Oncology

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.

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.

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.

Introduction Treatment decisions in advanced cancer often involve a balance between extending survival and preserving quality of life (QoL). Older adults frequently face complex choices because aggressive treatments may prolong life but also increase toxicity, hospitalisations, and functional decline. Understanding whether patient preferences influence real-world outcomes is essential for patient-centred oncology care. Summary This secondary analysis evaluated 706 adults aged ≥70 years with advanced incurable cancers enrolled in the GAP70+ trial. Patients were categorised based on whether they prioritised maintaining quality of life or prolonging survival when starting systemic therapy. 71.7% (506 patients) prioritised quality of life 8.4% (59 patients) prioritised survival The most common cancers were gastrointestinal (34.6%), lung (24.8%), and genitourinary (15.4%) Despite differing priorities, clinical outcomes were similar between groups: No difference in treatment modifications No difference in grade 3–5 treatment-related adverse effects No difference in hospitalisation rates No difference in survival at 6 months or 1 year Key Message Most older adults with advanced cancer prefer maintaining quality of life over extending survival, yet this preference did not translate into different treatment approaches or outcomes, suggesting that current oncology care systems may not adequately align treatment decisions with patient preferences.

Introduction Total neoadjuvant therapy (TNT) has become a major advance in locally advanced rectal cancer, helping improve systemic control, increase tumor response, and expand the possibility of organ preservation. However, most trials and guidelines still treat rectal cancer as a single disease entity. This review argues that this is an oversimplification. Tumor location matters, especially when comparing mid-rectal and low-rectal cancers, because anatomy, lymphatic drainage, surgical difficulty, functional impact, and treatment goals differ substantially. Summary This review highlights that low-rectal cancers and mid-rectal cancers should be approached as distinct clinical entities rather than managed uniformly. Low-rectal tumors, particularly those within 1 cm of the anal ring, present special challenges. They have more complex local anatomy, more difficult lymphatic patterns, a higher risk of positive circumferential margins, and major implications for continence, sphincter preservation, and quality of life. In these tumors, a more intensive TNT strategy may be justified, especially when the goal is organ or sphincter preservation. In contrast, mid-rectal tumors are often more straightforward surgically, with a better chance of standard resection and preservation of function. For these cancers, the review suggests that treatment de-escalation, particularly regarding radiotherapy, may be reasonable in selected patients. Drawing on data from more than 80 studies and trials, the authors propose a location-specific, patient-centred strategy: De-escalate treatment in selected mid-rectal cancers Intensify or optimise TNT in low-rectal cancers when preservation is a priority Take-home message The key disruptive idea is simple: rectal cancer is not one disease anatomically or functionally. Future TNT strategies should be tailored by tumor height, oncologic risk, and patient priorities, not applied uniformly.

Why this review matters Obesity is no longer viewed only as a metabolic disorder; it is now a major cancer-promoting state. This review explains how excess adiposity drives cancer through intertwined biologic pathways, including chronic inflammation, hormonal dysregulation, immune suppression, altered energy metabolism, DNA damage, and gut microbiome disruption. For clinicians, the key message is practical: obesity is a modifiable cancer risk factor, and meaningful weight loss may reduce future cancer burden. Main clinical message Overweight and obesity are associated with higher rates of multiple cancers, especially endometrial, colorectal, liver, gallbladder, pancreas, kidney, postmenopausal breast, oesophagal adenocarcinoma, ovarian, thyroid, gastric, prostate, and multiple myeloma. The review estimates that obesity contributes to about 10% of new cancers annually in the US, and even more in selected tumour types such as endometrial and hepatobiliary malignancies. Key biologic pathways The review highlights 5 major mechanisms:

1. Adipose tissue dysfunction: enlarged adipocytes produce excess estrogens, leptin, inflammatory cytokines, and less adiponectin.
2. Chronic inflammation: IL-6, TNF-α, prostaglandin E2, and related mediators create a pro-tumor microenvironment.
3. Immune escape: obesity impairs cytotoxic T cells and NK cells while increasing immunosuppressive myeloid-derived suppressor cells.
4. Metabolic support for tumours: adipose tissue supplies free fatty acids and other fuels for cancer growth.
5. DNA damage and microbiome changes: oxidative stress and dysbiosis increase genomic instability and mucosal inflammation. Important epidemiologic insights Cancer risk is not determined by BMI alone. Patients with metabolically unhealthy obesity appear to have the highest cancer risk. The review also stresses that childhood and adolescent obesity trajectories may influence cancer risk later in life. Interestingly, obesity increases postmenopausal breast cancer risk, but may show a different association before menopause. Weight loss and cancer prevention The review suggests that modest weight loss may not be enough. A threshold of more than 10% body weight reduction may be needed to produce measurable reductions in obesity-related cancer risk. Observational data suggest benefit with: Bariatric surgery, especially for endometrial cancer risk reduction GLP-1 receptor agonists, with retrospective data suggesting a lower incidence of some obesity-related cancers Metformin and related metabolic therapies, though stronger prospective evidence is still needed Practice implications Clinicians should view obesity management as part of long-term cancer prevention, not only cardiovascular and metabolic risk reduction. Counselling should move beyond BMI to include metabolic health, waist circumference, adiposity pattern, and sustained weight-loss strategies. Multimodal care combining lifestyle measures, pharmacotherapy, and, in selected patients, bariatric surgery may have future oncologic relevance. Limitations of the review Much of the evidence linking weight loss interventions to lower cancer incidence remains observational, not randomised. Several mechanistic pathways are strongly biologically plausible but not yet fully translated into cancer prevention trials. Bottom line Obesity promotes cancer through multiple biologic pathways, and meaningful sustained weight loss may reduce this risk. This review strengthens the concept that treating obesity is also part of cancer prevention.

