Lung cancer refers to malignancies that originate in the airways or pulmonary parenchyma. Worldwide, the disease affects 1.8 million people and is the cause of 1.6 million deaths a year.¹

Lung cancer is the fourth most commonly occurring malignancy in Ireland, with approximately 2,000 new cases diagnosed on average annually, per National Cancer Registry of Ireland data. The disease is now the most common cause of cancer death among both men and women in this country.

Risk factors

The principal risk factor for the development of lung cancer is cigarette smoking, being causative in approximately 90% of cases.² In sustained quitters, the risk falls for about 15 years following cessation, though never returns to that of a never-smoker and remains twice that of lifelong non-smokers.³

Other risk factors include radiation therapy; environmental factors such as inhalation of asbestos fibres and radon gas; chronic lung diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD); HIV infection; and genetics and dietary factors. 

Histological classification

Classification of lung carcinomas by histopathological subtype provides important information about prognosis and is essential for guiding optimal treatment. The World Health Organization 2004 Lung Cancer Classification System recognises several subtypes: adenocarcinoma (the commonest variant); squamous cell carcinoma; large cell carcinoma; adenosquamous carcinoma; small cell carcinoma; sarcomatoid carcinoma; carcinoid tumour; and salivary gland tumours. 

In 2011, a multidisciplinary expert panel comprising representatives from the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a major revision of the classification system for lung adenocarcinoma, emphasising the importance of a multidisciplinary approach.⁴

The routine testing for markers such as the epidermal growth factor receptor (EGFR) was also recommended, mutations in which predict favourable treatment responses to novel ‘targeted’ therapies (see below).

Clinical presentation

The majority of patients with symptoms at time of initial diagnosis already have advanced disease. Indeed, early stage lung cancer is frequently an incidental diagnosis when testing to rule out other diseases is performed (for example, computed tomography (CT) to assess for suspected acute pulmonary embolism). There is a variety of presenting features that patients may display, depending on the location and extent of locoregional and/or disseminated disease. 

The most common symptom is cough, which affects up to 75% individuals and is more usually observed in those with tumours that involve the central airways (squamous cell carcinoma or small cell carcinoma).⁶ Haemoptysis is reported in 25-50% of patients, though massive bleeding is rare. Haemoptysis that occurs in the context of a normal chest radiograph renders the likelihood of lung cancer low, although thorough evaluation of this patient group by means of CT thorax and bronchoscopy is still recommended.⁶ Dyspnoea is a frequently-reported symptom in lung cancer patients, though patient comorbidities (for example, COPD or heart failure) may contribute. Other common symptoms include hoarseness, chest pain and weight loss. 

One of the more dramatic presentations is of potentially life-threatening superior vena cava (SVC) obstruction syndrome. Such patients may complain of fullness in the head, facial congestion, headache and dyspnoea, while dilatation of neck veins with resultant facial oedema and development of prominent chest wall venous collaterals may be apparent on clinical examination.

Pancoast syndrome refers to lung tumours that originate in superior sulcus of the thorax and is characterised by pain due to bony destruction, Horner’s syndrome and atrophy of the hand muscles.

The liver, bones, adrenal glands and brain are the most frequent sites of metastases in the setting of lung cancer. Adrenal gland involvement is generally asymptomatic, whereas patients with bone metastases are often symptomatic with pain and may develop hypercalcaemia. Dissemination of the disease to the brain may be subclinical or be characterised by headache, vomiting, visual field loss, limb weakness, cranial nerve deficit or seizures.

Paraneoplastic effects of lung tumours are numerous but do not indicate cancer spread. Examples include hypercalcaemia, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), Lambert-Eaton myasthenic syndrome (LEMS), cerebellar ataxia, sensory neuropathy, limbic encephalitis, hypercoagulable disorders, dermatomyositis, polymyositis, and ectopic production of adrenal corticotrophin (ACTH) leading to Cushing’s syndrome.

