Trending Topics in Gastroenterology | GastroAGI

CRLM Prognosis Reimagined: From Static Scores to Dynamic Precision Oncology ESMO Open | April 2026

Introduction Colorectal cancer liver metastases represent a major determinant of survival in colorectal cancer, affecting more than half of patients. While hepatic resection remains the cornerstone of curative therapy, recurrence rates remain high, reflecting the biological heterogeneity of disease. Traditionally, clinical risk scores such as the Fong score have guided decision-making, but these models are largely based on static anatomical and clinical parameters, limiting their relevance in the era of precision oncology. Problem Statement Conventional clinical risk scores fail to capture tumor biology and dynamic disease behavior, limiting accurate prognostication and personalized treatment decisions in CRLM. Summary This review highlights a paradigm shift in CRLM risk stratification—from static clinical models to biologically informed and dynamic frameworks. Classical scores, although useful, are insufficient to predict long-term outcomes or treatment response. Emerging tools now incorporate molecular profiling (e.g., RAS, BRAF, MSI status), histological growth patterns, and liquid biopsy techniques such as circulating tumor DNA (ctDNA). Molecular markers refine prognosis and guide therapy, with KRAS and BRAF mutations indicating worse outcomes, while MSI tumors may respond better to immunotherapy. Histological growth patterns further stratify risk, with desmoplastic patterns associated with better prognosis and replacement patterns linked to aggressive disease. Most importantly, dynamic biomarkers such as ctDNA are transforming management. Preoperative ctDNA predicts recurrence risk, while postoperative ctDNA identifies minimal residual disease and can guide adjuvant therapy decisions with high accuracy. Overall, the integration of clinical, molecular, and dynamic data enables adaptive, real-time risk stratification. This evolving approach supports better patient selection, optimized timing of surgery and systemic therapy, and represents a major step toward true precision oncology in CRLM.

MORPHEUS-PDAC Umbrella Trial: The Oncologist | April 2026

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year survival of only 10–13%. A major biological challenge is its “cold tumor” microenvironment—characterized by dense stroma and poor immune cell infiltration—which renders conventional immunotherapy largely ineffective. Despite multiple trials, chemotherapy continues to dominate both first- and second-line treatment, with only modest survival benefits. Given repeated failures of traditional drug development in PDAC, there is an urgent need not only for effective therapies but also for innovative trial designs that can rapidly identify promising treatment combinations. Problem statement The central challenge is whether combining immunotherapy with agents targeting the tumor microenvironment can overcome immune resistance in PDAC and improve outcomes in previously treated patients. Summary The MORPHEUS-PDAC umbrella trial represents an innovative platform study designed to evaluate multiple atezolizumab-based combinations simultaneously in advanced, pretreated PDAC. The rationale was biologically strong: combining PD-L1 blockade with agents that enhance immune infiltration (motixafortide), improve antigen presentation (cobimetinib), or stimulate cytotoxic immune cells (simlukafusp alfa). However, despite this mechanistic promise, clinical efficacy was disappointing. In the second-line setting, objective response rates were very low (0–7%), comparable or inferior to standard chemotherapy. Even in the third-line setting, modest responses (14–16%) were observed, but without meaningful clinical impact. Safety profiles were manageable but did not translate into therapeutic benefit. The most important takeaway is not the failure of individual combinations but the confirmation of PDAC’s profound resistance to immunotherapy—even when biologically rational combinations are used. Importantly, the study highlights the value of platform trial designs, which allow rapid screening of multiple strategies with fewer patients and faster decision-making. In essence, while atezolizumab-based combinations failed to deliver clinical benefit, the MORPHEUS model may represent the future of drug development in difficult cancers like PDAC.

Duloxetine for Prevention of Oxaliplatin-Induced Neuropathy (OIPN): JCO Oncology Advances | April 2026

Introduction Oxaliplatin-induced peripheral neuropathy (OIPN) is a common, dose-limiting toxicity in colorectal cancer treatment, significantly impacting quality of life and long-term functional outcomes. Duloxetine, already proven effective for the treatment of established chemotherapy-induced neuropathy, has been explored as a preventive strategy. Problem Statement Despite multiple attempts, there is no established therapy to prevent OIPN. Whether early initiation of duloxetine (30 mg or 60 mg) can reduce the incidence or severity of neuropathy during oxaliplatin-based chemotherapy remains unclear, representing a critical unmet clinical need. Summary This randomised, double-blind phase II trial demonstrated that duloxetine, at both 30 mg and 60 mg doses, did not significantly reduce the incidence or severity of OIPN compared to placebo. Response rates were similar across all groups (~65–68%), indicating no preventive benefit. Importantly, duloxetine was well-tolerated with manageable toxicity. Overall, the study confirms that duloxetine should not be used for the prevention of OIPN and highlights the continued lack of effective preventive strategies in this setting.

