A study protocol for the CHinA National CancEr screening (CHANCES) trial: a randomized controlled study to compare the screening strategies for lung cancer and colorectal cancer

Abstract

Background

Well-implemented cancer screening strategies can significantly enhance early detection rates, leading to improved treatment outcomes and reduced mortality. However, there remains a paucity of high-quality evidence from developing regions. The CHinA National CancEr Screening (CHANCES) Trial aims to comprehensively evaluate and compare different screening strategies for lung cancer and colorectal cancer (CRC) in the Chinese population.

Methods

The CHANCES trial is a randomized controlled trial aimed at assessing the effectiveness of screening using low-dose computed tomography (LDCT) either annually or biennially for reducing lung cancer-specific mortality. Additionally, our trial seeks to evaluate the efficacy of various screening strategies for CRC. In this 5-year project, a total of 105,600 participants aged 50–74 from 25 provinces will be enrolled and randomized into one of three arms: (i) receiving five annual LDCT scans along with a single colonoscopy (n = 26,400); (ii) undergoing three biennial LDCT scans and five annual fecal blood tests using fecal immunochemical testing (FIT) (n = 39,600); (iii) opting for either a single colonoscopy or five annual FIT tests (n = 39,600). Participants with positive FIT findings will be recommended to undergo a diagnostic colonoscopy. The primary endpoint of this study is lung cancer-specific mortality, and cost-effectiveness analyses of the various screening strategies in the Chinese population are also planned.

Discussion

To our knowledge, this trial represents the first endeavor statistically powered to assess the potential reduction in lung-cancer-specific mortality through screening with LDCT annually or biennially compared to a no screening arm. Additionally, it seeks to explore the feasibility of integrating lung cancer and CRC screening in a developing nation setting. The anticipated findings from this study hold the potential to provide evidence-based recommendations for cancer screening programs, thereby advancing cancer prevention and control efforts not only in China but also globally.

Trial registration

ChiCTRN(Chinese Clinical Trial Registry Number), ChiCTR1900025257. Registered on 2019-08-18.

Background

Lung cancer stands as the foremost cause of cancer-related mortality worldwide, with an estimated 2.48 million new cases and 1.82 million deaths in 2022, as reported by GLOBOCAN [1]. Similarly, colorectal cancer (CRC) ranks as the third most prevalent cancer globally and the second most fatal in 2022 [1]. In China, lung cancer accounts for 37% of global cases and 40% of deaths, while CRC represents 30% of both cases and deaths worldwide [2]. Over recent decades, China has witnessed a steady rise in the incidence and mortality rates of both lung cancer and CRC [3]. This surge underscores the pressing need for effective strategies to alleviate the burden of these cancers, prompting the call for more robust evidence from large-scale randomized trials to inform healthcare policies.

While population-based randomized controlled trials (RCTs) have demonstrated mortality reduction in lung cancer and CRC through repeated screening, the majority of data on lung cancer screening efficacy originates from Western healthcare systems. Trials such as the U.S. National Lung Screening Trial (NLST) and the Dutch–Belgian NELSON trial in Europe have substantiated the significant reduction in lung cancer mortality with repeated low-dose computed tomography (LDCT) screening among high-risk populations [4, 5]. LDCT screening is widely endorsed as the evidence-based approach for early lung cancer detection [6]. However, optimal time intervals for repeated LDCT screening among high-risk populations in developing regions remain undetermined. Specifically, the comparative benefits and drawbacks of annual versus biennial screening intervals are yet to be elucidated, posing critical considerations for personal healthcare choices and national resource allocation.

In the realm of CRC screening, the United States Multi-Society Task Force on Colorectal Cancer advocates for colonoscopy every ten years and annual fecal immunochemical testing (FIT) as a primary screening regimen [7]. Nevertheless, no RCT has directly compared the impact of colonoscopy versus FIT screening on CRC mortality. Currently, five large-scale RCTs of FIT and/or colonoscopy are underway across the United States, China, and European nations [8, 9]. Given that screening effectiveness hinges on population compliance and test detection rates, uncertainties persist regarding the differential efficacy between colonoscopy and FIT screening programs, underscoring their critical implications for both individual and national healthcare decision-making.

To address these knowledge gaps, the China National Cancer Center (NCC), in collaboration with the U.S. National Cancer Institute (NCI), has initiated a multi-center population-based RCT known as the CHinA National CancEr Screening (CHANCES) Trial for lung and colorectal cancers. This landmark trial aims to ascertain whether annual or biennial LDCT screening can mitigate lung cancer-specific mortality among high-risk urban Chinese residents, while also assessing the efficacy and cost-effectiveness of diverse screening strategies for lung cancer and CRC.