Diagnosis and staging

Approximately 85% of patients with lung cancer are symptomatic at presentation. A timely diagnosis and accurate staging of patients with suspected lung cancer is critical in order that appropriate therapy can be administered. In order to streamline referral processes and expedite diagnostic work-up for patients suspected of having lung cancer, the National Cancer Control Programme completed the roll out of a national lung rapid access network across Ireland in 2011, encompassing eight expert referral centres. Chest radiography and contrast-enhanced CT of the thorax and upper abdomen are performed as routine at time of initial evaluation. Radiographic features suggestive of malignancy include the absence of a benign pattern of calcification in the detected pulmonary lesion, a nodule or mass that is increasing in size on serial imaging, a nodule with a spiculated or lobulated border, a large lesion (>3cm should be considered likely malignant unless proven otherwise) and a cavitatory lesion that is thick walled.⁷

The tumour-node-metastasis (TNM) staging system for non-small cell lung cancer (NSCLC) categorises tumours on the basis of primary tumour characteristics (T), the presence or absence of regional lymph node involvement (N), and the presence or absence of distant metastases (M).¹² The stages are:

• Stage 0 – T in situ N0M0
• Stage IA – T1a-1bN0M0
• Stage IB – T2aN0M0
• Stage IIA – T1a-2aN1M0 or T2bN0M0
• Stage IIB – T2bN1M0 or T3N0M0
• Stage IIIA – T3N1M0 or T1a-3N2M0 or T4N0-1M0
• Stage IIIB – T4N2M0 or T1a-4N3M0
• Stage IV – Any T Any N M1a-1b.

Positron emission tomography (PET) or PET-CT are complementary diagnostic modalities that provide a non-invasive assessment of TNM staging. PET is more accurate than CT alone in detecting occult disease and should be considered in patients being considered for radical therapy for localised disease (ie. surgical resection or localised radiotherapy), patients with suspected N2/N3 disease on the basis of CT and in those with limited stage small cell cancer (see below). The sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis is approximately 55% and 81%, respectively, compared to 77% and 86%, respectively, for PET scanning.⁸ However, false negative PET scans can occur in tumours of low metabolic activity, small nodules (8mm or less in diameter), and hyperglycaemic patients.

Solid and part-solid pulmonary nodules identified by CT scan require periodic follow up by serial CT scans according to the Fleischner criteria (updated by the American College of Chest Physicians (ACCP) guidelines, May 2013). Subjects are stratified into high risk or low risk groups, principally on the basis of smoking history, and followed up for two years to monitor for increase in nodule size. Detection of ground glass nodules (GGN), however, which may represent a slow growing adenocarcinoma, need longer follow up. The ACCP recommends that non-solid nodules measuring ≤ 5mm in diameter require no further evaluation, whereas those measuring > 5mm in diameter require annual surveillance with chest CT for at least three years, given the slow doubling time of these tumours.⁹

Tissue needs to be obtained to confirm the diagnosis of lung cancer. The best strategy to obtain material for histopathological evaluation is largely dependent on tumour location (that is, central versus peripheral) and size. Flexible bronchoscopy is generally most informative for central tumours when biopsies, brushings and washings of suspicious lesions can be obtained. For peripheral lesions, percutaneous CT-guided lung biopsy is the most commonly used approach, with expected diagnostic rates of 85-90% in lesions over 2cm. Standard bronchoscopy with fluoroscopic guidance is a potentially useful approach in larger peripheral lesions. In recent years, several new bronchoscopic technologies have emerged that may improve the yield of biopsies from peripheral lung nodules. These include electromagnetic navigation systems, virtual bronchoscopy, radial and convex endobronchial ultrasound, ultrathin bronchoscopy and guide sheath technology.¹⁰

Tissue confirmation when locoregional disease spread to local thoracic lymph node stations is suspected is also critical in order to accurately determine stage and inform optimum treatment approach. In this regard, endobronchial ultrasound-guided (often complemented by endoscopic ultrasound (EUS)) sampling of mediastinal and/or hilar lymph nodes has emerged as a highly accurate, safe and well tolerated approach to fully stage the mediastinum.¹¹ Other techniques to confirm nodal status include ultrasound guided neck lymph node sampling, mediastinoscopy, mediastinotomy and thoracoscopy. Brain imaging should be performed if symptoms or signs of metastatic disease are present or when evaluating what appears to be stage IIIA or B disease. 

