Gastrointestinal Cancers — Board Review Summary

Distilled from Johung (Yale) — 2026 ASTRO Refresher Course. Covers esophageal/GEJ, pancreas, HCC, rectal, and anal. High-yield weighted toward ABR testable content with emphasis on the post-ESOPEC perioperative era for GEJ adenocarcinoma, TNT cascade (RAPIDO 5-yr, PRODIGE 23 long-term, STELLAR), ablative pancreas (SMART/MAIBE), dMMR rectal immunotherapy (Cercek NEJM 2025), and the PLATO family for anal dose personalization.

PART I — ESOPHAGEAL / GEJ CANCER

Standard of Care by Stage (NCCN 2.2026)

Stage	Squamous Cell Carcinoma	Adenocarcinoma
Tis, T1a N0	Endoscopic resection (EMR/ESD) ± ablation	Endoscopic resection (EMR/ESD) ± ablation
T1b N0 / low-risk T2N0 (well-diff, <3 cm, no LVI)	Esophagectomy; cervical SCC → definitive CRT	Esophagectomy
High-risk T2N0, T1-2N+, T3-4a anyN	Pre-op CRT → Surgery ± ICI; or definitive CRT	Peri-op systemic (FLOT/D-FLOT) preferred; pre-op CRT → Surgery ± ICI; definitive CRT; peri-op/neoadj ICI if MSI-H/dMMR
T4b any N	Chemo alone; or induction chemo → CRT	Chemo alone; or induction chemo → CRT

Trimodality: CROSS Trial (Van Hagen NEJM 2012; Eyck JCO 2021 — 10-yr)

366 pts, T1N1 or T2-3N0-1, 75% adeno. CRT 41.4 Gy/23 fx + weekly carbo/taxol → surgery. 10-yr OS 38% vs 25% (HR 0.60). pCR 49% SCC / 23% ACA. Median OS SCC 81.6 vs 21.1 mo; ACA 43.2 vs 27.1 mo. Benefit primarily from reduced locoregional and LR+distant failure; isolated distant failure comparable (HR 0.76). R0 92% vs 69%.

NEOCRTEC5010 (Yang JCO 2018)

T1-4 N1 or T4N0 SCC, 100%. Cis/vinorelbine + 40 Gy/20 fx → Surgery vs Surgery alone. pCR 43%; median OS 100 vs 66.5 mo; R0 98% vs 91%.

PET-Directed Chemo: CALGB 80803 (Goodman JCO 2021)

257 pts esoph/GEJ ACA, T3/4 or N1. Induction FOLFOX vs carbo/taxol → PET restaging (day 36–42). <35% SUV decrease → cross over chemo during CRT (50.4 Gy). pCR in non-responders who crossed over to alternative chemo: FOLFOX-NR→carbo/taxol 18%; Carbo/taxol-NR→FOLFOX 20%. Induction FOLFOX responders had pCR 40.3% vs 14.1% for carbo/taxol responders — favors FOLFOX for ACA. Median OS 48.8 mo (responders) vs 27.4 mo.

Adjuvant Nivolumab: CheckMate 577 (Kelly NEJM 2021; ASCO 2025)

794 pts, stage II/III esoph or GEJ, s/p neoadj CRT + R0 resection with path residual disease, regardless of PD-L1. Nivo 240 mg q2wk×16, then 480 mg q4wk × total 1 yr vs placebo. Median DFS 22.4 vs 11.0 mo (benefit regardless of histology, larger in SCC; regardless of PD-L1). Distant recurrence 29% vs 39%; median DMFS 28.3 vs 17.6 mo. OS at 78-mo f/u: 51.7 vs 35.3 mo, p=0.1064 (not significant). G3-4 AEs 13% vs 6%.

CheckMate 577 is the anchor for adjuvant ICI after trimodality. Use requires: neoadj CRT + R0 + path residual (not ypCR).

Peri-op Chemo vs Pre-op CRT — The Big Comparison

Trial	Stage / Histo	Peri-op chemo	Pre-op CRT	Key Result
MAGIC (Cunningham NEJM 2006)	≥ stage II, gastric/GEJ/distal esoph ACA	ECF ×3 pre + ×3 post	—	5y OS 36% vs 23% (surgery alone)
FLOT4 (Al-Batran Lancet 2019)	≥cT2 and/or cN+, gastric/GEJ ACA	FLOT ×4+4	—	3y OS 57% vs 48% (ECF/ECX); pCR 16% vs 6%. Established FLOT.
POET (Stahl 2009/2017)	T3-4, GEJ/cardia ACA	Cis/5-FU/LV 15 wk	30 Gy/15 fx + cis/etop	5y OS 24.4% vs 39.5% (CRT); pCR 2% vs 16%; p=0.055
Neo-AEGIS (Reynolds 2023)	T2-3 N0-3, esoph/GEJ ACA	FLOT 15% or ECF/ECX/EOF	41.4 Gy/23 fx + carbo/taxol (CROSS)	3y OS 55% vs 57% — equivalent. pCR 4% vs 12%; CRM+ better with CRT
TOPGEAR (Leong NEJM 2024)	T3-4 anyN, GEJ/gastric ACA	FLOT or ECF/ECX	45 Gy/25 fx + 5-FU/cape	3y OS 55% vs 58% — equivalent. pCR 8% vs 17%; ypN0 42% vs 54%
ESOPEC (Hoeppner NEJM 2025)	T1N+ or T2-4a anyN, esoph ACA	FLOT ×4+4	41.4 Gy/23 fx + carbo/taxol (CROSS)	3y OS 57.4% vs 50.7%; 5y OS 50.6% vs 38.7% — FLOT wins. Median OS 66 vs 37 mo; pCR 16.7% vs 10.1%

ESOPEC is the major practice change. Peri-op FLOT now SOC for fit esophageal/GEJ ACA who are surgical candidates. But: pCR was unusually low in the CROSS arm (10% vs 23% historical) — possibly reflecting timing of surgery or delivery. ESOPEC does not apply to SCC (use CROSS/trimodality). Patterns of failure: LRR equivalent (20.2% vs 17.4%); distant recurrence lower with FLOT (31.5% vs 47.2%) — FLOT wins on systemic control.

