GI Oncology Daily Digest

RTOG 0848 is the long-awaited definitive test of whether adding fluoropyrimidine-sensitized chemoradiotherapy (CXRT) to adjuvant chemotherapy improves survival after curative-intent resection of pancreatic head adenocarcinoma. In this two-step Phase 3 trial, 354 patients who had completed 5 cycles of gemcitabine-based chemotherapy without progression were randomized to a 6th cycle ± CXRT (chemotherapy alone n=174, chemotherapy+CXRT n=180). The primary endpoint was not met: median OS was 2.6 vs 2.3 years and 5-year OS 23.1% vs 27.9% (HR 0.96, 90% CI 0.79–1.18, two-sided p=0.77). DFS trended in favor of CXRT (HR 0.82, p=0.089). Grade 4/5 toxicity was not increased, though grade 3 toxicity rose (38% vs 19%). The clinically important signal came from a prespecified treatment-by-nodal-status interaction: in node-negative patients, CXRT significantly improved both OS (p=0.0063) and DFS (p=0.014). The authors conclude that adjuvant CXRT does not benefit unselected patients but may help the node-negative subset — a hypothesis worth confirming with modern systemic backbones.

TESAR asked whether adjuvant chemoradiotherapy can serve as an organ-preserving alternative to completion total mesorectal excision (cTME) after local excision of high-risk pT1 / low-risk pT2 rectal cancer. This open-label Phase 3 non-inferiority trial across 25 Dutch and French hospitals randomized 197 (ITT) patients to adjuvant chemoradiotherapy (25 × 1.8 Gy to the mesorectum plus capecitabine) or cTME. At a median 50 months, 3-year locoregional recurrence was 5.0% vs 1.1% — formally failing the 7% non-inferiority margin (difference 3.9%, one-sided p=0.16), partly because loss of equipoise stalled accrual before the 302-patient target. However, four of five recurrences were salvaged, leaving a 3-year unsalvageable recurrence rate of just 1.3% vs 0%, and 3-year OS was identical (98.9% in both arms). The trade-off favored organ preservation elsewhere: the 3-year stoma rate was dramatically lower with chemoradiotherapy (2.6% vs 45.4%, p<0.0001), grade ≥3 toxicity was modest (9.5%), and quality of life was comparable or better. The authors argue these data challenge cTME as the automatic standard of care for this population.

This multicentre, single-arm Phase Ib/2a study tested fostroxacitabine bralpamide (fostrox) — a liver-targeted nucleotide prodrug that releases its active payload preferentially in hepatocytes — combined with standard-dose lenvatinib in 21 patients with advanced HCC who had progressed on first- or second-line therapy, most after immunotherapy. The recommended Phase 2 dose of fostrox was 30 mg, with no dose-limiting toxicities; fostrox-related adverse events were mainly transient neutropenia and thrombocytopenia, and there were no signs of treatment-related liver-function deterioration. Efficacy was encouraging for a refractory population: ORR 24%, DCR 81%, median time to progression 10.9 months, median PFS 6.7 months, and median OS 13.7 months. Tumour biopsies confirmed tumour-selective DNA damage, supporting the liver-targeting mechanism. The data support further investigation as a post-immunotherapy second-line option, though the small single-arm design tempers conclusions.

This single-center, non-comparative randomized Phase 2 trial enrolled 72 patients with locally advanced HCC, allocating them 1:1 to hepatic arterial infusion chemotherapy (HAIC) plus either toripalimab (TorHAIC) or sorafenib (SoraHAIC) every three weeks. The primary endpoint, 6-month PFS rate, was 63.9% for TorHAIC versus 61.1% for SoraHAIC. Secondary outcomes numerically favored the immunotherapy arm: median OS 20.9 vs 16.4 months and median PFS 9.1 vs 7.2 months. Grade 3–4 adverse events were less frequent with TorHAIC (33.3% vs 44.4%), as were serious adverse events (2 vs 5 patients). Because the trial was explicitly non-comparative and single-center, the numbers are hypothesis-generating rather than practice-changing, but they add to the case for combining locoregional HAIC with PD-1 blockade and warrant a Phase 3 confirmation.

Only a minority of H. pylori–infected individuals progress along Correa's cascade toward gastric cancer, and classical virulence markers explain little of this heterogeneity. The authors assembled 528 high-quality H. pylori whole-genome sequences spanning nonatrophic gastritis, atrophic gastritis, intestinal metaplasia, and gastric cancer, and performed bacterial genome-wide association analysis with explicit adjustment for population structure. Variants associated with advanced lesions were integrated into a random-forest H. pylori Genomic Risk Score (HpRS). HpRS discriminated strains linked to advanced (IM/GC) versus nonadvanced (NAG/AG) lesions with a mean cross-validated AUC of 0.902 (95% CI 0.892–0.912), held up in an internal test set (AUC 0.780), and generalized to two independent cohorts (AUC 0.871 and 0.843). Predictive SNPs mapped to core functions — DNA repair, translation, and lipid metabolism — suggesting a polygenic architecture. Co-authored by Nobel laureate Barry Marshall, the score is a proof-of-principle for strain-aware gastric-cancer risk stratification that could complement future prevention strategies.