Loss of methylthioadenosine phosphorylase (MTAP), which occurs in approximately 10-15% of non-small-cell lung cancers and other solid tumors, represents a key synthetic-lethal vulnerability linking tumor metabolism to epigenetic regulation. MTAP deletion disrupts the methionine salvage pathway, leading to accumulation of methylthioadenosine (MTA) and selective dependence on protein arginine methyltransferase 5 (PRMT5). This metabolic rewiring provides a unique therapeutic opportunity to target the MAT2A-PRMT5 axis. This review summarizes recent advances in understanding MTAP biology, including the PRMT5/MAT2A feedback network, tumor heterogeneity, and adaptive resistance mechanisms encompassing metabolic compensation, splicing plasticity, and immune-cold microenvironments associated with 9p21 co-deletion. Emerging clinical data on MTA-cooperative PRMT5 inhibitors and MAT2A inhibitors are discussed, alongside challenges in diagnostic accuracy, biomarker validation, and patient stratification. Despite encouraging early-phase activity, the translation of MTAP-directed therapy is constrained by diagnostic discordance, tumor adaptability, and the absence of prospective, biomarker-driven trials. Future progress will depend on harmonized detection methods, integration of metabolic biomarkers, and rational therapeutic combinations with targeted or immune-based approaches. Collectively, targeting the MTAP-MAT2A-PRMT5 axis exemplifies a metabolism-informed precision-oncology strategy with significant translational potential.
Acquired resistance and the immunosuppressive microenvironment remain major challenges in the treatment of advanced lung cancer. By leveraging dual-target synergy, bispecific antibodies (BsAbs) mediate multiple functions, including immune cell engagement, immune checkpoint blockade, and signaling pathway inhibition. These properties offer novel strategies to overcome existing therapeutic limitations. This review comprehensively describes the structural features and core mechanisms of action of BsAbs, reviews their key clinical advances in lung cancer, and analyzes ongoing clinical challenges, such as resistance, mechanism-based toxicities, and biomarker identification. Furthermore, it discusses future directions in structural optimization and combination therapy to provide insights for precision oncology in lung cancer.
T-cell engagers (TCEs) are a novel class of immunotherapeutic molecules that enhance immune responses to cancer by directing T cells to target tumour cells. Tumour-associated antigens have been identified for several solid malignancies, including delta-like ligand 3 (DLL3) for small-cell lung cancer (SCLC). Several DLL3-targeted TCEs are being developed for the treatment of SCLC, including tarlatamab, gocatamig and obrixtamig. Tarlatamab is approved by the United States Food and Drug Administration and represents a new standard of care in patients with pretreated SCLC. As experience with TCEs in SCLC increases, consensuses on optimal clinical settings and patient management are evolving. Rapid identification and effective management of potentially life-threatening immune-related side-effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are essential for successful treatment with TCEs. Here we briefly review the key studies of TCEs in development for solid tumours before providing a comprehensive discussion on the clinical management of TCE therapy in patients with SCLC. We consider issues related to clinical settings, patient evaluation and management of toxicities, with a particular focus on identification and treatment of CRS and ICANS, drawing on experience from other oncology settings. TCEs represent a transformative treatment option for SCLC, offering new hope for a disease traditionally associated with poor therapeutic outcomes. TCEs also, however, bring new challenges, including the effective management of immune-related side-effects and the logistical demands of treatment. Safe implementation will depend on robust infrastructure, multidisciplinary collaboration, and patient and caregiver education.
BACKGROUND:Curative R0-R1 resection is not always feasible in patients with extensive bilobar colorectal liver metastases (CRLM). When unresectatility is confirmed, the standard of care is palliative chemotherapy or more recently liver transplantation (LT) with very restrictive eligibility criteria. This exploratory study evaluated cytoreductive surgery as an alternative to chemotherapy alone in patients with initially unresectable CRLM responding well to systemic chemotherapy but ineligible to LT. METHODS:This prospective study (January 2017-January 2024) included patients with permanently unresectable CRLM involving >6 segments, with or without limited extrahepatic metastases. Those achieving a sustained partial response on RECIST criteria after ≥3 months of chemotherapy and not amenable to LT, underwent cytoreductive surgery defined as resecting or ablating all visible residual lesions while leaving disappearing liver metastases (DLMs) untreated-The primary endpoint was 5-year overall survival (OS); secondary endpoints included disease-free survival (DFS) and time to surgical failure (TSF). RESULTS:Of 330 patients undergoing CRLM resection, 33 were eligible, and 28 underwent cytoreductive surgery (18 major, 10 limited hepatectomies, frequently with ablation). Grade ≥ III complications at 3 months occurred in 4 patients (14%), including one mortality (3.6%). At 57- month median follow-up, 5-year OS was 47% (whole cohort) and 64% (operated patients), respectively. Liver recurrence occurred in 22 patients (79%), with a 5-year DFS of 17%. Recurrences were frequently managed with repeat hepatectomy and/or ablation, including second (n = 15) and third (n = 7) hepatectomies, resulting in a 5-year TSF rate of 36%. CONCLUSIONS:Cytoreductive surgery combined with chemotherapy is a strategy that may improve long-term survival in selected patients with unresectable CRLM. This favorable outcome is likely driven by highly selected tumor biology, by sustained response to chemotherapy and by the feasibility of repeat surgical resections for recurrences, rather than by the initial surgery alone.