Methods/ design

Study design

The CHANCES Trial for lung cancer and CRC represents a prospective, multi-center RCT operating within community populations. The trial comprises three arms and aims to enroll 105,600 high-risk individuals, with a male to female ratio of 7:3, across 25 geographically diverse urban study sites throughout China. Upon providing signed informed consent, eligible participants will be randomly assigned to one of the three groups in a 2:3:3 ratio (Fig. 1). The screening phase will span five years for all participants, followed by a minimum three-year follow-up period for a first-stage analyses. All individuals will be followed for at least ten years for the final evaluation. The three study arms are as follows:

• 1) Annual LDCT: This arm entails five annual LDCT screens in addition to one-time colonoscopy screening (n = 26,400). While a one-time colonoscopy can be scheduled at any point during the study period, baseline colonoscopy is preferred unless specifically declined by the participant.

• 2) Biennial LDCT: Participants in this arm will undergo biennial LDCT screens (total of 3 rounds) alongside five annual rounds of FIT screening (n = 39,600). Individuals with positive FIT results will be referred for diagnostic colonoscopy.

• 3) CRC screening (the LDCT control arm): Participants in this arm will have the option to choose between one colonoscopy or five rounds of FIT screening (n = 39,600), based on their personal preference. While colonoscopy is typically regarded as the “gold standard,” FIT will be made available to those who decline colonoscopy. Site staff will provide participants with information regarding the heightened risk of lung cancer, conduct health education sessions on cancer prevention, and encourage participation in lung cancer screening.

Fig. 1

Flow diagram of the study design

Study aims

The CHANCES Trial has two primary objectives: (1) to assess whether LDCT screening reduces lung cancer-specific mortality among high-risk Chinese urban residents, and (2) to determine the optimal screening interval (annual vs. biennial) for reducing lung cancer-specific mortality in LDCT screening arms. Supplementary Contexts provide further detail on secondary study aims.

Selection of study sites

Stringent criteria guided the selection of study sites. Each site exhibits a high incidence of lung cancer, ranking among the top three within its respective province, and is supported by a comprehensive regional or national cancer registry. Moreover, these sites are affiliated with local or provincial institutes for cancer prevention and control that are integrated into the China National Cancer Prevention and Control Network (NCPCN) and possess robust information technology infrastructure. Established by the China National Cancer Center (NCC) in 2018, the NCPCN serves as a comprehensive data fusion platform, amalgamating data from various sources including the national cancer registration system, national cancer screening programs, and the national anti-tumor drug surveillance program, which encompasses over 1 billion data records from more than 1,200 hospitals. Furthermore, the selection of study centers ensures diverse representation across China’s economic and geographical landscape. In total, 25 provincial study sites were identified for inclusion in the trial.

Randomization

The CHANCES Trial is spearheaded and overseen by the China NCC. Employing a centralized design, randomization is controlled by the China NCC, with stratification by study site. Randomization utilizes a blocked approach, with block sizes randomly selected at either 8 or 16. Enrollment into the trial is managed by individual study centers. Randomization is stratified based on gender (male and female) and age group (50–54, 55–59, 60–64, 65–69, 70–74) within each center.

Before randomization, an eligibility verification form is completed to ensure participants meet inclusion criteria and provide informed consent. Subsequently, each participant is assigned a unique identification (ID) number and allocated to a trial arm, which remains consistent throughout the study period. During the randomization process, new enrollees are cross-checked against existing participants to identify any potential duplicates.

Study population and recruitment

Eligible participants for this study must be between the ages of 50 and 74 and have been permanent residents of cities where screening sites are located for at least five years. Additionally, they must have one or more of the following defined risk factors: (a) a history of smoking equivalent to at least 30 pack-years, whether they are current smokers or former smokers who quit within the past 15 years; (b) a diagnosis of chronic obstructive pulmonary disease (COPD) or a history of diffuse interstitial pulmonary fibrosis; (c) exposure to one or more of eleven occupational carcinogens for more than five years; (d) non-smoking women exposed to second-hand smoke for more than 20 years from a family member or co-worker who meets the smoking history criteria. Participants with a history of tuberculosis must have been cured for at least two years. Detailed exclusion criteria are outlined in Supplementary Context.

