Lung cancer management in low and middle-income countries - current challenges and potential solutions

Lung cancer is the second-most prevalent cancer and, the most common cause of cancer-related mortality throughout the world. Evidence-based strategies to decrease its incidence and mortality are being implemented in different parts of the world. Smoking cessation policies are being actively publicized to decrease the incidence of tobacco related cancers including lung cancer. Screening program for early detection of localized lung cancer which can then be targeted by a multimodality approach utilizing surgery, radiation, chemoimmunotherapy to achieve cure is now becoming the standard in several high-income countries. Precision medicine in lung cancer is booming with metastatic non-curative cancers targeted with small molecule tyrosine kinase inhibitors. However, these advancements are not available all around the world. Inequalities exist in the management of lung cancer, mostly driven by the economic differences between the countries. Raising awareness to these international barriers is pivotal for improving lung cancer related


Take home message
• Almost 60% of lung cancer incidence throughout the world is seen in the low-and middle-income countries.• Several disparities exist in the screening, diagnostics, and management of lung cancer in the low-and middle-income countries when compared to the high-income countries.• Limited resources, economic restrictions, and lack of accessibility are the major causes for the differences seen in the management of lung cancer in the low-and middle-income countries.• Understanding the local limitations and implementing innovative strategies to overcome these problems can help bridge the worldwide gap seen in the management of lung cancer.

INTRODUCTION
The field of thoracic oncology witnessed immense growth in the last two decades.From the development of effective lung cancer screening guidelines which aim for an early diagnosis of asymptomatic and non-metastatic lung cancers to the advent of immunotherapy and targetable tyrosine kinase inhibitors which aim to improve the quality of life and survival in metastatic lung cancer patients, several breakthroughs have been made.However, lung cancer remains the most common cause of cancer-related mortality despite all the advances, accounting for about 1.8 million deaths worldwide in 2020. 1 Several inequalities exist in managing lung cancer worldwide, which ultimately contribute to the disparities in its incidence and mortality burden.One commonly encountered reason for these inequalities is the socio-economic variations in the different parts of the world.The World Bank list of economies divides the countries into four sub-groups based on their Gross National Income (GNI) per capita-low income, lower-middle income, uppermiddle income, and high income.Among the low-and middle-income countries, the age-standardized incidence and mortality are highest in Micronesia (36.4% and 34.9%, respectively) and Eastern Asian countries (34.4% and 28.1%, respectively), while its lowest in the Western-African region (2.2% and 2.1% respectively).Overall, about 60% of the world's lung cancer incidence is attributed to low-and middle-income countries, with the majority noted in the Asian continent. 1Hence, recognizing the challenges faced by the patients and physicians in these countries is essential to improve the global outcomes of lung cancer.

HEALTHCARE SYSTEM
Healthcare is divided into public and private sectors in most low-and middle-income countries.The government primarily sponsors public sector hospitals/universities, and they provide care to the patients at a low cost; however, most advanced diagnostics, procedures, and novel medications might not be readily available in these hospitals due to their cost limitations.The private sector hospitals tend to have an underlying for-profit motive.Though they have more access to the newer products, their use in public is limited to high-income or privately insured patients.Except for some upper-middle-income countries like China and Mexico, and a few lower-middle-income countries like Vietnam, most of the low-and middle-income regions do not have comprehensive nationally funded public health insurance programs that are able to cover the expensive testing and treatment required for lung cancer.Thus, patients must rely on private insurance or out-of-pocket payments which leads to financial toxicity.

