LCa is characterised by uncontrolled cell growth in the tissues of the lungs. More than 2.2 million new cases of LCa are reported annually. Furthermore, LCa is responsible for ~1.8 million deaths a year, representing the leading cause of cancer-related death.2,3
Data from the Cancer Association of South Africa (CANSA), show LCa is among the top three cancers in men in the country. In women, LCa is ranked seventh. According to CANSA, South Africans’ awareness of LCa is severely lacking. As a result, >66% of patients are diagnosed at a late stage when the disease has metastasised.4
Types of lung cancer
There are two main types of LCa: Non-small cell lung cancer (NSCLC, 80%-85%) and small cell lung cancer (15%-20%). The predominant subtypes of NSCLC include: Adenocarcinoma, which usually originates in peripheral lung tissue, and squamous cell carcinoma, which usually starts near a central bronchus.6
NSCLC often spreads to bone, as well as the brain, and the liver. Brain metastases account for most of the central nervous system tumours, being observed in up to 40% of patients with different cancer types.6
Causes of lung cancer
A 2022 study conducted in KwaZulu-Natal by Mbeje et al, shows that apart from tobacco smoking and exposure to passive smoke, alcohol consumption, increased exposure to occupational (eg exposure to silica, arsenic, chromium, cadmium nickel, and environmental carcinogenic substances (eg outdoor air pollution, domestic fuel smoke [wood burning], as well as a history of lung diseases (eg chronic obstructive pulmonary disease), and genetic factors (5.8% of patients present with germline mutations in hereditary cancer genes) are statistically significantly associated with the development of LCa.3,7
A study by Alexandrov et al shows that tobacco smoking is not only associated with the development of LCa, but at least 16 other types including cancers of the larynx, pharynx, oral, oesophageal, bladder, liver, cervix, kidneys, and pancreas.7,8
Furthermore, their study shows a direct link between the number of cigarettes smoked in a lifetime and the number of mutations in tumour DNA. The researchers found that, on average, smoking a packet of cigarettes a day leads to:8
- 150 mutations in each lung cell every year
- 97 in the larynx or voice box
- 23 in the mouth
- 18 in the bladder
- six in the liver.
According to the researchers, the more mutations there are, the higher the chance that these will occur in key cancer genes, which convert a normal cell into a cancer cell. Simply put: The more you smoke, the greater your risk of developing LCa.8
Bracken-Clarke et al caution that vaping and E-cigarettes also increase the risk of LCa – especially in younger patients. Vaping devices and E-cigarettes contain fluids that are either definite or probable oncogenes (eg nicotine derivatives [nitrosnornicotine, nitrosamine ketone], polycyclic aromatic hydrocarbons, heavy metals [including organometal compounds] and aldehydes/other complex organic compounds).9
It is important to note that even never-smokers can also develop LCa. It is estimated that LCa in never-smokers accounts for 10%-25% of cases, and its incidence is increasing, although the reasons remain unclear.3
What’s new in the management of patients with NSCLC?
According to the American National Cancer Institute (NCI), treatment decisions should be based on some of the following:10
- The histological type
- Tumour size and location
- Involvement of pleura
- Surgical margins
- Status and location of lymph nodes by station
- Tumour grade
- Lymphovascular invasion (indicates the presence or absence of tumour cells in lymphatic channels [not lymph nodes] or blood vessels within the primary tumour).
Surgery is potentially the most curative primary therapeutic option for LCa, but according to Souza et al, a small number of LCa patients are eligible for surgery because the majority (~75%) present with locally advanced or distant metastatic disease at diagnosis.6,10
Systemic therapy for cancer consists of anti-cancer agents administered into the system to damage or destroy cancer cells and hence cancer growth, which can be either molecularly targeted therapy, biological therapy such as immunotherapy, or chemotherapy (ChT).11
Historically, treatment of advanced LCa was limited to ChT. However, the identification of oncogenic driver mutations in NSCLC has dramatically changed the therapeutic approaches over the past few decades (see table 1).6
Targeted therapy, directed at the products of oncogenic driver mutations, and immunotherapy, using immune checkpoint inhibitors (ICIs), which facilitates the recognition of cancer as foreign by the host immune system, stimulates the immune system and alleviates the inhibition that allows the growth and spread of cancer cells, has been shown to significantly improve the overall survival (OS) of patients with advanced NSCLC.6,12
In 2015 to 2016, the two-year relative survival for NSCLC was 42% compared to 34% between 2009 and 2010. Between 1990 and 2020, the death rate from LCa dropped by 58% in males, and between 2002 and 2020, the death rate dropped by 36% in females.14
