Background Introduction

Lung cancer remains the second-most diagnosed cancer worldwide, as well as the most fatal, with 2,206,771 new cases in 2020 (11.6% of the total cancer cases) and 1,796,144 recorded deaths (18% of the cancer deaths).

Despite higher levels of incidence in High Income Countries (HICs), lung cancer has disproportionately high morbidity rates in Low and Middle Income Countries (LMICs). 65% of all cancer-related deaths in 2012 occurred in LMICs, with further increase likely to reach 75% by 2030, if the situation is not reversed. In Southeast Asia, lung cancer was the third most commonly diagnosed cancer (185,636 new cases; 7.8%), and the leading cause of cancer mortality, with 166,260 (10.9%) reported deaths.

The high rates of lung cancer fatalities can be associated with three types of issues, the awareness regarding signs, early-stage symptoms, and risk factors and screening options, late diagnosis, and lack of screening and treatment options. These issues lead to diagnosis at later stages, where treatment options are limited and more risky. Cancer screening has provided positive results for early detection of lung cancer in various countries, but still face various challenges in LMICs, both due to social and economic factors.

Table of Contents

Object

This research looks into the factors associated with lung cancer related deaths, and late diagnosis in LMICs and the literature present regarding the screening efforts and treatment options available worldwide, in order to present a case for decreasing the number of deaths caused due to lung cancer.

Lung Cancer and its Pathology​

Lung cancer is divided into two main sub-types, small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which accounts for approximately 85% of diagnosed lung malignancies. Related symptoms for NSCLC are nonspecific, usually manifested as lasting cough and dyspnea3.

Because of the commonness of symptoms, three-fourths of diagnosis of lung cancer malignancies present when the disease is locally advanced (stage IIIC) or metastatic (stage IV), when it has 5-year survival rates of 13% and 0%, respectively. If detected at stage IA, when the individual is usually asymptomatic, NSCLC can be treated with curative intent, with overall survival of up to 92%. The high contrast of these statistics showcases the importance of early detection of this disease through lung cancer screening, to improve survival in the high-risk populations.

Lung Cancer Awareness, Screenings, Prevention and Treatment in Low and Middle Income Countries

Low and Middle Income Countries (LMICs) suffer the highest number of lung-cancer related deaths, despite lower numbers of cases than High Income Countries (HICs). This trend is expected to continue, with over 2 million lung-cancer-related deaths expected in LMICs by 2040, contrasting with about 850,000 in HICs. These numbers are reflective of the socio-economic as well as economic barriers faced by patients at both a personal level, causing delays in checkups as well as at the healthcare setting level, leading to delays in diagnosis and treatments.

The high amount of deaths is also in some instances attributed to factors such as aging, cigarette smoking, alcohol use, unhealthy diet and lack of physical activity. Of these, cigarette and tobacco smoking remains the top risk factors worldwide, with 70% of all lung-cancer related deaths across the world associated with tobacco use. According to one study, the overwhelming majority of lung cancer develops in current or former smokers. Available evidence from our reviewed studies suggests that tobacco use is the most recognized risk factor for lung cancer. In never-smokers, inhalation of smoke, use of solid fuel and poor ventilation (especially in low-income countries) has been associated as a factor in the pathogenesis of lung cancer as well.

Due to the previously mentioned factors, lung cancer diagnosis in LMICs often happens at an advanced stage, causing delays in treatment and accelerating to terminal stages. . More than 90% of patients are already presenting symptoms at the time of diagnosis. Despite advancements in research regarding pathogenesis and successful clinical trials of new treatments, the estimated survival rate is only 18%, even in HICs

Awareness regarding the risk factors and symptoms, and access to healthcare facilities such as screening and low-cost treatment options are correlated to early detection and affect the success of treatment. The World Health Organization estimates that early detection and treatment can lead to up to 50% prevention of cancer-related deaths. Early detection is linked with more effective treatment, which in turn is related to the time patients take to seek help.

Successful population-based screening is pivotal to early-stage detection, and possibly life-saving treatment. One of the ways lung cancer can be identified and treated preemptively is through screening initiatives in high-risk populations. These programs however, face various challenges at all stages, from planning to implementation. Research has highlighted the limited effectiveness of community-level cancer awareness campaigns in some LMICs, which can be a result of socio-cultural barriers, among other factors. Consequently, smoking cessation, lowering exposure to second-hand smoke and x-rays for the chest, have been identified as preventative measures for lung cancer. Ine study also suggested that exercise may also lower chances of getting lung cancer.

