Clinical Efficacy Evaluation and Mechanism Study of Potential Advantageous Diseases of Acupuncture - Evaluation of Clinical Efficacy of Acupuncture in Improving Immune Response in Patients With Cervical Cancer
Phase: NA
Conditions: Cervical Cancer
Sponsor: Ying Zhang

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Project source: Central High-level TCM Hospital Clinical Research and Achievement Transformation
Capacity Improvement Project- -TCM Clinical Evidence-based Research Special Project
Item number: HLCMPP2023089
Evaluation of clinical clinical diseases and
Mechanism of acupuncture-
Acupuncture improves the clinical efficacy
evaluation of the immune response in cervical
cancer patients
Group leader: Guang'anmen Hospital, China
Academy of Chinese Medical Sciences
Project leader: Zhang Ying
Department undertaken by: Oncology Department
Contact number: 13311027150
Participating units:
Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences
Beijing Obstetrics and Gynecology Hospital affiliated to
Capital Medical University
Peking University Cancer Hospital (Beijing Cancer
Research Institute)
Cancer Hospital, Chinese Academy of Medical Sciences
Sichuan Provincial Cancer Hospital
Yueyang Hospital of Integrated Traditional Chinese and
Western Medicine affiliated to Shanghai University of Traditional Chinese
Medicine

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Hunan Provincial Cancer Hospital
The Affiliated Cancer Hospital of Chongqing University
Study years: November 2023-November 2026
Version number: 2.0
Version date: 20240701
catalogue
scenario summary...............................................................................................................................3
1. research background........................................................................................错误！未定义书签。
1. Current status of modern medical treatment of cervical cancer.............. 错误！未定义书签。
2. Advantages and limitations of immunotherapy for cervical cancer........ 错误！未定义书签。
3. Acupuncture therapy can regulate the immune function of tumor patients错误！未定义书签。
4. Research status and application prospect of acupuncture and moxibustion synergistic
immunotherapy for the treatment of cervical cancer...................................错误！未定义书签。
reference documentation:.............................................................................错误！未定义书签。
2. purpose of research......................................................................................... 错误！未定义书签。
1. Main purpose........................................................................................... 错误！未定义书签。
2. Secondary purpose...................................................................................错误！未定义书签。
3. Type and principles of the study design..........................................................错误！未定义书签。
1. Type of study design................................................................................错误！未定义书签。
2. Random method.......................................................................................错误！未定义书签。
3. Control method........................................................................................ 错误！未定义书签。
4. Sample size calculation............................................................................错误！未定义书签。
4. Case selection..................................................................................................错误！未定义书签。
1. Inclusion criteria...................................................................................... 错误！未定义书签。
2. Exclusion criteria..................................................................................... 错误！未定义书签。
3. Criteria for shedding................................................................................ 错误！未定义书签。
4. Termination of the study criteria............................................................. 错误！未定义书签。
5 End of treatment leads to follow-up phase criteria...................................错误！未定义书签。
6. Early study termination / site closure...................................................... 错误！未定义书签。

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5. Research methods and technical routes...........................................................错误！未定义书签。
1. Treatment plan......................................................................................... 错误！未定义书签。
2. No medication and treatment are allowed............................................... 错误！未定义书签。
3. Technology roadmap............................................................................... 错误！未定义书签。
Vi. Observation items and test time.................................................................... 错误！未定义书签。
1. Observe the project.................................................................................. 错误！未定义书签。
2. Observation time point.............................................................................错误！未定义书签。
Vii. Evaluation method of the main indicators................................................... 错误！未定义书签。
Viii. Observation of adverse events.................................................................... 错误！未定义书签。
1. Adverse event definition..........................................................................错误！未定义书签。
2. Get adverse event information.................................................................错误！未定义书签。
3. Observation and record of adverse events............................................... 错误！未定义书签。
4. Potential adverse events and management...............................................错误！未定义书签。
5. Assessment of adverse events..................................................................错误！未定义书签。
6. Serious adverse events.............................................................................错误！未定义书签。
7. Abnormal clinical test results and other abnormal indicators are considered as adverse
events or serious adverse events.................................................................. 错误！未定义书签。
IX. Research quality control and quality assurance............................................错误！未定义书签。
1. Set up a project research office................................................................错误！未定义书签。
2. Project objectives and task management................................................. 错误！未定义书签。
3. Use and management of project funds.....................................................错误！未定义书签。
4. Project quality control and management................................................. 错误！未定义书签。
5. Blood sample management......................................................................错误！未定义书签。
X. Statistical treatment........................................................................................错误！未定义书签。
Xi. Ethics of clinical research............................................................................. 错误！未定义书签。
Xii. Research progress........................................................................................ 错误！未定义书签。
Attachment 1 Efficacy Evaluation of Solid Tumors Version 1.1 (RECIST1.1)..............................35
Attachment 2 EORTC QLQ-C30 scale (Chinese version)................................. 错误！未定义书签。
Attachment 3 EORTC QLQ CX24 Questionnaire (Chinese version)................ 错误！未定义书签。
Attachment 4 Simple Fatigue Scale Chinese Version (BFI-C)........................................................39
Attachment 5 Insomnia severity Quantity Table (ISI).....................................................................40
Attachment 6 Brief Pain Assessment Scale (BPI-C)....................................................................... 41
Attachment 7 The Hamilton Depression Scale (HAMD)................................................................ 42

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Attachment 8: The Hamilton Anxiety Scale (HAMA).................................................................... 44

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scenario summary
project
name
Clinical efficacy evaluation and action mechanism of acupuncture
and moxibustion-Evaluation of acupuncture to improve the response
rate of immunotherapy in cervical cancer patients.
purpose
of
research
1. Clarify the synergistic effect and safety of acupuncture therapy on
immunotherapy for cervical cancer patients, and provide evidence-based
medical evidence for the clinical efficacy of acupuncture therapy in
immunotherapy for cervical cancer;
2. Patients' blood, stool and tongue coating samples were retained for
cytokine and 16S rDNA / metagenomic testing, and then further explored the
mechanism of acupuncture therapy to improve the immune response of patients
through microflora.
research
design
Prospective, multicenter, randomized controlled clinical study
Total
number
of cases
90 Cases
Case
selection
Inclusion criteria:
(1) Patients with metastatic, recurrent or persistent squamous cell
carcinoma, adenocarcinoma, adenosquamous carcinoma, or cervical cancer
unsuitable for surgery and / or radiation therapy;
(2) Age: 18-70 years old;
(3) Having at least one measurable lesion according to RECIST 1.1;
(4) The ECOG score is 0 or 1 point;
(5) The life expectancy exceeds 3 months;
(6) The patient has normal important organ function, specifically as
follows:
①Absolute neutrophil count (ANC) 1.510 ^ 9 / L;
②Platelet count: 8010 ^ 9 / L;
③Hemoglobin: 90g / L;
④Total bilirubin 1.5 upper limit of normal (ULN);
⑤Asparpartate aminotransferase (AST) and alanine aminotransferase
(ALT) 2.5 ULN;
Note: If the patient has liver metastasis, the AST and ALT levels are 5

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ULN;
⑥Creatinine 1.5 ULN or creatinine clearance 60 ml/min (Cockcroft-Gault
formula);
⑦Baseline albumin: 28g / L;
(7) Thyroid-stimulating hormone (TSH) level of 1 ULN;
(8) Patients may sign a written informed consent form.
Exclusion criteria:
(1) Histopathological diagnosis of tumors other than squamous cell
carcinoma, adenosquamous cell carcinoma, or adenocarcinoma;
(2) Participated in other clinical trials, or completed other clinical trials
within 4 weeks;
(3) Previous use of immune checkpoint inhibitors, including but not limited
to other anti-PD-1 and anti-PD-L1 antibodies;
(4) known history of allergy to any component of carlizumab or other
monoclonal antibodies;
(5) The current need to use immunosuppressive drugs;
(6) patients with any history of active autoimmune disease or autoimmune
diseases, including but not limited to the following diseases: hepatitis,
pneumonia, uveitis, colitis (inflammatory bowel disease), hypophysitis,
vasculitis, nephritis, hyperthyroidism and hypothyroidism, need intermittent use
of bronchodilators or other medical intervention of asthma patients;
(7) Clinically significant cardiovascular disease, including but not limited
to congestive heart failure (New York Heart Association (NYHA) grade> 2),
unstable or severe angina, severe acute myocardial infarction within 1 year prior
to enrollment, supraventricular or ventricular arrhythmias requiring medical
intervention, or QT interval 470 milliseconds (female);
(8) arterial thrombosis or venous thrombosis occurs within 6 months;
(9) Hypertension drugs are not well controlled by hypertension (systolic
blood pressure 140 mmHg and / or diastolic blood pressure 90 mmHg);
(10) Proteinuria (+ +) or total urine protein in 24 hours> 1.0 g;
(11) Coagulation abnormalities (INR> 2.0, PT> 16s), have a bleeding
tendency or are receiving thrombolysis or anticoagulant therapy;
(12) No recovery from previously administered adverse events (except

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alopecia) (i. e., grade 1 or baseline);
(13) Known as having active central nervous system metastases;
(14) Patients with a previous invasive malignancy and with any evidence of
disease within the past 5 years;
(15) Active infection that requires systemic treatment;
(16) History of immunodeficiency, including seropositivity for human
immunodeficiency virus (HIV) or other acquired or congenital
immunodeficiency diseases;
(17) Hepatitis B virus (HBV)> 2000 IU / ml or DNA 110 ^ 4 / ml; or
hepatitis C virus (HCV) RNA 110 ^ 3 / ml);
(18) Live vaccine was received within 4 weeks before the first trial
treatment;
(19) Patients with suspected intestinal obstruction or risk of vaginorectal
fistula or vaginal vesical fistula;
(20) Any other medical, mental or social condition whose rights, safety,
welfare, or ability to sign informed consent, collaboration and study
participation or may interfere with the interpretation of the results.
therapeutic
regimen
Trial group: acupuncture therapy + immunotherapy + targeted therapy /
acupuncture therapy + immunotherapy + chemotherapy
Control group: immunotherapy + targeted therapy / immunotherapy +
chemotherapy
Efficacy
assessment
Evaluation criteria and time:
1.1 Evaluation criteria: Treatment response was evaluated according to the
Efficacy Evaluation criteria for Solid Tumors version 1.1 (RECIST 1.1) (see
Annex 1);
1.2 Evaluation time: Start of treatment until 40 weeks, every 8 weeks ± 2
weeks, and then every 12 weeks ± 2 weeks until the end of treatment; patient
efficacy evaluation results should be maintained for at least 4 weeks.
2. Efficacy evaluation items:
2.1 Objective response rate (Objective response rate, ORR): including
comple teresponse (comple teresponse, CR), partial response (partial response,
PR);
ORR = (CR + PR) / 100% total.
2.2 Disease control rate (disease control rate, DCR): including comple

