Bojungikgi-tang for Anorexia in Colorectal Cancer Patients after Curative Resection and Chemotherapy: A Single-arm, Open-label, Single-center Trial

Article information

J Korean Med. 2024;45(4):150-167

Publication date (electronic) : 2024 December 1

doi : https://doi.org/10.13048/jkm.24063

Im-Hak Cho ¹^,^§

, Gyung Mo Son ²^,^§

, Jun-Yong Choi ¹^,³

, Hyeun Kyoo Shin ⁴^,

, Soyeon Kim ¹^,³^,

¹Department of Korean Medicine, The Graduate School, Pusan National University

²Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University College of Medicine

³Department of Korean Internal Medicine, School of Korean Medicine & Korean Medicine Hospital of Pusan National University

⁴Herbal Medicine Research Division, Korea Institute of Oriental Medicine

Correspondence to: Hyeun Kyoo Shin, Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, Tel: +82-42-868-9464, E-mail: hkshin@kiom.re.kr

Correspondence to: Soyeon Kim, Department of Korean Internal Medicine, School of Korean Medicine & Korean Medicine Hospital of Pusan National University, 20 Geumo-ro, Yangsan-si, Gyeongsangnam-do, Tel: +82-55-360-5954, E-mail: kimsy@pusan.ac.kr

^§

These authors contributed equally to this work.

Received 2024 October 21; Accepted 2024 November 12.

Abstract

Objectives

This study evaluated the effectiveness and safety of Bojungikgi-tang for colorectal cancer patients with anorexia.

Methods

This was a single-arm, open-label, and single-center trial, and suitable participants took the test drug (Bojungikgi-tang) three times a day before or between meals for six weeks (42 days). After registration of clinical trials (visit 2), they visited the hospital every three weeks (visits 3 and 4) and measured or tested the effectiveness or safety evaluation variables to analyze the results. The primary outcome was the anorexia/cachexia subscale (A/CS) of functional assessment of anorexia/cachexia therapy (FAACT) score.

Results

Eleven colorectal cancer patients were included in the ITT analysis. Colorectal cancer patients had significantly higher A/CS of FAACT scores after six weeks of Bojungikgi-tang administration compared to that at the baseline (p=0.0006). In the secondary outcomes, functional assessment of cancer therapy for patients with colorectal cancer (FACT-C) (p=0.0343) and the VAS score of anorexia (p<0.0001) showed a significant improvement after six weeks of treatment. No serious adverse events were associated with Bojungikgi-tang in colorectal cancer patients.

Conclusion

Bojungikgi-tang can be an effective and safe treatment for anorexia in colorectal cancer patients after curative resection and chemotherapy.

Keywords: Anorexia; Bojungikgi-tang; Clinical Trial; Colorectal Cancer

Introduction

Colorectal cancer is the third most common cancer in the world, with approximately 1.2 million new patients and 600,000 deaths reported per year¹⁾. According to statistics, in 2020, more than 1.9 million cases of colorectal cancer were reported²⁾. The primary treatment for non-metastatic colorectal cancer is surgical resection. If metastatic colorectal cancer is also resectable, primary colorectal cancer with simultaneous metastasis can be sequentially or simultaneously resected^3,4).

Surgical methods can be generally divided into open and laparoscopic surgery⁵⁾, and the range of resections varies depending on the location of the cancer⁶⁾. Surgery plays an important role in the treatment of colorectal cancer, but serious complications may be associated with morbidity and mortality⁷⁾. Despite improving surgical methods, 35% of patients who underwent colorectal cancer surgery suffer from complications after surgery⁸⁾. Colorectal cancer resection can lead to complications such as surgical site infection, anastomotic leakage, bowel perforation, mechanical bowel obstruction, intraperitoneal bleeding, and ileus^7,9). Long-term complications such as fecal incontinence and increased bowel movements can often occur after rectal cancer surgery and metastatic cases can cause symptoms that affect the quality of life, such as cachexia, anorexia, anemia, liver failure, biliary obstruction, and exacerbation of pulmonary function¹⁰⁾.

