ACUTE INTERSTITIAL PNEUMONIA 273 Management No treatment demonstrated to be of bene \201 t. In practice, treat infection (i ncluding consideration of unusual organisms) and consider steroids (often given at high dos e, e.g. intravenous methylprednisolone). High \202 ow oxygen. ITU admission and mechanica l ventilatory support usually required. Prognosis Overall mortality at least 50%, although dif \201 cult to predict in individuals. Survivors may stabilize, develop chronic progress ive interstitial lung disease, or experience recurrent exacerbations. 274 CHAPTER 30 Idiopathic interstitial pneumonias Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) De \201 nition \200\230Respiratory bronchiolitis \200\231 is a pathological term referring to the accumula tion of bronchiolar pigmented macrophages in cigarette smokers, and is asymptomatic in near ly all cases. A minority of smokers with respiratory bronchiolitis, however, develop a form of interstitial lung disease known as respiratory bronchiolitis-associated interstitial lu ng disease (RB-ILD). The exact relationship between RB-ILD and DIP is unclear \200\224 they may be considered as different forms of the same underlying disease, with DIP associated w ith a more extensive accumulation of macrophages throughout alveolar spaces. Epidemiology I nvariably occurs in current or previous smokers, typi- cally >30 pack years. Male:female 2: 1. Usual age of onset 30 \200\22340 years. Clinical features \200 \200 \200 Usually mild breathlessness and cough Small proportion have severe dyspnoea and respiratory failure Often crackles on examination. Investigations \200 PFTs often show restrictive or combined obstructive and restrictive picture, with mildly im paired gas transfer CXR Thick-walled bronchi, reticular or ground-glass change, may be norm al HRCT Centrilobular nodules, ground-glass change, thick-walled airways, often with associ ated centrilobular emphysema BAL typically reveals pigmented alveolar macrophages. Histology Accumulation of pigmented brown macrophages in terminal bronchioles. Patchy bronc hiolocentric distribution. These \201 ndings are frequently incidental in smokers, and so the diagnosis of RB-ILD requires consideration of clinical and imaging features in conjunc tion with histology. Management Smoking cessation is the mainstay of treatment. Cortico- st eroids are occasionally used, with uncertain bene \201 t. Prognosis Available data are lim ited; prolonged survival is common, although improvements in symptoms or physiology appear to occur in only a minority of patients. This page intentionally left blank 276 CHAPTER 30 Idiopathic interstitial pneumonias Desquamative interstitial pneumonia (DIP) De \201 nition Interstitial lung disease that oc curs in smokers and is associ- ated with the pathological \201 nding of abundant pigmente d macrophages located diffusely throughout alveolar air spaces. It may represent a more ext ensive form of RB-ILD, in which macrophages are restricted to peri- bronchiolar regions. Th e term DIP is misleading, as desquamation of epi- thelial cells is not responsible for the histological \201 ndings as previously thought; a more accurate term is \200\230alveolar macrophage pneumonia \200\231, although this is not in widespread use. Epidemiology Very r are. Majority of patients are smokers, although may also occur following inhalation of inor ganic dusts, including passive inhalation of cigarette smoke. Typically occurs aged 30 \200 \22350. Clinical features Onset of breathlessness and cough over weeks \200\223 months is t ypical. Clubbing is common. Investigations \200 PFTs Mild restrictive pattern common, sometimes with reduced gas transfer CXR may be normal , or may demonstrate reticular or ground-glass pattern particularly affecting lower zones H RCT Ground glass seen in all cases, typically lower zone or periph- eral predominance. Reti culation and honeycombing may be present, although tend to be mild BAL Increase in pigmente d macrophages. Histology Diffuse accumulation of pigmented macrophages in alveolar air spaces. Changes are uniform. Diagnosis Clinical and HRCT features are non-speci \201 c and surgical lung biop sy is required for diagnosis. Management Smoking cessation. Corticosteroids are often used, although their ef \201 cacy has not been studied. Prognosis Usually good prognosis. Impro vement in ground glass on HRCT may correlate with response to treatment. Survival 70% after 10 years. Fluctuating course with remissions and relapses may occur. This page intentionally left blank 278 CHAPTER 30 Idiopathic interstitial pneumonias Lymphoid interstitial pneumonia (LIP) De \201 nition Interstitial pneumonia characterized by diffuse lymphoid in \201 l- trates and often lymphoid hyperplasia. Previously