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teresponse (comple teresponse, CR), partial response (partial response, PR), and
stable disease (stable disease, SD).
DCR = (CR + PR + SD) / 100% of total cases.
2.3 Progression-free survival time (progression free survival, PFS): PFS is
defined as the time from initiation of this regimen and the first onset of disease
progression or death from any cause.
2.4 Overall survival (Overall survival, OS): the time from
randomization to death due to any cause.
2.5T lymphoid subset and NK cells: including CD3 +, CD4 +, CD8 +, CD4
+ / CD8 + and NK cells.
2.6 Level of tumor markers: SCC, CA125.
2.7 Quality of Life: This study used the QLQ-C30 quality of life
questionnaire (see Annex 2) developed by the European Center for Cancer
Research and Treatment (EORTC), the Quality of Life questionnaire for
Cervical Cancer Patients EORCT QLQ CX24 (see Annex 3), and the Chinese
version of the Simple Fatigue Scale (Brief Fatigue Inventory, BFI-C) (see
Annex 4), quantity tables (Insomnia Severity Index, ISI) (see attachment 5), the
Brief Pain Assessment Scale (Chinese Version of the Brief Fatigue Inventory,
BPI-C) (see Attachment 6), the Hamilton Depression Scale (Hamilton
Depression Scale, HAMD) (see Attachment 7), the Hamilton Anxiety Scale
(Hamilton Anxiety Scale, HAMA) (see Attachment 8)
2.8 Adverse events related to immunotherapy and targeted therapy and their
severity: Evaluation according to the evaluation criteria of adverse reaction
events in version NCI CTCAE V5.0, including but not limited to skin reactions,
pneumonia, colitis, nephritis, endocrine diseases, etc.
2.9 Safety indicators: including blood, urine, stool routine, liver function
(ALT, AST), renal function (Cr, BUN) examination, check at any time when
necessary.
statistical
method
1. Statistical software:
SAS 9.2 statistical software, efficacy indicators with full analysis set
(FAS) analysis and compliance protocol set (PPS) analysis, adverse reactions
should be safety data set (SS) analysis.
2. Statistical methods:

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All statistical tests were two-sided and P 0.05 will be considered to be
statistically significant. The proportion of shedding cases should not be greater
than 20%. Metering data description mean, standard deviation, median,
minimum value, maximum value, etc., count data description frequency,
percentage, etc. Measurement data were analyzed by t-test and rank sum test,
chi-square test and Ridit analysis, and survival data by Kaplan-Meier method,
Wilcoxon rank sum test or log-rank test. Multivariate survival analysis was
performed using a Cox proportional hazards regression model.
The study
period
November 2023-November 2026

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1. research background
1. Current status of modern medical treatment of cervical cancer
Cervical cancer is one of the most common gynecological malignant tumors. According to
the data of the National Cancer Center in 2022, [1], the incidence and mortality rate of cervical
cancer rank fourth among female tumors. In China, the incidence rate and mortality rate of cervical
cancer are relatively high. In 2020, there are about 110,000 new cases and 60,000 death cases in
China, [2], and the trend is younger. Despite significant progress in the screening and prevention
of cervical cancer in recent years, its five-year overall survival rate has only been maintained at
around 60%. The recurrence rate of advanced cervical cancer was as high as 70%, with a median
survival of only 16.8 months [3].
For recurrent / metastatic cervical cancer, treatment modalities are limited and ineffective,
and studies show that the 5-year survival rate for patients with recurrent / metastatic cervical
cancer is only about 17% [4-5]. For metastatic / recurrent cervical cancer patients, (2020 before)
NCCN guidelines have recommended: first-line treatment for paclitaxel and platinum and
combined bevacizumab chemotherapy, including overall survival (OS) is about 13 months,
second-line treatment for bevacizumab, topotecan, docetaxel, albumin paclitaxel and other single
agent chemotherapy, its progression free survival (PFS) is not more than 5 months, OS only about
10 months [6-7].
Moreover, because the disease itself, long-term treatment and complications seriously
threaten women's physical and mental health, the long-term quality of life of patients is generally
low. Therefore, how to reduce the rate of cervical cancer recurrence and metastasis and improve
the survival of advanced cervical cancer patients is an urgent clinical problem to be solved.
2. Advantages and limitations of immunotherapy for cervical cancer
Tumor immunotherapy is a therapeutic method to control and clear tumor by restoring the
normal anti-tumor immune response by initiating and maintaining the tumor-immune circulation.
At present, immunotherapy methods mainly include monoclonal antibodies, immune checkpoint
inhibitors, therapeutic antibodies, cancer vaccines, cell therapy, small molecule inhibitors and so
on.
The results of the KEYNOTE-826 study published in The New England Journal of Medicine
in 2021 show, The combination of pabolizumab compared with chemotherapy ± bevacizumab was
more than 15% in patients with persistent, recurrent / metastatic cervical cancer, Median PFS
increased by over 2 months of [8], Based on this study, The FDA approved pabolizumab in
combination with platinum-based chemotherapy ± bevacizumab as the first-line treatment for
PD-L1 positive (CPS 1) persistent, recurrent / metastatic cervical cancer. Opened a new chapter in

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immunotherapy for cervical cancer. For the second-line treatment of recurrent metastatic cervical
cancer, NCCN guidelines recommended pabolizumab or navulimumab monotherapy use,
KEYNOTE-158 study is a clinical trial of pabolizumab monotherapy for second-line cervical
cancer and included 98 cervical cancer patients, the results showed that the ORR of the overall
population was only 12.2%, the overall population median PFS and median OS were 2.1 and 9.4
months [9], respectively.
Based on the above results, it can be seen that for advanced recurrent and metastatic cervical
cancer, although ICI alone lasts for a long time, but the remission rate is low, especially for
patients with failed first-line treatment failure, its clinical efficacy is not satisfactory. Therefore,
many joint programmes have been explored in recent years. The CLAP study was a single arm and
phase clinical study of immunosuppressive agents combined with small molecule tyrosine kinase
inhibitors (tyrosine kinase inhibitor, TKI), namely carilizumab and apatinib mesylate for
second-line treatment of recurrent and metastatic cervical cancer. A total of 45 patients were
included, with an overall ORR of 55.6% and an overall median PFS of 8.8 months [10].
Although immunotherapy partly improves survival in patients with recurrent / metastatic
advanced cervical cancer, there is still a low response to immunotherapy in cervical cancer. The
reason may be that tumor cells secrete immunosuppressive factors such as TGF- β and IL-10
that attract immunosuppressive cells (such as regulatory T cells and bone marrow-derived
inhibitory cells) into the tumor microenvironment leading to immune tolerance [11]. Meanwhile,
long-term immune checkpoint blockade therapy may lead to T cell depletion and weaken the
immune response leading to immunoresistant [12]. Tumor-associated fibroblasts and macrophages
in the tumor microenvironment can also inhibit the immune response into the tumor and prevent
the immune cells from entering the tumor, leading to the inhibition of [13] by the tumor
microenvironment. At the same time, as activated T cells attack normal tissues, increase
inflammatory cytokines and autoantibodies [14], their immune-related adverse events could not be
ignored, including hypothyroidism (10.2%), appetite loss (9.2%), fatigue (9.2%), diarrhea (21%)
and other [15-16].
The above research results suggest that for second-line recurrent / metastatic cervical cancer
patients in line and above have entered the era of "dechemotherapy", despite the low response to
immunotherapy and epidemic-related adverse events, its application prospect is still very broad.
3. Acupuncture therapy can regulate the immune function of tumor patients
Acupuncture therapy can improve the body's immune function. On the one hand, acupuncture
can regulate the balance of Yin and Yang and the function of viscera and meridians of the human
body, but also can strengthen and dispel evil, and maintain the balance of the internal and external

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environment of the human body [17]. The subtle balance between T cell subsets is the central link
to maintaining the stability of the internal environment of the immune system, so it is an important
indicator to reflect the anti-tumor immune function of the body [18]. The study shows that
acupuncture treatment can increase the content of IL-2, IL-18, TNF-a and INF-A in tumor patients
and animal tumor-bearing models, increase the number of NK cells, macrophages, CD4 +, CD8 +
T cells, and B lymphocytes, activate and enhance innate and adaptive immunity, and at the same
time, reduce the content of IL 4, IL-6 and IL 10, so as to inhibit Th 2, cells and Treg cells, relieve
tumor immune suppression, and inhibit tumor growth [19-20]. The regulation mechanism of
acupuncture on the immune system of the body may be strengthening the foundation, so
acupuncture mostly focuses on the acupoints of the spleen and stomach and the acupoints of the
veins. Many scholars at home and abroad found that compared with the conventional treatment of
western medicine, acupuncture on acupoints, including Sanli, Guan Yuan, Tianhai and Sanyang,
can improve the T cell subsets such as CD4 +, CD8 + and CD4 + / CD8 + and NK cells, and
weaken the pro-inflammatory cytokines such as IL-1 β and TNF- α, thus improving the body's
immune function of the body to delay tumor growth [21-23]. The results of the above studies
suggest that acupuncture may have some synergistic potential for anti-tumor immunotherapy.
4. Research status and application prospect of acupuncture synergistic immunotherapy for
cervical cancer
Previous studies have demonstrated the efficacy and advantages of acupuncture in regulating
the immune function. Therefore, can acupuncture improve the immune status of cervical cancer
patients to improve the response rate of immunotherapy? At present, most studies focus on the
synergistic immune efficiency [24] of TCM therapy, and there are few research records on whether
acupuncture can be synergistic immunotherapy and reduce toxic and side effects. Moreover, most
cases were reported, with limited [25], mostly concentrated in the basic research stage. At present,
the clinical application of acupuncture combined with immunotherapy for cervical cancer patients
is not extensive, the preliminary basic research is weak, there is a lack of large-scale multi-center
clinical trials, and there is no high-level evidence to support the role of acupuncture in cervical
cancer immunotherapy. This study can fill the gap in the efficacy of acupuncture combined with
immunotherapy in cervical cancer patients, explore the mechanism of the synergistic effect of
acupuncture on immunotherapy in cervical cancer patients, and provide evidence-based medical
evidence for their treatment. To fill the gap of acupuncture in the treatment of cervical cancer.
reference documentation:
[1]ZHENG R S, ZHANG S W, SUN K X, et al.Cancer statistics in China, 2016［J］.Chin J Oncol, 2023, 45(3):
212-220.

