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About · curated by Nick Boehling, MD · @nb2276

2026-06-21

ARS Appropriate Use Criteria: Locoregionally Recurrent Rectal Cancer

TL;DRMargin-negative (R0) resection drives survival and local control; preop RT or systemic therapy downsizes tumor to improve R0 likelihood.

Why it mattersRadiation oncology

The RT lever here is downsizing for resectability: preop RT, or reirradiation in previously-treated pts, is endorsed to raise the odds of a margin-negative resection, the one determinant of survival and local control. Moves the decision to offer neoadjuvant (re)irradiation before attempted salvage resection.

Combined Curative Consensus / guideline

8 details 5 trials watching
  • 💊 Preop systemic therapy, RT, or both facilitate downsizing → improve likelihood of margin-negative resection
  • 🔍 RT and reirradiation endorsed mainly to downsize for resectability, not as standalone definitive therapy
  • 🔍 Five PICO questions addressed
    • Role of surgery
    • Role of preop/periop therapy
    • Role of nonoperative management (NOM)
    • Role of RT/reirradiation
    • Role of systemic therapy (chemo/IO)
  • 🔍 Evidence base: 116 peer-reviewed trials (Jan 2013–Jul 2025)
    • 10 well-designed (phase 2 randomized + phase 3)
    • 29 moderately designed (matched cohort + phase 2)
    • 76 retrospective (design limitations)
    • 1 meta-analysis
  • 🔍 Update to 2012 ACR recurrent-rectal-cancer AUC; multispecialty modified-Delphi (RAND/UCLA) consensus, 2 voting rounds
  • 📊 R0 (margin-negative) resection is the ultimate determinant of survival and local control
  • ⚠️ Evidence base mostly retrospective: 76 of 116 references, only 10 well-designed RCTs
  • Bottom line: no major change to current practice, reaffirms combined-modality therapy
📚 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
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

2026-06-02 ASCO Annual Meeting 2026

mRCAT-III NCT06507371

ForpMMR/MSS LARC, cT3-4N0/+, tumor ≤10cm from anal verge

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

Why it mattersRadiation oncology

The RT read is target volume: the experimental arm both spared elective nodal RT (tumor bed only) and added tislelizumab, so the pCR doubling can't isolate node-sparing's contribution. pCR is also blind to nodal failure, the very risk nodal omission creates, so EFS (pending), not pCR, gates whether to drop elective nodal coverage with IO.

vs leading data
  • Control pCR 28.6% matches SCRT + consolidation-chemo TNT benchmarks (e.g. RAPIDO); increment reflects added IO plus node-sparing

Combined Curative Phase 3 RCT Caveats dominate ASCO Annual Meeting 2026

mRCAT-III
EndpointExperimental (n=77)Control (n=77)P
pCR (ITT)61.0% (47/77)28.6% (22/77)<0.0001
MPR (TRG0+TRG1)77.9% (60/77)50.6% (39/77)<0.0001
+1 more figure
mRCAT-III
7 details 5 trials watching
  • 🔍 Phase 3 open-label RCT, N=154 (77/arm), 17 China sites; primary pCR by blinded independent central review
  • 🔍 RT: short-course 5Gy×5d (25Gy/5fx) both arms; experimental spared elective nodal RT (tumor bed only, no draining nodes)
  • 💊 Experimental added tislelizumab 200mg IV to the CAPOX backbone; control got CAPOX alone
  • 🔍 MSS/pMMR rectal is typically IO-refractory; a pCR doubling with PD-1 here is the provocative signal, pending confirmation
CONSORT flow
Randomized 154
Node-sparing SCRT + CAPOX + tislelizumab
allocated 77
analyzed 77
Conventional SCRT + CAPOX
allocated 77
analyzed 77
  • ⚠️ Confounded: experimental arm both spared nodal RT AND added tislelizumab, so pCR gain can't be attributed to node-sparing alone
  • ⚠️ pCR can't detect nodal failure, the risk omitting elective nodal RT creates; locoregional control and EFS unreported
  • ⚠️ Fewer severe GI AEs reported in experimental arm; no effect size reported in source
📚 Sources · 🐦 1 tweet

2026-06-01 ASCO Annual Meeting 2026

ctDNA in nonoperative management of stage II-III rectal cancer

ForMSS stage II-III rectal adeno, cCR/nCR after NAT, on watch-and-wait

TL;DRctDNA sensitivity only 41% for local regrowth (94% specificity) in NOM rectal ca; misses most salvageable regrowth, can't replace endoscopic surveillance.

Why it mattersRadiation oncology

The organ-preservation read: ctDNA can't replace endoscopic/MRI surveillance. At 41% sensitivity (12/29) it misses most local regrowths, the salvageable event RT-based watch-and-wait depends on. Its real value is flagging distant failure (74% sensitivity) and risk stratification, so keep imaging-led surveillance during NOM.