considere d to be a precursor to pulmonary lymphoma, and dif \201 cult to distinguish from lym- phom a histologically, it is now considered a distinct entity and is thought to only rarely unde rgo neoplastic transformation. Epidemiology Very rare. Commoner in women. May occur at any age. Causes/associations \200 \200 Idiopathic Connective tissue disease \200\224particularly Sj gren \200\231s syndrome, also rheu- matoid arthritis, SLE Immunode \201 ciency, e.g. HIV Infection, e.g. PCP, hepatitis B Autoimmune disease, e.g. haemolytic anemia, Hashimoto \200\231s thyroiditis, pernicious anemia, chronic active hepatitis, primary biliary cirrhosis, myasthenia gravis Drugs. \200 \200 Clinical features Gradual onset breathlessness and cough over several years. Fever, weight loss may occur. Crackles may be heard on examination. Investigations \200 Blood tests Mild anemia may occur; poly- or monoclonal increase in serum immunoglobulins is common CXR Lower zone alveolar shadowing or diffuse honeycombing HRCT Predominant ground-g lass change, often with reticulation and sometimes honeycombing and nodules BAL Non-clonal lymphocytosis Investigations to identify underlying cause (see above). \200 \200 Histology Diffuse in \201 ltrates, predominantly involving alveolar septa, sometimes with lymphoid hyperplasia or honey- combing. Cellular NSIP, follicular bronchiolitis, and lympho ma may give similar appearances. Management Steroids are frequently used and often appear t o improve symptoms. Prognosis Progression to extensive \201 brosis occurs in around one-t hird of patients. interstitial lymphoid 279 Chapter 31 Lung cancer Epidemiology and types 280 Clinical features 282 Investigations 284 Diagnostic procedures 2 86 Staging 288 Non-small cell lung cancer (NSCLC): surgery 290 NSCLC: chemotherapy 292 NSCL C: radiotherapy 294 Small cell lung cancer: treatment 296 Lung cancer: emerging areas 298 S uperior vena caval obstruction (SVCO): etiology and clinical assessment 300 Hypercalcaemia 304 Syndrome of inappropriate secretion of ADH (SIADH) 306 Spinal cord compr ession 308 Pulmonary carcinoid tumors 310 Pulmonary nodules 1 312 Pulmonary nodules 2 314 L ung cancer screening 316 CHAPTER 31 Lung cancer 280 Epidemiology and types Epidemiology \200 \200 \200 Nearly 38, 000 new cases diagnosed per annum in the UK Commonest cause of cancer death in m en and women in the UK 2:1 male:female, 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 rema ins higher than in non-smokers Risk of lung cancer may be increased by asbestos exposure, a rsenic and heavy metal exposure, and coexistent idiopathic pulmonary \201 brosis (IPF). \200 Types of lung cancer In practical terms, lung cancer is divided into two groups, which in \202 uence management and treatment decisions. Non-small cell lung cancer (NSCLC) \200 \200 Accounts for 75 \200\22380% of all lung cancers Squamous cell carcinoma is the commonest hi stological type. Usually presents as a mass on CXR, but may cavitate and look radiologicall y like a lung abscess. Rarely, there may be multiple cavitating lesions. Patients with hype rcalcaemia are most likely to have squamous cell carcinoma Adenocarcinoma may not necessari ly be smoking-related. Can occur in scar tissue or sites of \201 brosis. Can be a lung pr imary or a secondary from adenocarcinomas at other sites, especially if causing pleural in \201 ltration and subsequent pleural effusion Alveolar cell carcinoma is rare. It can rare ly cause copious sputum production (bronchorrhoea). Typically causes \202 uffy air space shadowing on CXR. Small cell lung cancer (SCLC) \200 \200 \200 \200 Accounts for 20 \200\22325% of all lung cancers Most aggressive of lung cancer subtypes Usu ally disseminated by the time of diagnosis (haematogenous spread) Frequently metastasizes t o liver, bones, bone marrow, brain, adrenals, or elsewhere Syndrome of inappropriate secret ion of antidiuretic hormone (SIADH) with hyponatraemia is common in small cell lung cancer Surgery usually not appropriate Chemo- and radiosensitive Untreated extensive stage small c ell lung cancer is rapidly progressive and has a median survival of 6 weeks. \200 \200 EPIDEMIOLOGY AND TYPES 281 WHO histological classi \201 cation of lung tumors, 2004 \200 \200 \200 \200 \200 \200 \200 \200 \200 Squamous cell carcinoma Small cell carcinoma Adenocarcinoma Large cell carcinoma Adenosquam ous carcinoma Sarcomatoid carcinoma Carcinoid tumors Salivary gland tumors Pre-invasive les ions. CHAPTER 31 Lung cancer 282 Clinical features Smokers and ex-smokers with chest symptoms, especially those aged over 50 , need investigation. Symptoms and signs These may be due to local tumor effects, metastatic tumor effects, or pa raneoplastic manifestations. Many patients have no speci \201 c signs. In