Effects of Traditional Chinese Medicine “Fuzheng Qingdu Decoction” on Autonomic Function and Cancer-Related Symptoms in Patients with Advanced Gastric Cancer undergoing Chemotherapy: A Controlled Trial

Abstract

Objective:

To evaluate the effects of Fuzheng Qingdu Decoction (FZQDD) on the autonomic function and cancer-related symptoms of patients with advanced gastric cancer undergoing chemotherapy to verify its clinical efficacy.

Methods:

Sixty-two patients with stage III or IV gastric cancer were included in this study. The patients were divided into 2 groups: the chemotherapy (33 patients) and chemotherapy with FZQDD (29 patients) groups. The primary outcome was the autonomic function of the patients before and after the interventions. The parameters that were used to assess autonomic function were deceleration capacity (DC) and acceleration capacity (AC) of heart rate and heart rate variability (HRV), which comprised standard deviation of the normal-normal interval (SDNN), root mean square of successive interval differences (RMSSD), low-frequency power (LF), high-frequency power (HF), total power (TP), and LF–HF ratio. The secondary outcomes were cancer-related symptoms and the quality of life.

Results:

DC and HRV parameters (ie, SDNN, RMSSD, LF, HF, and TP) were significantly decreased in the chemotherapy group; however, AC significantly increased after the interventions. No significant differences were observed in the DC, AC, and HRV parameters before and after the interventions in the chemotherapy with FZQDD group. Nevertheless, the changes in DC, AC, and HRV parameters (SDNN, RMSSD, HF, and TP) before and after the interventions were statistically significant between both the groups. FZQDD significantly improved the cancer-related symptoms and the quality of life of the patients.

Conclusions:

Oxaliplatin combined with S-1 (tegafur, gimeracil, and oteracil potassium) can impair autonomic modulation in patients with advanced gastric cancer. FZQDD can alleviate autonomic dysfunction by increasing the parasympathetic activity and decreasing the sympathetic tone, helping patients restore the dynamic sympathovagal balance, and significantly improving the cancer-related symptoms and the quality of life of patients.

Keywords

advanced gastric cancer autonomic modulation cancer-related symptoms traditional Chinese medicine deceleration/acceleration capacities of heart rate heart rate variability

Introduction

The global cancer statistics in 2020 have reported that gastric cancer (GC) is a common malignant tumor, accounting for 5.6% of all cancer cases, and the fourth leading cause of cancer-related deaths, with approximately 769 000 deaths each year.¹ Because the disease onset is not easily detected, most patients with GC are already at the advanced stage at the time of first diagnosis. Presently, chemotherapy is the main treatment modality for advanced GC, followed by targeted therapy and immunotherapy. However, issues such as a low 5-year survival rate and considerable side effects of chemotherapy remain.^2,3 Therefore, prolonging the survival time and decreasing chemotherapy-associated toxicity has become a breakthrough point in advanced GC treatment. In addition to the standard Western medicine, more and more traditional Chinese medicine (TCM) therapies have been accepted as a part of combination therapy for advanced GC.⁴ In clinical settings, Chinese herbs can be used for GC treatment either alone or as an adjunct to the traditional treatment regimens. Chinese herbal medicine can significantly affect advanced GC treatment by decreasing the chemotherapy-induced adverse reactions, treating cancer-related complications, and prolonging the survival time.^5
-9

Yang represents promotion and stimulation, whereas Yin represents inhibition and inactivation. In TCM, Yang is related to an exciting functionality, whereas Yin is related to an inhibiting functionality; both the energies balance each other.¹⁰ The Yin and Yang of TCM are strongly associated with the autonomic nervous system (ANS), with similarities between the two.^11,12 ANS comprises the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS); both the systems have definite excitatory or inhibitory effects on multiple systems in the human body. SNS and PNS regulate physiological activities via antagonistic and coordinated effects.¹³ Several patients with cancer suffer from ANS imbalance; this finding may be consistent with the imbalance in the Yin and Yang energy in TCM.^11,12,14 Traditional Chinese prescriptions are based on the theory that TCM promotes the Yin–Yang balance and that they may regulate the dynamic sympathovagal nerve balance. For example, Chien et al^11,12 have reported that Kuan-Sin-Yin, a TCM decoction, alleviates autonomic dysfunction and significantly improves Yang and Yin meridian energy in patients with metastatic colon cancer, which may be achieved by affecting the dynamic sympathovagal and the Yin–Yang balance. Dynamic sympathovagal balance conforms to the Yin–Yang concept of energy in TCM.^11,12