Peri-op Chemo + ICI: MATTERHORN (Janjigian NEJM 2025)

948 pts resectable gastric (67.5%) or GEJ (32.5%) ACA, stage II-IVA, 90% PD-L1 ≥1, 5% MSI-H. FLOT ×4+4 ± durvalumab q4wk×10. 2y EFS 67.4% vs 58.5% (HR 0.71); 2y OS 75.7% vs 70.4% (p=0.03). pCR 19.2% vs 7.2%. R0 91.5% vs 92.3%; G3-4 AEs equivalent (~71%). First positive peri-op ICI trial in GEJ/gastric ACA.

When to still employ CRT for esoph/GEJ ACA? Upper/mid esophagus or SCC; distal/GEJ unlikely to have surgery; not a FLOT/D-FLOT candidate; patient preference for organ preservation; TNT approach (CRT after FLOT/D-FLOT) for bulky tumors, risk of R1, extensive nodal disease, or poor induction response.

Gastric-Focused TNT: CRITICS II (Verheij GI ASCO 2026)

201 pts gastric/GEJ ACA, stage IB-IIIC. Chemo (DOC ×4) vs Chemo+CRT (DOC×2 → 45 Gy+carbo/taxol) vs CRT alone. 1y EFS 68% vs 84% vs 78%. pCR 8% vs 20% vs 13%. Suggests TNT with CRT may improve pCR.

Definitive Chemoradiation

Trial	Arms	Outcome
RTOG 8501 (Herskovic NEJM 1992; Cooper JAMA 1999)	CRT (50 Gy + cis/5-FU) vs RT alone 64 Gy	5y OS 27% vs 0%; 10y OS 20% with CRT. Established 50 Gy + cis/5-FU as standard
PRODIGE5/ACCORD 17 (Conroy Lancet Oncol 2014)	FOLFOX vs cis/5-FU, both with 50 Gy	Median OS 22.2 vs 17.5 mo (NS). FOLFOX reasonable alternative to cis/5-FU
ARTDECO (Hulshof JCO 2021)	Standard 50.4 Gy vs High 61.6 Gy SIB, carbo/taxol	3y LPFS 70% vs 73%, 3y OS 42% vs 39% — no benefit to dose escalation. G4 12% vs 14%; G5 5% vs 10%

Organ Preservation — Active Surveillance

Trial	Arms	Outcome
FFCD 9102 (Bedenne JCO 2007)	T3N0-1 SCC (88%): CRT only vs CRT→Surgery, responders only	2y LC 57% vs 66% (surgery); 2y OS 40% vs 34% — no OS benefit of surgery. Tx mortality 0.8% vs 9.3%
German Trial (Stahl JCO 2005)	T3-4 SCC: CRT alone vs CRT + Surgery	2y local PFS 41% vs 64%; 3y OS 24% vs 31% NS; mortality 4% vs 13%
SANO (van der Wilk Lancet Oncol 2025)	309 pts with cCR after CROSS: AS vs Esophagectomy	2y OS 74% vs 71% — non-inferior. DFS 35 vs 49 mo (NS). Distant mets 43% vs 34%. Better HRQoL at 6-9 mo with AS. 50% of AS pts spared esophagectomy

SANO surveillance schedule: cCR assessed at 6 wk (EGD+bx) and 12 wk (PET, EGD+bx, EUS+FNA of suspicious LNs). If CCR: PET/EGD/EUS q3mo×1yr, q4mo×1yr, q6mo×1yr, then annual. Only 35% achieved CCR; cN2-3 sustained CCR only 11%. Await ESOTRATE, CELAEC, ESORES, SANO-3 (with nivo).

Combining IO + Definitive CRT

EC-CRT-001 (Zhu Lancet Oncol 2023): Toripalimab + 50.4 Gy/cis/tax, 42 SCC pts — 62% CR, 1y OS 78%. 86% lymphopenia; 6 fistulas; 1 G5 pneumonitis.
NOBEL (Muto GI ASCO 2024): Nivo + 50.4 Gy/cis/5-FU, 42 SCC — 73% CR, 1y OS 93%.
Meta-analysis (Liu IJROBP 2025, 37 studies): Neoadj immuno-CRT OS HR 0.714; 3y OS 66.4% vs 57.3%.

Technology — Protons vs IMRT (Lin JCO 2020)

Phase IIB, 107 evaluable pts, stage I-III (89% ACA). PBT 50.4 CGE/28 fx vs IMRT. Total toxicity burden 2.3× higher with IMRT; post-op complication score 7.6× higher with IMRT. No difference in PFS/OS/pCR/QOL. NRG-GI006 phase III pending.

PART II — PANCREATIC CANCER

Standard of Care by Stage (NCCN 2.2025)

Stage	Management
Resectable, no high-risk features	Upfront resection → adjuvant chemo ×6 mo. Consider CRT if R1 or N0
Resectable + high-risk (indeterminate imaging, ↑CA 19-9, large primary/LNs, weight loss, severe pain)	Neoadj chemo (FOLFIRINOX or Gem/Abraxane) → resection → complete 6 mo chemo. Consider CRT for R1/N0
Borderline resectable	Neoadj chemo → consider RT → resection → complete 6 mo chemo. Consider CRT for R1, no prior RT
Locally advanced unresectable	Chemo 4-6 mo → consider CRT or SBRT

Adjuvant Chemotherapy Landmarks

Trial	Arms	Outcome
CONKO-001 (Oettle JAMA 2013)	Gem ×6 vs observation	5y OS 20.7% vs 10.4% — established adjuvant gem
ESPAC-3 (Neoptolemos JAMA 2010)	5-FU vs Gem ×6	Median OS 23.0 vs 23.6 mo NS; less AEs with gem
ESPAC-4 (Neoptolemos Lancet Oncol 2017)	Gem/Cape vs Gem ×6	Median OS 28.0 vs 25.5 mo
PRODIGE 24 (Conroy JAMA Onc 2022)	mFOLFIRINOX vs Gem ×6	Median OS 53.5 vs 35.5 mo; 5y OS 43.2% vs 31.4% — current SOC
APACT (Tempero JCO 2023)	Gem/Abraxane vs Gem ×6	Median OS 41.8 vs 37.7 mo

Adjuvant Chemoradiation: RTOG 0848 (Abrams ASCO 2024)

Pancreatic head ACA, R0 (83%)/R1, s/p gem-based chemo ×5 (NO FOLFIRINOX — enrolled before era) → randomize to chemo ×1 mo or chemo ×1 mo → CRT 50.4 Gy + 5-FU/cape. Overall no OS benefit but DFS improved (5y 21% vs 15%). Node-negative subgroup: both OS and DFS improved with CRT. 96% had post-op CA 19-9 <90. Questions remain: effect of FOLFIRINOX era, R1 benefit, neoadj vs adjuvant sequencing.

