Non-small cell lung cancer

Highlights
Summary Overview

Basics
Definition Epidemiology Aetiology Pathophysiology Classification

Prevention
Primary Screening Secondary

Diagnosis
History & examination Tests Differential Step-by-step Criteria Guidelines Case history

Treatment
Details Step-by-step

Emerging Guidelines Evidence

Follow Up
Recommendations Complications Prognosis

Resources
References Patient leaflets Credits Email Print Feedback Share Add to Portfolio Bookmark Add notes

History & exam

Key factors

presence of risk factors cough dyspnoea haemoptysis chest pain

weight loss

Other diagnostic factors

age 65 to 70 years male sex fatigue hoarseness confusion personality changes nausea and vomiting headache dysphagia bone pain and/or fractures weakness, paraesthesias and/or pain in C8/T1 distribution pulmonary exam abnormalities seizures cervical or supraclavicular adenopathy Horner's syndrome facial swelling dilated neck or chest/abdominal wall veins finger clubbing hypertrophic osteoarthropathy History & exam details

Diagnostic tests

1st tests to order

chest x-ray chest CT scan

Tests to consider

sputum cytology bronchoscopy biopsy pleural sampling mediastinoscopy video-assisted thoracoscopic surgery (VATS) thoracentesis MRI or CT of brain MRI of thoracic inlet PET-CT bone scan contrast-enhanced CT liver and adrenals PFT FBC LFTs serum calcium electrolytes and renal function EGFR mutation testing Diagnostic tests details

Treatment details

Ongoing
o o o o o

stage I and II surgical candidate surgery preoperative chemoradiotherapy postoperative chemotherapy postoperative radiotherapy non-surgical candidate radiotherapy chemotherapy stage IIIA surgical candidate preoperative chemotherapy or chemoradiation surgery postoperative chemotherapy, radiotherapy, or chemoradiation non-surgical candidate radiotherapy chemotherapy stage IIIB resectable with no contralateral mediastinal adenopathy preoperative chemotherapy + preoperative radiotherapy

o o

o o

o o

surgery postoperative chemotherapy unresectable or contralateral mediastinal adenopathy chemoradiation stage IV ECOG performance 0-2 (in bed <50% of the time) chemotherapy surgery of solitary metastatic lesion palliative radiotherapy ECOG performance 3-4 (in bed >50% of the time) supportive care Treatment details

o o o

Summary

The most common form of lung cancer, and comprises 3 major subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Most common in older adult smokers and exsmokers. Small tumours in the lung are often asymptomatic, so the majority of patients either have locally advanced or metastatic disease at diagnosis. Most common presenting symptoms are cough, chest pain, haemoptysis, dyspnoea, and weight loss.

A suspicious lung mass can be biopsied during bronchoscopy or using CT guidance. Staging studies (i.e., CT, PET, mediastinal sampling) are required to determine extent of local or regional disease and to evaluate for metastases. Treatment depends on stage of disease and patient comorbidities. Surgery, radiotherapy and chemotherapy are the most common modalities, but targeted biological agents are becoming increasingly important.

Definition
Lung cancer comprises a group of malignant epithelial tumours arising from cells lining the lower respiratory tract. Lung cancer is divided into 2 categories: non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for more than 85% of all lung cancers.[1] There are 3 main types of NSCLC (adenocarcinoma, squamous cell carcinoma and large cell carcinoma) and these are grouped into further subtypes.

Epidemiology
Worldwide, lung cancer is the most common non-cutaneous cancer and is increasing at a rate of 0.5% per year. Globally, lung cancer accounts for over a million deaths a year and remains the most common cause of cancer mortality worldwide, with 17.6% of the world total. [7] [8]Lung cancer is the third most common cancer type in Europe, with NSCLC accounting for 80% of all lung cancer cases. [8] [9] Incidence and mortality figures vary widely but appear to correlate with tobacco use. In 2000, worldwide smoking is estimated to have caused 85% of lung cancer in men and 47% of lung cancer in women, with the highest rates in Europe and North America. [7] In the US, lung cancer rates increased dramatically during the mid-1900s, a few decades following the rapid rise in tobacco use. Recent declines in the incidence rate of lung cancer may relate to reductions in tobacco use in more recent decades. The incidence of lung cancer in men began to decline in the 1980s. The incidence of lung cancer in women began to decline over 10 years later, in the late 1990s. The declining incidence of lung cancer has decreased the overall mortality rate. Between

1994 and 2002, the annual percentage decline in the age-adjusted mortality rate in men and women in the US was 0.9%. [10] Almost half of cases are now seen in developing countries, where mortality rates are also slightly higher. [7] In the US, one quarter of the population still smoke, indicating that lung cancer will continue as an important public health issue. Lung cancer is also the leading cause of cancer mortality in the US. An estimated 174,470 people were diagnosed and 162,460 died from lung cancer in the US in 2006. [10] The number of deaths from lung cancer is more than colorectal, breast, and prostate cancers combined. [10] After adjusting for age, the incidence of lung cancer is about 60% higher in men. According to the US National Cancer Institute's Surveillance Epidemiology and End Results (SEER) registry, lung cancer incidence rates are highest in black people and non-Hispanic white people and lowest in Native Americans, Hispanics and Asian/Pacific Islanders. [11]

Epidemiology
Worldwide, lung cancer is the most common non-cutaneous cancer and is increasing at a rate of 0.5% per year. Globally, lung cancer accounts for over a million deaths a year and remains the most common cause of cancer mortality worldwide, with 17.6% of the world total. [7] [8]Lung cancer is the third most common cancer type in Europe, with NSCLC accounting for 80% of all lung cancer cases. [8] [9] Incidence and mortality figures vary widely but appear to correlate with tobacco use. In 2000, worldwide smoking is estimated to have caused 85% of lung cancer in men and 47% of lung cancer in women, with the highest rates in Europe and North America. [7] In the US, lung cancer rates increased dramatically during the mid-1900s, a few decades following the rapid rise in tobacco use. Recent declines in the incidence rate of lung cancer may relate to reductions in tobacco use in more recent decades. The incidence of lung cancer in men began to decline in the 1980s. The incidence of lung cancer in women began to decline over 10 years later, in the late 1990s. The declining incidence of lung cancer has decreased the overall mortality rate. Between 1994 and 2002, the annual percentage decline in the age-adjusted mortality rate in men and women in the US was 0.9%. [10] Almost half of cases are now seen in developing countries, where mortality rates are also slightly higher. [7] In the US, one quarter of the population still smoke, indicating that lung cancer will continue as an important public health issue. Lung cancer is also the leading cause of cancer mortality in the US. An estimated 174,470 people were diagnosed and 162,460 died from lung cancer in the US in 2006. [10] The number of deaths from lung cancer is

more than colorectal, breast, and prostate cancers combined. [10] After adjusting for age, the incidence of lung cancer is about 60% higher in men. According to the US National Cancer Institute's Surveillance Epidemiology and End Results (SEER) registry, lung cancer incidence rates are highest in black people and non-Hispanic white people and lowest in Native Americans, Hispanics and Asian/Pacific Islanders. [11]

Pathophysiology
The 3 major subtypes of NSCLC are squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Approximately 32% of NSCLC are adenocarcinomas, which tend to be located more peripherally in the lung. [17] The relative frequency of adenocarcinoma is rising and is currently the most common histology in women and nonsmokers. [18] Adenocarcinomas are thought to metastasise early. Approximately 30% of lung cancers are squamous cell carcinomas, which tend to involve the central airways. As compared with adenocarcinomas, squamous cell carcinomas are thought to metastasise later in the disease course. Large cell carcinomas, accounting for about 10% of lung cancers, are undifferentiated tumours without histological features typical of a squamous cell or adenocarcinoma and tend to arise centrally. [17] A rare subset of poorly differentiated NSCLC is sarcomatoid carcinoma. [19] Bronchioloalveolar carcinoma (BAC) is a rare lesion, characterised by the growth of tumour cells along the surface of alveolar walls - so-called lepidic growth - with no evidence of tissue destruction or invasion. [20] As such it is best considered adenocarcinoma-in-situ (AIS), since lesions fulfilling the WHO definition of BAC show no evidence of invasion and patients with complete surgical resection have 100% 5-year survival. [21] [22] Lesions that show tissue invasion but also a component of lepidic spread should not be called BAC but instead are considered to be adenocarcinomas (with a lepidic component). Multi-focal lesions showing a lepidic growth pattern may occur. Some of these patients will have multiple synchronous AIS and, usually, at least one associated adenocarcinoma. [23] Other cases probably represent lepidic spread of otherwise invasive adenocarcinoma. Most of these cases show mucinous adenocarcinoma (also known as mucinous BAC) and may mimic pneumonic consolidation rather than present as a typical solitary pulmonary nodule. [23]

Classification
The 1999 World Health Organization/International Association for the Study of Lung Cancer histological classification of lung and pleural tumors NSCLC:

[2]

