• >39,000 new cases diagnosed per annum in the UK
• Commonest cause of cancer death in women in the UK
• ♂:♀ ≈ 2:1, but numbers decreasing in men, increasing in women, because of increasing smoking
• More women die from lung cancer than from any other cancer, including breast
• 90% smoking-related
• Stopping smoking decreases the risk, but the risk remains higher than in non-smokers
• Risk of lung cancer may be increased by asbestos exposure, arsenic and heavy metal exposure, pulmonary fibrosis, radiation exposure, and in patients with HIV.
Types of lung cancer
See Box 31.1. In practical terms, lung cancer is divided into two groups, which influence management and treatment decisions.
Non-small cell lung cancer (NSCLC)
• Accounts for ~80% of all lung cancers
• Squamous cell carcinoma is the commonest histological type. Usually presents as a mass on CXR but may cavitate and look radiologically like a lung abscess. Rarely, there may be multiple cavitating lesions. Hypercalcaemia may be a feature
• Adenocarcinoma may not necessarily be smoking-related. Can occur in scar tissue or sites of fibrosis. Can be a lung 1° or a 2° from adenocarcinomas at other sites, especially if causing pleural infiltration and subsequent pleural effusion. Adenocarcinomas have recently been reclassified (see Box 31.2)
• Bronchioloalveolar/bronchoalveolar cell carcinoma (BAC) is rare and has now been reclassified (see Box 31.2). It can rarely cause copious sputum production (bronchorrhoea). Typically causes fluffy airspace shadowing on CXR and may be multifocal, sometimes in both lungs.
Small cell lung cancer (SCLC)
• Accounts for ~15% of all lung cancers
• Most aggressive of lung cancer subtypes
• Usually disseminated by the time of diagnosis (haematogenous spread)
• Frequently metastasizes to liver, bones, bone marrow, brain, adrenals, or elsewhere
• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with hyponatraemia is common in SCLC
• Surgery usually not appropriate
• Chemo- and radiosensitive
• Untreated extensive stage SCLC is rapidly progressive and has a median survival of 6 weeks.
Symptoms and signs
These may be due to local tumour effects, metastatic tumour effects, or paraneoplastic manifestations. Many patients have no specific signs. In some, the lung cancer may be an incidental finding on CXR or CT performed for another reason.
Local tumour effects
• Persistent cough or change in usual cough
• Chest pain (suggests chest wall or pleural involvement)
• Unresolving pneumonia or lobar collapse
• Unexplained dyspnoea (due to bronchial narrowing or obstruction)
• Wheeze or stridor
• Shoulder pain (due to diaphragm involvement)
• Pleural effusion (due to direct tumour extension or pleural metastases)
• Hoarse voice (tumour invasion of the left recurrent laryngeal nerve)
• Raised hemidiaphragm (phrenic nerve paralysis)
• Horner’s syndrome (miosis, ptosis, enophthalmos, anhydrosis) due to apical or Pancoast’s tumour damaging sympathetic chain
• Pancoast’s tumours can also directly invade the rib and brachial plexus, causing C8–T1 dermatome numbness, shoulder pain, and weakness of small muscles of the hand.
Metastatic tumour effects
• Cervical/supraclavicular lymphadenopathy (common, present in 30%, and may be an easy site for diagnostic biopsy)
• Palpable liver edge
• Bone pain/pathological fracture due to bone metastases
• Neurological sequelae 2° to cerebral metastases (median survival of NSCLC with brain metastases is 2 months)
• Hypercalcaemic effects (due to bony metastases or direct tumour production of parathyroid hormone (PTH)-related peptide or PTH); see p. [link]
• Dysphagia (compression from large mediastinal nodes).
Endocrine syndromes are due to the ectopic production of hormones or hormonally active peptides. Neurological syndromes are due to antibody-mediated CNS damage.
• Cachexia and wasting
• Clubbing (up to 29% of patients; any cell type, more common in squamous and adenocarcinoma)
• Hypertrophic pulmonary osteoarthropathy (HPOA), often in association with clubbing, any cell type; more common in squamous and adenocarcinoma. Periosteal bone proliferation with symmetrical painful arthropathy (predominantly large joints, but hands and feet also affected)
• SIADH (mainly SCLC) in up to 10% of patients; see p. [link]
• Ectopic ACTH (Cushing’s syndrome, but due to rapid development; biochemical changes predominate, mainly SCLC) in 2–5% of patients
• Lambert–Eaton myasthenic syndrome (LEMS)—with SCLC. Affects proximal limbs and trunk, with autonomic involvement (dry mouth, constipation, erectile failure) and hyporeflexia (although reflexes return on exercising the affected muscle group), and only a slight response to edrophonium. Symptoms may predate diagnosis of lung cancer by up to 4y. Caused by autoantibodies against P/Q-type voltage-gated calcium channels. Decreased acetylcholine release at motor nerve terminals leads to the proximal weakness. Diagnosis made by autoantibody detection on radio-immunoprecipitation assay. EMG shows increased amplitude of muscle action with high-frequency stimulation, and repeated muscle contraction may lead to increasing strength and reflexes. Treatment of underlying SCLC may cause neurological improvement. If weakness is severe, IV immunoglobulin or plasmapheresis may give short-term benefits. 3, 4-diaminopyridine may increase muscle strength in 85% of patients. Prednisolone alone or with azathioprine or ciclosporin can increase muscle strength and provide long-term control in non-responders
• Cerebellar syndrome (usually SCLC)
• Limbic encephalitis (SCLC, also breast, testicular, other cancers). Occurs within 4y of diagnosis of cancer. Personality change, seizures, depression, subacute-onset confusion, and short-term memory loss. Diagnosed by pathological or radiological involvement of limbic system. Anti-Hu antibodies positive in 50% if associated with lung cancer
Infiltration of pulmonary lymphatics by tumour. May be due to lung cancer or breast, prostate, stomach, or pancreatic malignancies. Causes SOB, cough, and is often associated with systemic signs of advanced malignancy. May be visible on CXR as fine linear shadowing throughout both lung fields. Septal lines present. May look like pulmonary oedema. Easily diagnosed on CT. Oral steroid treatment and diuretics can give symptomatic relief, but it is usually a short-lived response. Often part of a rapid decline.