New guidelines from the NCCN
The 2023 American National Comprehensive Cancer Network (NCCN) guidelines for the management of NSCLC recommends the following initial treatment in patients with operable disease: Surgical exploration, resection, and mediastinal lymph node dissection or systematic lymph node sampling after pre-operative systemic therapy (if planned).13
In patients with inoperable stage N0 disease, radiotherapy, preferably stereotactic ablative radiotherapy, and adjuvant ChT for high-risk stages IB and IIB, followed by surveillance are recommended.13
In patients with stage NI disease, chemoradiation, and treatment with durvalumab are recommended for stage III and category 2A stage II disease, again followed by surveillance.14
Furthermore, the guidelines recommend that some patients with resectable NSCLC who are likely to receive adjuvant ChT may instead be treated with neoadjuvant systemic therapy after surgical evaluation.13
The panel does caution that neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet the criteria for resectability on initial evaluation.13
The panel recommends nivolumab platinum-doublet ChT as a neoadjuvant systemic therapy option for eligible patients with resectable (tumours ≥4cm or node-positive) NSCLC and no contraindications to treatment with programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) inhibitors.13
Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents, some oncogenic drivers (eg epidermal growth factor receptor [EGFR] exon 19 deletions, EGFR exon 21 L858R mutations, or anaplastic lymphoma kinase gene [ALK] fusions, which occur in ~7% of patients with lung adenocarcinoma) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors.6,13
EGFR mutations occur in 15%–40% of adenocarcinoma cases. Testing for PD-L1 status, EGFR mutations, and ALK fusions is recommended before administering neoadjuvant nivolumab platinum doublet chemotherapy in eligible patients with stage IB (only T5 4cm) to IIIA and stage IIIB (only T3N2).6,13
ChT regimens that may be used with neoadjuvant nivolumab include cisplatin either pemetrexed (non-squamous only), gemcitabine (squamous only), paclitaxel (any histology) or carboplatin either pemetrexed (non-squamous only), gemcitabine (squamous only), or paclitaxel (any histology).13
The panel recommends osimertinib as an adjuvant (also known as post-operative) therapy option for eligible patients with completely resected (R0) stage IB (only T5 4cm) to IIIA and stage IIIB (only T3N2) EGFR mutation-positive NSCLC who have previously received adjuvant ChT or are ineligible to receive platinum-based ChT.13
The panel recommends atezolizumab as an adjuvant therapy option for eligible patients with PDL1 of ≥1% and completely resected (R0) stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant ChT or adjuvant pembrolizumab for eligible patients with completely resected (R0) stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant ChT.13
Pembrolizumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated.13
Table 1: NCI treatment recommendations for patients with NSCLC10
- Global Initiative for Chronic Obstructive Lung Disease. [Internet]. World Lung Cancer Awareness Day – August 1, 2021. Available from: https://goldcopd.org/world-lung-cancer-awareness-day-august-1-2021/#:~:text=World%20Lung%20Cancer%20Awareness%20Day,Chronic%20Obstructive%20Lung%20Disease%20%2D%20GOLD
- Herbst MC. [Internet]. CANSA Fact Sheet on Lung Cancer. Available from: https://cansa.org.za/files/2022/02/CANSA-Fact-Sheet-on-Lung-Cancer-NCR-2019-web-January-2022.pdf
- De Alencar VTL, Figueiredo AB, Corassa M, et al. Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy. Frontiers Immunology, 2022.
- [Internet]. Lung cancer. Available from: https://cansa.org.za/lung-cancer/
- Prado MG, Kessler LG, Au MA, et al. Symptoms and signs of lung cancer prior to diagnosis: case-control study using electronic health records from ambulatory care within a large US-based tertiary care centre. BMJ Open, 2023.
- Souza VGP, de Araújo RP, Santesso MR, et al. Advances in the Molecular Landscape of Lung Cancer Brain Metastasis. Cancers (Basel), 2023.
- Mbeje NP, Ginindza T, Jafta N. Epidemiological Study of Risk Factors for Lung Cancer in KwaZulu-Natal, South Africa. Int J Environ Res Public Health, 2022.
- Alexandrov LB, Ju YS, Haase K, et al. Mutational signatures associated with tobacco smoking in human cancer. Science, 2016.
- Bracken-Clarke D, Kapoor D, Baird AM, et al. Vaping and lung cancer - A review of current data and recommendations. Lung Cancer, 2021.
- National Cancer Institute. [Internet]. Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version. Available from: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq
- Shahid K, Khalife M, Dabney R, Phan AT. Immunotherapy and targeted therapy - the new roadmap in cancer treatment. ATM, 2019.
- Shroff GS, de Groot PM, Papadimitrakopoulou VA, et al. Targeted Therapy and Immunotherapy in the Treatment of Non-Small Cell Lung Cancer. Radiol Clin North Am, 2018.
- Ettinger DS, Wood DE, Aisner DL, et al. NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, Version 2.2023. JNCCN, 2023.