Fuzheng Qingdu therapy forms the basis for harmonizing Yin and Yang, qi, and blood. This therapy can not only restore immune function but also remove dampness, resolve phlegm, and activate circulation to remove blood stasis.^15
-17 Fuzheng Qingdu Decoction (FZQDD) comprises the following 16 herbs: Astragalus membranaceus (Fisch.) Bunge 30 g, Atractylodes macrocephala Koidz. 10 g, Poria cocos (Schw.) Wolf 10 g, Dioscorea polystachya Turcz. 15 g, Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf 20 g, Citrus reticulata Blanco Pericarpium 10 g, Cynanchum otophyllum C.K.Schneid. 10 g, Smilax china L. 30 g, Salvia chinensis Benth. 20 g, Solanum lyratum Thunb. 30 g, Scleromitrion diffusum (Willd.) R.J.Wang 30 g, Perilla frutescens (L.) Britt. 10 g, Agastache rugosa (Fisch. et Mey.) O.Ktze. 10 g, Solanum nigrum L. 30 g, Pinellia ternata (Thunb.) Ten. ex Breitenb. 10 g, and Glycyrrhiza uralensis (Fisch.) 3 g. In our previous studies, we observed that the Fuzheng Qingdu therapy could improve the overall survival and progression-free survival of metastatic GC patients, and that FZQDD combined with S-1 (ie, tegafur, gimeracil, and oteracil potassium) plus oxaliplatin (SOX) regimen improved the clinical symptoms, increased the quality of life, and decreased the incidence of adverse reactions in patients with advanced GC.^15
-17 In addition, FZQDD could inhibit tumor growth in mice with GC. Further studies have revealed that FZQDD could inhibit the secretion of interleukin (IL)-6, transforming growth factor-β (TGF-β), and other inflammatory factors, inhibit the chemotaxis and recruitment of myeloid-derived suppressor cells (MDSCs), and downregulate the phosphatidylinositol-3-kinase (PI3K)/Akt (PI3K/AKT) pathway, thereby achieving anti-tumor effects.¹⁷ Accordingly, we hypothesized that FZQDD improves cancer-related symptoms and treats GC by regulating sympathovagal homeostasis; however, additional studies are warranted to prove this hypothesis.

Therefore, in the present study, we investigated the changes in the autonomic function and cancer-related symptoms of patients with advanced GC before and after FZQDD intervention.

Methods

Subjects

In the present study, we included patients with advanced GC who were treated at the Oncology Department of Yangzhou Hospital of TCM from December 2022 to July 2023. The inclusion criteria were as follows: (1) cytological or histological diagnosis of GC; (2) TNM stage of III or IV; (3) Karnofsky performance status score of >60 points; (4) expected survival time not less than 6 months; and (5) no energy drink (coffee, tea, alcohol) nor breakfast consumption for a minimum 3 h prior to measurement. The exclusion criteria were as follows: (1) patients with nonprimary GC or other tumors; (2) those who cannot eat food by mouth; (3) those with serious primary liver, lung, kidney, and other diseases that threaten life safety; (4) the use of alpha-blockers or beta-blockers; (5) previous cardiac diseases (ie, coronary heart disease, myocardial infarction, and arrhythmia); and (6) other factors that made the researchers believe that they were unsuitable for participation in the study. The Medical Ethics Committee of Yangzhou Hospital of TCM approved this study (registration number: 2022-43). All participants volunteered to participate in the study and signed the informed consent forms.

Therapies

The first-line chemotherapy regimen for advanced GC is the use of SOX regimen. Because Chinese herbal medicine has not yet become the standard therapy for advanced GC, the patients were free to choose whether they wished to receive FZQDD as an adjuvant therapy. This was a before–after study based on a nonrandomized controlled trial. Patients who were willing to receive FZQDD as an adjuvant therapy were classified as the chemotherapy with FZQDD group, whereas the remaining patients received only standard chemotherapy and were classified as the control group. To reduce bias in the experimental design, research assistants and those who evaluated the outcomes were blinded after they were assigned to specific intervention groups.

The chemotherapy group received only SOX chemotherapy regimen. The specific administration regimen was as follows: intravenous infusion of oxaliplatin at a dose of 130 mg/m², which was completed on the first day of treatment. S-1 was orally administered, once after 2 meals in the morning and evening, for 14 days at a dose of 40 mg/m².

The chemotherapy with FZQDD group received FZQDD combined with the abovementioned chemotherapy regimen. All the herbs used in this study were obtained from the pharmacy of Yangzhou Hospital of TCM. The herbs were added or removed based on the patient’s condition, decocted with water, and administered one dose a day, which was administered 2 times (ie, in the morning and evening). The patients were orally administered FZQDD during the treatment period.

