Increased Yin -Deficient Symptoms and Aggravated Autonomic Nervous System Function in Patients with Metastatic Cancer

Abstract

Objectives:

The objectives of this study were to investigate the differences in severity of yin-deficiency syndrome (YDS) and function of the autonomic nervous system (ANS) between patients with cancer with metastasis and those without metastasis.

Setting:

The setting was an outpatient clinic in a teaching hospital in central Taiwan.

Subjects:

The subjects were a total of 124 patients who had been diagnosed with cancer on the basis of pathologic and clinical findings. Among them, 61 had distant metastasis, and the other 63 had no evidence of metastasis. The two groups were similar in terms of age and gender.

Interventions:

The severity of YDS in each subject was evaluated using a questionnaire containing 12 items about symptoms and signs related to YDS. The severity of each symptom or sign was rated on a 4-point scale.

Outcome measures:

The total score on the questionnaire represented the severity of YDS. ANS function in each subject was evaluated by measuring heart rate variability (HRV), including time and frequency domains. The questionnaire data were coded, and statistical analysis was performed using SPSS version 12.0. Data were analyzed using the Student's t test or the χ² test.

Results:

The patients with metastasis had significantly higher average total YDS score and heart rate compared with the patients without metastasis. In contrast, they had significantly lower HRV, including standard deviation of the 5-minute average R-R interval, total power, very-low-frequency power, and low frequency (LF) power, but not high-frequency (HF) power and LF/HF ratio.

Conclusions:

The results of this study indicate that patients with metastatic cancer have more severe YDS and impaired ANS function than those without metastasis.

Introduction

C ancer is a major worldwide health problem. According to the annual statistics of the national health insurance organization, cancer is the leading cause of death in Taiwan. Patients with cancer can prolong their lives using various therapies, but they may experience uncomfortable side-effects, such as dry mouth, poor sleep or irritability, a sensation of heat over the palms or soles, facial flushing in the afternoon, night sweating, and constipation. Most of these symptoms, which may be also resulted from disease itself, are similar to those of yin-deficiency syndrome (YDS) in Traditional Chinese Medicine (TCM). According to TCM, YDS refers to a pathological status of the human body in lack of blood, other bodily fluids, and “essence.” Patients with YDS usually have several symptoms and signs including rapid and small pulse, tongue redness with loss or lack of the tongue coating, sleeplessness with irritability, dry mouth, blurred vision, tinnitus or loss of hearing, facial flushing, and dizziness.¹ YDS-related symptoms and signs may occur in patients with cancer as part of the natural disease process or after medical interventions such as surgery, chemotherapy, or radiotherapy.^2,3 In a previous study, we developed a questionnaire to quantitatively evaluate the severity of YDS in patients with cancer.⁴ In another study, we further investigated the correlation between the severity of YDS and the function of the autonomic nervous system (ANS), detected by heart rate variability (HRV), in patients with cancer.⁵ We found that the severity of YDS is correlated with a decrease in ANS function in patients with cancer. However, because of the small number of subjects in that study, we did not know whether metastasis was associated with the severity of YDS and ANS function in patients with cancer. Therefore, the aim of the present study was to investigate whether there are differences in YDS status and ANS function between patients with metastatic cancer and those without metastasis.

Materials and Methods

Subjects

In this study, 124 subjects with a mean ± standard deviation (SD) age of 57.4 ± 12.6 years were selected from outpatients from February 14, 2007 to January 15, 2008. The inclusion criteria for subjects were as follows: (1) diagnosis of cancer on the basis of pathologic and clinical findings; (2) ambulatory status and ability to perform all activities of self-care with the Eastern Cooperative Oncology Group (ECOG) performance scores of grade 2 or lower; and (3) agreement to sign an informed consent form and to participate in the study. Of the 124 subjects selected, 61 had metastasis and 63 had no evidence of metastasis.

Evaluation of the severity of YDS

The severity of YDS in each subject was evaluated using a questionnaire.⁴ This questionnaire was developed on the basis of the referential standard for the differential diagnosis of Shi-pattern proposed by the Association of Integrated Chinese and Western Medicine in China¹ and a review of the literature on yin-deficiency symptoms.^6

–9 The questionnaire contained 12 items, 1 on each of 10 symptoms and 2 signs related to pulse and the tongue. The symptoms were dry mouth, poor sleep or irritability, blurred vision, a sensation of heat over the palms or soles, facial flushing in the afternoon, night sweating, tinnitus or loss of hearing, dizziness, constipation, and decreased amount of urine with the urine having a deep yellow color. The signs were rapid and weak pulse and reduction or loss of the coating of the tongue with or without redness. The severity of each symptom was measured on a 4-point scale according to the frequency of its occurrence in 1 week (1 = never, 2 = sometimes, 3 =frequently, 4 = always). The total score resulting from the summation of the individual scores on the 12 items, referred to as the total yin-deficiency syndrome (TYDS) score, was used to represent the severity of YDS in each patient with cancer. The possible TYDS score ranged from a low of 12 points to a high of 48 points.

