Lung cancer screening in limited resource regions: the 3rd Brazilian Early Lung Cancer Trial (BRELT3/mobile ProPulmão)

Abstract

Aims

To describe tomographic findings in a high-risk lung cancer population in resource-limited Brazilian areas, quantify pulmonary nodules and lung cancer frequency, analyze challenges in lung cancer screening within the Brazilian public health system, assess lung function in individuals with moderate or severe emphysema, and evaluate the role of community health agents in recruiting high-risk populations.

Methods

This is a prospective, single-arm, longitudinal observational study involving individuals aged 50–80 years, current or former smokers with a smoking history of at least 20 pack-years, undergoing low-dose computed tomography (LDCT) with a 12-month follow-up. Screening results are classified according to Lung-RADS v2022 standards, with those rated as 3 or 4 undergoing further diagnostic assessments. The study aims to demonstrate the feasibility and effectiveness of lung cancer screening in socially vulnerable populations within resource-limited settings, providing essential insights to reduce mortality and improve health outcomes.

Conclusions

The findings will assist the development of policies on lung cancer screening in the public health system. The study’s dissemination plan includes a website, social media, and participation in scientific conferences.

Highlights

• The study targets remote regions in Brazil with limited access to healthcare, aiming to assess the feasibility and effectiveness of lung cancer screening in these underserved areas.

• Utilizes mobile LDCT units to bring advanced diagnostic capabilities directly to high-risk populations in remote locations, overcoming geographical barriers.

• Emphasizes the role of community health agents in recruiting participants and raising awareness about lung cancer risks and the importance of early detection.

• Involves a multidisciplinary team for the classification and management of lung nodules, with decisions made collaboratively through a Screening Board Committee.

Main points of the article

• Clinicians should identify eligible patients for chest LDCT screening based on age, smoking history and current or former smoking status.

• A multidisciplinary approach is crucial for developing individualized treatment plans for patients with lung nodules.

• Clinicians should integrate smoking cessation programmes into all patient care plans to reduce lung cancer risk and improve overall health.

• Patients must be educated about the importance of screening, the risks and benefits of chest LDCT, and the importance of following up and adhering to treatment.

• Community health agents play a vital role in raising awareness about lung cancer prevention and screening within the community, facilitating access to healthcare resources, and providing support to individuals at risk.

• High-risk individuals should be screened annually with chest LDCT to detect lung cancer early.

1. Introduction

Lung cancer is an aggressive disease with a high global incidence, estimated at approximately 2.2 million new cases and 1.8 million deaths in 2020 [1]. Although smoking prevalence is declining, the use of tobacco products remains the leading risk factor for lung cancer [2]. Another significant factor is exposure to carcinogenic agents in occupational settings [3]. In Brazil, it is estimated that 12.6% of the population are smokers, and almost 30 thousand deaths are due to lung cancer [4].

Substantial progress in lung cancer screening is attributed to the superior sensitivity and diagnostic capability of Low-Dose Computed Tomography (LDCT) over conventional chest radiography. This advancement has resulted in decreased mortality rates and improved diagnostic accuracy, markedly enhancing the early detection and treatment of lung cancer. Additionally, several studies indicate that chest LDCT is cost-effective for lung cancer screening [5–12].

However, there are few lung cancer screening studies in Latin America. The Brazilian Early Lung Cancer Detection Trial (BRELT) was the first to address this gap [13]. The subsequent BRELT1 and BRELT2 studies contributed with valuable data and insights on lung cancer prevalence and screening efficacy [14,15].

The current BRELT3 study aims to investigate the challenges associated with implementing lung cancer screening programs in remote regions distant from major urban centers, where access to healthcare and resources is often scarce. These remote regions are defined as geographically isolated areas with limited infrastructure, where residents face significant barriers to accessing specialized healthcare services due to factors such as long travel distances, lack of transportation, and inadequate local healthcare facilities. The Brazilian Constitution guarantees universal, equitable, and comprehensive access to healthcare, highlighting the importance of understanding the challenges in facing this commitment within a nation of vast dimensions and significant social and demographic disparities.