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[2]Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and
Mortality Worldwide for 36 Cancers in 185 Countries.CA Cancer J Clin.2021 May;71(3):209-249. doi:
10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
[3]Orbegoso C, Murali K, Banerjee S.The current status of immunotherapy for cervical cancer.Rep Pract Oncol
Radiother.2018 Nov-Dec;23(6):580-588. doi: 10.1016/j.rpor.2018.05.001. Epub 2018 May 18. PMID: 30534022;
PMCID: PMC6277269.
[4] Gao Longfei, Liu Jian. Prognosis analysis of different modalities for locally advanced cervical cancer [J].
Chinese General Medicine, 2022,20 (03): 395-398.
[5]Marret G, Borcoman E, Le Tourneau C.Pembrolizumab for the treatment of cervical cancer[J].Expert Opin
Biol Ther, 2019, 19(9): 871-877. DOI: 10.1080/14712598.2019.1646721.
. [6]Tsuda N, Watari H, Ushijima K Chemotherapy and molecular tar-geting therapy for recurrent cervical
cancer [J].Chin J Cancer Res, 2016, 28 (2): 241-253
. [7]Boussios S, Seraj E, Zarkavelis G, et al Management of patients with recurrent / advanced cervical cancer
beyond first line Platinum regimens: Where do we stand?a literature review [ J].Crit Rev Oncol Hematol, 2016,
108 (1): 164-174
[8]Colombo N，Dubot C，Lorusso D , et al.Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical
Cancer [J].N Engl J Med，2021，385（20）：1856-1867. doi: 10.1056/NEJMoa2112435
[9]CHUNG H C, ROS W, DELORD J P, et al.Efficacy and safety of pembrolizumab in previously treated
advanced cervical cancer: results from the phase ⅡKEYNOTE-158 study［J］.J Clin Oncol, 2019, 37(17):
1470-1478
[10]LAN C Y, SHEN J X, WANG Y, et al.Camrelizumab plus apatinib in patients with advanced cervical cancer
(CLAP): a multicenter, open-label, single-arm, phase Ⅱtrial［J］.J Clin Oncol, 2020, 38(34): 4095-4106.
[11]Muñóz-Godínez R, de Lourdes Mora-García M, Weiss-Steider B, et al.Detection of CD39 and a Highly
Glycosylated Isoform of Soluble CD73 in the Plasma of Patients with Cervical Cancer: Correlation with Disease
Progression.Mediators Inflamm.2020 Dec 7;2020:1678780. doi: 10.1155/2020/1678780. PMID: 33488292;
PMCID: PMC7803102.
[12]Vathiotis IA, Trontzas I, Gavrielatou N, et al.Immune Checkpoint Blockade in Hormone Receptor-Positive
Breast Cancer: Resistance Mechanisms and Future Perspectives [J].Clin Breast Cancer.2022;22(7):642-649.
[13]SUN Qin-Ying, WEI Xiang-Zhen, WANG Zhong-Lin et al.Primary and Acquired Resistance against
Immune Check Inhibitors in Non-Small Cell Lung Cancer[J].Cancers (Basel).2022;14(14):3294
[14]Postow MA, Sidlow R, Hellmann MD.Immune-Related Adverse Events Associated with Immune
Checkpoint Blockade.N Engl J Med.2018 Jan 11;378(2):158-168. doi: 10.1056/NEJMra1703481. PMID:
29320654.
[15]Naumann RW, Hollebecque A, Meyer T, et al .Safety and Efficacy of Nivolumab Monotherapy in Recurrent
or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial.J Clin
Oncol.2019 Nov 1;37(31):2825-2834. doi: 10.1200/JCO.19.00739. Epub 2019 Sep 5. PMID: 31487218; PMCID:
PMC6823884.
[16]Chung HC, Ros W, Delord JP, et al .Efficacy and Safety of Pembrolizumab in Previously Treated Advanced

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Cervical Cancer: Results From the Phase II KEYNOTE-158 Study.J Clin Oncol.2019 Jun 10;37(17):1470-1478.
doi: 10.1200/JCO.18.01265IF: 45.3 Q1 .Epub 2019 Apr 3. PMID: 30943124.
[17] Sun Nina, Tian Yuefeng. Analysis of the effects of acupuncture intervention on programmed death receptor
1 / SPI-ligand 1 [J] World Journal of Integrated Chinese and Western Medicine, 2020,15 (01): 178-182..
[18] Sun Hui, Zhang Bo, Qian Haihua, etc. Effect of warm acupuncture intervention on patient immune function
and intestinal microflora after radical resection of colorectal cancer [J]. Acupuncture study, 2021,46 (07):
592-597.
[19] Huang Jin, Li Shanshan, Wang Bin, etc. Progress in the mechanism of acupuncture in regulating tumor
immunosuppression [J]. Acupuncture study, 2020,45 (09): 767-770.
[20] Wu Yu, Shao Lijuan, Song Minghan and so on. Progress in acupuncture for the regulation of tumor immune
response [J]. Journal of Guangdong Pharmaceutical University, 2023,39 (03): 137-142.
[21]Zhang Z, Yu Q, Zhang X, Wang X, Su Y, He W, Li J, Wan H, Jing X.Electroacupuncture regulates
inflammatory cytokines by activating the vagus nerve to enhance antitumor immunity in mice with breast
tumors.Life Sci.2021 May 1;272:119259. doi: 10.1016/j.lfs.2021.119259. Epub 2021 Feb 23. Erratum in: Life
Sci.2022 Feb 15;291:119539. PMID: 33636172.
[22Chen L, Xu A, Yin N, Zhao M, Wang Z, Chen T, Gao Y, Chen Z.Enhancement of immune cytokines and
splenic CD4+ T cells by electroacupuncture at ST36 acupoint of SD rats.PLoS One.2017 Apr 13;12(4):e0175568.
doi: 10.1371/journal.pone.0175568. PMID: 28406959; PMCID: PMC5391063.
[23] Zhang Kun, Zhang Zeliang, Yu Qiquan, etc. Effect of acupuncture combined with acupoint application on
immune function in patients with stage non-small cell lung cancer [J]. Shanghai Journal of Acupuncture, 2019,38
(08): 831-835.
[24] Wang Wenjun, Zhang Xianwen, Xing Enming. Progress in TCM regulation of PD-1 / PD-L1 immune
checkpoint [J]. Medical Theory and Practice, 2022,35 (18): 3094-3096.
[25]Li J, Xu D, Liu Y, Cao Y, He J, Liao M.Acupuncture Treatment of Guillain-Barré Syndrome After Using
Immune Checkpoint Inhibitors: A Case Report.Front Neurol.2022 Jun 2;13:908282. doi:
10.3389/fneur.2022.908282. PMID: 35720101; PMCID: PMC9201402.
2. purpose of research
1. Main purpose:
Toexploretheclinicaleficacyandsafetyofacupuncturetherapyforimunotherapyinpatientswithrecurent/metastaticervicalcancer,andtoprovidevidence-basedmedicalevidencefortheclinicaleficacyofacupuncturetherapyincervicalcancerimunotherapy.
2. Secondary objectives:
Blood, stool and tongue coating samples were retained for cytokines and 16S rDNA /
metagenomic testing, and the mechanism of acupuncture treatment to improve patients' immune
response through microflora was further explored.

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3. Type and principles of the study design
1. Study design type:
Prospective, multicenter, randomized controlled clinical study.
2. Random method:
For this study, using the central randomization method, 90 patients with
recurrent / metastatic cervical cancer were included and divided into 8 study centers.
In each research center, pathological type, PD-L1 expression level, and
immunotherapy combined with targeted therapy / immunotherapy combined with
chemotherapy were used as stratification factors. The patients were divided into
control group (Group A) and test group (Group B), and the length of the group was
6 and the allocation ratio of 1 ∶1.
3. Comparative method:
This trial includes control group and trial group, trial group intervention measures:
acupuncture therapy + immunotherapy + targeted therapy / acupuncture therapy + immunotherapy
+ chemotherapy; control group intervention measures: immunotherapy + targeted therapy /
immunotherapy + chemotherapy.
4. Sample size calculation:
This study intends to conduct a preliminary exploratory study, using small samples for
clinical observation and literature review[1]The sample size of each group in the exploratory study
should be greater than 30.90 patients to be included in this exploratory study should be assigned to
the test group and the control group according to 1:1, with 45 cases in each group, which meets the
sample size of the small exploratory study。
[1] Shao STQ..A practical guide to drug clinical trials and gcp.Beijing: Peking University Medical Press, 2010:
3592. [Google Scholar]
四、Case selection
1. Inclusion criteria:
(1) Patients with metastatic, recurrent or persistent squamous cell carcinoma, adenocarcinoma,
adenosquamous carcinoma, or cervical cancer unsuitable for surgery and / or radiation therapy;
(2) Age: 18-70 years old;
(3) Having at least one measurable lesion according to RECIST 1.1;
Note: Measurable lesions are defined as lesions that can be accurately measured in at least
one dimension (the longest diameter recorded by computed tomography (CT) scan, magnetic

16
resonance imaging (MRI) is 10mm; lymph nodes must be 15mm on the short axis. Tumors within
the previously irradiated area will be designated as "nontarget" lesions unless progression is
recorded at least 90 days after completion of radiotherapy or a biopsy is performed to confirm
persistence.
(4) The ECOG score is 0 or 1 point;
(5) The life expectancy exceeds 3 months;
(6) The patient has normal important organ function, specifically as follows:
①Absolute neutrophil count (ANC) 1.510 ^ 9 / L;
②Platelet count: 8010 ^ 9 / L;
③Hemoglobin: 90g / L;
④Total bilirubin 1.5 upper limit of normal (ULN);
⑤Asparpartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 ULN;
Note: If the patient has liver metastasis, the AST and ALT levels are 5 ULN;
⑥Creatinine 1.5 ULN or creatinine clearance 60 ml/min (Cockcroft-Gault formula);
⑦Baseline albumin: 28g / L;
(7) Thyroid-stimulating hormone (TSH) level of 1 ULN;
Note: Patients with a free triiodothyronine [FT3] or a free thyroxine [FT4] level of 1 ULN
may be included.
(8) Patients may sign a written informed consent form.
2. Exclusion criteria:
(1) Histopathological diagnosis of tumors other than squamous cell carcinoma,
adenosquamous cell carcinoma, or adenocarcinoma;
(2) Participated in other clinical trials, or completed other clinical trials within 4 weeks;
(3) Previous use of immune checkpoint inhibitors, including but not limited to other
anti-PD-1 and anti-PD-L1 antibodies;
(4) known history of allergy to any component of carlizumab or other monoclonal antibodies;
(5) The current need to use immunosuppressive drugs;
Note:> 10 mg/d prednisone or equivalent dose were prohibited for 2 weeks prior to study
drug administration.
(6) patients with any history of active autoimmune disease or autoimmune diseases, including
but not limited to the following diseases: hepatitis, pneumonia, uveitis, colitis (inflammatory
bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism and hypothyroidism, need
intermittent use of bronchodilators or other medical intervention of asthma patients;

