Lung Cancer in Brunei Darussalam
Authors: Vijay Kumar Srinivasalu, Ravi Sekhar Patnaik, Lu Shir Kiong, Jacob Samuel Justin, Raden mas Jeffri Raden mas Ismail, Haji Zulkhairi Hj Mohamad, Babu Sukumaran, Sophie M. Ernst, Anne-Marie C. Dingemans
Journal: Journal of Thoracic Oncology (2024)

Brunei, the abode of peace, is known for its rich cultural heritage, with a monarchy that serves as the head of the state and government. It is one of the world's smallest countries and is located on Borneo Island and is part of the Southeast Asian countries. This small island nation is surrounded by the South China Sea in the north and on all other sides by the Malaysian state of Sarawak (Fig. 1). Brunei is known for its rainforests, which cover 78% of the country, and houses the largest palace in the world (Guinness Book of World Records). After achieving independence from Britain in 1984, the Raja Isteri Pengiran Anak Saleha (RIPAS) hospital was founded to meet the growing medical needs of people.1Raja Isteri Pengiran Anak Saleha (RIPAS)Hospital.http://moh.gov.bn/SitePages/RIPASH%20background%20history.aspxDate accessed: January 6, 2024Google Scholar Nevertheless, universal health care for Brunei citizens was well in place before independence, since 1958.2Tant E.M. Equity in Access to Healthcare in Brunei Darussalam: Results From the Brunei Darussalam Health System Survey (HSS) [Master's thesis]. Duke University, 2014Google Scholar Through the public health care system, citizens receive comprehensive medical and dental assistance free of charge. With a life expectancy at birth of approximately 74.2 years, Brunei performs strongly in various health indicators with a gross domestic product (GDP) per capita of approximately 16.68 billion US dollars in 2022,3World Health Organization. 2024 data.who.int, Brunei Darussalam [country Overview]. Accessed January 8, 2024.Google Scholar with a current health expenditure of 2% of GDP; this is well below the rates found in other high-income countries with an average of 8.8% of GDP on health from 2015 to 2019.4OECD (Organization for Economic Co-operation and Development)Health spending indicators.https://data.oecd.org/healthres/health-spending.htmDate accessed: January 8, 2024Google Scholar The budget for health care is largely contributed by oil and natural resources5Younas M. Yafar M. Comparative Analysis of health care delivery System: Pakistan vs. Brunei Darussalam.Int J Sci Res (IJSR). 2017; 6: 945-949Crossref Google Scholar through a single pool for revenue collection.6Myint C.Y. Pavlova M. Khin-Ni-Ni Thein Wim Groot "A Systematic Review of the Health- Financing Mechanisms in the Association of Southeast Asian Nations Countries and the People's Republic of China: Lessons for the Move towards Universal Health Coverage.".PLoS One. 2019; 14 (e0217278–e0217278)Crossref Scopus (38) Google Scholar With a population of approximately 450,000, the utilization of health care services is high. Each of the four districts has health centers or clinics for primary outpatient care and hospitals for secondary and tertiary care. The roadmap to health care designed by the Ministry of Health Brunei is aligned with the "Wawasan Brunei 2035," aiming to develop comprehensive health care systems that emphasize service excellence and healthy lifestyle practices, innovation, and excellence, alongside sustainability through resource optimization, transparency, good governance, and effective policies and regulations that ensure protection for all.7WHO (World Health Organization)UHC and SDG Country Profile 2018. Brunei Darussalam, 2018Crossref Google Scholar Studies have revealed a relatively low level of inequity in access and health care utilization by ethnicity, residence, health status, and income due to the availability of free national health services.2Tant E.M. Equity in Access to Healthcare in Brunei Darussalam: Results From the Brunei Darussalam Health System Survey (HSS) [Master's thesis]. Duke University, 2014Google Scholar Patients with oncological symptoms who approach the district hospitals are referred to a large multispecialty hospital (RIPAS) in the capital, Bandar Seri Begawan, for diagnostic workup followed by management at the specialized cancer hospital, Pantai Jerudong Specialist Centre (PJSC), The Brunei Cancer Centre, which was established in 2014. Cancer has been the leading cause of death for more than a decade in Brunei Darussalam, overtaking