Research into the cancer awareness and screening efforts in LMICs is a crucial element in identifying the association between  the risk factors, as well as symptoms of lung cancer. Improved  understanding of these associations can help inform improved awareness and screening programs, leading to early detection and treatment, lowering the chances of lung cancer-related deaths. 

Challenges in Lung Cancer Awareness and Screening in LMICs

It is necessary to increase the awareness of lung cancer signs and symptoms in order to improve screening results and early diagnosis.

Awareness is a major barrier to screening and patients seeking help in LMICs.  Lack of knowledge on lung cancer symptoms causes delays in patients seeking medical help, which proves  a need for public awareness campaigns to improve early health-seeking behaviors . The lack of awareness, along with lack of knowledge regarding the disease, is also associated with lack of resources, and socio-cultural barriers. This includes communication barriers, skepticism towards treatment effectiveness, victim-blaming mentality, and even physician unawareness towards screening guidelines, which presents a challenge in the identification of high-risk individuals in LMICs. Keeping these barriers in mind, screening approaches in LMICs need to be sensitive to local context in order to succeed.

Patients in LMICs also face infrastructure-related barriers towards screening, and screening programs similarly face issues reaching out to high-risk populations due to infrastructure issues as well. These issues are related to distance of patients from healthcare institutions, lack of access to transportation and roads, and lack of screening programs available in some communities.

One technique that showed positive results in breaking through these barriers is the employment of Community Health Workers (CHWs) for counseling of local populations and recruitment for screening programs. CHWs are part of the communities they work in, and better understand the population, which can help reduce stigma through  answering patient queries, and play a role between the healthcare system and the patient. In addition to awareness and counseling, CHWs may also be of assistance to clinicians and other health workers. A study conducted across four LMICs assessing the CHWs’ ability to screen for cardiovascular disease revealed the CHWs were able to conduct their tasks at levels comparable to the formally trained health professionals.

Misdiagnosis

Lack of awareness regarding the signs and symptoms of lung cancer are one of the reasons behind the misdiagnosis and late diagnosis of lung cancer in LMICs. The symptoms, and risk factors for TB and lung cancer often overlap, which does not make things any easier. A study by Ramachandran et al. reported that 29% of their patients with lung cancer had initially been diagnosed with TB before the correct diagnosis was made. Another study found that healthcare workers often put lung cancer patients on anti-TB treatment, resulting in referral delay to oncology specialists .

Access to healthcare, identification of high-risk patients, screening uptake, adherence and implementation, followed by the timely communication of results and referral to oncology departments, are the fundamental steps of organized screening programs, which will result in earlier detection and diagnosis. 

Palliative Care

Research on lung cancer awareness and palliative care interventions in LMICs is notably scarce. Thus, it is imperative to note down awareness campaigns for lung cancer, as well as the palliative care strategies implemented in LMICs, particularly in sub-Saharan Africa (SSA). This mapping will be vital in facilitating the identification of lung cancer risk factors, and related symptoms.


Evidence supports the notion that early palliative care can significantly reduce symptom burden, enhance patients’ quality of life, and importantly, lead to improved survival outcomes. Consequently, early integration of palliative care for individuals with lung cancer is strongly advocated to alleviate distressing symptoms, thereby improving the quality of life for both patients and their families.

Additionally, one study highlighted several palliative care options for lung cancer, including radiotherapy, supportive care, and chemotherapy, as effective therapeutic modalities.

Radiotherapy

Radiotherapy is a common treatment for patients of lung cancer, and part of most comprehensive cancer control plans. There is evidence that roughly half of all cancer patients require radiotherapy at some point in the management of cancer.

Knowledge of disease, State of research and treatment

The last few decades have brought multiple advancements in knowledge regarding lung cancer as well as breakthroughs in its treatment and management. While there are gaps in knowledge regarding certain risk factors, the new advancements in imaging, treatment options such as surgery, radiotherapy, and less toxic chemotherapy are remarkable. Combined with possibilities of early diagnosis with new screening strategies. These advancements produce positive outcomes in lung cancer treatment and survival of patients. The number of European Medicine Agency (EMA)-approved targeted therapies for patients with metastatic lung cancer has grown significantly over the past two decades as well.