Autonomic Function Analysis

With the patients in the supine position, a miniature electrocardiograph (HeaLink-R211B; HeaLink Ltd., Bengbu, China) was used to collect 5-min resting electrocardiograms before and after 2 weeks of treatment at a sampling rate of 400 Hz and V6 leads. The same operator conducted measurements both pre- and post-intervention.

QRS-waves showed the highest amplitude and the shortest duration among all waveforms of electrocardiogram signals, which are the most easily to recognize and evident waveforms. To extract the R peak of the electrocardiogram, we selected the efficient and classical Pan-Tompkins algorithm,¹⁸ since it is prevalent both in academy and industry. The deceleration capacity (DC) and acceleration capacity (AC) of heart rate were calculated using the phase-rectified signal averaging algorithm, based on the averaging data segments around R-R intervals longer or shorter than the preceding interval so as to quantify the average deceleration or acceleration of heart rate.^19,20 The frequency domain parameters of heart rate variability (HRV) were analyzed using the fast Fourier transform algorithm. The calculation processes for DC, AC, and HRV parameters were made according to the methods described in our previous study.²¹ The following HRV parameters were determined: standard deviation of the normal-normal interval (SDNN), root mean square of successive interval differences (RMSSD), low-frequency power (LF, 0.04-0.15 Hz), high-frequency power (HF, 0.15-0.4 Hz), total power (TP, 0-0.4 Hz), and LF–HF ratio (LF/HF). Kubios HRV Premium software (version 3.5, https://www.kubios.com, Magi Kubios Oy, Kuopio, Finland) was used to analyze the DC, AC, and HRV parameters.²²

Cancer-Related Symptoms and Quality of Life

Cancer-related symptoms and the quality of life were determined by the same chief TCM physician before and 2 weeks after the treatment. Based on the Guiding Principles for Clinical Research on New Chinese Medicine Drugs issued by the State Drug Administration of China, a TCM symptom scoring scale was developed for GC, and the symptoms of both the groups were scored, which included stomach ache, stomach bloating, loss of appetite, belching, acid reflux, nausea and vomiting, diarrhea, and fatigue.²³ The quality of life was evaluated using the Quality of Life Questionnaire developed by the European Organization for Research and Treatment of Cancer.^24,25 The TCM symptom scoring scale and the Quality of Life Questionnaire are presented in Supplemental Material 1.

Statistical Analysis

The estimation of the sample size was based on a previously published study,¹² and no specific statistical method was used to determine the sample size. The independent samples t-test, Mann–Whitney U test, or Chi-squared test was performed to compare the differences in the variables among the subgroups before the interventions. The paired sample t-test or Wilcoxon sign-rank test was performed to analyze the differences in the variables before and after the interventions. Cohen’s d value was used to characterize the effect sizes of the differences in DC, AC, and HRV in the subgroups before and after the interventions. The changes of DC, AC, and HRV between the 2 groups pre- and post-interventions were compared using the independent samples t-test or Mann–Whitney U test. SPSS Statistics 25.0 (IBM Corp., Chicago, Illinois, United States of America) was used to conduct statistical analyses. P < .05 was considered to indicate statistical significance.

Results

General Characteristics

In this study, a total of 74 patients with advanced GC who met the inclusion criteria were included, and 12 patients were excluded due to incomplete data (n = 6), spontaneous withdrawal (n = 3), FZQDD treatment interruption (n = 2), or poor electrocardiogram quality (n = 1). Sixty-two patients (41 males and 21 females) with advanced GC were enrolled in the final analysis. The patients were divided into 2 groups based on the treatment modalities: the chemotherapy group (33 patients) and the chemotherapy with FZQDD group (29 patients). The general characteristics and the information of comparisons between the variables of the 2 groups before the intervention are presented in Table 1.

Table 1.

Comparison of the Variables for the Chemotherapy Group and the Chemotherapy with FZQDD Group Before the Treatments.

