Herbal and pharmacological treatments in cancer-related fatigue

Cancer-related fatigue (CRF) has been defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and its treatment (1,2). Unlike typical fatigue, CRF is not proportional to recent activity, is not relieved by adequate sleep or rest, and interferes with usual functioning (3). CRF affects approximately 70–90% of patients receiving treatment for advanced cancer and frequently leads to reduced physical activity, muscle loss, reduced cognitive efficiency (4), emotional distress, anxiety, and depression, all of which are associated with reduced quality of life and decreased tolerance to treatment. A previous study of patients with advanced cancer reported that clinically significant fatigue at baseline was associated with worse survival outcomes and an increased risk of treatment-related adverse events compared with those without clinically significant fatigue (5). Given its significant negative impact on quality of life and clinical outcomes, systematic assessment and appropriate management of CRF have become essential components of comprehensive cancer care. CRF is a multifactorial condition driven by several factors including tumor-related inflammation (6), anemia, hormonal changes, side effects of anti-tumor treatment modalities (e.g., chemotherapy, radiation, and immunotherapy) (7,8), and emotional distress. In addition, CRF may be influenced by a variety of demographic, medical, psychosocial, behavioral, and biological factors (9), reflecting its complex and multifaceted nature. Although the underlying mechanisms of CRF have not been fully elucidated, several potential pathways have been proposed, including anemia, cytokine dysregulation, hypothalamic-pituitary-adrenal axis dysregulation, 5-hydroxytryptophan neurotransmitter dysregulation, and alterations in adenosine triphosphate (ATP) synthesis and muscle metabolism (9-11). Among these proposed mechanisms, dysregulation of proinflammatory cytokines [e.g., interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF)] have been extensively studied and has received considerable attention (12-16). Peripheral inflammatory cytokines can signal the central nervous system (CNS) and induce symptoms of fatigue and other behavioral changes by altering neural processes (17,18). Furthermore, it has been proposed that both cancer itself and the treatments used to eradicate it can activate the proinflammatory cytokine network, leading to fatigue through cytokine signaling within the CNS (19,20).

Treatment strategies for CRF include exercise, psychosocial and behavioral interventions, and pharmacological treatments. However, evidence supporting the effectiveness of pharmacological treatments for CRF remains limited, particularly with respect to their impact on survival outcomes, highlighting the need for further investigation.

To date, several pharmacological treatments have been investigated for the management of CRF. Hematopoietic growth factors have been shown to improve fatigue associated with chemotherapy-induced anemia (21). Methylphenidate, a CNS stimulant, has shown greater reductions in fatigue compared with placebo (22). In a large multicenter trial, modafinil, a non-amphetamine agent, has demonstrated significant benefit among patients who reported severe fatigue at baseline (23). In addition, dexamethasone has been reported to significantly improve fatigue and quality of life in patients with advanced cancer who had moderate to severe CRF (24). Several small phase II trials have evaluated agents targeting proinflammatory cytokines in patients with advanced-stage cancer. In a randomized trial, patients receiving dose-intensive chemotherapy who were treated with etanercept reported significantly less fatigue than those receiving chemotherapy alone (25). Furthermore, a nonrandomized study suggested that infliximab may reduce fatigue in the palliative care setting (26).

