Lidocaine Infusion Decreases Postoperative Lung Cancer Reoccurance and Metatasis Risk: a Multicenter Randomized Controlled Study
Phase: NA
Conditions: Non-Small Cell Lung Cancer, Recurrence, Survival Analysis
Sponsor: First Affiliated Hospital of Ningbo University

Official Study Title:
Lidocaine Infusion Decreases Postoperative Lung Cancer
Reoccurance and
Metatasis Risk: a
Multicenter Randomized Controlled Study
ClinicalTrials.gov Identifier:
NCT Number: Not yet assigned
Document Type:
[Protocol / Informed Consent Form / Other]
Date of Document:
[2025-11-29]
Principal Investigator:
[Huang Changshun, MD]
Institution:
[THE first affiliated hospital of Ningbo University/ Ningbo university]

Clinical research protocol
(Version number: V1.2, version date: Nov 29, 2025)
Perioperative lidocaine infusion for decreasing postoperative
reoccurrence and metastasis risk in patients with Non-Small
Cell Lung Cancer: a multicenter randomized controlled
study
Research background
Lung cancer is the leading cause of cancer-related deaths worldwide,
with 2.21 million patients dying from lung cancer in 2020, ranking
second. A study in the UK reported a 10-year survival rate of 7.6% for
males and 11.3% for females with lung cancer. The Chinese Center for
Disease Control and Prevention reports that the five-year survival rate for
lung cancer patients in China is 20% -30%. [1] Therefore, lung cancer
remains a major health issue of global concern. Surgery is one of the
main treatment methods for lung cancer. Although the perioperative
period is short, it may have a disproportionately significant impact on the
long-term trajectory of cancer. The physiological changes caused by
surgery can alter this dynamic. The wound healing response caused by
surgery leads
to stress,
inflammation,
and immune
suppression,
promoting metastatic conditions. Inflammatory response can promote
tumor circulation, thereby increasing the chances of recurrence and
metastasis. Therefore, using therapeutic agents to regulate surgical
response may avoid irreversible pro metastatic processes [3]. From this

perspective, lidocaine, as a mature and inexpensive drug, may provide a
feasible solution.
Lidocaine is a globally available and inexpensive medication
traditionally used for anesthesia of specific body parts. Intravenous
infusion of lidocaine has been proven to be an economical and convenient
method that can alleviate widespread inflammatory reactions during
surgery [4], and animal experiments have shown that it can also inhibit
the proliferation of lung cancer [5]. In vitro studies have shown that
lidocaine can inhibit cancer cell proliferation and induce cancer cell death
by reducing the epidermal growth factor receptor (EGFR) response and
inhibiting the activation of matrix metalloproteinase-9, which is crucial
for extracellular matrix degradation in malignant cells. Lidocaine can also
regulate gene expression by altering the DNA of malignant cells, thereby
reducing cancer growth and metastasis [6]. In addition, studies have
shown that the sympathetic nervous system has an impact on the survival
microenvironment of lung cancer, which can weaken the effectiveness of
postoperative chemotherapy [7]. However, lidocaine can inhibit the
excitation of the sympathetic nervous system, indicating the potential
value of lidocaine.
Surgical stress response leads to the release of pro-inflammatory
cytokines and inhibition of immune cell function [3]. Lidocaine has been
shown to alleviate inflammation in an in vivo model by reducing cytokine

release and subsequent metastasis. The clinical therapeutic dose of
lidocaine can also enhance the function of NK cells [8]. There are a large
number of NK cells in the lungs of lung cancer patients, which play a key
role in eliminating lung cancer and preventing metastasis formation [9].
In addition, lidocaine can block Src activation, thereby reducing the
invasiveness of cancer cells [10].
The consequences of cancer recurrence and metastasis highlight the
necessity of intervention in terms of increasing incidence rate, mortality
and financial burden [11]. A Cochrane review emphasized the necessity
of well-designed
randomized
controlled trials
to
reduce cancer
recurrence.
Cancer staging is indeed associated with recurrence, especially when
cancer cells migrate from the primary site. Stage I ground glass nodules,
even if the pathological type is invasive adenocarcinoma and larger than
3cm, still have a 5-year 100% survival rate. Stage III and IV lung cancer,
due to the invasive spread of cancer, surgery is usually not for cure, but
mainly for symptom relief, and lidocaine is unlikely to provide benefits.
Stage I solid nodular lung cancer involves vascular and pleural invasion,
while stage II involves vascular and lymphatic system invasion, requiring
extensive surgical resection [12]. These patients may benefit the most
from lidocaine and will be the main target of this study. We will recruit
patients with all cancer stages to understand potential differences in