some, the lung c ancer may be an incidental \201 nding on CXR performed for another reason. Local tumor effects \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Persistent cough, or change in usual cough Haemoptysis Chest pain (suggests chest wall or p leural involvement) Unresolving pneumonia or lobar collapse Unexplained dyspnoea (due to br onchial narrowing or obstruction) Wheeze or stridor Shoulder pain (due to diaphragm involve ment) Pleural effusion (due to direct tumor extension or pleural metastases) Hoarse voice ( tumor invasion of the left recurrent laryngeal nerve) Dysphagia Raised hemi-diaphragm (phre nic nerve paralysis) SVCO (see p 300) Horner \200\231s syndrome (meiosis, ptosis, enopthalm os, anhidrosis) due to apical or Pancoast \200\231s tumor Pancoast \200\231s tumors can dir ectly invade the sympathetic chain, brachial plexus, and rib. Cause weakness of small muscl es of the hand \200\224C5/6, T1 motor loss, and shoulder pain Metastatic tumor effects \200 Cervical/supraclavicular lymphadenopathy (common, present in 30%, and may be an easy site f or diagnostic biopsy) Palpable liver edge Bone pain/pathological fracture due to bone metas tases Neurological sequelae secondary to cerebral metastases (median sur- vival of NSCLC wi th brain metastases is 2 months) Hypercalcaemic effects (due to bony metastases or direct t umor production of parathyroid-hormone-related peptide or parathyroid hormone) see p 304 Dy sphagia (compression from large mediastinal nodes) \200 \200 Paraneoplastic syndromes Endocrine syndromes are due to the ectopic production of hormones or hormonally active peptides. Neurological syndromes are due to antibody mediated CNS dama ge. \200 Cachexia and wasting \200 Clubbing (up to 29% of patients; any cell type, more common in squamous and adenocarcinoma) Gynaecomastia SIADH (mainly SCLC) in up to 15% of p atients see p 306 \200 CLINICAL FEATURES 283 Ectopic ACTH (Cushing \200\231s syndrome, but due to rapid development; biochemical changes predominate, mainly SCLC) in 2 \200\2235% of patients Hypertrophic pulmonary osteo-arthrop athy (HPOA, often in asso- ciation with clubbing, any cell type; more common in squamous an d adenocarcinoma) Lambert \200\223Eaton myasthenic syndrome (or LEMS) \200\224with SCLC. Af fects proximal limbs and trunk, with autonomic involvement (dry mouth, constipation, erecti le failure) and hypore \202 exia (although re \202 exes return on exercising the affected muscle group), and only a slight response to edrophonium. Symptoms may predate lung cancer by up to 4 years. Caused by auto-antibodies against P/Q-type voltage-gated calcium chan- n els. Decreased acetylcholine release at motor nerve terminals leads to the proximal weaknes s. Diagnosis made by auto-antibody detection on radio-immunoprecipitation assay. EMG shows increased amplitude of muscle action with high frequency stimulation and repeated muscle co ntraction may lead to increasing strength and re \202 exes. Treatment of underlying SCLC c auses neurological improvement. If weakness is severe, IV immunoglobulin or plasmapheresis may give short-term bene \201 ts. 3,4-Diaminopyridine may increase muscle strength in 85% of patients. Prednisolone alone or with azathioprine or ciclosporin can increase muscle str ength and provide long-term control in non-responders Cerebellar syndrome (usually SCLC) Li mbic encephalitis (SCLC, also breast, testicular, other cancers. Occurs within 4 years of d iagnosis of cancer. Personality change, seizures, depression, sub-acute onset confusion and short-term memory loss. Diagnosed by pathological or radiological involvement of limbic sy stem. Anti-Hu antibodies positive in 50% if associated with lung cancer.) Glomerulonephriti s. \200 Lymphangitis carcinomatosa In \201 ltration of pulmonary lymphatics by tumor. May be due t o lung cancer or breast, prostate, stomach, or pancreatic malignancies. Causes shortness of breath, cough, and is often associated with systemic signs of advanced malignancy. May be visible on CXR as \201 ne linear shadowing throughout both lung \201 elds. Septal lines present. May look like pulmonary oedema. Easily diagnosed on CT. Oral steroid treatment an d diuretics can give symptomatic relief, but it is usually a short-lived response. Often pa rt of a rapid decline. Further information Maddison P, Newsom-Davies J. Treatment for Lambert \200\223Eaton myasth enic syndrome. Cochrane Database Syst. Rev 2005: CD003279 CHAPTER 31 Lung cancer 284 Investigations Patients should be referred under the \200\2302-week cancer wait \200\231 s cheme and should be seen within 14 days of referral. The aim of the investigations is to re ach a histological diagnosis and tumor stage, in order to determine the most appropriate tr eatment. Current