However, LMICs are disadvantaged due to a majority of Phase 3 oncology Randomized Clinical Trials (RCTs) being conducted by HICs, despite the evidence that randomized clinical trials from LMICs are more likely to identify effective therapies and have a larger effect size than RCTs from HICs.

Thoracic oncology has particularly experienced positive advancements due to improved understanding of the biology of adenocarcinoma. Earlier, the classification scheme was based on histopathology findings5, which was revised due to molecular and genetic data that enables us to subtype tumors, and develop targeted therapy as a result, resulting in more personalized care and treatment of patients with this type of lung cancer.

Along with the use of precision medicine, major strides have been made related to the treatment of NSCLC through the use of targeted therapy in early-stage NSCLC, immunotherapy, indicating successful outcomes in treating advanced lung cancer, and improved overall survival of patients. Now, treatments are shifting toward newer targeted and small molecule therapies to improve outcomes among NSCLC patients. These advancements in the diagnosis and treatment of lung cancer, particularly NSCLC, have been achieved with the help of molecular translational research, among other efforts.

This wave of advancements happened in multiple stages; first, advances in research led to better understanding of the disease, which led to the development of new treatments and management plans based on the discoveries, along with to improvements and modifications in clinical practice and molecular profiling. Together, these advancements and modifications led to new treatment plans that showed improvement in tumor response and patient survival.

LMICs have lagged behind in these advancements, due to the high costs of novel testing. Advancements in precision medicine are underlined by the inequities of lung cancer care across different countries, with disparities higher for those who live in rural areas, racial minorities, and patients from low and middle-income countries. Inequity in access to precision medicine should be dealt on patient as well as healthcare facility level.

Despite these issues, the recent breakthroughs in the fields of radiotherapy, and novel drugs show us that there are new advancements being made every day, and hope for the future of lung cancer.

Recent Breakthroughs in Lung Cancer Treatment

As of January 2024, the EMA has approved four treatments for resectable early-stage NSCLC, with more decisions pending

  1. Adjuvant osimertinib
  2. Adjuvant pembrolizumab
  3. Adjuvant atezolizumab
  4. Neoadjuvant nivolumab plus chemotherapy

Researchers at the Icahn School of Medicine at Mount Sinai have achieved a promising breakthrough in the treatment of small cell lung cancer (SCLC). Their study, published in *Science Advances* on September 27, titled “ATR Inhibition Activates Cancer Cell cGAS/STING-Interferon Signaling and Promotes Anti-Tumor Immunity in Small Cell Lung Cancer,” introduces an innovative approach that brings hope to patients facing this challenging illness.

The study focused on ATR (ataxia telangiectasia and Rad3-related protein), which is crucial for DNA repair in cancer cells. By inhibiting ATR, susceptibility of these cancer cells to treatments was increased, to boost the immune system’s capacity to target them.

The study investigated the effects of a novel drug, berzosertib (M6620/VX970), in combination with topotecan, for treating patients with relapsed small cell lung cancer (SCLC). The findings of the study indicate that this combination could be particularly effective for patients who relapsed. Additionally, tcombining ATR inhibitors with anti-PD-L1 antibodies—an immunotherapy known as an immune checkpoint inhibitor that enhances the immune system’s ability to recognize and attack cancer cells—may further improve patient outcomes.

The Mount Sinai team intends to propose a clinical trial to evaluate these new treatments by 2025, with hopes that this research will also extend its benefits to other difficult-to-treat cancers.

In a recent study led by Suresh Ramalingam, MD, executive director of the Winship Cancer Institute at Emory University, a new drug has demonstrated significant potential in treating a specific type of advanced lung cancer. Osimertinib, developed by AstraZeneca and marketed under the brand name Tagrisso, markedly prolongs the time patients live without their cancer worsening, providing the first effective therapy and renewed hope for those with stage III NSCLC harboring mutations in the epidermal growth factor receptor (EGFR), a protein that regulates cell division and survival.

Patients treated with Osimertinib achieved a median progression-free survival of 39.1 months, compared to only 5.6 months for those receiving a placebo. This indicates that Osimertinib reduces the risk of disease progression or death by an impressive 84%.