1.3.1. Squamous cell carcinoma

1.3.1.1. Papillary 1.3.1.2. Clear cell 1.3.1.3. Small cell 1.3.1.4. Basaloid
1.3.3. Adenocarcinoma

1.3.3.1. Acinar 1.3.3.2. Papillary 1.3.3.3. Bronchioloalveolar carcinoma 1.3.3.3.1. Non-mucinous (Clara/pneumocyte type II) 1.3.3.3.2. Mucinous

1.3.3.3.3. Mixed mucinous and non-mucinous or intermediate cell type 1.3.3.4. Solid adenocarcinoma with mucin 1.3.3.5. Adenocarcinoma with mixed subtypes 1.3.3.6. Variants 1.3.3.6.1. Well-differentiated fetal adenocarcinoma 1.3.3.6.2. Mucinous ('colloid') adenocarcinoma 1.3.3.6.3. Mucinous cystadenocarcinoma 1.3.3.6.4. Signet ring adenocarcinoma 1.3.3.6.5. Clear cell adenocarcinoma
1.3.4. Large cell carcinoma

1.3.4.1. Large cell neuroendocrine carcinoma 1.3.4.1.1. Combined large cell neuroendocrine carcinoma

1.3.4.2. Basaloid carcinoma 1.3.4.3. Lymphoepithelioma-like carcinoma 1.3.4.4. Clear cell carcinoma 1.3.4.5. Large cell carcinoma with rhabdoid phenotype
1.3.5. Adenosquamous carcinoma 1.3.6. Carcinomas with pleomorphic, sarcomatoid or sarcomatous elements

1.3.6.1. Carcinomas with spindle and/or giant cells 1.3.6.1.1. Pleomorphic carcinoma 1.3.6.1.2. Spindle cell carcinoma 1.3.6.1.3. Giant cell carcinoma 1.3.6.2. Carcinosarcoma 1.3.6.3. Pulmonary blastoma 1.3.6.4. Others

Small cell lung cancer:

1.3.2. Small cell carcinoma 1.3.2.1. Combined small cell carcinoma

Primary prevention
Patients should be asked about current smoking status on each presentation to medical care. Smokers should be educated about the health risks of smoking and advised to quit. Multiple options (non-pharmacological and pharmacological) are available to assist patients with smoking cessation.

Screening
Screening for lung cancer is not recommended. To date there is no class I evidence (randomised trials) demonstrating a survival benefit with screening, with either chest x-ray or spiral CT. [61] [62] [63] The US National Lung Screening Trial, sponsored by the National Cancer Institute, randomly assigned 50,000 smokers or former smokers to annual screening with chest x-ray or spiral CT. The study opened in 2002 and closed in 2004. [64] A preliminary report (November 2010) demonstrated a 20% reduction in lung cancer mortality, [65] which was confirmed in the final paper. [66]

Secondary prevention
Smoking cessation should be encouraged, even in patients with established lung cancer. There is evidence that there is a survival benefit in all lung cancer patient groups in those who stop smoking, and (especially where long-term survival is the aim of treatment, as in surgical resection) this should be considered an essential element of the management. [120]

Monitoring
After potentially curative treatment for lung cancer, patients should be followed regularly to assess for disease recurrence and treatment-related toxicity. For example, following radiotherapy patients may develop inflammation of the lung, termed pneumonitis. This is rarely lethal but may require treatment. Chemotherapy can depress blood counts, leading to

anaemia with fatigue and dyspnoea, thrombocytopenia (bleeding) and/or neutropenia (infection). Blood counts need to be monitored until they recover. A history and physical examination should be performed every 4 to 6 months for the first 2 years and annually thereafter. Imaging of the chest (chest x-ray or CT) should be performed on a similar schedule. For patients with metastatic disease who have completed palliative chemotherapy and/or radiotherapy, similar follow-up is recommended. Routine imaging in the absence of symptoms is generally discouraged.

Complications
Complicationhide all

post-obstructive pneumonia/hypoxia see our comprehensive coverage of Overview of pneum Pneumonia is common in lung cancer patients and is oft central, obstructing tumour. Patients may not present wit pneumonia such as fever, dyspnoea, and productive cou sometimes be difficult to interpret secondary to tumour-re

Antibiotics should be initiated. Relieving the obstruction i modalities can be used such as external beam radiother (temporary insertion of a radioactive source at the site of placement, laser debulking of obstructing tumour, photod surgical resection. Photodynamic therapy is a minimally involves the interaction of light, a photosensitising agent photosensitising agent is administered intravenously and throughout the body. Via a flexible fibre bronchoscope, a predetermined wavelength is focused on the endobronch

photosensitising agent absorbs photons of the appropria reactive oxygen species that are toxic to cancer cells.

Treatment should be instituted relatively quickly for patie compromise.

superior vena cava syndrome (SVCS) The most common cause of SVCS is lung cancer. Bulky medial extension of a right upper lobe tumour can compr (SVC), impeding the return of blood from the face and ar collateral pathways develop when the SVC is compresse of symptoms depend on the speed of obstruction. The sy facial and upper extremity oedema, dyspnoea, cough an examination demonstrates facial plethora and distended occasionally abdominal wall veins. [5] SVCS is rarely a medical emergency and every effort sh diagnosis before initiating therapy. Supplemental oxygen often helpful. Treatment depends on the clinical scenario patients will improve with radiotherapy and/or chemother take several days. Patients with marked symptoms shou relatively quickly. Endovascular stents may be effective w relief. Surgical intervention is rarely required. [5]

paraneoplastic syndromes Treatment of the underlying tumour often alleviates symp

syndromes. Other supportive measures depend on the u

Last updated: Mar 08

Prognosis
Survival
Survival after definitive treatment of NSCLC depends principally on stage of disease and ability to undergo standard treatment. Patients with adverse prognostic factors, including poor performance status and pretreatment weight loss, have a worse prognosis irrespective of treatment. Patients whose tumours are resected, usually with sampling of draining lymph nodes, are assigned a pathological stage. Pathological stage is more accurate than clinical stage, as clinical stage relies on radiographic imaging that has a finite sensitivity and specificity. Comparing outcomes (survival) of patients who are staged surgically with patients who are staged clinically is difficult for multiple reasons. Many of the medical contraindications that prohibit surgery, such as older age, poor performance status, severe concurrent medical illness and poor pulmonary function, are independent prognostic factors for survival. Furthermore, surgical upstaging (e.g., finding cancer in lymph nodes that appeared uninvolved by preoperative imaging) is known to occur in more than 20% to 25% of patients with clinical stage I disease. [115] With these caveats, the 5-year survival rates for patients undergoing surgical (pathological) staging are as follows: stage IA: 67%; stage IB: 57%; stage IIA: 55%; stage IIB: 39%; and stage IIIA: 23% to 25%. [119] Survival for clinically staged patients is as follows: stage IA: 61%; stage IB: 38%; stage IIA: 34%; stage IIB: 22% to 24%; stage IIIA: 9% to 13%; stage IIIB: 3% to 7%; and stage IV: 1%.

Case history
A 65-year-old man presents with a 2-month history of a dry persistent cough and 4.5 kg unintentional weight loss. He denies fevers, dyspnoea, sore throat, rhinorrhoea, chest pain or haemoptysis. Medical history is significant for COPD and hypertension. Family history is non-contributory. He smoked 1

pack of cigarettes daily for 40 years but quit 5 years ago. No adenopathy is palpable on examination and breath sounds are diminished globally without focal wheezes or crackles.

Other presentations
Lung cancer can present without symptoms. This is possibly due to the large functional reserve of the lungs and lack of pain fibres within the lung parenchyma. Consequently, lung cancer can present as an incidental mass on chest x-ray or CT. Eventually, patients develop symptoms from local tumour growth within the lung, including cough, dyspnoea, chest pain and/or haemoptysis. [3] [4] Haemoptysis typically consists of blood-tinged sputum. Massive haemoptysis is rare. Invasion of the pleura or chest wall can cause chest pain. Obstruction of major airways can cause dyspnoea, wheezing or post-obstructive pneumonia. A pneumonia that does not rapidly clear with antibiotics is cause for concern for lung cancer, especially in patients with a tobacco history. Lung cancer often spreads to mediastinal lymph nodes. Symptoms from mediastinal adenopathy are relatively rare. However, bulky adenopathy can cause hoarseness (impingement of the recurrent laryngeal nerve), paralysis of the diaphragm (impingement of the phrenic nerve), difficulty swallowing (impingement of the oesophagus) or superior vena cava syndrome, typically characterised by upper extremity and facial oedema, orthopnoea, cough and venous distension of the neck and chest wall. [5] Lung cancer can also present as a superior sulcus tumour (sometimes called a Pancoast tumour), most commonly presenting with shoulder pain. [6] These tumours may also compress and invade the brachial plexus (causing weakness and/or atrophy of the intrinsic muscles of the hand, paraesthesias and/or pain in a C8/T1 distribution) or sympathetic chain (causing Horner's syndrome characterised by ptosis, meiosis and ipsilateral anhidrosis). Other presentations include clubbing, hypertrophic osteoarthropathy and hypercalcaemia of malignancy.