cardiovascular disorders, ischemic heart disease, and stroke.8Brunei Darussalam Ministry of HealthHealth information booklet 2016.http://www.moh.gov.bn/Downloadables/Health%20Information%20Booklet%202016%20(21st%20Edition%20Revision%202).pdfDate accessed: January 23, 2024Google Scholar,9Lim M.A. Chong V.H. Ong S.K. Lim Y.C. Colorectal cancer in Brunei Darussalam: an overview and rationale for national screening programme.Asian Pac J Cancer Prev. 2019; 20: 3571-3580Crossref Scopus (6) Google Scholar The lifetime risk of developing cancer is extremely high in Brunei (one in four for males and one in three for females),10Ong S.K. Alikhan F. Lai D.T.C. et al.Population based lifetime risk estimation of malignant cancers in Brunei Darussalam.Brunei Int Med J. 2018; 14: 92-101Google Scholar in comparison to Malaysia with a risk of one in 10 for males and one in nine for females.11National Cancer Institute, Malaysia Ministry of HealthMalaysian National Cancer Registry Report 2007–2011.https://www.crc.gov.my/wp-content/uploads/documents/report/MNCRRrepor2007-2011.pdfDate accessed: January 4, 2024Google Scholar The age-standardized incidence rate per 100,000 persons for lung cancer in men was 24.2 and 17.8 for women as per the Brunei Darussalam Cancer Registry (BDCR).12Leong E. Ong S.K. Si-Ramlee K.A. Naing L. Cancer incidence and mortality in Brunei Darussalam, 2011 to 2020.BMC Cancer. 2023; 23: 466Crossref Scopus (1) Google Scholar The BDCR was established by the Ministry of Health in 2001 to provide a population-based database of all diagnosed cancers in Brunei Darussalam. All the health care professionals working at the hospital were encouraged to notify new cases of cancer to BDCR using a standardized notification form. The BruHIMS, Brunei health care information management system, has allowed data extraction and verification of cancer cases and improved the accuracy and completeness of the cancer registry.13Kong J.E. Ong S.K. Leong E. Naing L. Survival Analysis of Lung Cancer patients in Brunei Darussalam.Asian Pac J Cancer Prev. 2023; 24: 2389-2396Crossref Scopus (0) Google Scholar As per GLOBOCAN 2020, breast cancer and lung cancer were the first and second most common cancers as per incidence at 13.9% and 12.6%, respectively, but lung cancer had the highest mortality at 21.7% (94 of 437) (Figs. 2 and 3). Among men, lung cancer was the second most common cancer after colorectal cancer, whereas the top three most frequent cancers in females were breast, colorectal, and lung cancers. The predicted trends in cancer incidence are projected to rise by an alarming 108% between 2020 and 2040 with more than a 150% rise in cancer-related mortality between 2020 and 2040 in Brunei (Figs. 4 and 5). These worrisome statistics could be attributed to several factors including lifestyle changes, dietary habits, consumption of toxic substances including electronic smoking devices, lack of physical activity, and growing morbid obesity noted in nearly 14% of the population.14The World Factbook. Central Intelligence Agency, Washington, DC2021Google ScholarFigure 3Cancer-related mortality at Brunei Darussalam in 2020. Adapted from GLOBOCAN Cancer Today and Cancer Tomorrow.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Predicted trends in the incidence of new cancer cases in Brunei Darussalam. Adapted from GLOBOCAN Cancer Today and Cancer Tomorrow.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Predicted trends in cancer-related mortality in Brunei Darussalam. Adapted from GLOBOCAN Cancer Today and Cancer Tomorrow.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Owing to curbing the sales of cigarettes and tobacco products within the country in 2005 by the Ministry of Health and the high inflation of tobacco tax (almost 200%) to curtail local demand,15Ong S.K. Lai D.T. Wong J.Y. et al.Cross-sectional STEPwise approach to surveillance (STEPS) population survey of noncommunicable diseases (NCDs) and risk factors in Brunei Darussalam 2016.Asia Pac J Public Health. 2017; 29: 635-648Crossref PubMed Scopus (0) Google Scholar all licensed cigarette businesses ceased to operate. Despite these bold steps, a study in 2015 to 2016 revealed that approximately one in five adults is a current smoker, with prevalence of 36% in men compared with 4% among women.15Ong S.K. Lai D.T. Wong J.Y. et al.Cross-sectional STEPwise approach to surveillance (STEPS) population survey of noncommunicable diseases (NCDs) and risk factors in Brunei Darussalam 2016.Asia Pac J Public Health. 