Lung cancer

Lung cancer is one of the most common forms of cancer, with 13% of newly diagnosed cancer cases diagnosed as lung cancers, which equated to an estimated 1.8 million new cases in 2012. Lung cancer has a poor prognosis and is one of leading causes of cancer-related death (19% of all cancer deaths worldwide are attributed to lung cancer), resulting in 1.6 million deaths in 2012.1
  • In men, the highest age-standardised incidence rates for lung cancer are observed in Central and Eastern Europe (53.5 per 100,000) and Eastern Asia (50.4 per 100,000)1, Central-Eastern and Southern Europe (48.5–56.5 per 100,000)1
  • In women, lung cancer age-standardised incidence rates are highest in North America (33.8 per 100,000) and Northern Europe (35.8–37.0 per 100,000)1
  • Only 15% of lung cancers are detected when the tumour is in the early stage,2 which has an impact on survival rates: 5-year survival rate of patients with lung cancer in the US is 17.8%3
  • The median age of lung cancer diagnosis is 70 years and has been increasing over time4
Lung cancer incidence and mortality is higher in men than in women; however, the gap is narrowing in many economically developed countries, with these patterns largely reflecting changes in prevalence in cigarette smoking in men and women.5 In contrast, the incidence of lung cancer in never-smokers (people that have smoked no more than 100 cigarettes in their life) is higher for women than men.6 Air pollution and other environmental factors may also play a role.

(Click here for slides on NSCLC: epidemiology)

There are two main types of lung cancer:

1. Small cell lung cancer (SCLC)

Overall, 13.2% of all lung cancers are classified as small cell lung cancer (SCLC).3 This form of lung cancer is characterised by small, round cancerous cells with an enlarged nucleus and minimal cytoplasm.6 SCLC is classed as either limited disease (LD) or extensive disease (ED). Prognosis is generally poor, with overall survival rates at 5 years of up to 10%. However, patients with LD have a marginally more favourable prognosis than those with ED, with a 5-year survival rate of 14% reported in patients with LD.7,8

2. Non-small cell lung cancer (NSCLC)

NSCLC is the most common form of lung cancer, responsible for over 83.6% of lung cancer cases.3 There are three main subtypes of NSCLC:

  • Adenocarcinoma (45.0% of NSCLC cases3) is the most common form of lung cancer and the most common subtype of NSCLC. It develops in the mucus-secreting glands in the lining of the airways.9 Approximately 10% of Western and up to 50% of Asian patients with adenocarcinoma have epidermal growth factor receptor (EGFR) mutations.10 This subgroup of patients may benefit from targeted therapies, including EGFR inhibition by tyrosine kinase inhibitors (TKIs) or ErbB Family Blockers.
  • Squamous cell carcinoma (SqCC; 23.0% of NSCLC cases)3 develops in the squamous cells that line the airways and tends to spread locally. It is often caused by smoking, and has limited treatment options. Patients with SqCC are typically treated with platinum-based chemotherapy, which is standard first-line therapy. With the increasing understanding and determination of specific biomarkers, identifying a molecular target for SqCC is of key importance. EGFR mutations are rarely (<5%) found in SqCC, however, expression of wild-type EGFR tends to be high. Studies with patients with SqCC treated with EGFR tyrosine kinase inhibitors (TKIs) have shown improved clinical outcomes, which has led to the approval of the EGFR TKIs erlotinib and afatinib as second-line therapy.10,11
  • Large cell carcinoma (1.8% of NSCLC cases)3 is characterised by large, rounded cells that are seen when cancerous tissue is examined microscopically.12,13 This type of tumour lacks squamous or glandular differentiation and is therefore also known as undifferentiated carcinoma.13

 

The remaining cases of NSCLC include rarer subtypes, such as adenosquamous carcinoma and sarcomatoid carcinoma, and cases where the subtype is unknown.3

 

Fig. 1: Subtypes of NSCLC Subtypes of NSCLC

Source: Howlader et al. SEER Cancer Stats Review

(Click here for slides on NSCLC: epidemiology)

 

Prognosis and treatment for NSCLC

Prognosis and treatment for NSCLC is dependent on the stage of the disease.

  • In patients with early-stage NSCLC, surgical resection (usually lobectomy) is considered the most suitable treatment choice14
  • In multiple trials it has been demonstrated that overall survival is superior in patients with resectable stage I to IIIA NSCLC who undergo resection and complete mediastinal lymph node dissection, compared with patients who undergo resection and lymph node sampling (hazard ratio 0.63; 95% confidence interval 0.51–0.78; p≤0.0001)14
  • Stage III (late-stage) tumours can be successfully treated in some cases, but cure rates are much lower than in early-stage NSCLC. Patients with Stage IIIA and selected Stage IIIB disease have a poor 5-year survival rate (5–30%) with surgery alone, thus these patients should be offered surgery in addition to adjuvant therapy.15
Patients with stage IV disease are rarely successfully treated and are typically inoperable. The goal of therapy in these patients is to extend survival and improve their quality of life.15 As well as histological subtypes, NSCLC can be further subdivided into molecular subsets, based on the presence of oncogenic driver mutations. These mutations occur in genes that encode signalling proteins for cell proliferation and survival. Some cancers rely on expression of at least one of these genes to maintain a malignant phenotype. This concept is known as ‘oncogene addiction’ and has important clinical implications, as these genes could be used to develop a molecular targeted therapy.16 Important driver mutations in NSCLC have been identified in a number of genes, including EGFR (ErbB1), human epidermal growth factor (HER2 [ErbB2]), Kirsten rat sarcoma viral ongogene homolog (KRAS) and anaplastic lymphoma kinase (ALK).17

