1. Patients with advanced colorectal cancer undergoing chemotherapy constitute a significant demographic affected by cancer-related fatigue (CRF).

   CRF, as delineated by NCCN guidelines, is described as enduring, subjective physical, emotional, and/or cognitive weariness or fatigue related to cancer or its treatment, significantly interfering with daily life and function. It stands as one of the most common and severe accompanying symptoms among cancer patients, with durations extending up to five years for a quarter to a third of patients. The etiology of CRF is complex, with factors including tumor-related factors, treatment-related factors (surgery, radiotherapy, chemotherapy, immunotherapy, etc.), comorbidities (anemia, thyroid dysfunction, etc.), and psychosocial factors (anxiety, depression, etc.). CRF exerts various adverse effects on patients, significantly diminishing their quality of life, including changes in daily habits, decreased vitality, a sense of loss of control, social isolation, and exacerbation of other accompanying symptoms. Moreover, CRF may reduce patients' completion rates of anti-tumor treatment, consequently diminishing their survival periods, highlighting its substantial detrimental impact. Studies indicate that approximately 33% of colorectal cancer patients experience CRF after chemotherapy, with the incidence rising to two-thirds in advanced colorectal cancer patients, likely associated with multiple chemotherapy treatments and low nutritional status. Chemotherapy can lead to immunosuppression, tissue cell damage, and release of inflammatory cytokines. Among these, cytokines play a crucial role in CRF formation, inducing central fatigue through mechanisms such as anemia, cachexia, and disruption of the hypothalamic-pituitary-adrenal axis. Additionally, regimens such as oxaliplatin and its combinations (FOLFOX, FOLFIRI, FOLFOXIRI) used in colorectal cancer treatment can cause mitochondrial and energy homeostasis dysregulation, leading to skeletal muscle fatigue, with cumulative toxicity. Reduced energy intake due to chemotherapy often results in prolonged low nutritional status in colorectal cancer patients. Decreased synthesis of proteinaceous substances and accumulation of certain metabolites alter ATP metabolism within muscle cells, thereby precipitating peripheral fatigue.
2. The principal pathogenesis of cancer-related fatigue (CRF) in patients undergoing second-line treatment for colorectal cancer is spleen deficiency and dampness accumulation.

   Although ancient Chinese medical texts do not directly mention "colorectal cancer" or "tumors," traditional Chinese medicine has a deep-rooted understanding of similar symptoms associated with clinical manifestations, such as "intestinal tumors" and "accumulations," found in the "Inner Canon." The "Surgical Orthodoxies · Doctrine of Internal Infections" elucidates that spleen deficiency leads to the accumulation of damp toxins, which, over time, accumulate heat. This accumulation of damp-heat toxins flows into the intestines, resulting in poor local circulation of qi and blood and the coagulation of damp toxins into cancerous masses. Prolonged retention of tumors in the intestines depletes qi and injures body fluids, exacerbated by chemotherapy and targeted therapies, giving rise to a clinical presentation akin to traditional Chinese medicine's concept of "deficiency fatigue." This includes a series of symptoms such as visceral function decline, overall debilitation, weakness, lethargy, emaciation, and increased inclination toward sleep, aligning closely with the scope of CRF. The term "deficiency fatigue" was first documented by Zhang Zhongjing in "Synopsis of the Golden Chamber · Blood Stasis Deficiency Fatigue Disease Pulse Syndrome and Treatment," illustrating that spleen deficiency is the primary pathogenesis of deficiency fatigue and CRF. According to traditional Chinese medicine, CRF is predominantly characterized by deficiency patterns, often compounded with mixed patterns of deficiency and excess, with the affected organs primarily involving the spleen, lungs, liver, and kidneys, accompanied by pathological factors such as qi stagnation and damp turbidity. Second-line treatment patients with advanced colorectal cancer, following first-line chemotherapy or combined targeted therapy, often present with spleen and stomach deficiency, leading to inefficient transformation and transportation processes. The spleen has an inclination toward dryness while detesting dampness, yet internal damp evils originate and propagate due to the humid climate of the southern region, inducing internal dampness that exacerbates the deficiency of the spleen, resulting in a state of spleen deficiency and dampness accumulation within the body. This dampness, characterized by heaviness and turbidity, manifests as a sensation of head heaviness, overall lethargy, and heaviness and laziness in the limbs. Dampness, being a yin evil, easily obstructs the flow of qi and compromises yang qi, exacerbating spleen deficiency and intensifying the symptoms of deficiency fatigue. Hence, "spleen deficiency and dampness accumulation" constitute the primary pathogenesis of CRF in second-line treatment patients with colorectal cancer. The "Cangpo Liujun Prescription" is a commonly used prescription for the pattern of spleen deficiency and dampness accumulation, demonstrating certain efficacy in clinical prevention and treatment of CRF. Composed of Cang Zhu, Hou Po, Chen Pi, Ban Xia, Dang Shen, Bai Zhu, Fu Ling, and Gan Cao, this formula employs Cang Zhu and Hou Po to eliminate dampness and fortify the spleen, while Ban Xia and Chen Pi transform phlegm and regulate qi. Dang Shen, Bai Zhu, Fu Ling, and Gan Cao collectively tonify the spleen and boost qi, with all eight herbs synergistically promoting spleen health and dampness transformation, thereby ameliorating CRF-related symptoms. A preliminary retrospective study involving six patients with colorectal cancer who underwent first-line treatment and were planned for second-line treatment found that the Cangpo Liujun Prescription could reduce PFS-R scores, increase KPS scores, and improve patients' quality of life.
3. The differences in intestinal microbiota among colorectal cancer patients with different traditional Chinese medicine (TCM) patterns indicate that maintaining the stability of the microbiota is pivotal for alleviating cancer-related fatigue (CRF) symptoms.

