A Prospective Multi-Centered Registry-Based Observational Study for Patients With Cancer: Design and Rationale for Korean Medicine Cancer Registry (KMCARE)

Abstract

Background:

Cancer is one of the leading causes of death in most countries with an expected increased burden on healthcare systems. Since integrative medical treatments are not collected within the scope of existing cancer registries, the establishment of the Korean Medicine Cancer Registry (KMCARE), gathering integrative therapies, including conservative care and Korean medicine, is warranted.

Methods:

A prospective observational study based on the registry will be conducted in 5 Korean medical hospitals. A total of 650 eligible participants undergoing Korean medicine treatments within 1 month of a diagnosis of lung, colorectal, stomach, or breast cancer are anticipated to be enrolled in the registry. Data collected in the KMCARE can be classified into patient information, received treatments, and outcomes. The primary outcome is the Functional Assessment of Cancer Therapy-General Questionnaire score at 3 months. Secondary outcomes include the MD Anderson Symptom Inventory-Core and the Body Constitution Questionnaire at 3 and 6 months. After 6 months of follow-up periods, survival surveillance will be continued for additional 18 months. Descriptive and statistical analysis of primary and secondary outcomes, baseline data, safety, survival, and prognostic factors will be performed.

Discussion:

This is the first prospective, multi-centered, registry-based observational study of cancer patients in Korean medicine hospitals, which could reveal the current status of cancer patients receiving integrative cancer therapies, and provide better insight into the role of Korean medicine in palliative care for patients with cancer.

Trial registration:

Clinical Research Information Service (CRIS), KCT0007447.

Keywords

cancer Korean medicine nationwide observational study Registry palliative care

Introduction

Cancer is still the first leading cause for death in Republic of Korea and along with the increase in the geriatric population and advances in cancer treatment, its social burden has increased. More than 0.9 million Korean cancer patients or survivors were alive in 2020, and the number of people diagnosed with cancer increased by 18.8% compared to the past 10 years.¹ In the past, longer survival and absence of cancerous lesions in the body were considered to be of highest interest. However, with more patients experiencing cancer, interest in palliative care and quality of life in patients with cancer is inevitably growing.² In addition, patients with cancer have a more predictable and steadier history than those with other progressive diseases, such as congestive heart failure or chronic obstructive pulmonary disease. Building a structure and trajectory of palliative care extending from cancer is warranted.³

The pathophysiological characteristics of cancer include multiple symptoms. Symptoms are not only limited to physical changes following cancer and cancer-related treatments, but include psychological and general changes along with poor performance and malnutrition.^4,5 This symptom burden can result in significant distress. Early palliative care in a patient-centered approach can result in significant improvement in the quality of life of patients with metastatic cancer.⁶ Diverse treatment modalities from conservative pharmacological options to complementary and alternative medicine (CAM) should be considered for covering diverse symptoms and their severity in patients with cancer.

Traditional medical systems, including Korean Medicine, Traditional Chinese Medicine, Kampo medicine, have been widely used in East Asian countries for improving the symptoms of patients with cancer. The use of CAM including traditional medicine systems has gradually increased over the last 2 decades worldwide.⁷ Several meta-analyses and systematic reviews have supported its efficacy in improving the quality of life or reducing adverse reactions following cancer-related treatments.^8
-10 When cancer patients maintain good performance status longer, they could result in better clinical outcomes and survival in terms of keeping up planned schedules of major treatments.

Moreover, the medical system in the Republic of Korea is dualistic, and the national health insurance partially covers Korean medicine, including acupuncture and moxibustion. Diverse palliative care has also been officially and systematically provided. This system supports a registry study of the specific role of Korean medicine in patients with cancer.

To date, multiple registries or population-based studies have provided valuable information on the epidemiology, risks, benefits, and safety monitoring of traditional medicine in patients with cancer.^11,12 The Korean Medicine Cancer Registry (KMCARE) is the first registry of integrative therapies, including conservative care and Korean medicine. This registry would be able to provide better insight into the role of traditional medicine in the palliative care of patients with cancer. This registry aims to provide systematic and consistent information about integrative therapy including traditional medicine in the palliative care of patients with cancer.