Patients should be referred under the ‘2-week cancer wait’ scheme and should be seen within 14 days of referral. The aim of the investigations is to reach a histological diagnosis and tumour stage in order to determine the most appropriate treatment. Current government guidelines recommend patients should receive treatment without undue delay: within 31 days of the decision to treat and within 62 days of their urgent referral.
• History and examination, including smoking and occupational histories
• Spirometry pre-biopsy or surgery
• CXR (PA and possibly lateral)—location of lesion, pleural involvement, pleural effusion, rib destruction, intrathoracic metastases, mediastinal lymphadenopathy. CXR can be normal
• Blood tests, including sodium, calcium, and LFTs. Check clotting if biopsy planned
• Sputum cytology only indicated in patients who are unfit for bronchoscopy or biopsy
• Diagnostic pleural tap, if effusion present
• FNA of enlarged supraclavicular or cervical lymph nodes.
• CT neck, chest, liver, adrenals (contrast-enhanced) to assess tumour site and size Lung cancers frequently metastasize to the mediastinal lymph nodes, liver, and adrenals. CT can locate lesions amenable to biopsy (either the 1° tumour or a metastasis). Assesses size of local and regional lymph nodes. Poor at assessing whether enlarged nodes are reactive (inflammatory) or represent metastatic spread (79% sensitive, 78% specific). Can assess tumour invasion to mediastinum and chest wall
• USS of neck or liver may provide information about enlarged lymph nodes or metastases suitable for biopsy
• MRI Used to answer specific questions relating to tumour invasion/borders. Good for assessing brachial plexus involvement. No role in nodule assessment
• Bone scan Indicated if any suggestion of metastatic disease such as bony pain, pathological fracture, hypercalcaemia, raised ALP. Highly suggestive of bony metastases if multiple areas of increased uptake. Solitary lesion may require further evaluation
• CT head Indicated if any neurological evidence of metastatic disease such as persistent vomiting, fit, focal neurological signs, headache, unexplained confusion, or personality change. Consider in patients selected for treatment with curative intent, especially stage III disease
• Positron emission tomography (PET) scanning Imaging technique where metabolically active tissues, such as tumours, show increased uptake of radiolabelled 18-fluorodeoxyglucose (FDG). Improves the rate of detection of local and distant metastases. Useful for assessing regional and mediastinal lymph nodes (88% sensitive, 93% specific). This is increased if abnormal nodes are identified on CT. Now widely used and should be interpreted with the CT. Perform in:
• All patients considered for radical therapy to look for involved lymph nodes and distant metastases
• Patients with N2–3 disease on CT of uncertain significance, who are otherwise surgical candidates
• Candidates for radical radiotherapy
• Limited stage SCLC, staged by standard staging methods to identify metastases, as SCLC avidly takes up FDG.
PET-positive nodes that would exclude a patient from surgery should be confirmed as malignant with a biopsy, unless the pre-test probability of malignancy is high. PET may reveal a distant abnormality, other than the 1° lung cancer, which could be a solitary metastasis or a second cancer. It is important therefore to biopsy isolated PET abnormalities before determining that a cancer is not resectable.
occur in tumours with a low metabolic activity (such as BAC, carcinoid), small nodules, and hyperglycaemic patients. False positives occur in patients with benign pulmonary nodules with a high metabolic rate such as infective granulomata.
Patients fast 4h before the test, and, if they have diabetes, glucose should be within the normal range.
Should include a chest physician, radiologist, thoracic surgeon, oncologist, pathologist, lung cancer nurse, and palliative care specialist, who meet regularly in order to discuss patients and plan the most appropriate course of management.
The Department of Health and NICE in the UK have produced guidelines for performance in lung cancer care. These encourage access to the MDT in decision making for the treatment and investigation of all patients with lung cancer.
NICE lung cancer guidelines 2011. http://www.nice.org.uk.
Giving information to lung cancer patients. BTS Lung Cancer and Mesothelioma Specialist Advisory Group. April 2008. http://www.brit-thoracic.org.uk/Portals/0/Guidelines/Lung%20Cancer/WTSTPBTSfinal210408.pdf.
Investigations are performed to obtain a tissue diagnosis and to stage cancer in order to determine the most appropriate treatment. Aim to achieve diagnosis and staging with as few procedures as possible. Establishing diagnosis and presence of metastatic spread at a single test is desirable, if possible. Increasingly important to obtain adequate tissue to enable accurate histology ± molecular analyses (e.g. epidermal growth factor receptor (EGFR) activating mutations). Aspects of further investigation may be inappropriate if the patient has advanced disease, is frail with comorbid conditions, or does not want to pursue diagnosis. This should be documented in their notes to aid audit and cancer service evaluation.
Method of obtaining histological and cytological specimens. Suitable for central tumours. Tumours can be washed, brushed, and biopsied. Bronchoscopic samples are more likely to be histologically positive if there is:
• An ill-defined lesion on the CXR
• An endobronchial component to the tumour
• Tumour <4cm from the origin of the nearest lobar bronchus
• A segmental or larger airway leading to the mass.
Greater diagnostic yield if performed after CT scan, as radiologically abnormal areas can be targeted. Tumour position bronchoscopically may contribute to operative decisions: tumour confined to a lobar bronchus may be resectable with lobectomy; tumour <2cm from the main carina requires pneumonectomy; left vocal cord paralysis indicates inoperability due to tumour infiltration of the left recurrent laryngeal nerve; and a splayed carina occurs 2° to enlarged mediastinal nodes. Advanced bronchoscopic techniques (e.g. endobronchial ultrasound (EBUS), electromagnetic navigation guidance, or fluoroscopically guided bronchoscopy) may help obtain diagnostic samples.
Transbronchial needle aspiration (TBNA)
of lymph nodes (often combined with EBUS) can be performed to obtain tissue and allow staging at the time of bronchoscopy and may reduce need for mediastinoscopy (see p. [link]). May also be combined with EUS-FNA (endoscopic ultrasound-guided fine-needle aspiration).
of tumour or of an enlarged lymph node, especially in the neck, or of a metastasis (see Box 31.3). 85–90% sensitivity in lesions >2cm. Where possible, biopsy of a metastasis should be the investigation of choice, simultaneously giving staging and diagnosis.