response to lidocaine treatment.
Lidocaine has an inhibitory effect on tumor cells, which is mostly
based on animal studies, and toxic doses are often used in animal studies.
There are few high-quality studies in clinical practice. This study aims to
explore whether lidocaine infusion at a safe dose can bring the value of
prolonging survival for lung cancer patients after surgery, which is of
great significance.
Research objective
1. Main objective: To evaluate the effect of perioperative lidocaine
infusion on postoperative reoccurrence and metastasis in patients with
non-small cell lung cancer.
2. Secondary objective: To explore the value of perioperative lidocaine
infusion in prolonging the survival of patients with non-small cell lung
cancer
Research design types, principles, and experimental procedures
1. Research Design
This is a 1:1 parallel double-blind (patient and data collector blinded,
prepared by anesthesia nurses and administered by anesthesiologists)
randomized controlled trial comparing the efficacy of intravenous
infusion of lidocaine versus placebo/saline during minimally invasive
(thoracoscopic or robotic) surgery in lung cancer patients.
1.1 Sample size calculation

For the time to event outcome, use the median reoccurrence time of
similar populations in the literature to estimate the hazard ratio (HR). The
median reoccurrence time described in the literature is 18 months. If we
do not want to miss the 6-month improvement in event time in the
treatment group, then HR estimates the risk ratio of reoccurrence time at
18 months in the control group and 24 months in the treatment group.
Risk ratio=(risk rate of treatment group)/(risk rate of control group)
Risk rate=1/(median recurrence time)
Therefore,
the
risk
ratio
can
be
estimated
as:
Risk
ratio=(1/24)/(1/18)=18/24=0.75
The estimated risk ratio is 0.75, which represents a 25% reduction in
risk effect for the treatment group compared to the control group. The
sample size is based on the parallel design of the superiority program,
survival endpoint, 90% efficacy,
0.05
significance
level, bilateral
significance level, HR 0.75. Using PASS11 software, it is estimated that
each group requires 635 cases, and an increase of 10% would result in
700 cases per group. Therefore, the planned total sample size is 1400
patients with lung cancer.
2 、Case selection
In this experiment, qualified participants will be recruited from each
center, as the annual number of lung surgeries in each center reaches
around 8000 cases.

Inclusion Criteria
1. Age range: 18-80 years old.
2. Electively undergo minimally invasive (thoracoscopic or robotic)
surgery for clinical stage I and II lung cancer.
3. Willing and capable ofproviding consent.
Exclusion criteria
1. Palliative surgery without intention of cure.
2. ASA IV
3. Patients who are known or suspected to be allergic to lidocaine.
4. Patients who are currently pregnant or breastfeeding.
5.According to the Summary of Lidocaine Product Characteristics,
patients who may experience adverse reactions due to accumulation
of lidocaine intravenous infusion.
6. The current liver function is abnormal, with ALT or AST exceeding
the laboratory reference range by 2 times.
7. Currently severe renal insufficiency (blood creatinine ≥451umol/L
or
glomerular
filtration
rate
(calculated
by
MDRD
formula)<30ml/min).
8. Epilepsy.
9. Cardiac conduction abnormalities, including second or third degree
heart block without a pacemaker, left bundle branch block, sick sinus
syndrome,
and
pre
excitation
syndrome
(confirmed
by

electrocardiogram based on medical history), as well as patients in a
low cardiac output state with currently reduced left ventricular
ejection fraction.
10. Concurrent use with continuous infusion of other local anesthetics
(such as epidural).
11. Patients who use drugs that may cause exclusion reasons, including
Class I
and
III
antiarrhythmic
drugs
(such as
metoprolol,
amiodarone), cimetidine, and antiviral drugs. Qualifications will be
determined by local clinical doctors and verified by clinical trial
doctors.
12. Patients weighing less than 40kg
Termination criteria for the study (subjects experiencing conditions that
make it inappropriate to continue the study, including worsening of the
condition, serious adverse events, poor compliance, etc.)
Research methods
1. Intervention measures
Research drug (IMP)
2% lidocaine hydrochloride injection for infusion, prepared as a
50mL syringe and continuously pumped for administration.
Placebo
0.9% sodium chloride solution for infusion, prepared into a 50mL
syringe and continuously pumped for administration.