Methods

Objectives

KMCARE would provide information to answer the following questions: The primary research question is to evaluate the characteristics of the patients who visited a Korean medical hospital. The secondary objectives of this study are as follows: To evaluate the effectiveness of Korean medicine in patients with cancer concerning overall quality of life improvement and alleviating cancer-related symptoms, evaluate the safety of Korean medicine in patients with cancer according to the Common Terminology Criteria of Adverse Events ver. 5.0, evaluate the prognostic factors of cancer-related treatments according to pattern identification, and evaluate the overall and progression-free survival in patients with cancer.

Based on these questions, KMCARE would be able to contribute to the understanding of Korean medicine in cancer care in 4 key areas. First, it is the first registry of traditional medicine in cancer care, which would provide a structured model for collecting data concerning traditional medicine. Second, the data collected by KMCARE are consistent and standardized, and procured through the support of trained experts, electronic database systems, and periodic data monitoring. Third, KMCARE can comprehensively identify multiple symptoms and survival in patients with cancer. Moreover, our study is a multi-centered study involving 5 Korean medicine hospitals in 4 universities across the nation, which can provide comprehensive information beyond one institution. Fourth, KMCARE accesses real-world data in a timely manner, which is a direct and practical approach.

Study Design and Ethics

This single-arm prospective observational study is based on the KMCARE registry. Recruitment is performed from 5 hospitals in the Republic of Korea. The study population includes adult patients with one of the following primary cancer lesions that are most prevalent in Korea: the lungs, colorectum, stomach, or breast. Eligible participants will be followed up for 6 months to assess the cancer status, performance status, efficacy and safety of Korean medicine treatment, and quality of life in patients with cancer; survival will be assessed for an additional 18 months. A schematic of the study design is shown in Table 1.

Table 1.

Schedule for KMCARE Study Visits.

Study phase	Screening	Enrollment	Follow up		Surveillance
Visit (month)	v0(–1)	v1(0)	v2(3)	v3(6)	v4(9)	v5(12)	v6(15)	v7(18)	v8(21)	v9(24)	Unscheduled visit
Informed consent	○
Registration (Screening number)	○
Eligibility assessment	○
Sociodemographic characteristics	○
Vital signs and physical exams	○	○	○	○
ECOG performance status	○	○	○	○	○	○	○	○	○	○	○
Cancer history	○	○	○	○	○	○	○	○	○	○	○
Other medical history	○
Treatment history		○	○	○							○
FACT-G		○	○	○
MDASI-Core		○	○	○
BCQ		○	○	○
PGIC			○	○
Survival		○	○	○	○	○	○	○	○	○	○
Adverse events		○	○	○							○

Abbreviations: BCQ, Body Constitution Questionnaire; ECOG, Eastern Cooperative Oncology Group; FACT-G, Functional Assessment of Cancer Therapy-General; KMCARE, Korean Medicine Cancer Registry; MDASI-Core, MD Anderson Symptom Inventory-core; PGIC, Patient Global Impression of Change.

This study was approved by the institutional review board of each site prior to enrollment. All investigators adhered to the Declaration of Helsinki and Korean Good Clinical Practice Guidelines. The study protocol is registered with the Clinical Research Information Service (CRIS), Korean registration service for clinical trials (KCT0007447). This study will be performed based on protocol version 1.2, and the latest protocol will be updated in the CRIS in a timely manner.

Eligibility

The study population would consist of adult patients with confirmed lung, colorectal, stomach, or breast cancer. Participants diagnosed with histologically confirmed cancer among the 4 leading cancers in the Republic of Korea and who underwent Korean medicine treatments within 1 month were eligible for the study. Other inclusion criteria included patients with Eastern Cooperative Oncology Group performance status 0 to 3 and age ≥ 19. All the participants are required to consent to the study protocol after sufficient understanding and voluntarily sign an informed consent form.