RT QA matters (Tchelebi IJROBP 2024): 1/3 of RTOG 0848 plans had unacceptable deviations requiring resubmission (pre-op GTV contouring 60.7%; identifying the panc-jej 47.5%). Real-time QA and target delineation resources critical.

Neoadjuvant Trials (Resectable + Borderline)

Trial	Design / Key finding
SWOG S1505 (Sohal JAMA Onc 2021)	Resectable: peri-op FFX vs Gem/Abr. 2y OS 47% vs 48% — not superior to historical surgery-first. R0 85%, path response only 33%
NORPACT-1 (Labori Lancet Gastro Hepatol 2024)	77 pts Neoadj FFX ×4 vs 63 upfront surgery. ITT median OS 25.1 vs 38.5 mo (p=0.050) — neoadj WORSE. 21% never got neoadj FFX
Alliance A021501 (Katz JAMA Onc 2022)	BRPC. FFX ×8 → Surgery vs FFX ×7 → SBRT (33-40/5) or HypoFx (25/5) → Surgery. SBRT arm closed — inferior. R0 57% vs 33%; 18mo OS 66.7% vs 47.3%. ENI likely needed
PREOPANC (Versteijne JCO 2022 long-term)	Resectable+BRPC: pre-op CRT (Gem + 36 Gy/15 fx) → Surgery vs upfront surgery. Overall OS HR 0.73; BRPC subgroup HR 0.67, p=0.045; resectable no benefit. R0 72% vs 43%; 5y OS 20.5% vs 6.5%; ypN+ 35% vs 82%
PREOPANC-2 (Janssen Lancet Oncol 2025)	Resectable+BRPC: TNT FFX ×8 vs Gem/CRT. Median OS equivalent (21.9 vs 21.3 mo). ypN0 better with CRT (58% vs 47%, p<0.01)
ESPAC 5 (Ghaneh 2023)	BRPC, 90 pts: immediate sg vs neoadj Gem/Cape, FFX, or CRT (50.4 Gy/cape). 1y OS: 39% sg vs 78% Gem/Cape vs 84% FFX vs 60% CRT (p=0.0028). Short-course neoadj gives OS benefit

Locally Advanced Unresectable Disease

LAP-07 (Hammel JAMA 2016): CRT (54 Gy/cape) after induction gem improved LC, prolonged treatment-free interval — no OS benefit (but in gem era, pre-FOLFIRINOX).
CONKO-007 (Fietkau JCO 2025): 495 LAPC, induction chemo (81% FFX) → chemo vs chemo+CRT (50.4 Gy+gem). DFS/OS equivalent overall; in surgical patients: 5y OS 11% vs 25% with CRT; if received FFX: 12.7% vs 27.6%. R0 69% vs 50%; pCR 18% vs 2% in resected. CRT improves conversion to R0 resection.

Dose-Escalated / Ablative RT

Study / Regimen	Outcome
Reyngold MSKCC ablative (JAMA Onc 2021)	119 LAPC, BED 98 Gy. If >1cm from GI: 67.5 Gy/15 fx (BED 97.9). If ≤1cm from GI: 75 Gy/25 fx (BED 97.5). Median OS 26.8 mo; 2y LRR 32.8%; G3 UGIB 8%
SMART Trial (Chuong 2024)	136 LAPC/BRPC, no progression after 3 mo chemo. MR-guided 50 Gy/5 fx (BED 100) with real-time soft tissue tracking + gating. 2y OS 53.6%; 2y LC 78%. No acute/late G3 GI definitely attributed to RT
SMART vs HART (Chuong 2025)	50/5 SMART (n=91) vs 75/25 or 67.5/15 HART (n=120). 2y LF 6.5% vs 32.9% favoring SMART; 2y OS 31 vs 35% NS. Late G3+ toxicity 2.2% vs 9.2%
MAIBE Phase II (Reyngold ASTRO 2025)	48 unresectable after 3 mo chemo: 67.5/15 or 70/25 + cape. 28% resection; 2y OS 38% overall, 54% resected

NRG Consensus Target Volumes for Dose-Escalated RT (Sanford IJROBP 2025)

High-risk CTV: primary tumor + gross nodes + entire diameter of abutting vessels (CA, SMA, SMV, portal vein, splenic artery for tail) extending 5 mm along length if within 5 mm of gross tumor; include hazy peri-tumoral soft tissue.
Low-risk CTV (perineural/perivascular spread): 1 cm isotropic expansion around GTV + nodes; include pancreatic subregion (head/body/tail as relevant); celiac axis from aorta to bifurcation (start at celiac takeoff for tail/distal body, 1 cm above for head); CHA to GDA takeoff for head tumors. Crop out duodenum/kidneys/spleen. Inferior extent: SMA to first jejunal takeoff.
Dose per fraction: 5 fx: 10 Gy (high) / 6.6 Gy (low); 15 fx: 4.5 / 2.5 Gy; 25 fx: 3 / 1.8 Gy. Use 5 fx when feasible unless tumor invades stomach/bowel on EGD.

