Lung cancer is the second most common form of cancer in the UK (after skin cancer).

Causes

Smoking of tobacco is the main cause of lung cancer. Passive smoking (the inhalation of tobacco smoke by non-smokers) and environmental pollution (with radioactive minerals or asbestos, for example) are also risk factors.

Types

There are several types of lung cancer, each of which affects a different group of lung cells. The most common types are squamous cell carcinoma and small cell (or oat cell) carcinoma; the other main types are adenocarcinoma and large cell carcinoma. Each form of lung cancer has a particular growth pattern and response to treatment. Small cell carcinoma is the most highly malignant form of lung cancer; it grows rapidly and spreads very quickly throughout the body. In contrast, squamous cell carcinoma grows more slowly than the other forms and does not spread outside the lung until late in the course of the disease.

Symptoms 

The first and most common symptom of lung cancer is a persistent cough. Other symptoms include coughing up blood, shortness of breath, and chest pain. The tumour may obstruct the airway, causing pneumonia (inflammation in the lung), or involve the pleura (the double-layered membrane covering L the lung), causing an accumulation of fluid called pleural effusion. A tumour developing at the top of the lung may press on the nerves supplying the arm on that side, causing pain and weak- ness in the arm. Lung cancer can spread to other parts of the body, especially the liver, brain, and bones, causing pain and other problems in these areas.

Diagnosis and treatment

In most cases, the cancer is revealed in a chest X-ray or diagnosed from abnormal cells in a sputum sample. A doctor may also perform a bronchoscopy to view inside the airways. To confirm the diagnosis, a biopsy (tissue sample) is taken and is examined microscopically for the presence of cancerous cells (see cytology). Blood tests, and CT scanning or MRI, may be used in order to determine whether or not the cancer has spread to other areas. If lung cancer is diagnosed at an early stage, pneumonectomy (removal of the whole lung) or lobectomy (removal of the diseased lobe of the lung) may be a possibility. Surgery is usually considered only in cases in which the tumour is still relatively small and has not spread beyond the lung.

Anticancer drugs and radiotherapy may be used in order to contain the spread of the tumour and to treat any metastases (cancerous cells that have spread to other areas of the body). Small cell carcinoma is usually treated by means of radiotherapy and chemotherapy.

Noncancerous tumours

Noncancerous tumours occur less frequently than cancers. The most common of these tumours is a bronchial adenoma, which arises in the lining of a bronchus. Adenomas often cause bronchial obstruction; affected people may also cough up blood. Treatment of adenoma involves surgical removal of the tumour. Other rare noncancerous tumours include fibromas (which consist of fibrous tissue) and lipomas (which consist of fatty tissue). No treatment is necessary for these, unless the tumours are causing problems.

Lung cancer-small cell - non-technical article

Lung cancer-non-small cell - non-technical article

Lung cancer in detail - technical

Essentials 

Lung cancer is the most common malignant disease in the Western world. It has shown the greatest relative and absolute rise in mortality of any tumour this century in England and Wales, and particularly in Scotland. It causes 38 000 deaths per year in England and Wales, with 80% of these occurring in men. In the European Union there are 1.35 million deaths per year in men (the highest death rate from any tumour), and in women in 1995 it accounted for 24% of all female cancer deaths. In the United States of America it has been increasing in incidence by up to 10% per year since the 1930s, but over the last decade this trend has levelled off, particularly in men. Nevertheless, about 120 000 American men die of lung cancer each year, the figure for women being 34 000, similar to that for breast cancer. However, whereas the age-adjusted incidence in women increased by 4.1% per year between 1973 and 1994, between 1990 and 1994 the annual incidence rose by only 0.2%.

Age-standardized mortality rates for cancer show that in western Europe lung cancer in men was by far the commonest cause of death. Belgium has the highest mortality (77.16 deaths per 100 000 population) with Scotland (75.9) second, and England and Wales (60.9) fifth. The figures for central and eastern Europe are worse in that the death rates for lung cancer are rising exponentially, particularly in men—75.8/100 000 in the Czech Republic, 74.0 in Hungary, 69.4 in Poland, and 68.7 in Slovakia. For women, Scotland has the highest incidence (27.2, equal to the rate of breast cancer in Scottish women), with England and Wales (20.4) third. Age-adjusted lung cancer death rates in eastern Europe are still considerably less than in western European countries, ranging from 14.4 in Hungary to 6.8 in Slovakia. Perhaps the worst epidemic is in China, where 0.8 million men died in the year 2000 from smoking-related diseases. Of all deaths attributed to tobacco in China, 15% were due to lung cancer.

