9: Lung cancer

CHAPTER 9
Lung cancer


Abbreviations



ALK
anaplastic lymphoma kinase
APUD
amine uptake and decarboxylation
AVM
arterio‐venous malformation
CEA
carcinoembryonic antigen
CHART
continuous hyper‐fractionated accelerated radiotherapy
COPD
chronic obstructive pulmonary disease
CT
computed tomography
CXR
chest X‐ray
EBUS
endobronchial ultrasound
EGF
epidermal growth factor
EGFR
epidermal growth factor receptor
EMLA
echinoderm microtubule‐associated protein‐like 4
ENT
ear, nose and throat
EUS
endoscopic ultrasound
FDG
18F‐Fluorodeoxy glucose
FEV1
forced expiratory volume in 1 second
FNA
fine‐needle aspiration
FVC
forced vital capacity
Gy
Grey is a derived SI unit for ionising radiation
HPOA
hypertrophic pulmonary osteoarthropy
LCNS
lung cancer nurse specialist
MDT
multidisciplinary team
MRI
magnetic resonance imaging
NICE
National Institute of Health and Care Excellence
NSCLC
non‐small cell lung cancer
PD‐L1
programmed death ligand 1
PD‐L1R
programmed death ligand 1 receptor
PET‐CT
positron emission tomography with computed tomography
PORT
post‐operative radiation therapy
PSA
prostate specific antigen
PTH
parathyroid hormone
RCT
randomised controlled trial
SABR
stereotactic ablative radiotherapy
SCLC
small cell lung cancer
SIADH
syndrome of inappropriate anti‐diuretic hormone
SPN
solitary pulmonary nodule
SUV
standardised uptake value
SVCO
superior vena cava obstruction
TBNA
transbronchial needle aspiration
TLCO
diffusion capacity/transfer factor for CO
TWR
two‐week rule
UK
United Kingdom
VATS
video‐assisted thoracoscopic surgery
VEGF
vascular endothelial growth factor
WHO
World Health Organisation

Introduction


The majority (95%) of primary lung cancers are bronchogenic carcinomas which arise from the epithelial cells of the bronchial mucosa. These can be subdivided into non‐small cell lung cancer (NSCLC), which arises from the epithelial and glandular cells, and small cell lung cancer (SCLC), which arises from the neuroendocrine cells. Adenocarcinoma in situ, previously known as bronchoalveolar cell carcinoma (5%), arises from the alveolar cells. Mesothelioma, a malignant tumour of the pleura, is discussed in Chapter 12. Metastases to the lungs from other primary tumours, such as breast, colon, prostate, kidneys, ovary, and thyroid can also occur. In this chapter we will discuss primary lung tumours.


Lung cancer is the commonest fatal malignancy for both men and women in the UK and the third commonest cause of death in the UK. Worldwide, it accounts for one million deaths each year. Lung cancer has a poor prognosis because many types are rapidly growing, aggressive, and have usually metastasized at the time of presentation. In addition, lung cancer often presents late because many of the symptoms, such as cough and breathlessness, are non‐specific and common in smokers. There is no screening programme for lung cancer in the UK. Current studies are evaluating whether screening is feasible, cost‐effective, and likely to reduce mortality.


Epidemiology of lung cancer



  • Incidence: 40 000/year in UK.
  • Mortality: 34 000 deaths/year in UK.
  • Male: Female ratio is 1.5 : 1, largely reflecting previous smoking habits in men and women (Figure 9.1).
  • The prevalence of lung cancer in women is still increasing as there is a 30‐year lag between smoking and developing lung cancer (Figure 9.2). Lung cancer has overtaken breast cancer as the leading cause of cancer deaths in women.
  • There is a higher prevalence of lung cancer in the North of England and Scotland compared to the South of England reflecting the higher prevalence of smoking in those areas. Lung cancer is also commoner in the lower socio‐economic groups: this may be due to smoking habits as well as poor nutrition.
  • Survival: the overall 1‐year survival for lung cancer is still only 30% in men and 35% in women with a 5‐year survival of only 9.5% (Figure 9.3). There has been no convincing reduction in mortality despite some advances in diagnosis and treatment and the introduction of guidelines, pathways, and multidisciplinary working. This highlights the importance of prevention and early diagnosis.
Graph of adult population who smoked cigarettes (%) vs. year displaying 3 descending curves for male and female smoking prevalence and male lung cancer incidence and 1 ascending curve for female lung cancer incidence.

Figure 9.1 Lung cancer incidence and smoking trends for adults by sex, 1948–2010 in Great Britain, from Cancer Research UK.

Clustered bar graph illustrating the number of deaths and age‐specific mortality rates for lung cancer in UK, 2007, with ascending lines for male and female rates. Bars represent male and female deaths.

Figure 9.2 Number of deaths and age‐specific mortality rates for lung cancer in UK, 2007, from Cancer Research UK.

Graph illustrating the survival in lung cancer according to stage at diagnosis, with 7 descending curves of representing IA, IB, IIA, IIB, IIIA, IIIB, and IV.

Figure 9.3 Survival in lung cancer according to stage at diagnosis.


Source: from Staging at Cancer.org.