INTRODUCTION:Ewing sarcoma (ES) is a malignant bone tumor with high relapse rates, especially in multi-metastatic disease despite multimodal treatment. The role of maintenance therapy in ES remains undefined. We systematically reviewed clinical trial data to assess the feasibility and rationale for maintenance therapy in localized and metastatic disease, with the aim to help selecting drugs to introduce as maintenance therapy within the trial. METHODS:A PubMed search identified studies evaluating maintenance or metronomic therapy in ES and other pediatric sarcomas published between January 1990 and January 2020. Inclusion of articles required clinical use of maintenance therapy in pediatric (Ewing) sarcoma; case reports, preclinical studies, reviews, and phase I trials were excluded. A second PubMed search (February 2020-June 2025) updated the evidence base. Data on study design, patient characteristics, treatment regimens, and outcomes were extracted. RESULTS:Of 3040 records identified in the first search, 20 were included: 11 included ES patients, 9 in other pediatric sarcomas. The update yielded 9 additional studies (3 ES, 6 other sarcomas). Vinorelbine, alone or combined with low-dose cyclophosphamide, was most frequently investigated, mainly in heavily pretreated relapsed or refractory ES patients, showing modest clinical activity. Strongest evidence derived from rhabdomyosarcoma (RMS) patients, where the randomized EpSSG RMS 2005-trial demonstrated improved long-term survival with vinorelbine/cyclophosphamide maintenance. CONCLUSION:Vinorelbine plus low-dose cyclophosphamide represent a rational backbone for ES maintenance therapy, supported by evidence in RMS and limited ES data. Ongoing international efforts will define their clinical role when given for 6 months. Future studies should eventually clarify optimal duration, alternative agents, and long-term safety.
BACKGROUND:The growing population of cancer survivors is increasingly exposed to the long-term risk of second primary cancers (SPCs), which represents a major source of morbidity and mortality. While current prevention mainly relies on surveillance and screening, pharmacological and immunological strategies may offer opportunities to reduce SPC incidence in selected high-risk populations. METHODS:This narrative review synthesises current evidence on pharmacological prevention strategies for SPCs, including endocrine therapy, aspirin and non-steroidal anti-inflammatory drugs, PARP inhibitors, metformin, GLP-1 receptor agonists, statins, nicotinamide, immune checkpoint inhibitors, cancer vaccines, and microbiome modulation. Evidence from randomised trials, observational studies, translational research, and ongoing clinical trials was reviewed, with particular attention to SPC-specific endpoints, biological rationale, safety, and clinical applicability. RESULTS:The strongest evidence currently supports endocrine therapy for reducing contralateral breast cancer in patients with hormone receptor-positive breast cancer, and aspirin in selected populations such as Lynch syndrome carriers or patients with molecularly defined colorectal cancer. Other repurposed agents, including metformin, statins, GLP-1 receptor agonists, and nicotinamide, remain investigational, with most available data addressing incident cancer, recurrence, or surrogate endpoints rather than SPC prevention specifically. Immunological approaches are emerging as particularly promising strategies. Retrospective studies and exploratory analyses of randomised trials suggest that immune checkpoint inhibitors may reduce the occurrence of new malignancies, while neoantigen-based vaccines, especially in Lynch syndrome, provide an early proof of concept for cancer immunoprevention. CONCLUSIONS:Pharmacological prevention of SPCs is an expanding but remains a heterogeneous field. Current evidence supports a shift from broad chemoprevention toward biologically informed, risk-adapted prevention strategies. Future progress will depend on dedicated SPC-focused trials, biomarker-driven patient selection, long-term safety evaluation, and integration of pharmacological prevention into broader cancer interception programmes.