Aetiological factors

Tobacco

In every country, the increase in mortality from lung cancer has appeared to coincide with an increase in tobacco usage, particularly cigarette smoking, after what seemed to be an appropriate latent interval. Prospective studies, among which the long-term study of British doctors was particularly informative, confirmed the increased risk of death from lung cancer from any tobacco use, but most specifically that of cigarettes. There was a strong dose–response relationship with the number of cigarettes smoked, illustrated in Table 1. The most important variable in smoking intensity is the number of cigarettes smoked, but other variables include the depth of inhalation, number of puffs, butt length, use of a filter, and the type of tobacco smoked. Further evidence that the relationship was causal came from a study which documented reduction in mortality after stopping smoking: 15 years after cessation the risk of death fell from 15.8 times to twice that in nonsmokers, equivalent to 11% of that pertaining in those who continued to smoke. Stopping smoking before the age of 40 years greatly reduces the risk of developing smoking-related diseases.

Globally, there has been a huge change in cigarette consumption. Between 1970 and 1985 the overall world consumption rose by 7% while there was a drop of 25% and 9% in consumption in the United Kingdom and the United States of America, respectively. This is due to huge increases in Asia (22%), Latin America (24%), and Africa (42%). The current epidemic of smoking in China lags behind Western society by 20 years. Thus, in China in 1996 the average number of cigarettes smoked per adult male was 11 per day, a figure that that peaked in the West at 10 a day in 1980. Nearly one-third of the world’s smokers reside in China, who reported 1.3 million new cases of lung cancer in 2003.

Another disturbing trend is the increasing incidence among women. More women in developed nations will die of lung cancer than breast cancer. Due to historical smoking patterns the incidence rates of lung cancer in women are not declining, because smoking rates have not yet started to decline, as they have in men. Currently far more men than women are dying of this disease, but the gap is relentlessly closing. With regard to socioeconomic status, lung cancer is likelier to occur in the poor and less educated, which is a widespread pattern around the world. Primary prevention and smoking cessation must be directed at these groups.

Passive smoking

Evidence that passive smoking predisposes to lung cancer is far from certain. Approximately 15% of lung cancers occur in nonsmokers, and 5% of these have been attributed to passive smoking. However, the perceived risk to those working in smoke-filled environments has lead to a ban on smoking in public places in an increasing number of countries.

Occupation

People who develop lung cancer as a result of their occupation are a small but important group. The association with asbestos is now firmly established, various studies having identified that those exposed are at 4.9 to 7.3 times greater risk than those who are not. This risk is much enhanced if the asbestos industry worker smokes cigarettes; one study estimating this at 93 times higher than for nonsmokers not exposed to asbestos.

Exposure to radioactive isotopes, mainly radon daughters, is associated with a higher risk of lung cancer and occurs among various groups of miners, particularly those involved in extraction of pitchblende and uranium. Polycyclic aromatic hydrocarbons are believed to be responsible for the increased risk in workers in gas and coke ovens and in foundry workers. Workers in nickel refining, chromate manufacture, and the arsenical industry are also exposed to a higher risk of lung cancer. The amount of lung cancer caused by occupational exposure may well have been underestimated in the past, and a summary of the importance industrial products and processes involved is shown in Bullet list 1.

Bullet list 1 Industrial products and processes known to cause or suspected of causing lung cancer

Air pollution

The decline in male mortality is occurring earlier than would be expected from changes in smoking habits. The high mortality figures in the United Kingdom and Germany compared with France and Italy, for example, seem likely to be due in part to heavy industry and coal burning. Analysis by county in the United States of America shows an association between lung cancer deaths and counties with chemical, petroleum, ship-building, and paper industries. Legislation for cleaner air has caused both environmental and occupational pollution to fall dramatically in the past 30 years, and this has preceded changes in smoking habits.

