Clinical Study on the Prevention and Treatment of Postoperative Metastasis in Stage IIA-IIIA Lung Cancer With Negative Expression of Driver Genes by Fuzheng Quxie Recipe
Phase: PHASE2
Conditions: Lung Cancer
Sponsor: Jianhui Tian

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PROTOCOL
Title of research programme: Clinical study on the prevention
and treatment of postoperative metastasis in stage IIA-IIIA lung cancer
with negative expression of driver genes by Fuzheng Quxie Recipe
Research organization: Shanghai Municipal Hospital of
Traditional Chinese Medicine
Principal Investigator: Jianhui Tian
Version No.: 1.0, 2022.12.21

2
Efficacy of Fuzheng Quxie Formula for inhibitting
metastasis after surgery in stage IIA-IIIA lung cancer
with
negative
driver
genes:
study
protocol
for
a
multi-centre,
double-blind,
randomized
controlled trial
Abstract:
Background: Metastasis is the main reason for poor prognosis and high mortality of lung cancer.
Surgery and postoperative adjuvant chemotherapy are the first choice for patients with
driver-negative stage I to IIIA lung cancer. However, the incidence of postoperative recurrence
and metastasis did not significantly decrease. In China, traditional Chinese medicine (TCM) is
commonly used to treat cancer. TCM has the potential to be used as an adjuvant therapy for lung
cancer to reduce treatment related toxicity and improve clinical efficacy. In view of the positive
results of the basic study of Fuzheng Quxie Formula against lung cancer metastasis, we plan to
evaluate the efficacy of Fuzheng Quxie Formula against postoperative metastasis of stage IIA-IIIA
lung cancer that is negative for driver gene expression.
Methods: A multi-centre, double-blind, randomised, placebo-controlled parallel group controlled
trial will be conducted. Eligible patients will be randomised into a treatment group (daily Fuzheng
Quxie Formula granules + regular chemotherapy) and a control group (daily Chinese medicine
placebo granules + regular chemotherapy) in a ratio of 1:1. It is recommended that the
participants' chemotherapy be used strictly in accordance with the dosage, duration and usage as
recommended in the respective instructions and National Comprehensive Cancer Network (NCCN)
guidelines. Fuzheng Quxie Formula was administered orally, twice a day, in the morning and
evening, for 6 months. Follow-up after the end of medication, follow-up period of 3 years. After
the end of the programme, follow-up was continued until 5 years or until the subject died (or
progressed). The primary outcome was disease-free survival (DFS), and the secondary outcomes
were overall survival (OS), minimal residual disease (MRD), circulating tumour cells detection,
TCM symptom score, assessment of quality of life (QoL), immune indices, tumour markers,
peripheral blood systemic immune- inflammation index (SII), prognostic nutritional index (PIN)
and prognostic nutritional index (PNI)..
Discussion: This will be the first trial to evaluate the efficacy and safety of Fuzheng Quxie
Formula in inhibitting metastasis after surgery in stage IIA-IIIA lung cancer with negative driver
genes. The results of this randomised controlled trial will fill a gap in this study by showing
whether Fuzheng Quxie Formula combined with postoperative chemotherapy improves the
prognosis for patients with lung cancer.
Ethics and Dissemination: The Ethics Committee of Shanghai Municipal Hospital of Traditional
Chinese Medicine, Shanghai University of Traditional Chinese Medicine approved the study
protocol (approval no.: 2023SHL-KY-19-01, 2023/02/23). The study will also be supervised and

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managed by the Ethics Committee.
Keywords ：Fuzheng Quxie Formula, Lung cancer in stage IIA-IIIA, Negative driver genes,
Metastasis after surgery
Background
Lung cancer is one of the most common malignant tumours of respiratory system, with the
mortality rate perennially ranking first among all kinds of malignant tumours, which greatly
threatens the safety of human life
[1]. In developed countries (such as the United States), lung
cancer is still the malignant tumour with the highest number of deaths
[2]. In China, the latest data
shows that there are about 787,000 new cases of lung cancer, with an incidence rate of
57.26/100,000, ranking first in the national morbidity and cause of death by gender, causing
economic losses of up to 221.4 billion, and this economic and social pressure will continue to
increase
[3]. In recent years, due to the rapid advances in therapeutic modalities (e.g., molecular
targeted therapy, immunotherapy, etc.), the survival time of lung cancer has been extended, but the
5-year survival rate of lung cancer still persists at a low level
[4]. Distal metastasis is the main cause
of death in 90% of patients and there is a lack of effective treatment options
[5]. Surgery is currently
the first choice for patients with stage I to IIIA lung cancer, but metastasis after radical lung cancer
surgery is a bottleneck limiting its overall efficacy.
Currently, domestic and international guidelines related to lung cancer diagnosis and treatment
recommend that patients with stage IB (high-risk type) need to undergo postoperative
conventional chemotherapy, and that patients with stage IIA and IIIA must undergo conventional
chemotherapy after surgery
[6]. However, only about 5% of lung cancer patients have long-term
survival benefit
[7]. Studies have confirmed that the recurrence rate of patients with stage I lung
cancer after adjuvant chemotherapy is around 17.8%, and about 45.5% of patients with stage II-III
lung cancer may have recurrent metastasis. Among them, patients with stage I recurrence include :
63% are local recurrence, 40.5% are distant recurrence and 72% are new primary lung cancer
[8].
Wang Zezhou et al followed up the survival of 7753 patients operated for lung cancer and
confirmed that the 5-year survival rates of patients with stage IB, IIA, IIB, IIIA and IIIB lung
cancer were 78.5%, 78.2%, 62.9%, 49.3% and 33.0%, respectively. Therefore, standard
chemotherapy administered after surgery presents an overall poor role in the prevention of
recurrent metastasis in patients after radical lung cancer surgery. There is a need to develop new
diagnostic and therapeutic protocols.
With the development of molecular targeted therapy and immunotherapy, patients with
intermediate and advanced lung cancer who are positive for driver genes or have high PD-L1
expression can further benefit from targeted therapy or immunotherapy. Adenocarcinoma and
squamous carcinoma are common pathologies in lung cancer. A study that included 371 Chinese
lung cancer cases showed that the mutation types in lung adenocarcinoma were EGFR (60%),
TP53 (57%), KRAS (13%), PIK3CA (7%), and ALK (7%), whereas those in squamous lung
carcinoma included TP53 (87%), PIK3CA (43%), CDKN2A (20%), KMT2D (20%), and EGFR
(17%) mutations
[9]. For ALK/EGFR/ KRAS/ROS1/MET mutations, there are Several targeted
therapeutic agents have been approved, marketed internationally and in the health insurance. Wu
Yilong et al. conducted a clinical study confirming the benefit of ositinib in patients after radical
surgery for stage IB~IIIA lung cancer with driver gene EGFR positivity
[9,
10]. Meanwhile,
immunotherapy sequential treatment after chemotherapy for Radical resection of lung cancer