government guidelines recom- mend patients should receive treatment withou t undue delay: within 31 days of the decision to treat and within 62 days of their urgent r eferral. In out-patients \200 \200 \200 History and examination, including smoking and occupational histories Spirometry pre-biopsy or surgery CXR (PA and possibly lateral) \200\224location of lesion, pleural involvement, pleural effusion, rib destruction, intrathoracic metastases, mediastinal lymphadenopathy. C XR can be normal Blood tests, including sodium, calcium, and liver function tests. Check cl otting if biopsy planned Sputum cytology only indicated in patients who are un \201 t for bronchos- copy or biopsy Diagnostic pleural tap, if effusion present Fine-needle aspiration of enlarged supraclavicular or cervical lymph nodes. \200 Radiology \200 CT chest, liver, adrenals (contrast-enhanced) to assess tumor site and size Lung cancers fr equently metastasize to the mediastinal lymph nodes, liver, and adrenals. CT can locate les ions amenable to biopsy (either the primary tumor or a metastasis). Assesses size of local and regional lymph nodes. Poor at assessing whether enlarged nodes are reactive (in \202 a mmatory) or represent metastatic spread (79% sensitive, 78% speci \201 c). Can assess tumo r invasion to mediastinum and chest wall Ultrasound scan of neck or liver may provide infor mation about enlarged lymph nodes or metastases suitable for biopsy MRI Used to answer spec i \201 c questions relating to tumor invasion/ borders. Good for assessing brachial plexus involvement. No role in nodule assessment Bone scan Indicated if any suggestion of metasta tic disease, such as bony pain, pathological fracture, hypercalcaemia, raised alkaline phos phatase. Highly suggestive of bony metastases if multiple areas of increased uptake. Solita ry lesion may require further evaluation CT head Only indicated if any neurological evidenc e of metastatic disease, such as persistent vomiting, \201 t, focal neurological signs, h eadache, unexplained confusion, or personality change, especially if aggressive local treat ment is considered for primary tumor Positron emission tomography (PET scanning) Imaging te chnique, where metabolically active tissues such as tumors take up more of a radiolabelled 18- \202 uorodeoxyglucose (FDG) molecule. They then show as a \200\230hot-spot \200\231. Improves the rate of detection of local and distant metastases in patients with NSCLC. Usef ul for assessing regional and mediastinal lymph nodes (88% sensitive, 93% speci \201 c). T his is increased INVESTIGATIONS 285 if abnormal nodes are identi \201 ed on CT. Becoming more widely used and should be interp reted with the CT. Perform in: \200 All patients considered for radical therapy to look for involved lymph nodes and distant me tastases Patients with N2 \200\2233 disease on CT of uncertain signi \201 cance, who are o therwise surgical candidates Candidates for radical radiotherapy Limited stage SCLC staged by standard staging methods to identify metastases, as SCLC avidly takes up FDG \200 PET positive nodes that would exclude a patient from surgery should be con \201 rmed as ma lignant with a biopsy, unless the pre-test probability of malignancy is high. PET may revea l a distant abnormality other than the primary lung cancer, which could be a solitary metas tasis or a second cancer. It is important therefore to biopsy isolated PET abnormalities be fore determining that a patient \200\231s cancer is not resectable False negatives occur in tumors with a low metabolic activity (such as bronchoalveolar cell , 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 4 h before the test and if they have diabetes, glucose should be within the n ormal range Multidisciplinary team (MDT) Should include a chest physician, radiologist, thoracic surgeo n, oncologist, pathologist, lung cancer nurse, and palliative care specialist, who meet reg - ularly in order to discuss patients and plan the most appropriate course of management. The Department of Health in the UK has produced guidelines for performance in lung cancer c are. These encourage access to the MDT in decision making for the treatment and investigati on of all patients with lung cancer. Further information NICE lung cancer guidelines 2005. www.nice.org.uk Giving information to lung cancer patients. BTS Lung Cancer and mesothelioma Specialist Adv isory Group. April 2008. www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/ Lung%20 Cancer/WTSTPBTS \201 nds210408.pdf CHAPTER 31 Lung cancer 286 Diagnostic procedures Investigations are performed to obtain a tissue diagnosis and to stag e 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 metasta tic spread at a single test is desirable if possible. 