent iRT (median, 20.3 months [95% CI, 13.3 to not reached] vs 16.0 months [95% CI, 8.3-30.0]; adjusted hazard ratio, 0.68; 95% CI, 0.47-0.99; P&#x2009;=&#x2009;.045). Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. In refractory NSCLC, RT with ICI maintenance was associated with a numerically longer median real-world OS (11.2 months [95% CI, 7.9-20.6] vs 6.7 months [95% CI, 4.4-17.4]; P&#x2009;=&#x2009;.20). Addition of chemotherapy was not significant for real-world OS. Inverse probability of treatment weighting analyses produced similar estimates.<br/><br/>CONCLUSIONS AND RELEVANCE: In this cohort study, sequential iRT was associated with longer survival than concurrent iRT in patients with newly diagnosed advanced NSCLC, and chemotherapy was associated with longer survival. In patients with refractory NSCLC who survived at least 90 days, RT with ICI maintenance resulted in nonsignificantly longer survival and an unclear association with chemotherapy. These findings are hypothesis generating and support prospective randomized studies to define optimal sequencing of iRT and use of systemic treatment partners.
    📝 https://jamanetwork.com/journals/jamaoncology/fullarticle/2847148?guestAccessKey=6284363c-f1dd-46da-aa0e-8528e5ecca06&utm_source=twitter&utm_medium=social_jamaonc&utm_term=20674463146&utm_campaign=article_alert&linkId=952727864

    Combined Palliative Real-world evidence Caveats dominate

    Early signal

    RAD-IO

    ForT2-T4a N0M0 muscle-invasive urothelial bladder cancer

    TL;DR12-mo DFS 40/50 (80%, 95% CI 0.67-0.89) cleared the pre-set ≥75% GO bar for durvalumab added to 5FU/MMC chemoRT in MIBC.

    Why it mattersRadiation oncology

    RT is standard and transferable: 55Gy/20fx to bladder, plus 46Gy/20fx elective nodal coverage in the node-positive expansion, extending durvalumab-chemoRT preservation to N+ disease. 12-mo DFS 80% (40/50, 95% CI 0.67-0.89) cleared the pre-set ≥75% GO bar vs BC2001. Moves whether to layer IO onto a hypofractionated preservation backbone.

    RAD-IO
    +1 more figure
    Durvalumab (N=54): completed planned treatment 33 (61%), discontinued early 21 (39%).
    Durvalumab (N=54): completed planned treatment 33 (61%), discontinued early 21 (39%).
    8 details 4 trials watching
    Design

    Single-arm, multi-stage feasibility and safety trial testing durvalumab added to 5FU/MMC chemoradiation for bladder preservation. Benchmarked against BC2001 historical CRT data, not a randomised comparator.

    Population & inclusion

    T2-T4a N0M0 urothelial muscle-invasive bladder cancer, stratified by prior neoadjuvant chemotherapy (yes vs no). A stage-1 expansion added the first 6 node-positive pts.

    Regimen

    Durvalumab 1500 mg given neoadjuvant, synchronous, and adjuvant to 12 months post-chemoRT. Concurrent 5-FU 500 mg/m²/24h ×5 days and mitomycin C 12 mg/m².

    Radiotherapy

    55 Gy in 20 fractions to bladder (hypofractionated). Node-positive expansion added 46 Gy/20 fx elective nodal RT.

    Endpoints

    Primary: 12-month disease-free survival post-chemoRT, read against a GO/NO-GO framework (GO ≥75%, contextual 60-75%, NO-GO <60%).

    Results

    12-mo DFS 40/50 (80%), 95% CI 0.67-0.89, clearing the ≥75% GO bar. 33/54 (61%) completed planned durvalumab; investigators reported very high bladder-preservation and DFS vs prior trial data.

    Safety

    AEs reported in line with component therapies (chemoRT plus durvalumab). 21/54 (39%) discontinued durvalumab early.

    vs leading data

    Benchmarked against BC2001 (James, JCO 2016), where adding 5FU/MMC to RT gave DFS HR 0.78 (0.60-1.02), p=0.07. RAD-IO's 80% 12-mo DFS is claimed higher than prior data, but the comparison is non-randomised.