Introduction Colorectal cancer (CRC) screening strategies vary worldwide, with fecal immunochemical testing (FIT) widely used in population programs and colonoscopy dominating screening in the United States. The COLONPREV randomized trial previously showed that FIT-based screening was not inferior to colonoscopy for CRC incidence and mortality at 10 years, despite higher participation rates with FIT. However, colonoscopy consistently detects more premalignant lesions. This analysis explored an important clinical question: are the characteristics of precursor lesions different when detected through FIT-triggered colonoscopy versus primary screening colonoscopy? Summary This analysis from the COLONPREV trial compared colonoscopic findings in individuals undergoing primary screening colonoscopy with those undergoing colonoscopy after a positive FIT result. While colonoscopy detected more overall precursor lesions, individuals referred after abnormal FIT were significantly more likely to harbor advanced neoplastic lesions, including larger polyps (mean size 7.8 mm vs 5.6 mm), higher rates of villous architecture, and high-grade dysplasia. FIT-detected lesions were also more difficult to manage endoscopically, with higher rates of incomplete resection and surgical treatment. Despite these differences, lesion histology and anatomical distribution were similar between strategies. These findings suggest that FIT acts as a risk-stratification tool, enriching for clinically significant lesions among those referred for colonoscopy. Conversely, screening colonoscopy may detect and remove lesions at earlier stages, raising ongoing debate about potential overdiagnosis versus true cancer prevention. Long-term follow-up will determine whether these differences influence CRC incidence and outcomes.