Extrapulmonary neuroendocrine carcinomas (epNECs) are high-grade malignancies that arise from various anatomic sites and follow an aggressive clinical course. Most patients with epNEC present with metastatic disease at diagnosis and face a dismal prognosis, surviving less than a year. Despite treatment, disease progression is common and most patients rapidly succumb to the disease, which may limit participation in prospective clinical trials. Given the grim survival outcomes, in addition to the rarity and heterogeneity of the disease, high-quality data are lacking and epNECs remain poorly understood. While certain prognostic factors have been identified, many of these are controversial and are yet to be validated. This review summarizes existing evidence on survival, key prognostic factors, and the impact on patient quality of life in this understudied group of malignancies. Understanding survival patterns and key prognostic features of this aggressive group of malignancies is crucial to inform clinical decision-making and shape the design of future clinical trials. This review emphasizes a need for multicenter involvement to conduct clinical trials to develop more effective front-line therapies. Additionally, the current limited treatment landscape highlights the need to shift to a personalized, biomarker-driven treatment approach (e.g. DLL3), with a call for comprehensive, standardized biomarker testing for all epNECs.
Chondrosarcoma is a heterogeneous group of malignant bone tumors characterized by the production of neoplastic hyaline cartilage. These tumors are often indolent and typically resistant to conventional chemotherapy and radiotherapy, with surgical resection remaining the cornerstone of treatment. However, patients with unresectable or metastatic disease face poor outcomes due to the lack of effective systemic therapies. While advancements in systemic treatments - such as immunotherapy and anti-angiogenic agents - and novel radiation modalities like proton beam therapy and carbon ion therapy have shown some benefit in select cases, their overall efficacy remains limited, underscoring the urgent need for more effective treatment options. Emerging novel therapies are beginning to illuminate potential new treatment pathways. Current efforts are increasingly focused on targeting recurrent genetic alterations and dysregulated signaling pathways, including IDH mutations, DR5-mediated apoptotic pathway, hedgehog signaling, Src kinase pathway, the PI3K-Akt-mTOR axis, histone deacetylation, and angiogenesis. Although these targeted strategies are still under investigation, they show promise in overcoming therapeutic resistance and advancing personalized treatment. This review provides an overview of the clinical characteristics of major chondrosarcoma subtypes, key genetic alterations implicated in tumor pathogenesis, and recent advances in treatment strategies, including surgery, chemotherapy, radiotherapy, immunotherapy, and emerging targeted therapies.
Advances in hepatocellular carcinoma (HCC) treatment and patient profiling are driving a shift toward personalized, multimodality management. The enhanced efficacy of locoregional therapies (LRTs) and systemic regimens has expanded treatment options across palliative and curative settings. For patients eligible to curative-intent treatment, adjunctive approaches aim to enhance procedural feasibility and optimize patient outcomes. Bridging and downstaging to liver transplantation, while traditionally relying on intra-arterial therapies are now seeing emerging alternatives such as stereotactic body radiotherapy (SBRT) and systemic agents. In the perioperative setting, immune checkpoint inhibitor (ICI)-based regimens have shown robust pathological response rates and have significantly improved major pathological response and event-free survival for intermediate- to high-risk resectable patients in a recent phase III trial. For incurable disease, treatment intensification via multimodal combinations improves anti-tumor efficacy. Adding ICI-antiangiogenic regimens to transarterial chemoembolization has demonstrated improved response rates and progression-free survival in multiple phase III trials. Systemic-LRT combinations are also being explored in advanced HCC, with a recent phase III trial indicating SBRT's efficacy in this setting. Notably, curative conversion approaches are emerging to enable subsequent curative-intent treatment in select patients that were previously considered incurable. While multimodal care offers significant promise, its complexity necessitates a multidisciplinary approach to patient and treatment selection, and toxicity management. With multidisciplinary guidance, multimodality approaches promise to expand the path to cure for an increasing number of HCC patients.