    Applies to
    T2-T4a N0M0 muscle-invasive urothelial bladder cancer suitable for bladder-preservation chemoRT
    Does not represent metastatic disease, radical-cystectomy-preferred pts, or node-positive disease beyond the 6-patient expansion.
    Limitations

    Single-arm with a historical benchmark and no concurrent IO comparator; 12-mo DFS is an early surrogate; small N (~50 evaluable); node-positive experience limited to 6 pts.

    Rationale

    Single-arm feasibility stage, no randomised IO comparator; benchmarked against historical BC2001. 12-mo DFS an early surrogate at small N; met pre-set GO bar for further evaluation only.

    Monday clinic

    In T2-T4a N0M0 MIBC opting for bladder preservation, this supports durvalumab layered onto 5FU/MMC chemoRT as worth further evaluation; it does not yet establish that IO improves on chemoRT alone, and node-positive experience rests on only 6 expansion pts.

    Open questions
    📚 Sources · 🐦 3 tweets

    Combined Curative Phase 2 trial Early signal ASCO Annual Meeting 2026

    Management of MIBC After Pathologic Complete Response

    TL;DRReview of perioperative MIBC management after pCR: sandwich IO regimens continue adjuvant regardless of response, cisplatin-chemo alone moves to surveillance.

    Trials discussed

    SWOG 8710ABACUSCHECKMATE-274KEYNOTE-905VOLGANIAGARAVESPERKEYNOTE-B15

    Overall survival: HR 0.50.
    Overall survival: HR 0.50.
    8 details 3 trials watching
    Methods
    • 🔍 pCR used as primary endpoint in signal-seeking phase 2 trials
    • 🔍 pCR co-primary (not standalone) endpoint in phase 3 registrational trials
    • 🔍 High-risk residual disease (≥ypT2 or N+) post-neoadjuvant chemo → adjuvant therapy (CHECKMATE-274)
    • 💊 Post-pCR management by regimen
      • Sandwich IO (NIAGARA, EVP): continue planned adjuvant regardless of pathologic response
      • NIAGARA: resume durvalumab 8 mo post-cystectomy
      • Cisplatin-based chemo alone: surveillance after pCR is standard
    Results
    • 📊 pCR (pT0N0) post-neoadjuvant chemo = strong prognostic marker: SWOG 8710 85% 5-yr OS if pT0
    • 📐 Meta-analysis: pooled RR 0.19 for RFS with pCR
    • 📊 Perioperative regimens across trials
      TrialSettingComparisonResult
      NIAGARACis-eligibleGem/Cis + periop durvalumab24-mo OS 82.2% vs 75.2%
      VESPERCis-eligibleddMVAC vs Gem/Cis5-yr OS 66% vs 57%
      KEYNOTE-905Cis-ineligiblePeriop EVP vs cystectomy aloneOS HR 0.50
      KEYNOTE-B15Cis-eligiblePeriop EVP vs Gem/CisOS improved (under FDA review)
    Critique
    • ⚠️ Not all pts in perioperative trials completed adjuvant therapy, often due to toxicity
    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative ASCO Annual Meeting 2026

    Challenges SOC

    Neo-CRAG

    ForHigh-risk locally advanced gastric/EGJ (cT3N2-3 to cT4), fit for D2 resection

    Disease-free survival surrogate

    mDFS 52.7 vs 24.4 mo

    HR 0.750 (95% CI 0.607-0.928), P=0.008

    TL;DRAdding neoadjuvant chemoRT (45Gy/25fx) to periop XELOX improved mDFS 52.7 vs 24.4mo (HR 0.75) and mOS 67.5 vs 37.6mo in high-risk LAGC.

    Why it mattersRadiation oncology

    The RT read is clean attribution: both arms share the XELOX backbone and the CRT arm got dose-reduced chemo during RT, yet locoregional recurrence halved (9.4% vs 18.3%) with more ypN0 and downstaging. On 45Gy/25fx, this revives neoadjuvant chemoRT for high-risk D2-resected gastric/EGJ, on a non-FLOT backbone.