To address these challenges, the BRELT3 study focuses on key strategies, such as deploying a mobile LDCT unit equipped with the necessary technology and staffed by trained healthcare professionals to reach remote communities (Figure 1). Telemedicine integration plays a crucial role in this strategy by enabling local healthcare providers in remote regions to connect with specialists in urban centers. This facilitates real-time consultation, diagnosis, and treatment planning, thereby bridging the gap in healthcare access and ensuring timely and effective medical intervention.

Figure 1.

Lung cancer screening mobile unit, the "ProPulmão Respiratory Health Truck". (A) Prepared for transport; (B) CT scan; (C) Technician performing examination; (D,E) Prepared for patient care.

Additionally, community engagement and education efforts are being made, collaborating with local leaders, including community leaders and local health officials, to raise awareness about lung cancer risks and the importance of early detection. The study also emphasizes capacity building by training local healthcare workers in chest LDCT technology and lung cancer management, thereby improving the sustainability of healthcare improvements in these areas.

Data resulting from this study will contribute to the characterization of the Brazilian population profile most exposed to lung cancer, considering the heterogeneity and demographic dimensions of the country. The BRELT3 study’s findings are expected to provide valuable insights into the effectiveness of lung cancer screening in diverse settings, particularly in areas where traditional healthcare delivery models may be less effective.

The primary aim of this project is to describe tomographic findings in a mobile lung cancer screening program in a high-risk population in Brazilians’ remote regions. Secondary aims include report the prevalence of pulmonary nodules classified as Lung Imaging Reporting and Data System (Lung-RADS) v2022 [16] categories 3 and 4 as well as the occurrence of lung cancer; investigate the challenges and barriers to lung screening in the public health system in developing countries; describe the lung function pattern and clinical features of patients with moderate or severe emphysema primarily identified through chest LDCT scans and explore the role and involvement of community health agents in engaging the local population in a lung screening program in developing countries. To achieve these goals we developed a prospective, single-arm longitudinal observational study, with 1 year of follow-up.

2. Methods

The protocol will be carried out in multiple cities across Bahia – Brazil, utilizing one mobile unit equipped with a LDCT scanner. This mobile units will travel to designated urban and rural areas to reach high-risk populations, especially those with limited access to healthcare facilities. Each city will have pre-selected location to receive the mobile unit. Local healthcare professionals will collaborate with the research team to ensure the smooth execution of the protocol, including patient education and referral for follow-up care in the local health care network.

2.1. Participants

This study will include people aged between 50 and 80 years, self-reporting as respiratory asymptomatic (without dyspnea, thoracic pain, weight loss or productive cough), current or former smokers with a history of at least 20 pack-years, who have ceased smoking within the last 15 years, living in selected cities in the state of Bahia that will host a mobile cancer screening unit, including Salvador, Serrinha, Santo Antonio de Jesus and Feira de Santana. Exclusion criteria comprehend individuals unable to perform the chest LDCT examination, intolerance to the horizontal supine position for more than 10 minutes, presentation of highly suggestive symptoms of lung cancer, diagnosis of serious heart disease (defined as conditions requiring multiple medications, frequent hospitalizations, or ongoing care for heart failure or significant arrhythmias), diagnosis of severe lung disease, on multiple medications and/or requiring home oxygen therapy, history of chest radiotherapy or pregnancy.

2.2. Recruitment and training

The recruitment period was started on August 2023, and the duration of the recruitment period is one year, with subsequent follow-up consultations and procedures. Candidates for the program will be identified through publicity in the local media and through an active search for possible candidates with screening criteria to be conducted by community health agents in the cities that will receive the mobile unit.

Community health agents play a pivotal role within the Brazilian health system. They are tasked with assessing community needs, actively promoting health, and preventing disease [17].