Patient-derived xenografts (PDX) and patient-derived organoids (PDO) are widely used to model cancer and predict treatment response in matched patients. However, their predictive accuracy has not been systematically studied nor compared. We conducted a systematic review and meta-analysis of studies using PDX or PDO from solid tumors treated with identical anti-cancer agents as the matched patient, identifying 411 patient-model pairs (267 PDX, 144 PDO). Overall concordance in treatment response between patients and matched models was 70%, with no significant differences between PDX and PDO. Sensitivity, specificity, and positive and negative predictive value were also comparable. Patients whose matched PDO responded to therapy had prolonged progression-free survival. For PDX, this association held only when analyses were restricted to patient-model pairs with low risk of bias after applying a bias assessment metric. Together, these findings suggest that in some contexts, PDO perform similarly to PDX in predicting matched-patient response while potentially offering lower financial and ethical burdens. Given that both platforms have distinct strengths and weaknesses, they continue to serve complementary roles in translational cancer research. Additional prospective studies will be required before definitive recommendations can be made.
The standard of care (SoC) for locally-advanced (LA) head and neck squamous cell carcinoma (HNSCC) has remained relatively unchanged for decades, usually consisting of multimodal treatment that can include surgery, radiotherapy, and systemic therapy. Survival rates are low, so there is a key unmet need to improve clinical outcomes. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein-1 (PD-1) agents, redefined the SoC for recurrent/metastatic HNSCC, and based on recent positive outcomes in Phase III studies, the SoC for resectable LA-HNSCC has evolved to include ICI-based therapy; however, key challenges remain. Integrating ICIs within multimodal treatment strategies has, thus far, yielded very limited success in unresected LA-HNSCC, and intrinsic and acquired resistance to ICIs remains a challenge. In this review, we outline the current and evolving treatment landscape for both resectable and unresected LA-HNSCC, with a focus on emerging immunotherapy-based approaches. We summarize key completed studies, highlighting important insights and key learnings based on trial designs and observed clinical outcomes, and explore novel strategies that may enhance therapeutic efficacy and address limitations of ICIs. Finally, we review ongoing clinical trials of ICI-based regimens that are expected to further shape the treatment landscape for unresected LA-HNSCC.
Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with gastrointestinal (GI) malignancies and often negatively impact anti-cancer treatment delivery. A prothrombotic risk markedly varies across primary sites, from pancreatic, gastric to colorectal cancers and is influenced by tumor-driven inflammation, disease stage, and exposure to contemporary systemic therapies, including newly, immune checkpoint inhibitors, targeted agents, and antibody-drug conjugates. Despite its clinical relevance, current risk assessment models, including the pivotal Khorana score (KS), show limited accuracy in GI tumors and do not adequately account for treatment-related or biology-driven variability. This review synthesizes current evidence on the incidence, mechanisms, and clinical determinants of CAT in GI cancers and discusses approaches to primary thromboprophylaxis and secondary prevention, with attention to bleeding risk and cardiovascular considerations. Emerging strategies such as molecular profiling, inflammatory biomarkers, and ctDNA-based assessment of minimal residual disease (MRD) show promise for improving individualized risk prediction and guiding more precise anticoagulation strategies. A precision-medicine framework integrating tumor biology, dynamic biomarkers, and treatment-specific cardiovascular risk is needed to optimize CAT management and to inform future trials designed to refine primary and secondary prevention across the spectrum of GI malignancies.
Uveal melanoma (UM) is a biologically distinct melanoma subtype in which excellent local tumor control contrasts sharply with a high risk of delayed metastases. The frequent occurrence of distant relapse months to years after index local therapy suggests systemic dissemination early in the disease course. Inadvertently, many patients harbor minimal residual disease (MRD), comprising microscopic tumor cell populations that persist after primary tumor treatment and are undetectable by conventional imaging techniques. Historically, UM management has focused on local tumor eradication followed by surveillance, however, better understanding of the clinical trajectory of UM coupled with advances in systemic therapeutics have generated increasing interest in perioperative systemic approaches. Neoadjuvant therapy provides the opportunity to downsize the primary tumor, eliminate occult micrometastatic disease, dynamically evaluate disease biology, and inform further therapeutic decision-making. Adjuvant approaches aim to suppress or eradicate MRD following local control in patients at elevated risk of relapse. Although current evidence remains investigational or early-phase, perioperative systemic therapy represents an important research frontier in UM that holds the potential to reshape its therapeutic paradigm. Herein, we comprehensively synthesize the biological rationale, the latest data, and the ongoing clinical trials supporting perioperative systemic therapy, and discuss the emerging role of circulating tumor DNA (ctDNA) in the management of UM.