    Neo-CRAG
    EndpointCRTCTHR (95% CI), P
    Median DFS52.7 mo24.4 mo0.750 (0.607-0.928), P=0.008
    3-yr DFS55.6%42.4%—
    Median OS67.5 mo37.6 mo0.781 (0.628-0.970), P=0.025
    5-yr OS50.1%44.2%—
    7 details 2 trials watching
    Design

    Phase 3 open-label RCT, 1:1, N=620 (310/arm), 13 Chinese referral centers, enrolled 2013-2022. Primary: disease-free survival; secondary OS, pCR, R0, safety.

    Population & inclusion

    High-risk locally advanced gastric/EGJ adenocarcinoma: cT3N2-3M0, cT4aN+M0, or cT4bNanyM0; 36.3% EGJ (Siewert II/III). All planned standardized D2 gastrectomy.

    Regimen

    Both arms: 3 cycles preoperative + 3 cycles adjuvant XELOX (oxaliplatin 130, capecitabine 1000 BID D1-14, Q3W) around D2 gastrectomy.

    Radiotherapy

    CRT arm only: concurrent 45 Gy/25 fx begun after chemo cycle 1, with dose-reduced XELOX (oxaliplatin 100, capecitabine 825) during RT. RT is the sole added variable between arms.

    Results

    Primary DFS met and secondary OS positive, both favoring CRT; pathologic downstaging, ypN0, and locoregional control also improved (see figure and table).

    vs leading data

    Contrasts with CRITICS and TOPGEAR, where adding radiotherapy to a chemo backbone did not improve survival. A positive DFS/OS here reopens neoadjuvant chemoRT in high-risk, D2-resected LAGC.

    Applies to
    high-risk locally advanced gastric/EGJ (Siewert II/III) adenocarcinoma, cT3N2-3 to cT4b, fit for D2 gastrectomy on a XELOX backbone
    Does not represent FLOT-backbone, metastatic, or Western populations with lower D2-resection rates.
    Limitations

    Open-label; non-FLOT XELOX backbone limits transfer to current perioperative standard. Single-country (China) with high D2-resection quality; DFS (not OS) was the primary endpoint.

    Rationale

    Randomised phase 3, primary DFS and OS both hit, but positive chemoRT diverges from negative CRITICS/TOPGEAR; non-FLOT XELOX backbone limits transfer to current SOC.

    Monday clinic

    In high-risk cT3N2-3/cT4 gastric or EGJ adenocarcinoma planned for D2 gastrectomy on a XELOX backbone, these data support a DFS/OS and locoregional-control benefit from adding neoadjuvant chemoRT; the signal does not extend to FLOT-backbone or metastatic patients.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Phase 3 RCT Challenges SOC ASCO Annual Meeting 2026

    Confirmatory

    SWOG/NRG S1914 NCT04214262

    ForEarly-stage inoperable/surgery-declined NSCLC (T1-3N0M0 ≤7cm), ≥1 risk factor

    Overall survival

    HR 1.15

    95% CI 0.65-2.01, p=0.63; did not meet primary

    TL;DROS HR 1.15 (0.65-2.01), p=0.63: adding atezolizumab to SBRT did not improve survival in early-stage inoperable NSCLC; futility-stopped, excess toxicity.

    Why it mattersRadiation oncology

    Local control got worse with IO, not better: local failures 13% vs 7% adding atezolizumab, alongside null OS/PFS and a former/never-smoker harm signal (OS HR 2.50). SBRT alone stays standard for inoperable early-stage NSCLC, closing the add-IO-to-SBRT question negatively.

    6 details
    Design

    Phase 3 open-label RCT, 1:1, SWOG/NRG; N=403 eligible (201 S / 202 AS). Stopped at first interim for futility on OS and PFS. Median follow-up 12 mo (0.03-49).

    Population & inclusion

    T1-3N0M0 NSCLC ≤7cm, medically inoperable or declined surgery, ≥1 recurrence risk factor (diameter ≥2cm, SUV ≥6.2, moderate/poor/undifferentiated). Median age 73, median tumor 2.3cm, 89% ECOG 0-1.

