Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06394128 |
| Other study ID # |
CPLJF |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
April 30, 2024 |
| Est. completion date |
April 1, 2026 |
Study information
| Verified date |
April 2024 |
| Source |
First People's Hospital of Hangzhou |
| Contact |
Kaibo Guo |
| Phone |
+8618072946765 |
| Email |
guokaibo[@]zcmu.edu.cn |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this clinical trial is to learn if Cangpo Liujun Prescription works to treat
cancer-related fatigue in patients with advanced colorectal cancer undergoing second-line
chemotherapy with spleen deficiency and dampness excess. It will also learn about the safety
of Cangpo Liujun Prescription. The main questions it aims to answer are:
Does Cangpo Liujun Prescription improve the fatigue symptoms for participants? How about the
relationship between taking Cangpo Liujun Prescription and distribution of intestinal flora?
Researchers will compare Cangpo Liujun Prescription to a placebo (a look-alike substance that
contains no drug) to see if Cangpo Liujun decoction works to treat cancer-related fatigue in
patients with advanced colorectal cancer undergoing second-line chemotherapy with spleen
deficiency and dampness excess.
Participants will:
Take Cangpo Liujun Prescription or a placebo every day for 3 months Visit the clinic once
every 2 weeks for checkups and tests Keep a diary of their symptoms Take blood samples to
detect immune function and inflammatory factors Collected Feces for gut microbiota analysis
Description:
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.