Variables	Chemotherapy group (N = 33)	Chemotherapy with FZQDD group (N = 29)	P	t/U/X²
Gender (male/female)	23/10	18/11	.527	0.401
Age (years)	65.4 ± 12.8	67.9 ± 11.3	.408	−0.834
BMI (kg/m²)	21.0 ± 3.8	21.2 ± 3.3	.879	−0.153
Smoking (yes/no)	2/31	3/26	.880	0.023
Hypertension (yes/no)	13/20	9/20	.492	0.471
Diabetes (yes/no)	4/29	5/24	.834	0.044
TNM stage (III/IV)	12/21	11/18	.899	0.016
Mean HR (bpm)	73.2 ± 14.7	73.5 ± 14.2	.950	−0.063
DC (ms)	12.3 ± 9.4	11.9 ± 8.8	.860	0.177
AC (ms)	−12.1 ± 9.3	−11.6 ± 8.8	.836	−0.209
SDNN (ms)	13.8 [8.7, 21.4]	11.3 [8.3, 19.5]	.698	451
RMSSD (ms)	15.3 [7.6, 26.2]	13.1 [8.4, 22.3]	.549	436
LF (ms²)	48 [17, 109]	40 [16, 149]	.667	448
HF (ms²)	56 [26, 185]	58 [22, 177]	.838	464
TP (ms²)	160 [61, 313]	119 [60, 314]	.893	469
LF/HF	0.766 [0.294, 1.753]	0.634 [0.396, 1.754]	.827	463

Values are expressed as the number of patients or mean ± standard deviation or median [Q1, Q3].

The independent sample t-test or Mann-Whitney U test was used for each continuous variable, and the Chi-square test was used for each counting variable.

Abbreviations: BMI, body mass index; TNM, tumor-node-metastasis.

Treatments on the Autonomic Nervous System

Comparison of the results of DC, AC, and HRV parameters of the patients in the chemotherapy group before and after treatments revealed significant differences in DC (P = .002), AC (P = .007), SDNN (P = .005), RMSSD (P = .003), LF (P = .009), HF (P = .010), and TP (P = .001). Specifically, the values of DC (12.3 ± 9.4vs 8.2 ± 4.8), SDNN (13.8 [8.7, 21.4] vs 9.9 [6.7, 14.2]), RMSSD (15.3 [7.6, 26.2] vs 10.5 [6.1, 15.8]), LF (48 [17, 109] vs 20 [12, 61]), HF (56 [26, 185] vs 36 [14, 88]), and TP (160 [61, 313] vs. 79 [40, 155]) were significantly lower than those before the therapies. When compared with the pre-therapies data, AC (−12.1 ± 9.3 vs. −8.3 ± 5.0) was found to be significantly higher after the treatment (Figure 1). The DC (11.9 ± 8.8 vs 13.4 ± 10.4), AC (−11.6 ± 8.8 vs −12.5 ± 9.9) and HRV parameters SDNN (11.3 [8.3, 19.5] vs 14.8 [10.2, 22.2]), RMSSD (13.1 [8.4, 22.3] vs 17.3 [10.3, 26.8]), LF (40 [16, 149] vs 48 [21, 102]), HF (58 [22, 177] vs 79 [28, 240]), TP (119 [60, 314] vs 158 [62, 422]), and LF/HF (0.634 [0.396, 1.754] vs 0.642 [0.255, 1.107]) in the chemotherapy with FZQDD group were not statistically significant before and after treatments (Figure 1). The effect sizes of DC, AC, and HRV before and after treatments within the respective subgroups are shown in Figure 2.

Figure 1.

Differences in the parameters for subgroups of patients pre- and post-therapies. Values are expressed as the mean ± standard deviation or median [Q1, Q3]. The paired sample t-test or Wilcoxon sign-rank test was performed to analyze the differences. The values of chemotherapy group before and after intervention: DC (12.3 ± 9.4 vs 8.2 ± 4.8, P = .002, t = −3.299), AC (−12.1 ± 9.3 vs −8.3 ± 5.0, P = .007, t = 2.892), SDNN (13.8 [8.7, 21.4] vs 9.9 [6.7, 14.2], P = .005, Z = −2.814), RMSSD (15.3 [7.6, 26.2] vs 10.5 [6.1, 15.8], P = .003, Z = −2.975), LF (48 [17, 109] vs 20 [12, 61], P = .009, Z = −2.618), HF (56 [26, 185] vs 36 [14, 88], P = .010, Z = −2.564), TP (160 [61, 313] vs 79 [40, 155], P = .001, Z = −3.261), and LF/HF (0.766 [0.294, 1.753] vs 0.707 [0.331, 1.382], P = .728, Z = −0.348). The values of chemotherapy with FZQDD group before and after intervention: DC (11.9 ± 8.8 vs 13.4 ± 10.4, P = .403, t = .849), AC (−11.6 ± 8.8 vs −12.5 ± 9.9, P = .646, t = −0.464), SDNN (11.3 [8.3, 19.5] vs 14.8 [10.2, 22.2], P = .157, Z = −1.416), RMSSD (13.1 [8.4, 22.3] vs 17.3 [10.3, 26.8], P = .082, Z = −1.741), LF (40 [16, 149] vs 48 [21, 102], P = .705, Z = −.378), HF (58 [22, 177] vs 79 [28, 240], P = .358, Z = −0.919), TP (119 [60, 314] vs 158 [62, 422], P = .469, Z = −.724), and LF/HF (0.634 [0.396, 1.754] vs 0.642 [0.255, 1.107], P = .112, Z = −1.589).