SMOKING CESSATION
Tobacco use is suspected to have killed 8 million people in 2019 and is the most common risk factor for lung cancer worldwide. 2,3The tobacco cessation efforts by WHO (FCTC, NCD-GAP, MPOWER, and ENDS) have been instrumental in controlling the tobacco epidemic.The fourth edition of the WHO global report on the trends in the prevalence of tobacco use reported a global decline in tobacco use from 32.7% in 2000 to 22.3% in 2020. 4Lower-middle income groups had the highest drop in tobacco use (44% in 2000 to 24% in 2020), while the upper-middle income had the lowest and slowest drop (28% in 2000 to 24% in 2020).However, some of South-East Asian and Middle Eastern countries like Myanmar, Indonesia, and Lebanon still have a tobacco use prevalence as high as 50%. 4 Primary and secondary smoking abstinence has been shown to be associated with improved survival outcomes. 5In the National Lung Cancer Screening trial, there was a 20% reduction in cancer-related mortality with 7-year smoking cessation. 6espite the awareness and the evidence, there are about 49 countries that currently do not have a single national control measure, and a majority of them belong to lowand middle-income countries.In addition to cigarette use, other causes of nicotine exposure commonly encountered in low-and middle-income countries include second-hand tobacco smoke and the use of non-cigarette nicotine products like beedi, toombak. 2,7These products are generally cheaper and cause higher nicotine exposure. 8he incidence of lung cancer in non-smokers is increasing globally.Majority of the Asian women with lung cancer are non-smokers.Some of the risk factors for lung cancer that have been proposed in this population are outdoor air pollution, environmental exposures (arsenic, asbestos), genetic factors, benign pulmonary conditions (pulmonary fibrosis) etc. 9 In rural areas of India, indoor air pollutants like smoke from coal stoves and cooking oil have been attributed to lung cancer as well. 10Further case-control studies to help establish a definite causal relationship with these non-smoking factors is essential.

LUNG CANCER SCREENING
Wilson and Jungner laid down ten principles for disease screening in 1968, which are still used while deciding on screening recommendations for cancers. 11Lung cancer biology and epidemiology make it a disease that would highly benefit from screening.The United States National Lung Screening Trial (NLST) and the Dutch-Belgian NEderlands Leuvens Screening Onderzoek 12 trial both demonstrated a significant reduction in lung cancer-related mortality with the use of annual low-dose CT screening in high-risk individuals. 13,14United States Preventive Service Task Force (USPSTF) currently recommends LDCT for lung cancer screening in high-risk patients in the United States of America. 15he majority of the low-and middle-income countries with a high incidence of lung cancer, like India, Bangladesh, and Vietnam currently do not have screening guidelines established for lung cancer.In most low-and middle-income countries, nearly 80% of lung cancers are diagnosed as stage III or IV.Mortality in lung cancer is stage-dependent, with stage IV having the worst outcomes. 16Hence, early detection of lung cancer with the help of screening modalities can help decrease mortality.However, in practicality, several barriers exist for an effective implementation of lung cancer screening.A high prevalence of pulmonary infections like tuberculosis results in a high false positive rate. 17A positive screening test must be followed with several invasive and non-invasive interventions to ultimately lead to an accurate diagnosis.The imaging and interventional modalities needed for lung cancer screening can add to the already existing financial and infrastructure burden in the low-and middle-income healthcare systems. 17

MANAGEMENT OF NON-METASTATIC LUNG CANCER
The goal of treatment for non-metastatic lung cancer is the cure, primarily obtained with surgery or with definitive radiation in patients who are not surgical candidates.Adjuvant systemic therapy is added to stage II and III lung cancers to improve the cure and survival rates. 15urgery: Anatomic surgical resection (lobectomy and sometimes pneumonectomy) is the most common surgical procedure that is performed for an early-stage lung cancer with curative intent.The lung resection surgery can be performed via open thoracotomy, video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery. 18,19 Wile VATS and RATS are associated with faster recovery and lesser post-operative complications, there is no difference in cancer related survival outcomes compared to open thoracotomy. 20When surgical resection is indicated, open thoracotomy is the most commonly used approach in most low-and middle-income countries. 21VATS is being increasingly used in countries like Brazil and Vietnam. 22,23 RTS is less commonly available in most of these countries except for China, where robotic technology is rapidly advancing. 24,25In countries with a high incidence of pulmonary infections, like India and Nepal, there is a concern Lung cancer management in low and middle-income countries -current challenges and potential solutions International Journal of Cancer Care and Delivery for increased lung fibrosis and pleural adhesions making minimally invasive surgical resection less feasible. 26The availability of skilled surgical oncologists or thoracic surgeons and post-operative rehabilitation resources differ widely throughout the world.The disparities in resource availability results in lower surgical resection rates; however, the overall post-operative outcomes are similar to high-income countries. 27adiotherapy (RT): For stages I and II non-small cell lung cancer (NSCLC), definitive RT is used in patients who are not surgical candidates.In inoperable stage III tumors, it is used along with chemotherapy (concurrent or sequential).In stage IV lung cancer, it is used for treatment of brain metastasis or oligo-progression or symptomatic disease.In limited-stage small-cell lung cancer (SCLC), prophylactic cranial radiation is given following concurrent chemoradiation to the chest. 15Hence, radiotherapy is a vital part of treatment for all stages of lung cancer management.The availability of radiotherapy equipment and techniques is variable in each country.In general, there is a paucity of RT availability in low-and middle-income countries.For example, India has radiotherapy equipment to serve only half of its current population. 28Furthermore, only bigger cities within each country have established radiotherapy centers, making it difficult for the rural population to use them.Additionally, patients have a high wait time to receive RT due to limited availability.For instance, the average wait time for radiotherapy in Brazil is about 3-4 months. 22This can often result in the progression of the disease from a curative to non-curative stage or can cause the development of symptomatic metastasis intra-and extra-cranially.