Historically, community health agents have served as the crucial connection between healthcare professionals and the community. These agents will undergo comprehensive training covering the fundamentals of lung cancer, the significance of screening for early detection, primary risk factors, and guidelines for recommending screening. The training will include workshops and educational materials to ensure they are well-equipped to engage the community effectively.

2.3. Study design

A non-probabilistic sampling method will be used, whereby all patients encountered by the research team will be approached and invited to participate in the investigation. The initial contact and complete interview of participants are carried out by a multi-professional team, conducted by regular nurses trained in the protocol, which is essential for minimizing costs related to population recruitment, avoiding unnecessary initial medical consultations for an asymptomatic population.

We acknowledge that using a non-probabilistic sample may introduce selection bias, as it depends on the availability and willingness of individuals to participate, potentially limiting its representativeness of the broader population. This limitation may affect the generalizability of the findings, and caution is warranted when extrapolating results to other populations or regions.

Additionally, we acknowledge the limitation of not including a control group in our study design. The primary objective of this study is to assess the feasibility and practical implementation of mobile lung cancer screening in remote and underserved regions. Given the focus on logistical, infrastructural, and healthcare delivery challenges specific to these areas, a single-arm study was deemed appropriate to gather initial insights into the screening process and outcomes within the targeted population. The absence of a control group limits the ability to compare outcomes directly with standard care or alternative screening methods. However, the data collected will provide valuable preliminary evidence that can inform future, more comprehensive studies, including those with control groups, to evaluate the comparative effectiveness and long-term impact of mobile lung cancer screening programs.

One of the research team nurses will conduct the eligibility interview over the phone to identify and invite the potential participants. Three thousand individuals will be consecutively enrolled.

The included people will participate in the initial program interview conducted by one of the program’s nurses. This interview will include a detailed medical history to assess personal and family history, exposure to major risk factors for chronic respiratory disease, smoking history, and symptoms. Other risk factors for lung cancer, such as family history and occupational exposure, are also assessed in this interview. The included people will participate in the initial program interview conducted by one of the program’s nurses. This interview will include a detailed medical history to assess personal and family history, exposure to major risk factors for chronic respiratory disease, smoking history, and symptoms. Other risk factors for lung cancer, such as family history and occupational exposure, are also assessed in this interview. During the interview, participants will complete the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial questionnaire to estimate their lung cancer risk and the Fagerström Test for Nicotine Dependence to evaluate their level of nicotine addiction. At the end of the interview, following free and informed consent form signatures, participants will be sent directly to the chest LDCT.

Smoking cessation is a critical intervention to reduce the risk of lung cancer and cardiovascular disease. Individuals identified as smokers during the screening process are referred to local health units participating in the National Tobacco Control Program, coordinated by the Ministry of Health, where they can receive tailored support to help them quit.

The outcome variables include the results of the first chest LDCT, performed after the participant inclusion in the study, and, in specific cases, new chest LDCT performed after 3 or 6 months, depending on the characteristics of the findings and the results of the spirometry, that will be performed on participants who present emphysematous findings in chest LDCT classified as moderate or severe.

2.4. Spirometry and chest LDCT impact

Spirometry will be performed on participants presenting with emphysematous findings on chest LDCT classified as moderate or severe by radiologists. The results of spirometry will guide follow-up chest LDCTs, with more frequent monitoring for those with significant respiratory impairment. Emphysema will be classified into mild, moderate, and severe categories by experienced radiologists based on visual assessment of LDCT images, rather than relying on automated software [18].

2.5. Imaging and reporting

A 16-channel multidetector system from Philips Medical Systems (ANVISA registration number: 10216710325; model: CTV16PFA100) will be used to perform the chest LDCT. The parameters used will be 120 kVp, 60 mA, gantry rotation time of 0.5 s and pitch of 1.375. A single acquisition is made during inspiration, and the images are then reconstructed with 20 mm collimation, 5 mm increment and 1.25 mm thickness. The effective radiation doses range from 0.8 to 1.3 mSv, with a dose-length product between 69 and 86 mGy. All chest LDCT will be evaluated by radiologists with experience in lung cancer screening protocols. All chest LDCT exams will have Lung-RADS v2022 classification. A CAD system is not used in the initial analysis.