Aetiology of lung cancer


Several factors are implicated in the development of lung cancer. These are listed in Box 9.1.


Some 90% of lung cancers are related to smoking, which is the main risk factor. Before smoking became popular in the twentieth century, lung cancer was rare. The probability of developing lung cancer correlates to the number and duration of cigarettes smoked, quantified as the number of pack years. The earlier the onset of smoking, the higher the risk of developing lung cancer, as there is a 30‐year latent period.


A smoker of 20/day has 20× the risk of dying from lung cancer compared to a non‐smoker. The risk of developing lung cancer is halved every 5 years after smoking cessation but remains higher than for a non‐smoker. The prevalence of smoking is slowly reducing in the UK, with 17.7% of men smoking on average 12 cigarettes daily and 15.8% women smoking approximately 11 cigarettes every day. However, rates of smoking and lung cancer are increasing in China, India, and other developing countries.


In the past decade, evidence has accumulated that passive smoking, caused by exposure to the cigarette smoke from others, increases the risk of lung cancer 1.5 x. This evidence has resulted in a ban in smoking in public places in the UK. Children are particularly vulnerable to the effects of smoking, especially in places with little ventilation, such as cars. It is likely that there will be further legislation to protect children.


Chapter 15 discusses the carcinogenic properties of cigarette smoke and the seminal studies by Hill and Doll establishing the link between lung cancer and smoking. In Chapter 3 the NICE guidelines for smoking cessation are discussed.


Asbestos exposure is a risk factor for developing lung cancer. Asbestos exposure and smoking act synergistically and increase the risk of lung cancer 100 times compared to a non‐smoker. There is a latent period of 30–40 years from asbestos exposure to developing lung cancer. Asbestos exposure is also a risk factor for mesothelioma, a malignant tumour of the pleura, which is discussed in Chapter 10.


Pathophysiology of lung cancer


Damage to the bronchial mucosa by carcinogens causes squamous metaplasia which can progress to dysplasia, often in many separate areas. Some dysplastic cells then progress to become malignant. Areas of dysplasia can be visualised at bronchoscopy using fluoroscopy, but this is still largely a research tool.


The cancer initially invades local tissues, spreading to the parenchyma, pleura, pericardium, oesophagus, ribs, and muscle. This can result in cough, pain, breathlessness, dysphagia and pleural and pericardial effusions. Invasion of local nerves can cause vocal cord palsy (left recurrent laryngeal nerve), raised hemidiaphragm (phrenic nerve), and brachial plexus symptoms. The tumour can also spread to lymph nodes via the lymphatics and metastases to distant sites occurs haematogenously.


Clinical presentation of lung cancer


Lung cancer is a common condition, so all healthcare professionals should be alert to the possibility that patients with risk factors for lung cancer or a family history of malignancy, and who present with certain symptoms, may have lung cancer. Lung cancer can present with local or systemic symptoms, some of which are non‐specific. As most patients with lung cancer are smokers and likely to have chronic obstructive pulmonary disease (COPD), many of the symptoms, such as cough (which is the commonest symptom of lung cancer) and worsening breathlessness may be overlooked by the patient and the doctor (Box 9.2). A detailed clinical history and thorough examination should be conducted. Basic investigations, such as a chest X‐ray, should be conducted without delay and the patient referred to a specialist via the Two‐Week Rule Pathway if there is any concern. Some 15% of lung cancers are found incidentally in patients who have had a chest X‐ray (CXR) or computed tomography of the thorax (CT thorax) for other reasons, for example, during pre‐assessment for surgery.


Clinical signs of lung cancer


Patients with early, asymptomatic lung cancer may not have any abnormal signs and clinical examination will be normal. Box 9.3 details some possible signs in patients with lung cancer.


Ectopic secretion of hormones in lung cancer


Small cell lung cancers, which originate from the Kutchinsky neuroendocrine cells of the amine uptake and decarboxylation (APUD) system, can secrete ectopic hormones, so patients with hyponatraemia or hypercalcaemia may have an underlying malignancy.


Ectopic secretion of anti‐diuretic hormone (ADH) can occur in 15% of patients with SCLC resulting in hyponatraemia (serum sodium <139mmol/L). The patient can present with confusion and weakness. To make a diagnosis of syndrome of inappropriate ADH (SIADH) the serum osmolality must be <280 mosmol l−1 and the urine osmolality >500 mosmol l−1. Hyponatraemia due to SIADH can be managed by fluid restriction (1–1.5 l). If this fails, then pharmacological agents, such as demeclocycline, a vasopressin inhibitor or tolvaptan, a selective V2 receptor antagonist can be used.


Hypercalcaemia (serum corrected calcium >2.8mmol/L) in lung cancer can be due to the secretion of parathyroid hormone‐related (PTH‐related) peptide by squamous cell carcinoma which binds to the PTH receptors and increases bone and tubular resorption and decreases bone formation. Hypercalcaemia can also occur when there are bone metastases. Hypercalcaemia secondary to malignancy responds well to intravenous fluids, intravenous diuretics, steroids (prednisolone or dexamathasone), and intravenous bisphosphonate, such as pamidronate.