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patients with stage IB-IIIA lung cancer with high PD-1/L1 expression (≥1%) may also provide a
survival benefit and reduce the rate of metastasis. In addition, a study included 328 patients after
resection of stage IA-IIB non-small cell lung cancer (NSCLC) to examine their immune
checkpoint expression
[11]. The study showed that 62.0% (160/258) of the lung adenocarcinoma
group had PD-L1 <1%, and only 38.0% (98/258) had PD-L1
≥1%, suggesting that the
expression of immune checkpoints is low in lung adenocarcinoma patients
[12]. Therefore, for
patients with positive driver gene and high immune checkpoint expression after radical lung
cancer surgery, standardised diagnostic and treatment protocols that can benefit patients clinically
are already available. However, for patients with negative genes expression and low PD-1/L1
expression (≤1%) after radical lung adenocarcinoma surgery, who have poor chemotherapeutic
efficacy in the clinic and lack indications for molecularly-targeted or immunotherapeutic
treatments, the development of effective, scalable and specific
therapeutic protocols is urgently
needed.
In summary, the existing multidisciplinary treatments available for lung cancer metastasis, such
as chemotherapy, targeted therapy, and immunotherapy, have been developed based on alterations
to the genetic structure and function of the tumour cells themselves in the primary foci. However,
as tumour metastasis is often trans-organic and involves imbalances in the function of multiple
systems, the overall efficiency of current strategies for the prevention and treatment of lung cancer
metastasis is poor [15]. TCM, which stresses the holistic concept and dialectical treatment, and
committing to a people-centered approach, has unique advantages in preventing and treating
tumour metastasis
[13-15]. A large number of basic and clinical studies have confirmed that TCM can
significantly inhibit the metastasis of lung cancer, significantly prolong the survival period of
patients, and improve their quality of life
[16,
17]. Therefore, it is an important breakthrough to
overcome the bottleneck of tumour metastasis in clinic under the holistic view and syndrome
differentiation of TCM to understand the pathogenesis of lung cancer metastasis from a systemic
perspective, and then anchoring the key therapeutic targets to develop effective prevention and
treatment strategies
[18-20].
Professor Jianhui Tian 's group focuses on lung cancer metastasis research. Under the guidance
of a master of Chinese medicine Liu Jiaxiang's academic idea of "treating cancer by reforcing
healthy qi", and incorporating Lao Zi’s "Existence and non-existence give birth the one to the
other", modern oncology and immunology, the team suggests the core pathogenesis of cancer
metastasis in the subclinical stage of cancer --"Deficiency of Vital Qi and Hidden Toxin" theory.
According to the theory, immune disorders caused by immune senescence and immune escape are
"Deficiency of Vital Qi", while circulating tumour cells, quiescent cancer cells and tumour stem
cells are the modern biological connotations of "toxicity". The residual cancer cells after radical
treatment of lung cancer are the "Hidden Toxin". After radical lung cancer surgery, residual cancer
cells (hidden toxin) are latent in the body and in dormant or quiescent stage. When there is a
deficiency of vital qi, the efficiency of immune surveillance and immune clearance decreases, and
the cancer cells go from the quiescent phase to the proliferative phase, leading to the occurrence of
tumour metastasis. The team further found that myeloid-derived suppressor cells, regulatory T
cells, and circulating tumour cells ("hidden toxin") are important factors in the subclinical state of
lung cancer metastasis in clinical studies, and analysed their expression patterns
[21]. The team took
the lead in establishing the world's first human lung adenocarcinoma circulating tumour cell line
(CTC-TJH-01), as well as a platform for metastasis-specific studies of lung cancer
[22].