   Research has increasingly shown the relationship between disruptions in the gut microbiota and various diseases. For instance, compared to healthy individuals, the abundance of Clostridium and Haemophilus genera is significantly higher in cases of Qi and Yin deficiency, while Bacteroides, Gemmiger, and Prevotella genera are more prevalent in patients with Phlegm-Dampness syndrome. Contrasting wet-heat syndrome with non-wet-heat syndrome individuals reveals a higher abundance of Veillonella, Coprococcus, and Acidaminococcus genera in the latter. Additionally, studies on a spleen deficiency rat model demonstrated that intervention with Si-Jun-Zi-Tang significantly improved symptoms such as eye squinting, hunched back, and lethargy, potentially by modulating the immune system and gut microbiota (mainly lactobacillus, Dorea, and Butyricimonas genera).

   Comparing late-stage colorectal cancer patients with early-stage ones, the former exhibit higher spleen deficiency scores, accompanied by a significant increase in Prevotella, Escherichia-Shigella, and Bacteroides genera, while the abundance of Clostridium sensu stricto is notably reduced. Furthermore, our team investigated the differences in intestinal microbiota between colorectal cancer patients with a deficiency of righteous Qi and those with an abundance of pathogenic factors. We found that, compared to the healthy control group, the abundance of Clostridium difficile was reduced in the deficiency of righteous Qi group, while lactobacillus abundance increased. In contrast, there was a decrease in Prevotellaceae abundance and a significant increase in Streptococcaceae in the group with an abundance of pathogenic factors, providing a biological basis for TCM syndrome differentiation and treatment in colorectal cancer.

   Current pharmacological treatments for CRF, such as psychostimulants (e.g., methylphenidate), modafinil, paroxetine, and dietary supplements (e.g., coenzyme Q10, L-carnitine, guarana), have not yet achieved satisfactory efficacy and are associated with certain side effects. With further research, it has been discovered that the composition of the intestinal microbiota is closely related to the severity of CRF. The central nervous system plays a crucial role in inducing CRF. Cancer cells disrupt the stability of the gut microbiota during their development, and gut microbiota imbalance can indirectly affect the central nervous system via the gut-brain axis, further exacerbating CRF. Inflammation may be the primary driving factor affecting the gut-brain axis. Therefore, maintaining the stability of the microbiota is crucial for alleviating CRF symptoms. Traditional Chinese medicine (TCM) and its active ingredients can regulate the composition of the gut microbiota, thereby influencing the reshaping of the tumor microenvironment in colorectal cancer treatment, and TCM has indeed been shown to significantly improve CRF-related symptoms, warranting further investigation.
4. Scientific hypothesis and research significance. Based on the preliminary research findings and literature review, our team posits a rational hypothesis: the administration of Cangpo Liujun Prescription (CPLJ) may ameliorate cancer-related fatigue (CRF) symptoms in advanced colorectal cancer patients with Spleen Deficiency and Dampness Excess (SDDE) type by rectifying chemotherapy-induced intestinal microbiota dysbiosis (IFI), thereby reducing the levels of inflammatory factors in the body and modulating the gut-brain axis (refer to Figure 1). We propose to include CRF patients with SDDE type late-stage colorectal cancer, randomly assigning them into two groups (CPLJ group and placebo group), and comparing differences in patients' Progression-Free Survival-Related (PFS-R) scores, traditional Chinese medicine syndrome scores, quality of life assessments, immune function tests, inflammatory factor assays, objective response rates (ORR), disease control rates (DCR), as well as intestinal microbiota, aiming to offer a novel effective approach for TCM treatment of CRF in late-stage colorectal cancer, to explore new biomarkers for CRF and its translational research, and to further enrich the microcosmic differentiation system of intestinal microbiota in SDDE type late-stage colorectal cancer patients.