Introduction Locally advanced rectal cancer (LARC; stage II–III) has traditionally been treated with neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME). While effective for local control, this pathway often delivers modest complete response rates and exposes many patients to long-term bowel, urinary, and sexual dysfunction—especially those with low rectal tumors where a stoma risk and quality-of-life trade-offs are substantial. In parallel, immune checkpoint inhibitors (ICIs) have rapidly shifted the landscape for the dMMR/MSI-H subtype—where deep responses can enable organ preservation in selected patients—while combination strategies (ICI + CRT/TNT) are being explored for pMMR/MSS disease. This Chinese Society of Colorectal Surgery (CNSCRS) consensus provides practical standards for who to treat, how to treat, how to assess response, and how to follow patients, with a strong emphasis on perioperative safety and organ-sparing pathways. Why was this guidance required? Evidence in LARC has expanded quickly over the last ~5 years, with multiple phase 2 programs and evolving real-world practice—particularly around non-operative management after complete response. The “new bottleneck” is no longer whether ICIs work in dMMR/MSI-H disease, but how to operationalise testing, MDT decision-making, response assessment (including pseudoprogression), and safe perioperative management. For pMMR/MSS LARC, enthusiasm for adding ICIs to CRT/TNT is growing, but benefit is heterogeneous, and toxicity attribution is complex—needing standardisation. Key takeaways (Guidance distilled for clinicians) A. Diagnostics and decision-making (Foundational steps) Test MMR/MSI in all LARC before treatment—this is the gateway decision for immunotherapy strategy and Lynch screening. Preferred testing approach: IHC for MMR proteins + PCR for MSI (with validated panels); use certified labs where possible. Do not assume dMMR ≡ MSI-H in every case—discordance exists; dual testing can prevent missed eligibility. Manage LARC with ICIs through a formal MDT (surgery, medical oncology, radiation, radiology, pathology ± gastroenterology/pharmacy) and adjust strategy dynamically as response evolves. B. dMMR/MSI-H LARC (where immunotherapy is most established) Neoadjuvant ICI is a core strategy for stage II–III dMMR/MSI-H LARC; response depth can be substantial and may enable organ preservation in selected patients. Practical rhythm endorsed: treat → assess at ~3 months; if not at a complete clinical response, consider continuing ICIs and reassessing rather than rushing to surgery (with vigilance for non-responders). Organ preservation (watch-and-wait) becomes a realistic goal for motivated mid/low rectal dMMR/MSI-H patients who achieve a robust clinical complete response after adequate ICI exposure. This guidance places strong weight on structured surveillance during watch-and-wait to detect regrowth early (because salvage surgery must remain feasible). If the response is incomplete at ~6 months in a patient seeking organ preservation, the document supports CRT as a “rescue/bridge” strategy in selected high-risk settings, with watch-and-wait still possible if a complete response is achieved after CRT. Pseudoresidual disease/pseudoprogression is real after ICIs: imaging may overcall residual tumour; decisions should integrate endoscopy, MRI, biopsy, and MDT judgment. Adjuvant therapy after neoadjuvant ICI is not standardised; if a patient achieves pathological complete response, observation is reasonable; if residual disease persists, options include continuing the same regimen or switching to standard adjuvant chemotherapy—best individualised. C. pMMR/MSS (or unknown status) LARC (where combinations are exploratory) ICI monotherapy is not a reliable strategy for pMMR/MSS LARC; the guidance focuses on combinations (ICI + CRT/TNT/SCRT) rather than ICI alone. For pMMR/MSS LARC, the consensus supports considering LCRT + 3–6 cycles of ICI (concurrent or sequential) before TME in selected settings, recognising evidence is still largely phase 2 and heterogeneous. For higher-risk disease or technically challenging rectal preservation, TNT + ICI is a reasonable consideration (ideally in trials), with careful monitoring for cumulative toxicity. SCRT-based pathways (SCRT → chemo + ICI) are presented as another acceptable neoadjuvant option, with a practical cap that total immunotherapy duration generally should not exceed ~6 months in these perioperative constructs. Organ preservation in pMMR/MSS should be approached more cautiously than in dMMR/MSI-H; if a true clinical complete response occurs, watch-and-wait can be considered, but patients must be counselled that cCR is less predictable. Dual checkpoint blockade (PD-1 + CTLA-4) is not recommended routinely for pMMR/MSS neoadjuvant/organ-sparing therapy outside trials due to limited efficacy evidence and toxicity concerns. D. Local excision and organ preservation pathways After neoadjuvant ICI-based therapy, local excision can be an organ-sparing option in carefully selected downstaged cases (typically small residual disease), but must be MDT-led with clear salvage plans and high-quality pathology. E. Safety and perioperative management (non-negotiable) Implement baseline screening + active monitoring for immune-related AEs; the guidance flags myocarditis and pneumonitis as rare but high-risk entities requiring early detection systems. Surgery is generally advised after irAEs have recovered to ≤ grade 1, with enhanced perioperative vigilance; an MDT model for irAE management improves diagnostic speed and consistency. Practice-changing or confirmatory? Practice-changing for dMMR/MSI-H LARC (selected patients): This consensus operationalises a real shift: biomarker-first rectal cancer, where dMMR/MSI-H disease can be routed toward ICI-driven organ preservation pathways in experienced centres. The direction of travel is consistent with transformative response signals seen with PD-1 blockade in dMMR rectal cancer. More confirmatory / still-evolving for pMMR/MSS LARC: For MSS disease, this guidance is best read as a structured framework for carefully selected use (preferably trial-enriched) rather than a universal new standard, because long-term survival data and regimen-to-regimen comparisons remain unsettled. Compared with landmark trials MSK dostarlimab (dMMR LARC): The landmark signal that dMMR rectal tumours can achieve profound responses with PD-1 blockade underpins the organ-preservation ambition reflected in this consensus. OPRA (TNT → selective watch-and-wait): OPRA established a modern framework for response-adapted non-operative management after neoadjuvant therapy, showing that structured surveillance and salvage can be oncologically acceptable in well-managed systems—this consensus essentially extends that philosophy into the immunotherapy era (especially for dMMR). NRG-GI002 / pembrolizumab + TNT (mostly MSS): This program highlights the mixed and evolving nature of adding immunotherapy in unselected LARC—supporting the consensus’ cautious tone for pMMR/MSS strategies and its emphasis on trials and careful toxicity attribution. Controversies & unanswered questions What is the “minimum effective duration” of neoadjuvant PD-1 therapy for durable organ preservation in dMMR LARC? (6 months is common, but precision remains uncertain.) How should we define and validate cCR after ICIs? Imaging and endoscopic findings can be misleading due to immune infiltration/fibrosis; standardised response criteria are still maturing. Long-term oncologic safety of watch-and-wait after ICIs: early outcomes are excellent in series, but large, long follow-up datasets are still limited. Best regimen for pMMR/MSS LARC: Which combination (LCRT+ICI vs SCRT+chemo+ICI vs TNT+ICI), which sequencing, and which patients truly benefit remains an open field. Biomarkers beyond MSI/MMR (microbiome, immune microenvironment, novel checkpoints) are promising but not ready for routine perioperative decision-making. Bottom line for clinicians This Gut 2026 CNSCRS consensus converts a fast-moving evidence base into a workable clinical playbook: test MSI/MMR upfront, decide in MDT, use ICIs decisively in dMMR/MSI-H LARC (including structured organ preservation when cCR is achieved), and approach pMMR/MSS strategies with selection, vigilance, and trial-minded discipline.