In our study, we employ a one-time chest LDCT screening approach for lung cancer detection. This design is supported by evidence from the UK Lung Cancer Screening (UKLS) trial, which demonstrated that a single chest LDCT screening can significantly reduce lung cancer mortality. Other studies have reported that even a one-shot screening approach provides measurable benefits, making it a cost-effective strategy for lung cancer control, particularly in populations at high risk. The UKLS findings highlight the potential impact of such interventions, reinforcing the rationale for our study design in a similar context [19].

The one-year follow-up period in our study represents a limitation in assessing long-term outcomes such as cancer-related mortality and survival rates. While extended follow-up would provide more comprehensive insights into disease progression and long-term prognosis, our study is not designed to evaluate these endpoints. Instead, its primary objective is to describe the prevalence of pulmonary nodules and lung cancer, along with respective staging, within the target population. Despite the time limitation, the study still provides valuable initial data on lung cancer detection in underserved regions, offering insights into the feasibility and implementation of mobile LDCT screening. Furthermore, early-stage detection data can serve as a foundation for future studies with longer follow-up periods to assess survival and mortality outcomes more comprehensively.

2.6. Participant communication

Participants will receive written LDCT reports that include a QR code, allowing them to access their images and results digitally. This ensures transparency and ease of access to their health information. In addition, chest LDCT results will be provided to participants in a group session orientation for all chest LDCT classified as Lung-RADS 1 or 2.

Examinations classified as Lung-RADS 3 or 4 are discussed in an online tumor board meeting (Screening Board Committee) by a specialized medical team of radiologists, pulmonologists, thoracic surgeons, and oncologists.

To facilitate case analysis and discussion, clinical data and images are previously sent to the Screening Board Committee (SBC) and presented virtually during the online meeting. The SBC, conducted as a virtual multidisciplinary meeting, was also designed to reduce the impact of individual differences in image interpretation and ensure a more consistent approach to patient management. Following the presentation, SBC participants can vote using an online form with the main lung nodule approaches listed. Each case will be assigned a number and presented via Google Forms, where committee members can vote on management options. A consensus is reached when 70% or more of the votes align. In cases of disagreement, further discussion will determine the appropriate management.

Based on this discussion, further testing may be recommended following international recommendations to diagnose or rule out the possibility of lung cancer. Follow-up options are based on recommendations from the NCCN Lung Cancer Screening Guidelines and the American Society of Radiology according to the Lung-RADS staging categories. According to these recommendations, categories 1 and 2 include nodules with a benign appearance for which annual screening should be continued. Lung-RADS 3 or 4 should be evaluated based on size, solid component, and growth rate, and repeat imaging in three to six months or consider positron emission tomography (PET-CT) for nodules with a solid component greater than 8 mm. In higher suspicion cases, recommendations may include transthoracic puncture, bronchoscopy, or surgery for histopathologic confirmation of the possible diagnosis of lung cancer. Final lung nodule management will be defined by the medical practitioner in a shared decision-making process with the patient, adding local or social aspects not included on the initial SBC analysis.

Further diagnostic evaluations and continuity of care are provided through local and regional partnerships with private and public hospitals. Our research and administrative staff is dedicated to providing information and additional resources, such as transportation and local lodging, to ensure patient care.

The multidisciplinary team will monitor patients over a period of 12 months. Visits include the following procedures: chest LDCT, spirometry (for participants with pulmonary emphysema data classified as moderate or severe on chest LDCT), and medical consultations. Details of each step are described in Figure 2. The program will maintain regular contact with participants for one year to ensure appropriate follow-up over time. The follow-up period will be essential to monitor the development of nodules, perform additional tests as necessary, and ensure continuity of care.

Figure 2.

Lung cancer screening mobile unit workflow, starting with program dissemination in the communities receiving the mobile unit (yellow), through triage (gray), performing the tomography in the mobile unit (orange), to the decision-making process based on Lung-RADS classification (blue and green).