2017; 29: 635-648Crossref PubMed Scopus (0) Google Scholar There is, however, no current data available to assess its trend. There has also been a steep increase in the incidence of lung cancers among females in Brunei Darussalam, with a male-to-female ratio of 1.4:1, as noted in a retrospective study with most patients (86.3%) above the age of 50 years at the time of diagnosis. Malay was the most common ethnicity followed by Chinese, and more than half of the patients were residents of the Brunei-Muara district.13Kong J.E. Ong S.K. Leong E. Naing L. Survival Analysis of Lung Cancer patients in Brunei Darussalam.Asian Pac J Cancer Prev. 2023; 24: 2389-2396Crossref Scopus (0) Google Scholar The national cancer screening guidelines in Brunei Darussalam were established in 2019 for breast, colon, and cervical cancers, and setting up guidelines for screening lung cancers is in the pipeline. Stringent measures are adopted to reduce the nuisances of lung cancers by setting up tobacco cessation clinics and signboards to stop or reduce the use of electronic smoking devices or vape and nicotine-containing products. The Early Detection and Cancer Prevention (EDCP) department was also established for early detection and screening for genetically driven high-risk cancers including lung cancer and to provide genetic counselling for patients and relatives with a family history of lung cancer. Currently, there are no established guidelines or a national screening program for lung cancer in Brunei. Low-dose computed tomography (CT) is sometimes used but results in high false positives due to infections such as tuberculosis and melioidosis. Incidental pulmonary nodules are detected on chest radiographs done as part of a workup for chest infections or on CT scans done for other nonmalignant causes. Except for screening high-risk males who smoke, the females, who have never smoked or who smoke occasionally, are of Southeast Asian descent, and are at an increased risk of EGFR-mutant lung cancers, need to be addressed. Patients with a chronic persistent cough, hemoptysis, loss of appetite, loss of weight, or other symptoms suspicious of lung cancer present to the primary peripheral clinics at the district hospitals and are evaluated by general or family physicians and later referred to the large central hospital in the city (RIPAS) for specialist consultation and biopsy for histopathologic diagnosis followed by imaging for diagnostic workup. A suspicious chest radiograph result is followed by a CT scan, which is the primary imaging modality of choice for an individual with suspected lung cancer. Peripheral clinics are equipped to do routine chest radiographs with two district hospitals having provision for CT scans. On confirmation of histopathologic diagnosis, a staging workup is done with a CT-thorax, abdomen and pelvis or a positron emission tomography-CT done at the Department of Nuclear Imaging, PJSC, which was established in 2014. Since then, positron emission tomography-CT has been routinely used for staging of lung cancer in Brunei with magnetic resonance imaging-brain at baseline which is available only at RIPAS and PJSC. Lung tissue (if feasible) or tissue from a metastatic site for the confirmation of a histologic diagnosis is done through either a CT-guided lung biopsy or bronchoscopy with endobronchial ultrasound-guided and transbronchial fine-needle aspiration or lung biopsy. Owing to the constraints in localization of the lung lesion and adequacy of the sample obtained during bronchoscopy, CT-guided lung biopsy is the preferred choice when feasible. Endobronchial ultrasound-guided transbronchial fine-needle aspiration is done for sampling radiologically suspicious lymph nodes under moderate sedation in Brunei. Histopathology and cytopathology services are available at the large central hospital, RIPAS, for the diagnosis of lung cancer. Immunohistochemistry is available in-house for confirmation of the histologic diagnosis. For molecular studies, samples with stage IV adenocarcinoma and squamous cell or adenosquamous carcinoma (especially in females, never smokers, or light smokers) would be sent to an external laboratory (QASYA Labs, Malaysia) for EGFR, ALK, ROS-1, BRAF, and programmed death-ligand 1 status identification. EGFR testing will also be done in the adjuvant setting to