Curative Retrospective Early signal ASCO Annual Meeting 2026

ctDNA in nonoperative management of stage II-III rectal cancer
EndpointSensitivitySpecificityAccuracy
Local regrowth41% (12/29)94% (480/509)91% (492/538)
Distant mets74% (31/42)97% (611/627)96% (642/669)
9 details 2 trials watching
  • 🔍 INTERCEPT program (MD Anderson), retrospective, n=110 MSS rectal adeno with cCR/nCR after NAT on NOM, 2020-2024
  • 🔍 tumor-informed ctDNA (Signatera Exome); 669 serial draws analyzed per-sample; median f/u 25mo (IQR 18-37)
  • 🔍 NAT was TNT in 104/110 (CRT 5, chemo 1); initial response cCR 69 / nCR 41
  • 📊 events on NOM: local regrowth 23 (21%), distant mets 12 (11%)
  • 📊 ever-positive longitudinal ctDNA → worse 2yr local-regrowth-free and metastasis-free survival (log-rank p=0.0002)
  • 📊 first post-NAT ctDNA positive → lower regrowth-free/mets-free survival, but only n=12 evaluable (log-rank p=0.0006)
  • ⚠️ negative ctDNA misses most local regrowths (sensitivity 41%); the salvageable event, so it can't replace endoscopic/MRI surveillance
  • ⚠️ ctDNA+ at regrowth → more advanced salvage path: ypT3-4 75% (6/8) vs 21% (3/14), p=0.01
  • ⚠️ per-sample (n=669) denominator inflates n vs 110 pts; only 29 windows had regrowth, 12 pts evaluable for first-ctDNA
📚 Sources · 🐦 1 tweet

2026-05-31

MIRACLE-2

For1L MSS unresectable metastatic rectal ca, synchronous liver/lung mets

TL;DRORR 68%, mOS 23.2mo, 18% reached NED with upfront RT then systemic + PD1 in 1L unresectable MSS met rectal ca.

Why it mattersRadiation oncology

The RT read is upfront priming: HFRT to primary plus HFRT/SBRT to mets precedes systemic + PD1, and 18% (9/50) of unresectable pts reached NED, an unusual signal in immune-cold MSS. RT dose/fractionation isn't in source and no omission arm isolates its effect, so adding RT to a systemic backbone stays hypothesis-only.

vs leading data
  • MSS ~95% of mCRC and intrinsically IO-resistant; single-agent PD1 inactive in MSS

Combined Phase 1 Early signal

MIRACLE-2
10 details 4 trials watching
  • 🔍 Prospective single-arm phase I, N=50, 1L MSS unresectable met rectal ca, primary ≤10cm from anal verge
  • 🔍 RT given upfront: HFRT to primary, HFRT or SBRT to mets. Dose/fractionation not reported in source
  • 💊 Then FOLFOX-bev-tislelizumab (RAS/BRAF-mut) or FOLFIRI-cetux-tislelizumab (WT); RAS/BRAF mut in 56.0%
  • 📊 Efficacy outcomes (single-arm, N=50)
    EndpointValue95% CI
    ETS rate (1°)76.0%62.4-86.8%
    ORR68.0%53.6-80.0%
    DCR88.0%76.0-95.2%
    Median PFS9.3 mo7.1-11.5
    Median OS23.2 mo15.1-31.3
    Median DOR8.0 mo5.2-10.8
  • 📊 18% (9/50) reached NED; 1-yr OS 93.3%, 1-yr PFS 33.4%, 1-yr DOR 20%
  • ⚠️ Grade 3/4 TRAEs, heme-dominant
    • Lymphopenia 36.7%
    • Neutropenia 26.5%
    • Leukopenia 20.4%
  • ⚠️ RT-associated lymphopenia a plausible driver of the 36.7% G3/4 lymphopenia
  • ⚠️ RT contribution unmeasurable: no RT-omission arm, effect confounded with systemic + PD1
  • ⚠️ 1° EP is ETS (≥20% shrinkage at 8wk), an early surrogate not OS/PFS; mFU only 19.9mo (16.4-23.4)
  • ⚠️ Durability thin: 1-yr DOR 20%, mDOR 8.0mo despite high 1-yr OS
📚 Sources · 🐦 1 tweet

2026-05-18

OPERA Trial (5-year rectal preservation)

ForRectal cancer s/p neoadjuvant therapy, organ-preservation candidates

TL;DRW14 clinical exam (DRE+rectoscopy±MRI) reliably flags complete response; 5-yr organ preservation similar for cCR vs nCR (81% vs 77%).

Why it mattersRadiation oncology

The RT read: near-complete response carries nearly the same 5-yr organ-preservation rate as complete response (77% vs 81%), so radiation-induced nCR shouldn't trigger salvage TME. W14 clinical exam (DRE+rectoscopy, 98% MRI-concordant) lets you commit to watch-and-wait a month after NAT rather than waiting to W24.

Radiation Curative Phase 3 RCT Caveats dominate

8 details 3 trials watching
  • 🔍 Post-hoc analysis of OPERA (phase 3 rectal organ-preservation RCT), N=141; tests W14 decision vs the trial's prespecified W24 assessment.
  • 🔍 Arms not labeled in source slides; per published OPERA, Arm B = contact X-ray brachytherapy boost, Arm A = EBRT boost.
  • 📊 W14 clinical tumor response eval feasible in 122/141 (87%): 76% good response (cCR+nCR), 24% PR.
  • 📊 W14 good response and 5-yr organ preservation by arm
    EndpointArm AArm Bp
    W14 good response65%88%0.004
    5-yr organ preservation75%83%0.24
  • 📊 MRI concordance high: TRG1-2 in 98% (80/82) of clinical-CR pts.
  • 📊 5-yr OP similar for cCR vs nCR (81% vs 77%): near-complete response not prognostically inferior.
  • ⚠️ nCR reflects radiation side effects, not residual tumor (authors); should not justify radical surgery.
  • ⚠️ W14-vs-W24 timing not a randomized comparison; who proceeds to OP is selected, so the timing read is confounded.
📚 Sources · 🐦 1 tweet