Key learning points
- Squamous cell carcinoma, adenocarcinoma and lepidic adenocarcinoma are the most common subtypes of non-small cell lung cancer (NSCLC)
- Extent of disease for NSCLC is described in terms of tumour size and position, lymph node involvement and presences of metastases – this is known as the TNM staging system
- Treatment of NSCLC includes surgery, radiotherapy, chemotherapy and biologically targeted therapies such as EGFR inhibitors (e.g. gefitinib, erlotinib, afatinib, osimertinib)
Lung cancer is just one of many diseases associated with tobacco use. It is estimated that one person dies every six seconds in the world from smoking-related disease1. Although most lung cancers are smoking-related, there is increasing research and interest in the rise of lung cancers in those who have never smoked.
The histological classification of lung cancer includes small cell lung cancer (SCLC); non-small cell lung cancer (NSCLC), and neuroendocrine carcinoma (NET). SCLC is characterised by rapid growth and early dissemination. NSCLC is generally a more indolent tumour that consists of several histological subtypes and has a lesser propensity for early spread. The most common subtypes of NSCLC are squamous cell carcinoma, adenocarcinoma and an infiltrative form of adenocarcinoma called lepidic.
Pre-malignant lesions in NSCLC
Three pre-invasive lesions have been identified; atypical adenomatous hyperplasia (AAH), squamous dysplasia and carcinoma in situ (CIS), and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.2
Atypical adenomatous hyperplasia (AAH)
AAH are thought to represent precursors of adenocarcinomas. These are sometimes visualised on high resolution computed tomography (CT) scans of the thorax. They are variously described as ground-glass lesions, with or without solid components.
There is a group of adenocarcinomas that arise in patients (particularly women) who have never smoked. They often have mutations in oncogenes such as epidermal growth factor receptor (EGFR). In addition, mutations in the human epidermal growth factor receptor 2 (HER 2) are also seen in this group. Other mutations reported include tyrosine kinase members of the ErbB family.
The extent of disease is formally characterised using a TNM staging system (eighth edition). This defines the size and position of the primary tumour (T), involvement of lymph nodes (N) and the presence of metastatic disease (M).3,4 The combined American Joint Committee on Cancer (AJCC) staging separates NSCLC into stages I (most localised) to IV (disseminated).4,5
Lymph node involvement is determined on the basis of a combination of features, including lymph node size on computed tomography (CT) scan, uptake of radiolabelled fluoro-deoxy-glucose (FDG) seen on positron emission tomography (PET) scan and biopsy of mediastinal lymph nodes obtained either with the aid of endobronchial ultrasound (EBUS) or, more rarely, mediastinoscopy.
Treatment of NSCLC is dependent on the patient’s wishes, the extent of disease, the patient’s performance status (PS), location of the tumour and the detailed histological and molecular profile of the tumour. Treatment is usually aimed at either being radical (with curative intent) or palliative. Treatment modalities include surgery, radiotherapy, chemotherapy, and biologically targeted therapies, or a combination of the above. Lung function and PS allow an estimate of the patient’s ability to tolerate general anaesthesia and removal of segments, part or the whole of one lung.
Radical treatment associated with the best outcome is surgery, providing the tumour is resectable, there is no tumour spread and respiratory and cardiac comorbidity (such as ischaemic heart disease or chronic obstructive pulmonary disease [COPD]) do not preclude safe anaesthesia and surgery. Surgical removal of a tumour can be in the form of excision of the tumour and a small area of surrounding lung tissue (wedge resection); removal of segment(s) of the lung (segmentectomy); removal of part of the lung (lobectomy) or the whole of one lung (pneumonectomy). Sleeve resection is also possible. A sleeve resection refers to removal of part of a bronchus and the lobe affected by the tumour. An anastomosis is performed in order to reconnect the lung to the bronchus.
Radiotherapy is used as radical treatment in patients with localised and locally advanced NSCLC who have unresectable tumours, and in patients medically unfit for surgery. Small tumours, which cannot be excised, can be treated with radical radiotherapy as an alternative to surgery. The treatment of small localised NSCLC with high precision localised irradiation given in few fractions is termed stereotactic body radiotherapy (SBRT) or stereotactic ablative body radiotherapy (SABR). This is suitable for lesions <4 to 5 cm in maximum diameter.
Larger tumours with spread to loco-regional lymph nodes can be treated with fractionated external beam radiotherapy using a linear accelerator with fixed, moving or intensity modulated beams. This form of radiotherapy is the most frequently employed radiotherapy for patients with locally advanced NSCLC.
Radical radiotherapy is often given following surgery especially if the mediastinal lymph nodes sampled at surgery are positive for tumour. There is an ongoing randomised trial in the UK assessing the additional value of radiotherapy for previously unsuspected N2 disease. Radiotherapy is also used after surgery if there is microscopic disease suspected at the margin of tumour excision.
Larger tumours where conventional radical radiotherapy cannot safely be delivered are treated with lower dose fractionated irradiation (high-dose palliative radiotherapy). Radiotherapy is used as palliative treatment to control cancer-related symptoms in patients with advanced and/or disseminated disease.
Cisplatin/carboplatin-containing chemotherapy given before or after radical surgery or radical radiotherapy is associated with a small survival gain (4–5% at five years) additional to the primary treatment.
Chemotherapy is used prior to surgery (neoadjuvant treatment) to shrink the tumour to allow for radical excision of previously inoperable tumour and as an additional treatment (adjuvant chemotherapy) following surgery for more locally advanced tumours. Chemotherapy offers palliation in patients with metastatic (disseminated) disease and prolongs survival by approximately two months (measured as prolongation of median survival).
Biological targeted drugs, aimed at specific mutations, are now used for the treatment of NSCLC with tumours expressing the mutation. Current mutations are seen predominantly in adenocarcinoma subtype of NSCLC and are more common in non-smoking females and in South-East Asia.
The most frequently used agents are aimed at inhibiting the activity of EGFR at the intracellular level (EGFR tyrosine kinase inhibitors – TKIs). Commonly used EGFR inhibitors include gefitinib, erlotinib, afatinib, or osimertinib. Osimertinib is specific for the T790M mutation. Treatment with EGFR inhibitors is generally not effective in the absence of a specific mutation i.e. wild-type EGFR.
NSCLC with mutation in anaplastic lymphoma kinase (ALK) gene can be treated with an ALK inhibitor such as crizotinib, ceritinib and alectinib. Tumours with mutation in ROS1 can effectively be treated with crizotinib.
Immune checkpoint inhibitors are a new class of agents with efficacy in patients with tumours showing the presence of the biomarkers PD-1 and PD-L1 on the tumour surface. These treatments have been approved for use in patients with recurrent disease failing primary chemotherapy for disseminated tumours and for the primary tumour of metastatic NSCLC. Examples of this class of drug include pembrolizumab, nivolumab and atezolizumab.
It is now possible to treat individual metastases outside of the primary site in the chest, abdomen (e.g. liver and adrenal) and in the brain. Oligometastatic disease is defined as the presence of 1 to 3 (and occasionally up to 5) metastases either at presentation or at the time of recurrence. SABR is currently being used in oligometastatic NSCLC.
Palliation in Advanced Disease
Stage IV NSCLC and recurrent disease are generally incurable with either local or systemic treatment and management is aimed primarily at symptom control. Palliation may be achieved with symptomatic treatment not aimed at tumour eradication (e.g. painkillers) and with antitumor therapy including radiotherapy (localised symptoms), systemic therapy (chemotherapy, targeted agents and immunotherapy) or a combination of both.
Dr Michael Beckles, Consultant respiratory and general physician, Royal Free Hospital, London
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