However, chemotherapy after curative resection is usually recommended for the treatment of locally advanced colorectal cancer¹¹⁾. In patients with stage III and high-risk stage II colon cancer, the standard treatment is adjuvant chemotherapy¹²⁾. Antitumor agents for metastatic colorectal cancer include 5-fluorouracil (FU)/leucovorin, capecitabine, irinotecan, and oxaliplatin, and other drugs for targeted or immunotherapy^13,14). Unfortunately, these drugs cause side effects such as myelosuppression, gastrointestinal toxicity, and stomatitis, especially capecitabine, a pre-drug of 5-FU and an oral anticancer drug, causes hand-foot syndrome¹⁵⁾. Approximately 80% of colorectal cancer patients receiving 5-FU-based adjuvant chemotherapy suffer from gastrointestinal toxicity. Among them, chemotherapy-induced nausea and vomiting can be controlled using anti-emetic drugs, but symptoms such as anorexia are difficult to manage¹⁶⁾.

In addition, the prevalence of cachexia in colorectal cancer patients is 50–61%, and cachexia is associated with death in at least 20% of the patients¹⁷⁾. Cancer-related anorexia/cachexia is one of the most common clinical problems experienced by cancer patients after surgery and chemotherapy and negatively affect the patient's nutritional status and quality of life. For cancer-related anorexia/cachexia, megestrol is currently considered the best treatment in Western medicine¹⁸⁾. But it has serious side effects such as edema and thromboembolism¹⁹⁾.

In one study, chemotherapy and surgery were most often performed for treating colorectal cancer patients, and more than 50% of patients suffered from moderate or severe anorexia²⁰⁾. Another study found that patients with colorectal cancer had long-lasting negative physical and emotional symptoms not only during and after chemotherapy²¹⁾. Therefore, colorectal cancer patients suffering from long-term complications must be managed, even after surgery and chemotherapy are completed. As a study showed that herbal medicine is safe for advanced colorectal cancer patients²²⁾, some patients suffering from anorexia can seek herbal medicine as a safe alternative therapy²³⁾.

Bojungikgi-tang originated in China and is mainly used in East Asian countries for treating weakness, anorexia, indigestion, and immunity improvement²⁴⁾. According to Korea's Ministry of Food and Drug Safety, Bojungikgi-tang is used for the following symptoms: general weakness, fatigue, weakness after disease, anorexia, sweating while sleeping at night. We hypothesized that Bojungikgi-tang can effectively manage symptoms of anorexia that occurred after surgical treatment and chemotherapy. Therefore, this clinical trial aimed to verify the possibility of Bojungikgi-tang as a safe and effective treatment for colorectal cancer patients with anorexia after curative resection and chemotherapy.

Methods

1 Study Design

This was a single-arm, open-label, and single-center trial conducted at the Pusan National University Korean Medicine Hospital in Busan, Korea, from January 27, 2020 to December 31, 2021. Bojungikgi-tang was administered for six weeks (42 days) to investigate its effect on anorexia in colorectal cancer patients after curative resection and chemotherapy. The patients visited every three weeks for effectiveness and safety evaluation, and the detailed schedule is shown in Figure 1.

Fig. 1

Trial schedule

2. Participants

We notified the gastroenterology clinic to recruit colorectal cancer patients, and the physicians interviewed them to confirm whether they were eligible for the criteria. The data were collected by the clinical research coordinator (CRC). The participants fully understood the information on the clinical trial and then voluntarily agreed to participate.

1) Inclusion Criteria

Adults aged ≥ 19 years; confirmed histologically for rectal or colon cancer and completed curative resection and chemotherapy and no further chemotherapy; oral medicine intake; Eastern cooperative oncology group (ECOG) performance status score ≤ 2; anorexia after curative resection and chemotherapy, and score on the visual analog scale (VAS) for anorexia ≥ 40/100 mm (100 mm is the worst anorexia score); not taking megestrol acetate for stimulating appetite; fully understanding the clinical trial and communicating with their medical doctor about their symptoms or quality of life and who can fill out questionnaires; individuals who could follow-up during the clinical trial; and those with a life expectancy of three months or more.