During the one-year follow-up period, the study will monitor for serious adverse events or complications related to LDCT screening and subsequent diagnostic procedures. Although the risk of adverse events from LDCT is low, potential complications from follow-up invasive procedures, such as biopsies, will be closely tracked and categorized by severity and causality.

Additionally, secondary variables will include efficacy measures related to expected study outcomes. When evaluating efficacy, the importance of the positive predictive value of the chest LDCT method is highlighted. We expect that at least 6.3% of participants evaluated will likely have Lung-RADS 4 categories and between 0.7% and 3.1% will have lung cancer at the end of follow-up [14,15].

Chest LDCT exams will be evaluated by senior radiologists trained in the Lung-RADS classification, and trained staff will perform spirometry. A "senior radiologist" was defined as a radiologist with extensive experience in thoracic imaging, particularly in lung cancer screening, typically involving at least five years of dedicated practice and participation in specialized training programs. The anamnesis and selection of candidates are carried out using the same criteria established in standardized medical consultations for screening.

2.7. Incidental findings management

Incidental findings on chest LDCT, such as benign pulmonary nodules, emphysema, or other non-lung cancer-related abnormalities, will be managed according to established clinical guidelines. Participants with incidental findings will receive a detailed report explaining the findings and recommended follow-up actions. Depending on the nature of the finding, participants may be referred to their primary care physician or a specialist for further evaluation. The study team will provide participants with clear instructions and resources to ensure appropriate follow-up care.

2.8. Sample size

Initially, we plan for this study to include 3000 participants to evaluate our primary outcome based on convenience sampling. Based on the population pyramid projection and the prevalence of smoking in the Northeast region of Brazil, it is anticipated that a significant portion of individuals in the communities visited by the mobile unit will be at risk. Assuming an average population of one hundred thousand inhabitants for these variables and considering that approximately 19% of the population is over 50 years old, we can estimate a total of 19 thousand individuals within this age group. The sample size was determined based on the population and smoking prevalence on the cities visited by the mobile unit, as well as the unit’s capacity to conduct screenings within the planned timeframe for each location. As an implementation study, our main goal is to create effective lung nodule pathways of care in the region.

Considering the current prevalence of smoking in Bahia, which stands at about 9.7% [20], and factoring in an additional 10% representing probable ex-smokers, we arrive at an estimated population at risk of nearly 3 thousand individuals for each community visited. It’s important to note that this estimate excludes patients already diagnosed with chronic diseases and undergoing regular treatment. Taking into account the low participation rates in lung cancer screening, but also the support of the primary health care structure in the places visited by the mobile unit, we expect to reach 1000 people in each city.

2.9. Data analysis and quality control

For data quality control, a data bank using REDCap platform was performed, where case report forms will be fulfilled with demographic, sensible and exams data from all participants and this information will be stored and monitored in the mentioned bank and presented in real time to the research team through a Power BI dashboard. Often the imputed data are checked by sampling and in case of errors identification, the data entry team receives retraining as needed.

To minimize missing data, rigorous data collection protocol will be implemented, supported by REDCap, which flags incomplete entries for immediate correction. In cases where data are missing, statistical imputation methods, such as mean imputation, regression imputation, or multiple imputation, will be applied to estimate missing values.

We intend to use Statistical Package for the Social Sciences (SPSS) version 29 to perform statistical analysis. Descriptive statistics will be used to summarize the demographic characteristics of study participants. Categorical variables will be summarized in absolute and relative frequencies (percentages). Information on numerical variables will be expressed as means, standard deviations (SD), medians, and minimum and maximum values.

The following statistical methods will be used to analyze the results: Chi-square test, Mann-Whitney test, Student’s t-test, and ANOVA with Bonferroni’s post-hoc test, among others. For all statistical tests, the significance level adopted will be Type I error <0.05 or 5%.