17
Note: except for vitiligo, resolved pediatric asthma / atopic subjects.
(7) Clinically significant cardiovascular disease, including but not limited to congestive heart
failure (New York Heart Association (NYHA) grade> 2), unstable or severe angina, severe acute
myocardial infarction within 1 year prior to enrollment, supraventricular or ventricular arrhythmias
requiring medical intervention, or QT interval 470 milliseconds (female);
(8) arterial thrombosis or venous thrombosis occurs within 6 months;
(9) Hypertension drugs are not well controlled by hypertension (systolic blood pressure 140
mmHg and / or diastolic blood pressure 90 mmHg);
(10) Proteinuria (+ +) or total urine protein in 24 hours> 1.0 g;
(11) Coagulation abnormalities (INR> 2.0, PT> 16s), have a bleeding tendency or are
receiving thrombolysis or anticoagulant therapy;
(12) No recovery from previously administered adverse events (except alopecia) (i. e., grade 1
or baseline);
(13) Known as having active central nervous system metastases;
(14) Patients with a previous invasive malignancy and with any evidence of disease within
the past 5 years;
Note: Skin basal cell carcinoma, skin squamous cell carcinoma or cervical cancer in situ with
potentially curative treatment.
(15) Active infection that requires systemic treatment;
(16) History of immunodeficiency, including seropositivity for human immunodeficiency
virus (HIV) or other acquired or congenital immunodeficiency diseases;
(17) Hepatitis B virus (HBV)> 2000 IU / ml or DNA 110 ^ 4 / ml; or hepatitis C virus (HCV)
RNA 110 ^ 3 / ml);
(18) Live vaccine was received within 4 weeks before the first trial treatment;
Note: Administration of an inactivated virus vaccine against seasonal influenza is allowed.
(19) Patients with suspected intestinal obstruction or risk of vaginorectal fistula or vaginal
vesical fistula;
(20) Any other medical, mental or social condition whose rights, safety, welfare, or ability to
sign informed consent, collaboration and study participation or may interfere with the
interpretation of the results.
3. Loss standards:
①Poor compliance, do not cooperate with the treatment;
②Those who cannot adhere to the treatment if an accident occurs during the treatment
process;

18
③Self-withdrawal of patients during the trial;
④Lost to visit;
4. Termination of the study criteria:
①The subject volunteered to withdraw;
②The subject has poor compliance and the investigator cannot not continue the clinical
investigator;
③Subject experienced pregnancy, death, or was lost to follow-up;
④The Sponsor terminates the study;
⑤The competent administrative department cancels the test;
⑥Other circumstances deemed necessary to withdraw from the study.
The investigators should do their best effort to enable each subject to continue the
appropriate treatment unless stopping participation in the study is most beneficial. If the subject's
study treatment stops, the investigator should do his best to evaluate the subject's study results.
Subjects should also enter the follow-up period after treatment termination or withdrawal
from the study. The subject will receive periodic follow-up (once every 2 months, telephone or
outpatient follow-up) to learn about survival status, follow-up, the endpoint event (i. e. patient
death or follow-up after 2 years).
5. End of treatment and entry to follow-up phase criteria:
Treatment is stopped prior to follow-up in one of the following cases:
①Treatment cycle is up to 2 years;
②Patients with disease progression;
③Unacceptable toxic effects occur in patients;
④The use of contraindicated therapy, such as non-palliative radiotherapy or anticancer effect
of traditional Chinese medicine decoction and proprietary Chinese patent medicine oral, injection;
⑤The investigator decides to stop the protocol or the patient withdrew consent;
⑥Treatment can be discontinued if a patient with a confirmed complete response has
received at least 8 cycles of immunotherapy, including at least 2 cycles beyond the complete
response.
6. Early study termination / site closure:
Upon termination of the study, the Ethics committee and the regulatory B are reported. In the
event of early study termination or site closure, all study materials (except documents that must be
retained at the site) must be returned to the investigator. The investigator must keep the relevant

19
documents until notified of the destruction. Reasons for early termination of the trial or site closure
may be but not limited to the following reasons: discovery of new drug toxicity, results of any
interim analysis, subject enrollment and follow-up completion, non-protocol compliance, changes
to the study schedule, slow enrollment, or poor quality of clinical data.
5. Research methods and technical routes
1. Treatment plan:
1.1 Treatment regimen of the trial group: acupuncture therapy + immunotherapy +
targeted therapy / acupuncture therapy + immunotherapy + chemotherapy
1.1.1 Acupuncture therapy:
(1) Needle: disposable acupuncture needle (p0.340mm, 1.5 inch) and fixed pad specially
made by Suzhou Medical Supplies Factory Co., LTD., and low frequency electronic pulse therapy
instrument (G6805-1A) produced by Shanghai Huayi Medical Instrument Co., LTD., are selected.
(2) Point selection and positioning: (refer to the planning textbook of National Traditional
Chinese Medicine Colleges in Acupuncture (10th edition)):
main point:
Bilateral foot li: stomach meridian acupoint, located outside the calf, 3 inches below the calf
nose, 1 transverse finger outside the anterior tibial crest, the calf nose and exi connection.
Bilateral three Yin intersection: the spleen through the meridian acupoint, located in the
inner side of the calf, 3 inches above the medial malleolus, the medial edge of the tibia.
Guan Yuan: Ren Mai meridian acupoint, located in the lower abdomen, 3 inches below the
umbilical cord, on the front midline.
Qi sea: Ren meridian acupoint, located in the lower abdomen, 1.5 inches below the
umbilical cord, on the front midline.
Baihui: Du meridian acupoint, located in the head, before the middle of the hairline straight
up 5 inches.
Yintang: Du meridian acupoint, located in the head, the middle of the inner end of the two
eyebrows.
adjunct acupuncture points:
①Pain: bilateral, Hetian point, bilateral Tachong point.
Hepoint: large intestine, located in the back of the hand, the middle point of the radial side
of the second metacarpal.0.5-1 inch.
Taichong point: the liver meridian acupoint, located in the back of the foot, the first, the
second metatarsal bone, the base of the metatarsal bone and the front of the depression, or touch

20
the arterial beat.0.5-1 inch.
②Insomnia, anxiety, depression: temple temple, bilateral temples:
Temple point: Du meridian acupoint, located in the head, the middle of the hairline straight
0.5 inches.
Temple: through the outer strange hole, located in the head, when the brow tip and the eye
outer canthus, back about 1 horizontal finger in the depression.
③God fatigue: Zhongwan point, bilateral Shenmen point:
Zhongwan point: Ren meridian point, located in the upper abdomen, 4 inches in the
umbilical cord, on the front midline.
Shenmu point: heart meridian acupoint, in the anterior wrist area, the distal palar side, the
radial end of the flexor carpal tendon on the ulnar side.
④If the patient has urinary symptoms such as frequent urination, nocturia, urinary
incontinence, dysuria, discomfort in lower abdomen, perineal pain, after getting qi, the electrodes
are horizontally connected to the bilateral three yin crossing point.
(3) Operation method
The patient was placed in the supine position, and the local skin was routinely disinfected.
Zusanli: after vertically stabbing 0.5-1 inch with 0.3 40mm millineedle, uniform small
lifting twist 3 times, with the patient local acid, numbness and other qi feeling as the degree. After
obtaining gas, the electrodes of the electric needle instrument were connected laterally to the
needle handle of both sides, and the continuous wave was selected, the adjustment frequency was
2 Hz, and the current size was 0.5-2 mA.
Sanyin intersection: avoid nerves, slowly lower into 0.5-1 inch. If there is no electric shock
needle after puncture, turn for 3 times in the direction of needle, adjust the needle under the skin,
enter the needle tip again, and turn for 3 times later. If the patient has urinary symptoms such as
frequent urination, nocturia, urinary incontinence, dysuria, lower abdominal discomfort, perineal
pain, after getting gas, the electrode is horizontally connected to the needle handle of the bilateral
side, the continuous wave is selected, the adjustment frequency is 2 Hz, and the current size is
0.5-2 mA.
Guan Yuan point, gas sea point: straight stab 0.5-1 inch, uniform small range of lifting twist
3 times, to the patient's local acid, numbness and other qi feeling degree.
Baihui: flat thorn 0.5-0.8 inches, no technique.
Yintang: 1 inch from the middle depression of the inner section of the two eyebrows slightly
left or right to avoid the vein into the needle, puncture under the periosteum, the tip of the needle

21
down flat stab 0.5-1 inch.
If the patient has pain symptoms, Heu point straight stab 0.5-1 inch, Taichong point straight
stab 0.5-1 inch, uniform small range of lifting twist 3 times, to the patient local acid, numbness and
other gas feeling degree.
If the patient has insomnia or anxiety, depression of mood disorders, ting point, flat thorn
0.5-0.8 inches, not technique, bilateral temples straight or oblique stab 0.3-0.5 inches, uniform
small range of lifting twist turn 3 times, to the patient local acid, numbness and other gas feeling
degree.
If the patient is tired, Zhongwan point straight stab 1-1.5 inches, bilateral men point straight
stab 0.3-0.5 inches, uniform small range of twist 3 times, to the patient locally produce acid,
numbness and other gas feeling as the degree.
(4) Cycle and frequency:
Start simultaneously with immunotherapy, 1 cycle every 4 weeks, 1-2 injections per week,
and at least 4 injections per cycle. Each needle was left for 30 minutes.
1.1.2 Immunotherapy: Carrelizumab
①Usage and dosage: Carizumab (Carizumab for injection, manufacturer: Suzhou Shengdia
Biomedical Co., LTD., No. Approval number: S20190027), 200mg / time, intravenous injection,
once every 2 weeks)
②Frequency and course of treatment: use once for every 2 weeks, 1 cycle for every 4
weeks;
③Treatment cessation duration: use up to 2 years, patient disease progression, unacceptable
toxic effects, use of prohibited therapy, investigator decision to stop the regimen or patient
withdrawal of consent. Treatment could be discontinued if a patient with a confirmed complete
response had received at least 8 cycles of immunotherapy, including at least 2 cycles beyond the
complete response.
1.1.3 Targeted therapy: apatinib
①Usage and dosage: Apatinib (apatinib mesylate tablets, manufacturer: Jiangsu Hengrui
Pharmaceutical Co., LTD., approval number: H20140103), 250mg / time, orally, once a day.
②Drug reduction: If the patient has treatment-related adverse events, the amount of apatinib
can be reduced as follows:
Dose grade
dosage
initial dose
250mg, qd (250mg / 1 day)
Grade 1 dose
250mg, oral 2 days off 1 day (500mg / 3