2) Exclusion Criteria

Individuals who had symptomatic and uncontrolled brain or central nervous system metastasis, had other malignancies or with a history of other malignancies within 5 years from the screening visit (Except cured basal or squamous cell skin cancer, cervical epithelial cancer, thyroid cancer, prostate cancer or breast cancer); Total bilirubin levels higher than 2.0 mg/dL; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels higher than 2.5 times the upper limit for normal; Creatinine level higher than 1.5 times the upper limit for normal; uncontrolled pain ≥ numeral rating scale (NRS) 5 despite the use of analgesics; uncontrolled hypertension (Diastolic blood pressure > 100 mmHg or systolic blood pressure > 160 mmHg), diabetes, active infection or heart diseases such as symptomatic congestive heart failure or unstable angina; taking other herbal medicine or other medicines that are used for the same therapeutic purpose as that of the trial medicine or can affect the improvement of anorexia (e.g. corticosteroids, cyproheptadine) or health functional food, food and medical supplies containing main base materials even if it’s not used for the same therapeutic purpose, within 2 weeks at the screening visit; uncontrolled pleural effusion, ascites, pericardial effusion; a major psychotic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) and taking or should be taking psychiatry medications (except insomnia); alcoholism or drug dependence; a history of serious drug allergies or hypersensitivity to the investigational product (the main ingredient and its components); genetic problems such as galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption; pregnant, breastfeeding, planning to become pregnant or women of childbearing potential who do not agree with the appropriate method of contraception; participated in other clinical trials within 6 months (180 days prior to screening visit) or planned to participate in other clinical trials during the trial; a medical condition that would likely affect the results or individuals deemed inappropriate to participate by an investigator; parenteral or tube nutrition.

3. Sample Size

Based on a previous study in which Sipjeondaebo-tang was administered for four weeks for anorexia in cancer patients²⁵⁾, the sample size was calculated using the G-power program using the mean of 4.63 and the standard deviation of 4.50 for the difference value before and after the A/CS scale of FAACT. A two-sided test by paired t-test was performed, and a error was 0.050, b error was 0.10, and the power was 0.90, resulting in the total sample size of 13. In this study, since Bojungikgi-tang would be administered for six weeks, we assumed that approximately 15% more than the 20% dropout rate of previous similar studies would be lost. Therefore, the dropout rate was 35%, and the total calculated number of participants was 20.

4. Material

Bojungikgi-tang is a herbal medicine used in clinical practice with health insurance benefits in Korea, but traditional liquid-type medicine was manufactured for this study. Therefore, Bojungikgi-tang, in this study, received approval from the Ministry of Food and Drug Safety in Korea for the investigational new drug (IND). A pharmaceutical company (Hanpoong Pharm & Foods Co.) made Bojungikgi-tang for liquid medicine, and the herbal constituents are shown in Table 1. The participants took Bojungikgi-tang (75 mL per pack) three times a day before or during meals.

Table 1

Herbal constituents of Bojungikgi-tang

5. Outcomes

The primary outcome was a change in anorexia/cachexia subscale (A/CS) of functional assessment of anorexia/cachexia therapy (FAACT). The secondary outcomes were changes in functional assessment of cancer therapy: general (FACT-G), functional assessment of cancer therapy for patients with colorectal cancer (FACT-C), VAS of anorexia, weight, body mass index (BMI), skeletal muscle mass, high sensitivity C-reactive protein (hsCRP), metabolic tests (Na, K, Cl, BUN, creatinine) and T lymphocytes (CD4, CD8, and CD4/CD8 ratio).

6. Safety

All participants who took the research drug more than once were evaluated for safety. The safety outcomes are the frequency of adverse events and the frequency of abnormal findings of vital signs, physical examinations, clinical laboratory examination, and chest X-rays. The researchers explained all the adverse reactions that could occur after drug administration to the participants or their families, and made them report if the adverse events occurred.