Subcutaneous Pembrolizumab: Journal of Clinical Oncology | April 2026

Introduction Immune checkpoint inhibitors like Pembrolizumab have transformed oncology care across multiple solid tumours. Recently, a subcutaneous (SC) formulation has been introduced using hyaluronidase technology, promising faster administration, improved patient convenience, and reduced infusion burden. This transition from intravenous (IV) to SC delivery is being positioned as a patient-centred innovation in cancer care. Problem Statement Despite enthusiasm, the key question remains: does SC pembrolizumab truly improve patient outcomes or system efficiency—or is it primarily a commercial strategy? Several concerns emerge: Approval is based on pharmacokinetic non-inferiority, not clinical superiority No meaningful improvement in survival, efficacy, or safety Timing coincides with patent expiry, suggesting “patent hopping” Fixed high-dose SC regimens limit: Dose optimization Cost-saving strategies (e.g., weight-based dosing, vial sharing) Real-world “convenience” may be overestimated due to: Pre-injection logistics (drug warming, scheduling) Combination therapy with chemotherapy (no time saving) Increased system complexity (home administration challenges) Core issue: Is convenience being used to justify increased healthcare costs without added value?

FOLFIRINOX in Digestive NEC: J of Neuroendocrinology | April 2026

Introduction Digestive neuroendocrine carcinomas (NEC) are rare but highly aggressive malignancies with poor prognosis and limited therapeutic options. Standard first-line therapy consists of platinum plus etoposide, extrapolated from small-cell lung cancer, but outcomes remain suboptimal, particularly in colorectal NEC and tumours with intermediate Ki67 (20%–55%). In the absence of established second-line therapies, regimens effective in adenocarcinomas, such as FOLFIRINOX, are increasingly being explored in this setting. Problem Statement There is a significant unmet need for effective second-line or later-line treatment in digestive NEC. Current evidence is scarce, and treatment decisions are largely empirical, especially for patients progressing after platinum-based therapy or those with biologically distinct subgroups such as lower Ki67 tumours. Summary This Scandinavian multicenter retrospective study evaluated FOLFIRINOX in 50 patients with digestive NEC. The regimen demonstrated promising activity with an overall response rate of 44% and a disease control rate of 72%, alongside a median progression-free survival of 5.6 months. Notably, efficacy was maintained in challenging subgroups, including colorectal primaries, Ki67 <55%, and patients previously treated with platinum–etoposide. These findings suggest that FOLFIRINOX may represent a valuable therapeutic option beyond first-line treatment in NEC. Although limited by retrospective design, this study provides important real-world evidence supporting broader consideration of FOLFIRINOX in aggressive neuroendocrine malignancies.

Tumour Location in Resected Pancreatic Cancer: AJS | April 2026

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with survival rates rarely exceeding 10% at 5 years despite advances in surgery and systemic therapy. While tumour biology and stage are well-established prognostic factors, the role of tumour location—head versus body/tail—has remained controversial, with prior studies yielding inconsistent results. Problem Statement Existing evidence on the prognostic impact of tumour location in PDAC is limited by heterogeneity in study design, small sample sizes, and inadequate adjustment for confounding variables. This uncertainty creates difficulty in clinical decision-making, particularly regarding surgical risk stratification, perioperative planning, and patient counselling. Summary This large multi-institutional TriNetX analysis provides robust evidence that tumor location significantly influences outcomes after resection. Tumors located in the pancreatic head are associated with higher perioperative mortality, increased risk of sepsis, and worse long-term survival compared to body/tail tumors. Even after propensity matching, head tumors demonstrated shorter median survival and higher overall mortality, confirming tumor location as an independent prognostic factor. These findings highlight the need for location-specific surgical strategies, risk assessment, and postoperative management to improve outcomes in PDAC.

Top 10 GI Oncology Updates: Oncology News/ March 2026

1. ESOPEC Trial (Oesophagal Cancer) Neoadjuvant chemoradiotherapy may have underperformed due to radiotherapy quality issues (e.g., lymphopenia). Do not abandon the CROSS approach yet—patient selection remains key. 2. ORCHESTRA Trial (Metastatic CRC) Adding tumour debulking to chemotherapy in multiorgan metastatic CRC does not improve outcomes → systemic therapy remains the mainstay. 3. Rare Pancreatic Cancer – Targeted Therapy Molecular profiling of rare subtypes is opening new precision treatment pathways, highlighting heterogeneity in pancreatic cancer. 4. Federated Learning in Rare Tumours Global collaboration without sharing patient data is now possible → enables large-scale research in rare cancers with privacy preserved. 5. PERISCOPE II Trial (Gastric Cancer) CRS + HIPEC does not improve survival in gastric cancer with peritoneal spread and increases toxicity → systemic therapy remains standard. 6. AI-Based Treatment Selection (PDAC) AI models can personalise second-line therapy → FOLFIRINOX for fit patients Nal-IRI + 5FU for selected subgroups 7. BBOpCo Trial (MSS Colorectal Cancer) First signal that immunotherapy may work in MSS CRC → opens door for biomarkers and combination strategies. 8. Organoids in Oncology Patient-derived organoids may reduce drug failure rates and improve personalised therapy → future of translational oncology. 9. FLOT + Durvalumab (Gastroesophageal Cancer) Now approved → new perioperative standard, aiming to improve cure rates. 10. Aspirin in PIK3CA-Mutated CRC Adjuvant aspirin shows DFS benefit in selected patients → strong move toward biomarker-driven therapy.