Figure 2.

The effect size of variables for the subgroups pre- and post-therapies. Cohen’s d value was used to characterize the effect sizes of the differences. Chemotherapy group: DC (d = .574, 95% CI: 0.202 to 0.939), AC (d = .503, 95% CI: 0.137 to 0.863), SDNN (d = .617, 95% CI: 0.240 to 0.986), RMSSD (d = .638, 95% CI: 0.259 to 1.009), LF (d = .365, 95% CI: 0.010 to 0.715), HF (d = .492, 95% CI: 0.127 to 0.850), TP (d = .472, 95% CI: 0.109 to 0.829), and LF/HF (d = .020, 95% CI: −0.322 to 0.361). Chemotherapy with FZQDD group: DC (d = .158, 95% CI: −0.210 to 0.523), AC (d = .086, 95% CI: −0.279 to 0.450), SDNN (d = .318, 95% CI: −0.058 to 0.689), RMSSD (d = .406, 95% CI: 0.024 to 0.782), LF (d = .098, 95% CI: −0.268 to 0.462), HF (d = .243, 95% CI: −0.129 to 0.610), TP (d = .215, 95% CI: −0.155 to 0.581), and LF/HF (d = .344, 95% CI: −0.034 to 0.716).

To verify whether FZQDD influences ANS, we analyzed the variations of DC, AC, and HRV before and after treatments (post-therapies value minus pre-therapies value) for the subgroup patients. The changes of DC (−4.1 ± 7.2 vs 1.5 ± 9.2, P = .010), AC (3.8 ± 7.6vs −0.8 ± 9.5, P = .037) and HRV parameters SDNN (−2.6 [−12.7, 0.8] vs 2.6 [−3.8, 7.6], P = .003), RMSSD (−2.8 [−17.5, 0.7] vs 3.4 [−4.4, 11.3], P = .001), HF (−18 [-142, 14] vs 10 [−47, 113], P = .013), and TP (−47 [−218, 10] vs 35 [−124, 172], P = .008) between the 2 groups pre- and post-therapies displayed statistically significant differences (Figure 3).

Figure 3.

Change in DC, AC, and HRV, calculated as post-therapies value, minus pre-therapies value for the subgroups of patients. Values are expressed as the mean ± standard deviation or median [Q1, Q3]. The changes of DC, AC, and HRV were compared using the independent samples t-test or Mann–Whitney U test. The changes in the chemotherapy group versus chemotherapy with FZQDD group: DC (−4.1 ± 7.2 vs 1.5 ± 9.2, P = .010, t = −2.678), AC (3.8 ± 7.6 vs −0.8 ± 9.5, P = .037, t = 2.130), SDNN (−2.6 [−12.7, 0.8] vs 2.6 [−3.8, 7.6], P = .003, U = 265), RMSSD (−2.8 [−17.5, 0.7] vs 3.4 [−4.4, 11.3], P = .001, U = 241), LF (−20 [−60, 5] vs 5 [−52, 33], P = .051, U = 340), HF (−18 [−142, 14] vs 10 [−47, 113], P = .013, U = 303), TP (−47 [−218, 10] vs 35 [−124, 172], P = .008, U = 290), and LF/HF (−0.055 [−0.535, 0.674] vs −0.123 [−0.694, 0.160], P = .397, U = 418.5).

Treatments on the Cancer-Related Symptoms and Quality of Life

We compared the TCM symptom scores and the quality of life scores before the interventions between the 2 groups, with no significant difference (P > .05). After the interventions, fatigue, nausea and vomiting scores were significantly higher in patients receiving chemotherapy alone. When compared with the pre-intervention data, stomach ache, loss of appetite, acid reflux, fatigue, nausea and vomiting scores decreased significantly in patients receiving chemotherapy with FZQDD, and the other cancer-related symptoms improved. Compared with the pre-intervention data, no significant improvement was observed in the quality of life in the chemotherapy group. In the chemotherapy with FZQDD group, physical function and the overall quality of life scores improved significantly (Table 2).

Table 2.

Comparison of Cancer-Related Symptoms and the Quality of Life Scores Before and After Therapies.