Interventions

LDCT

Participants enrolled in the annual and biennial LDCT arms will undergo free LDCT scans according to the designated intervention protocols, ensuring that each scan includes 16 or more slices and is conducted at approved hospitals participating in the trial. The standard clinical procedures for LDCT scans will be followed, including scheduling appointments, obtaining informed consent, and conducting the LDCT examination. Detailed guidelines for LDCT imaging evaluation and pulmonary nodule management are provided in the supplementary context and figure (LDCT scan protocol and pulmonary nodule management).

Only hospitals adhering to the specified scan protocol will be eligible to participate in the trial, ensuring consistent quality across all study sites. Each LDCT image will be interpreted by experienced radiologists at the study centers, with a minimum of three years of lung cancer screening experience. All LDCT images will be transmitted to the China NCC via the NCPCN for further quality assessment. Additionally, approximately 1.5% of all images will be randomly reviewed annually by an expert panel at the China NCC to ensure ongoing quality control. This multidisciplinary expert panel, comprising experienced radiologists, thoracic surgeons, oncologists, and radiotherapy physicians, will be responsible for central reading and double-checking of the images. Ongoing central reading of images has demonstrated consistent diagnostic results, indicating high and uniform image quality across the study sites.

Colonoscopy

Colonoscopy procedures will adhere to standard clinical protocols, including pre-procedural blood testing for infectious diseases, bowel preparation, dietary instructions, and anesthesia administration if required [9]. Tissue specimens from clinically indicated biopsies will be collected for further pathological analysis, and all colonoscopy findings will be documented photographically. Colonoscopies will be performed by experienced endoscopists with at least five years of experience. An expert panel comprising experienced endoscopists and pathologists will conduct quality control assessments by randomly selecting and reviewing approximately 5% of colonoscopy and pathology documents each year.

FIT

FIT for hemoglobin will be provided to participants by the study sites after successful registration in the trial. Participants will receive instructions on how to interpret the results and identify a positive test. Study center staff will communicate FIT results to participants within three days of receiving the test kits. Participants can also upload their results to the study website for documentation. Invalid test results will prompt the provision of new test kits until a valid result is obtained. Participants with confirmed positive FIT results will be contacted for follow-up colonoscopy arrangements.

Patient and public involvement

Prior to beginning the process of recruitment, basic research information and potential benefits and harms of cancer screening will be disseminated to the target population in the selected study sites via multiple strategies, including all forms of advertisement (i.e., TV, radio, billboard, leaflets, and the Internet). At the recruitment phase, staff at the study sites will inform participants about the research questions, study design, and screening interventions. Potential benefits and harms of each screening modality will be discussed with participants. Screening tests in the study will be provided to participants at no cost. Costs for subsequent follow-up of abnormal tests and management will be borne by patients or their insurance carriers. Participants can quit the study and withdraw their informed consent at any time. Participants and the general public played no role in the design of the study.

Follow-up

The study will conduct both active and passive follow-up. For active follow-up, all participants in Arms 1 and 2, as well as participants in Arm 3 who choose FIT screening, will be interviewed when they return for the subsequent T1–T4 intervention. Participants in Arm 3 who choose the one-time colonoscopy screening and participants in any arm who refuse to undergo screening with any test will be interviewed to collect information such as health status and outcome by trained site staff via a telephone call, home visit, or other contact methods, such as WeChat or text messaging. For passive follow-up, linkage data from the cancer registry system (part of the database belonging to the NCPCN) will be performed annually to track the cancer cases. Information on deaths and cause of death will be linked to the national mortality surveillance system annually [10]. In addition, data linkage to local medical insurance, claim databases, and local hospital information systems will be used to verify the outcomes annually.

Contamination evaluation

The extra screening intervention attended by the participants beyond the study protocol are not allocated by randomization and may introduce bias to the study results. The study team will contact the participants whose screening findings are negative to complete a questionnaire interview in the last round of the intervention. Information regarding the diagnostic history or thoracic/colonic examinations will be collected. The contamination rate is anticipated controlling to be lower than 10%.

Data and biospecimen collection

Epidemiological investigation

Questionnaire interviews will be conducted by trained staff using a standard protocol to collect information regarding sociodemographic factors, occupational history, smoking status and history, dietary habits, physical exercise, mental and emotional health, co-morbidity, family history of cancer, and gynecologic disease history.