Patterns of Failure — The "Triangle Volume"

Extrapancreatic perineural and lymphatic failures cluster in the space bounded by celiac axis, SMA, CHA, and portal/SMV ("triangle"). Multiple series (Hill PRO 2022; Kharofa 2022; Zhu IJROBP 2019; Ponce PRO 2025) show recurrences concentrate at celiac trunk (~33%), near SMA (~28%), retroperitoneum (~27%), and aorticodiaphragmatic junction. Within 5-mm PTV→GTV strategies miss nodal basins — Miller IJROBP 2022 propensity study showed SBRT + ENI (40/5 + 25/5) cut 2y LRR from 44.6% to 22.6%.

Oligometastatic: EXTEND (Ludmir JCO 2024)

41 pts, ≤5 sites, ECOG 0-2, ≤4 prior lines. Chemo vs Chemo + MDT (SBRT 50/4, 70/10; primary to 40/5). Median PFS 10.3 vs 2.5 mo (HR 0.43); 1y PFS 42% vs 9%. Time to new lesion 14 vs 5 mo. Correlative: MDT activated CD8+ T cells and TCR diversity (abscopal-like immunologic signature).

PART III — HEPATOCELLULAR CARCINOMA

Standard of Care (NCCN 2.2025)

Stage	Management
Resectable or transplantable	Resection or transplant. Bridge: ablation, arterially-directed (TACE/TARE), RT → transplant
Liver-confined, unresectable, not transplant candidate	Locoregional: ablation / arterially-directed / RT; systemic therapy

Protons vs Photons (Sanford IJROBP 2019; NRG-GI003 pending)

Retrospective, 133 pts unresectable HCC, 45 Gy/15 fx or 30 Gy/5-6 fx. Proton RT associated with improved OS (HR 0.47); median 31 vs 14 mo; 2y OS 59.1% vs 28.6%. LC equivalent (93% vs 90%). Development of non-classic RILD at 3 mo → worse OS. NRG-GI003 phase III PBT vs photon RT 5 or 15 fx pending.

SBRT + Sorafenib: RTOG 1112 (Dawson JAMA Onc 2025)

177 LA HCC unsuitable/refractory/recurrent after resection/RFA/TACE; Child-Pugh A, plt >60, BCLC B/C, sum ≤20 cm, ≤5 foci, ≤3 cm extrahepatic; 74% MVI. Sorafenib alone vs SBRT 27.5-50 Gy/5 fx (median 35 Gy) → sorafenib. Median OS 12.3 vs 15.9 mo (HR 0.77, p=0.06 ITT; HR 0.72 MVA). Median PFS 5.5 vs 9.2 mo (HR 0.55). Vascular response in MVI: 9% vs 38%. G3+ similar (42% vs 47%); QOL improved at 6 mo (10% vs 35%).

TACE Alternatives / Combinations

Study	Design	Key Finding
Trendy (Mendez Romero 2023)	TACE-DEB vs SBRT 8-9 Gy × 6; N=30 (closed)	2y LC 43.6% vs 100%; TTP NS but favors SBRT; no G3+ with SBRT
Bush Cancer 2023	TACE vs PBT 70.2 Gy/15 fx; N=76	2y OS equivalent; LC HR 5.64 favoring PBT; PFS not reached vs 12 mo. Hospital days PBT 24 vs TACE 166. 28% lower cost with PBT
Chen IJROBP 2025 (Phase III)	TACE ± EBRT (median 55 Gy/15 fx); N=74 (closed)	3y LC 17.8% vs 56.6%; OS/PFS NS; toxicity comparable
Kim J Hepatol 2021 (Phase III)	Recurrent/residual HCC ≤3 cm: PBT 66 GyE/10 fx vs RFA	2y LPFS 92.8% vs 83.2% (ITT) — non-inferior to RFA; pneumonitis 32.5% w/PBT
Xi JCO 2025 (Phase III)	Recurrent HCC ≤5 cm: SBRT 36-54 Gy/3 fx vs RFA; N=166	2y LPFS 92.7% vs 75.8% favoring SBRT (HR 0.45); no difference in PFS/OS
START-FIT (Chiang ASCO GI 2026)	Unresectable HCC ≥5 cm + MVI: TACE + SBRT → Durva+Treme	ORR 73%, CR 42%; 18mo LC 96.6%, PFS 62%, OS 90%

SBRT as Bridge to Transplant

Wong Hepatology 2021: SBRT (n=40) vs TACE (n=59) vs HIFU (n=51). 1y tumor control 92.3% vs 43.5% vs 33.3%; drop-out 15.1% vs 28.9% vs 33.3%; pCR 48.1% vs 25% vs 17.9%. No difference in post-transplant OS/RFS.
Lee JAMA Netw Open 2024: 32 pts pre-DDLT, SBRT 35-50/5. 63% transplanted; pCR 75%; 5y OS 51.3%; 5y PFS 39.9%. Well tolerated.

Early-Stage (STRSPH — Sanuki IJROBP 2025)

35 pts solitary HCC 1-5 cm (median 2.3), SBRT 40 Gy/5 fx. 3y OS 82%; 3y LC 93%. G3-4 non-lab tox 11%. CTP score increase ≥2 in 34%.

Palliation: CCTG HE1 (Dawson Lancet Oncol 2024)

66 pts HCC or liver mets with pain refractory to standard tx. 8 Gy × 1 to liver + best supportive care vs BSC alone. Pain improvement at 1 mo: 67% vs 22%. No SAEs; 3mo OS 51% vs 33% (p=0.068).

PART IV — RECTAL CANCER

Staging MRI

T-stage by mesorectal fat invasion: T3a <1mm, T3b 1-5mm, T3c 5-15mm, T3d >15mm. MRF involved: <1 mm between tumor and mesorectal fascia. EMVI+: tumor signal extending within mesorectal vessels.
Risk factors for LR: T4, involved MRF/CRM, lateral pelvic LN, distal (<5 cm from verge), EMVI.