Differential diagnosis
Condition Differentiating signs/symptoms

Small cell lung cancer

Typical features include cough haemoptysis, chest pain, dyspn hoarseness (if recurrent laryng paralysis). Frequently unwell-lo short of breath, with signs of re weight loss.

Finger clubbing and hypertroph osteoarthropathy may be prese less common in small cell lung compared with NSCLC.

Usually wheezing from underly or bronchial obstruction, crackl post-obstructive pneumonia or or diminished breath sounds fr bronchial obstruction are prese early disease.

Facial and upper extremity swe distended neck veins, and dilat collateral vessels may indicate compression of the superior ve

Features related to distant met (e.g., bone pain and/or patholo

fractures from bony metastase confusion, personality change, weakness, focal neurological d nausea and vomiting, and head from brain metastases).

Brachial plexus involvement ca weakness and/or atrophy of the muscles of the hand and parae and/or pain in a C8/T1 distribut impact the sympathetic chain c Horner's syndrome (ptosis, me ipsilateral anhidrosis).

Metastatic cancer

Symptoms will relate to the site primary tumour and there may symptoms of pain, weight loss, cough, dyspnoea, clubbing, an wheezing. Physical findings ma not be present depending on n stage of tumour.

Pneumonia/bronchitis

Clinical and radiological feature bronchitis or pneumonia should with appropriate treatment.

Recurrent pneumonia or bronc smoker or former smoker shou suspicion of lung cancer.

Organising pneumonia (cryptogenic organising pneumonia or bronchiolitis obliterans organising pneumonia)

Normally presents as an influe illness followed by a second illn lasting 1 to 4 months, with lowfever, non-productive cough, m dyspnoea, and weight loss. So features pleuritic chest pain an

haemoptysis.

In most patients, auscultation r fine, dry lung crepitations. Fing is unusual.

Pulmonary tuberculosis

Cough longer than 2 to 3 week discoloured or bloody sputum, sweats and weight loss, loss o pleuritic chest pain.

Sarcoidosis

Cough, dyspnoea, fatigue, wei fever, night sweats, rash, eye p photophobia, blurred vision, re Pulmonary examination is usua unrevealing. Can affect any org physical findings depend on sp

organs affected. Skin lesions in maculopapular eruptions, subc nodular lesions and red-purple lesions.

Infectious granuloma

History may include travel to en areas, pet/animal exposures an leisure activities (e.g., caving).

May feature cough, dyspnoea, haemoptysis, weight loss, feve aches, skin lesions and night s Many possible causes: Histopl capsulatum, Mycobacterium tuberculosis,Coccidioides immitis, Cryptococcus neoformans,Aspergillus, Pseud a boydii, Fusarium spp, zygom and others. Non-specific skin findings may atypical mycobacteria and cryptococcosis. Lymphadenop active disease.

Amyloidosis

Weight loss, paraesthesias, dy and fatigue are the most comm symptoms associated with amy and are common to all systemi weight loss of >9 kg is common vessel involvement can cause claudication, calf and limb clau and, rarely, angina. Amyloid pu present in around 1 in 6 patien periorbital. Eyelid petechiae ar Hepatomegaly >5 cm below th costal margin is seen in 10% o and splenomegaly is usually of degree.

Rheumatoid arthritis

Arthralgias, pain, skin nodules, effusions, pleuritis, joint pain an deformity.

Wegener's granulomatosis

Cough, chest pain, dyspnoea, haemoptysis, rhinorrhoea, epis ear/sinus pain, hoarseness, fev anorexia, weight loss, palpable painful ulcers, uveitis, upper ai inflammation, and sinus pain.

Non-Hodgkin's lymphoma

Aggressive NHL lymphoma ma with fever, drenching night swe malaise, weight loss, cough, sh breath, abdominal discomfort, change in mental status, dizzin ataxia, pleural effusion, lymphadenopathy, pallor, purp jaundice, hepatomegaly, splen skin nodules, and abnormal ne exam. Low-grade NHL patients minimally symptomatic or asym

Hodgkin's lymphoma

Predominantly a disease of you Most patients present with a se month history of persistent ade most commonly of the cervical

Carcinoid tumour

Often asymptomatic with norm examination. May cause cough dyspnoea, haemoptysis, unilat wheezing, or post-obstructive p if tumour is endobronchial.

Tracheal tumours

Common symptoms include dy cough, haemoptysis, wheeze, Less commonly, hoarseness a dysphagia may be present.

Thyroid mass

Symptoms and signs depend o mass. May be visible/palpable anterior aspect of neck. May pr dysphagia, hoarseness, difficu breathing and pain in neck or t also be signs and symptoms o hypothyroidism depending on t of the mass.

Hamartoma

Usually asymptomatic with no findings. About 1% to 20% of le be endobronchial and can caus dyspnoea, wheezing or recurre infections, secondary to airway obstruction.

Arteriovenous malformation (AVM)

Dyspnoea is uncommon. May haemoptysis, pulmonary bruit, arteriovenous communications haemorrhagic telangiectasia in

mucous membranes and other Cyanosis and finger clubbing. Neurological symptoms from c aneurysms, cerebral emboli.

Bronchogenic cyst

Usually diagnosed in infancy a childhood, although 50% diagn 15 years of age. Approximately patients are asymptomatic. In a chest pain (often pleuritic) and (due to oesophageal compress

the most common symptoms. M feature recurrent cough and ch infection/pneumonia, superior v syndrome, tracheal compressio pneumothorax.

Thymoma/thymic carcinoma

Approximately 30% of patients thymoma are asymptomatic at diagnosis. May also present wi chest pain, signs of upper airw congestion, superior vena cava syndrome, dysphagia or hoars have features of paraneoplasti

syndromes associated with thy including myasthenia gravis, po lupus erythematosus, rheumat arthritis, thyroiditis and Sjogren syndrome. Around 30% of pati symptoms suggestive of myas gravis (e.g., ptosis, double visio

Germ cell tumour

Occur mostly in men aged 20 t About one third of patients are asymptomatic. Symptoms are the size of the lesion. May cau pain, breathing problems, coug fever, headache and fatigue.

History & examination

Key diagnostic factorshide all
presence of risk factors (common) Includes cigarette smoking; exposure to tobacco smoke, radon gas, or asbestos; and the presence of COPD. cough (common)

A new or persistent cough, especially in a current or former smoker, is suspicious and requires imaging of the chest. Cough is present at diagnosis in over 50% of patients with lung cancer and may be secondary to post-obstructive pneumonia, endobronchial tumour or pleural effusion. [4] dyspnoea (common) Present at diagnosis in the majority of patients. [3] Possible causes include tumour obstruction of the airway, underlying COPD, pneumonia, phrenic nerve paralysis or a pleural effusion. haemoptysis (common) Occurs in approximately 25% of patients. [4] Although massive haemoptysis is rare, patients with lung cancer often cough up blood-tinged sputum. Haemoptysis in a smoker is suspicious for lung cancer. chest pain (common) Chest pain or discomfort is present in approximately 33% of patients. [4] The lung is devoid of pain fibres. Therefore, most patients with chest pain have tumours invading the pleura or chest wall. However, even patients with early disease can present with chest discomfort. Shoulder pain is the most common

symptom in patients with superior sulcus tumours. [6] weight loss (common) Independent negative prognostic factor and should be specifically addressed. It is more common in patients with locally advanced or metastatic disease. Most clinical trials define clinically relevant weight loss as >5%. [41] [42] Other diagnostic factorshide all age 65 to 70 years (common) The median age of patients with lung cancer is 65 to 70 years. Less than 10% of cases are diagnosed before 50 years of age. [39] male sex (common) More common in men, but the age-standardised male-to-female incidence ratio for white patients is decreasing and is currently approximately 1.6 (60% higher in men). [39] fatigue (common) Non-specific symptom of lung cancer, and is often multi-factorial. pulmonary exam abnormalities (common) Auscultation of the lungs may demonstrate wheeze, crackles, decreased breath sounds, and dullness to percussion. hoarseness (uncommon)

2% to 18% can present with hoarseness, secondary to recurrent laryngeal nerve paralysis. [4] confusion (uncommon) A common symptom of brain metastases and electrolyte disturbances such as hypercalcaemia and hyponatraemia. Up to 25% of patients with lung cancer develop brain metastases. [40] personality changes (uncommon) Strongly suspicious of brain metastases in those affected with lung cancer. nausea and vomiting (uncommon) May indicate brain metastases. headache (uncommon) May indicate brain metastases. dysphagia (uncommon) May occur if the tumour itself or enlarged mediastinal lymph nodes have significantly impinged on the oesophagus. bone pain and/or fractures (uncommon) Pain or pathological fractures can result from bone metastases. The axial skeleton and proximal long bones are most frequently involved. [4] weakness, paraesthesias and/or pain in C8/T1 distribution(uncommon)