Manhire A et al. Guidelines for radiologically guided lung biopsy. Thorax 2003:58:920–34.
Biopsy of enlarged mediastinal lymph nodes to determine whether they are inflammatory or have malignant invasion. Suprasternal notch incision under general anaesthetic, blunt dissection, palpation, and endoscopic visualization and biopsy of nodes: paratracheal, prevascular, tracheobronchial, and anterior subcarinal. 93% sensitivity, 96% specificity. Technically more difficult if SVCO. Bleeding in <0.3%, left recurrent laryngeal nerve injury in 1%, pneumothorax, mediastinal emphysema, infection, oesophageal perforation (all rare). Repeat mediastinoscopies have lower positive yield and higher complication rate.
Biopsy of aorto-pulmonary, sub-aortic, phrenic, or hilar nodes. Metastatic involvement of nodes does not necessarily preclude curative surgical resection with a pneumonectomy. Also can assess direct tumour invasion of central pulmonary artery or thoracic aorta, which would preclude curative surgery. Right or left parasternal incision, blunt dissection, palpation, and endoscopic visualization and biopsy of nodes.
may be required to determine whether a pleural effusion contains malignant cells or is inflammatory, e.g. due to pneumonia caused by an obstructing lesion. Malignant effusions are evidence of M1 disease and hence are a contraindication to surgery.
It is sometimes difficult to obtain definitive cytology or histology preoperatively. If there is a high suspicion of malignancy, surgery can be performed regardless. Patients undergoing surgery are given a pathological stage, which is sometimes different to the clinical stage (after histologically examining resection margins, lymph nodes, and pleura).
Clinical and radiological tools categorize tumour size, location, regional and distant spread, and aid determination of most appropriate treatment. They can also therefore give prognostic information.
• SCLC is staged as limited or extensive but now also staged using the 7th edition of the TNM staging system (see Box 31.4):
• Limited Confined to ipsilateral hemithorax and supraclavicular lymph nodes. Median survival with treatment, 12 months; without treatment, 12 weeks
• Extensive Everything else. Median survival with treatment, 8 months; without treatment, 6 weeks
Table 31.1 Lung cancer clinical staging and survival
After treatment survival
T1 N0 M0
T2a N0 M0
T1a–2a N1 M0
T2b N0 M0
T2b N1 M0
T3 N0 M0
T1–2 N2 M0
T3 N1–2 M0
T4 N0–1 M0
T4 N2 M0
Any T, N3 M0
Any T, any N, M1
Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2007;2:706–14.Find this resource:
Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–23.Find this resource:
Much of the investigation of lung cancer is to determine whether a patient has disease that is potentially curable by surgery. Other treatment options include chemotherapy, radiotherapy, and best supportive care, i.e. symptom-based conservative management. The MDT decides the most appropriate choice of treatment which is then discussed with the patient.
The aims of surgery for lung cancer are to completely excise the tumour and local lymphatics, with minimal removal of normal functioning lung parenchyma.
• Stages I and II NSCLC are usually amenable to surgery if the patient is fit enough (see Fitness for surgery). This has a high chance of cure in stage I (70% in IA), and a reasonable chance in stage II. 10–20% of NSCLC patients undergo resection
• In stage IIIA tumours, surgery alone is unlikely to be curative, but adjuvant chemotherapy and radiotherapy can improve survival rates
• Stages IIIB and IV are not resectable
• Stages 0/tumour in situ often will have no defined 1° lesion amenable to resection. The natural progression of these tumours is still unknown; they may progress or regress with time.
Resectability of a tumour implies likelihood of complete removal by surgery; this is different from patient operability, which is determined by the patient’s fitness for surgery.
Fitness for surgery
• Global risk score May be useful for estimating risk of death (e.g. Thoracoscore)
• Age is not a contraindication, but increasing age is associated with an increased perioperative morbidity. Higher mortality risk if over 80 and if pneumonectomy, rather than lobectomy (14% mortality vs 7%, respectively). Right pneumonectomy has higher mortality than left pneumonectomy (more lung removed). 2y post-operative survival similar to that of other age groups
• Lung function Approaches vary. The 2013 American College of Chest Physicians (ACCP) guidelines suggest measurement of FEV1 and TLCO in all, with calculation of predicted post-operative (PPO) values. PPO FEV1 and PPO TLCO both >60% suggest low risk for death and complications and no further tests required. For values <60% but >30%, stair climb or SWT recommended. For values <30% (or SWT of <25 shuttles or <400m, or climb test <22m), full CPET recommended. If VO2max <35% predicted (or <10 mL/kg/min) consider patient for lung-conserving procedures or non-operative treatment. LVRS may be considered if a cancer is within an area of upper lobe emphysema
• Cardiovascular Postpone surgery if patient has had MI within 30 days. Cardiology opinion if patient has had MI within 6 months. Echo if they have heart murmur. Preoperative ECG for all
• Smoking Do not delay surgery to stop smoking, but counsel patients and offer NRT
• Nutritional Requirements should be optimized, with advice from a dietician, if necessary. Patients presenting with a preoperative weight loss of 10% or more ± performance status ≥2 are more likely to have advanced disease or comorbidities. Therefore, require careful staging and search for evidence of comorbidity.
Types of surgery
Lobectomy or bi-lobectomy for localized tumour, or pneumonectomy for tumour involving >1 or 2 lobes. If hilar nodes are infiltrated by tumour, a more radical lobectomy or a pneumonectomy is required. The local lymph nodes are removed in each procedure for pathological staging. Segmentectomy removes part of a lobe (supplied by a segmental bronchus) along the intersegmental planes and may be performed for a localized peripheral lesion with clear regional lymph nodes, especially if the post-operative respiratory function is predicted to be borderline. Wedge resection is another lung-preserving operation that removes only the tumour, with minimal surrounding lung parenchyma, but there is a higher local recurrence rate, however (up to 23%). Both segmentectomy and wedge resection should have ≥2cm clear margins around a tumour. Sleeve resections involve a lobectomy and the removal of a section of bronchus affected by tumour, forming an anastomosis between the airway proximal and distal to it. This may avoid a pneumonectomy. Resection margins should be macroscopically free from tumour. If there is limited local tumour invasion to the chest wall, this can be resected with a 5cm margin. Reconstruction with prosthetic material may be necessary if two or more ribs are resected, aiming to preserve the chest wall function.