2. Dose plan
Lidocaine is administered intravenously at an ideal body weight
(IBW) of 1.5 mg/kg starting from anesthesia induction, for 10-20 minutes,
and then continuously infused at 1-1.5 mg/kg/h until 12 hours after
returning to the ward, with a maximum rate of 120 mg/h. Use ideal
weight instead of actual weight to prevent toxicity in very overweight
patients. In patients with a weight lower than the ideal weight, the actual
weight should be used to calculate the dose. The patient needs to be
admitted to a highly dependent ward or equivalent facility for continuous
cardiac monitoring during lidocaine infusion. Patients in the placebo
group had the same infusion rate as those in the treatment group.
Example
IBW (Kg) initial dose (1.5 mg/kg) infusion rate (1.5 mg/kg/h)
40 3ml（10-20min）1-3ml/h
50 3.75ml（10-20min）1.25-3.75 ml/h
60 4.5ml（10-20min）1.5-4.5 ml/h
70 5.25ml（10-20min）1.75-5.25 ml/h
80 and above 6 ml (20 minutes) 2-6 ml/h
Table 1: Dose Guidelines Based on IBW (Broca Index): Male: Height
(cm) -100; Female: Height (cm) -105. Attention: For patients with a
weight lower than the ideal weight, the actual weight should be used to
calculate the dosage.

Therefore, for the placebo/saline group, if the IBW is 70kg, the patient
will receive an initial infusion of 0.9% sodium chloride at 5.25ml over
10-20 minutes, followed by an infusion at 1.75-5.25ml/h.
3. Dose adjustment
Dose changes are not allowed in this study. If the supervising
medical professional suspects acute systemic local anesthetic toxicity
symptoms, the infusion must be stopped and not continued. In this case,
supportive treatment and lipid rescue will be provided. The discussion on
the possible adverse events caused by lidocaine toxicity is as follows. If
the infusion is interrupted due to issues such as infusion pump failure,
catheter failure, or accidental disconnection, the infusion can be restarted
at the original rate and the event recorded.
4. Additional care and procedures
To reduce the possibility of confounding factors, general anesthesia
should be maintained under a combination of intravenous and inhalation
anesthesia. Postoperative care follows the unit's standard to enhance
postoperative rehabilitation protocol. The pain control program will be
consistent with the unit's standard procedure. However, during IMP
infusion, simultaneous continuous infusion of other local anesthetic drugs
(such as epidural or wound catheters) cannot be performed.
5. Postoperative analgesia management
To reduce the
possibility
of confounding factors,
general

anesthesia should be maintained under a combination of intravenous and
inhalation anesthesia. Postoperative care follows the unit's standard to
enhance postoperative rehabilitation protocol. The pain control program
will be consistent with the unit's standard procedure. However, during
IMP infusion, simultaneous continuous infusion of other local anesthetic
drugs (such as epidural or wound catheters) cannot be performed. After
the surgery, all patients were uniformly treated with sufentanil 2ug/kg
diluted to 100ml and pumped with 2ml/h for intravenous analgesia
6. Randomization
After obtaining consent, participants will be randomly assigned (1:1)
to receive intravenous lidocaine or placebo using a minimization
algorithm. The minimum criteria include age (<45 years, 45-65 years,
65-80 years), gender, trial center.
6. Observation project
Main outcome measure
Assess the reoccurrence time of lung cancer patients within 36
months from the date of surgery.
Secondary outcome measure
1. Disease free survival (DFS)
2. Objective remission rate ofpatients' diseases
3. Health related Quality of Life Questionnaire EQ-5D-5L
4. Cancer specific quality of life measured using the Functional

Assessment of Cancer Therapy (FACT-L) questionnaire.
Other observation indicators
1. The total length ofhospital stay, including readmission, is 36 months.
2. Changes in pro-inflammatory cytokine levels (IL-6, TNG - α) from
baseline on the third day after treatment and upon discharge.
On the 1st and 3rd day after treatment and at discharge, changes in
reticular fiber dissolution markers (matrix metalloproteinases MMP-9,
MMP-2) from baseline were observed.
3. Perioperative nausea, vomiting, delirium, pain control, and incidence
of cardiovascular accidents 6 and 12 months after treatment completion.
7、Efficacy evaluation criteria
Follow up chest CT scans at 6, 12, 18, 24, and 36 months after
surgery were conducted to evaluate whether lung cancer patients had
cancer reoccurrence and the time of reoccurrence within 36 months from
the date of surgery. And evaluate the cancer specific quality of life using
the lung cancer treatment function assessment questionnaire for patients.
The shortened recurrence time and improved specific quality of life
indicate therapeutic efficacy.
8. Observation of adverse events
Lidocaine can inhibit cancer cell proliferation at doses that have
minimal impact on normal cells. The infusion dose and duration selected