TNT Cascade — Key RCTs

Trial	Design	Result
PRODIGE 23 (Conroy Lancet Oncol 2021; Ann Oncol 2024 long-term)	461 cT3-4. TNT (FFX ×6 → CRT 50 Gy/cape → TME → FOLFOX/CAPE 3 mo) vs SOC (CRT → TME → chemo 6 mo)	pCR 28% vs 12%; ypN0 83% vs 67%. 3y DFS 76% vs 69%. 7y OS 81.9% vs 76.1% (p=0.033); 7y DFS 67.6% vs 62.5%; 7y MFS 79.2% vs 72.3%; cumulative LR 5.3% vs 8.1%
RAPIDO (Bahadoer Lancet Oncol 2021; Dijkstra 2023, 5-yr)	920 high-risk (cT4, cN2, EMVI, +MRF, +LPLN). Short-course 25 Gy/5 fx → CAPEOX×6 or FOLFOX×9 → TME vs CRT 50/50.4 Gy/cape → TME → adj chemo	pCR 27.7% vs 13.8%; 3y DM 19.8% vs 26.6%. 5y LR higher with SC-TNT: 10% vs 6% (p=0.027); if sphincter-preserving: 12.1% vs 4.8%; distal margin <1 cm: 25.4% vs 1.8%. More 3D-CRT in SC-TNT arm; enlarged lateral nodes predict
STELLAR (Jin JCO 2022)	599 cT3-4 or N1-2. SC 25 Gy/5 + CAPEOX×4 → TME vs CRT 50 Gy/cape	Non-inferior (3y DFS 64.5% vs 62.3%). 3y OS 86.5% vs 75.1% (p=0.033); 5y ΔOS +8.4%. 5y LR 8.7% vs 9.1%. More acute G3-4 with TNT (26.5% vs 12.6%)

SC TNT vs LC TNT debate: RAPIDO (SC-TNT) showed higher LR at 5 y; Polish II (SC+FOLFOX vs CRT+oxali) NS; STELLAR (SC + chemo then sandwich) non-inferior LR and better OS. If distal tumor, <5 cm from verge, or MRF threatened → prefer long-course CRT. Janus Trial (ongoing; T4N0, any T N+, T3N0 requiring APR) is testing FOLFIRINOX vs FOLFOX + 54 Gy+cape.

Selective RT Omission

Trial	Design	Result
PROSPECT (Schrag NEJM 2023)	1194 favorable T2N1 or T3N0-1 (excluded T4, ≥4 LNs, <3 mm CRM, non-LAR): FOLFOX ×6 → MRI; if >20% response → FOLFOX ×8 (no RT) vs CRT + FOLFOX	Only 9% needed CRT rescue. 5y DFS 80.8% vs 78.6%; 5y OS 89.5% vs 90.2%; 5y LC 98.2% vs 98.4%. pCR 21.9% vs 24.3%. FOLFOX arm: lower diarrhea pre-op, less fatigue/neuropathy and better sexual function at 1y post-op. CRT: less anxiety, appetite loss, mucositis, nausea during tx
CONVERT (Mei JCO 2026)	663 cT2N1 or cT3-4a anyN (MRF− and no obstruction): CAPOX ×4 → TME vs CRT 50 Gy/cape → TME	3y LRRFS 96.3% vs 97.4% — non-inferiority NOT demonstrated (low event rate). Similar DFS/OS. Distal tumors <5 cm from verge: LRRFS worse with chemo alone (HR 3.6, p=0.06). Less long-term AEs with chemo alone

ASTRO Guideline (Wo PRO 2025) — when to omit RT: Mid-to-upper rectal tumor >5 cm from verge; cT2-3a/b; mrCRM ≥2 mm; N0-N1 mesorectal nodes; no EMVI; >20% primary response to neoadj chemo; LAR planned (not APR); patient not pursuing organ preservation.

Short-Course (Historical Comparators)

Bujko Br J Surg 2006 (n=312): SC 25/5 vs LC CRT 50.4+bolus 5-FU/LV — LR 9% vs 14.2%, 4y OS 67% vs 66% NS. TROG 01-04 (Ngan JCO 2012, n=326): equivalent overall, but tumors <5 cm from verge LR 12.5% SC vs 0% LC. Polish II (Cisel Ann Oncol 2019, n=515): SC+FOLFOX×3 vs CRT+oxali; LR 35% vs 32% NS, 8y OS 49% both.

Non-Operative Management / Watch & Wait

OPRA (Garcia-Aguilar JCO 2022; Verheij JCO 2023)

324 stage II/III. INCT-CRT (chemo→CRT) vs CRT-CNCT (CRT→chemo); CRT 54 Gy, FOLFOX/CAPEOX ×4 mo. If cCR → active surveillance (DRE/sig q4 mo ×2y, q6mo ×3y; MRI q6mo ×2y, annual ×3y). 5y DFS equivalent (~70%). 5y TME-free survival 39% (chemo first) vs 54% (RT first). 94% of regrowths within 2 yrs. Organ preservation ~50%.

OPERA: CRT + Brachy Boost (Gerard Lancet Gastro Hepatol 2023)

148 pts cT2-T3a/b, low-mid rectum, <5 cm diameter, cN0-N1 <8 mm. CRT 54 Gy/cape vs CRT 45 Gy+ contact X-ray boost (CXB) 90 Gy/3 fx to rectal applicator surface (before CRT if <3 cm). 3y organ preservation 59% vs 81% (p=0.0026); if <3cm: 63% vs 97%.

International Watch & Wait Registry (van der Valk Lancet 2018)

1009 pts, 47 institutions. 87% cCR. 2y local recurrence 25.2%; 88% within first 2 yrs, 97% in bowel wall. 78% of regrowths resectable by TME (88% R0). 5y OS 85%; 5y DFS 94%.

ASTRO ARS AUC for NOM (Anker IJROBP 2024)

NOM strongly recommended when TME would require permanent colostomy or compromise continence. Restaging at 8-12 weeks post-CRT is essential. 54-56 Gy/27-31 fx + concurrent chemo → consolidation chemo recommended. Surveillance: H&P/CEA q3-6mo ×2y then q6mo to 5y; DRE + flexible sigmoidoscopy q3-4mo ×2y; MRI q3-6mo ×2y; CT CAP q6-12mo ×5y; colonoscopy at 1y.

dMMR Rectal Cancer — Cercek NEJM 2022/2025

MMRd stage II/III rectal cancer (5-10% of rectal cancers). Dostarlimab 500 mg q3wk ×9 (6 mo) → if cCR, RT and TME omitted. Original: 12/12 cCR; NEJM 2025 update: 49 pts completed tx, ALL had cCR (100%); 37 sustained CCR ≥12 mo; 2y RFS 96%. G3-4 AEs rare (5%). Ongoing: AZUR-1 single-arm phase II.