Variables	Chemotherapy group (N = 33)				Chemotherapy with FZQDD group (N = 29)
Variables	Pre-values	Post-values	P	t	Pre-values	Post-values	P	t
Stomach ache	1.64 ± 0.49	1.45 ± 0.56	.110	1.644	1.79 ± 0.77	1.28 ± 0.53	.002	3.360
Stomach bloating	1.82 ± 0.68	1.61 ± 0.61	.090	1.750	1.72 ± 1.03	1.48 ± 0.63	.182	1.367
Loss of appetite	1.91 ± 0.58	1.67 ± 0.54	.058	1.966	1.83 ± 0.66	1.41 ± 0.57	.012	2.703
Belching	1.58 ± 0.61	1.45 ± 0.51	.211	1.277	1.41 ± 0.50	1.28 ± 0.45	.326	1.000
Acid reflux	1.76 ± 0.61	1.61 ± 0.50	.057	1.971	1.59 ± 0.50	1.14 ± 0.44	.001	3.822
Nausea and vomiting	1.09 ± 0.63	1.39 ± 0.56	.031	−2.261	1.03 ± 0.63	0.69 ± 0.47	.002	3.360
Diarrhea	1.55 ± 0.51	1.36 ± 0.49	.056	1.979	1.52 ± 0.51	1.41 ± 0.50	.264	1.140
Fatigue	1.27 ± 0.67	1.63 ± 0.78	.026	−2.334	1.28 ± 0.70	0.93 ± 0.46	.005	3.025
Physical function	66.87 ± 5.65	67.88 ± 5.88	.169	−1.407	67.59 ± 4.95	75.86 ± 3.29	<.001	−8.500
Role function	62.12 ± 11.98	62.63 ± 11.81	.712	−0.373	61.50 ± 9.02	62.07 ± 10.82	.713	−0.372
Emotional function	62.63 ± 4.72	63.13 ± 6.26	.601	−0.529	63.51 ± 4.68	64.66 ± 3.63	.103	−1.684
Cognitive function	63.64 ± 10.59	64.14 ± 11.12	.712	−0.373	61.50 ± 9.02	63.80 ± 6.41	.211	−1.279
Social function	61.62 ± 8.82	62.12 ± 7.54	.711	−0.373	61.50 ± 10.06	62.64 ± 11.49	.489	−0.701
Overall quality of life	67.93 ± 7.25	68.69 ± 7.23	.083	−1.789	65.23 ± 5.49	76.15 ± 2.92	<.001	−9.904

Values are expressed as the mean ± standard deviation or median [Q1, Q3].

Bold P values indicate statistical significance (P < .05).

The paired sample t-test or Wilcoxon sign-rank test was performed to analyze the differences.

Discussion

FZQDD Promotes the Dynamic Sympathovagal Balance

Autonomic modulation is crucial for maintaining the dynamic balance between the internal and external environments and proper life activities.²⁶ Previous studies have suggested that ANS imbalance (PNS underactivity and/or SNS overactivity) is correlated with malignancy development.²⁷ The non-invasive detection techniques DC, AC, and HRV have been used to indirectly demonstrate ANS functions.^19,28,29 Growing evidence indicates that ANS functions (shown by DC, AC, or HRV) are closely related to blood biomarkers, cancer state/progression, and survival time in patients with GC.^30
-33 Hu et al³² indicated that decreased HRV was related to the advanced clinical stage, tumor size, tumor infiltration, lymph node metastasis, and distant metastasis in patients with GC. The low HRV group revealed higher levels of C-reactive protein than did the high HRV group.³² In addition, HRV parameters in patients with GC were significantly correlated with the levels of C-reactive protein, prealbumin, and fibrinogen.³⁰

Previous studies preliminarily investigated the short-term or long-term effects of chemotherapeutic drugs on ANS in patients with malignancies.^34
-37 Caru et al³⁴ observed noticeable alterations in the ANS after doxorubicin intervention in patients with childhood acute lymphoblastic leukemia. Ekholm et al³⁵ reported ANS impairment post-paclitaxel therapy. Stachowiak et al³⁶ showed that doxorubicin exerted a remarkable effect on the ANS in patients with breast cancer. The mechanism of autonomic dysfunction caused by chemotherapeutic drugs is multifaceted and complex. The etiology of autonomic modulation impairments induced by chemotherapeutic drugs, such as platinum compounds, taxanes, and anthracyclines, may involve oxidative stress, cell damage, and inflammatory pathways.^14,38

