Cancer is associated with abnormal growth of cells where uncontrolled cell growth is present. In some cases, this growth may metastasize, which will lead to invasion of adjacent tissue such as the spreading of disease into surrounding tissues. Lung cancer is compromised of two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) and upon this diagnosis, treatment is recommended to the patient.
Lung cancer is the world's most common cancer with 1.3 million new cases diagnosed every year1. In the UK alone, the number of diagnosed new cases has now reached more than 37,000 each year, and approximately 33,500 people die from lung cancer each year2. This accounts for 6% of all deaths and roughly one in five of all cancer deaths in the UK3. More men than women develop lung cancer and is the second most common cancer (~16%) after prostate cancer, whereas for women, it is the third most common cancer (~11%) after breast and bowel cancer4. Its prevalence is more common as we become more elderly with the average age of onset in the mid-70s2. Lung cancer is often thought to be a disease associated with well-developed countries, wealthy countries such as the western world. The fast-paced development of previously deprived countries, which are now becoming richer and as a result the incidence is rising rapidly, associated directly with changes in cigarette consumption4. Figure 1 shows the variation in lung cancer related deaths associated with changes in smoking patterns4.
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Figure Stages of world tobacco epidemic4
The main cause of lung cancer is of great controversy and any explanation for it, must take into account the substantial increase and subsequent decrease in the incidence of lung cancer in the past century. Additionally, geographical distributions of the tumour(s) must also be considered. Taking all relevant factors into account, it can be said that environmental factors are believed to be the primary cause rather than genetic factors/composition, as it is not possible for the genetic make-up of the population to transform at a fast rate. There may be a genetic predisposition to lung cancer as not all heavy smokers develop lung cancer. However, these individuals may only develop lung cancer on exposure to carcinogens such as cigarette smoke.2 The close relationship between smoking trends and deaths (Fig. 1) is inevitable and it is almost certain that the major cause of lung cancer is smoking. Susceptibility to lung cancer is related to the total number of cigarettes consumed2.
Doll and Hill followed up their retrospective studies in the UK in the 1950s with a prospective study of more than 40,000 male doctors5. Hammond and Horn6 undertook similar studies in the USA with even larger groups. A steady increase in the number of deaths from lung cancer with increasing cigarette consumption was seen i.e. a dose-response effect was seen. They also showed that subtle variations in the manner by which a cigarette is smoked and the type of cigarette used had an effect on the lung cancer incidence and subsequent death5-7.
All studies have shown a distinct reduction in mortality rates due to lung cancer in those who have stopped smoking cigarettes than with those who have continued to smoke2. Evidence of this is present in Doll and Hill's study which observed more than 50% of smokers stopped during the 20-year study8. Between 1954 and 1965, the death rate from lung cancer fell by 38%, whereas it rose by 7% for all men in the country (along with increased tobacco consumption)8.
The second most common cause of lung cancer is attributable to exposure to radon9 - a radioactive gas released from the ground and is a known human carcinogen, increasing risks of lung cancer9.
Subsidiary causes include passive smoking and exposure to carcinogens, such as asbestos dust, radioactive materials, arsenic, nickel, chromate, mustard gas and products of coal distillation, which are encountered or inhaled at work. Air pollution increases the risk of lung cancer however its effect is minimal in comparison to that of cigarette smoking. Additionally, various studies have shown that patients with vitamin A deficiency have a higher risk of lung cancer10.
Lung cancer is associated with several different types of cancer which develop in the lung, where differentiation is achieved by analysis of appearances' through a microscope. Of the NSCLC type, there are subtypes, for which, each behave in a different manner. Squamous lung cancer is the most common kind of lung cancer. The cells are flat surfaced, hence squamous cell, and they produce keratin (normally found in skin and hair). It mainly affects the large bronchi, and spreads by invading the local tissues, subsequently into lymph nodes and into the bloodstream. This often leads to extensive dysplastic changes. Adenocarcinoma is a tumour, which derived from glandular tissue. These tumours usually develop beneath the mucosal lining of the airways, with many starting at the periphery of the lung. The influence of smoking does not appear to be to the same extent as other types of lung cancers. Large cell lung cancer tumours usually develop in the central or peripheral part of the lungs. This type is predominantly found in smoker and they spread within the airways, to the lymph glands and subsequently the bloodstream.
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Figure . Lung cancer histology. Top left, Adenocarcinoma characterised by heterogeneous differentiation in the same tumour. Top right, Small cell carcinoma characterised by the presence of cytokeratin differentiation with keratinisation and intercellular bridges. Bottom left, Large cell carcinoma characterised by sheets and nest with extensive necrosis, large nuclei with prominent nucleoli, and lack of definitive evidence of squamous or glandular differentiation. Bottom right SCLC characterised by round to fusiform nuclei, nuclear molding, faint or absent nucleoli, and scant cytoplasm11.
SCLC tumours are small and fragile, which grow and spread rapidly through the bloodstream to other organs, and usually develop from the central part of the lung. These cells secrete a large amount of polypeptide hormones leading to a wide range of paraneoplastic syndromes of which the most common is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and ectopic adenosorticotrophin syndrome.
Carcinoid is a rare type of lung cancer that develops from the special hormone-producing cells. It is much less malignant than SCLC and is more common in young people.
Mesothelioma is a tumour of the membrane (pleura) surrounding the lung and is separate from the chest wall. This tumour is usually associated with previous years of asbestos exposure and a plueral effusion usually arises, where fluid accumulates between then lung and chest wall.