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Under the theory of "Deficiency of Vital Qi and Hidden Toxin", the group established the
treatment method of "supporting vital qi" and "dispelling hidden toxin", and created a Chinese
medicine formula for inhibitting postoperative metastasis of early- and middle-stage non-small
cell lung cancer. In this formula, Sheng Huang Qi, Fu Ling, Bai Zhu tonify spleen and stomach to
"strengthen earth to generate metal"; Bei Sha Shen, Tian Dong, Mai Dong nourishes yin and
moistens the lungs; Hai Zao, Xia Ku Cao, Kun Bu, which soften and resolve hard mass, and Bai
Hua She She Cao, Shi Jian Chaun, Shi Shang Bai, which clear heat, detoxifying to dispers nodules.
Through in-depth clinical and basic research, the team has obtained the scientific basis for
Fuzheng Quxie Formula to inhibit metastasis: ①Fuzheng Quxie Formula has the clinical effect of
preventing recurrence and metastasis: the team, in cooperation with Shanghai Lung Hospital,
carried out a prospective clinical study, which confirms that the DFS rates of early and middle
stage NSCLC patients after intervention with Fuzheng Quxie Formula were 98.8% and 96.5% in 1
and 2 years, respectively, which were higher than 95.3% of the patients in the pure follow up
group. (ii) The mechanism of inhibiting metastasis by Fuzheng Quxie Formula may be to regulate
the immune function to promote apoptosis of circulating tumour cells: intra-group comparison of
immune indexes before and after the study suggests that the peripheral blood NK, CD3+ and IgM
content of the treatment group after intervention of Fuzheng Quxie Formula increased
significantly (P＜0.01), and at the same time, it can reduce the number of circulating tumour cells
in the blood ( P<0.01), suggesting that Fuzheng Quxie Formula has the tendency to regulate
patients' immunity and inhibit circulating tumour cells to control tumour progression; (iii)
Mechanism study found that Fuzheng Quxie Formula can improve immune function and restore
the state of body immune balance: Fuzheng Quxie Formula can up-regulate the expression of
positive immune cells, such as NK cells and T-cell subpopulations, which have an inhibitory and
killing effect on tumour cells, and down-regulate positive immune cell expressions, which
promote tumour cell proliferation, metastasis, immune escape, and so forth, Down-regulate the
expression of negative immune cells such as myeloid-derived suppressor cells and regulatory T
cells, which promote the proliferation, metastasis and immune escape of tumour cells; inhibit and
remove circulating tumour cells in the peripheral circulation; and influence and regulate the
metabolic reprogramming of tumour cells in terms of sugar, fat and amino acids. Meanwhile, the
theory of "Deficiency of Vital Qi and Hidden Toxin" guided the construction of clinical efficacy
prediction and metastasis risk assessment model for TCM treatment of lung cancer (Journal of
Traditional Chinese Medicine, 2022), which found that maintaining peripheral immune
homeostasis is an important basis for TCM to inhibit lung cancer metastasis, and optimised and
enriched the prognostic assessment system of lung cancer. Fuzheng Quxie Formula has been
applied as an in-hospital preparation for many years, and has successfully entered the process of
joint development of new drugs with enterprises.
Therefore, in response to the urgent clinical needs of postoperative patients with IIA-IIIA
non-small cell lung cancer who are negative for driver gene expression, we attempted to
objectively evaluate the efficacy of Fuzheng Quxie Formula in inhibitting metastasis of IIA-IIIA
non-small cell lung cancer who are negative for driver gene expression, and to actively explore the
establishment of a combined prevention and treatment programme of TCM and Western medicine
by designing a clinical study protocol in line with the international norms.
1 Methods
1.1 Trial Design

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A prospective clinical study of combined Chinese and Western medicine for the prevention and
treatment of metastasis after radical lung adenocarcinoma in postoperative stage IIA-IIIA
non-small cell lung adenocarcinoma patients with negative driver gene expression was conducted
in a randomised, double-blind, placebo-parallel controlled, multicentre clinical trial design.
Participants from 7 study centres: Shanghai Municipal Hospital of Traditional Chinese Medicine,
Shanghai Pulmonary Hospital, Shanghai Chest Hospital, Shanghai General Hospital, and
Shanghai TCM-Integrated Hospital Affiliated to Shanghai University of Traditional Chinese
Medicine. Firstly, the clinical study will obtain written informed consent from the participants.
Eligible participants will be randomly assigned in a 1:1 ratio to the treatment group (daily
Fuzheng Quxie Formula granules + regular chemotherapy) and the control group (daily Chinese
medicine placebo granules + regular chemotherapy). The treatment group was Fuzheng Quxie
Formula granules, and Components of Fuzheng Quxie Formula is shown in Table 1. The drug was
supplied by Jiangyin Tianjiang Pharmaceutical Co. 5% of the drug content of the treatment group
was made into a control placebo drug, provided by Jiangyin Tianjiang Pharmaceutical Co., Ltd,
which had the same odour, colour and appearance as the test drug, but had no significant drug
treatment effect.
Table 1. Components of Fuzheng Quxie Formula.
Chinese name
Latin name
Parts of the substances
Amount (g)
Sheng Huang Qi
Udis Astragalus
Root
15
Jiao Bai Zhu
Frixum Atractylodes
Root tuber
15
Bai Fu Ling
Alba Poria
Root tuber
15
Bei Sha Shen
Adenophora Septentrionalis
Root
15
Zhe Mai Dong
Ophiopogon japonicus
Root tuber
15
Dang Shen
Codonopsis pilosula
Root
15
Shu Yang Quan
Shuyang Spring
Whole herb
15
Xia Ku Cao
Prunella vulgaris
Flowering fruit spike
15
Sheng Mu Li
Udis Ostreis
Shell
15
Shi Jian Chuan
Ishimi Chuan
Above-ground parts
15
Shi Shang Bai
Cupressus Lapis
Whole herb
15
Hai Zao
Alga
Dried algae
15

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1.2 Study Population and Eligibility Criteria
The sources of cases for this study were inpatients and outpatients admitted from 1 July 2022 to
30 June 2025 with negative expression of driver genes in postoperative stage IIA-IIIA lung
adenocarcinomas with qi and yin deficiency. Inclusion for observation should be no later than 6
weeks postoperatively. Screening will be based on inclusion and exclusion criteria (Table 1).
Table 1. Study Inclusion and Exclusion Criteria.
Inclusion criteria
Exclusion criteria
①Patients with clinical staging of stage IIA-IIIA lung
adenocarcinoma after radical surgery, patients within 6
weeks after surgery;
②Driver gene negative (no EGFR, ALK, ROS1
mutations), PD-1/L1 expression <1%;
③Fulfilling the diagnostic criteria for the lung qi and
yin deficiency type, the primary symptoms are cough,
low sputum, shortness of breath, low or muffled voice,
weakness,
and
thirst
without
wanting
to
drink.
Secondary symptoms include spontaneous sweating,
nocturnal sweating, five heartburns, red tongue or teeth
marks on the sides of the tongue, and a weak pulse. At
least two primary symptoms and one of the secondary
symptoms are present;
④Patients aged between 18 and 75 years;
⑤
Patients
with
basically
normal
blood
and
biochemical
indicators,
without
serious
viral
or
bacterial infections; without organ failure and serious
①Patients with incomplete resection or whose cancer
has undergone recurrence or metastasis;
②Patients who are being treated with other drugs or
therapies (including other Chinese herbal medicines,
immunological drugs, radiotherapy, etc.);
③Patients who are themselves mentally ill and have a
lack of autonomous behaviour;
④Women who are pregnant, preparing for pregnancy
or breastfeeding;
⑤Combined heart, lung, brain, liver, kidney and
haematopoietic system and other serious diseases,
psychiatric patients;
⑥
Allergic
or
known
hypersensitivity
to
the
components of the drug;
⑦Patients who are participating in other clinical trials
or have participated in other clinical trials within 3
months;
⑧Alcohol and/or psychoactive substances abuse, drug