MANAGEMENT OF METASTATIC LUNG CANCER
Metastatic lung cancer is treated primarily with systemic agents to help improve quality of life, progression-free survival, and overall survival.The goal of treatment is palliative and not curative.Hence, it remains the most common cause of lung cancer-related mortality worldwide, with an average 5-year survival of 5-7% in the United States of America. 29The systemic treatment in lung cancer underwent radical progress in the last decade with the dawn of immunotherapy and targetable tyrosine kinase inhibitors which are now readily available for patients in the highincome countries like the North American and European countries.However, most of the major clinical trials that led to the approval of these agents (especially immunotherapy trials) had minimal to no accrual from the low-and middleincome countries located in the Middle East, South Asia, and North and South African regions.This lack of inclusivity precipitates a lack of awareness, availability, and accessibility which along with the high economic burden results in lower utilization of these novel agents in low-and middle-income countries.
Tyrosine Kinase Inhibitors (TKI): Understanding the oncogenic drivers and targeting them with small molecule TKI revolutionized the management of non-small cell lung cancer (NSCLC).However, TKI use in most low-and middleincome countries is limited due to the lack of comprehensive molecular testing, lack of access to several TKIs, and the cost of the medication.It is thought that less than 50% of patients with NSCLC throughout the world receive molecular testing, 30 and the most commonly cited reasons for under testing are lack of availability/access and the cost.In Brazil, EGFR evaluation is estimated to be used in only half of the metastatic NSCLC due to the lack of advanced diagnostics. 22,31In Nepal, the samples for comprehensive testing are sent to India and are generally associated with high expenses. 26Like testing, there is also a stark difference in the availability of TKIs between high-income and lowincome countries.Currently, several TKIs targeting EGRF, ALK, ROS, NTRK, BRAF, MET, RET, and most recently, KRAS G12C are approved and available in the USA and Europe.Out of all these mutations, EGFR is the most commonly encountered targetable mutation in NSCLC, with prevalence much higher in the East Asian population (EGFR mutation is noted in about 15% of NSCLC patients in the USA while it's frequency can be as high as 60% in East Asian countries). 32China is one of the few Asian countries in the upper-middle income group that actively participated in several TKI studies and currently has access to multiple TKIs targeting EGFR mutation, including Osimertinib. 33owever, the same cannot be said about the rest of South-East Asian countries.In Malaysia and Vietnam, Erlotinib and Gefitinib are the only available EGFR-TKIs in the public sector with reduced costs and national reimbursements.The rest of the EGFR TKIs must be fully paid for by the patients.The out-of-pocket monthly cost of Osimertinib is about 2000$ in Malaysia and 8000$ in India/Brazil. 34A similar trend is seen with TKIs targeting mutations other than EGFR, with monthly costs ranging from 2000$ to 10,000$. 28ence, their use is limited as a second-line treatment for affluent patient populations in the tertiary healthcare systems. 23,357][38][39] Similarly, in small cell lung cancer (SCLC), an addition of immunotherapy to chemotherapy improved OS and PFS irrespective of PDL1 immunohistochemistry. 40,41 Immunotherapy is also responsible for producing a durable clinical benefit. 18,42Currently, atezolizumab and durvalumab (PDL-1 inhibitors) are FDA approved for metastatic SCLC and, atezolizumab, pembrolizumab, cemiplimab (PD1 inhibitors) and nivolumab/ipilimumab (PD-1/CTLA4 inhibitor combination) are approved for metastatic NSCLC. 15mmunotherapy is also recommended in non-metastatic NSCLC.Durvalumab significantly improved survival in stage III NSCLC when given following chemoradiation. 43tezolizumab in the adjuvant setting improved diseasefree survival for PDL-1 positive resectable stage II and IIIA NSCLC. 44Additionally, neoadjuvant nivolumab in combination with chemotherapy has been shown to improve pathological complete response rates in resectable stage I to IIIA NSCLC.
Lung cancer management in low and middle-income countries -current challenges and potential solutions

