GI Oncology Daily Digest

This is the molecular ancillary study of PRODIGE-24/CCTG PA6, the phase III trial that made adjuvant mFOLFIRINOX (mFFX) the standard after resection of pancreatic ductal adenocarcinoma. Tumour DNA sequencing succeeded in 317 of 350 tumours (168 mFFX, 149 gemcitabine), with transcriptomic subtyping by the PurIST classifier, four PDAC driver genes, 24 homologous-recombination-repair (HRR) genes, and single-base-substitution signatures. Two findings stand out. First, PurIST subtype was prognostic within the mFFX arm — classical tumours had markedly better disease-free survival than basal-like tumours (stratified HR 0.48, 95% CI 0.31–0.77). Second, and more provocatively, the mFFX benefit over gemcitabine was confined to KRAS-mutant tumours (sHR 0.60, 95% CI 0.45–0.79, p<0.001), with no benefit detected in KRAS-wild-type tumours and a formal interaction test of p=0.010. HRR gene status was not predictive, and the mFFX advantage held across SBS-signature-positive and -negative subgroups. The authors are careful: these results do not support a change in adjuvant strategy, mFFX remains standard, and the KRAS-wild-type observation is hypothesis-generating.

A secondary analysis of a randomized controlled trial in which 157 patients discharged after colorectal cancer surgery received either dietary advice alone (n=77) or dietary advice plus three months of oral nutritional supplements (ONS, n=80) while undergoing adjuvant chemotherapy. At three months the conventional nutritional markers — body weight, BMI, skeletal muscle index, albumin, haemoglobin — showed no significant separation between arms, which is the result most nutrition trials stop at. The clinical endpoints did separate. Chemotherapy modification (dose reduction, delay, or discontinuation) occurred in 17.5% of the ONS group versus 35.1% of controls (p=0.01), and at five years the ONS group had lower all-cause mortality with a hazard ratio of 0.58 (95% CI 0.34–0.98, p=0.04). The mechanism is unexplained by the nutritional indices measured, which the authors acknowledge and flag for further study.

A PROSPERO-registered systematic review and meta-analysis (CRD42024508349) of non-implantable intraoperative radiotherapy (IORT) in colorectal cancer, covering 25 studies and 2,664 patients searched through November 2023. The techniques pooled are IOERT, kilovoltage IORT, and HDR-IORT; typical doses were 15 Gy (range 10–20) for IOERT and HDR-IORT and a median of 12.5 Gy for KV-IORT. Patients receiving IORT trended toward better 5-year overall survival, with IOERT contributing most of that difference, and showed a clearer advantage in long-term local control (OR 2.08, 95% CI 1.19–3.64), stronger still in the IOERT subset (OR 2.23, 95% CI 1.07–4.65). Importantly for a modality that gets rejected on safety grounds, IORT was not associated with higher rates of anastomotic leakage, pelvic collections, wound complications, or bowel obstruction. The authors are appropriately restrained about heterogeneity across the included studies.

A single-arm phase II trial (ChiCTR1900024628) of neoadjuvant concurrent chemoradiotherapy with nedaplatin plus paclitaxel or albumin-bound paclitaxel and 41.4–50.4 Gy in locally advanced esophageal squamous cell carcinoma. Of 49 enrolled patients, 33 proceeded to surgery, giving a pathological complete response rate of 30.3% — in the range reported for cisplatin-based neoadjuvant chemoradiotherapy, which matters because nedaplatin is used specifically to reduce nephrotoxicity and emesis. Overall survival was worse in resected patients with positive postoperative nodes (HR 3.92, 95% CI 1.30–11.80, log-rank p=0.009). Immunohistochemical profiling of paired biopsies and surgical specimens found that higher FOXP3 expression before (HR 0.14) and after (HR 0.23, p=0.03) treatment associated with better outcomes, while post-treatment TIGIT upregulation trended toward worse prognosis (HR 7.10, 95% CI 0.79–63.65) — all with wide confidence intervals and framed by the authors as hypothesis-generating.