Bronchopleural fistula, respiratory failure, infection, phrenic nerve damage causing diaphragmatic paralysis, recurrent laryngeal nerve damage causing hoarse voice, prolonged chest wall pain. Mortality: 1–3.5% for wedge resection, 2–4% for lobectomy, 6–8% for pneumonectomy. Risk increases with increasing age, associated ischaemic heart disease, impaired respiratory function, and poor performance status.
Patients are often followed up by the chest clinic on a 6–12-monthly basis for CT or CXR review for 5y (although there is no clear evidence on the necessity of such prolonged follow-up in lung cancer). This is to ensure they are radiologically clear of tumour recurrence, and there is not a second 1° tumour. They should also be advised to seek earlier review if they have symptoms of persistent haemoptysis or new cough, weight loss, new chest pain. If histology shows incomplete resection margins, post-operative chemoradiotherapy would be given to try and improve local disease control.
Consider in patients with stages III–IV disease, WHO performance status 0–1/2 (see p. [link]), even if they are asymptomatic from their cancer (greater toxicity in those with poorer performance status). 40% respond temporarily (see Box 31.5 for criteria used to assess response). Small improvement in symptom control and QoL, compared with best supportive care, shown in RCTs. Limited survival gains, 6–7 weeks, compared with best supportive care. Median survival with chemotherapy in stage IV lung cancer: 10 months (Ps0), 7 months (Ps1), 4 months (Ps2).
• Combination chemotherapy (the use of >1 drug) is superior to single-agent chemotherapy, improving survival rates when compared with single agent at 6 and 12 months. Commonly used first-line regimens include gemcitabine (or docetaxel/paclitaxel/vinorelbine) plus a platinum-containing drug (carboplatin or cisplatin), usually for four cycles. Combination pemetrexed/cisplatin has been used as an option for first-line treatment of patients with locally advanced or metastatic adenocarcinoma/large cell tumours
• Combined chemoradiotherapy may be given with curative intent for some patients with stage III disease (or lower stages, not suitable for surgery)
• Inhibitors of EGFR, an important mediator of cell growth, differentiation, and survival, are used in selected patients. Activating mutations in EGFR (typically affecting never-smoking women ± Asian ethnicity) occur in a small proportion of NSCLC. Patients found to have this mutation with locally advanced or metastatic NSCLC may be treated by gefitinib or erlotinib
• Side effects of chemotherapy Nausea, myelosuppression, ototoxicity, peripheral neuropathy, nephropathy if dehydrated. Alopecia with taxanes
• Patients are monitored during chemotherapy with repeat CT, usually after two cycles, to establish whether they have partial response, stable disease, or progressive disease, despite chemotherapy. This CT influences decisions regarding further chemotherapy
• Second-line treatments (e.g. docetaxel monotherapy) can be given in patients who relapse and are of good performance status
• Recent evidence suggests benefit to the oral tyrosine kinase inhibitor crizotinib as second-line therapy for tumours with rearrangements of the anaplastic lymphoma kinase (ALK) gene. A phase III study showed crizotinib increased progression-free survival from 3 to 7.7 months.
Oken MM et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–55.
is the use of radiation or chemotherapy (or both) following complete surgical resection to improve survival. Adjuvant chemotherapy has been found to have significant survival advantages, compared with surgery alone in trials, including International Adjuvant Lung Cancer Trial and Japan Lung Cancer Research group. Those with stage IB or stage II disease had a 69% 5y survival vs 54% in those treated with surgery alone. Cisplatin-based combination treatment is now offered post-operatively to patients with good performance status (Ps0/1) and T1–3 N1–2 M0 NSCLC and should be considered in those with T2–3 N0 M0 NSCLC tumours >4cm. Adjuvant radiotherapy trials have shown no evidence of a survival benefit, except possibly in those with N2 disease.
uses non-surgical therapy (radiotherapy/chemotherapy) as the initial treatment. Preoperative chemotherapy has been shown in the multicentre LU22 trial to downstage a third of patients but with no improvement in survival vs surgery alone. Post-operative complications and QoL were no worse in the chemotherapy group. A subsequent meta-analysis suggested a 12% survival benefit when compared with surgery alone, equivalent to 5% improvement in 5y survival. It is important, however, not to delay surgery, and current practice is usually to offer surgery followed by adjuvant chemotherapy for selected patients. Chemotherapy may also be given in the context of a trial, aiming to downstage a tumour and allow resection.
Burdett S et al. Chemotherapy and surgery vs surgery alone in NSCLC. Cochrane Database Syst Rev 2007;3:CD006157.Find this resource:
Gilligan D et al. Pre-operative chemotherapy in patients with resectable NSCLC. Lancet 2007; 369:1929–37.Find this resource:
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected NSCLC. N Engl J Med 2004;350:351–60.Find this resource:
May be given for:
• Curative intent (high dose)
• Palliative control (high dose)
• Symptom relief (low dose).
Radiotherapy has no benefit following complete 1° tumour surgical resection.
is high-dose radiotherapy given with curative intent.
• Recommended for patients with localized chest disease <5cm, stages I–III with performance status 0–1 (see Box 31.6), who are resectable but unfit for surgery or do not want surgery
• Various regimes are used in different centres. CHART (continuous hyperfractionated accelerated radiotherapy) delivers small radiation doses tds for 12 days (e.g. 54Gy in 36 fractions over 12 days; patients need to remain inpatient for their treatment; severe dysphagia more likely). Conventionally fractionated radiotherapy delivers, e.g. 66Gy in 33 fractions over 6.5 weeks or 55Gy in 20 fractions over 4 weeks
• Stereotactic ablative radiotherapy (SABR)/stereotactic body radiation therapy (SBRT) allows the delivery of very high radiation doses to small early stage lung cancers, with good local control outcomes. Increasingly used in early stage patients unfit for surgery. The treatment course is shorter (typically given in 3–5 fractions) and is usually associated with an acceptable toxicity profile
• Need PFTs, including lung volume and TLCO before radiotherapy. FEV1 should be ≥1.5l.
