Qian-Qian Niu,Yuan-Hong Zhao,Zhi-Li Zhao,Li-Na Yan,Zheng Li

1Department of Oncology,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300385,China;2Department of Preparation,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300385,China.

TMR Cancer

Clinical efficacy of Qingxin Fupi Jieyu formula in the treatment of 28 cases with digestive tract cancer-related cognitive impairment

Qian-Qian Niu1#,Yuan-Hong Zhao1＊,Zhi-Li Zhao1#,Li-Na Yan1,Zheng Li2＊

1Department of Oncology,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300385,China;2Department of Preparation,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300385,China.

#Qian-Qian Niu and Zhi-Li Zhao are the co-first authors of this paper.

＊Corresponding to:Yuan-Hong Zhao,Department of Oncology,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,88 Changling Road,Xiqing District,Tianjin 300385,China.E-mail: yuanhongzh98@163.com.Zheng Li,Department of Preparation,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,88 Changling Road,Xiqing District,Tianjin 300385,China.E-mail:lizhenga200@163.com.

Highlights

The incidence of digestive tract cancer-related cognitive impairment has been growing up.Qingxin Fupi Jieyu formula is effective and safe in the treatment of digestive tract cancer-related cognitive impairment.

Abstract

Objective:This study aimed to explore the efficacy and safety of Qingxin Fupi Jieyu formula (the herbal formula has the function of clear away the heart fire,tonify spleen,and relieve depression,QXFPJYF) in treating digestive tract cancer-related cognitive impairment (CRCI).Methods:28 subjects with digestive tract CRCI were treated with QXFPJYF for 6 weeks.The scores of Montreal Cognitive Assessment and Mini-Mental State Examination were observed at four-time points (baseline,week 2,week 4,week 6).Besides,anxiety and depression scores and tumor markers were measured.Results:The scores of Montreal Cognitive Assessment and various fields were elevated steadily after treatment,such as visuospatial/executive,attention,language,delayed recall,and orientation.The differences were statistically significant (P＜0.05) besides language score.The scores of Mini-Mental State Examination and various factors were elevated gradually at week 2,week 4 and week 6,including language and praxis,attention and calculation,recall and orientation,and the differences were statistically significant (P＜0.05)except for recall score.The results also showed the change of tumor markers were not obvious,but anxious and depressed emotions were improved.More importantly,no subjects developed with obvious adverse reactions during the study.Conclusion:The finding indicated that QXFPJYF treated digestive tract CRCI with great efficacy and safety,which improved cognitive function from several fields.Nevertheless,the current study was limited by sample and medical ethics,and which was a self-control trial,some limitations needed to be acknowledged,further high-quality research is required to explore and verify it.

Keywords:Digestive tract cancer-related cognitive impairment,Qingxin Fupi Jieyu formula,Traditional Chinese medicine,Chinese herbal medicine,Clinical study

Abbreviations:

CRCI,cancer-related cognitive impairment; QXFPJYF,Qingxin Fupi Jieyu formula; MoCA,Montreal Cognitive Assessment; MMSE,Mini-Mental State Examination; TCM,traditional Chinese medicine; CNS,central nervous system; MCI,mild cognitive impairment; pts,points; AFP,alpha-fetoprotein; CA199,carbohydrate antigen 199;CA724,carbohydrate antigen 724;CYFRA21-1,cytokeratin 19 fragment.

Competing interests:

The authors declare that there is no conflict of interest.

Citation:

Qian-Qian Niu,Yuan-Hong Zhao,Zhi-Li Zhao,et al.Clinical efficacy of Qingxin Fupi Jieyu formula in the treatment of 28 cases with digestive tract cancer-related cognitive impairment.TMR Cancer 2020,3(3):94-100.

Executive Editor:Rui-Wang Zhao.

Submitted:24 Februay 2020,

Accepted:04 March 2020,Online:09 April 2020.