Smoking accounts for almost 30% of all cancer deaths in patients with lung cancer; it is responsible for 87% deaths in men and 70% of deaths in women.18 At least 50 carcinogens have been identified in tobacco smoke.19 A causal association with lung cancer has also been shown for consumption of cigars, cigarillos, pipes, bidis and water pipes.20 Although there is an approximate 20-fold increase in lung cancer risk for smokers compared with never-smokers,21 an increasing number of never-smokers are being diagnosed with NSCLC. It is not clear whether this is due to an increase in the incidence rates of NSCLC in never-smokers or to an increase in the proportion of never-smokers in developed countries.22 Rates of lung cancer incidence in never-smokers are higher for women, particularly Asian women.6 Never-smokers, women and East Asians are also more likely to have a driver mutation in the EGFR (ErbB1) gene.6 These mutations have important clinical implications, as they determine treatment selection.10,23 Other causative agents for lung cancer include prolonged contact with asbestos, radon gas or certain other chemicals. Prior non-malignant lung diseases also increase the risk for lung cancer.24,25

The signs and symptoms of lung cancer may take many years to appear, are usually non-specific, and are often confused with symptoms of less serious conditions, such as flu or bronchitis.26 Early symptoms include coughing, haemoptysis, dyspnoea, loss of appetite, fatigue and recurring infections, while signs of advanced stages of lung cancer include bone pain, headaches, jaundice, swelling of the face, arms or neck, and lumps in the neck or collar bone region.27

Owing to the non-specific nature and the late onset of symptoms, approximately two-thirds of patients with lung cancer present with advanced stage or metastatic disease,28 which is associated with a very low cure rate.29

A wide range of diagnostic procedures are used to diagnose lung cancer including:30

Imaging studies
Radiography (X-rays), ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) or bone scans.

Blood tests
Baseline blood tests, which include renal and liver function tests (LFTs) and tests for calcium and lactate dehydrogenase (LDH) levels, can indicate the existence and severity of acute or chronic tissue damage.

Sputum tests
Samples of sputum are not routinely used for all patients. These tests are usually performed for patients with centrally located nodules or masses and who are unable to tolerate or do not want to undergo bronchoscopy.

Biopsies
Cells or tissues are removed from the lungs and examined microscopically to make a definitive diagnosis of cancer. If the cells are cancerous, they may be studied further to detect the rate of growth and extent of the cancer. Common biopsy techniques include:31

  • Transbronchial biopsy – A bronchoscope (thin viewing instrument) is inserted orally into the windpipe to examine the bronchi and lungs, and a tissue sample is taken
  • Needle biopsy – After a local anaesthetic has been given, and with the aid of CT scans or fluoroscopy, a needle is guided through the chest wall to obtain a tissue sample
  • Thoracoscopic (or video-assisted thoracic surgery [VATS]) biopsy – After a general anaesthetic has been given, an endoscope is inserted through the chest wall into the chest cavity. Biopsy tools can then be inserted through the endoscope
  • Open biopsy – After a general anaesthetic has been given, an incision is made in the skin on the chest and a piece of lung tissue is surgically removed.
  • Liquid biopsy – Minimally invasive techniques, such as exfoliative cytology and aspiration cytology, may be used in patients with advanced disease.32 In addition, the use of surrogate sources of DNA, such as blood, serum and plasma samples, which often contain circulating free tumour DNA or circulating tumour cells, is emerging as a new strategy, referred to as ‘liquid biopsy’32

Histopathology
Cancerous cells or tissue obtained by biopsy or surgery are examined to determine the histology of the lung cancer. The morphology and cell characteristics may be examined and their responses to antibodies and immunohistochemical markers evaluated.34

Cancer stage refers to the size and/or extent of the original (primary) tumour and the spread of cancer cells in the body. The stages are listed in the table 1 within available treatment options. The grade of a cancer describes a tumour based on the morphology of the tumour cells under a microscope. Cancers are graded as low-, intermediate- or high-grade.35 Low-grade cells are slower to divide and the cancer is generally less aggressive, whereas high-grade cells divide more quickly and the cancer is more likely to spread.35

Tumour samples are tested for various biomarkers, using techniques such as genome sequencing to detect mutations or rearrangements in DNA. Current clinical guidelines recommend that all patients with NSCLC be tested for EGFR (ErbB1) mutations and ALK rearrangements.10,22,36 Biomarker testing at the time of diagnosis is becoming increasingly important with the availability of therapies targeted to specific
molecular pathways.