High-dose palliative radiotherapy
is given to patients with symptomatic disease, good performance status, no evidence of metastases, and who will be able to tolerate a high-dose regime. An example of such a regime would be 36–39Gy in 12–13 fractions over 6 weeks. Improves median survival by 2 months.
is given for symptom relief in patients who would be unable to tolerate high-dose palliative radiotherapy or those with evidence of metastases. Symptoms palliated include pain, haemoptysis, breathlessness, or cough.
is used in combination with oral steroids for relief of SVCO by tumour, although stenting performed via CT angiography is now the treatment of choice, where possible. Radiotherapy takes ~10 days to be effective.
Limited stage SCLC may be appropriate for surgical resection if there is no evidence of metastases (T1–2a N0 M0). This is rare. It requires further assessment with brain and bone scanning/PET imaging ± bone marrow biopsy if there is an unexplained abnormal FBC. The patient should also be considered for post-operative combination chemotherapy for treatment of micro-metastases, especially if histology was only determined at operation.
Combination chemotherapy is used for limited and extensive SCLC.
• Etoposide with either cisplatin or carboplatin is the standard regime
• Given 3-weekly, commonly for 4–6 cycles
• Different regimes are selected, according to performance status
• Patients with performance status 3 may benefit from less intensive outpatient chemotherapy on a 3-weekly basis
• Patients are carefully assessed, and, if there is no sign of a response to treatment, based on CXR or CT scan, they may be switched to second-line agents, although there is limited evidence of benefit
• Patients with relapsed SCLC but good Ps may be offered anthracycline-containing regimes or further platinum-based treatment for a maximum of six cycles. Oral topotecan is an option if they are unable to tolerate IV chemotherapy. Response rates to second-line chemotherapy are low (~10%)
• 80–90% response if limited disease; 60–80% if extensive disease
• Chemotherapy may increase median survival to 12 months in limited disease.
• Patients with limited stage disease (which is encompassable in a radical radiotherapy volume) with Ps0/1 should have consolidation radiotherapy to the chest disease, with the first or second cycle of chemotherapy. If unfit for combination treatment, give after chemotherapy completion if they have a response or partial response
• Prophylactic cranial radiotherapy is advised at completion of chemotherapy for those with limited disease or those with extensive disease and good prognostic factors. This improves survival by 5.4%
• In patients with extensive disease, including cerebral metastases, or poorer performance status, chemotherapy is given first. If there is a good response, palliative thoracic radiotherapy may be given
• Of benefit to symptomatic bone metastases, cord compression, SVCO.
Radiofrequency ablation (RFA)
applied via a probe inserted into a nodule/tumour under CT guidance, with sedation. Barbs/tines extrude from needle once in the tumour and cause tissue death by thermal necrosis. Lesions initially increase in size and density, and may cavitate, but then become fibrotic scar tissue. May become a tool to treat patients with 1° lung cancer unsuitable for curative surgery/radiotherapy due to comorbid disease, used with radiotherapy. The size of the cancer that can be treated is limited (maximum 5cm, best results with <3cm). Peripheral lesions are easier to access. Side effects of therapy: pleuritic chest pain, pneumothorax, empyema, haemoptysis, haemorrhage, low-grade fever. FEV1 should ideally be >1L. Tumour follow-up with contrast-enhanced imaging, as ablated tissue does not enhance. Used currently mainly in pulmonary metastases from GI or renal cell cancers, or sarcomas, which are not suitable for surgical resection, but also some data for 1° NSCLC. In 153 patients with 1° or metastatic medically inoperable lung cancer, 78% 1y survival rate, 57% 2y, 27% 5y (Simon CJ et al. Radiology 2007;243:268–75). No long-term RCT reported.
such as oral thalidomide, acting as an angiogenesis inhibitor are being tried. These may offer medium-term survival benefits in both SCLC and NSCLC.
Targeted molecular therapy
Lung cancer is said to be at the leading edge of targeted ‘personalized’ molecular therapy, which may become more effective than using traditional cytotoxic agents. The presence or absence of these molecular target molecules seems to determine response to traditional treatments. The cellular targets under investigation include EGFR mutations, ALK translocations, RAS mutations, HER2 mutations, protein kinase C, vascular endothelial growth factor, and cyclo-oxygenase 2. Gene expression profiling may be used to determine the prognosis and response to therapy and to identify the mechanisms of tumour biology. In the future, lung cancer staging may also address the molecular biology of a tumour.
Dy GK, Adjei AA. Novel targets for lung cancer therapy. J Clin Oncol 2002;20:2881–94.Find this resource:
Detterbeck FC et al. Executive Summary. Diagnosis and management of lung cancer, 3rd edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2013;143:7S–37S.Find this resource:
http://www.roycastle.org, patient network, 0333 323 7200.
Obstruction of the flow of blood in the SVC results in the symptoms and signs of SVCO. It is caused by two different mechanisms (which may coexist): external compression or invasion of the SVC by tumour extending from the right lung (four times more common than the left lung), lymph nodes, or other mediastinal structure; or due to thrombosis within the vein.
The commonest cause (~85%) is malignancy. Lung cancer and lymphoma together cause 95% of malignant SVCO.
• Lung cancer Up to 4% of lung cancer patients will develop SVCO at some point during their disease. Up to 10% of SCLC present with SVCO
• Lymphoma Up to 4% of lymphoma patients will develop SVCO, most commonly in non-Hodgkin’s lymphoma. This usually occurs due to extrinsic compression of the SVC by enlarged lymph nodes
• Other malignant causes Thymoma, mediastinal germ cell tumours, tumours with mediastinal metastases (commonest is breast cancer).
include granulomatous disease, intrathoracic goitre, and central venous lines, Port-A-Cath®, and pacemaker wires (causing thrombosis). In the past, SVCO was commonly due to untreated infection, e.g. syphilitic thoracic aortic aneurysm or fibrosing mediastinitis (due to actinomycosis, TB, blastomycosis, or Aspergillus). These are all now rare.
• Facial and upper body oedema, with facial plethora, often with increased neck circumference, and a cyanotic appearance
• Venous distension of the face and upper body. SVCO due to malignancy usually develops over days to weeks, so an adequate collateral circulation does not have time to develop. Pemberton’s sign—facial plethora, distress, and sometimes stridor after lifting the arms above the head for a few minutes—may suggest the diagnosis
• Headache—worse on bending forwards or lying down
• Cough/haemoptysis or other signs of an underlying lung malignancy
• Hoarse voice
• Syncope/dizziness (reduced venous return)
is usually made clinically from the signs of facial and upper body swelling, with distension of superficial veins across the chest wall, neck, and upper arms.