Antiangiogenic therapies have been extensively investigated in advanced/metastatic gastric cancers, but also in neoadjuvant settings. The anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) monoclonal antibody ramucirumab was the first antiangiogenic agent approved for HER2-negative metastatic gastric adenocarcinomas and remains a standard second-line treatment either alone or in combination with paclitaxel. Other VEGFR-targeting agents, such as the tyrosine kinase inhibitors (TKI) regorafenib and apatinib, have failed to demonstrate any survival benefit in the first-line settings, while providing modest improvements in pretreated patients, even when combined with Immune Checkpoint Inhibitors (ICI). Despite showing no significant benefit in Caucasian patients, apatinib has been approved in China for pretreated patients with advanced/metastatic gastric cancer. Dose-limiting toxicities, and the lack of robust predictive biomarkers for patients' stratification may both contribute to the limited efficacy of these multi-target tyrosine kinase inhibitors in gastric cancers. Several ongoing clinical trials mostly conducted in China suggest that new generation of antiangiogenic agents, particularly bispecific antibodies targeting both VEGF and Programmed Cell Death 1 (PD-1) or its ligand PD-L1, may offer greater efficacy with reduced toxicity. However, these promising preliminary data await mature overall survival results as well as clinical validation in the global population. Developing more effective drugs is closely linked to identifying reliable predictive biomarkers, which are crucial for guiding patients' selection, monitoring treatment response and optimizing therapeutic combinations and sequencing. Although several biomarker candidates have been explored, reliable predictors are still awaited. This review summarizes current evidence and explores the future of antiangiogenic agents in gastric cancers.
Brain metastases from breast cancer (BCBMs) are a major cause of morbidity and mortality and remain a critical unmet clinical need across molecular subtypes. Their incidence is rising as improved systemic therapies prolong survival in metastatic breast cancer and advances in neuroimaging allow earlier detection of central nervous system (CNS) disease. Historically, management relied mainly on local approaches such as surgery and radiotherapy because many systemic agents have limited ability to cross the blood-brain barrier. However, the therapeutic landscape is rapidly evolving with the development of systemic treatments showing clinically meaningful intracranial activity. In hormone receptor-positive/HER2-negative disease, treatment options are expanding with targeted and novel endocrine-based therapies that may achieve therapeutically relevant CNS concentrations. In addition, targeting the PI3K/AKT/mTOR pathway and the increasing use of antibody-drug conjugates (ADCs), including trastuzumab deruxtecan in HER2-low and-ultralow disease, may further broaden systemic strategies. In HER2-positive breast cancer, brain-penetrant tyrosine kinase inhibitors and highly active ADCs have significantly improved outcomes. Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. Lastly, in triple-negative breast cancer, outcomes remain poor, but ADCs, immunotherapy-based strategies, and PARP inhibitors for germline BRCA-mutated disease are under investigation. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.
Claudin 18.2 (CLDN18.2) is an attractive therapeutic target in gastric cancer (GC). Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, has been approved in combination with chemotherapy as a first-line treatment option for patients with HER2-negative and CLDN18.2-positive gastric adenocarcinoma. This review summarizes current advances in CLDN18.2-targeted therapies for GC, with a focus on the clinical development of monoclonal antibodies (mAbs), particularly zolbetuximab and emerging next-generation antibodies, as well as mAb-based combination strategies. This review also summarizes CLDN18.2-targeted antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor (CAR)-T cell therapy, highlighting emerging therapeutic strategies. Furthermore, major challenges and considerations in clinical and translational research are outlined. In conclusion, precision targeting of CLDN18.2 represents a promising approach in GC therapy, shifting from conventional chemotherapy to biomarker-guided strategies. Continued development of next-generation agents and rational combination therapies may enhance outcomes and expand benefit.
The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its administration within an immunologically active, treatment-naïve microenvironment that enhances immune priming and anti-tumor response. Despite encouraging clinical data, including the pivotal KEYNOTE-689 trial and multiple phase II studies, methodological heterogeneity in trial design, endpoint definitions, and response criteria currently hampers data comparability and the establishment of new standards of care. This expert narrative review proposes a structured framework for standardizing clinical, pathologic, imaging, and translational endpoints in HNSCC nIO trials, highlighting harmonized definitions of pathologic response, practical reporting templates, and methods to evaluate immune priming. Standardization of response evaluation, biomarker integration, and trial methodology is essential to accelerate the translation of neoadjuvant immunotherapy into routine clinical practice for HNSCC.