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. Bronchoscopy Method of obtaining histological and cytologica l speci- mens. Suitable for central tumors. Tumors can be washed, brushed, and biopsied. Br onchoscopic samples are more likely to be histologically positive if there is: \200 \200 \200 \200 An ill-de \201 ned lesion on the CXR An endobronchial component to the tumor Tumor less th an 4 cm 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 b e targeted. Tumor position bronchoscopically may contribute to operative decisions: tumor c on \201 ned to a lobar bronchus may be resectable with lobectomy, tumor <2 cm from the mai n carina requires pneumonectomy, left vocal cord paralysis indicates inoperability due to t umor in \201 ltration of the left recurrent laryngeal nerve, and a splayed carina occurs s econdary to enlarged mediastinal nodes. Transbronchial needle aspiration of lymph nodes can be performed to aid staging at the time of bronchoscopy. Also EUS-FNA (endoscopic ultrasou nd guided \201 ne-needle aspirate) or endoscopic bronchial ultra- sound (EBUS) \200\224al l may reduce need for mediastinoscopy/otomy and are less invasive (see p 754). CT/USS-guide d biopsy of tumor or of an enlarged lymph node, especially in the neck, or of a metastasis (see box opposite). 85 \200\22390% sen- sitivity in lesions >2 cm. Biopsy of a metastasis g ives valuable staging infor- mation as well as also diagnosing the primary. Mediastinoscopy Biopsy of enlarged mediastinal lymph nodes to determine whether they are in \202 ammatory or have malignant invasion. Suprasternal notch incision under general anesthetic, blunt di ssection, palpation, and endoscopic visualization and biopsy of nodes: paratracheal, prevas cular, tracheobronchial, and anterior subcarinal. 93% sensitivity, 96% speci \201 city. Te chnically more dif \201 cult if SVCO. Bleeding in <0.3%, left recur- rent laryngeal nerve injury in 1%, pneumothorax, mediastinal emphysema, infection, oesophageal perforation (all rare). Repeat mediastinoscopies have lower positive yield and higher complication rate. Med iastinotomy Biopsy of aorto-pulmonary, sub-aortic, phrenic, or hilar nodes. Metastatic invo lvement of these nodes does not necessarily preclude curative surgical resection with a pne umonectomy. Also can assess direct tumor invasion of central pulmonary artery or thoracic a orta, which would preclude curative surgery. Right or left parasternal DIAGNOSTIC PROCEDURES 287 incision, blunt dissection, palpation, and endoscopic visualization and biopsy of nodes. Th oracoscopy may be required to determine whether a pleural effusion contains malignant cells or is in \202 ammatory, for example, due to pneu- monia caused by an obstructing lesion. Malignant effusions are evidence of T4 disease and hence are a contraindication to surgery. Operative It is sometimes dif \201 cult to obtain de \201 nitive cytology or his- tology pre-operatively. If there is a high suspicion of malignancy, surgery can be performed rega rdless. Patients undergoing surgery are given a pathological stage, which is sometimes diff erent to the clinical stage. This is because resection margins, lymph nodes, and the pleura can be sampled histologically. Radiologically guided lung biopsy Indications \200 \200 \200 \200 New or enlarging mass, not amenable to bronchoscopy Multiple chest nodules in patient not k nown to have malignancy Persistent undiagnosed single or multiple focal in \201 ltrates Hi lar mass. Pre-biopsy preparation \200 Discuss with MDT \200 Recent spirometry, with FEV1 >35% pre dicted \200 Check APTT and PT ratios <1.4 and platelets >100 000/mL. If not, discuss with hematologist to determine whether it is safe to proceed Recent imaging available High risk patients should have overnight admission following biopsy Written information for patient, with informed signed consent. \200 \200 Biopsy preparation \200 \200 \200 \200 Perform without sedation if possible Use USS if possible Local anesthetic to skin and subcu taneous tissue Perform at least two passes, may use FNA or cutting needle. FNA high diagnos tic yield for malignant lesions (95%), but less for benign (10 \200\22350%). Cutting needle s as good for malignancy and better for benign diagnoses. Operator decision. Post-biopsy \200 \200 \200 Observation by staff for 1 h in case of complications Erect CXR 1 h after biopsy and review ed by doctor Manage any pneumothorax according to BTS guidelines (p 373). Small pneumothora ces often resolve spontaneously, but may need in-patient admission if there are concerns. Complications \200 \200 20% chance of pneumothorax, 3% require chest drain Haemoptysis 5%, death 0.15%. Manhire A et al. Guidelines for radiologically guided lung biopsy. Thorax 2003: 58: 920 \200\22334 CHAPTER 31 Lung cancer 288 Staging