2.10. Ethics and dissemination plan

This research strictly follows the Brazilian Ethical guidelines (Res. 466/12; RDC 837/2023) and international guidelines, such as ICH E6 (R2), and Good Clinical Practices-Document of Americas), ensuring scientific integrity, reproducibility, traceability and reliability of the study. Participants are informed about the objectives and procedures, and written informed consent is obtained. Ethical measures guarantee data privacy and confidentiality, respecting fundamental scientific research principles and the Brazilian Data Protection Law (Law No. 13709/2018). This study is designed to adhere to the highest standards of human research practices, prioritizing the transparent disclosure of all outcomes [21]. The commitment to good practices seeks transparency in the disclosure of results, regardless of their nature. This approach aims to enhance both the credibility and the replicability of the study’s findings. The study is approved by the SENAI-CIMATEC Institutional Review Board through a CAAE number 67431523.6.0000.9287, with a financial support from the Bristol-Myers Squibb Foundation for the development of the mobile unit and chest LDCTs, Boehringer Ingelheim Brazil for spirometry, Diagnósticos da América S.A. (DASA) for CT reports, AstraZeneca Brazil and Lung Ambition Alliance for educational activities and Ethicon Brazil and Panther Brazil for medical devices.

Regarding the potential risks in this study, radiation exposure from chest LDCT screening and subsequent diagnostic procedures contributes to an increased cumulative radiation exposure. However, the individual risk of developing lung cancer from radiation in screening programs is relatively small (0.2%-1%) compared with the risks associated with smoking (approximately 16%) [22,23]. Patients who undergo invasive diagnostic procedures following lung cancer screening with chest LDCT in real-world settings may experience complications. The majority of these complications are classified as minor or intermediate in severity. The data from the medical record and interview will be confidential and restricted. Access to the study database will be limited to principal investigators. Although best efforts will be mobilized to ensure the anonymity of all records, there is a potential risk of accidental breach of anonymity.

The BRELT3 will implement a comprehensive communication strategy to actively disseminate the study findings. The communication strategy of this study in the public health system, in constant development with the research team, involves a wide-ranging dissemination plan that includes the creation of the ProPulmão website for information sharing, the use of social media platforms for engagement, participation in scientific conferences to connect with the research community, and conducting technical workshop tours. Furthermore, the strategy incorporates issuing press releases to reach a broader audience, hosting a significant high-level event to discuss key findings, and organizing workshops and roundtable discussions facilitated by a professional communication agency to foster dialogue with the scientific community and disseminate knowledge. In addition, the research team will develop meetings in the cities where participants were included, with the aim of informing the population and health government managers about the study findings and also raise awareness, as well as motivation to lung screening public policies.

3. Conclusions

The findings from the BRELT3 study are expected to provide valuable insights into the feasibility and effectiveness of lung cancer screening in underserved populations within remote regions of Brazil. This study underscores the importance of deploying mobile LDCT units, leveraging telemedicine, and engaging community health agents to overcome barriers to healthcare access. The results aim to inform future policies and strategies for lung cancer screening, with the ultimate goal of reducing mortality and improving health outcomes in similar low-resource settings [24,25].

A key limitation of this study is its focus on the state of Bahia, which may restrict the generalizability of its findings to other regions with different demographics, healthcare access, or infrastructure. The unique social, economic, and health challenges in Bahia may not fully reflect those in other parts of Brazil or Latin America, potentially limiting the broader applicability of the study’s conclusions. Future research should aim to replicate and validate these findings in diverse regions to better assess the scalability and adaptability of mobile lung cancer screening programs in varying contexts.

Additionally, the risk of overdiagnosis was acknowledged; however, the use of LDCT was prioritized due to its proven sensitivity and ability to detect early-stage lung cancer, which is crucial for improving patient outcomes. Another limitation of this protocol is the 12-month follow-up period. This timeframe was determined based on the logistical and resource constraints associated with conducting large-scale studies in remote areas. It was selected to provide initial, actionable insights into the screening program’s effectiveness. Recognizing the importance of long-term follow-up, subsequent phases of the research will include extended monitoring.