Background

With the rising incidence of malignancy,cancer-related cognitive impairment (CRCI) has also been widely concerned by oncologists.In those patients with non central nervous system (CNS) malignant tumors(including breast cancer,prostate cancer,cervical cancer,and colorectal cancer),the incidence of CRCI is about 17% to 75%,which seriously threatening patients' quality of life and overall survival [1].The pathogenesis of CRCI is not yet understood,which may be considered to be related to chemotherapy [2],preoperative anesthesia [3] and other anti-cancer therapies,as well as patients'individual factors such as age,race,heredity,cognitive reservation [4,5],and even sensory disorders [6].Another possible explanation for the digestive tract CRCI is the brain-gut axis.It is closely related to several emotional diseases such as Alzheimer's disease [7],sleep disorders[8],depression[9],et al.

Our previous research found that CRCI is often accompanied by emotional diseases such as anxiety and depression,and it could be attributed to the“emotional disorder” of traditional Chinese medicine(TCM).The “emotional disorder”location is mainly in the heart,liver,and spleen in as described in TCM,which is a disease argued deficiency in origin and excess in superficiality(Benxu Biaoshi in TCM,means“The body is already weak and sick on the basis of weakness.”).A variety of anti-cancer treatments have impaired normal physiological functions,resulting in the dysfunction of Qi and Xue in TCM,and then damage the cognitive function.Therefore,Qingxin Fupi Jieyu formula (QXFPJYF) is established to treat emotional diseases based on the theory of five elements in TCM.The core formula is modified based on Zuojin Wan (a traditional formula in TCM).The whole formula is precise and straightforward,and it is effective in improving cancer-related anxiety,depression,and insomnia[10-12].

We have noticed that the incidence of digestive tract CRCI has been growing up.However,although the clinical incidence of gastrointestinal CRCI is high,the attention rate and diagnosis rate are low.Also,there have been no previous reports of treatment of gastrointestinal CRCI.The purpose of this study was to examine the effects of QXFPJYF on the intervening digestive tract CRCI.

Materials and methods

Subjects

Patients with digestive tract CRCI attended the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from December 1,2016 to December 31,2018,were recruited.The local Ethics Committee has approved this study,and all subjects fulfilling the inclusion criteria were provided written informed consent.

Diagnostic criteria.According to the Chinese Diagnosis and Treatment Standards for Common Malignancy compiled by the National Health Commission of China,all subjects were diagnosed with digestive tract malignancy by clinical,imaging,or pathological evidence.It includes esophageal,gastric,esophageal-cardiac junction,small intestinal,and colorectal cancer(The digestive tract in this study only involved muscular canal).The pathological classification criteria were based on WHO general histology and the clinical stages were classified according to the AJCC Clinical Staging System(version 8).Certainly,all the subjects fulfilled the following diagnostic criteria for cognitive impairment[13]: (1) patients who were concerned by clinicians or other participants in the cognitive area; (2) there was objective abnormal evidence of cognitive function in one or more areas; (3) those who normally lived in daily life; (4) those who didn't yet meet the diagnostic criteria for dementia.

Inclusion criteria.Criteria for selecting the subjects were as follows: (1) the participants had to be at least 18 years old,regardless of male or female; (2) those were diagnosed with the digestive tract and CRCI; (3)KPS score was over 50; (3) those who were able to accept Chinese herbal medicine for 3 months; (4) no previous medical history with idiopathic mental disorders and dementia; (5) those who had abilities of speech expression and verbal comprehension;(6)those who volunteered to cooperate and fill in the relevant content of the scale with good compliance; (7) the estimated survival time was longer than 3 months.

Exclusion criteria.Criteria for excluding the subjects were as follows: (1) the patients had a history of CNS diseases,such as craniocerebral trauma,cerebrovascular disease,Parkinson's disease,Alzheimer's disease,poisoning,et al.; (2) those who could not complete the cognitive function scale with communication disorders;(3)those who had a medical history of mental retardation,psychosis,and other mental illnesses; (4) and those who were addicted to drugs,alcohol,and narcotics.