DC symbolizes the PNS tone, whereas AC is a quantitative metric of the SNS regulatory ability.^19,29 The present results indicated that the SOX chemotherapy regimen significantly decreased DC and increased AC, indicating that it could cause autonomic dysfunction. When compared with patients in the chemotherapy group, those in the chemotherapy with FZQDD group exhibited significantly higher DC and lower AC after the interventions. Thus, this study showed that FZQDD could increase the PNS tone (indicated by DC) and decrease SNS activity (indicated by AC) in patients with advanced GC. SDNN is the overall variability of HRV and reflects the activity of the PNS and SNS. RMSSD reflects the vagal nerve activity. LF is regulated by the PNS and SNS. HF is related to the PNS activity. TP corresponds to the PNS and SNS activities.²⁸ The present results showed that the HRV parameters SDNN, RMSSD, HF, and TP increased significantly after the interventions in the chemotherapy with FZQDD group relative to that in the chemotherapy group. This finding implied increased autonomic activity and adaptability (shown by SDNN) and vagal nerve activity (indicated by RMMSD and HF) in patients after the FZQDD intervention.

The Possible Mechanism by Which FZQDD Improves Cancer-Related Symptoms and the Quality of Life

Multiple studies have demonstrated that different forms of TCM therapies, such as Chinese herbal medicine, acupuncture, Tai Chi, and Qigong, can improve cancer-related fatigue, cancerous pain, and specific quality of life in patients with cancer, possibly by promoting the dynamic sympathovagal balance.^11,12,39
-41 Lee et al’s⁴⁰ study indicated that cancer survivors experienced significantly reduced cancer-related fatigue and exhibited a substantial increase in the HRV indicators SDNN, TP, and HF after 12 weeks of Qigong exercise. Zhou et al⁴¹ showed that Tai Chi could alleviate cancer-related fatigue in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. An improvement in the ANS balance might contribute to the mechanism of Tai Chi for cancer-related fatigue management in this population.⁴¹ Although the scales/questionnaires used in clinical practice are valid and reliable, individuals’ answers are based on subjective feelings or opinions and may not truly reflect the physical and mental health of patients with cancer. Conversely, ANS functions can effectively help monitor cardiorespiratory activities and reveal the benefits and effects of TCM-based treatment on physical and psychological functions in real time. The combination of ANS functions and scales/questionnaires used in clinical practice may improve the accuracy of the evaluation of TCM efficacy.

The biomarker HRV potently indicates the ability of the body to regulate physical and emotional responses.⁴² Reduced PNS activity indicates reduced complexity, loss of flexibility, and increased overall fragility.⁴³ Furthermore, higher vagus-mediated HRV is positively correlated with social engagement and well-being.^44,45 The present results showed that FZQDD significantly improved most cancer-related symptoms, such as fatigue, nausea and vomiting, and the quality of life, which may be related to increased PNS activity and reduced SNS tone. Observational studies showed that vagus-mediated HRV parameters were negatively correlated with the levels of inflammatory markers such as tumor necrosis factor (TNF)-α, IL-6, and C-reactive protein, which are associated with macrophage activation regulation and peripheral pro-inflammatory cytokine synthesis via the cholinergic anti-inflammatory pathways.^10,46 Conversely, SNS overactivity was associated with increased pro-inflammatory cytokine production.⁴⁷ Therefore, we believe that FZQDD may regulate the sympathovagal balance, thereby improving cancer-related symptoms and the quality of life.

The Pharmacological Explanation and Mechanism of FZQDD in the Treatment of GC

The principles of “monarch,” “minister,” “assistant,” and “messenger” in TCM theory suggest that each herbal ingredient in FZQDD plays a specific function and is integrated and arranged under this principle to produce a network regulatory effect. In FZQDD, Astragalus membranaceus is the monarch drug. Poria cocos, Atractylodes macrocephala, Scleromitrion diffusum, Solanum lyratum, and Solanum nigrum are the minister drugs. From the perspective of the Western medicine and pharmacology, all 6 herbs or their components have been shown to possess anti-inflammatory, anti-oxidant, and immunomodulating, as well as anticancer effects.^48
-53 For example, Astragalus polysaccharides, extracted from Astragalus membranaceus, could promote the activities of T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages and induce the expression of a variety of chemokines and cytokines.⁴⁸ Poria Acid, derived from Poria cocos, could inhibit the invasion and metastasis of GC cells, as well as could inhibit the matrix metalloproteinase protein expression and epithelial-mesenchymal transformation process in GC cells.⁴⁹ However, in terms of the overall effect of FZQDD, the possible synergies or superpositions between these herbs warrant further exploration. In our previous studies, FZQDD combined with SOX chemotherapy regimen could prolong the progression-free survival in advanced GC patients, reduce the incidence of adverse reactions (ie, anemia, thrombocytopenia, nausea and vomiting), and improve the clinical symptoms and quality of life.^16,17 In addition, FZQDD improves the tumor microenvironment by inhibiting the proliferation of MDSCs and the secretion of IL-6, TGF-β and other inflammatory factors.¹⁷ Thus, further research is required to evaluate the potential biological mechanism of FZQDD combined with SOX chemotherapy regimen.