Furthermore, the study’s approach can serve as a model for other low-resource regions facing distinct challenges. Validation in diverse settings is essential to ensure that the strategies employed—such as mobile units, telemedicine, and community engagement—can be adapted to meet local needs and conditions. Scalability will depend on tailoring these interventions to address specific regional barriers, including transportation difficulties, variations in healthcare infrastructure, and cultural differences in healthcare engagement. Expanding the application of this model could contribute significantly to global efforts to reduce lung cancer mortality, particularly in underserved populations.

We acknowledge the importance of quantifying cumulative radiation exposure in studies of repeated LDCT scans. Although our manuscript mentions radiation risks, its primary focus is on the feasibility and implementation of the lung cancer screening programme. Therefore, a detailed quantification of cumulative exposure is beyond the scope of this study. However, future research could further explore this aspect, particularly as long-term follow-up data become available, to better understand the potential risks associated with repeated screening in this type of scenario.

Author’s contributions

Each author contributed to the study’s conception, design, and manuscript preparation in line with the journal’s authorship guidelines. All authors reviewed and approved the final manuscript and take responsibility for its content and integrity. Ricardo Sales dos Santos: Conceptualization; Methodology; Resources; Writing – Review and Editing; Supervision; Funding acquisition. Ricardo S. Figueiredo: Conceptualization; Methodology; Writing – Original Draft. Juliana P. Franceschini: Methodology; Writing – Original Draft; Project administration. Cesar Augusto de Araújo Neto: Conceptualization; Writing – Review and Editing; Supervision; Funding acquisition. Almério de Souza Machado Júnior: Conceptualization; Methodology; Writing – Review and Editing. Bruno Hochhegger: Conceptualization; Methodology; Writing – Review and Editing. Mario Claudio Ghefter: Conceptualization; Methodology; Writing – Review and Editing. Ulisses Amancio Pereira Neto: Methodology; Writing – Original Draft; Project administration. Petrucio Abrantes Sarmento: Conceptualization; Methodology; Writing – Review and Editing. Igor Barbosa Ribeiro: Methodology; Investigation; Data Curation. Daniel Augusto Xavier Carvalho: Methodology; Investigation; Data Curation. Felipe S. Passos: Methodology; Investigation; Data Curation. Caio Santos Holanda: Methodology; Investigation; Data Curation. Marcel Samuel Blech Hamaoui: Methodology; Investigation; Data Curation. Gustavo Borges da Silva Teles: Conceptualization; Investigation; Data Curation; Writing – Review and Editing. Carolina Alves Neves: Methodology; Investigation; Data Curation. Helena Alves Costa Pereira: Methodology; Investigation; Data Curation. Jackline Pereira Leto: Methodology; Investigation; Data Curation. Adelmo de Souza Machado Neto: Methodology; Investigation; Data Curation. Audrey Cabral Ferreira de Oliveira: Investigation; Data Curation; Formal analysis. Fernando Nunes Galvão de Oliveira: Conceptualization; Writing – Review and Editing; Supervision. Clarissa Mathias: Conceptualization; Writing – Review and Editing. César Garcia Machado: Conceptualization; Writing – Review and Editing. Josiane Dantas Viana Barbosa: Conceptualization; Writing – Review and Editing; Supervision. Marine Oliveira Barbosa Santos: Methodology; Investigation; Data Curation. Crislaine Gomes da Silva: Resources; Data Curation; Formal analysis. Mariana Moreira da Silva: Investigation; Data Curation. Lila Teixeira de Araújo: Methodology; Writing – Original Draft. Álvaro A. Cruz: Conceptualization; Writing – Review and Editing; Supervision.

Funding Statement

This study was supported by funding from: Bristol-Myers Squibb Foundation, Boehringer Ingelheim Brazil, Diagnósticos da América S.A. (DASA), AstraZeneca Brazil, Ethicon Brazil, and Panther Brazil.

Disclosure statement

No potential conflict of interest was reported by the author(s).