Methods

Intervention.All the subjects were treated with QXFPJYF (composed of Huanglian (Coptis),Baijili(Tribulus terrestris),Wuzhuyu (Evodia),Sharen(Amomum villosum) and Ganjiang (Dried ginger))based on syndrome differentiation.For example,Zhishi (Fructus aurantii),Muxiang (Costusroot) and Houpo (Magnolia officinalis) were added to patients with abdominal distension.Adding Chuanlianzi(Szechwan chinaberry fruit),Yanhusuo (Rhizoma corydalis)and Yujin(Radix curcumae)to subjects with stomachache.Adding Chenxian (Agilawood) and Xuanfuhua (Iinula flower) to subjects with frequent belching.Adding Muli (Oysters),Wuzeigu (Cuttlefish bone) and Duanwalengzi (Calcined arca) to subjects with acid reflux.Adding Huomaren(Pomegranate rind)and Gualouren (Gourd seeds) to subjects with constipation.Adding Zhuru (Bamboo shavings),Shengjiang (Ginger) and Zhibanxia (Pinellia ternate)to subjects with nausea and vomiting.All the Chinese herbal medicine used were provided by the boutique pharmacy of the First Affiliated Teaching Hospital of Tianjin University of Traditional Chinese Medicine.

Medication.Subjects were asked to take a 150 ml decoction of half dose twice a day.Every 2 weeks was a course of treatment,and the outcomes were observed continuously after 3 courses.

Outcome measures

Primary outcome measures.The scores of Montreal Cognitive Assessment (MoCA): including visuospatial/executive (5 points (pts)),naming (3 pts),memory (0 pt),attention (6 pts),language (3 pts),abstraction (2 pts),delayed recall (5 pts) and orientation (6 pts).To reduce the bias of education level on the results,add 1 pt if the education was less or equal than 12 years.The total score ranged from 0-30 pts,greater than 26 pts indicates normal.The higher the score,the better their cognitive function.

The scores of Mini-Mental State Examination(MMSE): including orientation (10 pts),registration (3 pts),attention and calculation(5 pts),recall(3 pts),and language and praxis (9 pts).The total score was 30 pts.According to education level,the impairment was defined as follows [14]: a score below 17 pts to illiterate patients,20 pts to primary school culture patients,and 24 pts to patients with more than 6 years of education.

Secondary outcome measures.Anxiety was judged by the generalized anxiety disorder scale: there are 7 items,each item scored 0-3 pts,and the total score ranged from 0-21 pts.0-4 pts for no anxiety,5-9 pts for mild anxiety,10-14 pts for moderate anxiety,and 15-21 pts for severe anxiety.

The PHQ-9 depression screening scale judged depression:there are 9 items,each item scored 0-3 pts,and the total score ranged from 0-27 pts.0-4 pts for no depression,5-9 pts for mild depression,10-14 pts for moderate depression,15-19 pts for moderately severe depression,and 20-27 pts for severe depression.

Tumor markers: carcinoembryonic antigen,alpha-fetoprotein (AFP),ferritin,carbohydrate antigen 199 (CA199),carbohydrate antigen 724 (CA724) and cytokeratin 19 fragment(CYFRA21-1).

Safety outcome measures.Blood routine(white blood cell,red blood cell,platelet,hemoglobin),liver function(alanine transaminase,aspartate transaminase)and renal function (blood urea nitrogen,creatinine)were recorded.

Quality assurance

Concerning the assessment of CRCI,anxiety,and depression,the subject should be adopted by communication staying calm relatively.The researchers who professionally trained filled in the requirements with unified instructions and scored according to the patients' oral narration and written answers.Each assessment took about 15-20 minutes following the rules of scales seriously.

Statistical analysis

Excel software (version 2003) was used to input and manage the data,and statistical analysis were carried out using SPSS (version 21.0).The measurement data were tested for normality and homogeneity of variances.An independent t-test was used if the data was in accordance with normal distribution,and expressed as mean ± standard deviation.Measurement data with non-normal distribution were expressed as median (inter-quartile range),the nonparametric test was used for comparison.Multiple groups of data at the same level were tested by repeated measurement analysis of variance.The difference was considered statistically significant whenP＜0.05.