7. Statistical Analysis

For effectiveness evaluation, full analysis set (FAS) analysis based on the intention-to-treat (ITT) principle is used as the main analysis, and per protocol (PP) analysis is performed as a secondary analysis. If the ITT analysis requires treatment of missing values, the last observation carried forward (LOCF) method is used. The statistical significance criterion for variables including primary and secondary outcomes is set to a significance level of 5%. Statistical analysis for safety evaluation was conducted on participants who took the test drug more than once, and an investigator checked the safety-related data at least once via a visit/phone call after taking the test drug. For continuous data, the paired t-test was performed for normally distributed variables, and the Wilcoxon signed rank test was performed for non-normally distributed variables. All analyses were conducted using SPSS 23 for Windows (SPSS inc., Chicago, IL, USA) program.

The adverse events were analyzed for each symptom and showed as a frequency. Likewise, abnormalities in vital signs, physical examination, clinical laboratory examination, and chest X-ray were also indicated by frequency.

Results

1 Baseline and Disease Characteristics

During the study period, a total of 12 colorectal cancer patients were recruited in the study. One patient was excluded at screening because he was taking a corticosteroid, a drug that could affect the improvement of anorexia, and this corresponds to the exclusion criteria. Another subject was dropped out because he missed visiting period (Figure 2). Table 2 shows information about the characteristics of the participants.

Fig. 2

Flow diagram of the participants

Table 2

Baseline and disease characteristics of the participants

2. Primary Outcome

The mean scores of the A/CS of FAACT on visit 2 (baseline) and visit 4 (6 weeks after baseline) were 23.4±9.1 and 30.0±11.2, respectively. The mean difference was 6.6±4.5 and the score at visit 4 increased significantly (p=0.0006) compared to that at the baseline (Table 3).

Table 3

Primary outcome: A/CS of FAACT

3. Secondary Outcomes

In the FACT-G, no significant difference was observed between the values at the baseline and at visit 3 or 4. In the FACT-C, the mean difference between visits 3 and 2 was 0.8±2.4, which was not a significant difference (p=0.4291). However, the FACT-C score at visit 4 increased significantly compared to that at the baseline (p=0.0343). In the VAS score for anorexia, at both visits 3 and 4, the VAS score decreased significantly (p=0.0083 and p<.0001, respectively) compared to that at the baseline. Comparing the values at visits 3 and 4 with that at the baseline, no significant differences were observed in weight, BMI, and skeletal muscle mass (Table 4).

Table 4

Secondary outcomes: FACT-G, FACT-C, VAS of anorexia, weight, BMI, and skeletal muscle mass

The mean and mean difference of CD4/CD8 ratio, CD4 levels, and CD8 levels at baseline and visit 4 are presented in Table 4. No significant differences were observed between the levels at visit 4 and at the baseline in the CD4/CD8 ratio, CD4 levels, and CD8 levels. No significant differences were observed between the baseline and visit 4 in metabolic test results and hsCRP levels (Table 5).

Table 5

Secondary outcomes: CD4/CD8 ratio, CD4, CD8, metabolic tests, and hsCRP

4. Safety

1) Adverse Events

Three serious adverse events (SAE) occurred (Table 6). The first SAE patient was admitted to another hospital due to dizziness that occurred after visit 2. Subsequently, the symptoms improved, but he dropped out because he could not attend visit 3. The second SAE patient had generalized weakness, acute kidney injury, fever, and vomiting on follow-up, but a pelvic abscess was later found and administered treatment. Subsequently, the initially reported adverse event (AE) improved and follow-up was ended. The third SAE patient was hospitalized to a nursing hospital due to generalized weakness on follow-up. Table 7 shows the frequency of reactions in the four participants who reported adverse events, and several reactions could overlap in individual persons.

Table 6

Analysis of adverse events

Table 7

Types and frequency of adverse events

2) Vital Signs and Physical Examinations

The frequency of the abnormalities in vital signs and physical examinations is shown in Table 8. Abnormal levels of systolic blood pressure (SBP) was less than 100 mmHg or higher than 140 mmHg, and abnormal levels of diastolic blood pressure (DBP) were less than 60 mmHg or higher than 90 mmHg. Through physical examinations, the participants' past and current diseases were identified. One person was receiving antibiotic treatment simultaneously due to an infection caused by chemoport.

