Pancreatic ductal adenocarcinoma and edema: reassessing cachexia markers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Despite decades of intense research, the survival outlook for patients has remained dismal. Contemporary literature often cites a 5-year survival rate approaching 13% for pancreatic cancer; however, this aggregate figure masks critical biological and histologic distinctions. When pancreatic neuroendocrine tumors (PNETs), which have substantially better outcomes, are excluded, the true 5-year survival rate for PDAC remains in single digits (~8%), a figure that has shown only marginal improvement over the last two decades (1,2). This sobering reality demands a re-examination of not only therapeutic strategies but also the biological processes and clinical variables that shape outcomes in PDAC.

Unlike many other solid tumors, PDAC is frequently diagnosed in patients very late and at a stage when they already exhibit significant functional decline. Weight loss, fatigue, anorexia, sarcopenia, and systemic inflammation is routinely observed at the time of diagnosis (3). As a result, the majority of patients are not candidates for aggressive multi-agent chemotherapy regimens such as folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) or liposomal irinotecan, folinic acid, fluorouracil, oxaliplatin (NALIRIFOX) (4). In real-world clinical practice, gemcitabine-based chemotherapy, often combined with nab-paclitaxel (GnP), remains the most commonly used systemic treatment for majority of PDAC patients who have poor performance status. While this regimen provides modest survival benefit [8.5 vs. 6.7 months with gemcitabine alone [phase III trial of weekly nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer (MPACT)] and symptom palliation, it is also associated with cumulative toxicity and functional deterioration particularly through muscle wasting or cachexia (5).

Cancer cachexia according to consensus definition is “weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height [body mass index (BMI) <20 kg/m²] or skeletal muscle mass (sarcopenia)” (6). Multiple studies have demonstrated that loss of skeletal muscle mass during the course of treatment independently predicts worse survival, irrespective of tumor stage or treatment modality (6). Cachexia contributes to chemotherapy intolerance, dose reductions, treatment discontinuation, and diminished quality of life. Paradoxically, while cachexia is recognized as a major determinant of outcome, it remains poorly addressed in routine clinical care (6). Supportive interventions such as nutritional counseling or appetite stimulants are commonly employed. However, these practices are not widely adopted. Moreover, chemotherapy itself can exacerbate muscle loss, even in patients with radiographic disease control, further accelerating functional decline (6).

Against this backdrop, the study by Davis and colleagues provides a critical and timely contribution to the field (7). Their work highlights an overlooked confounding effect of treatment-related edema on computed tomography (CT) based measurements of skeletal muscle mass.

Edema is common in patients with PDAC and arises from multiple mechanisms, including systemic inflammation, hypoalbuminemia, venous and lymphatic obstruction, postoperative fluid shifts, and chemotherapy-induced vascular permeability (8). Despite its prevalence, edema has rarely been accounted for in studies evaluating muscle loss. In their paper, Davis and colleagues demonstrate that edema can spuriously inflate measurements of total skeletal muscle area at the L3 vertebral level. More significantly, automated segmentation methods may misclassify fluid-laden subcutaneous fat or interstitial fluid as muscle. This could lead to the paradoxical appearance of muscle gain in patients who are, in fact, losing muscle mass. These findings have implications, as they suggest that prior studies relying on total skeletal muscle area may have systematically underestimated the true burden of muscle wasting in PDAC.

A key highlight of this study is the identification of psoas skeletal muscle area as a metric that is largely impervious to the confounding effects of edema. The iliopsoas muscle is the primary hip flexor, formed by the psoas major and iliacus muscles. It originates from the lumbar spine and inner pelvis and inserts onto the lesser trochanter of the femur. Psoas skeletal muscle plays a key role in hip flexion, posture, walking, and stabilizing the lower spine.

Davis and colleagues demonstrated that unlike total skeletal muscle area, psoas muscle area consistently declined between diagnosis and follow-up regardless of edema status and remained strongly associated with overall survival. Loss of psoas muscle area was associated with a more than three-fold increase in mortality risk, a finding that persisted across tumor stages, treatment modalities, and demographic subgroups (7). From a practical standpoint, the analysis of psoas muscle area offers several advantages. It is anatomically distinct from subcutaneous compartments prone to fluid accumulation, can be measured reproducibly, and may be amenable to high-throughput automated analysis provided they are appropriately validated.