Clinical and radiological tools categorize tumor size, location, regional and dista nt spread, and aid determination of most appropriate treatment. They can also therefore giv e prognostic information. \200 Small cell lung cancer is staged as: \200 Limited con \201 ned to ipsilateral hemi-thorax and supraclavicular lymph nodes. Median su rvival with treatment 12 months, without treatment 12 weeks Extensive everything else. Medi an survival with treatment 8 months, without treatment 6 weeks Non-small cell lung cancer is commonly classi \201 ed using TNM staging system (see box op posite). Frequency of patient stage at diag- nosis: \200 \200 \200 I and II \200\22420% III \200\22435% IV \200\22445%. Table 31.1 Lung cancer clinical staging and survival Stage TNM subset After treatment survival (%) 1 year 5 years 0 Tis ? ? IA T1 N0 M0 91 61 IB T2 N0 M0 72 38 IIA T1 N1 M0 79 34 IIB T2 N1 M0 61 24 T3 N0 M0 55 22 IIIA T1 N2 M0 50 13 T2 N2 M0 50 13 T3 N1 \200\2232 M0 56 9 IIIB T4 N0 \200\2232 M0 37 7 T1 \200\2234 N3 M0 32 3 IV Any T, Any N, M1 20 1 STAGING 289 TNM Staging of Lung Cancer (American Joint Committee on Cancer and the Union Internationale Contre le Cancer) Extent of primary tumor (T) Tx Primary tumor cannot be assessed, or tumor proven by pres- e nce of malignant cells in sputum or bronchial washings but not visualized by imaging or bro nchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor <3 cm surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar br onchus T2 Tumor >3 cm, or in main bronchus, >2 cm distal to carina or invading visceral pleura, or associated with atelectasis or obstruc- tive pneumonitis that extends to the hilar region, but does not involve whole lung T3 Tumor of any size which invades chest wall, diaphragm, parietal pericardium, mediastinal pleura, or tumor in main bronchus <2 cm distal to carina, or associated atelectasis or obs tructive pneumonitis of the entire lung T4 Tumor of any size invading: mediastinum, heart, great vessels, trachea, esophagus, carin a, vertebral body, or separate nodules in the ipsilateral lobe as primary tumor, or maligna nt pleural or pericardial effusion Regional lymph nodes (N) Nx Cannot be assessed N0 No regional lymph node metastasis N1 Ipsilateral peribronchial and/or ipsilateral hilar nodes and intra- pulmonary nodes involve d by direct extension of tumor Ipsilateral mediastinal and/or subcarinal nodes Contralatera l mediastinal, hilar nodes, or any scalene or supra- clavicular nodes N2 N3 Distant metastasis (M) Mx Cannot be assessed M0 No distant metastasis M1 Distant metastasis present, including separate nodules in different lobes Further information Mountain CF. Revisions in the International System for staging lung can cer. Chest 1997; 111: 1710 \200\22317 Mountain CF, Dresler CM. Regional Lymph Node Classi \201 cation for Lung Cancer Staging. C hest 1997; 111: 1718 \200\22323 CHAPTER 31 Lung cancer 290 Non-small cell lung cancer (NSCLC): surgery Much of the investigation of lung cancer is to determine whether a patient has disease that is potentially curable by surgery. Other treat ment options include chemotherapy, radiotherapy, and best supportive care, i.e. symptom-bas ed conservative management. The MDT decides the most appropriate choice of treatment which is then discussed with the patient. Surgery The aims of surgery for lung cancer are to completely excise the tumor and local ly mphatics, with minimal removal of normal functioning lung parenchyma. \200 Stages I and II non-small cell lung cancers are usually amenable to surgery if the patient is \201 t enough (see below). This has a high chance of cure in stage I (70% in IA), and a reasonable chance in stage II. 10 \200\22320% of NSCLC patients undergo resection In stag e IIIA tumors, surgery alone is unlikely to be curative, but adjuvant chemotherapy and radi otherapy can improve survival rates. These patients should be recruited to clinical trials Stages IIIB and IV are inoperable Stages 0/tumor in situ often will have no de \201 ned pr imary lesion amenable to resection. The natural progression of these tumors is still unknow n; they may progress or regress with time. \200 Resectability of a tumor implies likelihood of complete removal by surgery; this is differe nt from patient operability, which is determined by the patient \200\231s \201 tness for surgery. Fitness for surgery \200 Age is not a contraindication, but increasing age is associated with an increased peri-oper ative morbidity. Higher mortality risk if over 80 and if pneumonectomy, rather than lobecto my (14% mortality vs 7%, respectively). Right pneumonectomy has higher mortality than left pneumonectomy (more lung removed). 