Pathology

A detailed understanding of the natural history, pathology, and pathogenesis of bronchial carcinoma is becoming increasingly important as the assessment, management, and prognosis of the disease depends largely upon the cell type and the presence or absence of metastases at the time of presentation. It has been estimated that about seven-eighths of a tumour’s life will have passed when it is diagnosed, and that the vast majority will be disseminated at the time of diagnosis.

Bronchogenic carcinomas seem to arise most commonly in segmental and subsegmental bronchi in response to repetitive carcinogenic stimuli or inflammation and irritation. The mucosal lining is most susceptible to injury at the bifurcation of bronchial structures. Dysplasia is followed by carcinoma in situ, when the entire thickness of the mucosa may be replaced by proliferating neoplastic cells. These changes may be strictly localized or multicentric, and are thought to be a field cancerization effect, sometimes causing synchronous primaries. Tumour infiltration follows loss of the basal membrane. The precise origins of small-cell carcinomas remain an enigma, and those of adenocarcinomas are not precisely defined. The latter may arise from the mucosal lining or from the submucosal bronchial mucous glands. A significant number of lung tumours arise in the periphery of the lung, perhaps three-quarters of adenocarcinomas and large-cell anaplastic malignancies, one-third of squamous (or epidermoid) carcinomas, and one-fifth of small-cell carcinomas.

Adenocarcinoma has become the commonest cell type; it is more prevalent in eastern Asia and the United States of America where approximately 50% of new lung cancers are adenocarcinomas. Squamous-cell lung cancer still accounts for up to one-half of new cases in Europe and one-third in eastern Asia and the United States. There has been a slow decline in the prevalence of small-cell lung cancers to 15–20% of new diagnoses, with 10–15% of the less easily differentiable large-cell tumours comprising the rest. Adeno-, squamous-, and large-cell tumours are grouped as non-small-cell lung cancers (NSCLC) as their staging and treatment is similar. From studies of growth rates of radiologically measurable primary tumours, adenocarcinomas have a volume-doubling time of 90–120 days, squamous-cell 60 days and small-cell 30 days, making this last cell type extremely aggressive.

Squamous (epidermoid) carcinoma

These tumours are composed predominantly of flattened to polygonal neoplastic cells that tend to stratify, form intercellular bridges, and elaborate keratin. About 60% present as obstructive lesions in lobar and main-stem bronchi. The tumours tend to be bulky and to produce intraluminar granular or polypoid masses, hence distal pneumonia and abscess formation are common, and cavitation is seen in about 10%. The cells are usually well differentiated, but in some cases differentiation is poor and the appearances are those of predominantly anaplastic cells, frequently arranged in the classical pattern of stratifying sheets.

Small-cell anaplastic carcinoma

This is now recognized as a pathologically and clinically distinct form of lung cancer. The tumour is composed of neoplastic cells with dark oval to round spindled nuclei and scanty, indistinct cytoplasm arranged in ribbons, nests and sheets. The cells tend to crush easily on biopsy, and extensive areas may be necrotic. This type of tumour presents as a proximal lesion in 75% of cases and may arise anywhere in the tracheobronchial tree and rapidly invade vessels and lymph nodes, disseminating widely even before symptoms arise from the primary tumour. More than one-half of the patients have extensive, advanced disease at presentation. The cells secrete peptides which cause clinical syndromes in 10% of cases.

Adenocarcinoma

This tumour forms acinar or granular structures, having prominent papillary processes, and may be mucin-provoking. About 70% appear to originate peripherally in the lung and they are frequently fairly circumscribed. The initial presentation is a pleural effusion in about 10% of cases. If related to bronchi, they tend to cuff and stenose the lumen. They occasionally arise in old tuberculous scars.

Large-cell carcinoma

These tumours, which have been described as an unclassified category, include all tumours that show no evidence of maturation or differentiation. They are composed of pleomorphic cells with variable enlarged nuclei, prominent nucleoli and nuclear inclusions, and abundant cytoplasm, and they are mucin-producing in many instances. The tumours tend to be bulky and are often necrotic. They are frequently peripheral, invade locally and disseminate widely, with about one-half of patients having disseminated disease on presentation. Although these tumours are highly malignant and undifferentiated, the cure rate after surgery is surprisingly high, but radiotherapy is ineffective in controlling the disease. Large-cell carcinoma is a smoking-related disease in more than 90% of patients.