Table 8

Frequency of abnormal values in vital signs and physical examinations

3) Clinical Laboratory Test and Chest X-ray

Complete blood cell count (CBC), white blood cell (WBC) differential count and liver and renal functional test (LRFT) were conducted as a clinical laboratory test at baseline and visit 4. In addition, chest X-rays were also performed, and the frequency of the abnormal findings are shown in Table 9.

Table 9

Frequency of abnormal values in clinical laboratory test and chest X-ray

Discussion

A total of 11 individuals participated in this study, eight of whom were diagnosed with rectal cancer, three were colon cancer, and all underwent laparoscopic resection. The stages were diverse, and two patients had liver and lung metastasis, respectively. Also, seven of the rectal cancer patients underwent ileostomy repair surgery before or during participation in this study. Laparoscopic low anterior resection (LAR) is an essential operation for rectal cancer, and ileostomy is generally performed to prevent postoperative complications, so the patients undergo additional surgery²⁶⁾. In patients with colorectal cancer, surgery is a factor that affects various physical functions²⁷⁾, and in a long-term perspective, gastrointestinal problems may occur²⁸⁾.

In addition, all received chemotherapy before or after surgery, with seven patients receiving capecitabine alone, two receiving combination therapy of capecitabine and oxaliplatin, one receiving combination therapy of capecitabine, bevacizumab, and FOLFOX (5-fluorouracil (FU), leucovorin, and oxaliplatin), and one receiving FOLFRI (5-FU, leucovorin, and irinotecan) treatment. Capecitabine is also used as the first line for metastatic colorectal cancer treatment because it is not inferior to 5-FU/leucovorin in disease progression and overall survival and has a better response rate and is easier to administer than 5-FU^29,30). Combination therapies containing oxaliplatin or irinotecan significantly improve the survival rate of patients with metastatic or advanced colorectal cancer³¹⁾. However, the combination of capecitabine and oxaliplatin or irinotecan increases the incidence of adverse effects on the gastrointestinal tract³²⁾. In one study of combination therapy of bevacizumab and XELOX (capecitabine and oxaliplatin), anorexia (44.4%) was reported after hand-foot syndrome (77.8%), which is the most adverse effect³¹⁾. Therefore, we conducted a single intervention group study by administering Bojungikgi-tang to treat the anorexia after curative resection and chemotherapy. We suggest managing long-term gastrointestinal dysfunction and anorexia caused by chemotherapy in colorectal cancer patients after surgery, considering effective and safe treatment.

Bojungikgi-tang is an herbal medicine made by Dongwon Lee of the Jin Dynasty of China and consists of 10 kinds of herbs. In modern times, it is often used to treat general fatigue, anorexia, and indigestion, and to prevent opportunistic infections in the elderly and weak persons³³⁾. Most cancer patients who have undergone surgery and chemotherapy complain of weakness and fatigue, so Bojungikgi-tang can be used for them³⁴⁾. In an animal experiment to study the effectiveness of Bojungikgi-tang on cachexia induced by colon cancer, the tumor weight in Bojungikgi-tang group decreased, and it was found that Bojungikgi-tang did not affect the growth rate of tumors³⁵⁾. A clinical study reported that Bojungikgi-tang significantly improved anorexia and indigestion in patients with severe esophageal cancer without hematologic adverse events, and increased CD3 expression in colorectal cancer patients who received FOLFIRI chemotherapy and Bojungikgi-tang in combination³⁶⁾. Bojungikgi-tang can improve immune function in cancer patients and reduce toxicity and side effects caused by chemotherapy³⁷⁾. Therefore, in this study, the effectiveness and safety of Bojungikgi-tang for anorexia after surgery and chemotherapy in colorectal cancer patients were examined through various outcomes.

The primary outcome of this study, A/CS of FAACT, measures the degree of anorexia in cancer patients. It comprises of 12 questions³⁸⁾, and lower score correlate with more severe anorexia. The mean score before the administration of Bojungikgi-tang was 23.4, which was less than 24, so it can be diagnosed as anorexia³⁹⁾, and the mean score after six weeks of medication is 30.0. There was a study⁴⁰⁾ that regarded a cut-off score of A/CS of FAACT in cancer patients as less than 37. Since it was analyzed, including breast cancer, lung cancer, and prostate cancer patients, it is difficult to consider it a specific cut-off value for colorectal cancer patients. According to a study, it is still a score corresponding to anorexia, but the symptoms might have improved because it significantly increased (p<0.05) compared to the score before the administration of Bojungikgi-tang.