The investigation and treatment of SVCO was previously considered a medical emergency. SVCO is now not considered to be immediately life-threatening, making treatment less urgent and allowing a definitive diagnosis to be made prior to treatment. The exception to this rule is the patient who presents with stridor or laryngeal oedema, which is a medical emergency.
• CXR Up to 85% have an abnormal CXR (as lung malignancy is the commonest underlying disorder). Mediastinal widening is common
• CT chest with contrast can stage the underlying malignancy and image the venous circulation and collateral blood supply
• Histological diagnosis Usual practice is to obtain a tissue diagnosis of the underlying disease before starting treatment, as the underlying diagnosis can alter treatment markedly. Symptomatic obstruction will have been developing for some weeks prior to presentation, and, in the clinically stable patient, a delay of 24–48h, whilst the correct underlying diagnosis is obtained, is warranted. Radiotherapy prior to biopsy can lead to problems making a subsequent histological diagnosis, and, similarly, high-dose steroids can make the diagnosis of lymphoma difficult. Diagnostic samples may be obtained using:
• Pleural fluid cytology
• US-guided biopsy of an extrathoracic lymph node (e.g. supraclavicular or cervical nodes—low risk)
• Bronchoscopy, or mediastinoscopy if no endobronchial disease, may be needed, depending on CT features. There may be increased risk of bleeding post-biopsy because of venous congestion, and anaesthesia is theoretically more risky because of possible associated tracheal obstruction or pericardial effusion (potentially leading to haemodynamic compromise due to cardiac tamponade), though these can be anticipated from the CT scan
See Box 31.7.
depends on the underlying disease and is unrelated to the duration of SVCO at presentation. The majority of SVCO is due to mediastinal spread of carcinoma of the lung, so the overall prognosis is generally poor but depends on the patient’s performance status, stage and extent of disease, and the cell type.
Definition and aetiology
A serum calcium level over 2.75mmol/L is considered abnormal; borderline values need repeating. In malignancy, a raised calcium is due to increased osteoclast activity, either from bony metastases or the production of PTH-related protein. A serum level over 3.25mmol/L is rare outside malignancy although can occur in sarcoidosis.
Values over 3mmol/L are usually symptomatic. Common symptoms are confusion, weakness, nausea, reduced fluid intake, and constipation. There may be a short QT interval on ECG and renal failure.
Exclude other causes of hypercalcaemia, and identify the tumour, although, in most patients with malignant hypercalcaemia, the diagnosis of malignancy will already be known. The PTH will be suppressed in malignant hypercalcaemia but raised in hyperparathyroidism. The phosphate will tend to be low in hyperparathyroidism and hypercalcaemia due to ectopic PTH, and normal/high in sarcoidosis, metastatic bone disease, and with excess vitamin D. Check for renal failure.
See Box 31.8.
Definition and aetiology
Excessive retention of water relative to electrolytes due to inappropriate production of antidiuretic hormone (ADH). Hence, there is hyponatraemia (<135mmol/L), hypo-osmolality, a urine osmolality >100mosmol/kg, a urine sodium concentration usually above 40mmol/L, normal acid–base (and potassium), and usually a low plasma urea concentration. Diuretic-induced hyponatraemia will be accompanied by evidence of dehydration, e.g. raised urea. Causes of SIADH include:
• Drugs, e.g. carbamazepine, fluoxetine, high-dose cyclophosphamide
• Post-major surgery
• HIV infection
• CNS disorders, e.g. stroke, infection, psychosis
• SCLC, either ectopic ADH production or stimulation of normal ADH production (poor prognostic factor).
Lethargy and confusion often when sodium levels fall below 130mmol/L and nearly always when below 120mmol/L.
A low sodium in the presence of a low urea and an appropriate clinical setting may be adequate to make a diagnosis. If sodium depletion/water overload are a possible alternative cause of hyponatraemia, they should be accompanied by a urine osmolarity <100mosmol/kg (or a specific gravity <1.003 or a urine sodium <40mmol/L). Therefore, values increasingly above this are suggestive of SIADH (unless the patient is on loop diuretics when, of course, the urinary sodium concentration will be higher).
See Box 31.9.
This is a medical emergency requiring prompt treatment within 24h to prevent irreversible paraplegia and loss of bowel and bladder function.
Definition and aetiology
Spinal cord compression occurs commonly in patients with metastatic cancer (in about 5% of all cancer patients, particularly breast, lung, and prostate cancer). It may be the first presentation of cancer but often occurs in patients with a known 1° tumour. Cord compression is commonly caused by direct spread from a vertebral metastasis into the extradural space (most commonly, thoracic spine) or, less commonly, from pressure on the cord from a 1° tumour in the posterior mediastinum or the retroperitoneum, or by pressure from a mass of retroperitoneal nodes. It is unusual to have a metastasis within the cord itself, although meningeal spread can occur. Spinal cord compression causes interruption of the arterial supply to the cord and subsequent infarction.
Patients frequently experience back pain initially, due to associated vertebral collapse. This precedes any neurological signs. Pain is not, however, universal. Neurological signs may be non-specific: weak legs, constipation, urinary incontinence. Leg weakness develops over hours to days, with associated sensory loss. Loss of bladder and bowel sensation is a late sign and usually heralds irreversible paraplegia within hours or a few days. Examination reveals bilateral upper motor neurone signs in the legs, with increased tone, weakness, brisk reflexes, and extensor plantars. There may be sensory loss in the legs, particularly with a loss of proprioception and a sensory level on the trunk. Sensory loss in the saddle area, with decreased rectal tone, suggests a cauda equina lesion. The bladder may be palpable.
Have a low threshold for investigating a patient with known cancer with back pain.