22
reduction
days)
Grade 2 dose
reduction
250mg, 1 day off 1 day (250mg / 2 day)
Note: carilizumab is not allowed; apatinib is not allowed to increase the dose again after the
reduction.
1.1.4 Chemical therapy:
The specific chemotherapy regimen, drug usage and dosage, and the frequency of
chemotherapy should be determined by the oncology clinicians according to the NCCN guidelines
(2023) and the patient's condition.
1.2, Treatment regimen of the control group: immunotherapy + targeted therapy /
immunotherapy + chemotherapy
.11.2 Immunotherapy: Carrelizumab
①Usage and dosage: Carizumab (Carizumab for injection, manufacturer: Suzhou Shengdia
Biomedical Co., LTD., No. Approval number: S20190027), 200mg / time, intravenous injection,
once every 2 weeks)
②Frequency and course of treatment: once for every 2 weeks, and 1 cycle for every 4
weeks;
③Treatment cessation duration: use up to 2 years, patient disease progression, unacceptable
toxic effects, use of prohibited therapy, investigator decision to stop the regimen or patient
withdrawal of consent. Treatment could be discontinued if a patient with a confirmed complete
response had received at least 8 cycles of immunotherapy, including at least 2 cycles beyond the
complete response.
1.2.2 Targeted therapy: apatinib
①Usage and dosage: Apatinib (apatinib mesylate tablets, manufacturer: Jiangsu Hengrui
Pharmaceutical Co., LTD., approval number: H20140103), 250mg / time, orally, once a day. The 4
weeks is 1 cycle.
②Drug reduction: If the patient has treatment-related adverse events, the amount of apatinib
can be reduced as follows:
Dose grade
dosage
initial dose
250mg, qd (250mg / 1 day)
Grade 1 dose
reduction
250mg, oral 2 days off 1 day (500mg / 3
days)
Grade 2 dose
250mg, 1 day off 1 day (250mg / 2 day)

23
reduction
Note: carilizumab is not allowed; apatinib is not allowed to increase the dose again after the
reduction.
1.2.3 Chemical therapy:
The specific chemotherapy regimen, drug usage and dosage, and the frequency of
chemotherapy should be determined by the oncology clinicians according to the NCCN guidelines
(2023) and the patient's condition.
1.3 Other Therapy:
Both groups may be treated with symptomatic supportive care according on their disease. The
investigator should record in detail the treatment of both groups, including the following aspects:
①pain management; ②nutritional support; ③psychopsychological intervention; ④tumor
treatment prevention and side effects.
2. No medication use and treatment:
The use of other antitumor therapy except carilzuzumab + apatinib / carilzumab + chemical
therapy, including non-palliative radiotherapy, other Chinese medicine injections with anti-tumor
effect, TCM decoction, proprietary Chinese medicine, other anti-tumor drugs or treatments as
specified by the protocol, is prohibited.
3. Drug distribution:
First, the appropriate amount of drugs is delivered to the research centers according to the
expected progress of the trial, and then distribute the drugs during the trial according to the actual
progress. Distribued by the site site s at the site to authorized staff. The drug distribution process
should be recorded accordingly, and the researcher must sign the drug distribution sheet and record
the use and recovery of the drug. In order to ensure the timely supply of drugs, the drug alert
quantity is set in advance, and once the stock is insufficient, timely distribution.

24
4. Technology roadmap: Vi. Observation items and test time
1. Observation items:
1.1 Demographic data:
Name, date of birth, contact information, residence, occupation, smoking history, alcohol
consumption, personal history, family genetic history, history of drug and food allergy.
1.2 Diagnostic data:
Time to diagnosis of cervical cancer, unit of diagnosis, pathology type, pathological grade,
site of metastasis, previous treatment, PD-L1 expression, TNM stage; past history and complicated
disease.
1.3 Efficacy indicators:
Evaluation criteria and evaluation points: The target lesions were evaluated according to the
treatment response according to the efficacy evaluation criteria for solid tumors, version 1.1
(RECIST 1.1) (see Annex 1); every 8 weeks until 40 weeks, and then every 12 weeks until the end
of treatment; the patient efficacy evaluation results should be maintained for at least 4 weeks.
1.3.1Objectivefectiverate(ObjectiveResponseRate,OR):ORreferstotheproportionofpatientswhosetumorvolumereductionreachestheprespecifiedvalueandcanmaintaintheminimum
timelimitrequirements.Includingcasesincludingcompleteresponse(completeresponse,CR),partialresponse(partialresponse,PR).
ORR = (number of CR cases + number of PR cases) / 100% of total cases.
1.3.2 Disease control rate (disease control rate, DCR): DCR refers to the proportion of
patients whose tumor volume decreases or stabilizes the prespecified value and can maintain the
minimum time limit requirements. Cases that include a comple teresponse (comple teresponse,
CR), partial response (partial response, PR), and stable disease (stable disease, SD).
DCR = (CR + PR + SD) / 100% of total cases.
1.3.3 Progression-free survival time (Progression Free Survival, PFS): PFS is the time from

25
randomization to the onset of tumor progression or death.
1.3.4 Overall survival (Overall survival, OS): the time from randomization to
death from any cause.
1.3.5T Lymphoid subset and NK cells: including the levels of CD3 +, CD4 +, CD8 +, CD4 +
/ CD8 +, and NK cells.
1.3.6 Tumor markers: including: SCC, CA125.
1.3.7 Quality of Life: This study used the QLQ-C30 quality of life questionnaire (see Annex 2)
developed by the European Center for Cancer Research and Treatment (EORTC), the Quality of
Life questionnaire for Cervical Cancer Patients EORCT QLQ CX24 (see Annex 3), and the
Chinese version of the Simple Fatigue Scale (Brief Fatigue Inventory, BFI-C) (see attachment 4),
insomnia severity, count tables (Insomnia Severity Index, ISI) (see attachment 5), the Brief Pain
Assessment Scale (Chinese Version of the Brief Fatigue Inventory, BPI-C) (see Attachment 6), the
Hamilton Depression Scale (Hamilton Depression Scale, HAMD) (see Attachment 7), the
Hamilton Anxiety Scale (Hamilton Anxiety Scale, HAMA) (see Attachment 8).
(According to the evaluation criteria of adverse reaction events in NCI CTCAE V5.0): routine
blood, urine and stool tests before treatment and every two cycles; electrocardiogram, liver
function (ALT, AST), renal function (Cr, BUN) tests, if necessary.
1.3.8 Adverse events and their severity related to immunization, treatment and targeted therapy:
Evaluation according to the evaluation criteria of adverse reaction events in NCI CTCAE V5.0, including
but not limited to skin reactions, pneumonia, colitis, nephritis, endocrine diseases, etc.
1.3.9 Safety indicators: blood, urine, routine stool test, liver function (ALT, AST), and renal
function (Cr, BUN) test.
1.4 Blood Samples:
After the patients signed the informed consent, 6ml + 2ml, 5g, and tongue coating samples
were kept within 4 weeks, every 6 weeks / 12 weeks before enrollment, at disease progression,
including 6ml blood samples for cytokine detection.2ml blood sample, stool sample 5g and tongue
coating sample were used for 16S rDNA / metagenome technology to complete the intestinal,
blood and oral microbial examination to explore the mechanism of action.
2. Observation time point:
2.1 Pre-enrollment examination-Domestic Demand completed 4 weeks before the
start of treatment:
①General information collection: name, date of birth, contact information, residence,
occupation, smoking history, drinking history, personal history, family genetic history, history of

26
drug and food allergy;
②Collection of disease information and diagnosis data: time of diagnosis of cervical cancer,
unit of diagnosis, pathological type, pathological grade, the site of metastasis, previous treatment,
PD-L1 expression, TNM stage; past history and comorbid disease;
③Vital signs: heart rate, respiration, blood pressure, and body temperature;
④Physical examination, clinical symptoms, patient tongue coating, pulse image and
traditional Chinese medicine syndrome;
⑤ECOG score, EORTC QLQ-C30, EORCT QLQ CX24, and MDASI-TCM questionnaires;
⑤Blood routine, urine routine, stool routine, liver and kidney function, electrocardiogram;
⑥Tumor markers, T lymphoid subsets and NK cell levels, cytokines detection;
⑦Imaging examination: chest, abdomen, pelvic enhanced CT, if contrast allergy, plain chest
CT, abdominal, pelvic MRI or CT; brain CT or MRI, whole body bone scan or PET-CT
examination.
⑧Keep biological samples from patients, including: blood sample 6ml + 2ml, stool sample
5g, and tongue coating sample.
2.2 Examination during the treatment period:
2.2.1 Every 8 weeks / 12 weeks ± 2 weeks, completion is required:
①Vital signs: heart rate, respiration, blood pressure, and body temperature;
②Physical examination, clinical symptoms, patient tongue coating, pulse image and
traditional Chinese medicine syndrome;
③ECOG score, EORTC QLQ-C30, EORCT QLQ CX24, and MDASI-TCM questionnaires;
④Blood routine, urine routine, stool routine, liver and kidney function, electrocardiogram;
⑤Tumor markers, T lymphoid subsets and NK cell levels, cytokines detection;
⑥Chest, abdomen, ministry, pelvic CT / MRI examination according to the needs of the
disease: the efficacy evaluation is confirmed at least 4 weeks after the study of PR and CR, and the
subsequent PFS and imaging examination should be the same as the examination method when
entering the group, and the same examination method must be adopted;
⑦Keep biological samples from patients, including: blood sample 6ml + 2ml, stool sample
5g, and tongue coating sample.
2.4 Follow-up visit:
①Follow-up of all the subjects in this study;