Bronchioloalveolar carcinoma

There has been considerable controversy as to whether this tumour, which has the least association with tobacco smoking, arises from alveolar or bronchial epithelium, but derivation from the alveolar type II cell has been suggested. The tumour tends to spread as cuboidal or columnar ‘epithelium’ along the lining of the alveoli, with single or multiple rows of cells and often papillary formation. There is production of a large amount of mucus in 20% of cases, and it is believed that malignant cells shed into the mucus may carry over into the contralateral lung. The tumour can spread within a lobe and occupy it fully. Sometimes, however, the tumour is multicentric in origin, and diffuse nodular lesions are to be found on radiographic examination. Invasion of neighbouring tissue and lymph nodes is common, but extrathoracic spread is unusual. There is some resemblance to metastases from adenocarcinomas emanating from other organs, which sometimes leads to confusion. The tumour tends to grow along alveolar septae as a framework, and it may be difficult to distinguish from metastatic tumours from colon, breast, or pancreas.

Carcinoid tumours

Genetics and biology

Genetic influences may play a role in the development of lung cancers, particularly in patients under 50. In one study, lung cancers were attributable to a mendelian dominant inheritance pattern in 27% of patients under 50, but only 9% of those over 70.

The ras family of oncogenes (H, K, and N) was the first to be described in association with lung cancer. Mutations of ras genes occur in 20 to 40% of NSCLC, especially adenocarcinomas, and the presence of K-ras mutations is linked with significantly shortened survival.

Lung cancer cells not only show mutations that activate dominant cellular proto-oncogenes, but also genetic mechanisms that inactivate recessive tumour suppressors. The commonest abnormality is a deletion in the short arm of chromosome 3, which is found in over 90% of small-cell lung cancer and 50% of NSCLC patients. Other sites of loss of heterozygosity include 11p, 13q, and 17p. Tumour suppressor genes have been identified in inherited cancers, mainly in studies of familial retinoblastoma. Mutations in TP53 occur in 75% of small-cell lung cancer and 50% of NSCLC. The gene is located on the short arm of chromosome 13q14, and it is thought that it may normally protect cells against accumulation of mutations. Depletions and mutations of TP53 are linked with metastatic disease. Alterations of p53 protein have been found in early bronchial neoplasia, and may be a useful marker for the early detection of lung cancer. Other markers, including heterogenous nuclear ribonuclear protein A2/B1 overexpression in sputum, may allow earlier detection of tumours.

Several monoclonal antibodies have been generated against lung-cancer-associated antigens. Thirty-six monoclonal antibodies raised against small-cell lung cancer have been grouped into eight clusters. No antigen is specific for small-cell lung cancer. Antibodies belonging to the major cluster (cluster 1) are directed against the neural-cell adhesion molecule (NCAM), but the nature of the other antigens remains unclear. Studies of both small-cell and NSCLC cell lines show that NCAM secretion is associated with a neuroendocrine phenotype irrespective of the histological type of lung cancer. Monoclonal antibodies may have a therapeutic value when coupled with a radionuclide or a toxin. Radiolabelled antibodies can be used to detect minimal disease in bone marrow aspirates or biopsy specimens.

The growth factors bombesin/gastrin-releasing peptide, insulin-like growth factor 1 (IGF-1), and transferrin stimulate can all stimulate tumour growth. There is much interest in attempts to retard or disrupt these processes.

Recent interest in the expression of the epidermal growth factor receptor (EGFR) tyrosine kinase in lung cancers has demonstrated it to be up-regulated in 70% of squamous-cell cancers and 50% of adenocarcinomas. This has led to trials with the small-molecule inhibitors gefitinib and erlotinib. A few patients have substantial responses to these drugs, with molecular analysis revealing that specific mutations within the regulatory domains predict such sensitivity. Amplification of the gene provides additional predictive information. EGFR mutations occur largely in adenocarcinoma and are more prevalent in Asians.