Superior sulcus tumours can invade the brachial plexus causing weakness and/or atrophy of the intrinsic muscles of the hand, and paraesthesias and/or pain in a C8/T1 distribution. seizures (uncommon) A symptom of brain metastases. cervical or supraclavicular adenopathy (uncommon) The most common sites of regional spread are the hilum and mediastinum. The next echelon of lymph node spread is the supraclavicular fossae and cervical chains. In a proportion of cases the supraclavicular lymphadenopathy is impalpable, but detectable by ultrasound examination of the neck. [43] Horner's syndrome (uncommon) Triad of ptosis, meiosis and ipsilateral anhidrosis occurs most frequently in patients with superior sulcus tumours, which can invade the sympathetic plexus. facial swelling (uncommon) May indicate compression of the superior vena cava, either from mediastinal adenopathy or a right upper lobe tumour extending centrally into the mediastinum. dilated neck or chest/abdominal wall veins (uncommon)

Distended neck veins or venous collaterals on the chest or abdominal wall may indicate compression of the superior vena cava. finger clubbing (uncommon) More common in NSCLC than in small cell lung cancer. [44] hypertrophic osteoarthropathy (uncommon) Painful arthropathy of the wrists, ankles, and knees with periosteal new bone formation. More common in cases of adenocarcinoma. Risk factorshide all

Strong cigarette smoking There are numerous epidemiological studies linking lung cancer and cigarette smoking. [12] [13] [14] Tobacco smoke contains multiple carcinogens including polynuclear aromatic hydrocarbons, aromatic amines, N-nitrosamines, and other organic and inorganic compounds. [16] environmental tobacco exposure Environmental tobacco smoke (second-hand smoke) is an important cause of lung cancer and approximately 2% to 3% of lung cancer cases may be attributed to it. In an analysis of 37 published epidemiological studies, the relative

risk of a non-smoking woman who has a smoking husband being diagnosed with lung cancer was 24% higher (relative risk 1.24) than a nonsmoking woman with a non-smoking husband. [24] chronic obstructive pulmonary disease There are numerous studies showing an excess risk of lung cancer in patients with chronic obstructive pulmonary disease even when the smoking history is corrected for. This excess risk is variously estimated as between 2- and 6-fold and is higher the more severe the impairment of the FEV1. [25] family history A history of lung cancer in a first degree relative is associated with an approximate doubling of the risk, independent of the smoking history. [26] This relative risk is as high as 5-fold where the cancers develop in first degree relatives under the age of 60 years. radon gas exposure Uranium is normally found in the earth's crust. Upon decay, radon gas is produced, which can percolate into homes. Radon gas is inert but decays with a half-life of 3.8 days into polonium 214 and polonium 218. Both substances emit alpha-particles that damage DNA and can lead to malignant transformation.

Numerous case-control studies have associated both occupational (mining) and residential radon exposure to lung cancer. Radon may contribute up to an estimated 10% of all lung cancer cases. [27] [28]

Weak asbestos exposure Asbestos fibres are carcinogens that lodge in the lung and are a risk factor for lung cancer, especially in smokers and for heavily exposed people. [29]Epidemiological data have linked asbestos with lung cancer, with or without asbestosis, a diffuse interstitial lung fibrosis secondary to asbestos exposure. [30]

Diagnostic tests
1st tests to orderhide all
Test

chest x-ray A standard PA chest x-ray is an inexpensive and simple pain and/or haemoptysis. In some centres a lateral ches

In patients with diagnosed lung cancer, chest x-rays can and evaluate for re-expansion of a collapsed lung after a

radiotherapy). A chest x-ray is recommended on a routine basis (every thereafter) after definitive treatment of lung cancer.

chest CT scan A new abnormality on chest x-ray needs to be further as scan including the upper abdomen. [45] A chest CT shou especially smokers, with problematic symptoms raising a lung cancer, even if there is a normal chest x-ray. Intrave distinguish lymph nodes from vessels, especially in the h Treatment recommendations often hinge on whether spr occurred. CT is non-invasive but has limitations. For med 60%, specificity is approximately 80%, positive predictive and negative predictive value is about 85%. [46] [47] After treatment, follow-up CT scans are occasionally indi trials or where there is a genuine concern that there is a disease not easily evaluated on a simple chest x-ray.

Tests to considerhide all

Test

sputum cytology A non-invasive and relatively simple diagnostic method. centres. The specificity is high but the sensitivity is low, a

usefulness in terms of patient management. [32] Moreov which cannot be achieved with sputum cytology, can now chemotherapy. More likely to be positive with central lesions than with p

bronchoscopy Bronchoscopy, typically performed with a flexible bronch procedure in which the proximal bronchial tree can be di areas biopsied. [48] Endobronchial masses can be biopsied with forceps. En and alveolar lavage increase the diagnostic yield. Transb accessible parenchymal lesions and mediastinal lymph n ultrasound guidance can be done. [33] [36] [35] [34][49] Overall, the sensitivity for centrally located lesions is high for peripheral lesions is lower and depends on number o proximity to the bronchial tree. In general, endobronchial brushings or washings. Detection of small peripheral lesions (<2 cm) is improved ultrasound. [50] Bronchoscopy can be repeated after definitive treatment completed.

biopsy Pathological confirmation of malignancy is the only widel definitive diagnosis of lung cancer. Tissue is sampled fro

Transthoracic needle aspiration biopsy, typically using C suspicious peripheral pulmonary lesions that are not acc

Transbronchial needle aspiration biopsy of accessible pa lymph nodes is also now widely practiced and can be ca endobronchial ultrasound guidance. The use of endobro number and levels of mediastinal nodes than can be sam also be used to access other mediastinal nodes plus the

Alternatively, lymph node biopsy can provide information of disease. Sampling is either of nodes in the supraclavic accessed via endobronchial ultrasound, [33] [34] [35] [36 (EUS) [51] or surgically via mediastinoscopy, video-assis open surgical procedure.

pleural sampling Many patients present with a pleural effusion, and cytolo give sufficient material to obtain a cytological diagnosis i biopsy using Abram's or Cope's needles is of very limited thoracoscopy (which can be either 'medical' or 'surgical')

mediastinoscopy Treatment recommendations often hinge upon presence nodes. Mediastinoscopy is considered the most sensitive procedure, and endobronchial ultrasound is often used. T

involves a small horizontal incision in the low neck, throu lymph nodes along the trachea and below the carina are performed under general anaesthesia.

Paratracheal and subcarinal lymph nodes can be assess

The overall sensitivity of cervical mediastinoscopy is app predictive value of about 90%. [47]

video-assisted thoracoscopic surgery (VATS) VATS can be used to evaluate aorticopulmonary window access to paraoesophageal and pulmonary ligament lym

thoracentesis Thoracentesis involves placing a needle between the rib that has accumulated in the pleural space. Ultrasound is small pleural effusions.

MRI or CT of brain Patients with locally advanced NSCLC, especially adeno harbouring brain metastases and should be staged with curative treatment is proposed.

MRI of thoracic inlet For patients with superior sulcus tumours, MRI of the tho assessing resectability.

PET-CT PET-CT is complementary to CT, facilitating accurate as regional, and distant disease. [52] PET is considered a standard staging study for patients confirmation of abnormal findings is often necessary due known metastatic disease, PET is unnecessary.

The PET accuracy for mediastinal staging is as follows: t 85%, specificity about 90%, positive predictive value bet predictive value approximately 93%. [46] [53]

bone scan Should be ordered when patients have new bone pain or Not necessary if staging with PET is performed, which is scan. [54] Test sensitivity is between 60% and 100%. Specificity is contrast-enhanced CT liver and adrenals

Important for staging, but usually done in conjunction wit

PFT FEV1 and diffusion capacity of lung for carbon monoxide all patients with lung cancer anticipated to undergo surge radiotherapy. [37] [38] Patients with marginal function ca radionuclide studies (e.g., quantitative perfusion scan) as There is debate on the precise criteria for determining fit radical chemoradiotherapy). The most recent guidelines testing. [56] In the UK, the British Thoracic Society (BTS for some years and recommend that postoperative FEV1 predicted. A preoperative FEV1 should be >1.5 L for lobe pneumonectomy. Other factors, such as sex and stature interpreting preoperative PFTs. Most specialist thoracic s guidelines to be poorly evidence-based and that they exc patients who would be suitable for surgery. The BTS gui and detailed discussion on a case-by-case basis with an surgeon is recommended in patients of borderline fitness Spirometry is a sensitive predictor of postoperative comp

FBC Baseline blood counts are necessary before treatment is performed.

Chemotherapy, and to a lesser degree radiotherapy, can necessitating baseline and periodic analysis of blood cou LFTs May be elevated if hepatic metastases.

Lone elevation of alkaline phosphatase level may indicat

serum calcium Elevated in hypercalcaemia of malignancy, more commo electrolytes and renal function Recommended as baseline before treatment is initiated.

Hyponatraemia may be related to the syndrome of inapp although this is more commonly seen in small cell lung c

EGFR mutation testing Testing for mutations of the tyrosine kinase gene that en receptor (EGFR) in tumour cells enables targeted therap patients.