Participants with the following conditions would be ineligible: underlying comorbidities (other than cancer) resulting in systemic function deterioration, such as severe dementia, cerebrovascular disease, end-stage renal disease, aspartate aminotransferase or alanine aminotransferase levels exceeding 3 times the upper normal limit, any emergency situations that would take precedence over Korean medicine, requirement of major surgery or surgical intervention, or pregnancy or breastfeeding during the study period.

Four lesions of cancer including lung, colorectal, stomach, and breast cancer were selected according to the cancer incidence and cancer mortality rates in Republic of Korea and a prior survey study.^1,13 Those sites of cancer showed high cancer incidence and cancer mortality rates in common,¹ and consist almost two-thirds of cancer patients visiting Korean medicine hospital.¹³

Study Procedures

Follow-up assessments would be performed at 3 and 6 months. The terms, efficacy, and safety of the therapies received by the participant would be included in the registry data, and additional assessments, including the Functional Assessment of Cancer Therapy-General (FACT-G), MD Anderson Symptom Inventory-core (MDASI-Core), and Body Constitution Questionnaire (BCQ), would be performed. After 6 months, surveillance follow-up would be performed for an additional 18 months. A total of 24 months of follow-up was scheduled.

Data Collection

This is a prospective observational study that will not control any interventions. Demographic information, radiologic images including computed tomography scan or magnetic resonance imaging, and blood test data will be obtained from the patient. Computed tomography scans should be accompanied with written reports by professional radiologists. Major treatment histories, including medical history, surgery, chemotherapy, and radiation therapy, will be investigated to obtain cancer-related information. In addition, a structured survey on herbal medicines, acupuncture, electroacupuncture, moxibustion, and cupping as Korean medicine-related treatments would be conducted. CAM is defined as any treatment with purpose of cancer care, but not conventional therapy including surgery, radiation therapy, chemotherapy, and hormonal therapy. For other CAM-related treatments, structured surveys will be conducted in 3 categories: external interventions, such as hyperthermia, administrative interventions, and others, such as cognitive behavioral therapy.

Assessment and Safety

The primary outcome would be the FACT-G score at 3 months. The FACT-G, which was developed by the Functional Assessment of Chronic Illness Therapy group and validated in 2013, is a key questionnaire that efficiently investigates the most frequently occurring symptoms experienced by patients with cancer and their quality of life.¹⁴

Secondary outcomes include the MDASI-Core and the BCQ. The MDASI-Core is a multi-symptom assessment, to evaluate several symptoms including pain, fatigue, nausea/vomiting, sleep disturbance, dyspnea, cognitive impairment, anorexia, and mood. The BCQ was developed by Lu et al to evaluate the body condition in terms of Yin deficiency, Yang deficiency, and stasis type. The BCQ is a reliable and validated questionnaire.¹⁵ Overall and disease-specific survival will also be recorded. Adverse events and safety, including laboratory test results, will be recorded. Adverse clinical events will be graded based on the Common Terminology Criteria for Adverse Events version 5.0. Causality will also be assessed according to the World Health Organization Uppsala Monitoring Center causality system. The global impression of the patient will be assessed using the Patient Global Impression of Change (PGIC), a seven-point Likert scale for global impression.

Recruitment

Participants will be recruited nationwide through local advertisements and flyers that will be handed out locally. Broadcast notifications will be posted on the board of each hospital. Recruitment began in April 2022, and will end in June 2026.