This is practice-changing for dMMR rectal cancer. Standard MMR/MSI testing on all new rectal cancers is essential; dMMR patients can be offered IO with deferral of CRT/surgery entirely.

pMMR Rectal Cancer + IO

STELLAR II (Jin ESTRO 2025): 218 pMMR, T3-4 N1-2 (mostly distal). SC-RT + CAPEOX/FOLFOX + sintilimab (anti-PD-1) vs same without sintilimab. CR 46% vs 25%. Phase 3 DFS pending.
PRIME RT (Roxburgh ESTRO 2025): 46 pts; CRT or SC + durvalumab → FOLFOX. 6mo cCR 52% overall, 67% with SC-RT arm.
Systematic review (Ansab 2025, 6 RCTs): PD-1 inhibitors significantly improved pCR (OR 2.10, p=0.001), significant in pMMR subgroup.

PART V — ANAL CANCER

Standard of Care (NCCN 4.2025)

Stage	Regimen
Anal canal: T1-T4N0-N1, PA nodes that fit in RT field	5-FU/mitomycin + RT or capecitabine/mitomycin + RT. 5-FU/cisplatin + RT (cat 2B alternative)
Peri-anal: T1N0, well-mod, no sphincter involvement	Local excision with margins ≥1 cm
Peri-anal: T1N0 poorly diff, T2-T4N0, any T N+	5-FU/mitomycin + RT; or cape/mito; or 5-FU/cis (2B)

Local excision (Feng ASTRO 2025): conditionally OK if margins adequate, sphincter preserved, close f/u. cT1N0 anal margin: margin ≥1 cm. Superficially invasive anal canal (well-mod, no LVI/PNI): margin ≥2 mm.

Historical Landmarks

Trial	Design	Key Finding
Nigro (1983)	30 Gy + 5-FU + mito	cCR 16/28 → established CRT paradigm (originally as preoperative)
UK ACT-1 (Northover 1996)	RT alone vs CRT (45 Gy + boost ± 5-FU/mito); N=585	5y LC 68% vs 43%; OS equivalent 58% vs 53% (CRT established)
EORTC (Bartelink 1997)	Same design; N=110	5y LC 70% vs 52%, OS 58% vs 53%
RTOG 87-04 / ECOG 1289 (Flam 1996)	CRT ± mitomycin, 45-50.4 Gy + 5-FU	Mito improves CFS 71 vs 59%; DFS 73 vs 51%. Mito is required
RTOG 9811 (Ajani 2008; Gunderson JCO 2011)	CRT 5-FU/mito vs induction cis/5-FU → CRT cis/5-FU	Colostomy 10% vs 19% (mito better); 5y OS 78% vs 71%; 5-FU/mito is standard, cis NOT superior
ACT II (James Lancet Oncol 2013)	2×2: 5-FU/mito vs 5-FU/cis; ± maintenance	3y PFS 74% vs 73%. Neither cis nor maintenance chemo is superior
RTOG 0529 (Kachnic IJROBP 2013)	Dose-painted IMRT 50.4/42 Gy (T2N0) or 54/50.4/45 Gy (T3-4/N+) + 5-FU/mito	G3+ GI 21% vs 36% (9811); G3+ derm 23% vs 49%. Established IMRT

IMRT Contouring (key differences across guidelines)

Guideline	Primary CTV	Primary Dose	Elective Nodal
RTOG 0529	GTVp + 2.5 cm isotropic, expanded to include anal canal	54 Gy/30 fx (T2N0 → 50.4/28); GTVn >3cm: 54, <3cm: 50.4	45 Gy/30 fx or 42 Gy/28 fx
AGITG (Ng IJROBP 2012)	GTVp + whole anal canal from ano-rectal junction to verge + sphincters, then +2 cm isotropic respecting anatomic boundaries	54/30 (non-bulky T2 → 50.4/28); nodes 50.4-54	45/30 or 42/28
UK	GTVp + 1.5 cm (1 cm if T1N0), expanded to include canal/sphincters, exclude bone/muscle if not involved	53.2 Gy/28 fx (T1-T2N0 → 50.4/28); GTVn >3cm: 53.2, <3cm: 50.4	40 Gy/28 fx
NOAC (Nordic) risk-adapted	Standard elective volume	—	External iliac only if T3-4 or N+; superior border: inf SI joint for T1-2N0 not into rectum; 2 cm above if tumor extends <1 cm into rectum

Feng ASTRO Guideline (PRO 2025) — Dose & Tissue Summary

ASTRO 2025 endorses risk-adapted contouring (RTOG 0529 / AGITG / UK all acceptable). De-intensified dosing (DECREASE, ACT 4) supported for T1-T2N0 <4 cm in select protocols. CRT with 5-FU/mito or cape/mito remains SOC. Normal-tissue tolerance: general IMRT pelvic constraints (small bowel, femoral heads, genitalia, bone marrow); intrafraction vaginal dilator (DILANA trial) for vaginal stenosis.