Step-by-step diagnostic approach

Persistent cough with or without haemoptysis and weight loss in a smoker over the age of 50 are key features that should alert the clinician to the possibility of lung cancer. However, lung cancer can present without symptoms as an incidental mass on chest x-ray or CT.

History
Symptoms of a primary tumour include cough, haemoptysis, chest pain and/or dyspnoea. Some patients may present with hoarseness, secondary to recurrent laryngeal nerve paralysis. Patients may also present with nonspecific symptoms such as weight loss or fatigue. Smoking history, nutritional status and performance status (an objective assessment of the patient's ability to perform activities of daily living) should be specifically addressed. Most patients develop distant metastasis during the course of their disease. The most frequent sites of distant metastasis are the lungs, liver, brain, bone and adrenal glands. Symptoms depend on the sites and extent of involvement. Pain or fractures can develop as a result of bone metastasis. Lung cancer is the most common cause of brain metastasis. [31] Common symptoms include confusion, personality change, seizures, weakness, focal neurological deficits, nausea and vomiting, and headaches.

Physical examination
The general appearance of the patient is important. The patient may appear unwell and short of breath, and have evidence of recent weight loss. The neck and supraclavicular fossae should be carefully examined for adenopathy. Finger clubbing and hypertrophic osteoarthropathy may be present. Though the pulmonary examination is normal in some patients with early lung cancer, most present with 1 or more findings during auscultation. The following symptoms are common: wheezing from underlying COPD or bronchial obstruction; crackles due to post-obstructive pneumonia or

atelectasis; and diminished breath sounds from bronchial obstruction, pleural effusion and/or COPD. Pleural effusions can be assessed with percussion of the lung fields, showing a characteristic dullness. Facial and upper extremity swelling, distended neck veins and dilated collateral vessels on the chest or abdominal wall may indicate compression of the superior vena cava. Superior sulcus tumours can invade the brachial plexus causing weakness and/or atrophy of the intrinsic muscles of the hand, and paraesthesias and/or pain in a C8/T1 distribution. Additionally, these tumours can impact the sympathetic chain causing Horner's syndrome (ptosis, meiosis and ipsilateral anhidrosis).

Investigations
Selecting the appropriate diagnostic and staging studies for an individual patient is complex, and a multi-disciplinary team approach is recommended. This should include a thoracic surgeon, medical oncologist, radiation oncologist, respiratory physician, pathologist and diagnostic radiologist. Numerous imaging modalities are used to stage lung cancer, but not all studies need be obtained on all patients. A chest x-ray and contrast-enhanced CT of the chest and upper abdomen are standard and help define the primary tumour and evaluate for regional spread.

A standard PA chest x-ray is an inexpensive and simple initial step to evaluate cough, chest pain and/or haemoptysis. In some centres a lateral chest x-ray may be performed as well. A new abnormality on chest x-ray needs to be further assessed with contrast-enhanced CT. A chest

CT should also be obtained in patients, especially smokers, with problematic symptoms and a normal chest x-ray.
Pathological confirmation of disease is of great importance before treatment can commence, although in some cases this is only finally established when the lesion is surgically resected. The choice of which test is used to gain a tissue sample depends on the location of the lesion.

The simplest method is sputum cytology. However, although the specificity is high, the sensitivity low, and the cost may outweigh the usefulness in terms of patient management. [32] Moreover, accurate histological analysis, which cannot be achieved with sputum cytology, can now aid in the selection of appropriate chemotherapy. Cytology is more likely to confirm the diagnosis in central lesions than in peripheral lesions. More invasive but safe procedures include flexible bronchoscopy and transthoracic needle aspiration biopsy. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes is now widely practised and can be carried out with or without endobronchial ultrasound guidance. The use of endobronchial ultrasound expands the number and levels of mediastinal nodes

that can be sampled. Endoscopic ultrasound can also be used to access other mediastinal glands plus the left adrenal gland.

Bronchoscopy is performed when CT abnormalities (e.g., a mass or adenopathy) are accessible to the bronchoscope. Also used to assess new and/or unexplained pulmonary symptoms (e.g., haemoptysis, wheezing, cough). Flexible bronchoscopy requires conscious sedation. During the procedure, the tracheobronchial tree is carefully examined. Endobronchial tumours can be biopsied. Washings, brushings, and bronchoalveolar lavage are performed. Suspicious parenchymal lesions and mediastinal lymph nodes that are accessible can also be biopsied. Endobronchial ultrasound can also be used to biopsy mediastinal lymph nodes and some submucosal tumours, [33] [34] which can provide information regarding tissue diagnosis and stage in a single procedure. [35] [36] Transthoracic needle aspiration biopsy is often necessary for peripheral lesions that are inaccessible to bronchoscopy. If a pleural effusion exists, thoracentesis collects cells for cellular evaluation of malignancy, and CT-guided biopsy of the pleura is possible in some patients. Ultrasound guidance is recommended except in very large effusions.

In some special situations, a patient can be treated for presumed cancer if the history, physical examination and radiological imaging (ideally PET-CT) are most consistent with cancer, and when a biopsy is not possible. However, this is a rare situation. After a pathologic diagnosis is obtained, further staging studies are obtained to guide appropriate treatment.

PET-CT is a valuable staging tool and helps identify occult regional and distant disease. Although PET-CT is an effective modality to stage the mediastinum, tissue sampling of the mediastinum via mediastinoscopy or endobronchial ultrasound remains the most accurate method and is often indicated. Video-assisted thoracoscopic surgery (VATS) can be used to evaluate aorticopulmonary window lymph nodes. VATS also allows access to paraoesophageal and pulmonary ligament lymph nodes. A bone scan should be obtained if the patient has new bone pain or the alkaline phosphatase is elevated, to determine presence of bone metastasis. However, if staging with PET is performed, the bone scan is unnecessary, as PET is more accurate.

A head CT or MRI is indicated in patients with early-stage NSCLC if brain metastases are suspected based on symptoms. Patients with locally advanced NSCLC, especially adenocarcinoma, are at higher risk of harbouring brain metastases and should be staged with a head CT or MRI if aggressive local therapy is recommended. For patients with superior sulcus tumours, MRI of the thoracic inlet may be helpful in assessing resectability, though high-quality multi-slice CT imaging is probably as good in most circumstances. Pleural effusions are relatively common in lung cancer patients and portend a poor prognosis, approaching that of metastatic disease. Therefore, pleural effusions need to be evaluated by thoracentesis if there is no other evidence of metastatic disease.

Ancillary studies
An FBC, chemistry panel, and LFTs including alkaline phosphatase should be performed in all patients as baseline tests before initiation of treatment and to detect paraneoplastic syndromes such as hypercalcaemia of malignancy, cancer-related anaemia and, rarely, ectopic ACTH secretion (Cushing's syndrome, resulting in hyperglycaemia and hypokalaemia). In metastatic disease, alkaline phosphatase levels can be elevated, indicating potential bone or liver metastases.

All lung cancer patients anticipated to receive chest radiotherapy or surgery should have PFTs performed, including FEV1 and diffusing capacity of the lung for carbon monoxide. [37] [38] Testing for mutations of the tyrosine kinase gene that encodes the epidermal growth factor receptor (EGFR) in tumour cells enables targeted therapy to be considered in a subset of patients, particularly never-smokers and those with non-squamous histology (i.e., adenocarcinoma and large cell carcinoma).

Click to view diagnostic guideline references.

Diagnostic criteria
Non-small cell lung cancer UICC/IASLC staging (7th edition, 2007)

[58]

The 6th edition [59] of the staging classification produced by the International Union Against Cancer (UICC) and adopted by the American Joint Committee on Cancer (AJCC) has now been superseded by the staging classification produced by the UICC and the International Association for the Study of Lung Cancer (IASLC), 7th edition. [58]

The Eastern Cooperative Oncology Group (ECOG) performance status[60]

These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing and how the disease affects the daily living abilities of the patient, and to determine appropriate treatment and prognosis:

Grade 0: fully active, able to carry on all predisease performance without restriction Grade 1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work

Grade 2; ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours Grade 3: capable of only limited self-care; confined to bed or chair >50% of waking hours Grade 4: completely disabled; cannot carry on any self-care; totally confined to bed or chair Grade 5: dead.