Small cell lung cancer has traditionally been staged according to a two-stage system originally introduced by the Veterans’ Affairs Lung Study Group (VALSG). Limited-stage disease is defined as tumour burden that is confined to a single hemi-thorax and ipsilateral supraclavicular lymph nodes, representing the maximum tolerable field for thoracic radiation therapy. By comparison, extensive-stage disease is present when the tumour extends beyond these boundaries. However, use of the TNM staging system for SCLC is also encouraged.

All patients diagnosed with lung cancer should be discussed in a multidisciplinary forum. The multidisciplinary team is usually represented by specialists in the fields of radiology, pathology, respiratory medicine, thoracic surgery, medical and radiation oncology and palliative care. 

Lung cancer screening

For over 50 years, researchers have examined different diagnostic techniques to see if early detection of asymptomatic lung cancer was possible and, more importantly, if such approaches could reduce mortality. In the 1970s and 1980s, chest x-ray with or without sputum cytology analysis was extensively studied in a number of trials on both sides of the Atlantic as a potential screening tool. Results from these various efforts were uniformly negative, including the recently-published large PLCO trial.¹³

However, in 2011 results from the pivotal US National Lung Screening Trial (NLST) demonstrated that the use of annual low-dose helical CT (LDCT) scans reduced lung cancer specific and overall mortality in a high-risk population when compared to standard chest x-ray. Cost effectiveness of this intervention is unknown and very high false-positive rates (ie. detection of benign nodules) are usual.¹⁴ Nevertheless, the positive results of the NLST study led the US Preventive Services Task Force to issue a Grade B recommendation for annual low-dose CT scan for high-risk adults aged 55-80 years. Suitable candidates are considered to be smokers or former smokers (if quit within previous 15 years) with at least a 30 pack-year smoking history. Discontinuation of screening once the individual has not smoked for more than 15 years or has a limited life expectancy was emphasised.¹⁵ There are several large randomised trials of low-dose CT screening still in progress in Europe and as yet there is no formal national screening programme in any European country.

Treatment and outcome

Surgical resection is recommended for early stage NSCLC: stages IA, IB, IIA, and IIB. For patients with limited disease, a minimally invasive approach such as video-assisted thoracic surgery is preferred. Systematic mediastinal lymph node sampling or dissection at the time of anatomic resection is of critical importance and informs accurate pathological staging. For patients with incomplete surgical resections, adjuvant radiotherapy can be considered in an effort to improve local control. The use of adjuvant chemotherapy for stage II and IIIA NSCLC is recommended and confers an overall survival benefit. Stereotactic radiotherapy has emerged as an effective and well-tolerated approach for node negative tumours up to approximately 5cm in size in patients unfit or unwilling to proceed to surgery. Survival five years from resection in pathologic stage IA disease is approximately 70%, but falls to below 60% in pathologic stage IB cancers.¹⁶

Patients with stage III NSCLC and good performance status should be considered for concurrent chemoradiotherapy using a platinum-based cytotoxic regimen. Induction therapy followed by resection, ideally as part of a study protocol, may be appropriate in selected fit patients with stage IIIA disease.¹⁷ In patients with unsuspected N2 nodal involvement discovered after curative intent surgery, adjuvant therapy should be considered.

Patients with stage IV disease are treatable, but not curable. Platinum-based doublet chemotherapy regimens have been shown to improve survival, enhance quality of life and be cost effective. No single combination strategy has definitively been shown to improve survival over others. There are additional data however indicating that three-drug combinations using targeted therapies may augment survival rates. In patients with known EGFR mutations and stage IV NSCLC, firstline therapy with an EGFR tyrosine kinase inhibitor (gefitinib, erlotinib or afatinib) is recommended based on superior response rates. In patients who do not progress during the traditional four cycles of standard platinum based doublet chemotherapy, maintenance therapy with a single low toxicity agent has the potential to prolong survival.¹⁸

The optimal treatment of early stage small cell lung cancer with limited stage disease is concurrent chemotherapy with hyperfractionated radiotherapy, provided performance status is adequate. Use of platinum-based combination regimens confers significant improvement in survival. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or cycle two of chemotherapy. Prophylactic cranial irradiation improves overall survival in patients with complete or partial response to initial therapy. Median survival is around 17 months, and the five-year survival rate is about 20%.¹⁹ Chemotherapy consisting of a platinum agent plus etoposide or irinotecan should be offered to fit patients with extensive stage disease. However, prolonged patient survival is very rare.¹⁹

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