The FACT-G used in this study consists of a total of 27 questions in four fields: physical, functional, social/family, and emotional wellbeing to evaluate the quality of life⁴¹⁾. The higher the score, the higher the quality of life. In this study, there was no significant difference in scores before and after an intervention. The FACT-C consists of nine additional colorectal cancer-specific questions⁴²⁾, which means that the higher the score, the higher the quality of life. The score after six weeks of taking Bojungikgi-tang was significantly higher than that at the baseline, suggesting that Bojungikgi-tang can improve the quality of life of colorectal cancer patients.

This study used VAS to measure the patient's subjective symptoms of anorexia. In a study using VAS to measure nausea and anorexia induced by chemotherapy in uterine cervical or corpus cancer, 5–25 mm was considered to be no significant nausea and anorexia⁴³⁾. In addition, in a study calculating the cut-off of VAS for cancer patients, 70 or less was considered as a cut-off value⁴⁰⁾. Referring to the previous studies, in this study, the VAS of anorexia in baseline was high at 71.4, and after three weeks and six weeks were significantly decreased to 53.6 and 33.6, respectively. Therefore, it means that the degree of anorexia complained by the patients is significantly improved.

No significant difference was found in CD4, CD8, and CD4/CD8 ratio between baseline and after intervention in this study. In previous studies comparing cellular immunity in colorectal cancer patients receiving chemotherapy, CD4 and CD4/CD8 ratio was significantly increased when chemotherapy and herbal medicine treatment were administered at the same time^44,45). Previous studies showing significant increases in CD4 and CD4/CD8 ratios indicate that combining chemotherapy and Bojungikgi-tang reduces damage to cell immunity and helps immune cells effectively identify and remove tumor cells⁴⁶⁾. The normal range of cellular immune indicators in normal adults is 40.2% (95% CI 30.75–49.60%) in CD4, 31.3%(95% CI 20.06–42.52%) in CD8, and 1.7(95% CI 0.39–3.02) in CD4/CD8 ratio, not considering factors such as gender, age, and race⁴⁷⁾. According to the normal range, the cellular immune indicators of baseline in this study are not low, but there is no significant change between before and after administration of Bojungikgi-tang. Since CD4 T cells have various effects on antitumor activity depending on the subset⁴⁸⁾, further studies on cellular immunity of colorectal cancer patients who have completed surgery and chemotherapy are considered necessary.

In one study, when Western medicine-based chemotherapy and herbal medicine were combined for colorectal cancer patients, the adverse effects were not or slightly significantly different from those of the group that was administered only chemotherapy⁴⁹⁾. We have one subject who was admitted to another hospital due to dizziness and was unable to participate in the process after visit 2. Since this patient was taking narcotic analgesics due to cancer pain, the patient discontinued this trial, but follow-up revealed that the adverse reaction was relieved after stopping narcotic analgesics. Therefore, we considered this adverse event to be less relevant to Bojungikgi-tang. No differences were observed between before and after Bojungikgi-tang administration in term of clinical laboratory test results, vital signs, physical examinations, and chest X-rays performed for safety evaluation. Therefore, Bojungikgi-tang can safely alleviate anorexia in patients with colorectal cancer who have completed chemotherapy and curative resection.

The limitations of our study were as follows. First, it was a single-group study without a control group, with a small sample size; thus, further clinical trials should be systematic and large-scale. Second, the administration of Bojungikgi-tang did not improve the body composition and anemia of colorectal cancer patients. This was because the participants not only had cancers of various stages and past histories but we also could not consider the individual's nutritional condition and diet. When designing future studies, the nutritional condition should be considered through the daily caloric intake of patients with anorexia. Third, since patients who completed chemotherapy were selected as participants, how Bojungikgi-tang affected anorexia in colorectal cancer patients undergoing chemotherapy could not be determined. Nevertheless, this study is meaningful because it verified that Bojungikgi-tang has the effect of improving the anorexia in colorectal cancer patients after curative resection and chemotherapy and the safety of having no serious side effects in cancer patients.