Ectopic ACTH secretion is rare (2–5% with SCLC), but presents with raised cortisol and Cushing’s syndrome.


Management of superior vena cava obstruction (SVCO)


Patients with SVCO present with headaches, distended, engorged, pulseless neck veins, collateral veins on the chest and arms, and facial oedema. The CXR may show a mass on the right side of the thorax and a widened mediastinum. The diagnosis can be confirmed with a contrast CT thorax which can identify the anatomical structures and collateral circulation. Invasive contrast venography and Doppler scanning may be helpful in assessing the extent of the obstruction. Severe SVCO can present as an emergency and must be discussed with the respiratory and radiology consultants. Management depends on the patient and the imaging, but includes commencing dexamethasone (up to 8 mg twice a day), after tissue biopsy if possible. Insertion of a metallic stent by an interventional radiologist can be considered in an emergency, and anticoagulation must be considered if there is thrombus present. Radiotherapy for NSCLC and chemotherapy for SCLC can reduce the obstruction but may take weeks to be effective.


Management of a patient suspected of having a lung malignancy


Lung cancer has a poor prognosis because patients often present late with evidence of local or distant metastases. This may be because neither the patient nor the doctor is alert to the common symptoms of lung cancer, which are often non‐specific. Currently there is no screening programme to detect lung cancer early. Other factors resulting in low survival rates for lung cancer in the UK include poor surgical rates of only 15% compared to at least 20% in the USA and in Europe. Patients with lung cancer also have significant co‐morbidities which often preclude radical treatment.


To improve early referral, diagnosis, and treatment, patients with symptoms or signs suggestive of lung cancer must be referred as a two‐week rule (TWR) to the respiratory team. The patient must be seen by a consultant respiratory physician within 14 days of referral, have all investigations completed within 28 days of referral, be discussed at the lung cancer multidisciplinary team (MDT) meeting and have treatment within 62 days of the original referral. These timeframes are likely to reduce in the next few years.


Clinical assessment of patient with suspected lung cancer


Patients should have a detailed history and examination (see Box 9.2, Box 9.3). In addition, the World Health Organisation (WHO) performance status, oxygen saturation, and spirometry must be noted (Box 9.4).


Investigations for patients suspected of having lung cancer


Blood tests should include full blood count to exclude anaemia and infection, urea and electrolytes, liver function test, clotting, corrected calcium and plasma and urine osmolalities if there is hyponatraemia.


Radiological investigations includes a plain chest X‐ray followed by a contrast staging CT scan of thorax and abdomen. Box 9.5 details chest X‐ray changes that need to be investigated further. Rarely, with central tumours or with small tumours, the chest X‐ray may appear normal. If the patient has unexplained symptoms or signs, which includes haemoptysis, a staging CT scan is indicated even if the chest X‐ray appears normal.


A staging CT scan of thorax and abdomen with contrast will show the primary tumour, lymph node enlargement within the thorax, local lung metastases and distant metastases to liver, adrenal glands and bone (Figure 9.12).

Image described by caption.

Figure 9.12 CT thorax showing a suspicious, spiculate mass in the right upper lobe.


A CT‐PET scan is required for accurate staging and is essential if radical treatment is being considered. A CT‐PET scan is done in a specialist centre and can ‘up’ or ‘down’ stage the CT staging. A CT‐PET has a sensitivity of 95% and a specificity of 83% for lung cancer.


A CT‐PET is poor at detecting slow‐growing tumours, such as adenocarcinoma in situ and carcinoid tumours, and poor at detecting brain metastases. False positive CT‐PET scans can also be found with infective and inflammatory processes. The standardised uptake value (SUV max) is used to calculate the FDG uptake (Figure 9.13). An SUV max <2.5 suggests a benign lesion (Figure 9.14).

Image described by caption.

Figure 9.13 PET scan showing an FDG‐avid lesion in the right upper lobe suspicious of lung cancer.

Image described by caption.

Figure 9.14 CT and PET scans showing a non‐FDG‐avid nodule in the left lung.


A bone scan may be indicated if the patient has bone pain or hypercalcaemia to see if there are bony metastases, although this can also be detected with a CT‐PET scan.


An MRI scan of the thorax can determine if the tumour involves the chest wall and may be required if resection of the chest wall is being considered. It is also useful for assessing the extent of the disease in superior sulcus tumours. An urgent MRI scan is indicated for spinal cord compression. An MRI brain may be required if there is indication of an operable brain metastasis.


A CT brain scan is required if the patient has neurological symptoms or signs suggestive of brain metastases. It is also done routinely in patients who are being considered for radical treatment.


Histological diagnosis


The NICE guidelines (2011) stipulate that histological diagnosis should be obtained in at least 85% of patients presenting with lung cancer. However, an invasive procedure carries a risk of morbidity and even mortality. The patient must be fully informed of the potential risks and benefits of any invasive procedures and must be prepared to accept these risks.