• MRI of the spine is the investigation of choice to demonstrate the level of the cord compression
• CT is less reliable but can also be helpful, if MRI is not available
• Plain spine X-ray may show vertebral metastases, but this is usually unhelpful, as there is no imaging of the spinal cord. Time should not be wasted in obtaining a plain X-ray
• Bone scan shows vertebral metastases but again does not image the spinal cord. Earlier scans showing bony metastases may alert the physician to the possibility of future cord compression
• If patient is not known to have underlying malignant disease, a search for a 1° tumour should be performed but must not delay treatment of the spinal cord compression. Take full history (weight loss, anorexia, specific symptoms), and perform full examination, CXR, blood tests, PSA, and myeloma screen.
See Box 31.10.
A Dutch study showed 66% of patients with metastatic cord compression (from all cancers) admitted to rehabilitation centres were discharged and the average survival post-discharge was 808 days. 52% were alive at 1y.
Patients who are mobile at presentation have the best prognosis and are likely to have preserved neurological function following treatment. If there is some preserved motor function, 25% will be able to walk post-treatment. If paraplegia is present pre-treatment, <10% will be able to walk afterwards. Loss of bladder function for >24–48h cannot be reversed.
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These are uncommon 1° lung tumours, comprising 1–2% of all lung tumours. More common in women; typical age at presentation is 40–50y. They are a form of neuroendocrine tumour and can have similar histological appearances to SCLC. Occasionally associated with multiple endocrine neoplasia type 1 (MEN 1).
Although typically slow-growing benign tumours, more aggressive subtypes exist, with metastatic potential. Commonly, they are located endobronchially but can also be located peripherally in the lung parenchyma.
• Endobronchial carcinoids can cause isolated wheeze, dyspnoea, infection, haemoptysis, or persistent lobar collapse
• Parenchymal carcinoids are often asymptomatic, being detected on routine CXR
• Carcinoid syndrome, with flushing, tachycardia, sweats, diarrhoea, wheeze, and hypotension, occurs in 1% of pulmonary carcinoid tumours
• Carcinoid tumours can also be associated with Cushing’s syndrome, due to ectopic tumour ACTH production.
• CXR may reveal a well-defined tumour, which should be further characterized on CT. Tumourlets is the description given to multiple endobronchial or parenchymal carcinoid tumours. PET has decreased sensitivity for detecting carcinoid tumours, compared with NSCLC (75% in one study)
• Bronchoscopy is performed for accessible endobronchial carcinoid tumours. They typically appear to be intraluminal, cherry red, and covered with intact epithelium. Bronchial brushings may be adequate for a histological diagnosis. Bronchial biopsy had been previously thought to be associated with the risk of significant bleeding, although case series suggest the risk is likely to be low. However, some avoid biopsy altogether and proceed to surgical resection, based on a clinical diagnosis. CT-guided biopsy may be preferred for peripheral tumours
• Histological diagnosis can be difficult, as the appearances can be similar to those of SCLC. Special stains and immunohistochemistry are used to help differentiate between the two. Clinically, however, these tend to be quite different conditions, and clinical details can aid pathological diagnosis. Carcinoid tumours are characterized as being typical or atypical. They each have a characteristic pattern:
• Typical carcinoids have no necrosis, occasional nuclear pleomorphism, and absent or late mitoses. Distant metastases are rare, and metastasis to lymph nodes occurs in 5–20% of cases. The 5y survival is 87–100%, and 10y survival is 82–87%
• Atypical carcinoids may show focal necrosis and often have nuclear pleomorphism. There is increased mitotic activity and increased levels of MIB-1 expression (an immunohistochemical marker of cell proliferation). They have distant metastases in ~20% and metastasize to the lymph nodes in 30–70% of cases. The 5y survival is 30–95%, and 10y survival is 35–56%.
• Patients with isolated pulmonary carcinoid tumours should be considered for surgical resection. Resection is ideally limited, removing minimal amounts of normal lung parenchyma. Tumour resection is associated with resolution of any features of the carcinoid syndrome
• If the tumour is atypical or close to the resection margin, patients should be followed up with repeat CXR on an annual basis. Radiotherapy is not performed
• Endobronchial resection may be rarely possible in highly selected patients with an intraluminal polypoid tumour with no CT evidence of an extraluminal component. Careful bronchoscopic and imaging follow-up is essential
• Tumour size does not relate to the presence of lymph node metastases, and, therefore, local lymph nodes should be sampled perioperatively
• In the 1% with carcinoid syndrome, serotonin antagonists, such as octreotide or lanreotide, can be used for treatment. Isolated liver metastases can be treated with resection, arterial embolization, or RFA. Metastatic aggressive carcinoid tumours can be treated with chemotherapy, such as etoposide, cisplatin, and 5-fluorouracil, although limited trial efficacy data mean there is no standard regime. Peptide receptor radioligand therapy (e.g. therapeutic (131)I MIBG or (177)Lu-octreotate) is offered in some centres. Studies are examining the role of other drugs, such as mTOR inhibitors (e.g. everolimus) and tyrosine kinase inhibitors (e.g. sunitinib), with a possible benefit associated with addition of everolimus to long-acting octreotide therapy.
These are focal, round, or oval areas of increased opacity in the lung, measuring <3cm in diameter. They are detected on CXR or CT. Greater use of CT and thinner slice spiral CT scanning has led to increased detection rates. CT allows the precise localization of a nodule and reliable determination of its features. It has a high sensitivity of detecting nodules of >5mm in diameter. Volumetric analysis using CT-aided software means that a 3D nodule can be simulated to aid nodule characterization and assess whether its volume has increased over time.
• The majority of pulmonary nodules are benign (see Table 31.2), although exact numbers depend on the characteristics of the population screened
• 20–30% of patients with lung cancer may present with a solitary pulmonary nodule
• Of the nodules detected on CT in smokers with a normal CXR, between 1% and 2.5% will be malignant
• The Early Lung Cancer Action Project screening programme in the USA used CT scans in over-60-year-olds, with at least a 10 pack year history of smoking, and found non-calcified nodules in 23%, which were seen on CXR in 7%. 11% of these nodules were malignant on biopsy
• Early detection of these malignant nodules might alter the management of the patient, with surgical resection of a stage I cancer.