Clinical examination process and diagnosis information

Clinical information will be collected, including the examination duration, completeness of LDCT scan and colonoscopy, bowel preparation status (and adequacy of sedation if used), complications, polyp features (i.e., number, position, size, color, and shape), description of other abnormal findings, and pathology diagnosis.

Health economic evaluation

The provider perspective of health services is adopted. To answer questions on the cost effectiveness for lung and CRC screening, the direct costs of materials, equipment, personnel, and drug, as well as unit-cost data regarding the costs of each screening strategy and stage-specific, as well as histology-specific cancer treatment, will be collected from all study sites and the national reimbursement data system. Tree-based models will be applied including a natural history component when analyzing these data.

Biospecimen collection and handling

All participants will be invited to donate blood and stool samples before performing their screening tests (LDCT, FIT, and colonoscopy), and biopsy specimens after their colonoscopy exam. Biospecimen collection will be required at baseline (T0) and follow-up (T1–T4). Detailed information regarding the biospecimen handling is shown in supplementary context (Biospecimen collection and handling). All biospecimens will be transported to the China NCC Biobank for long-term preservation and future research.

Construction of a web-based data management system

All information, including epidemiological risk factors, clinical examination and diagnosis, LDCT and colonoscopy images, health economics parameters, and biospecimen collection, will be collected, real-time transferred, and documented in a web-based data management system utilizing the NCPCN.

Statistical consideration and analyses

Sample size

The projected accrual of this trial is about 105,600 participants (26,400 in Arm 1, 39,600 in Arm 2, and 39,600 in Arm 3). Follow up is expected to be at least 10 years from the randomization. Sample size and power calculations for the primary endpoint of the CHANCES Trial, the lung cancer mortality, used an approach developed by Hu and Zelen [11]. This approach allows for the staggered entry of participants and analyses based on calendar time instead of time in the study. Parameters for the Hu-Zelen model are listed in Supplementary Tables 1 and were estimated using data from the NLST ^[4]. With about 105,600 participants enrolled between 2020 and 2023, the first three years of the trial, it has a statistical power of 90% for detecting a 30% lung cancer mortality reduction between 5-annual LDCT and no LDCT arms, and the same power for detecting a 20% lung cancer mortality reduction between 3-biennial LDCT and no LDCT arms. The mortality reductions of 30% and 20% may be achieved in an analysis conducted on events occurring through 2027 (annual vs. no LDCT) and 2029 (biennial vs. no LDCT).

Statistical analysis

Analysis for the primary outcome will be a comparison of confirmed lung cancer deaths in the three arms. The mortality rate will be calculated as the ratio of the number of deaths due to type-specific cancer to the person-years at risk for each study arm. The primary analysis will be by intention to treat, but ancillary per-protocol analyses will also be conducted. Person-years will be estimated from the date of randomization. Contingency table analysis and analysis of variance will be used to compare categorical and continuous variables, respectively. between the respective arms. The descriptive statistics will be used to examine differences in incidence and mortality across the different screening arms. Statistical software, including SAS V.9.2 and R V.3.4.1 (R Foundation for Statistical Computing, Vienna, Austria), will be used. For health economic evaluations, a decision-tree Markov model will be used to evaluate the cost-effectiveness of each screening strategy for lung cancer and CRC using the software of TreeAge Pro (TreeAge Software, Inc., MA, USA).

Data monitoring committees and data management

The data and safety monitoring board (DSMB), an independent group of experts, comprising radiologists, endoscopists, thoracic surgeons, pathologists, biostatisticians, epidemiologists, ethicist, health economist, and laboratory physician will monitor data collection and analysis, and make recommendations concerning the continuation, modification, or termination of the trial. Interim analysis will be developed with DSMB cooperation. All data will be transmitted to the Central Data Management Team at the China NCC, where secure databases are constructed, and analyses are performed. Adverse events will be recorded in standardized forms and reported to the committee. Paper documents are also securely stored by the China NCC.

Trial status

This screening trial is currently in the participant recruitment and data collection phase. A total of 66,252 eligible participants have been randomised and are under respective screening in the three groups as of March 2023.We anticipate that the recruitment and baseline screening will be completed by December 2024. As this is a five-year project, we will finish the trial by December 2028.

Discussion

To the best of our knowledge, this is the first RCT with adequate power to assess the effectiveness of lung cancer screening using LDCT in a developing nation, as well as the first to integrate multi-center screening for lung cancer and CRC in a community-based population.