The investigation that gives the most information about the diagnosis and staging with the least risk to the patient should be chosen. For example, if there are enlarged lymph nodes of more than 10 mm maximum short axis on CT, then these should be sampled by endobronchial ultrasound (EBUS)‐guided biopsy or transbronchial needle aspiration (TBNA). Neck ultrasound and sampling of visible lymph nodes is also advised. Several samples may need to be taken to get sufficient tissue to identify the mutational status of the tumour which can guide treatment. While it is important to take adequate samples, the patient should not be put at any risk. Histology obtained from a biopsy is preferred to cells obtained from brushings and washing alone, although often, as the case with a pleural effusion, a cytological diagnosis may be sufficient.


Sputum cytology can be helpful in 40% of cases and more likely to be diagnostic with central tumours. This may be the only way to get cytological confirmation if the patient is too unfit for an invasive procedure such as a bronchoscopy.


A flexible fibre‐optic bronchoscopy is often the first investigation used to obtain tissue if the tumour is endobronchial and central. The tumour can be directly visualised and the distance of the tumour from the carina and the extent of obstruction of the bronchus can be noted. Bronchoscopy can also identify vocal cord palsy.


Biopsies, brushings and washings (bronchoalveolar lavage) can be taken directly from the tumour site through the bronchoscope for histological diagnosis. Sometimes, although no definite endobronchial lesions are seen, mucosal abnormalities may be visible which can be biopsied. The centre of a large tumour mass is often necrotic, so samples may not be diagnostic, even when large pieces of tissue are obtained. Other limitations to obtaining an adequate sample include poor patient tolerance of the procedure and vascular tumours that bleed easily. A rigid bronchoscopy, which is done under general anaesthetic, gives the operator more control, and may increase the diagnostic yield with difficult cases and when the tumour is near the carina.


If the tumour is peripheral, then a CT‐guided fine needle aspiration (FNA) conducted by the radiologist is diagnostic in 90–95% of cases when the lesion is >2 cm. It is not possible to undertake an FNA on a lesion <1 cm (Figure 9.15). Patients referred for this must have reasonable spirometry, normal oxygen saturation, be able to hold their breath and able to lie down flat. CT‐guided FNA is usually contraindicated in patients with an FEV1 of less than 1 L and with severe emphysematous lung disease on CT scan as their risk of pneumothorax is high and they will not be able to safely tolerate it. The overall pneumothorax risk of a CT‐guided FNA is 20%.

Image described by caption.

Figure 9.15 CT‐guided FNA of lung mass showing needle in the lung mass.


The other risk of lung biopsy is bleeding, with 8% experiencing haemoptysis post‐procedure. If the patient is on an anticoagulant, then this must be stopped several days prior to the procedure and clotting checked. The patient may need to be treated with low molecular weight heparin in the interim if necessary. Patients on aspirin should be informed not to take aspirin on the day of the procedure.


Sampling of enlarged, PET positive lymph nodes will ensure accurate staging which can determine whether the patient should receive radical or palliative treatment. Transbronchial needle aspiration (TBNA), endobronchial ultrasound (EBUS), and endoscopic ultrasound (EUS) can be used to biopsy paratracheal and peribronchial nodes. A mediastinoscopy can be done under general anaesthetic by a thoracic surgeon to sample mediastinal lymph nodes.


Cytology obtained by pleural aspiration of a pleural effusion can be diagnostic of lung cancer, but histology is preferable as tissue is required for molecular testing. A video‐assisted thoracoscopic (VATS) pleural biopsy done under general anaesthetic can be diagnostic when there is pleural involvement. Histological diagnosis of lung cancer can also be made by taking a biopsy from an extra‐thoracic site, such as a cervical or supraclavicular lymph node, the liver, adrenal, skin or bone (Figure 9.16). This may be necessary when CT‐guided FNA of the primary lung lesion is not possible.

Image described by caption.

Figure 9.16 Histology of adenocarcinoma from a CT‐guided biopsy of lung mass.


While every attempt should be made to obtain a histological diagnosis, this is often limited by the patient’s poor performance status (WHO performance status 3 or 4) and co‐morbidities (Figure 9.17, Figure 9.18). The decision not to pursue a histological diagnosis should be made at the lung cancer MDT after discussion with the patient and family. Pursuing a histological diagnosis may not be recommended in frail patients with a poor performance status, and in patients with extensive disease who are only suitable for palliation. Some patients may choose not to pursue further investigations for a variety of reasons and their wishes must be respected, so long as all the information has been given in a clear way. Good and empathetic communication is essential when dealing with patients with lung cancer.

Image described by caption.

Figure 9.17 Histology of squamous cell carcinoma from a CT‐guided biopsy of lung mass.

Image described by caption.

Figure 9.18 Histology of small cell carcinoma from an endobronchial biopsy.


Other investigations required in a patient with suspected lung cancer includes spirometry to assess the patient’s fitness for a procedure, such as a CT‐guided biopsy. If this suggests an airways obstruction, then the patient should be given optimal treatment to improve symptoms. A full lung function with transfer factor is required when planning radical treatment, such as surgery or radiotherapy. An ECG and echocardiogram may be necessary prior to radical treatment if the patient has a cardiac history.


Classification of lung cancer


Non‐small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Small cell lung cancer (SCLC), previously called oat‐cell cancer, is more aggressive and accounts for 20% of lung cancers.