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1.3 Concurrent Treatment
On the one hand, during the trial, drugs that affect the evaluation of therapeutic efficacy, such as
chemotherapeutic drugs, targeted drugs, bio-immune agents, Chinese medicine injections, and
other drugs that are clearly indicated in the instructions to be used for anti-tumour purposes, shall
not be used in combination. On the other hand, detailed records should be made of the combined
diseases or symptoms that existed before the start of the trial, and the drugs or other therapies that
need to be continued or added must be recorded in the case report form with the generic name of
the drug or the name of the other therapies, the dosage, the reason for use, the number of times of
use, and the time of use, etc., so that they can be analysed and reported at the time of the summary.
1.4 Sample Size
The calculation of the sample size of this clinical trial is based on the statistical results of the
"Chinese Medicine Clinical Research on Common Malignant Tumours (Lung Cancer)" conducted
by this group in the Third Round of Shanghai Three-Year Action Plan of Traditional Chinese
Medicine. Based on the group's previous clinical research on the survival and immune function
effects on patients after radical NSCLC surgery, the 5-year disease-free survival rate was 90.2% in
the treatment group and 78.3% in the control group. Sample size was calculated using PASS.15
software, and Survival-Two Survival Curves-Test(Inequality)-Logrank Tests were applied. set
Power=0.8, α= 0.025 (unilateral), according to the control group and experimental group 1:1,
combined with the basis of the previous research, taking the Proportion Surviving as Input Type,
S1(Proportion Surviving - Control) = 0.783, S2(Proportion Surviving - Treatment) = 0.90, T0
(Survival Time) = 5 years, Accrual Time (Integers Only) = 2 years, uniform enrolment, the rate of
shedding in each group is 10%, the calculation can be calculated to obtain a total sample size of
317 cases, 158 cases in the treatment group and 159 cases in the control group. At the same time,
there are five clinical trial centres in this study, according to the sample size estimation
requirements of multifactorial analysis, the introduction of one more confounding factor needs to
increase the sample size of each group by 15-25 cases, and this study considers an increase of 20
cases in each group. Therefore, 178 cases need to be collected in each group, and the total sample
size of the two groups is 356 cases (Table 2).
heart disease (TBIL <68 μ mol/L, AST <90 IU/L,
CREA <350 μmol/L, WBC >3.5×109/L and < 12×
109/L, PLT >80×109/L, HCT >0.20)
⑥Those with a tumour PS score ≤2 and no other
serious comorbidities;
⑦The patients themselves gave informed consent to
participate in the study by signing an informed consent
form with good compliance;
⑧Non-pregnant and lactating patients;
⑨Passing the chemotherapy-related indicators;
⑩Those who have no allergic reaction to the
ingredients in the formula.
abusers and dependent persons;
⑨Other
pathologies
or
conditions
that,
in
the
judgement of the investigator, have the effect of
reducing the likelihood of enrolment or complicating
enrolment,
e.g.,
frequent
changes
in
the
work
environment, unstable living conditions, and other
conditions that predispose to loss of visits.
TBIL: Blood bilirubin, AST: aspartate aminotransferase, CREA: creatinine, WBC: white blood cell count, PLT:
platelet count, HCT: erythrocyte pressure, PS: Performance staus.

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Table 2. Sample size estimation for each centre.
research centre
treatment group
control group
total
Shanghai Municipal Hospital of Traditional Chinese Medicine
38
38
76
Shanghai Pulmonary Hospital
35
35
70
Shanghai Chest Hospital
35
35
70
Shanghai General Hospital
35
35
70
Shanghai TCM-Integrated Hospital
35
35
70
total
178
178
356
1.5 Subject Withdrawal
Trial suspension refers to the stopping of a clinical trial in the middle of a trial that has not yet
been completed as planned. The purpose of trial suspension is mainly to protect the rights and
interests of the subjects, ensure the quality of the trial and avoid unnecessary economic losses.
Discontinuation of the trial is required in the following cases: 1. Serious safety problems occurred
in the trial, the trial should be promptly suspended; 2. The trial found that the drug treatment effect
is too poor, or even ineffective, does not have clinical value, the trial should be discontinued, on
the one hand, to avoid delaying the effective treatment of subjects, while avoiding unnecessary
economic losses; if there is a disease progression or serious adverse reactions can be initiated by
the withdrawal of the protection mechanism, i.e., the inclusion of evaluable cases, the later
assessment of efficacy data to invalid for carry-over. The lack or loss of efficacy is assessed by the
investigator (not the subject). 3. Significant errors in the clinical trial protocol are identified during
the trial, making it difficult to evaluate drug effects; or a well-designed protocol has undergone
important deviations in its implementation, and further continuation makes it difficult to evaluate
drug effects; 4. The sponsor requests suspension (e.g., financial reasons, management reasons,
etc.); 5. Withdrawal of the trial by the administrative authority, etc.
1.6 Compliance
We will record the number of medications returned by participants to calculate utilisation rates.
We will take measures to improve adherence, including asking them to complete a statement as
part of the informed consent process, emphasising the importance of completing the study.
2 Trial Procedures
2.1 Stratified randomisation and blind implementation
The stratified random grouping scheme used in this study was prepared by a statistician. The
entire study population that met the inclusion criteria was allocated according to the stratified
random grouping scheme. The sample size for each stratum was a multiple of the group size. The
stratification factors were different sub-centres. A teacher of medical statistics, who was not
related to the data management and statistical analysis of this trial, generated a random table
through Statistical Product and Service Solutions (SPSS) software, and the test group: control
group was randomly coded in a ratio of 1:1 using the block randomisation method, and the length
of the selected block (block) and the random seed parameter, etc., were sealed together as
confidential data in a blinded bottom. After blinding, the blinders of the statistical unit handed
over the sealed blinds to the unit in charge of the clinical study, including the first-level blinds and