Clinical features

Lung cancers present late in their natural history. In general, death will occur when a tumour load reaches 1 kg, which is equivalent to 40 volume doubling times, yet halfway through the lifespan of a lung cancer—20 volume doublings—it is only 1 mm in diameter. It becomes visible on a chest radiograph at about 1 cm and the typical size at presentation with symptoms or signs is 3–4 cm. CT and PET will identify lesions as nodules when they are considerably smaller, but most incidentally discovered nodules tend to be benign, making investigation problematic.

The clinical features of lung cancer are very variable: they can be respiratory, but all too often they are constitutional and attributable to metastatic disease. In one series of 678 consecutive patients only 27% presented with symptoms related to the primary tumour. Most had either nonspecific symptoms, including anorexia, weight loss, and fatigue (27%), or specific symptoms of metastatic disease (32%). However, in about 5% of patients the presentation is a radiographic abnormality found by chance on routine examination. These patients tend to have a better prognosis (18% 5-year survival) than those with symptoms related to the primary tumour (12% 5-year survival). There is usually a considerable time delay between the patient noticing a symptom and presenting to a primary care physician, which varies in different studies from 4 months to 2 years, with the specific exception of haemoptysis, when the mean delay from first symptom to first visit is much shorter at about 43 days (range 0–256 days). There may also be a delay between first presentation to a physician and the realization that there may be a lung cancer present. One study identified a delay of 56 days (range 0–477 days). This is understandable in the context that an average primary care physician (in the United Kingdom) sees a new lung cancer only every 9 months or so, and in a Dutch study of patients presenting with cough (11 092 separate patient encounters), lung cancer was not listed as a separate entity amongst the 20 most common eventual causes.

Clinical symptoms and sign of lung cancer can be subdivided into those arising from the lung itself; from the extrapulmonary intrathoracic structures; extrathoracic metastases; and from endocrine, metabolic, and neurological (paramalignant) syndromes (Table 2).

Intrapulmonary symptoms

Cough is the most common initial presenting symptom, but because it is a symptom of so many respiratory disorders, the possibility of tumour may be overlooked and cough may be attributed to some other cause, particularly in smokers who have had chronic bronchitis for many years. Patients with a persistent cough should have a chest radiograph, particularly if they are smokers over 40 years of age. A change in the cough habit is significant and also requires investigation. If the trachea or main bronchi are involved, the cough may be harsh in character and may be accompanied by wheezing or stridor. If cough is manifestly ineffective, with its explosive ability lost, involvement of the recurrent laryngeal nerve should be suspected.

Expectoration of sputum may be due to irritation of the tumour in a major airway or to infection occurring distal to partial bronchial obstruction. The value of sputum cytology in diagnosis is described below.

Haemoptysis, which is the sole presenting symptom in about 5% of cases and occurs at some stage in the disease in 50% of patients, is a symptom not easily ignored by patient or physician. The degree varies from streaking of the sputum with blood to larger amounts, but massive haemoptysis (>200 ml) is rare, except as a terminal event when the tumour may erode a large pulmonary blood vessel. The most significant description given by patients is that of coughing up blood every morning for several days in succession.

Wheeze may be observed in a few patients. Localized persistent wheeze, often volunteered to come from one side of the chest, even after coughing is a significant observation indicating obstruction of a larger or central airway.

Stridor is a feature that is poorly recognized and often confused with wheeze. It is due to narrowing of the glottis, trachea, or major bronchi, and is best heard after the patient coughs and then breathes in deeply with the mouth open.

Dyspnoea is a presenting symptom in only a few patients. As the disease progresses dyspnoea is inevitable, being proportional to the amount of lung involved, either directly by tumour replacement or indirectly by endobronchial disease causing airway narrowing or obstruction. Progressive breathlessness is also a feature of malignant pleural and, rarely, pericardial effusion, superior vena caval obstruction, and lymphangitis carcinomatosis.

Chest discomfort is a common symptom, occurring in up to 40% of patients at diagnosis. The discomfort is often of an ill-defined nature and may be described in terms of intermittent aching somewhere in the chest. Definite pleural pain may occur in the presence of infection, but invasion of the pleura by tumour is often painless. However, invasion of the ribs or vertebrae causes continuous, gnawing, localized pain. A tumour in the superior pulmonary sulcus (Pancoast tumour) can cause progressive constant pain in the shoulder, upper anterior chest, or interscapular region, soon spreading to the arm once the brachial plexus is invaded. Other symptoms of this type of tumour include weakness and atrophy of the muscles of the hand, Horner’s syndrome, hoarseness, and spinal cord compression at levels D1 and D2.