    Radiotherapy

    SBRT both arms (SoC backbone): 3-8 fractions, BED ≥100 Gy. Stratified by central vs peripheral, <4 vs ≥4cm, PS 0-1 vs 2.

    Regimen

    Atezolizumab 1200mg IV Q3wk ×8 (neoadjuvant, concurrent, adjuvant); SBRT initiated at cycle 3.

    Endpoints

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

    Safety

    G≥3 AEs 12% AS (21 G3, 1 G4, 1 G5 respiratory-failure death) vs 2% S. Excess toxicity with no efficacy gain.

    vs leading data

    Prior randomized phase 2 (**PMID 37478883, I-SABR, nivolumab+SBRT) suggested benefit adding IO; S1914 with atezolizumab does not confirm** and shows harm signals.

    Applies to
    early-stage (T1-3N0) medically inoperable or surgery-declined NSCLC with recurrence risk factors, treated with definitive SBRT
    Does not represent operable, node-positive, or locally advanced NSCLC.
    Limitations

    Open-label; stopped early at interim (median f/u 12mo, only 49 deaths). Former/never-smoker harm is an exploratory subgroup; central review of local recurrence ongoing.

    Results
    EndpointSASHR (95% CI), p
    2yr OS82%80%1.15 (0.65-2.01), p=0.63
    2yr PFS71%60%1.35 (0.89-2.06), p=0.16
    FailureSAS
    Local7%13%
    Regional2%3%
    Distant4%5%
    Endpoint (never/former smokers)HR (95% CI), p
    OS2.50 (1.11-5.59), p=0.03
    PFS2.16 (1.15-4.04), p=0.01
    Rationale

    Phase 3 stopped for futility; adding IO to SBRT gave no OS/PFS benefit and excess toxicity, reaffirming SBRT-alone SOC and not confirming the prior phase 2 signal.

    Monday clinic

    In medically inoperable or surgery-declined early-stage (T1-3N0) NSCLC treated with definitive SBRT, this argues against adding atezolizumab, and does not extend to node-positive or locally advanced disease.

    Open questions
    • Biomarker/PD-L1 subset that benefits from adding IO to SBRT
    • Whether excess local failures with IO hold on central review
    • Reconciling harm signal with prior phase 2 IO+SBRT benefit
    📚 Sources · 📄 1 paper
    📄 PAPER Simone, Charles B.; Daly, Megan Eileen; Redman, Mary Weber et al. · Journal of Clinical Oncology (2025-06)
    SWOG/NRG S1914: Randomized phase III trial of induction/consolidation atezolizumab + SBRT versus SBRT alone in high risk, early-stage NSCLC.
    doi article →
    Abstract
    8003 Background: Stereotactic body radiation therapy (SBRT) is the standard of care (SoC) for early stage, medically inoperable non-small cell lung cancer (NSCLC). While rates of in-field control exceed 90%, regional and distant control after SBRT remain suboptimal. A prior phase II randomized trial suggested a benefit to adding immunotherapy (PMID 37478883). SWOG/NRG S1914 (NCT#04214262) is a randomized phase III trial evaluating neoadjuvant, concurrent and adjuvant atezolizumab plus SBRT for early-stage NSCLC vs SoC. Methods: Eligible patients (pts) had T1-3N0M0 NSCLC ≤7cm, were medically inoperable or declined surgery, and had ≥1 risk factor for increased recurrence: tumor diameter ≥2 cm, ≥6.2, moderately/poorly/undifferentiated histology. Randomization was to SoC SBRT (S [3-8 fractions, biologically effective dose ≥100 Gy]) or neoadjuvant, concurrent and adjuvant atezolizumab (AS [1200 mg IV Q3 week, 8 cycles]) with SBRT initiated with cycle 3, stratifying by tumor location (central vs peripheral), size (&lt;4 cm vs ≥4cm) and ECOG performance status (PS, 0-1 vs 2). The primary objective was to compare overall survival (OS) between the arms. Secondary objectives included comparisons of progression free survival (PFS), failure patterns, toxicity and quality of life (QoL). OS and PFS were compared using a 1-sided stratified log-rank test at the 2.5% level, confidence intervals (CI) are 95%. The accrual goal was 432 eligible pts. Results: From 8/13/20 - 9/6/24, 417 pts were randomized, 403 met eligibility [201 to S, 202 to AS]. Accrual closed at the first interim analysis for futility based on OS and PFS per design. Median follow-up for pts still alive was 12 (range: 0.03-49) months. Median age was 73 (41-91) years and 89% had PS 0-1. Median tumor diameter was 2.3 cm. No protocol treatment was received for 6 pts on S and 8 on AS. With 49 deaths, OS was not different between the arms (HR (CI): 1.15(0.65-2.01), p=0.63; 2-year OS: 82% S vs 80% AS). With 88 events, PFS was not better with AS (HR (CI): 1.35(0.89-2.06), p=0.16); 2-year PFS was 71% on S vs 60% on AS. Regional (2% vs 3%) and distant (4% vs 5%) failures were not different; there were more local failures with AS (13% vs 7%). Among former (53%)/never (3%) smokers, AS had worse OS and PFS than S (HR(CI): 2.50 (1.11-5.59), p=0.03); HR(CI): 2.16(1.15-4.04), p=0.01), respectively. Grade (G) ≥3 adverse event (AE) rates were 12% on AS (N=21 G3, 1 G4, 1 G5 respiratory failure) vs 2% on S (N=3 G3, 1 G4). Conclusions: In the first reported phase III trial to assess immunotherapy (IO) added to SBRT in early-stage NSCLC, IO failed to improve survival. More G ≥3 adverse events were reported with AS. Central review of local recurrence events is ongoing. Additional investigation into subgroups, PD-L1 status, QoL and blood/tissue are pending to determine whether there are subsets who can benefit from this combination and shed further insights into these findings. Clinical trial information: NCT04214262 .
    📝 https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8003