In the April 2025 issue of Pancreas, Otsu and colleagues reported the results of a phase II randomized controlled trial evaluating the supportive effect of Koujin (TJ-3020) powder, a traditional herbal medicine derived from red ginseng, in patients with unresectable or recurrent pancreatic cancer treated with gemcitabine and nab-paclitaxel (GnP) (27). The study examined whether Koujin powder could alleviate CRF in patients with advanced pancreatic cancer receiving palliative chemotherapy. A total of 40 patients were enrolled and were randomly assigned to either the Koujin power group (red ginseng; total dose, 2.0 g per day) or the no medication control group. CRF was assessed using the Cancer Fatigue Scale (CFS), a validated 15-item questionnaire with each item rated on a 5-point Likert scale, to evaluate physical, mental, cognitive, and comprehensive fatigue domains. The primary endpoint was the changes in CFS scores (physical, mental, cognitive, and comprehensive fatigue) during the two-month treatment period with GnP. No significant differences in CFS score changes were observed between groups. Therefore, the study concluded that oral administration of red ginseng powder at a dose of 2.0 g per day did not reduce CRF in patients with advanced pancreatic cancer receiving GnP. Several important considerations should be noted when interpreting the results of the present study. First, although the study was initially designed to enroll 56 patients, it was terminated after the enrollment of only 40 patients due to the global shortage of nab-paclitaxel. Consequently, the study may have been underpowered to detect a clinically meaningful difference between groups. Second, while previous studies reported the benefit of red ginseng powder over a 16-week period (28), the duration of administration in this study was limited to 8 weeks, suggesting that the treatment period may have been insufficient to observe a measurable effect on CRF. Third, the efficacy of red ginseng powder may vary according to cancer type. Patients with advanced pancreatic cancer frequently experience pancreatic exocrine insufficiency, which could impair gastrointestinal absorption of orally administered herbal medicines. Furthermore, medication adherence was not assessed, which may have affected treatment exposure and outcomes. Finally, details regarding concomitant supportive care were not reported. Interventions such as exercise and other supportive care known to influence CRF may have confounded the results (29,30).

With growing interest in dietary and herbal supplements for the management of fatigue, several studies have examined their efficacy in patients with CRF (Table 1) (31-44). Ginseng is one of the most extensively investigated herbal agents in traditional Chinese medicine. In Asia, ginseng extract has traditionally been used by both healthy individuals and patients with chronic illness or cancers to restore and enhance vital energy (45,46). Given its multiple effects on the CNS and cortisol production, ginseng has been investigated as a potential treatment for fatigue, including CRF (47). However, clinical studies have generally failed to demonstrate statistically significant benefits for CRF. Several factors may contribute to the absence of robust effects observed with individual herbal agents. First, most trials have been limited by small sample sizes, increasing susceptibility to random variation. Second, heterogeneity in herbal composition, preparation methods, phytochemical standardization, dosing schedules, and patient populations has made comparisons across studies difficult. In contrast, a large multicenter randomized controlled trial conducted in the United States reported that American ginseng was associated with beneficial effects for patients with CRF, particularly among patients undergoing active cancer treatment (34).

The present study differs from previous studies, which were largely conducted in the adjuvant setting (28,48,49). All patients in the present study received chemotherapy for metastatic or recurrent pancreatic cancer. Surgery for pancreatic cancer is typically more invasive than those for other malignancies, and postoperative patients with pancreatic cancer may experience greater physical and mental fatigue. Considering the inconsistent results across studies, it may be important to select appropriate candidates for CRF interventions in patients with pancreatic cancer based on objective measures, including potential biomarkers.

Among potential candidate biomarkers, the growth differentiation factor 15 (GDF15)/glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) axis has recently attracted considerable attention (50). Chemotherapeutic agents such as cisplatin can induce mitochondrial dysfunction, which contributes to chemotherapy-related neuropathy and cognitive impairment. This mitochondrial dysfunction promotes the release of mitokines, including GDF15. Binding of GDF15 to its receptor, GFRAL, mediates the anorectic response associated with cancer. A previous preclinical study demonstrated that GDF-15 induced behavioral fatigue and administration of a GFRAL-neutralizing antibody largely prevented cisplatin-induced decrease in wheel running and accelerated recovery in mice. These findings suggest that the GDF-15/GFRAL axis may represent a promising therapeutic target for the treatment of CRF (51).

In conclusion, CRF is a clinically significant condition that adversely affects not only quality of life but also survival outcomes in patients with cancer. Accordingly, in addition to the development of pharmacological interventions, including herbal medicines, the identification of reliable biomarkers to stratify appropriate candidates for therapeutic intervention will be essential for optimizing future treatment strategies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article did not undergo external peer review.

Funding: The study was supported by a KAKENHI grant from Japan Society for the Promotion of Science (JP22H02841 to T.H.) and by grants from Takeda Science Foundation and the Daiichi Sankyo TaNeDS Funding Program (to T.H.). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0030/coif). The 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/.

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