Fever, chills, and night sweats may occur due to chest infection, but fever may very rarely be present in rapidly progressive tumours without evidence of infection, particularly if there are hepatic metastases.

Extrapulmonary, intrathoracic symptoms

Invasion of adjacent, mainly mediastinal, structures can give rise to certain specific clinical features. Involvement of the last cervical and first thoracic segment of the sympathetic trunk by cancer produces Horner’s syndrome. Malignant infiltration of the recurrent laryngeal nerve—almost always the left branch because of its course adjacent to the left hilum—gives rise to vocal cord paralysis. The right recurrent laryngeal nerve is occasionally affected in the base of the neck. Recurrent aspiration pneumonias may follow vocal cord paralysis.

Extension of the tumour with invasion or compression of the superior vena cava or by paratracheal lymphadenopathy results in the characteristic features of superior vena caval obstruction—awareness of tightness of the collar, fullness of the head, and suffusion of the face (particularly after bending down), blackouts, breathlessness, and engorgement of veins with a downward venous flow in the neck, the upper half of the thorax, and arms, often accompanied by oedema of the face.

Dysphagia is due to compression of the oesophagus from without by tumour metastases in subcarinal lymph nodes and only rarely to direct invasion. Cardiac and pericardial metastases usually occur late in the disease and are manifested clinically by tachycardia, arrhythmias, pericardial effusion, and breathlessness. Invasion of the phrenic nerve results in elevation and paralysis of a hemidiaphragm.

Involvement of the ribs, spine, and pleura are extrathoracic manifestations. Very rarely bronchogenic carcinoma causes spontaneous pneumothorax. It must not be forgotten that spread of tumour to the other lung may occur, or that synchronous primaries may coexist.

Extrathoracic metastatic symptoms

About 30% of patients present with symptoms due to distant metastases, the most common sites being bones, liver, adrenal glands, brain and spinal cord, lymph nodes, and skin. Metastases to nodes are frequent and should be sought with great care, particularly those in the scalene area, which are usually the first to be involved. The best position for examination for these is from behind with the patient seated relaxed in a chair. The side affected usually corresponds to the side of the lung lesion, the exception being that tumours from the left lower lobe may metastasize to the nodes in the right scalene area. Involvement of the nodes in the floor of the supraclavicular fossa is equally common.

Bony metastases are common, particularly in small-cell tumours, and occur predominantly in the skull, ribs, vertebrae, humeri, and femora. They cause pain as a presenting symptom in up to 25% of patients. Early involvement may be detected by a rise in alkaline phosphatase of bony origin, isotope scanning, or biopsy. Conventional skeletal surveys are often unhelpful and misleading.

Liver secondaries are common and may be silent, although a rise in liver enzymes, particularly alkaline phosphatase of liver origin, may be an early sign. CT scans and ultrasonography may detect involvement in a liver which is not clinically enlarged, but as the metastases develop the liver becomes grossly enlarged with an irregular outline.

Metastases to the brain may account for the presenting symptom in lung cancer in 4% of patients and may be encountered at some time in the illness in 30%. The symptoms simulate those of any expanding brain tumour.

The adrenal glands are involved in 15 to 20% of patients, rarely producing symptoms. The skin should be examined for the presence of the typical, slightly bluish, umbilicated lesions of tumour spread. Subcutaneous metastases may be found at almost any site.

It is recommended that organ-specific scans are only conducted in patients with organ-specific symptoms, or with general symptoms such as weight loss or malaise. Lack of energy and, more particularly, loss of interest in normal pursuits are symptoms of great importance; a sense of vague ill health commonly occurs.