Atezolizumab + FOLFOX in Stage III CRC: NEJM| March 2026

Introduction Stage III colon cancer is traditionally treated with adjuvant oxaliplatin-based chemotherapy such as FOLFOX. However, tumours with mismatch repair deficiency (dMMR) represent a biologically distinct subgroup with high immunogenicity and responsiveness to immune checkpoint inhibition in metastatic settings. Whether this immunotherapy benefit can be translated into the curative, adjuvant setting has remained a critical unanswered question. The ATOMIC trial addresses this gap by evaluating the addition of atezolizumab, a PD-L1 inhibitor, to standard mFOLFOX6 in resected stage III dMMR colon cancer. Problem Statement Despite standard adjuvant chemotherapy, recurrence rates in high-risk stage III colon cancer remain significant. dMMR tumours, although prognostically favourable in early stages, still demonstrate recurrence risk in stage III disease. The key clinical challenge has been whether incorporating immunotherapy early—before recurrence—can meaningfully improve disease-free survival and potentially cure rates. Summary In this phase III trial, adding atezolizumab to mFOLFOX6 significantly improved outcomes. At a median follow-up of 40.9 months, 3-year disease-free survival was 86.3% in the combination group compared to 76.2% with chemotherapy alone, translating to a 50% reduction in recurrence or death risk. This represents one of the first strong pieces of evidence supporting immunotherapy in the adjuvant setting for colon cancer. However, this benefit came with increased grade 3–4 adverse events (84.1% vs 71.9%), highlighting the need for careful patient selection. Overall, this study marks a major step toward precision oncology in early-stage colon cancer, potentially redefining the standard of care for stage III dMMR disease.

Adjuvant Therapy After Neoadjuvant Treatment in Resected Pancreatic Ann of Surg Onco — March 2026

Introduction The management of pancreatic ductal adenocarcinoma (PDAC) has increasingly shifted toward the use of neoadjuvant therapy (NAT) before surgical resection. NAT aims to improve resectability, treat micrometastatic disease early, and select patients with favourable tumour biology. However, an important unresolved question is the role of adjuvant therapy (AT) after patients have already received NAT followed by surgery. It remains unclear whether additional postoperative chemotherapy provides a survival benefit and how the type and duration of NAT influence the need for AT. Summary This multicenter study analysed 651 patients with PDAC who received NAT followed by surgical resection between 2010 and 2019. Patients were categorised according to the NAT regimen: Gemcitabine-based NAT: 200 patients (30.7%) 5-fluorouracil (5-FU)–based NAT: 362 patients (56%) Switched NAT regimen: 89 patients (13.7%) Key findings: Median overall survival (OS): Gemcitabine-based NAT: 19 months 5-FU–based NAT: 26 months Switched regimen: 21 months 5-FU–based NAT was associated with improved survival compared with gemcitabine-based NAT (HR 0.81, p = 0.04). The optimal NAT duration was approximately 3.6 months. Adjuvant therapy significantly improved survival overall (HR 0.61, p < 0.001). However, the survival benefit of AT diminished when NAT duration exceeded 5 months, suggesting that prolonged preoperative treatment may reduce the need for postoperative chemotherapy. Clinical Implication In patients undergoing resection for PDAC after NAT, 5-FU–based neoadjuvant regimens appear superior to gemcitabine-based therapy. Adjuvant chemotherapy remains beneficial, particularly when preoperative NAT duration is short, highlighting the importance of personalising postoperative therapy based on prior treatment exposure.

First-Line Chemotherapy and Durvalumab in Advanced BTC: Oncology Advances — March 2026

Patients with advanced biliary tract cancer (BTC) often have limited life expectancy, making quality of life and time spent receiving medical care (“time toxicity”) important considerations when selecting systemic therapy. This multicenter retrospective study evaluated whether adding durvalumab to gemcitabine–cisplatin (GCD) increases healthcare-related time burden compared with gemcitabine–cisplatin alone (GC). The study included 193 patients treated between 2019 and 2024 across centres in the United States, Japan, and Brazil. Among them, 102 received GCD and 91 received GC. The median time on treatment was 156 days, and the median proportion of time spent in healthcare systems was 14.4%. Most healthcare contacts consisted of planned visits (11.9%), while unplanned visits were uncommon (1.8%). Although patients receiving GCD remained on treatment longer than those receiving GC (212 vs 134 days), the overall time to toxicity was similar between groups (27 vs 18 days). Time toxicity strongly correlated with treatment duration and progression-free survival, indicating that longer treatment exposure naturally increases healthcare contact time. Multivariable analysis showed that younger patients and those with poorer performance status experienced higher time toxicity. Overall, the study highlights time toxicity as an important patient-centred metric in advanced cancer care. The addition of durvalumab to gemcitabine–cisplatin prolongs treatment duration without increasing the proportion of time spent receiving healthcare, providing useful information for shared decision-making between clinicians and patients when balancing survival benefits and quality of life.