Results

Baseline characteristics

Among the patients,21 were male,and 7 were female,the eldest was 87 years old and the youngest was 44 years old,the average age was 65.96 ± 9.82 years old,and the average body mass index was 21.68 ± 3.34 kg/m2.About the educational level,there were 0 case of uneducated,17(60.7%)cases of primary school and below(educational years ≤6 years),8 cases(28.6%)of secondary school and below (educational years ≤12 years),and 3 cases (10.7%) of university and above(educational years ＞12 years).As for past medical history,there were 14 cases(50.0%)of hypertension,5 cases of diabetes (17.9%) and 6 cases (21.4%) of coronary heart disease,17 cases (60.7%) had a history of smoking,14 cases(50.0%)had a history of drinking,and 7 cases (25.0%) had a family history of cancer.In terms of tumor staging,there were 0 case in stage I,5 cases (16.9%) in stage Ⅱ,6 cases (29.4%) in stage Ⅲand 17 cases (53.7%) in stage IV.In the matter of previous treatment,20 cases (71.4%) had received surgery,16 cases (57.1%) had received chemotherapy,2 cases (7.1%) had received targeted therapy.In general,in addition to TCM,5 cases (17.9%) had received 1 treatment,8 cases (28.6%) had received 2 treatments,and 15 cases (53.6%) had received 3 treatments.In terms of cancer metastasis,there were 6 cases (21.4%) with lymph node metastasis,15 cases(53.6%) with liver metastasis,5 cases (17.9%) with lung metastasis,and 3 cases (10.7%) with abdominal metastasis.

Safety evaluation

There was no obvious malaise and adverse reaction observed.In the aspect of routine chemical analysis,there was no significant change in white blood cell,red blood cell,hemoglobin,platelet before and after treatment.There were 3 cases with above-normal alanine transaminase and 7 cases with above-normal aspartate transaminase at baseline and week 6,there were 2 cases with below-normal creatinine and 1 case with above-normal blood urea nitrogen at baseline,but normal at week 6,which had no obvious clinical significance.

Comparison of the cognitive assessment scale scores MoCA (Figure1,Table1).Among all the subjects included,the scores of MoCA and various fields rose steadily at week 2,week 4,and week 6,including visuospatial/executive,attention,language,delayed recall,and orientation.The differences were statistically significant (P＜0.05) besides language scores.The naming score increased gradually at week 2 and week 4,and the abstraction went up only at week 6.Both differences were statistically significant (P＜0.05).

MMSE (Figure2,Table2).Among all the subjects included,the scores of MMSE and various factors were elevated gradually at week 2,week 4 and week 6,including language and praxis,attention and calculation,recall and orientation,and the differences were statistically significant (P＜ 0.05) except for recall score.The registration score increased at week 2 and week 4,and the difference was statistically significant(P＜0.05).

Outcome of anxiety and depression

In terms of anxiety disorder,there were 10 cases(23.8%) with mild anxiety,9 cases (21.4%) with moderate anxiety,and 4 cases (9.5%) with severe anxiety before QXFPJYF treatment.At week 6,2 cases with moderate anxiety improved to mild anxiety,1 case with mild anxiety improved to no anxiety,and there were no significant changes in other patients.

Comparison of tumor markers before and after treatment

At week 6,several tumor markers decreased than before,including CA199,AFP,CA724,and CYFRA21-1.However,none of these differences were statistically significant(Table3).

Figure1 Trends of MoCA scores

Figure2 Trends of MMSE scores

Table1 Comparison of the MoCA scores(pts,±s)

Table1 Comparison of the MoCA scores(pts,±s)

Note: *,comparison of baseline,week 2,and week 4; **,comparison of baseline and week 6 using Z value.