27
②Start-up time of follow-up: follow-up started after treatment, follow-up to end point event
(i. e. patient death or follow-up after 2 years);
③Frequency and content of follow-up: follow-up once every 12 weeks ± 1 week, and
observe the patients' medication category, physical condition score, tumor markers and imaging
examination. Among them, tumor markers and imaging examination can be selected. For subjects
who did not have disease progression at the time of withdrawal from this clinical study, imaging
follow-up was required every 8 weeks (± 1 week) until disease progression or the subject
received other treatments.
七、Evaluation method of the main indicators
Evaluation of effectiveness: CT, ultrasound, and tumor markers were performed before
treatment, every 8 / 12 weeks after ± 1 week of treatment. When necessary, brain MRI and bone
scan were performed as evaluation methods. During the follow-up period, patients were followed
up once every 12 weeks ± 1 week to record the survival status, including optional CT, ultrasound,
tumor markers, brain MRI, etc.;
Safety evaluation: blood routine, urine routine, stool routine, liver and kidney function, and
electrocardiogram were used as the evaluation methods.
Viii. Observation of adverse events
1. Adverse event definition:
Adverse event (AdverseEvent, AE) is an adverse medical event after a patient or a clinical
trial subject receives a drug but not necessarily causally related to treatment. Adverse events are
the main factors affecting the safety of drugs and should be emphasized in the process of clinical
trials.
Any adverse medical event since the subject voluntarily signed the informed consent and
entered the trial until the last follow-up should be attributed to the trial drug. An adverse event can
be any adverse and undesirable signs (including abnormal laboratory findings), symptomatic or
temporal medication-related disease regardless of a causal relationship to treatment. Changes due
to normal growth and development without frequency or severity above the normal range were not
considered adverse events. Adverse events include the following:
①All suspected adverse drug reactions;
②All reactions due to drug overdose, abuse, withdrawal, allergy, toxicity, or "no expected
pharmacological effects of the drug";
③Obviously unrelated diseases;

28
④Injury or accident (it must be a medical event). Note: If a medical condition is known to
cause an injury or accident (e. g., a fall caused by vertigo), then the medical condition (vertigo)
and an accident (fall) should be reported as two different adverse events. The result of this incident
(e. g. hip fracture with a fall) should be recorded under notes;
⑤Abnormal findings during physical examination or laboratory examination. If the physical
examination and laboratory numerical treatment are normal before and after, there will be no such
adverse events occurring; if abnormal before treatment and normal after treatment, the causes
before and after normal should be analyzed according to the study needs, not an adverse event; but
if normal before treatment and abnormal after clinical treatment and the abnormal are adverse
event; abnormal before and after treatment, the doctor experience and the industry should have
clinical significance, or take further examination (except for review).
2. Obtaining the adverse event information:
①AEs were learned from the subject's self-description (e. g. visit visits, log cards, etc.).
After each visit of the treatment, the subject will be asked about the adverse event. The
question at the first visit could be: " Are there any health problems ever since you started taking
the study medication?"Can you ask any health problems since your last visit?”。
②Adverse events are informed from the visit examinations and laboratory results.
Although this approach has the advantages of sufficient judgment basis, intuition and data
traceability, whether the design of safety in the test protocol is complete is an important
influencing factor of the informed route. The study physician applied concise medical terms to
report all adverse events found.
③Tracing that adverse events originated from concomitant medication.
Concomitant drugs in large-scale clinical trials with long study periods are often complicated,
and the emergence of new synergistic drugs and replacement drugs often indicates the occurrence
of AEs. For example, during a follow-up visit, the patient told the doctor that "amoxicillin" was
used during a recent observation period. When recording the combined medication information, it
is important to ask the patient about the reason why he is taking amoxicillin, because the patient
may have had an adverse event of "upper respiratory tract infection".
3. Observation and recording of Adverse events:
When filling in the AE report form, specifically describe the occurrence of adverse events,
including the time, severity, duration, measures taken and outcome. All adverse events shall be
recorded in the designated CRF adverse event table. Try to fill in the medical diagnosis, do not list
the symptoms, if the disease name can not be confirmed, try to write a symptom form.

29
Collection of adverse events based on physical examination and laboratory indicators often
requires comparison with the baseline specified in the test protocol. If the data change is within the
baseline range specified in the protocol, it is not an adverse event; if the data change (rise or
decrease) is significant, it is an adverse event to be recorded; if the change is large, the start and
termination time, and the clinical trial.
All adverse events including any symptoms and laboratory abnormalities during the clinical
trial should be followed until the adverse event disappears or further follow-up as the investigator
is no longer necessary.
4. Possible adverse events and treatment:
4.1 Possible adverse events and management:
Apatinib mesylate: may appear hypertension, bone marrow suppression, diarrhea, vomiting,
proteinuria, abnormal liver function, appetite, rash, fatigue, such as adverse reactions, if patients
with adverse reactions, should be evaluated by the researchers and oncology clinicians, pause or
reduce medication, at the same time can be symptomatic treatment for patients.
Carilizumab: adverse reactions may be hepatitis, abnormal liver function, pneumonia,
reactive capillary hyperplasia, nephritis, hypothyroidism, thrombocytopenia and other reactions. If
the patient has adverse reactions, the drug should be suspended after evaluation by the investigator
and oncology clinician, and the patient can be given symptomatic treatment.
Chemotherapy possible adverse events and treatment: there may be bone marrow suppression,
nausea, alopecia, hair loss, neurotoxicity, neurotoxicity and urinary toxicity adverse reactions, if
patients with adverse reactions, should be evaluated by the researchers and oncology clinicians,
decided to suspend medication, reduce dosage or change chemotherapy regimen, etc., can give
patients symptomatic treatment at the same time.
4.2 Possible adverse events and management of acupuncture:
Acupuncture therapy may have adverse reactions, such as acupuncture, injection, needle
bending, folding, pain, hematoma, infection, etc. If the patient has adverse reactions, the treatment
should be stopped immediately, all needles should be pulled out, and the patient can be given
symptomatic treatment. After evaluation by the investigator and acupuncture clinicians, it is
decided whether the next acupuncture treatment is feasible.
If any adverse event occurs in the clinical trial, whether the trial drug is causal, the
responsible doctor should take the necessary measures to give treatment and rescue. For the
adverse events occurring during the trial, the type, degree, occurrence time, duration, treatment
measures and treatment process should be recorded in the CRF, and whether they are related to the
test drug used and the control drug. After the adverse event occurs, the investigator may decide

30
whether the subject will discontinue the clinical trial according to the condition. Cases
discontinued due to serious adverse events should be followed up and the outcome should be
recorded.
5. Assessment of adverse events:
5.1 Date of occurrence of the adverse event:
The date of the first adverse symptoms or signs or abnormal laboratory parameters (the date
of examination showing a clinically significant abnormal result) can be considered as the date of
occurrence. For asymptomatic / complication / concomitant disease, the date of diagnosis is the
date of occurrence (date of diagnostic examination).
5.2 Severity of adverse events:
When completing the adverse event form for the CRF, the investigator should use the NCRC
Common Adverse Event Evaluation criteria to describe the intensity of version 5.0).
All the causal analysis of the relationship between adverse events and trial drugs, "definitely
related", "very likely related", "probably related", "probably related", "definitely unrelated" five
levels, the first three drugs. Causal analysis consideration has the following five aspects:
①Whether there is a reasonable sequence relationship between the time of drug initiation
and the time of suspected adverse drug reactions (Adverse Drug Reaction, ADR) (drug
occurrence));
②Whether the suspected ADR meets the known ADR of the drug (literature);
③Whether the suspected ADR can be explained by concomitant medication, previous
medication, patient clinical conditions, or other therapies (other explanations);
④Whether the suspected ADR disappears or decreases after withdrawal or reduction
(withdrawal reaction);
⑤After reexposure to the same drug, whether the suspicious ADR appears again (reuse).
The investigator assessed the possible association between adverse events and trial drug and
concomitant medication, according to the table below.
Consider factors
Drug use
In
accordance
with the
literature
Other
explanations
Stop the
drug
disappear
Again with
reproduction
Certainly related
＋
＋
－
＋
－
I t ' s l i k e l y t o
b e r e l e v a n t
＋
＋
－
＋
？

31
Note: "+" indicates positive; "-" indicates no; "±" indicates difficult positive or negative; "?"Shall not know.
5.3 Return of Adverse Events:
Evaluation of adverse signs and symptoms and progression of abnormal changes seen in the
laboratory using the following categories:
①Recovery: recovery signs and symptoms disappear or the subject recovers; examination
values return to normal or return to baseline;
②Relief: the severity of improvement was reduced by a grade or more, or mild symptoms
and disappearance, or the indicators returned to the level before the trial treatment;
③Not recovered / no disappeared: no recovered symptoms, seen and various indicators did
not improve; according to the data of the last visit during the observation period, the severity
relative to the first occurred caused irreversible abnormalities;
④Recovery but with sequelae: some symptoms and seen recovery, some of the seen into
sequelae;
⑤Death: Death has a direct causal relationship to the adverse events discussed."A direct
causal relationship" means that the adverse event discussed is the cause of death or the adverse
event is indeed related to death;
⑥Unknown: not during the unknown administration of the test medication or at the end of
the trial according to the protocol.
5.4 Date of adverse event conclusion:
Record the conclusion date of "recovery", "improvement", "not recovery", "recovery but with
sequelae" or "death". When the date of the conclusion cannot be clearly recorded, the content date
of the conclusion or the date of the judgment may be taken as the conclusion date. In principle,
except for permanent, irreversible adverse events or any preexisting chronic complication, the
Probably about
＋
＋
±
±
？
It may not matter
＋
－
±
±
？
Certainly irrelevant
－
－
＋
－
－

32
events deemed "not recovered" should be visited until the subject recovers. The conclusion date
should be described in the notes. Given the permanent, irreversible adverse event or worsening of
any pre-existing chronic complication until the subject recovers, this fact and the date of judgment.
6. Serious Adverse Events:
6.1 Definition of serious adverse events:
Serious adverse events are those occurring during the study phase meeting one or more of the
following criteria:
①die;
②threat to life;
③Need hospitalization or prolonged hospitalization;
④Permanent or serious disability;
⑤Leading to congenital malformation defects.
Some medical events that have not caused death, life danger or hospitalization should be
considered serious adverse events after appropriate medical judgment to the subject or to avoid
medical or surgical treatment.
6.2 Record and reporting of serious adverse events:
In case of serious adverse event during the test, whether related to the test drug, emergency
treatment should be taken immediately. The investigator must report to the State Medical Products
Administration, the National Health Commission, Jiangsu Henrui Pharmaceutical Co., Ltd.,
Suzhou Shengdiya Biological Pharmaceutical Co., Ltd., and the provincial drug administration
authorities within 24 hours of knowing the serious adverse events. And at the same time (24 hours)
report to the branch of research unit, and by the branch of the research unit immediately report to
the responsible unit (China academy of Chinese medicine sciences cross gate hospital), then by
subject responsible unit reported to the unit ethics committee, and within 30 days in other research
center. See the contact number in the table below.
unit
contact
s
contact number
Research Group of Guang'anmen Hospital,
China Academy of Chinese Medical
Sciences
Wang
Yan
18435227044
Ethics Committee of Guang'anmen Hospital,
Chinese Academy of Chinese Medical
Sciences
Qiao
Jie
010-88001552
7. Abnormal clinical test results and other abnormal indicators as adverse events