decide on osimertinib for stages II and III NSCLC. In patients with no adequate tissue available for histologic diagnosis, a liquid biopsy can be performed, and the plasma sample will be sent to Foundation Medicine for diagnostics and molecular analysis. With the recent incorporation of next-generation sequencing (NGS) in the universal European Society for Medical Oncology guidelines of lung cancer for advanced NSCLC,16Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Google Scholar the use of NGS tumor sequencing to detect actionable alterations has increased significantly, and these tests are outsourced to Foundation Medicine or CARIS Life Sciences. Metastatic NSCLC was the most common tumor type that was analyzed through NGS for the detection of actionable alterations.17Srinivasalu V.K. Sanusi F.M. Idris N.B. et al.Comprehensive genomic analysis: a hype or hope.Ann Oncol. 2022; 33: S1383-S1430Google Scholar A multidisciplinary tumor board consisting of medical oncologists, pathologists, radiation oncologists, nuclear medicine consultants, pulmonologists, pain and palliative care physicians, and cardiothoracic surgeons meets once a week to discuss all patients diagnosed with lung cancer for further plan on management. The cardiothoracic surgery department is based at RIPAS hospital, which is a large central multispeciality hospital located in Bandar Seri Begawan. Conventional video-assisted thoracic surgery has been performed since the late 2000s. For tumors less than 2 cm or with borderline lung function, sublobar resections such as segmentectomy will be performed. Tunneled indwelling catheters can be inserted for patients with recurrent malignant pleural effusions. Radiotherapy for lung cancer is delivered by the Department of Radiotherapy at PJSC, The Brunei Cancer Center, Brunei, since its establishment in 2016. The treatment approach for lung cancer includes neoadjuvant, adjuvant, definitive, or palliative setting, depending on the cancer stage and indication. Stereotactic ablative body radiotherapy is considered in medically inoperable limited-stage lung cancer. Conventional fractionated radiotherapy doses are 60 Gy, and all the planning and CT simulations with motion management accessories for breath-hold or respiratory-gated delivery are available in-house. There is access to image-guided intensity-modulated radiotherapy, stereotactic ablative body radiotherapy, volumetric-modulated arc radiotherapy, and tomotherapy. There is a lack of data on the most prevalent histologic subtypes of lung cancer in Brunei. On retrospective analysis of all patients with lung cancer treated at PJSC, TBCC, which is the standalone center equipped for oncology care, 223 new patients with lung cancer were treated between 2016 and 2022. The SCLC type was found in 4%, and the rest were of NSCLC (Fig. 6). On molecular analysis for stage IV adenocarcinoma and females with squamous or adenosquamous histology, age less than 40 years, and who never smoke, we found a high percentage of EGFR alterations (43%) and only 4% had KRAS mutations. Limited-stage SCLC is treated with concurrent chemoradiotherapy followed by prophylactic cranial irradiation, whereas extensive-stage SCLC is treated with a chemoimmunotherapy combination (atezolizumab or durvalumab with platinum-based doublet chemotherapy). In a highly selected small proportion of early-stage SCLC based on size and location, surgery or local ablative radiotherapy will be considered. In a relapsed refractory setting based on the time of relapse, the burden of disease, and patient performance status, we consider rechallenge of platinum-based chemotherapy or local radiotherapy in selected cases after multidisciplinary tumor board or consider second-line chemotherapy such as irinotecan, topotecan, immune checkpoint inhibitors, or CAV regimen (cyclophosphamide, adriamycin or doxorubicin, and vincristine). In the management of NSCLC, followed by surgery, adjuvant platinum-based chemotherapy is the standard of care for stages II and III lung cancer. In the neoadjuvant setting, nivolumab is used with combination chemotherapy in patients with stages II to III NSCLC. In the adjuvant setting, pembrolizumab and atezolizumab are available. Inoperable stage III cancers are treated with chemoradiotherapy followed by durvalumab in a maintenance setting for patients without evidence of disease progression with platinum-based chemoradiotherapy as per the PACIFIC trial.18Antonia S.J. Villegas A. et al.PacificDurvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref Scopus (3081) Google Scholar The ADAURA trial has changed our adjuvant strategy with osimertinib used in EGFR mutation-positive adenocarcinoma of the lung.19Herbst R.S. Wu Y.L. John T. et al.Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non–small-cell lung cancer: updated results from the phase III randomized ADAURA trial.J Clin Oncol. 2023; 41: 1830-1840Crossref PubMed Scopus (0) Google Scholar Stage IV lung cancers based on the alteration detected and common EGFR-mutant lung cancers are treated with gefitinib, erlotinib, osimertinib (preferred), afatinib, or platinum-based chemotherapy with or without tyrosine kinase inhibitor. On progression of an EGFR-mutant NSCLC, we perform a repeat biopsy (tissue or liquid) whenever feasible and look for resistant mechanisms including MET amplification or exon 14 skipping mutation, and capmatinib is available for the treatment of MET alterations. Uncommon EGFR mutations are treated with afatinib or osimertinib. Alectinib (preferred), crizotinib, and ceritinib are available for the treatment of ALK-positive NSCLC, and crizotinib is routinely used in ROS-1–positive patients. For BRAF V600E-positive NSCLC, dabrafenib and trametinib are available for treatment on a name-patient basis. In oncogene driver mutation-negative lung cancer, platinum-based doublet chemotherapy alone or in combination with immunotherapy with or without an antiangiogenic agent is approved. In patients with high programmed death-ligand 1, that is, greater than or equal to 50%, single-agent immunotherapy pembrolizumab is approved in both squamous and nonsquamous lung cancers (Fig. 7). The palliative and home care department functioning out of PJSC assists patients with logistic issues or comorbidities to receive care at home. They comprise palliative physicians and professional caregivers such as nurses, assistants, and therapists who make routine visits to the respective houses to assess their general condition, address their medical needs with catheter changes, check feeding tube patency, monitor home oxygen cylinder, and check the supply of their pain medications to provide a better quality of life. They also closely liaise with the medico-social workers to provide social and emotional support to the patient and their families. With access to novel immunotherapeutic drugs and tyrosine kinase inhibitors, the clinical outcomes of lung cancers in Brunei have improved enormously. As the number of patients with advanced disease at the time of the diagnosis is on an uptrend, it is essential to incorporate effective screening strategies for high-risk individuals to detect malignant lesions at an early stage and design studies to include female, nonsmoker patient population with a significant family history of lung cancer or other cancer as part of nationwide screening programs. With growing evidence of carcinogenesis and the use of vapes or electronic smoking, immediate efforts need to be taken to reduce the use of such harmful devices, especially in young adults. In the era of personalized medicine, where novel molecules targeting a specific alteration or pathway are making inroads into our day-to-day practice, access to these newer drugs gets challenging; hence, setting up clinical trials in the region would provide access to newer treatments and expand treatment options contributing to the betterment of health care. With the health sector heavily relying on the government subsidies incurred from the sale of oil and natural resources, a strong decline in revenue from these sources would affect the funding and hamper the sustainability of the health system in the country. Vijay Kumar Srinivasalu: Conceptualization; Methodology, Data curation; Writing- original draft. Ravi Sekhar Patnaik: Conceptualization; Methodology. Lu Shir Kiong: Conceptualization; Methodology. Jacob Samuel justin: Conceptualization; Methodology, Writing- original draft. Raden mas jeffri raden mas ismail: Conceptualization; Methodology. Haji Zulkhairi hj Mohamad: Conceptualization; Methodology. Babu Sukumaran: Conceptualization; Methodology. Sophie Ernst: Conceptualization; Methodology, Data curation; Writing- review & editing. Anne Marie Dingemans: Conceptualization; Methodology, Data curation; Writing- review & editing. The authors declare no conflict of interest.