    Combined Curative Phase 3 RCT Confirmatory

    Confirmatory

    Multicenter TMT Bladder Preservation Analysis (n=369)

    ForMuscle-invasive bladder, cT2-T4aN0M0, median age 76

    TL;DRCLR 63.7% in 369 MIBC pts on definitive TMT; 5-FU-based CRT and better image guidance predicted higher complete local response.

    Why it mattersRadiation oncology

    The two modifiable levers here are RT delivery and chemo backbone, both in the radonc's hands: 5-FU-based CRT predicted higher CLR (OR 4.9) and weekly portal imaging lower CLR (OR 0.35, p<0.001), favoring daily volumetric IGRT. Technique, not just patient selection, moved local control.

    8 details 4 trials watching
    Design

    Multicenter retrospective cohort, Spain 2010-2022, N=369 treated with definitive TMT (maximal TURBT + concurrent chemoRT). Multivariable logistic regression for predictors of complete local response.

    Population & inclusion

    cT2-T4aN0M0 muscle-invasive bladder. Median age 76, 85.1% male. Node-positive and metastatic disease excluded by staging.

    Radiotherapy

    Image-guidance quality tracked with local control: weekly portal imaging predicted lower CLR (OR 0.35, p<0.001), favoring daily volumetric IGRT; VMAT showed a non-significant favorable trend. RT dose/fractionation not reported in source.

    Regimen

    Concurrent chemoradiotherapy. 5-FU-based CRT predicted higher CLR (OR 4.9, 95% CI 1.1-22.1, p=0.038).

    Endpoints

    Primary: complete local response (CLR). Secondary: OS, CSS, recurrence patterns, salvage cystectomy.

    Results

    CLR 63.7%. Disease progression 28.8% (local 10.1%, systemic 10.7%, combined 8.7%). Salvage cystectomy 9.7%.

    Applies to
    cT2-T4aN0M0 MIBC selected for definitive bladder-preserving TMT at European centers
    Does not represent node-positive or metastatic disease, or pts triaged to upfront radical cystectomy.
    Limitations

    Retrospective, non-randomised; CLR predictors exploratory and confounded by treatment era. No head-to-head vs radical cystectomy; RT technique detail and CLR-survival effect sizes absent from source.