We conducted a single-group clinical trial to verify that Bojungikgi-tang is an effective and safe treatment for the anorexia in colorectal cancer patients after curative resection and chemotherapy.

Acknowledgement & Funding

This research was supported by grants from the Korea Institute of Oriental Medicine (KIOM) (grant numbers: KSN1812240, KSN2013310, and KSN2021310).

Notes

Conflicts of Interest

The authors declare that they have no conflicts of interests.

Ethical statement

This research was reviewed and approved by the institutional review board (IRB) of the Pusan National University Korean Medicine Hospital (registration number PNUKHIRB-2020002). Informed consent was obtained from all participants.

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Latin name	Doses (g)
Ginseng Radix	1.33
Atractylodis Rhizoma Alba	1.33
Astragali Radix	1.33
Angelicae Gigantis Radix	1.00
Citri Unshius Pericarpium	0.67
Zizyphi Fructus	0.67
Bupleuri Radix	0.67
Glycyrrhizae Radix	0.50
Cimicifugae Rhizoma	0.33
Zingiberis Rhizoma	0.17

Characteristics	Participants (n = 11)
Age (years)	66.2±11.6

Sex (n)
Male	8 (72.7%)
Female	3 (27.3%)

Height (cm)	163.0±7.7

Weight (kg)	56.5±7.6

BMI (kg/m²)	21.3±3.1

Smoking (n)
Yes	0 (0%)
No	11 (100%)
Former smoker	0 (0%)

Drinking (n)
Yes	1 (9.1%)
No	10 (90.9%)

Localization (n)
Colon	3 (27.3%)
Rectum	8 (72.7%)

Clinical stage (n)
I	2 (18.2%)
II	3 (27.3%)
III	4 (36.4%)
IV	2 (18.2%)

ECOG (n)
0	4 (36.4%)
1	7 (63.6%)
2	0 (0%)

Antitumor drug (n)
Capecitabine	7 (63.6%)
Capecitabine+oxaliplatin	2 (18.2%)
Capecitabine+bevacizumab+FOLFOX^a	1 (9.1%)
5-FU +FOLFIRI^b	1 (9.1%)

	Visit	Mean±SD	P-value
FACT-G score	V2 (Baseline)	66.3±14.2
	V3 (3weeks)	64.8±8.6	0.7198
	V4 (6weeks)	69.1±10.2	0.5274

FACT-C score	V2 (Baseline)	14.3±3.6
	V3 (3weeks)	15.1±4.0	0.4291
	V4 (6weeks)	17.1±5.2	0.0343^*

VAS of anorexia (mm)	V2 (Baseline)	71.4±13.6
	V3 (3weeks)	53.6±22.0	0.0083^**
	V4 (6weeks)	33.6±26.9	<.0001^***

Weight (kg)	V2 (Baseline)	57.1±7.4
	V3 (3weeks)	57.2±7.3	0.6830
	V4 (6weeks)	57.6±7.3	0.2129

BMI (kg/m²)	V2 (Baseline)	21.5±3.0
	V3 (3weeks)	21.6±2.9	0.7736
	V4 (6weeks)	21.7±2.9	0.2775

Skeletal muscle mass (kg)	V2 (Baseline)	24.3±4.8
	V3 (3weeks)	24.1±5.1	0.5482
	V4 (6weeks)	23.9±5.0	0.3379

	Visit 2 (baseline)	Visit 4 (6 weeks)	D(V4-V2)	P-value
CD4/CD8 ratio	1.7±1.3	1.7±1.2	0.0±0.3	0.6973^†
CD4 (%)	31.4±10.3	30.3±10.3	−1.1±4.6	0.9219
CD8 (%)	25.4±13.4	24.5±13.4	−0.9±2.3	0.2188
Na (mmol/L)	138.4±2.5	138.3±2.9	−0.1±1.5	0.8461
K (mmol/L)	4.1±0.4	4±0.6	0.0±0.4	0.8390
Cl (mmol/L)	104.7±4.2	103.8±3.8	−0.9±3.6	0.4241
BUN (mg/dL)	17.9±5.2	19.7±6.4	1.8±6.6	0.1055^†
Creatinine (mg/dL)	0.9±0.3	1±0.5	0.1±0.3	0.4063^†
hsCRP (mg/L)	0.6±1	0.8±1.3	0.2±0.8	0.5703^†