Conclusion

The research looked at various contributing factors contributing to the inequity in the pathology, awareness, treatment, and management of lung cancer in Low and Middle Income Countries, to highlight the multi-level issues faced by the patients in LMICs, at personal as well as healthcare facility-level.

The evidence shows that the solution is multifactorial, and a holistic approach targeting both socio-cultural issues at the patient level, as well as minimizing gaps in research and treatments at healthcare level are required to address the issues posed by lung cancer.

References

  1. https://www.thelancet.com/journals/lansea/article/PIIS2772-3682(24)00080-5/fulltext

  2.  Cavallo J, D’Cruz A. Taking Action Against Cancer: Celebrating 20 Years of World Cancer Day. The ASCO Post. 2020.

  3. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-09561-0#ref-CR3
  4. https://www.thelancet.com/journals/lansea/article/PIIS2772-3682(24)00080-5/fulltext
  5. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2017.00194/full#B2
  6. https://www.nature.com/articles/s43018-020-00142-z#ref-CR4

  7.   Shah SC, Kayamba V, Peek RM Jr, Heimburger D. Cancer control in low-and middle-income countries: is it time to consider screening? J Glob Oncol. 2019;5:1–8.

  8. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-09561-0#ref-CR4

  9.  Ezzati M, Riboli E. Can noncommunicable diseases be prevented? Lessons from studies of populations and individuals. Science. 2012;337(6101):1482–7.

  10. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2017.00194/full#B4
  11. https://erj.ersjournals.com/content/56/5/2002949#ref-9
  12. https://erj.ersjournals.com/content/56/5/2002949#ref-10

  13.  Nwagbara UI, Ginindza TG, Hlongwana KW. Health systems influence on the pathways of care for lung cancer in low- and middle-income countries: a scoping review. Glob Health. 2020;16(1):23

  14.  Quaife SL, Forbes LJL, Ramirez AJ, Brain KE, Donnelly C, Simon AE, et al. Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK. Br J Cancer. 2013;110:12.

  15.  Birt L, Hall N, Emery J, Banks J, Mills K, Johnson M, et al. Responding to symptoms suggestive of lung cancer: a qualitative interview study. BMJ Open Respir Res. 2014;1(1):e000067.

  16.  Athey VL, Suckling RJ, Tod AM, Walters SJ, Rogers TK. Early diagnosis of lung cancer: evaluation of a community-based social marketing intervention. Thorax. 2012 ;67(5):412–7

  17. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2017.00194/full#B5

  18. Knaul FM, Arreola-Ornelas H, Rodriguez NM, et al. Avoidable mortality: the core of the global cancer divide. J Glob Oncol. 2018;4:1–12

  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0008
  20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0021
  21. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-09561-0#ref-CR18
  22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0044
  23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0045
  24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0014
  25. https://www.nature.com/articles/s43018-020-00142-z#ref-CR63
  26. https://www.nature.com/articles/s43018-020-00142-z#ref-CR63
  27. https://www.nature.com/articles/s43018-020-00142-z#ref-CR62
  28. https://www.nature.com/articles/s43018-020-00142-z#ref-CR74
  29. https://www.nature.com/articles/s43018-020-00142-z#ref-CR67
  30. https://www.nature.com/articles/s43018-020-00142-z#ref-CR68
  31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0026
  32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245978/#cit0028
  33. https://ascopubs.org/doi/pdf/10.1200/GO.21.00029
  34. https://ascopubs.org/doi/full/10.14694/EdBook_AM.2013.33.327#core-bibr2-EdBookAM201333327
  35. https://ascopubs.org/doi/full/10.14694/EdBook_AM.2013.33.327#core-bibr4-EdBookAM201333327
  36.  Lancet infographic - NSCLC - final (thelancet.com)
  37. https://jamanetwork.com/journals/jamaoncology/article-abstract/2775243
  38.  Lancet infographic - NSCLC - final (thelancet.com)
  39.  New Mount Sinai Research Brings Hope for Small Cell Lung Cancer Patients | Mount Sinai - New York
  40. https://medicalxpress.com/news/2024-06-lung-cancer-treatment-free-survival.html#:~:text=%22The%20impressive%20progression-free%20survival%20results%20from%20the%20LAURA%20Phase%20III