De-escalation: PLATO Family + DECREASE

Trial	Design	Result
PLATO ACT 3 (Phase II)	T1N0-Nx anal margin s/p local excision: margin >1 mm → obs; ≤1 mm → CRT 41.4 Gy/23 fx + cape, involved field	—
PLATO ACT 4 (Gilbert Lancet Oncol 2025)	T1-T2 <4 cm N0, randomize: standard 50.4 Gy/28 vs reduced 41.4 Gy/23 fx + cape/mito	6mo cCR 87% vs 92%. More RT breaks (26% vs 15%) & chemo dose mods (49% vs 37%) with standard. Acute G3+ 46% vs 35%. 3y LC pending
ECOG EA 2182 DECREASE	T1-T2N0 <4 cm: standard 50.4/42 Gy full pelvis + mito/5-FU×2 vs de-intensified (T1: 36/32; T2: 41.4/34.5) true pelvis + 5-FU×1 or cape	Closed; 2y DC >85% target, HRQoL endpoint. Results pending

Dose Escalation: PLATO ACT 5 (Hawkins GI ASCO 2026)

T2N+, T3-4 anyN. Standard 53.2 Gy/28 vs escalated 58.8/28 vs 61.6/28, all 40 Gy/28 elective, + cape/mito. Phase II primary: G3+ neutropenia (6-9%, all acceptable). Both escalation arms moved to phase III. 6mo cCR ~66% all three arms — no early benefit to dose escalation. 3y LC primary endpoint pending.

Proton Therapy (Lee IJROBP 2024)

39 pts stage I-III, RTOG 0529 dosing with 5-FU/mito. Acute toxicity similar to photon RTOG 0529. Overall G2+ late 46% vs 75% (p=0.01); G2+ derm 0% vs 25% (p<0.01); G3+ similar. Oncologic outcomes comparable.

IO + CRT for High-Risk Anal Cancer

EA 2165 (ongoing): T3-T4N0 or T2-T4N1 → standard CRT + adjuvant nivolumab ×6 cycles. Target 2y DFS 65% → 78%. N=383 accrued.
RADIANCE: T2 >4cm, N+, T3-4; CRT ± durva q4wk ×12. 3y DFS endpoint.
INTERACT-ION (Kim Lancet Oncol 2025): 54 stage III SCC, induction mDCF (docetaxel/cis/5-FU) + ezabenlimab ×3-5 → restage → if major response: involved-node CRT + cape/mito + ezabenlimab maintenance; if not: standard CRT. 40wk cCR 87% (INRT) and 69% (standard CRT).

PART VI — CROSS-CUTTING HIGH-YIELD POINTS

ESOPEC (2025) replaces CROSS as SOC for resectable esophageal adenocarcinoma — peri-op FLOT over CRT → surgery. 5y OS 50.6% vs 38.7%. Still use CROSS for SCC, cervical esophageal, non-FLOT candidates, or organ preservation.
CheckMate 577: adjuvant nivo after neoadj CRT + R0 with path residual (not ypCR). DFS benefit regardless of histology/PD-L1; OS not significant.
MATTERHORN: first positive peri-op ICI + FLOT for gastric/GEJ ACA. 2y OS 75.7% vs 70.4% (p=0.03).
SANO validates active surveillance after CROSS for esophageal cCR — 50% of pts with CCR can avoid esophagectomy. Only 35% achieve CCR; cN2-3 sustained CCR only ~11%.
PREOPANC → BRPC subgroup benefits from pre-op gem-based CRT (HR 0.67 OS). Resectable subgroup: no RT benefit. PREOPANC-2: TNT FFX equivalent to Gem/CRT.
SMART Trial (50/5 MR-guided ablative): 2y OS 53.6%, 2y LC 78% in LAPC. Best when >3 mo chemo done, no progression, CA 19-9 <500.
NRG consensus pancreas CTV: triangle volume — celiac/SMA/CHA/portal-SMV space. High-risk CTV includes entire vessel diameter if within 5 mm of gross disease.
RTOG 1112: SBRT 27.5-50 Gy/5 fx (median 35) + sorafenib improves OS vs sorafenib alone in HCC with MVI (HR 0.72 on MVA). Vascular response 38% vs 9%.
Xi JCO 2025: SBRT non-inferior (and better 2y LPFS 92.7% vs 75.8%) to RFA for recurrent HCC ≤5 cm. Kim J Hepatol 2021: protons non-inferior to RFA for ≤3 cm.
CCTG HE1: 8 Gy × 1 to liver for pain palliation — 67% pain response vs 22% BSC alone.
PROSPECT: favorable T2N1 / T3N0-1 (excluded T4, ≥4 LNs, CRM <3 mm, non-LAR) can safely skip RT if >20% FOLFOX response; only 9% need CRT rescue. Better sexual function / less fatigue at 1y post-op vs CRT arm.
PRODIGE 23 at 7y: OS benefit of TNT (81.9% vs 76.1%) with FFX ×6 upfront → CRT → TME → adjuvant FOLFOX ×3 mo.
RAPIDO 5y: caution with SC-TNT for low tumors — LR higher (10% vs 6%; distal margin <1 cm: 25.4% vs 1.8%). Use LC CRT for distal, MRF-threatened, or sphincter-preserving cases.
OPRA: watch-and-wait after TNT, organ preservation ~50%. 94% of regrowths within 2 yrs, nearly all in bowel wall. Salvage surgery after regrowth has equivalent DFS to upfront TME.
OPERA: contact X-ray brachy boost (90 Gy/3 fx to surface) increases 3y organ preservation from 59% → 81%; in tumors <3 cm, 63% → 97%.
Cercek dostarlimab NEJM 2025: 100% cCR in dMMR rectal cancer — obviates RT and TME. Check MMR/MSI on every rectal cancer.
Anal cancer: 5-FU + mito + IMRT (RTOG 0529) is SOC. Neither cis nor maintenance chemo superior (ACT II). Mito required (RTOG 87-04).
PLATO ACT 4 (de-escalation for T1-T2 <4cm N0): 41.4/23 fx may be sufficient — 6mo cCR 92% vs 87% standard, fewer breaks.
PLATO ACT 5 (escalation for T3-4/N+): both 58.8 & 61.6 Gy survived phase II safety — but 6mo cCR all ~66%. 3y LC pending.
Anal protons: G2+ late 46% vs 75%; G2+ derm 0% vs 25%. No G3+ difference.
Pancreas ablative doses (memorize): SMART 50/5 (BED 100); Reyngold 67.5/15 (BED 98) if >1 cm from GI, 75/25 if ≤1 cm. NRG: high-dose per fx 10 (5fx), 4.5 (15fx), 3 (25fx); low-dose 6.6, 2.5, 1.8.
Esophageal definitive RT dose ceiling 50 Gy (RTOG 8501 / ARTDECO) — dose escalation to 61.6 SIB did not help LC or OS.
Esophageal SCC > ACA pCR with CRT (49% vs 23% CROSS); SCC more likely durable response to definitive CRT / AS.