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second-level blinds made according to the random number, and the blinds were sealed in duplicate
at the unit in charge of the clinical study.
A two-level blinded design was used, with the first level being the group corresponding to each
case number (e.g., group A or group B) and the second level being the treatment corresponding to
each group (test or control). The randomised coding table was created by the statistical unit, and
the two levels of blinded bottoms were individually sealed in duplicate and stored in the team
leader's unit and in the quality control office, respectively. When all the case report forms (CRFs)
were entered into the database, and after questioning, verification, and blinding audit, the data
were locked (Locked), and the first unveiling of blinding (i.e., clarifying Groups A and B) was
carried out by the staff member who kept the blinded bottoms, which was handed over to
biostatisticians to enter into the computer, and then statistically analysed after linking up with the
data files. When the statistical analyses were completed a second blinding was carried out to
clarify the test and control groups.
Blinding may be broken in emergency situations when the investigator believes that knowledge
of the medication taken by the subject is beneficial for the management of adverse events. This
should be done by the investigator and a detailed record of the reason, time and place of blind
breaking should be recorded and signed. Within 24 hours of the blinding, the responsible (lead)
unit of the clinical trial and the clinical supervisor as well as the statistically relevant personnel
should be notified and the reason for the blinding should be explained. Once the contingency letter
has been opened, the numbered subject will be withdrawn from the trial and treated as a dropout
case, and the investigator should record the reason for withdrawal on the case report form. All
contingency letters will be retrieved at the end of the trial along with the case report form for
blinded audit at the end of the trial.
2.2 Method of administration
Chemotherapy regimen selection: chemotherapy regimens will be selected according to NCCN
guidelines, and patients will be treated with platinum-based chemotherapy according to one of the
following regimens for 3 weeks each for 4 cycles: (1) NP regimen: vincristine, 25mg/m2 on day 1,
cisplatin, 75mg/m2 on day 1; (2) GP regimen: gemcitabine, 1,250mg/m2 on days 1 and 8, and
75mg/m2 on day 1; (3) DP regimen: docetaxel, 75 mg/m2 on day 1 and cisplatin, 75 mg/m2 on
day 1; (4) AP regimen: pemetrexed, 500 mg/m2 and cisplatin, 75 mg/m2 on day 1; and (5) TC
regimen: paclitaxel, 200 mg/m2 on day 1 and carboplatin, area under the curve (AUC) 6 on day 1,
and patients intolerant of cisplatin will be given area under the curve (AUC) 5-6 on day 1 (AUC)
5-6 given carboplatin. All chemotherapeutic agents will be administered intravenously in both
groups. The chemotherapeutic agents were administered strictly according to the appropriate
instructions and NCCN guidelines for recommended dosage, duration and usage.
For oral administration of traditional Chinese medicine, each bag was soaked in 400 ml of
boiling water at 100°C for 20 minutes, divided into 2 portions, each with a content of 200 ml. 200
ml was taken orally twice a day, in the morning and in the evening.
2.3 Test period
Chinese medicine treatment period is 6 months. Follow-up period: 3 years after the end of dosing.
After the end of the programme, follow-up will continue until 5 years or until the subject dies (or
progresses).
2.4 Discontinuation Criteria
First, during the course of medication, if the subject develops an aggravation of the condition

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he/she should discontinue the use of the test drug, complete the post-evaluation of the efficacy and
the relevant laboratory tests to end the trial, and the subject will be counted as an invalid eligible
case for inclusion in the PPS. Second, if the investigator believes that other circumstances make it
inappropriate for the subject to continue using the test drug.
2.5 Data Collection and Management
2.5.1 Data management system
All the original data in the case report form will be backed up and entered into the database by two
people, proofread each other and correct the entry errors, and after checking the accuracy with the
original data in the case report form, the data will be locked and then statistically analysed.
Construct a high-quality clinical research database, incorporate it into the unified management of
the big data platform of the Oncology Research Centre, and conduct long-term tracking and
follow-up of the research subjects.
2.5.2 Establishment of Data Steering Committee
The subject leader, statisticians and clinical scholars will work together to formulate standard
treatment protocols, design trial protocols, organise the formulation and approval of various
standard operating procedures, organise the formulation and approval of research plans, approve
and decide whether to continue the trial, as well as approve the dissemination of trial results and
write reports on the results.
2.5.3 Establishment of a Data Safety and Monitoring Board (DSMB)
Investigators (clinicians, not involved in the inclusion of participants) and statisticians were
responsible for designing the CRF, assessing the adequacy of the participant recruitment process,
evaluating
data
quality,
outcome
safety
assessment,
outcome
and
effect
assessment,
recommending continuation of the trial, and reviewing and approving the dissemination of the
results and the draft report: a database administrator (full-time) was responsible for the
management of the database; an ombudsman was responsible for the monitoring of the data: a data
entry clerk 2 persons responsible for data entry.
2.5.4 Data capture and database management
Accurately collect and record process management information data and resultant measurement
indicators and inspection data of observation items. A two-person, two-track entry into the
electronic case information system (EDC) system is used, and after the entry is completed, the
double data are checked and logical consistency verified. The database uses EDC for data
management.
2.5.5 Data security and monitoring
Data monitoring before the start of the clinical trial is generally on-site verification; real-time
online monitoring and online quality control of the EDC system during the trial; the final data
monitoring is carried out after the completion of the trial data collection, and the external data
materials are reviewed and accepted.
2.5.6
Database Locking
After the completion of the interim analysis of the clinical trial and the data monitoring at the end
of the trial, report to the DSMB, the subject leader, with a list of data monitoring, and lock the
database after obtaining a written signature of approval.
2.6 Outcomes
2.6.1 Baseline data observation
Demographic data: gender, age, height, weight, etc.; Vital signs: such as blood pressure, heart rate,