Treatment Options
Treatme Patient group nt line Treatmenthide all stage I and II surgical candidate 1st surgery preoperative chemoradiotherapy Surgery, ideally performed by a specialist thoracic surgeon, is the standard treatment for early-stage NSCLC. Fitness for

Treatme Patient group nt line Treatmenthide all stage I and II surgery should be assessed by an expert multi-disciplinary team. The evidence base is incomplete to provide precise guidance, but 2 reviews provide a good basis for decision-making. [78] [79] For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. In some patients more complex procedures such as sleeve resection or chest wall resection may be required. More limited surgery, such as a wedge resection or segmentectomy, is often

Treatme Patient group nt line Treatmenthide all stage I and II necessary in older patients or those with comorbidities or impaired lung function, but is associated with a higher rate of recurrence. [68] Access to the chest is usually via a thoracotomy, although minimally invasive techniques (e.g., video-assisted thoracic surgery) are gaining favour, owing to shorter hospitalisations and less postoperative pain. Sampling or dissection of mediastinal lymph nodes is recommended. Surgery provides the best chance of cure for earlystage NSCLC but can be

Treatme Patient group nt line Treatmenthide all stage I and II associated with significant morbidity. The 30-day mortality rate is approximately 1% to 3% after lobectomy and 3% to 12% after pneumonectomy. For patients undergoing preoperative chemoradiotherapy, the mortality rate is even higher after pneumonectomy, especially right pneumonectomy. [69] Intraoperative and postoperative complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia,

Treatme Patient group nt line Treatmenthide all stage I and II pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula. adjunct [?] postoperative chemotherapy Postoperative chemotherapy is generally offered to patients with stage IB and stage II disease. [73] [74] There is less convincing evidence for the use of preoperative (neoadjuvant) chemotherapy. [78] The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. All regimens have the

Treatme Patient group nt line Treatmenthide all stage I and II potential to cause bone marrow suppression, nausea/vomiting, alopecia and fatigue. Other side effects are specific to the particular agent. Cisplatin-based regimens are recommended. Carboplatin-based regimens can be considered in select patients who are not felt to be appropriate candidates for cisplatin. The optimal regimen is based on the individual patient characteristics including disease stage, previous regimens, and use of concomitant

Treatme Patient group nt line Treatmenthide all stage I and II radiotherapy or surgical resection. Specialist advice must be sought. adjunct [?] postoperative radiotherapy Radiotherapy should be considered for high-risk patients with stage II disease (positive or close margins, lymph node involvement in the mediastinum and/or extracapsular extension). [77] Routine postoperative radiotherapy in patients with completely resected tumours and none of these risk factors has been shown to be detrimental to long-term survival. [91] [77]

Treatme Patient group nt line Treatmenthide all stage I and II

Side effects depend on the size of the radiation field, the dose and the adjacent organs (the lungs and oesophagus, in particular), which unavoidably receive some radiation. The most common side effects are fatigue, skin erythema/desquamation and oesophagitis. Most patients develop some degree of oesophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough and fever occurring 1 to 6

Treatme Patient group nt line Treatmenthide all stage I and II months after completing treatment. Pneumonitis is rarely fatal and treated symptomatically with oral corticosteroids and oxygen as needed. Most patients develop some degree of lung fibrosis after radiotherapy, but this is usually asymptomatic unless the pre-treatment lung function was poor, in which case dyspnoea can be a major problem. Rare complications include oesophageal stricture and bronchial stenosis, which are more common when higher doses of radiation are prescribed. [37] [90] [89] T

Treatme Patient group nt line Treatmenthide all stage I and II here is no convincing evidence of benefit from prophylactic cranial irradiation in patients undergoing radical treatment for NSCLC. [76] nonsurgical candidate 1st radiotherapy Early-stage NSCLC patients who are medically inoperable should receive either conventional external beam radiotherapy or stereotactic body radiation. Side effects depend on the size of the radiation field, the dose and the adjacent organs (the lungs and oesophagus, in

Treatme Patient group nt line Treatmenthide all stage I and II particular), which unavoidably receive some radiation. The most common side effects are fatigue, skin erythema/desquamation and oesophagitis. Most patients develop some degree of oesophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough and fever occurring 1 to 6 months after completing treatment. Pneumonitis is rarely fatal and treated symptomatically with oral corticosteroids and

Treatme Patient group nt line Treatmenthide all stage I and II oxygen as needed. Most patients develop some degree of lung fibrosis after radiotherapy, but this is usually asymptomatic unless the pre-treatment lung function was poor, in which case dyspnoea can be a major problem. Rare complications include oesophageal stricture and bronchial stenosis, which are more common when higher doses of radiation are prescribed. [37] [90] [89] plus [?] chemotherapy The choice between the many chemotherapeutic

Treatme Patient group nt line Treatmenthide all stage I and II regimens is complex and needs to be managed in a consultant oncology unit. Cisplatin-based regimens are recommended. Carboplatin-based regimens can be considered in select patients who are not felt to be appropriate candidates for cisplatin. Similarly, non-platinum-containing regimens can be used in select patients who cannot tolerate cisplatin or carboplatin. The optimal regimen is based on the individual patient characteristics

Treatme Patient group nt line Treatmenthide all stage I and II including disease stage, previous regimens and use of concomitant radiotherapy or surgical resection. All regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia and fatigue. Other side effects are specific to the particular agent.

stage IIIA surgical candidate 1st preoperative chemotherapy or chemoradiation Preoperative chemotherapy or chemoradiation should be

Treatme Patient group nt line Treatmenthide all stage I and II considered. The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. Cisplatin-based regimens are recommended. Carboplatin-based regimens can be considered in select patients who are not felt to be appropriate candidates for cisplatin. Similarly, non-platinum-containing regimens can be used in select patients who cannot tolerate cisplatin or carboplatin. The optimal regimen is based on the individual

Treatme Patient group nt line Treatmenthide all stage I and II patient characteristics including disease stage, previous regimens, and use of concomitant radiotherapy or surgical resection. There is evidence in more advanced disease of better outcomes in patients with nonsquamous tumours treated with a combination of pemetrexed and cisplatin as compared to those with squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] However, this approach has not be

Treatme Patient group nt line Treatmenthide all stage I and II studied specifically in patients with more limited stage IIIA disease. All regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other side effects are specific to the particular agent.

plus [?]

surgery Surgery is ideally performed by a specialist thoracic surgeon. For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. More limited surgery, such as a wedge

Treatme Patient group nt line Treatmenthide all stage I and II resection or segmentectomy, is often necessary in older patients or those with comorbidities but is associated with a higher rate of recurrence. [68] Access to the chest is usually via a thoracotomy, although minimally invasive techniques (e.g., video-assisted thoracic surgery) are gaining favour, owing to shorter hospitalisations and less postoperative pain. Sampling or dissection of mediastinal lymph nodes is recommended. Intraoperative and postoperative

Treatme Patient group nt line Treatmenthide all stage I and II complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula. plus [?] postoperative chemotherapy, radiotherapy, or chemoradiation Postoperative chemotherapy, radiotherapy, or chemoradiotherapy should be considered. Concurrent chemoradiation may be more effective than sequential chemoradiation, [86] [87] a

Treatme Patient group nt line Treatmenthide all stage I and II lthough this is controversial, [88] and administration of radiation and chemotherapy together (concurrently) is also more toxic than administering them sequentially.[C Evidence] Specialist advice must be sought. nonsurgical candidate 1st radiotherapy Stage III NSCLC patients whose tumours are inoperable should receive either conventional external beam radiotherapy or stereotactic body radiation. [81] Side effects depend on

Treatme Patient group nt line Treatmenthide all stage I and II the size of the radiation field, the dose and the adjacent organs (the lungs and oesophagus, in particular), which unavoidably receive some radiation. The most common side effects are fatigue, skin erythema/desquamation and oesophagitis. Most patients develop some degree of oesophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough and fever occurring 1 to 6 months after completing

Treatme Patient group nt line Treatmenthide all stage I and II treatment. Pneumonitis is rarely fatal and is treated symptomatically with oral corticosteroids and oxygen as needed. Most patients develop some degree of lung fibrosis after radiotherapy, but this is usually asymptomatic unless the pre-treatment lung function was poor, in which case dyspnoea can be a major problem. Rare complications include oesophageal stricture and bronchial stenosis, which are more common when higher doses of radiation are used. [89] [37] [90]

Treatme Patient group nt line Treatmenthide all stage I and II adjunct [?] chemotherapy The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. Cisplatin-based regimens are recommended. Carboplatin-based regimens can be considered in select patients who are not felt to be appropriate candidates for cisplatin. Similarly, non-platinum-containing regimens can be used in select patients who cannot tolerate cisplatin or carboplatin.[A Evidence]

Treatme Patient group nt line Treatmenthide all stage I and II

The optimal regimen is based on the individual patient characteristics including disease stage, previous regimens and use of concomitant radiotherapy or surgical resection. All regimens have the potential to cause bone marrow suppression, nausea/vomiting, alopecia and fatigue. Other side effects are specific to the particular agent.

stage IIIB resectable with no 1st preoperative chemotherapy + preoperative radiotherapy

Treatme Patient group nt line Treatmenthide all stage I and II contralate ral mediastin al adenopat hy

It is recommended that patients with potentially resectable T3-4 N0-1 M0 lesions should receive preoperative chemotherapy and radiotherapy (45 Gy). The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. Cisplatin-based regimens are recommended. There is evidence in more advanced disease of better outcomes in patients with nonsquamous tumours treated with a combination of pemetrexed and