    Rationale

    Retrospective real-world European cohort; no randomised TMT-vs-cystectomy comparator. Reinforces guideline-recognized bladder preservation; predictor findings exploratory.

    Monday clinic

    In cT2-T4aN0M0 MIBC pts already committed to bladder-preserving TMT, this favors daily volumetric IGRT and 5-FU-based chemoRT for local control; it does not inform the upstream TMT-versus-radical-cystectomy choice or node-positive/metastatic disease.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Retrospective Confirmatory ESTRO Congress 2026

    Caveats dominate

    RADIOSA (MFS post-hoc)

    ForOligorecurrent prostate cancer eligible for metastasis-directed SBRT

    TL;DRPost-hoc MFS 16.6mo vs not reached, HR 0.39 favoring SBRT + 6mo ADT over SBRT alone in oligorecurrent prostate.

    Why it mattersRadiation oncology

    The additive read is the eugonadal MFS: benefit persisted after testosterone recovery (p<0.05), so the ADT effect is not just on-treatment suppression of imaging progression. That argues against reading RADIOSA's MFS split as a testosterone artifact, and moves the SBRT-alone vs SBRT + short-course ADT decision in oligorecurrence.

    Also covered Jun 12

    RADIOSA (MFS post-hoc)
    EndpointArm A (SBRT)Arm B (SBRT + ADT)Effect size
    Metastatic progression32/51 (62.7%)19/51 (37.3%)log-rank p=0.00079
    Median MFS16.6 mo (95% CI 12.83-NA)not reachedHR 0.3894 (0.2201-0.6888), p=0.00119
    +1 more figure
    Methods: N=102 randomized 1:1; median follow-up 49.23 months (95% CI 42.47-54.8).
    Methods: N=102 randomized 1:1; median follow-up 49.23 months (95% CI 42.47-54.8).
    8 details 5 trials watching
    Design

    Phase II randomized trial, 1:1, N=102, Arm A SBRT alone vs Arm B SBRT + 6-month ADT. Median follow-up (reverse KM) 49.23 months (95% CI 42.47-54.8). This report is a post-hoc analysis of MFS and eugonadal MFS.

    Population & inclusion

    Oligorecurrent prostate cancer. Detailed eligibility (number of lesions, imaging modality, prior local therapy, PSA thresholds) not reported in source.

    Radiotherapy

    SBRT to the oligorecurrent sites in both arms. Dose, fractionation, and target volume are not reported in source, which limits transfer to a specific practice.

    Endpoints

    MFS defined as randomisation to any M1 metastatic recurrence on imaging. Eugonadal MFS measured from testosterone recovery to new metastasis or last follow-up. KM curves compared by log-rank; HRs from Cox models.

    Results

    Effect sizes are in the figure caption table. All Arm B pts except two reached testosterone recovery within follow-up.

    Applies to
    oligorecurrent prostate cancer treated with metastasis-directed SBRT with or without 6-month ADT
    Does not represent de novo metastatic, castration-resistant, or polymetastatic disease.
    Limitations

    Post-hoc analysis; MFS was not the prespecified primary endpoint. No OS reported in source, so the surrogate carries the read. Toxicity and SBRT technique parameters absent from source.

    Discussion

    The eugonadal analysis is the substantive contribution: separating the benefit from on-treatment castration addresses the standing objection that ADT simply delays imaging-detected progression. Whether that reflects durable synergy between ablation and transient androgen suppression, as the authors argue, is hypothesis-generating at N=102.

    Rationale

    Post-hoc endpoint analysis of a phase II trial; MFS was not the prespecified primary. Design dominates the read despite the clean randomisation and mature follow-up.

    Monday clinic

    In oligorecurrent prostate cancer being considered for metastasis-directed SBRT, this supports the discussion of adding 6-month ADT over SBRT alone; it does not address de novo metastatic or castration-resistant disease, and the SBRT dose and target volume are not stated in the source.

    Open questions
    📚 Sources · 🐦 1 tweet

    Combined Curative Phase 2 trial Caveats dominate ESTRO Congress 2026