Histological diagnosis is made from the morphological characteristics of the cells and the immunophenotyping. The biopsy is first processed and assessed by routine haematoxylin and eosin (H + E) stained sections. In most cases, a reliable diagnosis of NSCLC or SCLC can be made, although when the tumour is very poorly differentiated, this can be difficult. With advances in chemotherapy and immunotherapy, it is no longer acceptable to classify tumours simply as NSCLC.


Immunocytochemistry is required to classify NSCLC as squamous cell carcinoma or adenocarcinoma. Immunocytochemistry is a technique in which antigens in the tumour cells are bound to antibodies with attached chemical markers that allow them to be visualised in tissue sections. Many antibodies are available and their affinity to the different tumour markers has often been found empirically. The sensitivity and specificity are therefore variable, and it is normal to use a panel of antibodies. It can be difficult to differentiate between a primary lung adenocarcinoma and metastases from prostate, breast, and colon. Other markers may be helpful in differentiating between lung and metastases from other organs. By using these methods, over 90% of tumours can be classified accurately.


Tissue should be conserved for molecular mutation testing, such as for Epidermal Growth Factor Receptor (EGFR,) programmed death ligand 1 and its receptor (PD‐L1), and anaplastic lymphoma kinase (ALK). NICE guidelines recommend that the majority of NSCLC should have testing for EGFR. EGFR inhibitors are discussed later in this chapter.


There has been a change in the type of lung cancer over the last decade, with a decrease in squamous cell carcinoma and an increase in adenocarcinoma. This may be due to an increase in the low‐yield brands of cigarettes with filters which result in more peripheral deposition of carcinogens.


Staging of NSCLC


The TNM classification is used to stage NSCLC (Tables 9.1 and 9.2). The TNM classification was revised by the International Staging Committee of the International Association for the study of Lung Cancer. Data was collected on 68 463 patients with NSCLC and 13 032 patients with SCLC between 1990 and 2000. The modifications were recommended because of differences in survival and prognosis. Although it is not used in routine practice, staging that includes size of tumour, the histological type, late recurrence risk, and the age of the patient is more accurate. Accurate staging guides management and enables a more accurate prognosis to be made. Table 9.3 details the overall survival of patients with NSCLC according to the stage of the disease.


Table 9.1 Eighth edition of TNM classification of NSCLC.























































T = Size of tumour in CM.
TX: primary tumour cannot be assessed, or tumour cells in sputum or bronchial cells, but not visualised at bronchoscopy.
T0: No evidence of primary tumour.
Tis: Carcinoma in situ.
T1: Tumour ≤3 cm in greater dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in main bronchus).
T1mi: minimally invasive adenocarcinoma.
T1a: tumour ≤1 cm or less in greatest dimension.
T1b: tumour >1 cm and < 2 cm in greatest dimension.
T1c: tumour >2 cm but <3 cm in greatest dimension.
T2: tumour >3 cm but <5 cm or with any of the following features: involves main bronchus regardless of distance to the carina, but not involving the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonia that extends to the hilar region either involving part or the entire lung.
T2a: tumour >3 cm but <4 cm in greatest dimension.
T2b: tumour >4 cm but <5 cm in greatest dimension.
T3: tumour >5 cm but <7 cm in greatest dimension or one that directly invades any of the following: parietal pleura, chest wall (including superior sulcus tumours), phrenic nerve, parietal pericardium: or separate tumour nodule (s) in the same lobe as the primary.
T4: tumour >7 cm or of any size that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary.
N = regional lymph node involvement
NX: Regional lymph nodes cannot be assessed.
N0: No regional evidence of metastasis.
N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral, or contralateral scalene, or supraclavicular lymph node(s).
M = distant metastasis
M0: No evidence of distant metastasis.
M1: Distant metastasis.
M1a: Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or malignant pleural or pericardial effusion.
M1b: Single extrathoracic metastasis in a single organ.
M1c: Multiple extrathoracic metastases in a single, or multiple organs.

Table 9.2 Staging using the TNM classification for NSCLC eighth edition.



























































































Stage T N M
Occult Tx N0 M0
0 Tis N0 M0
IA T1 N0 M0
IA1 T1mi N0 M0
T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a‐c, T2a, b N1 M0
IIIA T3 N0 M0
IIB T1a‐c, T2a, b N3 M0
T3, T4 N2 M0
IIIC T3, T4 N3 M0
IV Any T Any N M1
IVA Any T Any N M1a, M1b
IVB Any T Any N M1c

Table 9.3 Overall 5‐year survival for NSCLC.


Source: www.cancer.org/cancer.




























Stage 5‐year survival rate (%)
IA 49
IB 45
IIA 30
IIB 31
IIIA 14
IIIB 5
IV 1

Staging of SCLC


The majority of SCLC present with evidence of metastases. If the disease is confined to the thorax, then it is staged as “limited”, and if there is evidence of spreading outside the thorax, then it is staged as “extensive”.


Management of lung cancer


Treatment decisions are made by the lung cancer multidisciplinary team (MDT) after consideration of the histological cell type (including immunocytochemistry), radiological stage, performance status of patient, lung function, co‐morbidities, and the wishes of the patient.