Treatme Patient group nt line Treatmenthide all stage I and II cisplatin as compared to those with squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] Specialist advice must be sought. plus [?] surgery Surgery is ideally performed by a specialist thoracic surgeon. For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. More limited surgery, such as a wedge resection or segmentectomy, is often

Treatme Patient group nt line Treatmenthide all stage I and II necessary in older patients or those with comorbidities but is associated with a higher rate of recurrence. [68] Access to the chest is usually via a thoracotomy, although minimally invasive techniques (e.g., video-assisted thoracic surgery) are gaining favour, owing to shorter hospitalisations and less postoperative pain. Sampling or dissection of mediastinal lymph nodes is recommended. Intraoperative and postoperative complications include haemorrhage, infection,

Treatme Patient group nt line Treatmenthide all stage I and II cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula. plus [?] postoperative chemotherapy The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. There is evidence in more advanced disease of better outcomes in patients with nonsquamous tumours treated with a combination of pemetrexed and cisplatin as compared to

Treatme Patient group nt line Treatmenthide all stage I and II those with squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] Specialist advice must be sought. unresecta ble or contralate ral mediastin al adenopat hy 1st chemoradiation Chemotherapy or chemoradiation should be considered. The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. Chemoradiation regimens should use a platinumbased regimen, preferably

Treatme Patient group nt line Treatmenthide all stage I and II with cisplatin, plus radiotherapy (60-66 Gy). Concurrent chemoradiation is now considered more effective than sequential chemoradiation in terms of survival to 2 years, [86] [87] [92] althou gh it is also more toxic than sequential administration.[C Evidence] stage IV ECOG performan ce 0-2 (in bed <50% 1st chemotherapy The choice between the many chemotherapeutic regimens is complex and

Treatme Patient group nt line Treatmenthide all stage I and II of the time) needs to be managed in a consultant oncology unit. Four to 6 cycles of a platinum-based regimen typically consisting of 2 agents is usually recommended. [92] [93] [A Evidence] There is evidence in more advanced disease of better outcomes in patients with nonsquamous tumours treated with a combination of pemetrexed and cisplatin as compared to those with squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85]

Treatme Patient group nt line Treatmenthide all stage I and II adjunct [?] surgery of solitary metastatic lesion Patients with a solitary metastatic lesion can be considered for surgery. Stereotactic radiotherapy has not yet been demonstrated to be superior to surgery for this purpose. palliative radiotherapy Radiotherapy can be effective in palliating symptoms of advanced intrathoracic disease (e.g., haemoptysis, chest pain, shortness of breath) as well as symptoms caused by metastatic sites (e.g., bone, brain).

adjunct [?]

Treatme Patient group nt line Treatmenthide all stage I and II ECOG performan ce 3-4 (in bed >50% of the time) 1st supportive care Patients with stage IV NSCLC and ECOG performance 3-4 are treated with best supportive care, including symptomatic relief.

Ongoing Treatment approach

Treatment regimens vary depending on the stage of cancer. Stage I to IIIB lung cancer is potentially curable and, hence, curing the patient is the main goal. For patients with stage IV disease or advanced stage III (stage III disease with many comorbid conditions, making aggressive therapy impractical), the goal of treatment is to reverse, delay or prevent symptoms due to the local or metastatic tumour. Care of patients with lung cancer should be undertaken by a multi-disciplinary team in a consultant oncology centre. Good palliative and supportive care is important at all stages of the disease and in advanced NSCLC has been shown to confer advantages both in terms of quality of life and survival. [67]

Early-stage NSCLC (stage I-II), medically operable

Initial treatment should be surgical resection, ideally performed by a thoracic surgical oncologist. For patients with sufficient pulmonary reserve, lobectomy (removal of an entire lung lobe) is generally preferred over wedge resection (excising a section of the lobe), the latter being associated with a higher rate of recurrence. [68] Access to the chest is usually via a thoracotomy, although minimally invasive techniques (e.g., video-assisted thoracic surgery) are gaining favour since they require shorter hospitalisations and are associated with less postoperative pain. Sampling or dissection of mediastinal lymph nodes is recommended. Surgery provides the best chance of cure for early-stage NSCLC but can be associated with significant morbidity. The 30-day mortality rate is approximately 1% to 3% after lobectomy and 3% to 12% after pneumonectomy. For patients undergoing preoperative chemoradiotherapy, the mortality rate is even higher after pneumonectomy, especially right pneumonectomy. [69] [C Evidence] Intraoperative and postoperative complications include haemorrhage, infection, cardiac ischaemia, stroke, cardiac arrhythmia, pneumonia, prolonged air leak, chylothorax, pulmonary oedema, and bronchopleural fistula. Patients with completely resected NSCLC are at risk of developing metastatic disease. Adjuvant chemotherapy has been shown to improve survival in patients with stage II disease and is also generally offered to patients with stage IB disease. [70] [71] [72] [73] [74] There is little evidence for efficacy in smaller tumours. [75] The optimal regimen is based on the individual patient characteristics including disease stage, previous regimens, and use of concomitant radiotherapy or surgical resection.[C Evidence] The choice is complex and needs to be managed in a specialist oncology unit. There is no evidence for the benefit of prophylactic cranial irradiation after radical therapies in NSCLCs. [76] Postoperative radiotherapy generally is not given to patients with early-stage NSCLC with negative surgical margins, but it should be considered for highrisk patients with stage II disease (those with positive or close margins or lymph node involvement in the mediastinum and/or extracapsular extension). [77]

Early-stage NSCLC (stage I-II), medically inoperable

There is no internationally agreed definition of 'medical operability'. Decisions about fitness for radical treatment need to be taken by an experienced multidisciplinary team taking account of recent published guidelines. [78] [79] Early-stage NSCLC patients who are medically inoperable should receive either conventional external beam radiotherapy [80] or stereotactic body radiation (SBRT), [81] [82] [83] with adjuvant chemotherapy. Conventional radiotherapy consists of daily treatments for approximately 6 to 7 weeks (approximately 2 Gy each day to 60-70 Gy). SBRT is a new and potentially more effective technique that uses a few very large treatments (12-20 Gy each day to 48-60 Gy). Only select lung cancers are appropriate for SBRT. Percutaneous radiofrequency ablation is proposed by several authors, but no class 1 randomised trial data have been published. [84]

Stage IIIA NSCLC, medically operable

In patients with stage IIIA disease who are medically fit for surgery, preoperative chemotherapy or chemoradiation should be considered. [70] [71] [72] [C Evidence] Cisplatin-based regimes are recommended. There is evidence in more advanced disease of better outcomes in patients with non-squamous tumours who are treated with a combination of pemetrexed and cisplatin as compared with those who have squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] However, this approach has not been studied specifically in patients with more limited stage IIIA disease. Surgery, ideally performed by a specialist thoracic surgeon, is the standard treatment for these patients. For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. More limited surgery, such as a wedge resection or segmentectomy, is often necessary in older patients or those with comorbidities, but it is associated with a higher rate of recurrence. Access to the chest is usually via a thoracotomy, although minimally invasive techniques (e.g., video-assisted thoracic surgery) are gaining favour, owing to shorter hospitalisations and less postoperative pain. Sampling or dissection of the lymph nodes is recommended.

Postoperative chemotherapy, radiotherapy or chemoradiotherapy should be considered. Concurrent chemoradiation may be more effective than sequential chemoradiation, [86] [87]although this is controversial, [88] and administration of radiation and chemotherapy together (concurrently) is also more toxic than administering them sequentially.[C Evidence]

Stage IIIA NSCLC, medically inoperable

Eligibility for surgery should be assessed by an expert multi-disciplinary team. The evidence base is incomplete to provide precise guidance, but 2 reviews provide a good basis for decision-making. [78] [79] In patients with stage IIIA disease who are not candidates for surgery, either conventional external beam radiotherapy or stereotactic body radiation should be given. [81] Side effects depend on the size of the radiation field, the dose and the adjacent organs (the lungs and oesophagus, in particular), which unavoidably receive some radiation. The most common side effects are fatigue, skin erythema/desquamation and oesophagitis. Most patients develop some degree of oesophagitis during treatment. The most common late complication is pneumonitis, which is characterised by dyspnoea, dry cough, and fever occurring 1 to 6 months after completing treatment. Pneumonitis is rarely fatal and is treated symptomatically with oral corticosteroids and oxygen as needed. Most patients develop some degree of lung fibrosis after radiotherapy, but this is usually asymptomatic unless the pre-treatment lung function was poor, in which case dyspnoea can be a major problem. Rare complications include oesophageal stricture and bronchial stenosis, which are more common when higher doses of radiation are used. [89] [37] [90]

Stage IIIB NSCLC

Patients with potentially resectable tumours (T3-4 N0-1 M0) receive preoperative chemotherapy and radiotherapy (60-66 Gy). The choice between the many chemotherapeutic regimens is complex and needs to be managed in a consultant oncology unit. Cisplatin-based regimens are recommended. There is evidence in more advanced disease of better outcomes in patients with non-squamous tumours who are treated with a combination of pemetrexed and cisplatin as compared with those with

squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] For patients with resectable lesions and no contralateral lymph nodes, preoperative chemotherapy should be followed by surgery, ideally performed by a thoracic surgical oncologist. For patients with sufficient pulmonary reserve, lobectomy or pneumonectomy is preferred. More limited surgery, such as a wedge resection or segmentectomy, is often necessary in older patients or those with comorbidities but is associated with a higher rate of recurrence. [68] Postoperative chemotherapy is given.