in this study are within the recommended range of the latest international
consensus statement on the safe use of intravenous lidocaine infusion.
Lidocaine should be administered intravenously at an initial dose of no
more than 1.5mg/kg of ideal body weight, with an initial infusion time of
at least 10 minutes. During the maintenance period, the infusion rate of
1.5mg/kg/h should not exceed 24 hours, and the maximum infusion rate
should not exceed 120mg/h. The above medication should be calculated
based on ideal body weight. If the actual body weight is lower than the
ideal body weight, it should be calculated based on the actual body
weight. When toxicity occurs, according to the guidelines of the British
and Irish Society of Anesthesiologists, lidocaine infusion can be
temporarily suspended and treatment can be carried out using readily
available 20% intravenous lipids in the operating room and intensive care
unit.
9. Quality Control and Quality Assurance in Research
Strictly follow relevant SOPs during the clinical research process,
conduct unified training before the implementation of the study, and
monitor IMP/placebo infusion as part of the standard care for patients.
Due to the infusion of IMP/placebo from the start of surgery until 12
hours after returning to the ward, all participants were hospitalized during
the infusion period. The infusion rate table will be provided to the
research team to minimize user errors during administration. The data

will be collected at the hospital during routine hospital appointments and
postoperative recovery periods. We will strive to collect outcome data
from all randomly assigned participants, regardless of whether they
received IV lidocaine/placebo. Communicate with the surgeon and
strictly follow the diagnosis and treatment plan according to the protocol.
Strictly develop a follow-up plan form. The data is recorded using
Redcap software.
10. Statistics process
Statistics will be recorded and managed using Redcap data, and
analyzed using SPSS21 software. The analysis will be conducted
according to the intention to treat principle. The statistical analysis plan
for this study includes summarizing baseline data, conducting primary
outcome analysis using time to event analysis, and conducting additional
survival analysis. Baseline variables
such as age
group,
gender,
comorbidities,
ASA
classification,
cancer
stage,
cancer
TNM
classification,
pathological
type,
neoadjuvant
targeted
therapy,
radiotherapy, and chemotherapy will be summarized using appropriate
descriptive statistical methods, using mean and standard deviation or
median and quartile range (depending on the applicability of continuous
variables). The categorical variables will be summarized using the
frequency and percentage of participants in each category. Researchers
will use EDC to fill out CRF. The data will be stored on a secure server.

The source documents of CRF report information will be archived in the
center and available for monitoring, IRB/IEC review, and regulatory
inspection as needed. According to applicable regulations, researchers
must retain all research records/documents.
The main outcome is defined as the time of cancer reoccurrence
within 36 months after surgery in patients with stage I and II lung cancer.
Multiple Cox regression models will be used to analyze the main results
and adjust the truncated data. The truncated data includes participants
who have not experienced recurrence or death within 36 months, as well
as those who have been lost to follow-up or withdrawn from the study.
The risk ratio will be estimated by comparing the risk rates ofthe placebo
group and the lidocaine group, taking into account the truncated data of
the participants and adjusting for covariates. In addition, Kaplan Meier
plots will be used to visualize and compare survival distributions, while
Log rank tests will evaluate the differences between the two groups.
We will use the study drug allocation (x=0 placebo, x=1 lidocaine) as the
independent variable, the time of cancer recurrence or death as the
dependent variable, and age group (<45, 45-65, 65-80), gender, number
of comorbidities, ASA classification,
cancer staging, neoadjuvant
radiotherapy, and chemotherapy as adjusted covariates.
Clean the experimental data and construct an analysis dataset suitable for
statistical analysis. Data quality control is achieved through the accuracy

(numerical range), reasonableness (whether the category is reasonable),
and handling of missing data (by checking and supplementing missing
data). Then conduct statistical analysis. Missing data will be compensated
through multiple imputation and pattern mixing methods to explore the
robustness of treatment effect estimation. We will explore the reasons for
missing data, such as loss to follow-up or withdrawal, and report them.
We will seek clarification of missing data through routine data collection
with the clinical team. Resolve data queries before analysis.
11、Ethics in Clinical Research
Clinical research will follow relevant regulations such as the Helsinki
Declaration of the World Medical Assembly. The clinical study will only
be conducted after the ethics committee approves the trial protocol before
the start of the research. Before each participant is enrolled in this study,
the researcher is responsible for fully and comprehensively introducing
the purpose, procedures, and potential risks ofthis study to the participant
or their representative, and signing a written informed consent form. The
participant should be informed of their right to withdraw from this study
at any time, and the informed consent form should be kept as a clinical
research document for future reference. During the research process, the
personal privacy and data confidentiality of the subjects will be protected.
Research time
January 2026 December 2026: Project initiation, completion of data

collection for 400 patients
January 2027 December 2027: Complete data collection and mid-term
analysis for 600 patients
January 2028 to October 2028: Complete data collection for 400 patients
October 2028 to December 2028: Data organization and statistical
analysis. Complete the paper writing and submit the SCI paper as soon as
possible.
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