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respiration, etc.; General clinical data: co-morbidities and medications, etc.; Other data: such as
education level, marital status, etc.
2.6.2 Baseline tumour assessment and risk factors
Time of diagnosis, pathological type, degree of differentiation, tumor node metastasis (TNM)
classification of tumour, gene mutation status, etc.; Comorbidities; Surgical procedure, history of
preoperative adjuvant therapy; Smoking status; family history of illness.
2.6.3 Safety indicators
Blood routine; Liver and kidney functions: alanine aminotransferase (ALT), menthionine
aminotransferase (AST), glutamyl transpeptidase (γ-GT), blood creatinine (CREA), urea nitrogen
(BUN), urinary protein (UPr), etc.; Electrocardiogram; Adverse events and serious adverse events
(detailed records at any time). The above examinations were tested once before the test, once
every month during the treatment period, and once every 6 months during the follow-up period.
2.6.4 Efficacy indicators
Main efficacy indicator is DFS. Refers to the time between the start of randomisation and disease
recurrence or death (from any cause). Imaging: Chest CT examination before the start of treatment
and every 6 months after surgery. Patients found to have recurrent metastases were discharged
from the group for standardised treatment when the pathological diagnosis was clear. Observation
and follow-up until 5 years after surgery, disease-free survival rate, disease-free survival and
median survival calculation. Secondary efficacy indexes includs OS, MRD, Circulating tumour
cellS detection, TCM symptom score, QoL, Immune indicators, Tumour markers, SII, PIN, PNI.
OS: Endpoint indicator, defined as the time from the start of randomisation to death due to any
cause. Overall survival and median survival calculations were performed with observational
follow-up up to 5 years postoperatively. MRD: Second-generation sequencing NGS method is
used to detect MRD in peripheral blood of the study subjects to obtain the superior population
screening model for TCM treatment; Circulating tumour cell detection: Detect 1 time each before
and after intervention. Specimen collection method: 10ml of venous blood was taken from the
patient's median elbow vein with EDTA blood collection tube, the blood collection tube was
repeatedly inverted and mixed, centrifuged at 2000g for 10min, the supernatant was retained, and
in order to further remove the redundant cellular components, it should be centrifuged again at
8000g for 10min. separated plasma was frozen and stored at -80℃or extracted immediately
according to the extraction kit instruction steps respectively. The remaining blood cells should be
added to saline to replenish 10ml and then immediately isolate the circulating tumour cells. TCM
symptom score: According to the "Shanghai TCM disease diagnosis and treatment routine", 10
TCM symptoms of cough, sputum, chest pain, chest tightness, shortness of breath, fatigue, loss of
appetite, insomnia, dry mouth and throat and spontaneous sweating were observed, and the
severity was scored according to 0-3, which was recorded once before and 6 months after the
intervention. Significant effect: the reduction of TCM symptom score is greater than or equal to
70% after the intervention; Effective: the reduction of TCM symptom score is greater than or
equal to 30% and less than 70% after the intervention; Ineffective: the reduction of TCM symptom
score is less than 30% after the intervention or elevated compared with the previous one. Quality
of life assessment: The Quality of Survival Scale for Lung Cancer Patients EORTC QLQ-LC43
was used, which consists of EORTC QLQ-C30 (core scale) and EORTC QLQ-LC13 Th
(characteristic subscale of lung cancer). It mainly scores lung cancer patients on 5 domains related
to functioning, general clinical symptoms, characteristic sub-symptoms, general health status and

13
financial difficulties, and is recorded once before and 6 months after the intervention. The higher
the score of function-related domains, the worse the function of the organism; the higher the score
of general clinical symptoms and characteristic sub-symptoms, the more serious the symptoms;
the higher the score of general health status, the better the status; the higher the score of economic
hardship status, the more difficult the economic hardship. Immune indicators: Cellular immunity
(CD3, CD4, CD8, CD16, CD56), regulatory T cells, myeloid-derived suppressor cells MDSCs,
natural killer cells NK, IL-1, IL-2, IL-6, IL-8, IL-10. 1 test before and 6 months after intervention.
Tumour markers: CEA, CA125, CA153, Cyfra21-1, SCC before and after treatment. At least 1 test
before intervention and 6 months after intervention. SII and PIN: The inflammatory response,
immune status and nutritional status of the body affect the tumour microenvironment and
prognosis of tumour patients. Studies have shown that tumour-associated inflammation, especially
host-associated systemic inflammation, is closely related to tumour development and progression,
as well as survival of cancer patients. SII is a comprehensive immune-inflammatory index,
calculated based on the results of platelet, neutrophil, and lymphocyte counts. SII is a more
objective predictor of the prognosis of patients with various types of tumours. It represents the
balance between inflammation and immunity in tumour patients. Inflammation, in turn, can
influence tumour progression by affecting the host's immunity and response to anti-tumour therapy.
PNI is a nutritional prognostic indicator that can be used to reflect the nutritional and immune
status of tumour patients and is calculated from serum albumin and circulating lymphocyte counts.
PNI is a nutritional prognostic indicator that can be used to reflect the nutritional and immune
status of tumour patients. Malnutrition is very common in patients with malignant tumours,
especially advanced tumours Day plays a crucial role in the process of tumour progression. There
is also a relationship between tumour-associated inflammation and nutritional status. Studies have
shown that tumour-secreted inflammatory mediators, including tumour necrosis factor (TNF) and
IL-6, lead to a loss of appetite and affect nutritional intake. And nutritional and immune status is
associated with tumour progression and prognosis. The formula is as follows: SII=peripheral
blood platelet count (*10/L) x peripheral blood neutrophil count (*10/L)/peripheral blood
lymphocyte count (*10%/L). PNI:Serum albumin(g/L)+Lymphocyte count(10/L)*5. Critical
values were calculated based on ROC curves, and based on the critical values, the above indexes
were divided into high level and low level groups.
2.7 Safety Assessments
2.7.1 Safety background information related to the medicines used in the trial
According to the preclinical study, clinical trial information and drug composition, it is necessary
to pay attention to the observation of the changes in the haematopoietic system, digestive system
and urinary system of the patients during the trial, such as the number of red blood cells,
haemoglobin content, blood creatinine and urea nitrogen, liver function and so on.
2.7.2 Observation and recording of adverse events
Observation and recording: The investigator should carefully observe any adverse events
occurring in the subjects during the clinical study period, and require the subjects to truthfully
reflect the changes in their condition after the administration of the drug, avoiding induced
questions. While observing the efficacy, pay attention to the observation of adverse events or
unanticipated toxic side effects (including symptoms, signs and laboratory tests). Regardless of
whether the adverse event is related to the test drug or not should be recorded in detail in the CRF
form, including the time of the appearance of the adverse event, symptoms, signs, degree, duration,