33
or serious adverse events:
If some abnormal laboratory findings (e. g., clinical biochemistry, hematology, urinalysis),
or other abnormal indicators (e. g., electrocardiogram, vital signs, etc.) are clinically significant
and meet the definition of some or some serious adverse events, they must be recorded as adverse
events or serious adverse events. Clinically significant abnormal laboratory findings and other
abnormalities found after medication, or present at baseline assessment and aggravated after study
entry, should be considered as an adverse event or serious adverse event.
However, clinically significant abnormal laboratory findings or other abnormalities
regarding the studied disease were found unless the investigator determines that the subject is
more severe than expected and is not included in adverse events or serious adverse events.
Abnormal laboratory findings or other abnormalities present at the beginning of the study but not
aggravated were also not included in adverse events and serious adverse events.
Death due to disease progression was not reported as a serious adverse event.
IX. Research quality control and quality assurance
1. Establish a project research office:
The project research office is set up by the project leading unit, which is responsible for the
implementation of the project funds and the coordination between the project participating units.
The research office is composed of the person in charge of the undertaking unit and the core
research members, who are responsible for the design of the research objectives, contents and
technical routes of the subject task, the training of researchers, and the coordination and
communication with the cooperative unit. Hold regular project meetings to coordinate the project
progress and solve the practical problems in the project implementation process.
2. Project objectives and task management:
With the project undertaking unit as the core, the oncology departments of major hospitals
across the country were evaluated, and the units with sufficient disease sources and certain clinical
research experience were selected as the cooperative units, and the national clinical research base
of TCM was mainly selected. Implement procedural and network management for the participating
units. Establish a special task management mechanism to supervise the completion of tasks in the
stage. Establish a file management system for the original research data. Implement the
performance evaluation system of mainly management by objectives and combining process
management with management by objectives. Clear responsibilities and rights, clear division of
labor, and regular feedback on the progress of the project.
3. Use and management of project funds:

34
Establish the project funds supervision group, set up the secondary financial review system,
composed of the financial personnel of the project undertaking unit and the participating unit;
supervise and review the use way and progress of the project funds irregularly, and urge the
participating units to calculate the funds for special purposes.
4. Project quality control and management:
Introduction and promotion of "ISO" quality management system, personnel at all levels
accept necessary management consciousness and quality awareness training, establish quality
control system in the project implementation process, formulate relevant quality control measures
and evaluation scheme, select CRO this research quality control and supervision, such as clinical
data collection specification, data verification quality control measures, and task completion of
task verification and quality control, form the quality verification document report and archive
management.
5. Blood sample management:
Keep blood samples for coding, encryption, after the study did not use blood samples for at
least 8 years, anonymous stored in China academy of Chinese medicine sciences cross hospital
biological library, and send personnel to watch, during and without the consent of the study, no
anyone to borrow, transfer samples, if using the blood samples, submit the relevant application to
explain the purpose, the use of blood samples, to eliminate the use of blood samples collected in
illegal and harm the interests of patients.
X. Statistical treatment
Statistical software: Using SAS 9.2 statistical software, the full analysis set (FAS) analysis,
and safety data set (SS) analysis should be performed for adverse reactions. Statistical method: All
statistical tests are two-sided, and P 0.05 will be considered statistically significant. The proportion
of shedding cases should not be greater than 20%. Metering data description mean, standard
deviation, median, minimum value, maximum value, etc., count data description frequency,
percentage, etc. Measurement data were analyzed by t-test and rank sum test, chi-square test and
Ridit analysis, and survival data by Kaplan-Meier method, Wilcoxon rank sum test or log-rank test.
Multivariate survival analysis was performed using a Cox proportional hazards regression model.
Xi. Ethics of clinical research
Clinical research will follow the provisions of the Declaration of Helsinki. The clinical study
was performed after ethics committee approval of the trial protocol prior to study initiation. Before
each subject is included in the study, the investigator has the responsibility to present the subject or
his agent about the purpose and procedures and possible risks to the study and sign a written

35
informed consent to inform the subject that they have the right to withdraw from the study at any
time, and the informed consent shall be retained as a clinical study document for future reference.
During the study, the personal privacy and data confidentiality of the subjects will be protected,
and the subject's personal information will not be disclosed. The positive or negative results of this
study will be published, and the personal privacy of the patients will not be disclosed in the
published articles.
Xii. Research progress
From February 2024 to March 2024, a clinical research database will be established,
and researcher training will be conducted through ethical approval, and the project task
assignment and launch meeting will be held.
From April 2024 to September 2024,50% of cases were collected, the enrolled cases
were followed up, clinical observation form, follow-up form, data entry and verification, and
regular monitoring. Data were collected for an interim summary. Hold the subject treatment
control and supervision meeting to improve the quality and efficiency of enrollment.
From October 2024 to March 2025, the enrolled cases were follow-up, fill in the clinical
observation form, follow-up form, data entry and check, and regular monitoring. Hold the
project conclusion and evaluation meeting to prepare for the conclusion. Completed CRF
tables and follow-up tables were recovered.
From April 2025 to December 2025, complete all data follow-up, data entry, cleaning,
and submit to clean database of statistical experts for statistical analysis; statistical analysis
data, outcome measurement, determine the efficacy after treatment, adverse reactions, and
summarize; summarize data, and prepare for project acceptance.

36
Attachment 1 Efficacy Evaluation of Solid Tumors Version 1.1 (RECIST1.1)
The treatment response was evaluated according to the efficacy evaluation criteria of solid
tumors, version 1.1 (RECIST1.1), and the target lesions were evaluated as follows:
CR complete
remission
PR partial
remission
SD disease is
stable
PD PD
Quantitation of
target lesions
estimate
All target lesions
were lost and lasted no
less than 4 weeks; all
pathological lymph
nodes were <10mm
and lasted no less than
4 weeks.
The sum of
diameters of all
target lesions
showed a baseline
reduction of at
least 30% and
duration not less
than 4 weeks.
PR was not
achieved, nor PD,
and lasted no less
than 4 weeks.
The sum of the
diameter of all
target lesions
increases by at
least 20% (the
smallest sum of the
comparison study,
and the absolute
value of the sum of
the diameters must
increase by at least
5mm for no less
than 4 weeks.
Qualitative
assessment of
non-target
lesions
Disdisappearance
of non-target
lesions.
Non-CR / non-PD;
One or more non-target foci
persisted.
New lesions
not have
not have
The appearance
of one or more
new lesions
Tumor
biomarkers
epistrophy
Tumor marker levels were not in the normal range
Other
instructions
Record of lymph nodes as target lesions: even if the short diameter shrinks to
<10mm, it needs to be recorded and counted as the sum of the diameters. Therefore
lymph nodes need to be recorded separately for facilitate assessment of CR.
The target lesion is too small to measure: if the radiography suggests that the target
lesion disappear, it can be recorded as 0mm; if the target lesion is indeed present but only
too small to measure, the default record is 5mm.
Divided or combined lesions during treatment: record the sum of the longest
diameter of all divided lesions, and record the longest diameter of the combined lesions.
If the non-target lesion is assessed as definite progression, there must be a global

37
level of severe change, even if the target lesion is assessed as SD or PR, the overall tumor
burden needs to be increased enough to stop treatment before discontinuing treatment.
Attachment 2 EORTC QLQ-C 30 scale (Chinese version)
EORTC L Scale QLQ-C 30 (V3.0) Chinese version of the questionnaire
target date:
Note: We want to know something about you and your health, please answer all the
following questions by yourself. The answer here is not "right" or "wrong", only required to
hit the number that best reflects your situation. The information you provide will be kept
strictly confidential.
not have
some
match
extraordinary
1. Do you have difficulty in
doing some strenuous activities,
such as carrying heavy shopping
bags or suitcases?
2. Is it very difficult for you to
walk over long distances?
3. Is it difficult for you to walk in
a short distance outdoors?
4. Do you need to stay in bed or
in a chair during the day?
5. Do you need help when eating,
dressing, bathing or going to the
bathroom?
In the past one week:
6. Are you restricted in your
work and daily activities?
7. Are you restricted in pursuing
your
hobbies
or
leisure
activities?
8. Do you have any shortness of
breath?
9. Do you have any pain?
Do you need a break?
11.
Have
you
had
trouble
sleeping?

38
12. Do you feel weak?
13. Do you lose your appetite (do
you have no appetite)?
14. Do you feel sick?
15. Did you ever vomit?
16. Do you have constipation?
17. Do you have diarrhea?
18. Are you feeling tired?
19. Does the pain affect your
daily activities?
20.
Do
you
have
difficulty
concentrating on doing things,
such as reading a newspaper or
watching TV?
21. Are you feeling nervous?
22. Are you worried?
23. Do you feel irritable?
24.
Do
you
feel
depressed
(depressed)?
Do
you
have
trouble
remembering it?
26. Does your physical condition
or treatment affect your family
life?
27. Does your physical condition
or treatment affect your social
activities?
28. Does your physical condition
or
treatment
put
you
into
financial difficulties?
For the following questions, select a number between 1 and 7.
29. How do you evaluate your overall health in the past week?
1
2
3
4
5
6
7
Very poor, very good
30. How do you evaluate your total quality of life in the past week?
1
2
3
4
5
6
7

39
Very poor, very good
Attachment 3 EORTC QLQ CX24 Questionnaire (Chinese version)
EORTC QLQ-C X24 (V3.0) Chinese version questionnaire
target date:
Note: We want to know something about you and your health, please answer all the
following questions by yourself. The answer here is not "right" or "wrong", only required to
hit the number that best reflects your situation. The information you provide will be kept
strictly confidential.
not have
some
match
extraordinary
1. Have you ever smoked any
tendons in your stomach?
2.
Do you have a problem with
your visceral activity?
3. Is there any blood in your
stool?
4. Do you have any symptoms of
frequent urination?
5. Do you feel pain or burning
when you urinate?
6.
Do
you
have
any
urine
leakage?
7. Is there a problem with you?
8.
Do
your
legs
have
any
oedema?
9. Do you feel any pain in your
lower back?
10. Do you feel numbness or
pain in your hands or feet?
11. Do you have pain in your
vagina or vagina?
12. Will your vagina remove a
foreign body?
13. Do you have bleeding from
your vagina?