2-year post-operative survival similar to that of other age groups Lung function FEV1 >1.5 L post-bronchodilator for lobectomy, >2 L post-bronchodi lator for pneumonectomy or more than 60% of pre- dicted. Borderline cases may require furth er lung function assessment (arterial saturations, full PFTs including TLCO, isotope perfus ion scan, exercise testing) in order to calculate whether predicted post- operative FEV1 >4 0% in association with TLCO >40% Cardiovascular Postpone surgery if patient has had MI with in 6 weeks. Cardiology opinion if patient has had MI within 6 months. Echo if they have hea rt murmur. Pre-operative ECG for all CNS If any history of TIAs, strokes, or carotid bruits : need carotid Doppler studies and vascular surgeon opinion if necessary Nutritional Requir ements should be optimized, with advice from a dietician if necessary. Patients presenting with a pre-operative weight loss of 10% or more performance status \211 2 are more like ly to have advanced disease or comorbidities. Therefore require careful staging and search for evidence of comorbidity. NSCLC: SURGERY 291 Types of surgery Lobectomy or bi-lobectomy for localized tumor, or pneumonectomy for tumor involving more than one or two lobes. If hilar nodes are in \201 ltrated by tumor a more r adical lobectomy or a pneumon- ectomy is required. The local lymph nodes are removed in eac h procedure for pathological staging. Wedge excision removes only the tumor with minimal su rrounding lung parenchyma, and may be performed for a local- ized peripheral lesion with cl ear regional lymph nodes, especially if the post-operative respiratory function is predicte d to be borderline: there is a higher local recurrence rate, however (up to 23%). Sleeve re sections involve a lobectomy and the removal of a section of bronchus affected by tumor, fo rming an anastomosis between the airway proximal and distal to it. This may avoid a pneumon ectomy. Resection margins should be macroscopically free from tumor. If there is limited lo cal tumor invasion to the chest wall, this can be resected with a 5-cm margin. Reconstructi on with prosthetic material may be necessary if 2 or more ribs are resected, aiming to pres erve the chest wall function. Post-operative complications Bronchopleural \201 stula, respiratory failure, infection, p hrenic nerve damage causing diaphragmatic paralysis, recurrent laryngeal nerve damage causi ng hoarse voice, prolonged chest wall pain. Mortality: 1 \200\2233.5% for wedge excision, 2 \200\2234% for lobectomy, 6 \200\2238% for pneu- monectomy. Risk increases with increasing age, associated ischaemic heart disease, impaired respiratory function, and poor performan ce status. Following surgery Patients are often followed up by the chest clinic on a 6 \200\22312-mont hly basis for CXR review for 5 years (although there is no clear evidence on the necessity of such prolonged follow up in lung cancer). This is to ensure they are radiologically clea r of tumor recurrence, and there is not a second primary tumor. They should also be advised to seek earlier review if they have symptoms of persistent haemoptysis or new cough, weigh t loss, new chest pain. If histology shows incomplete resection margins, post-operative rad iotherapy would be given to try and improve local disease control. Further information BTS/SCTS. Guidelines on the selection of patients with lung cancer for surgery. Thorax 2001; 56: 89 \200\223108 CHAPTER 31 Lung cancer 292 NSCLC: chemotherapy Consider in patients with stage III \200\223IV disease, WHO performance status 0 \200\2232 (see p 295), even if they are asymptomatic from their cancer (greater t oxicity in those with poorer performance status). 40% respond tempo- rarily. Small improvem ent in symptom control and quality of life com- pared with best supportive care shown in RC Ts. Limited survival gains, 6 \200\2237 weeks compared with best supportive care. Median su rvival with chemotherapy in stage IV lung cancer: 10 months (Ps0), 7 months (Ps1), 4 months (Ps2). Combination chemotherapy (the use of more than one drug) is superior to single agent chemot herapy, improving survival rates when compared with single agent at 6 and 12 months (51% vs . 