In some forms of cancer, the levels of biomarkers can provide an indication of the stage of a tumour and the prognosis.37

Three main types of treatment are used in the management of lung cancer, which can be used as monotherapies or in combination are surgery; radiotherapy; and systemic therapy, which includes chemotherapy and targeted therapy.38 The stage of a patient’s cancer determines the treatment approach (Table 1).38 For patients with advanced or metastatic NSCLC, there is a high unmet medical need for clinically effective and well‑tolerated therapies.39 Most patients with advanced or metastatic lung cancer are treated with chemotherapy regimens that provide an overall survival of less than one year, and are associated with a variety of adverse effects.39

Table 1: Treatment is dependent on cancer stage

Stage

Extent

 

Stage I

Cancer is present only in one part of the lung and has not spread to the lymph nodes.

The tumour can often be removed with surgery. Chemotherapy is sometimes used after surgery (adjuvant chemotherapy) to reduce the chance of recurrence. Chemotherapy and/or radiotherapy may sometimes be given before surgery to shrink the tumour; this is known as neo-adjuvant chemotherapy.

Stage II

Cancer has spread to nearby lymph nodes or nearby tissues, e.g. chest wall.

It may also be possible to remove stage II NSCLC with surgery, and chemotherapy or radiotherapy is often given following surgery to reduce the risk of recurrence.

Stage III

Cancer has spread more extensively within the chest and, generally, to the major lymph nodes. Large tumours have invaded surrounding organs and lymph nodes outside the chest.

Although surgery may be considered as an option at this stage, this is often not possible because the cancer may have spread too far. Chemotherapy, on its own or combined with radiotherapy, may be given before an operation. If surgery is not possible, radiotherapy can be given instead. In some cases, chemotherapy given on its own, or in combination with radiotherapy, will be the only treatment used. For some patients with locally advanced or metastatic NSCLC, newer targeted treatments may also be used.

Stage IV

Cancer has spread (metastasised) to distant parts of the body, e.g. to the liver or bones.

Cancer has spread (metastasised) to distant parts of the body, e.g. to the liver or bones The aim is to control symptoms and maintain a good quality of life for as long as possible. Radiotherapy may be used to shrink the cancer and reduce symptoms such as pain. Chemotherapy may be given before or after radiotherapy, and may shrink the cancer and improve quality of life for some people. For some patients with locally advanced or metastatic NSCLC, newer targeted treatments may also be used.

 

Treatments that target specific molecular markers or structures in tumour cells are increasingly becoming available. These treatments have developed as a result of a greater understanding of the molecular biology and pathogenesis of NSCLC. In particular, two processes have been identified as major contributors to the pathology of NSCLC: tumour cell signal transduction and tumour angiogenesis.40,41

In tumour cells, elements of signal transduction pathways are often mutated or overexpressed relative to normal cells. An important group of signal transduction elements in tumour cells is the ErbB Family of receptors.42 In NSCLC, genetic mutations may occur, most commonly in the EGFR (ErbB1) gene, which dysregulate signal-transduction pathways, resulting in malignant cells.43 Blocking the whole ErbB Family may lead to a more successful blockade of the ErbB Family signalling pathway.44

Afatinib (GIOTRIF®)* is the first irreversible ErbB Family Blocker that inhibits signalling from all ErbB Family receptors. Afatinib is approved for use in patients with EGFR mutation-positive (EGFR M+) NSCLC and in patients with locally advanced or metastatic NSCLC of squamous histology, progressing on or after platinum-based chemotherapy.45

Angiogenesis is an essential process for normal growth and development, including for functions such as embryonic development, wound healing and restoring blood flow to damaged tissues. However, it is also vital for tumours to grow and spread to other organs. The development of new blood vessels in tumours requires the interaction of growth factors, such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), with their receptors FGFR, PDGFR and VEGFR.46,47 Some tumours harbour an overamplification of the FGFR or PDGFR genes, and inhibition of the associated signalling pathways may provide a direct anti-tumour effect.47,48 Furthermore, in response to VEGFR blockade, FGFR signalling may also serve as an escape pathway for tumour growth. Therefore, inhibition of multiple pathways, including the FGFR pathway, may inhibit tumour escape mechanisms.49

Approximately 25% of patients with advanced NSCLC show disease progression after the initial cycle of first-line chemotherapy, and most patients will eventually experience relapse and require subsequent therapy.50 Despite a significant amount of research in this area, there have been no new treatments for these patients for some time and until recently, no combination regimens were available in this setting.10,50–52

By focusing on the molecular and cellular changes that are specific to the cancer, targeted therapies may be more effective than current treatments and less harmful to normal cells, thereby reducing unwanted treatment-related adverse effects. The goal of targeted therapies is to offer personalised treatment according to a patient’s genetic make-up.23,36

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