		Participants (n = 11)	P-value
AE	Yes	4 (36.36%)	0.3657^‡
AE	No	7 (63.64%)	0.3657^‡

Serious AE	Yes	3 (75.00%)	0.3173^‡‡
Serious AE	No	1 (25.00%)	0.3173^‡‡

Severity	Mild	1 (25.00%)	0.7788^‡‡
	Moderate	2 (50.00%)
	Severe	1 (25.00%)

Causation	Related	0 (0.00%)	1.0000^‡‡
	Probably related	0 (0.00%)
	Possible related	0 (0.00%)
	Probably not related	2 (50.00%)
	Not related	2 (50.00%)
	Unknown	0 (0.00%)

Other management taken	None	1 (25.00%)	0.3173^‡‡
	Concomitant use of therapeutic drugs	0 (0.00%)
	Non-drug treatment	0 (0.00%)
	Prolongation of hospitalization	3 (75.00%)

Management related to test drug	None	1 (25.00%)	0.7788^‡‡
	Reduction	0 (0.00%)
	Re-administration after temporary discontinuation	2 (50.00%)
	Discontinuance	1 (25.00%)

Consequences of adverse events	Recovered	2 (50.00%)	0.7788^‡‡
	Sequelae after recovery	1 (25.00%)
	In recovery	0 (0.00%)
	Not Recovered	1 (25.00%)
	Dead	0 (0.00%)
	Undetermined	0 (0.00%)

Types of AE	Frequency
Ileus	1
Dizziness	2
General weakness	2
Constipation	1
Vomiting	1
Fever	2
Hydronephrosis	1
AKI	1
Pelvic abscess	1

	Visit 2 (baseline)	Visit 3 (3 weeks)	Visit 4 (6 weeks)
Vital sign
SBP	3	2	5
DBP	3	1	1
Pulse	0	1	1
Body temperature	0	0	0
Respiratory rate	0	0	0

Physical examination
Nutritional condition	0	0	0
Respiratory system	1	1	0
Dermatology	0	0	0
Endocrinology	1	0	0
Otolaryngology	0	0	0
Gastroenterology	11	10	10
Cardiovascular system	3	2	2
Musculoskeletal system	1	1	1
Renal/Urology	3	3	3
Neuropsychiatric system	0	0	0
Other	1	1	0

	Visit 2 (baseline)	Visit 4 (6 weeks)
Clinical laboratory test
WBC	2	1
Seg. neutrophil	2	1
Monocyte	0	1
Lymphocyte	5	1
Eosinophil	0	2
Basophil	0	0
RBC	7	7
Hemoglobin	6	5
Hematocrit	2	5
Platelet	1	0
MCV	4	3
MCH	1	1
MCHC	0	1
Total bilirubin	1	1
AST	0	2
ALT	0	2
ALP	2	1
BUN	1	2
Creatinine	1	3
Uric acid	0	2
Total protein	3	0
Albumin	2	1
Na	1	1
K	0	2
Cl	2	2
hsCRP	4	2
CK	0	0

Chest X-ray
Cardiomegaly	2	2
Stabilized tuberculosis	1	1
Pleural effusion	1	0

Article information

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Methods

1 Study Design

2. Participants

1) Inclusion Criteria

2) Exclusion Criteria

3. Sample Size

4. Material

5. Outcomes

6. Safety

7. Statistical Analysis

Results

1 Baseline and Disease Characteristics

2. Primary Outcome

3. Secondary Outcomes

4. Safety

1) Adverse Events

2) Vital Signs and Physical Examinations

3) Clinical Laboratory Test and Chest X-ray

Discussion

Acknowledgement & Funding

Notes

References

Article information Continued

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