Chinese and Western Integrative Medicine for Stage IIIb-IVb Non-Small Cell Lung Cancer: Design and Rationale of a Multi-center,Prospective Registry (NSCLC-Chinese and Western Integrative Medicine cohort)

Abstract

Introduction:

This planned multicenter observational study will evaluate the overall survival of those undergoing integrated Chinese and Western medicine for stage IIIb-IVb non-small cell lung cancer and analyze the factors related to the prognosis.

Method and Analysis:

The prospective cohort will enroll patients with stage IIIb-IVb NSCLC from March 1, 2019, to December 31, 2025, and follow them for 5 years. We plan to collect data on the patients’ demographics, treatment, overall survival, and factors related to the prognosis.

Ethics and Dissemination:

The institutional review board and ethics committee reviewed the study protocol. All patients will provide informed consent before enrollment.

Trial registration number: ChiCTR1900021430

Introduction

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The overall survival of advanced NSCLC is limited and the 5-year survival rate of stage IV patients is less than 10%. ¹ In the last 10 years, the 5-year relative survival rate has increased but remains low. ²

In China, traditional Chinese medicine (TCM) is widely used in combination with Western medicine. A comprehensive treatment strategy integrates TCM with Western medicine (WM). Studies have shown that the therapeutic effect of integrated medicine is better than that of TCM or WM alone. However, large-scale, long-term follow-up studies of this are still lacking.

Registries provide essential information on patients seen in clinical practice and are increasingly being used to improve knowledge and patient care. ³ We have designed a multicenter, prospective registry of NSCLC treated with integrated TCM and WM known as Lung Cancer–Integrated Chinese and Western Medicine. This study will collect data on lung cancer in China prospectively to investigate risk factors for patient survival, such as the overall treatment, quality of life (QOL), and overall survival (OS).

We plan to establish a long-term follow-up database to change real-world data into real-world evidence of integrated Chinese and Western therapy in advanced lung cancer. A secondary aim is to explore the exposure risk factors that affect the prognosis of stage IIIb-IVb NSCLC.

Methods

Study Design

This study is a multi-center observational prospective cohort study of 3 patterns of therapy: TCM plus chemotherapy, TCM plus targeted therapy, and TCM plus immunotherapy. A flow chart of the study is shown in Figure 1.

Figure 1.

Flow chart of the study.

Participants

We will enroll patients diagnosed with stage IIIb-IVb NSCLC at the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine and Sun Yat-sen University Cancer Center from March 2019 to December 2025. The follow-up period is 5 years. All patients must have a histological or cytological pathological diagnosis, and the clinical staging follows the eighth edition of the NSCLC staging criteria. ⁴

Criteria

Inclusion criteria are patients (of any age or gender) diagnosed with stage IIIb-IVb NSCLC from 2019/03/01 to 2025/12/31, who receive both Chinese herbal medicine (CHM; Chinese medicine decoction or patent medicine) and Western Medicine (chemotherapy, targeted therapy, or immunotherapy), and are willing to be followed via our follow-up protocol.

Exclusion criteria are refusal to cooperate with the follow-up process and any condition that may prevent the subject from completing the follow-up process, including but not limited to severe uncontrollable organic lesions or infections, unstable angina, congestive heart failure, severe liver/kidney dysfunction, uncontrolled central nervous system metastasis, significant intracranial hypertension or neuropsychiatric symptoms, and/or difficult-to-control neurological, psychiatric, or mental disorders.

Recruitment

We will continually enroll participants without selection. The sample size will depend on the number of patients meeting the inclusion criteria during the study period.

Data Collection

Eligible patients will be identified by review of the electronic medical records of the study centers, and patients who do not reach the study outcome (death) will continue to be followed regularly. The following relevant variables (risk factors) will be collected: patient demographics, including age, sex, education, nationality, etc.; personal history, including smoking history, underlying diseases, etc.; diagnostic data on lung cancer, including pathology, the primary focus, metastatic lesions, and oncogene status (including epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ros oncogene 1 [ROS-1], programed cell death ligand 1 [PD-L1], tumor mutation burden [TMB], etc.); Chinese diagnostic data will include TCM syndrome type, which refers to a classification system used in TCM to describe disharmonic patterns in the body that can lead to various diseases or health conditions.

Treatment-related data will be collected at different times. First, before enrollment, we will collect the type of surgery, chemotherapy regimen, radiotherapy, targeted therapy, and efficacy evaluation. During follow-up, we will collect the treatment information, including chemotherapy, radiotherapy, targeted therapy, immunotherapy, and the type and period of Chinese medicine, including the oral TCM decoctions, pills, capsules, and injections, and then evaluate efficacy according to the Response Evaluation Criteria in Solid Tumors (RECIST). Next, data on patient-reported outcomes will be collected (patients will report their QOL and adverse effects). Finally, outcome data will be collected. This will include the OS and cause of death. The OS is the length of time from enrollment that patients diagnosed with the disease are still alive. QOL will be measured using the European Organization for Research and Treatment-QOL questionnaire and the lung cancer-specific module (EORTC QLQ-C30 and QLQ-LC13). ⁵

Data Management

Researchers will record the clinical data in an electronic data-capture system (EDC) developed to collect and manage information in this study. It has been designed to integrate with WeChat, the most widely used instant messaging platform in China. Patients will receive follow-up reminders and a QOL scale. Researchers will abstract clinical data from the medical records. Research nurses will call the participants regularly regarding follow-up appointments. A data manager group has been established to monitor clinical data. Data confidentiality will be protected during and after the study. The data will be analyzed only in this study.