Paramalignant syndromes

Endocrine and metabolic manifestations

Many of the unusual manifestations of malignant disease are the result of endocrine and metabolic manifestations of the cancer itself. Cancer cells appear to be able to synthesize polypeptides that mimic virtually all the hormones produced by conventional endocrine organs—hence the term ‘ectopic hormones’. From time to time the clinical features resulting from ectopic hormone secretion precede those of the pulmonary tumour, emphasizing the importance of a high index of suspicion in such circumstances. Ectopic hormone measurement cannot, however, be used for screening purposes. These syndromes can occur in up to 10% of patients with lung cancer.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

The continued secretion of vasopressin (ADH) in excess of the body’s needs leads to retention of water in both the intracellular and extracellular compartments. The cerebral oedema resulting from water intoxication can cause drowsiness, lethargy, irritability, mental confusion, and disorientation, with fits and coma being the most profound features. Peripheral oedema is remarkably rare. The patient is usually asymptomatic until the sodium falls below 120 mmol/litre, when the hyponatraemia is dilutional in type with a low serum osmolality. Urine osmolality usually exceeds 300 mosmol/kg. The commonest cancer causing this syndrome is small-cell lung cancer, where it is clinically obvious in 1 to 5% of cases, with subclinical involvement detectable by a water-loading test in more than 50%. Restriction of fluid to a daily intake of 700 to 1000 ml may redress the hyponatraemia, but demethylchlortetracycline (demeclocycline) 600 to 1200 mg daily is often highly effective, making water restriction unnecessary. The syndrome resolves promptly (within 3 weeks) with combination cytotoxic chemotherapy in 80% of patients with small-cell lung cancer, but commonly recurs at, or predicts, relapse.

Ectopic ACTH syndrome

Secretion of an adrenocorticotrophic substance by a small-cell carcinoma or bronchial carcinoid leads to bilateral adrenal hyperplasia and to secretion of large amounts of cortisol. The onset of symptoms may be so acute that death may occur within a few weeks, when the typical features of Cushing’s syndrome do not have time to develop. However, it is a common paramalignant syndrome and increased levels of ACTH may be detectable in up to 50% of patients with small-cell lung cancer, with Cushing’s itself described in 1 to 5% of these patients. The chief clinical features are thirst and polyuria, oedema, pigmentation, and hypokalaemia. Hypertension and profound myopathy may also be present. Serum cortisol is often grossly elevated, with loss of the normal diurnal rhythm; the level is not suppressed by dexamethasone; and hypokalaemic alkalosis can be severe, with plasma potassium less than 3.0 mmol/litre and bicarbonate more than 30 mmol/litre. Drugs which block adrenocortical steroid biosynthesis may produce partial and reversible medical adrenalectomy, and metyrapone in doses from 250 mg thee times daily to 1 g four times daily may cause temporary relief of symptoms. Removal of the tumour, if practicable, will cause remission, particularly if the cause is a carcinoid tumour. Small-cell lung cancers with this syndrome seem to respond poorly to chemotherapy.

Hypercalcaemia

Hypercalcaemia may be associated with ectopic secretion of parathormone by squamous-cell cancers but is more commonly due directly to the presence of multiple bone metastases. The primary tumour may also produce a cAMP-stimulating factor or a prostaglandin causing hypercalcaemia. A protein with parathormone-like activity has been purified from lung cancer cell lines. Increased bone resorption as the explanation for hypercalcaemia has been attributed to the parathormone like protein released from cancer cells. The incidence in patients with lung cancer ranges from 2 to 6% at presentation, to 8 to 12% during the course of the disease. Hypercalcaemia is unlikely to cause symptoms unless the serum calcium exceeds 2.8 mmol/litre, and levels much higher than this are sometimes encountered. The main clinical features are nausea, vomiting, abdominal pain and constipation, polyuria, thirst and dehydration, muscular weakness, psychosis, drowsiness, and eventually coma. Immediate treatment is to relieve fluid depletion, and large volumes of intravenous saline (up to 5 litres in 24 h) may be required. Intravenous bisphosphonates followed by oral maintenance therapy is now the treatment of choice.

Gynaecomastia

Swelling of the breasts, which may be painful, occurs mainly in the subareolar area, and there may be atrophy of the testes. The association is chiefly with large-cell carcinomas. Increased gonadatropin production is the cause.

Other endocrine manifestations

Hyperthyroidism is a rare feature, but neither goitre nor eye signs are prominent. Spontaneous hypoglycaemia, the masculinizing syndrome in young women, and hyperglycaemia are very rarely encountered. Pigmentation associated with α- and β-melanocyte-stimulating hormone may occur.