KEY LANDMARK TRIALS (memorize)

Trial	Disease	One-line takeaway
CROSS (2012/2021)	Esoph/GEJ T1N1 / T2-3N0-1	41.4/23 + carbo/tax → surgery: 10y OS 38% vs 25%. Foundational for trimodality
NEOCRTEC5010 (2018)	Esoph SCC T1-4N1/T4N0	Cis/vinorelbine + 40/20 → sg: pCR 43%, OS 100 vs 66.5 mo
CALGB 80803 (2021)	Esoph/GEJ ACA	PET-directed chemo change during CRT improves pCR in non-responders
CheckMate 577 (2021)	Esoph/GEJ, path residual after CRT + R0	Adjuvant nivo 1y: DFS 22.4 vs 11.0 mo; OS NS
MAGIC (2006) / FLOT4 (2019)	Gastric/GEJ ACA peri-op	FLOT×4+4 established as SOC (3y OS 57 vs 48%)
Neo-AEGIS / TOPGEAR	Esoph/GEJ ACA	Peri-op chemo = CRT → sg for 3y OS
ESOPEC (2025)	Esoph ACA T1N+/T2-4a	FLOT beats CROSS-CRT: 3y OS 57.4 vs 50.7%; distant mets driver
MATTERHORN (2025)	Gastric/GEJ ACA resectable	Peri-op FLOT + durva: 2y OS 75.7% vs 70.4% (p=0.03), pCR 19.2 vs 7.2%
RTOG 8501 (1992/1999)	Esoph definitive	50 Gy + cis/5-FU: 5y OS 27% vs 0%. Established 50 Gy ceiling
ARTDECO (2021)	Esoph definitive	61.6 Gy SIB did NOT improve LC or OS over 50.4
SANO (2025)	Esoph cCR after CROSS	2y OS 74% vs 71% — AS non-inferior to esophagectomy
CONKO-001 (2013)	Pancreas adj	Gem adj: 5y OS 20.7% vs 10.4% obs
PRODIGE 24 (2022)	Pancreas adj	mFOLFIRINOX: median OS 53.5 vs 35.5 mo (gem)
RTOG 0848 (2024)	Pancreas head R0/R1	Adjuvant CRT: DFS benefit overall; OS + DFS in node-negative subgroup
PREOPANC (2020/2022)	Resectable + BRPC	Gem + 36/15: BRPC subgroup OS HR 0.67 (p=0.045); R0 72% vs 43%
PREOPANC-2 (2025)	Resectable + BRPC	TNT FFX vs Gem/CRT: OS equivalent (21.9 vs 21.3 mo); ypN0 better with CRT
Alliance A021501 (2022)	BRPC	FFX+SBRT arm closed; FFX alone 18mo OS 66.7% (better than historical)
CONKO-007 (2025)	LAPC	Induction chemo ± CRT (50.4 Gy): in surgical pts 5y OS 11% vs 25% with CRT
SMART (2024)	LAPC / BRPC	MR-guided 50/5: 2y OS 53.6%, 2y LC 78%
EXTEND (2024)	Oligomet pancreas	Chemo+MDT SBRT: PFS HR 0.43; systemic T-cell activation
RTOG 1112 (2025)	LA HCC with MVI	SBRT 27.5-50/5 + sorafenib: OS HR 0.72 MVA; vascular response 38% vs 9%
Bush 2023 (PBT vs TACE)	HCC	PBT 70.2/15: equal OS but better LC (HR 5.64), less hospitalization
Xi JCO 2025	Recurrent HCC ≤5cm	SBRT 36-54/3: 2y LPFS 92.7% vs 75.8% (RFA)
CCTG HE1 (2024)	Liver pain palliation	8 Gy × 1: 67% pain response vs 22%
Dutch/German (2012)	Rectal T3-4/N+	Preop RT ↓ LR (~5-7% vs 10-14%), no DM benefit
PRODIGE 23 (2024 long-term)	Rectal cT3-4	TNT FFX→CRT→TME: 7y OS 81.9 vs 76.1%
RAPIDO (2021/2023 5y)	High-risk rectal	SC-TNT: pCR 28%, lower DM; but 5y LR higher (10% vs 6%); caution for distal tumors
STELLAR (2022)	Rectal cT3-4/N+	SC+CAPEOX: non-inferior DFS, 3y OS 86.5% vs 75.1%
PROSPECT (2023)	Favorable rectal T2N1/T3N0-1	FOLFOX ± RT: only 9% need RT; 5y DFS 80.8 vs 78.6%; better QoL in FOLFOX arm
OPRA (2022)	Rectal stage II/III	TNT + W&W: organ preservation ~50%; 94% regrowths in 2y
OPERA (2023)	Small cT2-T3a/b rectal	CXB boost 90/3: 3y organ preservation 81% vs 59%
Cercek (2022/2025)	dMMR rectal II/III	Dostarlimab x9 (6mo): 100% cCR, 2y RFS 96%, RT+TME omitted
UK ACT-1 (1996/2010)	Anal canal	RT+5-FU/mito > RT alone (5y LC 68 vs 43%)
RTOG 87-04 (1996)	Anal canal	Mito required: CFS 71% vs 59%
RTOG 9811 (2008/2011)	Anal canal	5-FU/mito beats 5-FU/cis: colostomy 10 vs 19%; 5y OS 78 vs 71%
ACT II (2013)	Anal canal	Neither cis nor maintenance chemo superior
RTOG 0529 (2013)	Anal canal	Dose-painted IMRT: halved G3+ GI and derm toxicity vs 9811
PLATO ACT 4 (2025)	Anal T1-T2 <4cm N0	41.4/23 short-term cCR equivalent to 50.4/28 with fewer breaks
INTERACT-ION (2025)	Stage III anal SCC	Induction mDCF+ezabenlimab → involved-node CRT: 40wk cCR 87%