Data Security

Only registered, authorized users can use the system. Each user is assigned a unique identifier and password. Password aging has been used to prompt regular password modification and limit the potential of unauthorized access to the system. To maximize security, passwords must have at least 8 characters and contain a combination of lower and uppercase letters, characters, and numbers. Each user has a specific level of permissions and access to data.

Researchers are allowed to view the de-identified anonymous data. Doctors can add, view, edit, or delete data for their patients. The study owner can view all the data and the users can specify who registers in the study process.

De-identification irreversibly eliminates the link between individual patients and their data, making it almost impossible to re-establish a link. This ensures the preservation of patient confidentiality and anonymity. To achieve the highest security level, only specific Internet Protocol (IP) addresses are allowed to connect to Linux virtual private servers through a secure socket shell. This ensures that only authorized devices can connect to the database in addition to authorized use.

The database is in a secure environment, and all database processes run in a unique environment with an identifier that is not shared by other system processes.

Statistical Methods

For the baseline analysis, the overall baseline will be described as the basic character of the participants and the risk factors related to the survival of NSCLC. Continuous variables will be compared using a t-test or Wilcoxon test, while categorical variables will be compared using the χ² test or Fisher’s exact test.

During the observation period, survival rates and 95% confidence intervals (CIs) will be analyzed to determine the 1-, 2-, 3, and 5-year survival. All time-to-event data, including OS and progression-free survival (PFS), will be summarized using Kaplan–Meier methods. Groups will be compared using the log-rank test. A Cox proportional hazards model will be used for univariate and multivariate analyses.

We will compare the groups for interested clinical questions. We will use several methods to control confounding between the groups. First, multivariate-adjusted logistic regression will be used to establish the relationship between dependent and independent variables. Second, propensity-score matching (PSM) will be used to identify a control patient cohort with similar baseline characteristics. Third, inverse probability of treatment weighting (IPTW) will be calculated as the inverse of the treatment group’s propensity score and the inverse of (1 – propensity score) for the control group. All data will be processed using Empower Statistical Software (www.empowerstats.com, X&Y Solutions Boston, MA, USA) and R (http://www.R-project.org).

Ethics and Dissemination

This research will follow the relevant provisions of the Declaration of Helsinki of the World Health Assembly. The clinical study will be performed after Ethics Committee approval. Before each eligible patient is enrolled in the study, we will make a complete, comprehensive explanation of the purpose, procedures, and possible risks of the study to the patients or their agents and obtain informed consent. The patients will have the right to withdraw from the study at any time and the signed informed consent form will be kept as a clinical research document for future reference. The confidential data we collect will be protected during and after the study. This protocol was reviewed by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine. Approval no. of the ethics committee: NO. ZYYECK (2018) 105.

Discussion

Recently, much progress has been made in treating NSCLC, such as minimally invasive diagnosis and treatment techniques and advances in targeted therapy and immunotherapies. The treatment of advanced NSCLC includes chemotherapy and targeted therapy, immunotherapy based on biomarkers.^{6 -9}

Several studies have reported the benefits of combining TCM and WM in advanced NSCLC. A retrospective study found that comprehensive TCM treatments significantly reduce the progression risk, improve the prognosis, and prolong the survival of patients with advanced NSCLC. ¹⁰ Combining TCM in the treatment of NSCLC can reduce the adverse effects of radiotherapy, and improve the patients’ quality of life (QOL). ¹¹ TCM improves the QOL and 1-year survival rate of NSCLC patients on maintenance therapy. ¹² A meta-analysis showed the potential therapeutic value of CHM in improving the clinical outcome and overcoming drug resistance and toxicity as adjunctive therapy to EGFR tyrosine kinase inhibitors. ¹³ However, these studies were either retrospective or small trials and had limited value as evidence. A large prospective cohort is needed.

A syndrome is a basic unit and key concept in TCM theory. It differs from a disease or symptom. A TCM syndrome is the abstraction of a major disharmonious pathogenesis. Syndrome differentiation and treatment are the core of TCM, which requires treating patients by inspecting, listening, smelling, questioning, and taking the pulse at different times in different places. Based on this principle, TCM treats different stages of cancer in different ways. Chinese medicine can treat the side effects of WM and enhance its effectiveness in clinical practice.

Chinese medicine is widely used and accepted in China. ¹³ Clinical studies have demonstrated that combined treatment with TCM and WM improves the survival and QOL of patients with NSCLC. ¹⁴ TCM combined with targeted drugs in the treatment of NSCLC can enhance the efficacy of the targeted drugs, reduce toxic side effects, such as rashes, diarrhea, and nausea, reverse the resistance to targeted drugs, and improve the body’s immunity and QOL. ¹⁵ TCM combined with targeted drugs provides a new path for treating NSCLC. Previously, we showed that TCM increases the effect of gefitinib treatment by downregulating the PI3K/Akt/mTOR pathway and upregulating autophagy. ¹⁶

The combination of TCM and chemotherapy can reduce the side effects of chemotherapy, improve efficacy, and improve the patients’ QOL. TCM combined with chemotherapy improves the survival of advanced NSCLC patients with essence and qi deficiency.^{17 -19} TCM might be maintenance therapy for advanced NSCLC patients.^{20 -22} CHMs such as ginseng and Astragalus reduce fatigue and chemotherapy toxicity, while improving the TCM symptom score, psychological status, physical condition, and QOL.^23,24

However, the long-term effects of integrated treatment are unknown. As randomized control trials have failed to answer this, a long-term follow-up study is needed. As there is no established national registry system in China, we plan to develop the first cohort of patients receiving integrated TCM and WM.

Conclusion

A cohort study will be established to provide real-world evidence for the effectiveness and safety of TCM and WM for non-small cell lung cancer. The follow-up results will be used to assess the prevention, detection, and treatment of NSCLC in Chinese patients. We plan to present the study results at international meetings.