In our previous study, 16 herbs included in FZQDD contained 166 compounds, and 237 target genes that contributed to GC treatment, indicating that FZQDD is a multitarget and multilink holistic intervention for GC.¹⁷ The protein–protein interaction network analysis revealed that AKT1, STAT3, MAPK3, HSP90AA1, and TP53 were most likely regulated by FZQDD.¹⁷ Current evidence suggests that chronic stress may result in overexcited SNS and promote norepinephrine release from sympathetic nerve endings, thereby affecting immune functions and promoting GC proliferation and metastasis via related signaling pathways, such as the PKA-MAPK/STAT3 signaling pathway.^54
-56

Our previous studies have demonstrated that the potential target pathways of FZQDD include IL-17, TNF, apoptosis, PI3K-Akt, and P53 signaling pathways, suggesting that FZQDD can facilitate GC treatment by improving inflammation, affecting tumor microenvironments, and inducing tumor cell apoptosis.¹⁷ The excessive activity of the SNS increases the release of pro-inflammatory cytokines and alters tumor microenvironments, thus participating in various processes including tumorigenesis, progression, metastasis, and multidrug resistance.⁵⁷ FZQDD may exert its anti-tumor effects via multiple components, targets, and pathways, and one of these mechanisms may be the regulation of the dynamic sympathovagal balance.

Limitations

Nevertheless, the study has certain limitations. First, some background variables that may affect the ANS, such as physical activity, were not included. Second, the correlation between autonomic modulation and survival time could not be inferred because of the short observation period. Third, this study is a cross-sectional clinical study, and the potential biological or pharmacological mechanisms of FZQDD combined with SOX chemotherapy regimen need to be studied further. To address these limitations, studies with larger sample sizes, more detailed background variables, and prospective designs should be performed to investigate the association between autonomic functions and GC prognosis.

Conclusion

This study mainly presents information on the changes in DC, AC, and HRV in patients with advanced GC undergoing chemotherapy before and after FZQDD intervention. The results implied that SOX chemotherapy regimen can result in autonomic dysfunction. FZQDD alleviates autonomic modulation impairments by increasing the PNS tone and decreasing the SNS activity, and improves cancer-related symptoms and the quality of life.

Supplemental Material

sj-doc-1-ict-10.1177_15347354241229414 – Supplemental material for Effects of Traditional Chinese Medicine “Fuzheng Qingdu Decoction” on Autonomic Function and Cancer-Related Symptoms in Patients with Advanced Gastric Cancer undergoing Chemotherapy: A Controlled Trial

Supplemental material, sj-doc-1-ict-10.1177_15347354241229414 for Effects of Traditional Chinese Medicine “Fuzheng Qingdu Decoction” on Autonomic Function and Cancer-Related Symptoms in Patients with Advanced Gastric Cancer undergoing Chemotherapy: A Controlled Trial by Chengjia Yuan, Shuang Wu, Yang Wu, Cuiling Tian, Zaichuan Wang and Xiaochun Zhang in Integrative Cancer Therapies

Footnotes

Acknowledgements

We thank Bo Shi of Bengbu Medical College for his help with the autonomic function analysis.

Author Contributions

XZ: writing—review and editing, supervision and resources. CY: data collection and writing—original draft preparation. SW: data analysis and writing—original draft preparation. YW: data analysis. CT and ZW: writing—original draft preparation. All authors contributed to the article and approved the submitted version.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the Science and Technology Program of Yangzhou (grant number YZ2023064), the Traditional Chinese Medicine Science and Technology Development Plan Project of Jiangsu Province (grant number ZD202013), and the construction project of Zhang Xiaochun’s Academic Inheritance Studio of Famous and Aged Chinese Medicine Experts in Jiangsu Province.

Informed Consent Statement

The Medical Ethics Committee of Yangzhou Hospital of TCM approved this study (registration number: 2022-43). All participants volunteered to participate in the study and signed the informed consent forms.

ORCID iDs

Chengjia Yuan

Shuang Wu

Yang Wu

Supplemental Material

Supplemental material for this article is available online.

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