Projects MoCA Visuospatial/Executive Naming Attention Language Abstraction Delayed recall Orientation Baseline 21.46±1.00 2.89±0.32 2.54±0.51 3.18±0.72 2.50±0.58 1.86±0.36 2.68±0.72 4.93±0.38 Week 2 22.96±0.96 3.18±0.61 2.64±0.49 3.61±0.83 2.57±0.57 1.86±0.36 2.89±0.69 5.32±0.48 Week 4 23.96±0.92 3.32±0.61 2.82±0.39 3.75±0.84 2.68±0.48 1.86±0.36 2.93±0.66 5.71±0.46 Week 6 25.21±0.92 3.71±0.76 2.82±0.39 4.04±0.88 2.71±0.46 2.00±0.00 3.32±0.82 5.75±0.44 F/Z 81.980 10.920 7.560* 13.347 2.273 -2.000** 9.840 26.533 P 0.000 0.000 0.001 0.000 0.105 0.046 0.000 0.000

Table2 Comparison of the MMSE scores(pts,±s)

Table2 Comparison of the MMSE scores(pts,±s)

Note: *,comparison of baseline,week 2,and week 4.

Projects MMSE Orientation Registration Attention and calculation Recall Language and praxis Baseline 23.39±0.92 8.75±0.59 2.79±0.42 2.93±0.60 1.93±0.54 7.00±0.86 Week 2 24.36±0.73 9.11±0.69 2.86±0.36 3.21±0.50 2.04±0.58 7.14±0.80 Week 4 25.29±0.71 9.43±0.50 3.00±0.00 3.36±0.56 2.14±0.53 7.36±0.91 Week 6 26.04±0.84 9.54±0.51 3.00±0.00 3.61±0.63 2.18±0.55 7.75±0.84 F 44.306 14.001 3.545 18.185 2.778 8.895 P 0.000 0.000 0.043* 0.000 0.062 0.000

Table3 Comparison of tumor markers Q2(Q3-Q1)

Discussion

CRCI refers to the cognitive impairment of cancer patients in anti-cancer therapy,mainly mild cognitive impairment (MCI),and malignant tumors in the CNS are common.TCM unified standard has not yet been established for the disease name and syndrome differentiation of MCI.The occurrence of CRCI has severely affected the life quality of tumor patients.Recently,the diagnosis and treatment of non-CNS CRCI just like breast cancer,which has been paid more and more attention.However,there are no standardized and feasible clinical guidelines,and there have been little therapies about CRCI.Previous studies have only involved in physical therapy,such as psychotherapy and cognitive rehabilitation treatment [10-12].Evidence for psychotropic drugs is rare to some extent[15].At present,most researchers thought that the pathogenesis of MCI was complexed in TCM,Qi deficiency,phlegm,and blood stasis were the main syndrome factors [16].The main treatment principles were replenishing Qi,nourishing blood,tranquilizing the mind,tonifying kidney,and filling marrow [17].Most of these studies have primarily focused on acupuncture [18],and Chinese herbal medicine intervention has hitherto received scant attention by scholars in the past.

This study was set out to assess the effects of QXFPJYF on digestive tract CRCI,and the results suggested that the scores of MMSE and MoCA were elevated significantly at week 2,week 4 and week 6.QXFPJYF gradually improved the cognitive function in many fields.For example,visuospatial/executive,attention and calculation,especially in visuospatial and executive,delayed recall,attention,and orientation.Further analysis showed that QXFPJYF relieved anxiety and depression of subjects.Surprisingly,the levels of several tumor markers decreased after treatment,including CA199,AFP,CA724,and CYFRA21-1.Therefore,it is possible that QXFPJYF could resist tumor by affecting biochemical blood indexes.Moreover,no subjects developed severe adverse effects and damage to the liver or kidney,further demonstrating the safety of QXFPJYF.What was curious about this result was that patients suffered from CRCI,mainly in visuospatial and executive,attention,registration,and orientation.This finding was not completely consistent with the MCI [19].It is necessary to further explore the pathogenesis in combination with large sample imaging and neuropathological examination.

The contribution of this study has been to confirm the efficiency of QXFPJYF on digestive tract CRCI by self-control,which highlighted the advantages of TCM and provided evidence for the further improvement of TCM treatment strategy of CRCI.However,a number of limitations needed to be noted regarding the present study.Limited by medical ethics and sample size,the observation time was short,the quality of life of subjects had not been evaluated,and the pharmacological mechanism of QXFPJYF was not fully understand.Therefore,further high-quality trials with large-sample,multi-center are needed to verify the current results.