Evaluation of ANS function

ANS function was measured with an HRV analysis system, Lab VIEW, which was developed by the Department of Automatic Control Engineering, Feng Chia University, Taichung, Taiwan.^10,11 The HRV analyses follow the standards proposed by Malik.¹² The dependent variables were physiologic parameters, including both time and frequency domains. The time domain included heart rate and the 5-minute average R-R interval (SDANN). The frequency domain included total power, low-frequency (LF) power, high-frequency (HF) power, very-low-frequency (VLF) power, and LF/HF ratio.¹² Both the SDANN and total power values reflect the total ANS activity.¹² LF power reflects sympathetic nervous system activity^12,13 or the autonomic outflows for baroreflex modulation.¹⁴ In contrast, HF power reflects parasympathetic nervous system activity.¹² The LF/HF ratio represents the balance between sympathetic and parasympathetic activity.¹²

Study procedure

After signing a written consent form, each subject was evaluated for the severity of YDS using the above-described questionnaire. The questionnaire items pertaining to symptoms were completed by a well-trained nurse practitioner. A medical doctor who did not know the results of the questionnaire items related to symptoms performed pulse diagnosis and tongue examination of subjects in a separate room. This doctor had 15 years of clinical experience in Chinese medicine and was qualified as a special physician by the Association of Integrated Chinese and Western Medicine in Taiwan. After completion of the questionnaire, each subject rested by lying on a bed for 10 minutes in an air- and temperature-controlled room, and then HRV was measured using a Lab VIEW device. This test took 5 minutes. Data from Lab VIEW were downloaded immediately to a computer.

Statistical analysis

The questionnaire data were collected and coded, and statistical analysis was performed using SPSS version 12.0. Data were analyzed using description analysis, unpaired Student's t test, or χ² test. The statistical significance of differences between groups was calculated, with the level of statistical significance set at p < 0.05.

Results

Subject characteristics

As shown in Table 1, 124 patients with cancer (53 male and 71 female) were included in this study. The mean ± SD age of the subjects was 57.4 ± 12.6 years. The group with metastasis (36 females and 25 males) had a mean age of 62.3 ± 12.7 years. The group without metastasis (35 females and 28 males) had a mean age of 52.6 ± 10.7 years. No statistically significant differences in gender or age were found between the two groups. More than half of patients (57.1%) in the nonmetastasis group had been diagnosed with cancer within the past year, compared with less than half of patients (36.1%) in the metastasis group. All of the subjects were ambulatory and capable of performing all activities of self-care, with ECOG performance scores of grade 2 or lower.

Table 1.

Characteristics of Studied Subjects (N = 124)

Variable	Metastasis (n)	Nonmetastasis (n)
Gender
Female	36	35
Male	25	28
Age (mean ± SD years old)	62.3 ± 12.7	52.6 ± 10.7
Primary locations of cancer
Head and neck	8	10
Lung	8	2
Breast	12	28
Gastrointestinal tract	26	15
Others	8	7
The time diagnosed from cancer
<1 year	22	36
1–2 year	11	11
2.1–5year	16	11
Above 5 years	12	5

SD, standard deviation.

TYDS score, heart rate, and HRV in patients with cancer with and without metastasis

As shown in Table 2, the TYDS score was significantly higher in patients with metastatic cancer than in those without metastasis (25.1 ± 5.3 versus 21.5 ± 5.3 points; p < 0.0001 analyzed by unpaired Student's t test). Similarly, the heart rate was significantly higher in the metastasis group than in the nonmetastasis group (86.8 ± 16.8 versus 75.8 ± 11.0 beats/min, p < 0.0001). In contrast, the SDANN, total power, VLF power, and LF power were significantly lower in the group with metastasis than in the group without metastasis (p < 0.01 for all). No statistically significant differences were found in HF power and LF/HF ratio between the two groups.

Table 2.