The key decision is whether the patient is suitable for radical, potentially curative treatment: surgery or radiotherapy. This can be followed by adjuvant treatment, either chemotherapy, radiotherapy, or both.


If the cancer is too advanced for radical treatment or the patient is unfit for radical treatment, then palliative options, which include chemotherapy and radiotherapy, can be considered. Palliation also includes procedures such as insertion of an endobronchial stent and draining of a pleural effusion with pleurodesis to relieve breathlessness. When patients have advanced disease and a poor performance status, then symptom control may be the best option. In the next section the various treatment options are discussed.


Surgery


The aim of surgery in lung cancer is to remove the tumour completely and it offers the only real chance of a cure. The latest figures from the National Lung Cancer Audit show that only 15% of patients with lung cancer in the UK have surgical resection. Although this is an improvement from previous years, it is poor compared to figures in Europe and USA, where over 20% of patients had surgical resection.


This low resection rate may be because patients with lung cancer present late with locally advanced or widely disseminated disease. However, there is evidence that not every patient who is suitable for surgery is referred for a surgical opinion. Of those undergoing resection, only 30% will be alive in 5 years. The prognosis depends on the final pathological stage of the cancer.


Surgery with curative intent should be considered in patients who are medically fit (WHO performance status 0 or 1), who have a reasonable lung function, and who have no significant co‐morbidities. This includes NSCLC Stages Ia to Stage IIIa (up to T3N1M0).


Surgery includes the removal of a lobe (lobectomy) or the entire lung (pneumonectomy). A pneumonectomy would be indicated if hilar nodes are found to be involved. The aim is to ensure that the resection margins are macroscopically free of tumour. The local lymph nodes are removed at surgery for pathological staging.


If the patient’s lung function and performance status are poor, then a wedge resection or segmentectomy can be considered for peripheral tumours. The tumour, with a small amount of surrounding lung tissue, is removed. Where appropriate, bronchoangioplastic or sleeve resections may sometimes be possible to preserve the lung function. The mortality for this procedure is 1–3.5% and the tumour recurrence rate is about 23%.


Those who have had a lobectomy have better survival rates than segmentectomy for tumours >3 cm. Local recurrence after lobectomy is less compared to segmentectomy regardless of the size of the tumour. A Cochrane meta‐analysis of 11 RCTs showed that 4‐year survival was increased in patients with Stage I, II and IIIA NSCLC who underwent lobectomy and complete mediastinal lymph node dissection compared to those who had complete resection and lymph node sampling. There were differences in operative mortality between the groups, with more complications in the lymph node dissection group.


Surgery is occasionally considered for selected patients with Stage IIIA NSCLC (T4N0M0, T4N1M0, T1‐3N2M0) as part of radical multimodality management with neoadjuvant chemotherapy and/or radiotherapy which may reduce the tumour size. Restaging may confirm operability. Stage IIIB NSCLC and Stage IV NSCLC are considered inoperable.


Neurosurgical resection can be considered for a solitary brain metastasis. The staging described in the section refers to the TNM classification version 7.


Essential investigations prior to surgery


A staging CT scan with contrast of the thorax and upper abdomen, which is an essential investigation for all patients with lung cancer, will demonstrate tumour anatomy, location, and size, with an accurate measurement of the T‐stage. CT also demonstrates abnormal enlargement of loco‐regional lymph nodes based on the size in the short axis and gives information about other diseases, such as emphysema. A PET‐CT will clarify lymph node involvement and detect occult metastases and is essential prior to surgery.


Fitness for surgery


The average mortality risk for lobectomy in the UK is 2–3%. In assessing fitness for surgery, the operative mortality, the risk of peri‐operative myocardial events and the risk of post‐operative dyspnoea should be considered. Patients should also be counselled regarding commonly occurring complications associated with lung resection.


Although age is not an absolute contraindication, patients aged over 80 do have an increased morbidity and mortality. Patients over 80 who have a lobectomy have a 7% mortality compared to 2–3% in younger patients. Those over 80 undergoing a pneumonectomy have a 14% mortality compared to 5–6% in younger patients. Despite this, the increased resection rates seen in recent years have been most marked in the older age group, probably reflecting a longer life expectancy.


Lung function is used in the pre‐operative assessment to estimate the risk of operative mortality and the impact of lung resection on quality of life, especially in relation to post‐resection dyspnoea. Although often regarded as being very important in assessing patients for surgery, forced expiratory volume in 1 second (FEV1) has not been shown to be an independent predictive factor for perioperative death and best serves as a useful predictor of postoperative dyspnoea. Diffusion capacity (TLCO) is an important predictor of post‐operative morbidity and should be performed in all patients regardless of spirometric values. A TLCO of greater than 40% predicted is required for surgery to be considered.


Although values of FEV1 > 1.5 L for a lobectomy and FEV1 > 2 L for a pneumonectomy were previously used in recommending surgery, surgical resection should still be offered to patients at moderate to high risk of post‐operative dyspnoea and associated complications if it is felt that this is the better treatment option and the patient is willing to accept the higher risk.