40
14. Do you have a red flush or a
sweat in your vagina?
15.
Do
you
feel
unattractive
because
of
your
illness
or
treatment?
16. Do you feel the lack of young
women because of your illness or
treatment?
17. Are you not satisfied with
your body?
In the last 4 weeks:
18. Have you ever been worried
that having sex can be very
painful?
19. Are you sexually active?
If you have been sexually active in the past four weeks, please answer the following
questions:
20. Does your penis feel dry
during sexual activity?
21.
Does
your
vagina
feel
shorter?
22. Does your vagina feel very
tight?
23. Do you feel pain during sex
or other sexual activities?
24.
Do
you
enjoy
sexual
activities?
Attachment 4 Simple Fatigue Scale Chinese Version (BFI-C)
Simple Fatigue Scale BFI-C, Chinese version of the questionnaire
target date:
Note: In order to give us a better service for you, you are invited to fill in this scale. In our life, most of us
will have time to feel very tired or tired, the 0 in the table represents no fatigue, the larger the number, the
heavier the degree of fatigue, 10 represents the most tired you can imagine. The information you provide
will be kept strictly confidential.
0
1
2
3
4
5
6
7
8
9
10

41
1. Please choose a numerical value that can describe
how much you are getting tired right now.
2. Please choose a value that describes how tired you
were in the past 24 hours.
3. Please choose a value that describes your worst
fatigue in the past 24 hours.
4. Please choose the way of fatigue in the past 24 hours
A. Effects on the daily activities
B . Influence on emotions
C . Effect on the ability to walk
D. Impact on daily life (including daily housework and
normal work)
E. Influence on the relationships between others
F. Effects on everyday interests
Attachment 5 Insomnia severity Quantity Table (ISI)
Insomnia severity Quantity Table (ISI)
target date:
Note: In order to give us a better service for you, you are invited to fill in this scale. The scale is a simple
tool for screening for insomnia and includes seven items to assess the nature and symptoms of sleep
disturbances in subjects. For sed in people aged 17 – 84 years. For each of the following questions, choose
the most appropriate answer.
not
have
a
little
some
more
a
great
many
1. Describe the severity of your most recent (e. g., the last 2 weeks) insomnia problem.
A.difficulty falling asleep
B. Maintain sleep difficulties
C.early awakening
2. Your satisfaction with your current sleep patterns
3. To what extent do you think your sleep problems interfere with
your daytime functions (e. g., daytime fatigue, ability to handle
work and daily tasks, attention, memory, mood, etc.):
4.4. How much does your insomnia affect or damage your quality
of life compared with others:
5. How much concern / frustration do you have about your current

42
sleep problems:
Attachment 6 Brief Pain Assessment Scale (BPI-C)
Concise Pain Assessment Scale (BPI-C)
target date:
Note: In order to give us a better service for you, you are invited to fill in this scale. The 0 in this table
represents no pain, and the larger the number is, the heavier the pain is, and the 10 is the most pain you can
imagine. The information you provide will be kept strictly confidential. For each of the following questions,
choose the most appropriate answer.
0
1
2
3
4
5
6
7
8
9
10
1. Most people have experienced pain throughout their lives (such as mild headaches, post-sprain pain,
toothache). Do you now feel other types of pain?
whether or not
2. Please select the part of your pain in the figure below, and express the part of the most severe pain in X:
0
1
2
3
4
5
6
7
8
9
10
3. Please select a number to indicate your most severe
pain in the past 24 hours.
4. Please select a number to indicate the slightest degree
of your pain in the past 24 hours.
5. Please select a number to indicate the average level of
your pain over the past 24 hours.
6. Please select a number to indicate your current pain
level.
7. How much has your pain relieved in the past 24 hours due to medication or treatment? Please select a
percentage below to indicate the degree of pain relief.
0
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%

43
8. Please select a number below to indicate the impact
of pain on you in the past 24 hours.
0
1
2
3
4
5
6
7
8
9
10
A. Impact on daily life.
B . The effect on the mood.
C . Effect on the ability to walk.
D. Impact on daily life (including outside of work and
housework).
E. Influence on the relationships between others.
F. Effects on sleep.
G. Impact on an interest in life.
Attachment 7 The Hamilton Depression Scale (HAMD)
The Hamilton Depression Scale (HAM D)
target date:
Note: In order to give us a better service for you, you are invited to fill in this scale. For each of the
following questions, choose the most appropriate answer.(1. asymptomatic; 2. light; 3. medium; 4.
heavy; 5. Very heavy.)
orde
r
numb
er
project
specific description
gra
de
Patient
score
1
Depress
ion
do not appear
0
The complaint is only when asked
1
Express it spontaneously in speech;
2
This emotion can be expressed from expression,
posture, voice, or crying without words
3
The
patient's
spontaneous
and
non-spontaneous
language
(expressions,
movements)
are
almost
completely manifested by this emotion
4
2
feeling
of
guilty
do not appear
0
Blame yourself and feel that you have affected
others
1
Think you have committed a crime, or think about
past mistakes and mistakes
2
That the current disease is a punishment for their
own mistakes, or a criminal delusion
3
Criminal delusion is accompanied by accusations or
threatening hallucinations.
4
3
idiocto
nia
do not appear
0
I feel alive
1
I hope I have died, or I often think of something
2

44
related to death
Negative perception (suicidal thoughts)
3
Serious suicidal behavior
4
4
difficu
lty
falling
asleep
do not appear
0
1
2
The
chief
complaint
sometimes
has
difficulty
falling asleep, that is, half an hour after going
to bed
The chief complaint had difficulty falling asleep
every night
5
Sleep is
not deep
do not appear
0
1
2
Sleep shallow many evil dreams
Wake up in the middle of the night (before 12 pm)
(excluding bathroom use)
6
early
awakeni
ng
do not appear
0
1
2
Wake up early, an hour earlier than usual, but you
can fall asleep again
I can't fall asleep again after waking up early
7
Work and
interes
t
do not appear
0
1
2
3
4
Ask questions and tell them
Spontaneously directly or indirectly express the
loss of interest in activities, work or study, such
as feeling listless, hesitant, unable to insist or
need to force yourself to work or activities
Hospital labor or entertainment for less than 3
hours
Stop working due to the current illness, inpatients
do not participate in any activities or without the
help of others
8
slow
do not appear
0
Mild delay was noted on the psychiatric examination
1
Significant mental retardation was found on the
mental examination
2
Mental examination is difficult to conduct
3
Unable to answer questions (stiff)
4
9
intense
do not appear
0
Check the examination
1
Obviously mental distracted or small movements
2
Can
not
sit
still,
ever
standing
during
the
examination
3
Rub your hands, bite your fingers, pull your hair,
and bite your lips
4
10
Mental
anxiety
do not appear
0
When asked, he complained
1
Spontaneous expression
2
The expression and speech reveal obvious anxiety
3
Apparently frightened
4
11
somatic
anxiety
do not appear
0
1
mild

45
*
2
3
4
Moderate, with positive above symptoms
Severe, the above symptoms are serious, affect the
life or need to be treated
Seriously affect life and activities
12
gastroi
ntestin
al
symptom
do not appear
0
1
2
Loss of appetite, but eat by yourself without
encouragement
Eating requires urging or requests or laxatives or
digestive aids
13
constit
utional
symptom
do not appear
0
heaviness in the limbs, back, or neck, backache,
headache, muscle pain, general fatigue or fatigue
1
The above symptoms are obvious
2
14
Sexual
symptom
s
(decrea
sed
libido,
menstru
al
disorde
r, etc.)
do not appear
0
mild
1
severe
2
Can not be sure, or this item is not suitable for
the candidate.(Not included in the total score)
15
hypo
do not appear
0
Too much attention to the body
1
Think repeatedly consider health issues
2
Suspicion
3
A suspected disease delusion with hallucinations
4
16
lose
weight
do not appear
0
Weight loss of more than 1 kg within a week
1
Weight loss of more than 2 kg within a week
2
17
insight
Know oneself sick, the performance is melancholy
0
Know
you
are
sick,
but
due
to
poor
food,
environmental problems, busy work, virus infection
or need to rest
1
Completely deny illness
2
* Physiological symptoms of anxiety, including dry mouth, abdominal bloating, diarrhea,
beating, abdominal cramps, palpitations, headache, excessive ventilation and sighs, and
frequent urination and sweating.
Attachment 8: The Hamilton Anxiety Scale (HAMA)
Hamilton Anxiety Scale (HAMA)
target date:
Note: In order to give us a better service for you, you are invited to fill in this scale. For each of the
following questions, choose the most appropriate answer.(1. asymptomatic; 2. light; 3. medium; 4. heavy; 5.

46
Very heavy.)
1
2
3
4
5
1. Anxiety: worry, worry, feel that the worst thing is going to happen, easy to provoke
2. Tension: nervous, easy to fatigue, can not relax, emotional reaction, easy to cry,
shake, feel uneasy
3. Fear: fear of the darkness, strangers, solitude, animals, rides or travel and crowded
occasions
4. Insomnia: difficult to fall asleep, easy to wake up, dream, nightmare, night shock,
feel tired after waking up
5. Cognitive function: or memory and attention disorders. Unable to focus on attention,
poor memory
6. Depression mood: loss of interest, lack of pleasure to the previous hobbies,
melancholy, early wake up, heavy day and light night
7. Muscle system symptoms: muscle soreness, twitching, inflexible, teeth beating,
voice shaking
8. Sensory system symptoms: blurred vision, chills, fever, weakness, and tingling
9. Cardiovascular system symptoms: tachycardia, palpitations, chest pain, vascular
beating, fainting, cardiac leakage
10. Respiratory symptoms: chest tightness, suffocation, sigh, and dyspnea
11. Gastrointestinal symptoms: dysphagia, indigestion, intestinal movement, diarrhea,
low weight sensation, constipation
12. Genitourinary symptoms: urinary frequency, urgency,
menopause, apathy,
impotence
13. Plant nervous system symptoms: dry mouth, flushing, pale, easy to sweat, "goose
bumps", etc
14. Meeting behavior performance: (1) general performance: tension, facial tension,
restless feet, hands shaking, frown, high muscle tension, sigh breathing, pale: (2)
physiological performance: swallowing, well, quiet heart rate, breathing fast (20 times /
points), tendon reflex, tremor, pupil amplification, eyelid beating easy to sweat,
eyeball.