Data Management and Monitoring

We designed a data dictionary according to the protocol before establishing a database for the study. Data will be recorded in an electronic data capture system (EDC), or a web-based database (MyTrials, Bethesda software, Seoul, Republic of Korea). The authorized clinical research coordinator would record the data, and the data safety monitoring committee would access the database to monitor, audit, and lock or release data. Automatic queries would be generated in a timely manner in response to the recorded data according to predefined algorithms. Initial and interim meetings will be periodically held to monitor the integrity and consistency, coordinate data collection, address concerns, and determine whether the study should be continued or terminated. However, the interim monitoring interval, which is planned bimonthly, could be changed according to the anticipated risk of the study at each study site.

Statistical Considerations

Sample size

Due to the nature of this observational study, no sample size calculation have been performed but the anticipated number of 650 participants was chosen to satisfy the normal distribution and confirm the safety of Korean medicine, based on the assumption of the number of possible enrollment patients at each site according to a prior survey study.¹³ Advanced or metastatic cancer patients with high dropout rate due to worsening of performance status and significant mortality rate are expected to be enrolled in this registry study. The 5 study sites are distributed across the country.

Statistical considerations

Descriptive analysis will be used to assess baseline data, diagnosis and therapeutic procedures, including mean and proportions. Statistical analyses for evaluating the changes of the FACT-G, BCQ and MDASI-Core at 3 and 6 months will be performed according to the intention-to-treat (ITT) principle. Cutoff values will be processed according to the last observation carried forward (LOCF) method. The full analysis set (FAS) will exclude the following participants: those who fail to meet the eligibility criteria but were discovered after enrollment in the study, those who have never visited the hospital after enrollment, and those who have never received Korean medicine treatment following enrollment.

A statistical significance level of .05 and a 2-sided test will be used. Continuous data are presented as means and standard deviations, while categorical data are presented as frequencies and percentages. Continuous data will be analyzed using Student’s independent t-test or Wilcoxon signed-rank test, based on the normality results, and categorical data will be analyzed using the chi-square test or Fisher’s exact test. If necessary, median values and confidence intervals will be calculated. Unless stated otherwise, all the data will be analyzed using independent Student t tests and analysis of variance (ANOVA).

A subgroup analysis will be performed according to the primary cancer lesion. Results, including the FACT-G, BCQ, and MDASI-Core, will be analyzed using a linear mixed model in the entire group or subgroup analysis. An analysis of covariance (ANCOVA) will also be performed using baseline data as covariates. Survival data, including overall and progression-free survival, would be analyzed using Kaplan–Meier survival analysis. Significance will be evaluated using the log-rank test. Univariate and multivariate analyses will be performed to identify the risk factors. The Cox proportional hazard ratio model will be used to estimate each variable. Death is regarded as an event, and the last time confirming survival is regarded as a censored event. This is a single-group study. ; therefore, a comparison is not possible. However, if necessary, external control or database can be utilized to compare baseline characteristics, survival, safety, and prognostic factors. Analyses will be performed using the statistical program PASW ver. 25.0 (SPSS Inc., IL, USA).

Discussion

Cancer is one of the leading causes of death in most countries; moreover, the burden on the healthcare system is increasing along with higher mortality attributed to cancer.¹⁶ Although astonishing developments in cancer treatment have been established, a great deal of information concerning cancer still remains unknown. Thus, multiple cancer registries are being established to understand cancer and patients with cancer. The following registries have been launched: the Northern and Yorkshire Cancer Registry and Information Service (NYCRIS), Thames Cancer Registry, Australian Clinical Quality Registries, and Canadian Cancer Registry. In Korea, the National Cancer Center is also establishing a registry for each type of cancer, which aims to use valuable clinical data by collecting data related to diagnosis, staging, treatment, and outcomes under the name of the National Cancer Data Center in collaboration with various external databases.¹⁷

However, existing cancer registries have certain limitations concerning the quality of life of patients with cancer. Most cancer registries focus on the incidence, pattern of treatment, response rate, and rate of survival.¹⁸ Data concerning the complications and quality of life following cancer are insufficient. In addition, owing to the rapidly changing pace of oncology care, clinical registries are not always in synchrony with current clinical practice.¹⁹ Cancer-related symptoms are independent predictors of survival and the severity of symptoms experienced by patients with cancer is sometimes not directly proportional to the tumor burden.²⁰ By collecting cancer-related symptoms, consistency and rationale of palliative cancer care may become possible.