Several other investigations can be useful for assessing the fitness of patients with moderate to high risk of post‐operative dyspnoea and borderline lung function: ventilation and perfusion scintigraphy (VQ scan), quantitative CT or MRI, cardiopulmonary exercise testing and shuttle walk testing.


Patients should be informed that smoking increases the risk of pulmonary complications. They should be strongly advised to stop smoking, prescribed medication to aid smoking cessation, and referred to a smoking cessation clinic. Smoking cessation is discussed in Chapter 3.


Patients with co‐morbidities will require appropriate investigations prior to referral for surgery. Cardiac problems are common, so patients may require an ECG, echocardiogram, and a cardiac opinion. Surgery should be avoided within 30 days of a myocardial infarction. Patients with coronary artery disease should have their medical treatment and secondary prophylaxis optimised as soon as possible.


It is essential to rule out metastases prior to referral for surgery. Although a CT‐PET scan can detect most metastases, it is not good at detecting brain metastases, so a CT brain should be done.


Post‐operative complications


Complications of lung resection can be divided into three categories. Pulmonary complications include atelectasis, pneumonia, empyema, prolonged air leak, basal collapse, hypoxaemia, and respiratory failure. Post‐operative air leaks often occur from a breach in the visceral pleura, so drains are placed at the time of surgery to deal with this. In most cases, prolonged drainage is sufficient and rarely is re‐operation necessary to seal the leak. Bronchopleural fistula is a serious complication after pneumonectomy, with a high morbidity and mortality. The bronchial stump dehisces, and the pneumonectomy space inevitably becomes infected. Early mobilisation and physiotherapy are vital to reduce some of these complications. Cardiovascular complications include arrhythmia and myocardial infarction. Other common complications include bleeding, wound infection, and chronic chest wall pain.


Follow‐up post‐surgery


All patients who have had surgery for lung cancer should be discussed at the Lung MDT with the full surgical and pathological report where decisions regarding the need for adjuvant chemotherapy or radiotherapy can be made. Patients who have had surgery for lung cancer require careful and regular follow‐up for 5 years, with regular CXR and CT thorax at 12 months. The patient should be advised to report any symptoms of concern.


If the resection margins are not clear or nodal disease is found at surgery, then radiotherapy can reduce the chance of local recurrence, although it does not improve survival. There is no evidence that patients with Stage IA NSCL who have clear resection margins benefit from adjuvant chemotherapy or radiotherapy, although a significant number will eventually develop local or distant metastases. For Stage IB disease, chemotherapy may offer survival benefits if the tumour is >4 cm. Chemotherapy may be effective in patients with Stage II and Stage IIIA NSCLC after surgery.


Post‐operative radiation therapy (PORT) does not improve the outcome of patients with completely resected Stage I NSCLC.


Table 9.4 compares the differences in 5‐year survival rates with CT and pathological staging. Table 9.5 describes the 5‐year survival after surgery for NSCLC.


Table 9.4 Differences in 5‐year survival rates with CT staging and pathological staging.
























































CT staging 5 year survival (%) Pathological staging 5 year survival (%)
CNO without surgery 42 pN0 56
CNO with surgery 50
CN1 without surgery 29 pN1 38
CN1 with surgery 39
CN2 without surgery 18 pN2 22
CN2 with surgery 31
CN3 without surgery 7 pN3 6
CN3 with surgery 21
M1a (nodules in another ipsilateral lobe) 16
M1a (pleural metastases) 6
M1b (contralateral lung nodule 3
M1b (distant metastases) 1

Table 9.5 5‐year survival after surgery for NSCLC.









Stage IA (T1N0M0): 70%
Stage IB (T2N0M0): 40%
Stage II (T1‐2N1M0): 25%

Radiotherapy


Radical radiotherapy


Radical radiotherapy with curative intent can be given either alone or as part of a multi‐modal treatment approach with chemotherapy and/or surgery. Radical radiotherapy can be considered for patients with early stage NSCLC (Stages I, II, IIIA) who are not suitable for surgery due to co’morbidities or those who decline surgery. Squamous cell carcinomas are more radiosensitive than adenocarcinomas. One‐year survival after radical radiotherapy is 60% for Stage IA and 32% for Stage IB NSCLC.


A sub‐group of patients with small peripheral tumours are suitable for complex highly focused stereotactic ablative radiotherapy (SABR) which is associated with excellent local disease control. Radical radiotherapy is also the mainstay of treatment for patients with locally advanced inoperable disease, either as single modality treatment or combined with chemotherapy. This can be given either concomitantly or sequentially and is associated with improved outcomes. Patients need to have a good WHO performance status of 0–1 and have FEV1, FVC and TLCO>40% predicted. Stereotactic treatment could be considered in patients with worse lung function.


Modern radiotherapy planning and delivery techniques ensure adequate doses are delivered to the tumour with limited damage to the surrounding normal tissues. Standard radical fractionation schedules comprise of 60–66 Gy given in 30–34 daily fractions over 6–7 weeks. There is evidence to suggest that accelerating the course of treatment and completing it over a shorter time is associated with improved outcomes. This can be done either by increasing the number of fractions given per day (hyper‐fractionation), for example, using the continuous hyper‐fractionated accelerated radiotherapy (CHART) schedule, or by increasing the dose given per fraction (hypo‐fractionation), for example, 55 Gy given in 20 daily fractions over 4 weeks.