Differences in TYDS and HRV Parameters Between Metastasis Group and Nonmetastasis Groups

	Metastasis (n = 61)	Nonmetastasis (n = 63)
Variables	Mean ± SD	Mean ± SD	t	p
TYDS	25.1 ± 5.3	21.5 ± 5.3	−3.72	0.000
HR (bpm)	86.8 ± 16.8	75.8 ± 11.0	−4.29	0.000
SDANN	20.7 ± 12.0	28.5 ± 12.3	3.57	0.001
Total power (msec²)	571.7 ± 624.8	960.5 ± 752.7	3.13	0.002
LF/HF ratio	1.60 ± 1.83	1.87 ± 1.36	0.97	0.334
Power (VLF, msec²)	206.6 ± 198.0	439.8 ± 400.7	4.13	0.000
Power (LF, msec²)	111.8 ± 147.3	225.2 ± 209.5	3.5	0.001
Power (HF, msec²)	135.4 ± 186.4	185.3 ± 219.4	1.36	0.176

SD, standard deviation; TYDS, total yin-deficiency syndrome; HRV, heart rate variability; HR, heart rate; bpm, beats per minute; SDANN, 5-minute average R–R interval; LF/HF, low frequency/high frequency.

Metastasis rate in patients with cancer with different degrees of YDS

As shown in Table 3, patients with cancer were divided into three groups according to their TYDS score: low (≤17 points), middle (18–23 points), and high (≥24 points). The metastasis rate was significantly higher in the group with high TYDS scores (42/65, 64.6%) than in the groups with low (6/19, 31.6%) and middle (13/40, 32.5%) TYDS scores (p = 0.002 analyzed by χ² test).

Table 3.

Metastasis Rate in Patients with Cancer and Different Degrees of Total Yin-Deficiency Score (TYDS)

	Status of metastasis
Variable	N	Metastasis rate n (%)	p
TYDS
≤17	19	6 (31.6)
18–23	40	13 (32.5)	0.002
≥24	65	42 (64.6)

All patients were divided into 3 groups according to their TYDS by 25th percentile (≤17 scores), 25th–75th percentile (18–23 scores) and 75th percentile (≥24 scores).

Metastasis rate in patients with cancer with different heart rates and HRVs

As shown in Table 4, patients with cancer were divided into three groups according to their heart rate, SDANN, total power, VLF power, and LF power: low (<25th percentile), middle (25th–75th percentile), and high (>75th percentile). Patients with cancer with high heart rates (>90 beats/min) had a higher metastasis rate (26/33, 78.8%) than those with low (8/29, 27.6%) and middle (27/62, 43.5%) heart rates (p < 0.0001). In contrast, the metastasis rate was higher in patients with cancer with low SDANN (<14.4), total power (<208.0), VLF power (<89.0), and LF power (<32.4).

Table 4.

Metastasis Rate in Patients with Cancer Different and Degrees of Heart Rate and Heart Rate Variability

	Status of metastatic
Variables	N	Metastasis rate n (%)	p
HR			0.000
<70	29	8 (27.6)
70–90	62	27 (43.5)
>90	33	26 (78.8)
SDANN			0.013
<14.4	31	22 (71.0)
14.4–32.3	62	28 (45.2)
>32.3	31	11 (35.5)
Total power			0.013
<208.0	31	22 (71.0)
208.0–1041.7	62	28 (45.2)
>1041.7	31	11 (35.5)
VLF power			0.001
<89.0	31	21 (67.7)
89.0–415.7	62	33 (53.2)
>415.7	31	7 (22.6)
LF power			0.001
<32.4	31	23 (74.2)
32.4–211.2	62	30 (48.4)
>211.2	31	8 (25.8)

All subjects were divided into 3 groups according to their heart rate (HR), 5-minute average R–R interval (SDANN), total power, very low frequency (VLF) power and low frequency (LF) power with 25th, 25th–75th, and 75th percentile.

Discussion

In TCM, yin refers to components of the human body, including blood, other bodily fluids, and “essence.” YDS is defined as a pathologic state with yin-related dysfunction. It is commonly seen in patients with cancer during the therapeutic process.^8,9 So far, there is no gold standard for the diagnosis of YDS in TCM. Usually, TCM doctors make the diagnosis by subjective observation. Lee et al. have developed a yin-deficiency questionnaire with good validity.⁷ However, it consists of 10 items related to subjective symptoms. In a previous study, we developed another questionnaire containing 10 similar symptom-related items and 2 signs related to pulse and tongue to evaluate the severity of YDS in patients with cancer.⁴ The severity of YDS in each subject was expressed by the TYDS score, obtained by summing the scores for the 12 individual items. We found that the survival length of patients with cancer is negatively correlated with the severity of YDS.⁴ Among the 12 symptoms and signs, both signs of rapid, small pulse and tongue redness with reduction or loss of the tongue coating are most important for the prediction of the survival length in patients with cancer.⁴ These results suggest that the combination of 10 symptoms and 2 signs (related to pulse and tongue) is better than the 10 symptoms alone in the evaluation of YDS.