International Journal of Cancer Care and Delivery
Despite the ever-increasing evidence and indications for immunotherapy in high-income countries, their availability and utilization in low-and middle-income countries continue to remain low.Sudan does not have access to any immunotherapy agents or PDL-1 testing. 45In South Africa, no checkpoint inhibitors are available for first-line treatment and Pembrolizumab is the only available IO in the secondline setting. 21In India, IOs are sold as branded medications and have an average cost of 2000-4000$ per vial, which significantly restricts their use (especially in the first-line setting). 28Similar trends of restricting IO use to second-line setting are seen in most low-and middle-income countries in the Middle Eastern, North African (MENA), and Southeast Asian regions due to a financial burden.Owing to the lack of widespread global accessibility due to its cost, immunotherapy was not included in the essential medicine list by WHO. 46hemotherapy: Due to the cost and unavailability of most TKIs and IOs, platinum-based doublet chemotherapy remains the standard of care for first-line treatment of metastatic NSCLC and SCLC in low-and middle-income countries.In patients with NSCLC who have a driver mutation, every attempt is made to get cost-effective access to TKIs.In scenarios when the TKIs are unavailable or not affordable, chemotherapy is given in the first-line setting.There is not much discrepancy in the availability of most first-and second-line chemotherapy agents except for Pemetrexed which has limited availability in countries like South Africa and Malaysia.

SUMMARY AND PERSPECTIVE
In summary, every single aspect of lung cancer management, from epidemiologic risk mitigation to the availability of palliative treatment, is strongly influenced by the resources available in a country.These differences in the resources are often attributed to the financial burden of treatments, lack of accessibility and lack of awareness.Some of the potential solutions are: 1. Lung cancer prevention and screening: Implementing tobacco control policies like nicotine-replacement therapies, smoking-related cancer awareness campaigns and a nationwide ban on tobacco use in the public places can help decrease the prevalence of lung cancer.Use of plain packaging and graphic pictorial warnings on nicotine products has been shown to decrease their attractiveness especially to young population 47,48

Figure 1 .Figure 2 .
Figure 1.Age-standardized incidence and mortality rates of lung cancer; source WHO 2020 data 49,50nal guidelines for management: Several lowand middle-income countries like Sudan, Nepal, and Georgia do not have national consensus guidelines for managing lung cancer and rely on National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) guidelines.NCCN has harmonized guidelines for countries in the Sub-Saharan Africa, the Middle East, North Africa, and the Caribbean regions.49,50However,there are no international guidelines that are focused on managing cancer for patients from South Asia, South-East Asia, Pacific Islands, and Latin America, which also have several low-and middle-income countries.Establishing national guidelines for managing lung cancer can help provide uniform care to patients within each country.Once these guidelines are made publicly available throughout the country, then, the insurance providers (both public and private Lung cancer management in low and middle-income countries -current challenges and potential solutions International Journal of Cancer Care and Delivery