The findings of Davis and colleagues compel a broader reassessment of how disease progression and overall function of patients with PDAC is measured and interpreted. Inaccurate measurement of muscle loss has likely delayed recognition of cachexia as a modifiable determinant of outcome rather than an inevitable consequence of disease. By disentangling true muscle wasting from fluid-related artifacts, this study could potentially create an opportunity to intervene more effectively.

This raises the question whether the presented findings have applicability or can be incorporated in the clinical setting? Muscle mass and body composition are increasingly incorporated as exploratory or secondary endpoints, yet failure to account for edema may lead to misclassification and misleading conclusions. Future studies should incorporate edema-inclusive metrics, such as psoas muscle area, when evaluating muscle loss and its association with outcomes. By demonstrating that edema distorts traditional muscle metrics and that psoas muscle area provides a more reliable alternative, this study by Davis and colleagues lays the foundation for a more precise and clinically relevant approach to cachexia research in PDAC.

Despite the important insights provided in this paper, several limitations merit consideration. The study is observational in nature and limited by a relatively modest sample size, which may restrict statistical power, particularly in subgroup analyses stratified by edema status. The semiquantitative approach used to define edema is based on opacifications within subcutaneous fat. This may result in misclassification, as edema confined to intramuscular or deep visceral compartments cannot be reliably detected using this method. Additionally, reliance on CT scans obtained at variable time intervals and across heterogeneous treatments introduces potential confounding related to differences in disease trajectory, treatment intensity, and supportive care practices. The use of automated segmentation for total skeletal muscle area, while pragmatic, may have amplified the very measurement biases under investigation, as manual validation was limited to the psoas muscle. Finally, although the association between psoas muscle loss and survival is compelling, causality cannot be inferred, and it remains unclear whether psoas muscle loss is a direct driver of poor outcomes or a surrogate marker of aggressive disease biology and systemic inflammation. Future studies incorporating larger samples size, longitudinal functional assessments, standardized imaging protocols, and interventional designs will be essential to confirm these findings and translate them into actionable clinical strategies.

In a landmark study in which Burris et al, compared gemcitabine to 5-fluorouracil (5-FU), the concept of clinical benefit response (CBR) incorporated pain, performance status, and importantly dry weight (9). This ensured that improvements reflected true functional or nutritional gains rather than fluid shifts. This was an early recognition that host factors matter as much as tumor metrics. In the context of Davis et al., just as dry weight prevented misinterpretation of edema-related weight changes. Without edema measurements, we risk underestimating the severity of PDAC cachexia and misjudging therapeutic impact.

In a disease where cure remains elusive for most patients, the correct and timely assessment of functional decline could help in preserving performance status. This may be an alternative strategy available to extend survival, improve quality of life. The focus should shift to host factors that have silently shaped PDAC outcomes for decades and to integrate cachexia and muscle preservation into the core therapeutic framework of pancreatic cancer care.

Acknowledgments

After writing the editorial, ChatGPT5.1 was used to check for grammatical errors and to improve the flow of the text. AI was not used in idea generation or content creation. It was only used for fixing grammar and flow.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0216/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0216/coif). M.W.S. reports research funding: SystImmune, Endevica Bio, GSK, Tyra, Teva, Marengo, OBI Pharma, IDEAYA, Binhui, Astellas, Takeda, Mersana Therapeutics, Summit, J-Pharma, and Beijing Biostar; consulting: Genentech, Oncologic Drug Advisory Committee (US World Meds); and royalty: UpToDate. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Kratzer TB, Wagle NS, et al. Cancer statistics, 2026. CA Cancer J Clin 2026;76:e70043. [Crossref] [PubMed]
2. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21. [Crossref] [PubMed]
3. Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol 2013;10:90-9. [Crossref] [PubMed]
4. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
5. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
6. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489-95. [Crossref] [PubMed]
7. Davis EW, Park MA, Basinski TL, et al. The Impact of Edema on Skeletal Muscle Changes among Patients with Pancreatic Ductal Adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2025;34:1609-17. [Crossref] [PubMed]
8. Saito Y, Takekuma Y, Komatsu Y, et al. Impact of baseline hypoalbuminemia on peripheral edema induced by gemcitabine and nab-paclitaxel for pancreatic cancer treatment. Support Care Cancer 2025;33:938. [Crossref] [PubMed]
9. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13. [Crossref] [PubMed]