Table 31.2 Causes of pulmonary nodules
Benign hamartoma (developmental abnormality, containing cartilage, epithelium, and fat. Can contain smooth muscle. Slow-growing. Can be seen at any age, especially 40+; often calcify)
Management options for patients with pulmonary nodules
Baseline CT scan showing nodule >4mm, then repeat after an arbitrary time interval (guided by risk factors e.g. smoking) such as 3 and 12 months, or 3, 6, and 12 months. The Fleischner Society (and recently the ACCP) have proposed suggested follow-up protocols for solitary pulmonary nodules (solid and ground glass), dependent on patient cancer risk and nodule size. If the nodule has increased in size or shows features of malignancy, consider biopsy or proceed straight to surgical resection. PET scan may be helpful, in combination with CT (PET/CT), if the nodule is indeterminate or increasing in size but cannot be biopsied.
useful in lesions >7mm. Malignancy sensitivity >95%, specificity >80%. False positives with granulomatous, infectious, and inflammatory nodules. False negatives with low metabolic activity tumours (e.g. bronchoalveolar cell carcinomas).
Using wedge resection/segmentectomy, if nodule has grown on serial imaging, has high clinical/radiographic likelihood of malignancy or has a positive FDG-PET scan. Nodule may need to be localized preoperatively, using a radiographically placed hook wire or injection of methylene blue.
Factors that suggest a pulmonary nodule is malignant
• Size >1cm
• Smokers, older age
• Increasing volumetrically determined growth rates over time (volume doubling time 30–480 days, although bronchoalveolar cell carcinomas may have doubling time up to 900 days)
• Increased enhancement with contrast, suggesting increased vascularity (>15 Hounsfield units)
• Increased FDG uptake with PET, compared with normal tissue. Estimated sensitivity of PET is 97% for identifying a malignant process
• Occult extrathoracic disease identified on PET scanning
• Irregular or spiculated margin, with distortion of adjacent vessels—the ‘corona radiata’ sign
• Associated ground-glass shadowing
• Cavitation with thick irregular walls
• Pseudocavitation within nodule—bronchoalveolar cell carcinoma.
Factors that suggest a pulmonary nodule is benign
• Stable or decreasing size for 2y
• Nodule resolves during follow-up
• Lack of enhancement with contrast
• Smooth, well-defined margins (although 21% of smooth nodules may be malignant)
• Benign pattern of calcification: central, diffuse solid, laminated, or ‘popcorn-like’—related to prior infections or calcification in a hamartoma
• Intranodular fat—likely hamartoma
• Cavitation with thin smooth walls
• Younger age
• Resident in histoplasmosis endemic areas such as North America.
Pulmonary nodule with extrathoracic malignancy
In a patient with pre-existing malignancy, a pulmonary nodule could be a metastasis, new lung cancer, or benign disease. The histology of the extrapulmonary neoplasm and the patient’s smoking history influence this. These cases need discussion within the cancer MDT to determine whether nodule biopsy or treatment of the underlying 1° cancer would be the most appropriate management.
One study determined the likelihood of a pulmonary nodule being a new 1° or metastasis, based on the site of the original cancer.
• New lung 1° more likely if the 1° tumour is head and neck, bladder, breast, bile ducts, oesophagus, ovary, prostate, stomach
• Metastasis more likely if the 1° tumour is melanoma, sarcoma, testes
• Either new 1° or metastasis possible if the 1° tumour is salivary gland, adrenal, colon, parotid, kidney, thyroid, thymus, uterus.
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This is an area that is currently under investigation. Screening programmes are based on the premise that the early detection of lung cancer and any subsequent intervention will improve the patient’s survival. To be detectable on CXR, a lung cancer needs to be 1cm diameter and 3–4mm diameter to be detectable on CT. Low-dose CT (LDCT) have been used for screening studies, delivering an average dose of 1.5mSv, compared with 8mSv for a standard CT. LDCT finds nodules in 10–50% of those screened, and these have a significant false positive rate of 96.4% (CXR, 94.5%).
There is no evidence of reduction in lung cancer mortality from CXR or sputum cytology screening studies. A recent CT screening study demonstrated a mortality benefit, but this needs confirming in ongoing studies.
• Four previous CXR screening studies in the 1970s were negative, of which the Mayo Lung Project has been the most studied. This compared 4-monthly CXR and sputum cytology for 6y in smokers 45y old or older of 20+/day, with infrequent or no screening in a control group. 206 cancers were found in the study group and 160 in the control group, but all-cause mortality was not affected by screening, even at 20y
• More recent studies have used low-dose spiral CT scanning. The Early Lung Cancer Action Project (ELCAP) in New York recruited 1, 000 symptom-free volunteers aged 60+ with a 10 pack year history of smoking, who would be fit for a thoracotomy. There was no control group. Baseline CXR and CT were performed. Non-calcified nodules were present in 23% of patients at baseline on CT. Repeat CT was performed for nodules <5mm; nodules >6mm were biopsied, and nodules >11mm received standard care. 2.7% of all the patients entered had malignant nodules with stage I disease in 2.3%. All but one patient had their cancer surgically resected
• International ELCAP screened 31, 567 asymptomatic over-40-year-olds at risk for lung cancer between 1993 and 2005. The median age was 61. 13% had a positive result, requiring follow-up at baseline CT and 5% at annual CT. Lung cancer was diagnosed in 1.5% of people (85% stage I), with 411 having resection and 57 having radiotherapy ± chemotherapy. There was no non-treatment randomized control group, so it is still difficult to interpret whether the earlier diagnosis and intervention led to longer survival
• The National Lung Screening Trial (NLST) evaluated annual LDCT vs CXR screening in 53, 454 patients aged 55–74y with a 30 pack year smoking history (including those who quit within 15y), showing a 20% reduction in lung cancer and 6.7% reduction in all-cause mortality in the CT arm. 320 patients would need to be screened to prevent one lung cancer death. Notably, the trial was delivered in specialist centres, with low complication rates, and such mortality benefits may not be reproducible in other centres
• Other randomized trials (e.g. DANTE, NELSON, and the Danish Randomized Lung Cancer CT Screening trials) are ongoing
• Given the results of NLST, the ACCP has recommended that high-risk smokers aged 55–74 should be offered annual LDCT screening, but only if provided in the same care environment as was provided in NLST. CXR and sputum cytology are not recommended. Such screening recommendations are contentious, given ongoing clinical trials, the radiation exposure associated with screening, and lack of evidence for optimal screening duration.
• The role of PET in screening also needs to be evaluated.
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