49% and 25% vs. 22%, respectively). \200 Commonly used \201 rst-line regimens include gemcitabine or vinorelbine plus a platinum-c ontaining drug (carboplatin or cisplatin), usually given for 4 cycles Side-effects Nausea, myelosupression, ototoxicity, peripheral neuropathy, nephropathy if dehydrated. No alopecia Patients are monitored during chemotherapy with repeat CT, usually after 2 cycles, to esta blish whether they have partial response, stable disease, or progressive disease, despite c hemotherapy. This CT in \202 uences decisions regarding further chemotherapy Second-line t reatments can be given in patients who relapse and are of good performance status. Taxanes (paclitaxel, docetaxel) are the most commonly used agents. These cause alopecia. Adjuvant therapy is the use of radiation or chemotherapy following complete surgical resect ion to improve survival. Adjuvant chemotherapy has been found to have signi \201 cant surv ival advantages compared with surgery alone in recent trials, including International Adjuv ant Lung Cancer Trial and Japan Lung Cancer Research group. Those with stage IB or stage II disease had a 69% 5-year survival vs. 54% in those treated with surgery alone. This treatm ent is now offered to patients with completely resected stage IB, II, and IIIa NSCLC. Adjuv ant radiotherapy trials have shown no evidence of a survival bene \201 t, except possibly in those with N2 disease. Should only be given in the context of a trial. Neo-adjuvant chem otherapy uses a non-surgical therapy (radio- therapy/chemotherapy) as the initial treatment . Pre-operative chemo- therapy has been shown in the recent multi-center LU22 trial to down stage a third of patients, but with no improvement in survival vs. surgery alone. Post-oper ative complications and quality of life were no worse in the chemotherapy group. A subseque nt meta-analysis suggested a 12% survival bene \201 t when compared with surgery alone, eq uivalent to 5% improve- ment in 5 year survival. It is important, however, not to delay sur gery and it is unclear as yet whether these results will change current practice. Chemother apy may also be given in the context of a trial, if surgery is not initially feasible due t o stage IIIa disease, aiming to downstage the tumor and allow resection. Unclear survival b ene \201 ts thus far. NSCLC: CHEMOTHERAPY 293 EGFR inhibitors EGFR (epidermal growth factor receptor) is an important mediator of cell gr owth, differentiation, and survival. It is over- expressed in 40 \200\22380% of NSCLC patie nts. New EGFR inhibitors include: \200 Ge \201 tinib (Iressa) Oral preparation used vs. placebo in patients refractory or intoler ant of their latest chemotherapy. No signi \201 cant difference in median survival time be tween the two groups Erlotinib (Tarceva) Shown to signi \201 cantly improve survival in pa tients with previously treated stage IIIB or IV NSCLC vs. placebo (6.7 vs. 4.7 months, p = 0.001). No bene \201 t shown in combination with chemo- therapy as a \201 rst-line treat ment. Used as second- or third-line therapy in NSCLC, but funding issues in UK. Response evaluation criteria in solid tumors (RECIST) \200\224 method of measuring response of a tumor to treatment (particularly in chemotherapy trials) Target lesion = all measurable lesions up to a maximum of 5 lesions per organ and 10 lesion s in total, representative of all involved organs. Record and measure sum of their longest diameter. Non-target lesions = all other sites of disease, which are recorded at baseline. Measurements of these lesions are not required, but presence or absence of each is noted du ring follow-up. Evaluation of target lesions \200 \200 Complete response (CR) \200\224disappearance of all target lesions Partial response (PR) \200\224at least a 30% decrease in the sum of the longest diameter of target lesions Progre ssive disease (PD) \200\224at least a 20% increase in the sum of the longest diameter of ta rget lesions Stable disease (SD) \200\224neither suf \201 cient shrinkage to qualify for P R, nor suf \201 cient increase to qualify for PD. Evaluation of non-target lesions \200 Complete response (CR) \200\224disappearance of all non-target lesions and normalization of tumor marker level Incomplete response/stable disease (SD) \200\224persistence of one or m ore non-target lesion(s) and/or maintenance of tumor marker level above the normal limits P rogressive disease (PD) \200\224appearance of one or more new lesions and/or unequivocal pr ogression of existing non-target lesions. Further information Burdett S et al. Chemotherapy and surgery vs. surgery alone in NSCLC. C ochrane Database Syst Rev 2007; 3: CD006157 Gilligan D et al. Pre-operative chemotherapy in patients with resectable NSCLC. Lancet 2007 ; 369: 1929 \200\22337 The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected NSCLC. NEJM 2004; 350: 351 \200\22360 NSCLC Collaborative Group. Chemotherapy in NSCLC: a meta-analysis using updated data on ind ividual patients from 52 randomized clinical trials. BMJ 1995; 311: 899 \200\223909 CHAPTER 31 Lung cancer 294 NSCLC: radiotherapy May be given for: \200 \200 \200 Curative intent (high dose) Palliative control (high dose) Symptom relief (low dose). Radiotherapy has no bene \201 t following complete primary tumor surgical resection. CHART (continuous hyperfractionated accelerated radiotherapy) is high- dose radiotherapy gi ven with curative intent. \200 