Integrative medicine may have the potential to alleviate symptoms, improve the quality of life, and extend survival in patients with cancer. Previous cohort studies have revealed that integrative medicine, including traditional Chinese or Korean medicine, improves survival in patients with cancer.^21
-24 Acupuncture with analgesics is more effective than analgesics alone for relieving cancer-related pain. For non-pain-related symptoms in patients with cancer, various traditional medical interventions, including acupuncture, moxibustion, herbal medicine, and meditation, are generally effective when combined with conventional treatment or usual care. Non-pain symptoms include sleep disturbances, fatigue, anorexia, and peripheral neuropathy.²⁵

In addition to Korean medicine, the use of other integrative medicine modalities, such as mistletoe (Viscum album L.) extract or vitamin C is also high, which reaches over 30% of the patients with cancer who visit Korean medical hospitals.¹³ Integrative medicine tends to be used alongside conventional treatment, and an increasing trend is observed with 49% of the patients with cancer using it over the past years.²⁶ Integrative medicine in Korea also has a very unique status within the dual medical system of Korea that includes both conventional medicine and Korean medicine.²⁷ The use of Korean medicine was monitored under the national healthcare insurance system; thus, the actual use can be reviewed specifically and precisely. Because integrative medical treatments are not collected within the scope of existing cancer registries, designing and establishing a cancer registry for integrative medicine, including Korean medicine, are warranted.

Study limitations: First, total sample size was small for observational study and the follow-up period also short. The target sample size and the follow-up period of this study was determined based on the previous survey of the potential co-researchers in this study considering the clinical practice in Korean Medicine hospitals. Second, this is a single-arm prospective observational study without control group. Further researches with statistical sample size calculation and nationwide long term follow-up period with control group are necessary.

Conclusions

This non-interventional observational study aims to serve a predetermined public health purpose by establishing the KMCARE registry. KMCARE is intended to capture prospective structured data on any integrative oncology treatment in the form of a predefined protocol under the principle of inclusivity and timely connection with real-world evidence. Upon assessing these registration data, we may be able to determine the effectiveness and safety of Korean medicine in patients with cancer before deciding its implementation. The data collected in the KMCARE can be classified into patient information (eg, demographic characteristics, medical imaging, and laboratory test results), type of treatments received (eg, standard cancer treatment and integrative oncology treatments), and outcomes (eg, FACT-G, MDASI-Core, and BCQ) from cohort participants. By collecting these variables, we expect to determine association with various internal and external databases and utilize them as big data at the national level in the future.

Footnotes

Author Contributions

Conceptualization, Methodology, Writing—Original draft: Jee Young Lee. Data curation, Investigation: Hayun Jin. Investigation, Validation: Su Bin Park. Project administration, Methodology: Eun Hye Kim. Investigation, Writing—Original draft: Jee-Hyun Yoon. Project administration, Supervision, Conceptualization, Writing—Review & Editing: Seong Woo Yoon.

Data Availability

The data of this study are available from the corresponding author upon reasonable request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HF20C0038).

Ethical Statement

This study was reviewed and approved by the Institutional Review Boards of Kyung Hee University Korean Medicine Hospital at Gangdong (KHNMCOH 2022-03-009), Kyung Hee University Korean Medicine Hospital (KOMCIRB 2022-05-003-005), Daejeon Korean Medicine Hospital of Daejeon University (DJDSKH-22-BM-11), Wonkwang University Jeonju Korean Medicine Hospital (WUJKMH-IRB-2022-0005), and Daegu Korean Medicine Hospital of Daegu Haany University (DHUMC-D-22005-AMD-02).

ORCID iDs

Jee Young Lee

Su Bin Park

Eun Hye Kim

Seong Woo Yoon

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