14
laboratory test indexes, treatment methods, after, results, follow-up time, etc., and should be
recorded in detail in the case of the combined use of medication, in order to analyse the relevance
of the adverse event to the test drug, the record should be signed and dated. Medical treatment of
subjects: When adverse events are detected, the investigator may take necessary treatment
measures according to the condition, such as adjusting the dosage, temporarily interrupting the
medication, etc., and decide whether to terminate the trial. In the event of serious adverse events,
the unit undertaking the trial study must immediately take the necessary treatment measures to
protect the safety of the subjects.
2.7.3 Judgement of severity
Mild: mild discomfort, the subject can tolerate does not affect the treatment, do not need special
treatment, no effect on the subject's recovery. Medium: moderate discomfort, intolerable to the
subject, requiring special treatment, and having a direct impact on the subject's recovery. Severe:
severe discomfort, endangering the life of the subject, death or disability, requiring immediate
emergency treatment.
2.7.4 Judgement of causal relationship with drugs
Indicators of causal judgement in the determination of adverse events include: 1. whether the time
of initiation of the drug is reasonably related to the appearance of the suspected adverse reaction; 2.
whether the suspected adverse reaction corresponds to the type of adverse reaction known for the
drug; 3. whether the suspected adverse reaction can be explained by the effect of the combination
of the drugs, by the patient's clinical condition, or by the effect of other therapies; 4. whether the
suspected adverse reaction disappears or is alleviated by discontinuation or reduction of the dose;
and 5. whether the suspected adverse reaction disappears or is alleviated after re-exposure to the
drug. Whether the same reaction recurs after re-exposure to the suspected drug. Criteria for
determining causality: according to the above 5 judgement indicators in order (Table 3). Based on
Table 4, determine the relationship between the following 5 levels of adverse events and the
medicinal product: 1-certainly related, 2-maybe related, 3-cannot be determined, 4-maybe not
related, 5-certainly not related. The incidence of adverse events was calculated using the total
number of cases 1+2+3 as the numerator and all the enrolled cases available for adverse event
evaluation as the denominator.
Table 3. Adverse event causation judgements.
Judgement results
Judgement indicators
1
2
3
4
5
Certainly relevant
+
+
-
+
+
Possibly relevant
+
+
-
+
?
Undetermined
+
+
±
±
?
Possibly irrelevant
+
-
±
±
?
Definitely irrelevant
-
-
+
-
-
Description: + affirmative, - negative, ± difficult to affirm or deny, ? Circumstances unknown.
2.7.9 Reporting and Handling of Adverse Events
The occurrence of any adverse event, such as the subjective discomfort of patients and abnormal
laboratory tests, should be taken seriously, carefully analysed, and immediate measures should be
taken to protect the safety of the subjects. Record in detail in the CRF form and retest in 24 hours

15
and 7 days and 14 days as appropriate. Record its persistence, regression and disappearance.
Handling of Serious Adverse Events: Any serious adverse event that occurs during the trial must
be reported immediately to the Medical Ethics Committee of the lead unit or the principal
investigator by completing the Serious Adverse Event Report Form (SARF), and in the case of
serious adverse reactions, to the State Food and Drug Administration (SFDA) within 24 hours.
Notify the telephone number and contact person of the unit listed in the CRF form. When a patient
has an emergency, the principal investigator of the research unit can open the emergency letter of
the corresponding number taken by the patient (but there must be two witnesses present, and make
corresponding records), according to the drug and the symptoms of the appropriate treatment, and
notify the clinical monitor of the results of the treatment, and the researcher should be recorded in
the case report form in detail on the reason for the breakthrough of blinding, date, treatment,
results and sign. All adverse events should be followed up until they are properly resolved or the
condition is stabilised. The method of follow-up can be inpatient, outpatient, home visit, telephone,
or newsletter, depending on the type and severity of the adverse event.
Statistical Analysis
Statistical software such as SPSS 25.0 and GraphPad Prism were used for data analysis and
statistical graphing in this study, with a test level of α taken as 0.05 and two sided test, giving
point estimates and 95% confidence intervals.
Case data collectively: full analysis set (FAS): all cases who were randomised, took the study
drug at least once and had at least one post-dose efficacy assessment constituted the FAS
population of the study.Missing data in the efficacy-related part of the FAS population will be
supplemented using a carry-over of data from the last previous observation.FAS will be used for
the All analyses. Compliance with the protocol set (PPS), the criteria for the PPS and its
population will be finalised in the data and will include at least the following criteria: 1.
Compliance with the enrolment criteria set out in the trial protocol; 2. Completion of all scheduled
visits; 3.No medication or treatment used during the trial that could have affected the evaluation of
efficacy. The PPS is a secondary population for the evaluation of efficacy in this study.
Measurement data obeying normal distribution were expressed as mean and standard deviation;
two independent samples t-test was used for inter-group differences, and paired t-test was used for
pre- and post-treatment comparisons within the group; if the data as a whole did not obey the
normal distribution of measurement data, the median (1st quartile, 3rd quartile) was used,
Wilcoxon rank-sum test was used for inter-group differences, and paired samples rank-sum test
was used for pre- and post-treatment comparisons within the group; count data were expressed as
frequencies and numbers; and PPS was the population of this study. and test; count data were
expressed as frequency (n), constitutive ratio (%), and rate (%), and differences between groups
were tested by chi-square test (Fisher's exact probability test was used if the chi-square test was
not satisfied); grade data were expressed as frequency and constitutive ratio, and differences
between groups were tested by the Wilcoxon rank-sum test for independent samples.
Survival data DFS, OS were obtained using the Kaplan-Meier method and by plotting
Kaplan-Meier curves to provide a visually intuitive depiction of differences between treatment
groups. The estimation of treatment effect will be expressed by the hazard ratio (HR) and its 95%
Confidence interval (CI) estimated by stratified COX model. The dataset included in the statistics
is based on Intention-to-treat (ITT) analysis.