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is characterised by a high prevalence of severe muscle wasting (sarcopenia) and fatty muscle infiltration (myosteatosis), yet chemotherapy dosing still relies on body surface area (BSA), a metric that does not reflect individual patients' lean body mass (LBM) or muscle quality. A growing body of evidence from oncology meta-analyses demonstrates that low skeletal muscle mass (sarcopenia) independently predicts chemotherapy toxicity across multiple cancer types, and that myosteatosis is associated with significantly increased mortality risk. We performed a systematic review to determine whether CT-based body composition metrics better predict chemotherapy toxicity and survival outcomes in PDAC than conventional BSA-based dosing. METHODS:We searched PubMed and EMBASE (up to 10 April 2026) according to PRISMA 2020 guidelines. Of 340 identified records, a total of 16 were included after screening and eligibility assessment: 14 primary studies/abstracts (10 retrospective cohorts, 1 prospective study, 3 conference abstracts); 2 prior systematic reviews were appraised qualitatively for contextual background. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and AMSTAR-2 for systematic reviews. Conference abstracts were assessed qualitatively; their inclusion and associated limitations are transparently acknowledged. Data were extracted on severe (grade ≥ 3) toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), dose-limiting toxicities (DLT), treatment modifications, and overall survival. Body composition measures assessed included skeletal muscle index (SMI) and skeletal muscle density (SMD) (surrogates for muscle quantity and quality, respectively), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and longitudinal changes in these parameters. RESULTS:Muscle quality (low SMD/myosteatosis) was as predictive of severe toxicity as muscle mass (SMI) in multiple studies, and when low SMI and SMD co-occurred, patients had significantly higher odds of grade ≥ 3 toxicity (odds ratio ∼ 1.7 in the largest cohort of 636 patients). Patients receiving high chemotherapy doses relative to LBM (e.g. >5.8 mg of nab-paclitaxel per kg LBM) were significantly more likely to experience DLT (p = 0.028), whereas standard BSA-normalised dosing did not discriminate risk. Early skeletal muscle loss (≥7.9% SMI decline within 2 months of FOLFIRINOX) was linked to a fourfold higher risk of mortality (HR 4.02; 95% CI 1.54-10.5). Overall, CT-derived body composition measures consistently outperformed BSA for toxicity and outcome prediction, although evidence remains largely retrospective and heterogeneous. Automated CT body composition analysis was demonstrated to be feasible, supporting integration into routine PDAC care. CONCLUSIONS:CT-derived body composition metrics, particularly LBM-normalised dosing parameters and serial skeletal muscle measurements, appear to provide a more patient-tailored, physiologically relevant approach to chemotherapy dosing in PDAC than exclusive reliance on BSA. Given the predominantly retrospective evidence base and limited prospective validation to date, these findings should be interpreted as hypothesis-generating rather than practice-changing. Prospective trials of LBM-adapted dosing protocols are needed to validate their impact on toxicity and survival.
Background Early onset pancreatic cancer (EOPC), defined for the primary analysis as pancreatic ductal adenocarcinoma (PDAC) diagnosed before the age of 50 years, is an increasingly recognised clinical and epidemiological entity. Because published studies use heterogeneous age thresholds, the present review prespecified <50 years as the main definition and interpreted studies using other cutoffs in sensitivity or narrative analyses. Methods We systematically searched PubMed, EMBASE, and the Cochrane Library for studies published between January 1990 and December 2024 that reported outcomes specific to EOPC. Search terms were reformatted with standard quotation marks and included "pancreatic cancer", "pancreatic adenocarcinoma", "pancreatic ductal adenocarcinoma", "early onset", "young onset", "young adult", "age < 50", "age less than 50", and "premature". Meta-analytic procedures and epidemiological interpretation were re-reviewed with statistical/epidemiological input. Results 40 studies encompassing more than 285,000 patients were included. Global incident EOPC cases increased from 24,480 (1990) to 42,254 (2021), representing a 72·6% rise. Age-standardised prevalence rate increased by 17·0% (1·65 per 100,000 in 2021). EOPC patients have a 3·08% per year increase in the youngest age group (20-29 years) over 2010-2021. Germline pathogenic variants were identified in 17·3% of EOPC patients (vs 6·4% in older cohorts; OR 2·41, 95% CI 1·87-3·11). EOPC patients were more likely to receive treatment (OR 2·95, 95% CI 2·54-3·43; I2 = 13%) and showed modestly improved overall survival (pooled HR 0·89, 95% CI 0·80-0·99; I2 = 16%) compared with average or late onset disease. Conclusions EOPC is an increasingly recognised and clinically challenging subset of PDAC. The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.