In this study, we investigated the difference in severity of YDS between patients with cancer with distant metastasis and those without metastasis. The results revealed significantly higher TYDS scores in the metastasis group than in the nonmetastasis group. These results indicate that YDS may worsen in patients with cancer during metastasis. In this study, heart rate was significantly higher in the metastasis group than in the nonmetastasis group. Because increased heart rate is a sign of YDS, this suggests that increased heart rate may lead to the development of YDS among patients with metastatic cancer.

Both SDANN and total power were significantly lower in the metastasis group than in the nonmetastasis group. These results indicate that patients with cancer may develop impairment in ANS function. Study of the frequency domain of HRV revealed that LF power and VLF power were significantly lower in the metastasis group than in the nonmetastasis group. However, no significant differences were found in HF power and LF/HF ratio between the two groups. The significance of LF power in HRV is still controversial. In previous studies, LF power was considered to be related to sympathetic nervous system activity¹² because it increased activation of sympathetic “tone” but decreased after bilateral sympathetic stellectomy in dogs.¹³ In recent reports, LF power was found to predominantly reflect the autonomic outflows for baroreflex modulation¹⁴ but was not correlated with sympathetic nervous activity in patients with heart failure.^15

–20 On the other hand, the significance of VLF power is not yet fully known. It may in part reflect the function of the ANS in the regulation of body temperature and peripheral vasoconstriction and vasodilatation.^21,22 Decrease in VLF power has been reported to be related to increased mortality in patients with heart disease such as myocardial infarction²³ and congestive heart failure.²⁴ These results suggest that patients with metastatic cancer may have impairment of ANS function in the regulation of body temperature and blood pressure, which, in turn, may increase their mortality.

The results of this study also showed that patients with cancer with high TYDS scores and heart rate (in the 75th percentile) had a significantly higher metastasis rate than those with low TYDS scores and heart rate (in 25th percentile). These results indicate that increased YDS severity or heart rate may be associated with a high rate of metastasis. In contrast, patients with cancer with low SDANN, total power, VLF power, and LF power (in the 25th percentile) had a significantly higher metastasis rate than those with high SDANN, total power, VLF power, and LF power (in the 75th percentile). These results indicate that increased TYDS score and worse ANS dysfunction may be associated with a higher metastasis rate in patients with cancer.

The reason that ANS function worsens during metastasis is not yet fully understood. Both disease process and therapeutic intervention may influence ANS function. In a review of the literature, pheochromocytoma was reported to be associated with increased LF/HF ratio and was suspected to be hyperactive in the sympathetic nerve.²⁵ On the other hand, decreased ANS function was found in patients with acute leukemia^26,27 and increased intracranial pressure caused by brain tumors.²⁸ Chemotherapy with vincristine²⁹ or paclitaxel³⁰ was found to decrease ANS function in patients with acute lymphoblastic leukemia or advanced breast cancer. In this study, no studied patients had pheochromocytoma or brain metastasis. One (1) patient had acute leukemia without metastasis. His HRV was measured a half year after successful bone marrow transplantation after aggressive chemotherapy. All of the other patients with or without metastasis received chemotherapy or radiotherapy. Therefore, it cannot be determined whether the decrease in ANS function in patients with cancer derives from the disease process itself or from therapeutic intervention. However, patients with cancer with metastasis had a longer duration of cancer than those without metastasis. Therefore, they might have received more frequent and aggressive chemotherapy and had more serious malnutrition, possibly inducing a disturbance in ANS function. Thus, it is possible that both the disease process and therapeutic intervention are factors in decreased ANS function in patients with cancer during metastasis.

In summary, cancer metastasis was found to be associated with increased YDS severity and impairment of ANS function in patients with cancer. The management of YDS and ANS dysfunction should be considered in the treatment of patients with cancer with metastasis. Some Chinese herbal prescriptions such as Sha-Sheng-Mai-Dong-Tang and Liuwei Dihuang are widely used for improvement of yin deficiency in TCM. Whether these agents can improve ANS function and YDS in patients with cancer with metastasis warrants further investigation.

Footnotes

Acknowledgments

We thank Dr. Anita S. Mannikarottu, PhD, Adjunct Assistant Professor, Department of Surgery, Albany Medical Center, New York, NY, for revision of this article.

Disclosure Statement

No competing financial interests exist.

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