16
Discussion
Lung cancer is the leading malignant tumour in China in terms of deaths, and metastasis is the key
cause. With the advances in diagnostic and treatment technologies (e.g., postoperative
chemotherapy, targeted therapy, immunotherapy), the survival time and quality of life of
postoperative patients have been improved to some extent. However, there is still a lack of
effective standardised diagnostic and treatment protocols for postoperative radical lung cancer
patients with negative driver gene expression, which has led to this specific group of patients
becoming a challenge in the clinic that restricts the improvement of the overall efficacy of lung
cancer, and at the same time, causes the society and families to incur huge medical costs.
This research programme inherits the theoretical advantages of Chinese medicine's "the Holistic
Concept" and the thought of "Precentive Treatment of Diease", inherits the academic thought of
"Treating Cancer by Reforcing Healthy Qi", and gives full play to the advantages of systems
biology, Precision medicine and Chinese medicine. Based on the theory of "Deficiency of Vital Qi
and Hidden Toxin", the research target is located in IIA-IIIA stage IIA-IIIA lung cancer patients
who are negative for the expression of driver genes after radical surgery, and carry out a
multi-centre clinical study on the combination of chemotherapy with Chinese medicine to prevent
and control the recurrence and metastasis of IIA-IIIA stage IIA-IIIA driver gene-negative NSCLC
after radical surgery. The study clarified the comprehensive efficacy of TCM in regulating the
internal environment of the body's immune function state to reduce recurrence and metastasis,
with a view to obtaining high-level evidence-based medical evidence and forming a standardised
diagnostic and treatment protocol of TCM for preventing and treating recurrence and metastasis of
postoperative cancer that can be promoted and applied, so as to promote the improvement of the
therapeutic efficacy of postradical treatment of lung cancer patients. Secondly, based on the results
of the study, the advantageous population of TCM for the prevention of recurrence and metastasis
was screened out by combined MRD detection, and histopathology, circulating tumour cells,
tumour-associated exosomes, immune indexes and other related indexes of postoperative patients
with stage IIA-IIIA lung adenocarcinoma who were negative for the expression of driver genes
were detected, and the therapeutic efficacy prediction model of postoperative patients with stage
IIA-IIIA lung adenocarcinoma who were negative for the expression of driver genes was jointly
established, so as to To improve the precise treatment level of lung cancer after radical surgery and
promote the overall prevention and control efficiency of lung cancer.
Acknowledgments
We are grateful to Staff of the Clinical Research Centre of Shanghai Municipal Hospital of
Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine for his expert
assistance with the writing of the study protocol.
List of Abbreviation
TCM, traditional Chinese medicine
NCCN, National Comprehensive Cancer Network
DFS, disease-free survival
OS, overall survival
MRD, minimal residual disease
QoL, quality of life
SII, systemic immune- inflammation index

17
PIN, prognostic nutritional index
NSCLC, non-small cell lung cancer
PNI, pharmaceutical news index
TBIL, blood bilirubin,
AST, aspartate aminotransferase
CREA, creatinine
WBC, white blood cell count
PLT, platelet count
HCT, erythrocyte pressure
PS, performance staus.
ALT, alanine aminotransferase
AST, menthionine aminotransferase
γ-GT, glutamyl transpeptidase
BUN, urea nitrogen
UPr, urinary protein
SPSS, Statistical Product and Service Solutions
CRFs, the case report forms
EDC, electronic case information system
DSMB, data safety and monitoring board
TNM, tumor node metastasis
TNF, tumour necrosis factor
SARF, the Serious Adverse Event Report Form
SFDA, the State Food and Drug Administration
FAS, full analysis set
PPS, compliance with the protocol set
HR, the hazard ratio
ITT, Intention-to-treat
GCP, Good Clinical Practice
Availability of Data and Material
The results of our study will be presented at relevant scientific conferences and/or magazines. The
raw trial data will be published on the China Clinical Trial Registration website within 6 months
of trial completion.
Ethics Approval and Consent to Participate
The trial will be conducted in accordance with Good Clinical Practice (GCP) guidelines; it will be
supervised and managed by The Ethics Committee of Shanghai Municipal Hospital of Traditional
Chinese Medicine, Shanghai University of Traditional Chinese Medicine. The investigational plan
was approved by Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine (approval no.: 2023SHL-KY-19-01). All participants
would sign the informed consent before joining the trial.
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