The debate continues regarding the optimal frequency of LDCT screening, whether annual or biennial. While more frequent screening may increase the detection of lung cancer cases and potentially reduce mortality, it also raises the risk of false positives and overdiagnosis. Therefore, striking a balance between reducing referral and false-positive rates while maintaining the effectiveness of lung cancer screening is crucial. Findings from the Multicentric Italian Lung Detection (MILD) Trial suggest that biennial screening could be as effective as annual screening, as evidenced by comparable lung cancer stage distributions between the annual and biennial screening arms [12]. However, the MILD trial may lack the power to detect differences in lung cancer mortality between the two screening intervals. Modeling analyses have also raised concerns about the ability to detect stage IA lung cancer with a two-year screening interval [13]. The results of our RCT will offer essential insights into LDCT-based lung cancer screening strategies, not only for China but also globally.

The feasibility of annual versus biennial lung cancer screening is a pivotal question in the realm of early detection and prevention. In Europe, ongoing trials such as the SUMMIT and 4-IN-THE-LUNG-RUN are actively investigating the optimal screening intervals, both of which focused on heavy smokers. These trials offer valuable insights that can be compared with data from Chinese populations to understand regional variations in lung cancer progression. Factors such as genetic predispositions, environmental exposures, and healthcare infrastructure can influence the preclinical development of lung cancer and subsequently affect the efficacy of screening intervals. By examining these geographical differences, we can better tailor screening programs to the specific needs of the populations in different regions, thereby enhancing the effectiveness of lung cancer detection and ultimately improving patient outcomes.

Concurrently, ongoing studies are investigating the efficacy of colonoscopy and FIT in relation to CRC incidence and mortality in Europe and North America [8]. The Nordic-European Initiative on Colorectal Cancer found no significant reduction in CRC mortality in the invited screening group compared to the group without invitation or screening during a median follow up of 10 years, with only 42% of the invited group undergoing screening [14]. A more pronounced effect of screening on CRC mortality reduction may be expected with longer follow up. Meanwhile, baseline screening results from an RCT in six centers in China since May 2018 revealed a higher compliance rate for FIT (94.0%) compared to colonoscopy (42.5%), yet colonoscopy detected advanced neoplasms at a higher rate (2.40%) than FIT (1.13%), with an odds ratio of 2.16 (95% confidence interval 1.61–2.90; P < 0.001) [15]. The disparity in compliance rates and detection outcomes between colonoscopy and FIT highlights the need for a thorough examination to determine the optimal CRC screening recommendation. Therefore, our trial aims to address this issue and assess whether offering individuals a choice of screening strategies, as in Arm 3 of our study, leads to higher participation rates and subsequently more effective reduction in CRC mortality. It’s noteworthy that this study is the first randomized controlled trial on CRC screening conducted in individuals at high risk of both lung cancer and CRC cancer.

In the present study, we chose to obtain informed consent prior to randomization, consistent with standard practice in most clinical trials. Some studies employ a design in which randomization occurs before obtaining informed consent. These trials are often conducted in countries with population registry systems that allow for follow-up of the control arm without participants’ knowledge of their status. However, in our study, individuals in the control arm (Arm 3) are explicitly informed that they are at high risk for lung cancer and are offered the option of undergoing either a one-time colonoscopy or annual FIT for five years. They are followed up using both active methods (e.g., telephone calls, home visits) and passive methods (e.g., linkage with population registries). Moreover, randomization prior to informed consent may enhance the generalizability of study results by reducing pre-selection bias. Specifically, adherence rates in the intervention arm may more accurately reflect real-world conditions. However, this approach can lead to increased withdrawal rates, as participants may choose to leave the study upon learning of their intervention allocation, potentially compromising statistical power and study efficiency. In both scenarios, adherence to intention-to-treat analyses is crucial. These analyses include all participants according to their randomized treatment assignment, regardless of adherence or withdrawal during the trial. This method prevents bias and ensures the trial’s findings accurately reflect real-world conditions, maintaining the integrity and reliability of the study results. It helps in evaluating the true effectiveness and safety of treatments, guiding clinical decision-making and regulatory decisions effectively.

In summary, this multi-center population-based RCT will evaluate the effectiveness of LDCT screening versus LDCT control with only CRC screening, as well as annual and biennial LDCT screening strategies. Additionally, three colorectal screening strategies will be compared within the same study population. Successful execution of this trial will provide insights into mortality reduction, as well as the feasibility and utility of lung cancer and CRC screening initiatives in China. The results will serve as a valuable resource for policymakers in the development of future national screening programs.