Symptoms that indicate lung cancer likeliness include12:
Dyspnoea (shortness of breath)
Haemoptysis (coughing up blood)
Chronic coughing or change in coughing pattern
Chest pain/abdomen pain
Cachexia, fatigue, and loss of appetite
Dysphonia (hoarse voice)
Clubbing of the fingernails
Dysphagia (difficulty swallowing)
Lung cancer symptoms often present themselves late with a worsening cough and in some cases, only chest pain is reported initially. In most instances, the cancer has already spread from the origin on presentation of symptoms. The symptoms develop dependant on the type of cancer and it's stage; obstructive features may arise from benign or malignant tumours as well as paraneoplastic disorders. Note, many of the symptoms experienced by patients are non-specific (e.g. bone pain, fever, weight loss).
Treatment of lung cancer is designed according to the extent of the disease and general fitness of the patient. The major curative for of treatment is surgery2. Radiotherapy can produce a cure in a small minority of cases and also help common symptoms. Chemotherapy has shown to prolong the quantity and quality of life in advanced stage disease as well as providing symptomatic relief2.
Targeted therapies are a form of treatment which inhibits the proliferation of cancer cells by interfering with receptors or proteins unique to cancer cells. Commonly, targeted therapy is associated with the use of biological products, cells, or proteins2. These can include hormones, antibodies, targeted small molecules, and vaccines2. Epidermal growth factor receptor (EGFR) is expressed on many types of cancer cells, especially in NSCLC. On binding of epidermal growth factor to these receptors, tyrosine kinase produces signals causing the proliferation of cells (Fig. 3).
Figure . Activation and inhibition of EGFR. EGFR is a transmembrane receptor composed of 2 units (left). When ligands (e.g. transforming growth factor Î± (TGFÎ±) or epidermal growth factor) bind, intracellular tyrosine kinase (TK) is activated. This binding leads to phosphorylation of several tyrosine residues, which act as docking sites to specific molecules that activate in turn multiple signalling pathways, including MAPK and P13K. Net result is production of proteins promoting cell growth, differentiation, and angiogenesis. EGFR signalling might be inhibited (right) by extracellular monoclonal antibody (MAb; e.g. cetuximab, EMD72000, or ABX-EGF), or intracellular tyrosine kinase inhibitors (TKI; e.g. gefitinib or erlotinib).13
Erlotinib and gefitinib
Erlotinib is a EGFR tyrosine kinase protein inhibitor, preventing autophosphorylation of tyrosine kinase. It binds reversibily to adenosine triphosphate (ATP) binding site on the receptor. Approximately 70-80% of NSCLCs over express this receptor (EGFR), which is therefore an attractive target for treatment. Its mode of action is shown above in Fig 3. In the USA, erlotinib is used as a second- or third-line treatment for advanced NSCLC. Gefitinib was the first selective EGFR tyrosine kinase inhibitor. Research has shown a mutation in the EGFR tyrosine kinase domain is responsible for the inappropriate activation of the anti-apoptotic Ras signalling cascade on only gefitinib sensitive-NSCLCs14,15. These types of mutations are normally associated with adenocarinoma types which are commonly seen in Asians, women and non-smokers14. These drugs are used when other treatments, largely platinum-based chemotherapy has failed. The main advantage of these drugs, is that they can be administered orally, but are prone to some side-effects such as rash, diarrhoea, loss of appetite and fatigue.
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Cetuximab is an IgG1 monoclonal antibody which binds to the extracellular domain of EFGR to block ligand binding, resulting in inhibition of autophosphorylation of EFGR. Recent studies have shown a beneficial effect of combination therapy with chemotherapy. The FLEX study showed an improved overall survival of 11.3 months compared with 10.2 months with cisplatin plus vinorelbine with chemotherapy16. This improved survival observed with cetuximab has not been seen with chemotherapy combined with either erlotinib or gefitinib17. Treatment is reasonably well tolerated, with adverse effects from a phase I trial including fever and chills, asthenia, skin toxicity and nausea18.
Angiogenesis of lung cancer cells increases as the tumours increase in size. Without its own blood supply, the cancer cannot continue to grow. VEGF-A is believed to be the major mediator in tumour angiogenesis. In growing tumours, VEGFR-1 and VEGFR-2 influence angiogenesis and VEGFRs have been identified on the surface of tumour cells related to NSCLCs. Bevacizumab is an anti-angiogenic monoclonal antibody drug which recognises and blocks vascular endothelial growth factor A (VEGF-A)17. It has a long half-life of 17 to 21 days after IV infusion. Recent studies have shown more than 50% of patients with lung cancer that has spread, survival for >12 months19. It is used in the treatment of NSCLC, in combination with chemotherapy.
Figure . Bevacizumab mechanism of action. VEGFR1 (also known as Flt1) and VEGFR1 (also known as Flk1 or KDR) are expressed on the surface of tumour cells. VEGFR2 is thought to be the major mediator of cell mitogenesis, survival and microvascular permeability, whereas VEGFR1 mediates tumour growth and metastasis, inclduing the stimulation of metalloproteinases (MMPs). tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator20.
Lung cancer is a heterogeneous disease and accordingly, for successful treatment of the disease, it is essential to identify specific molecular targets, and provide treatment for patients in relation to their biological profile. More than 500 novel molecular targeted therapy products are currently being developed for potential treatments. Ideally they will be more effective and have fewer side effects in comparison to older drug therapies. To this present day, there has not been no targeted therapies approved for use in the treatment of SCLC as there have been more negative findings in research than positive ones21. Clinical research targeting SCLC treatment therapies and are still premature however discoveries of novel targets on a daily basis will help push forward treatment potential.