Stage IV NSCLC (metastatic disease)

For patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (in bed <50% of the time), [60] 4 to 6 cycles of a platinum-based regimen typically consisting of 2 agents is usually recommended.[B Evidence] Surgical removal of a solitary lesion may be appropriate in these patients. Radiotherapy is effective in palliating symptoms of advanced intrathoracic disease (i.e., haemoptysis, chest pain, shortness of breath) as well as symptomatic metastatic sites (e.g., bone and brain metastases). One study has demonstrated that high-quality palliative care, instituted from shortly after the time of diagnosis, can lead to improvements in both quality of life and survival in patients with advanced disease. [67] Patients with ECOG performance status 3-4 (in bed >50% of the time) are treated with best supportive care.

Recurrence
Developing a recurrence after definitive treatment of lung cancer portends a poor prognosis, and salvage therapy is only rarely successful. Local recurrence within the chest after surgery should be treated with additional surgery (if possible) and/or local radiotherapy with or without chemotherapy, similarly as for unresectable stage III disease.

Salvage of a recurrence after radiotherapy for locally advanced NSCLC disease is poor. Additional radiotherapy may be considered and palliative chemotherapy may be useful in some patients.

Emerging treatments
Selecting chemotherapy regimen on the basis of specific cell type There is evidence in more advanced disease of better outcomes in patients with non-squamous tumours treated with a combination of pemetrexed and cisplatin as compared with those with squamous cell tumours, in whom the combination of gemcitabine and cisplatin is more effective. [85] However, this approach has not been studied specifically in patients with more limited stage IIIA disease. In the UK, NICE has approved the use of pemetrexed as first line in patients with locally advanced or metastatic non-squamous NSCLC. [94] Tumour expression of the DNA repair enzyme, ERCC1 (excision repair cross-complementation group 1), has been shown to predict for cisplatin resistance in NSCLC, and a large randomised trial has confirmed this in patients with adenocarcinoma. [95] Maintenance chemotherapy There is emerging evidence that maintenance chemotherapy after first-line chemotherapy in advanced NSCLC improves progression-free and overall survival. The most studied compound in this regard is pemetrexed, which also appears to be well tolerated in this setting, [96]although this treatment has not been approved for NHS use in the UK. Bevacizumab Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), a regulator of angiogenesis. Angiogenesis is an essential process for tumour growth. VEGF is often over-expressed in NSCLC. In a randomised study, bevacizumab increased the median survival of patients with metastatic NSCLC from 10.3 months with chemotherapy alone to 12.3 months with chemotherapy and bevacizumab (p=0.003). [97] Treatmentrelated deaths were more common in patients receiving bevacizumab, primarily from pulmonary haemorrhage, which was mostly confined to patients with central squamous cell tumours. A later study, the AVAiL trial,

has confirmed a significant improvement in progression-free survival in the first-line treatment of advanced non-squamous NSCLC in combination with cisplatin and gemcitabine.[98] In this study pulmonary haemorrhage was not a significant problem, a finding confirmed in another study that excluded patients with squamous cell carcinoma. [99] Bevacizumab is US Food and Drug Administration (FDA)-approved for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC when given in combination with carboplatin and paclitaxel. It is not approved for use in the UK and is unlikely to be in the near future. Erlotinib Erlotinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The EGFR is often expressed in NSCLC cells and is important in cell growth, proliferation, invasion and metastasis. In a randomised study, erlotinib increased the median survival of patients with metastatic NSCLC who had previously received 1 to 2 prior chemotherapy regimens, from 4.7 months with placebo to 6.7 months with erlotinib (p<0.001).[100] [C Evidence] Rash and diarrhoea were the primary side effects of treatment. Erlotinib monotherapy is FDA-approved for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. In the UK this has been approved as second-line therapy in patients with advanced (stage IIIB or stage IV) NSCLC who are not considered suitable for treatment with docetaxel. [101] There is some evidence of benefit from maintenance therapy with erlotinib after firstline chemotherapy. [102] Gefitinib Gefitinib inhibits the intracellular tyrosine kinase domain of the EGFR. The EGFR is often expressed in NSCLC cells and is important in cell growth, proliferation, invasion and metastasis. Two randomised trials showed no survival benefit for gefitinib when combined with standard chemotherapy in patients with metastatic NSCLC in the first-line setting. [103] [104][105] [B Evidence] The FDA has approved gefitinib only in cancer patients who have already taken the medicine and whose doctors believe it is helping them. A trial carried out in East Asia, almost exclusively on non-smoking patients (many of whom were female with adenocarcinomas) has demonstrated a significant improvement in progression-free survival with gefitinib used as first-line treatment in patients with stage IIIB or stage IV NSCLC who had

EGFR mutations demonstrated in their tumours. [106] [107] Gefitinib has therefore been licensed by the European Medicines Agency for use as firstline treatment in patients who are EGFR-mutation-positive. In the UK, NICE has approved it for use in the first-line treatment of locally advanced or metastatic disease that have been shown to have a positive EGFR mutation status. [108] A review of prospective clinical trials has confirmed a significant benefit in terms of progression-free survival in patients who are EGFRmutation-positive. [109] An improvement in progression-free survival has also been demonstrated in poor performance status patients who had EGFR FISH-positive tumours. [110] Vandetanib Vandetanib is an oral inhibitor of vascular epithelial growth factor receptor (VEGFR), epithelial growth factor receptor (EGFR), and some specific tyrosine kinases. One large phase 2 study has shown a significant improvement in progression-free survival when it is used in combination with docetaxel in patients with advanced NSCLC previously treated with chemotherapy. [111] It is not yet in widespread use. Cetuximab Cetuximab has been used, but there is no evidence of a major benefit of its use in the first-line treatment, with one study showing no survival benefit when it is combined with standard first-line combination chemotherapy. [112] Stereotactic body radiotherapy (SBRT) The standard treatment for patients with stage I NSCLC who are considered inappropriate for surgical intervention is radiotherapy, typically 60 to 70 Gy in 2-Gy fractions over 6 to 7 weeks. SBRT is a unique approach that involves a few very large fractions of radiation given within 7 to 10 days. A common prescription is 60 Gy in 3-Gy fractions. Local failure is common after conventional radiotherapy. SBRT allows a higher biological dose to be delivered to the tumour (60 Gy delivered in 1 week is more potent than 60 Gy delivered in 6 weeks). This may decrease the risk of recurrence. Large daily doses are feasible because only small volumes are treated, and the highdose regimen is designed to tightly conform to the tumour. This minimises the dose to surrounding critical structures. Appropriate patient immobilisation, reproducible set-up between fractions and some method to account for respiratory motion are critical. Preliminary results are promising, especially in

terms of improved local control, but there are few reports with mostly short follow-up. [82] [83] Increased pulmonary toxicity has been seen when perihilar and central tumours are treated with SBRT. [83] A phase I dose escalation study by the Radiation Therapy Oncology Group for this patient subgroup is in development. Until additional data are available, conventional radiotherapy may be safer for central lesions. This treatment can be delivered using a variety of treatment units including a modified linear accelerator, TomoTherapy and CyberKnife, or using protons. Additional technologies are available to increase the accuracy of radiotherapy (such as on-board imaging, cone-beam CT), and may be particularly useful for such focused high-dose radiation treatments. There is no convincing evidence that it is superior to the surgical removal of cerebral metastases in lung cancer. [113] Video-assisted thoracoscopic surgery (VATS) For early-stage NSCLC, lobectomy is standard treatment. This is usually accomplished with a thoracotomy. Minimally invasive techniques such as VATS are gaining favour due to shorter hospitalisations, less postoperative pain, more rapid recovery and shorter chest tube duration. A thoracoscopic resection requires an access incision approximately 5 cm in length as well as 1 to 2 smaller incisions for ports. Rib spreading with retractors is not necessary. [114] The extent of pulmonary resection and mediastinal lymph node dissection is equivalent to what is performed with thoracotomy. [115] Although there have been no randomised trials comparing VATS and thoracotomy, retrospective series suggest that a VATS lobectomy, when performed using sound oncological technique, is an effective approach. [116] [117] Radiofrequency ablation Radiofrequency ablation may be an option for the treatment of some patients with early stage (I or II) disease who are medically unfit for surgery. It should be considered only in circumstances where there is access to a radiological team highly experienced in the technique. [84] Photodynamic therapy There is emerging evidence that photodynamic therapy might be useful in some patients with early-stage disease affecting the mucosa of the major airways. However, this is best seen as a subject for further research rather than a routine treatment. [118]