Side effects of thoracic radiotherapy include breathlessness, cough, tiredness, nausea, skin reaction, and dysphagia. Post‐radiation pulmonary fibrosis can also occur, causing breathlessness.


Palliative radiotherapy


Palliative radiotherapy can improve symptoms of pain and haemoptysis in patients with lung cancer. It can also be effective in treating bone and brain metastases. Radiotherapy can also relieve breathlessness secondary to lobar collapse caused by tumour obstruction.


Radiotherapy may be indicated as emergency treatment in patients with spinal cord compression who are not suitable for neurosurgical intervention. It can be considered for mediastinal compressive symptoms, such as SVCO, stridor, and dysphagia. Palliative radiotherapy schedules include 36 Gy in 12 daily fractions, 20 Gy in 5 daily fractions and single fractions of 8–10 Gy, depending on treatment intent and the patient’s performance status. Endobronchial brachytherapy may also be considered for local disease control.


Chemotherapy


Chemotherapy forms part of the potential treatment modality for most patients diagnosed with lung cancer. It is rarely curative but is the only option for most patients with SCLC and in many patients with NSCLC. Most lung cancers are disseminated at presentation and chemotherapy offers systemic treatment. It can also be given as adjuvant treatment to increase survival after surgery. It is often given in combination with radiotherapy to increase treatment response and survival. Neo‐adjuvant chemotherapy can be given to downstage a tumour in the hope that this will make it radically treatable. There is usually a good initial response to chemotherapy with a reduction in tumour size and an improvement in symptoms in 70% of patients. Patients who are unfit for radical treatment may benefit from palliative chemotherapy.


Assessing fitness for chemotherapy


The toxicity of chemotherapy needs to be considered when offering patients systemic treatment. Underlying coronary artery disease, renal impairment, tinnitus, and peripheral neuropathy are particularly relevant. The functional status of the patient should be assessed using either the WHO performance status or the Karnofsky scoring system. The potential benefits and side effects of treatment should be discussed with the patient.


Chemotherapy for NSCLC


NICE guidelines (2011) recommend that chemotherapy is considered for patients with Stage III and IV NSCLC with a performance status of 0 or 1. Treatment can prolong life by two months and increase one‐year survival from 5% to 25%. There are many clinical trials recruiting patients who should be offered the chance to participate.


Combinations of drugs are given at intervals of four weeks, up to six cycles of treatment, with careful monitoring of clinical and radiological response. Third‐generation drugs, which include docetaxel, gemcitabine, paclitaxel, vinorelbine, and pemetrexed are given together with platinum drugs, carboplatin, or cisplatin. It is not within the scope of this book to discuss the details of chemotherapy drugs.


Adjuvant chemotherapy can be given after radical treatment, either radiotherapy or surgery. It is given after surgery for Stage IB disease when the tumour is >4 cm and for Stage II and Stage III lung cancer. A platinum‐agent or a third‐generation drug except pemetrexed can be given.


Neo‐adjuvant chemotherapy should be considered is patients who are not radically treatable. Chemotherapy could downstage the tumour, making it suitable either for radical radiotherapy or surgery.


Chemotherapy for SCLC


NICE guidelines recommend that patients with SCLC should be seen by a medical oncologist within a week of diagnosis. Surgery should be considered for patients with early‐stage SCLC (T1‐2aN0M0) with a good WHO performance status of 0 or 1. Patients with SCLC undergoing surgery will require adjuvant chemotherapy. Radiotherapy may also be an option for early stage SCLC.


Chemotherapy can improve survival from 3 months to 12 months in limited SCLC and from 6 weeks to 12 weeks in extensive SCLC. Drugs used to treat SCLC include Topisomerase 1 poison (Topotecan), Topisomerase 11 poison (Etoposide) and the platinum drugs, carboplatin and cisplatin.


Palliative chemotherapy


A combination of a third‐generation drug and a platinum drug is given if the patient can tolerate it without toxicity and the renal function is reasonable. Combinations of drugs given at intervals of 3 weeks, up to a maximum of six cycles, can improve symptoms.


Side effects of chemotherapy


The side effects of chemotherapy include systemic symptoms, such as nausea, vomiting, and diarrhoea which can be managed with antiemetics and fluids. Bone marrow suppression a few days after chemotherapy can result in anaemia, neutropenia, and thrombocytopaenia. Neutropenic sepsis is a real concern and must be considered in all patients who present feeling unwell. Neutropenic sepsis should be managed according to the NICE guidelines. It includes careful clinical assessment, septic screen (blood culture, urine culture, and chest X‐ray), barrier nursing, and immediate intravenous antibiotics, usually tazocin and gentamicin.


Treatment response


Response to treatment is assessed according to an improvement in symptoms and radiological improvement. Radiological treatment response is classified as defined in Box 9.6.

Jun 4, 2019 | Posted by in RESPIRATORY | Comments Off on 9: Lung cancer
Premium Wordpress Themes by UFO Themes