Neuromyopathies

A variety of poorly understood neurological syndromes can occur with lung cancer. The diagnosis of a paramalignant neurological syndrome should only be made once other causes including electrolyte imbalance, metastatic disease, cerebral and spinal vascular disease, infection, and toxicity from associated treatment have been eliminated. The main neurological syndromes include the Lambert–Eaton myasthenic syndrome (LEMS), limbic encephalopathy, polyneuropathy, cerebellar degeneration, retinopathy, and autonomic neuropathy. LEMS is the most widely recognized of these disorders and presents with gradual onset of proximal limb weakness, more noticeable in the legs than the arms. Difficulty in swallowing and dryness of the mouth are common, although diplopia is rare. The symptoms may be worse in the mornings and improve as the day progresses. Physical examination will confirm weakness and loss of tendon jerks, but the latter can be restored for a few minutes by performing tasks of repetitive forced contractions (post-tetanic potentiation).

Neurological paramalignancies are associated almost exclusively with small-cell lung cancers, affecting up to 4% of cases. Recent studies of consecutive new patients with small-cell lung cancer reported LEMS in 1.6%, polyneuropathy in <1%, subacute cerebellar degeneration in <1%, and limbic encephalitis in <1%. The severity of the syndromes is not related to tumour bulk and seems to occur more frequently in patients with limited disease; in some a primary tumour is not detected before death, despite disabling symptoms.

Nearly all the neurological paramalignant syndromes are associated with the presence of type 1 antineuronal nuclear antibodies (ANNA-1), also known as anti-Hu antibodies. Small-cell lung cancers express Hu antigen and up to 20% of these patients have detectable circulating levels of anti-Hu antibodies, although not all will develop paramalignant disorders.

The response of these syndromes to effective chemotherapy of the underlying tumour is variable. Improvement is uncommon with motor or sensory neuropathies, or with cerebellar degeneration. However, LEMS can be associated with a better overall prognosis, and the condition responds to specific therapy with 4-aminopyridine which appears to potentiate the release of acetylcholine at the nerve receptor end plate.

Finger clubbing and hypertrophic pulmonary osteoarthropathy

Finger clubbing accompanies a variety of intrathoracic disorders. Gross clubbing is readily recognizable; its early presence may best be demonstrated by the ability to rock the nail on its abnormally spongy bed; the nail fold angle will become obliterated as increased transverse curvature of the nail develops. Clubbing of the toes can be present but is less pronounced.

Hypertrophic pulmonary osteoarthropathy (HPOA), which is a systemic disorder, may be preceded by finger clubbing alone. It consists of a painful symmetrical arthropathy, usually of the ankles, knees, and wrists, and periosteal new bone formation in the distal limb long bones. Associated finger clubbing can be gross. Clubbing and HPOA can be associated with any cell type of lung cancer, but mostly with squamous and adeno, and very rarely with small cell types. The affected areas are hot and painful and sometimes oedematous, making walking difficult. Removal of the tumour is followed by immediate regression, but symptoms recur if the tumour recurs.

Clubbing is much more common than HPOA, occurring in up to 25% of patients presenting with lung cancer. It seems to be commoner in women than men, and in NSCLC compared to small-cell, while HPOA is seen in <5% of patients with NSCLC.

Miscellaneous

The haematological effects of lung cancer are normally nonspecific. Normocytic normochromic anaemia is the most common finding. Leucoerythroblastic anaemia denotes bone marrow infiltration and is particularly likely in small-cell lung cancer. Venous thrombosis and thrombophlebitis due to hypercoagulability are common complications of malignancy and may precede the detection of the underlying cancer; recurrent migratory phlebitis resistant to anticoagulation is an ominous feature. Marantic endocarditis is extremely rare, as are skin rashes such as acanthosis nigricans, dermatomyositis, hypertrichosis languinosa, and erythema gyratum repens. Rarely, the nephrotic syndrome due to membranous glomerulonephritis is encountered.

Investigation and staging

The investigations used to make the diagnosis and assess the stage of lung cancer will vary according to the presentation, the cell type, and the age and general condition of the patient.

The rapid doubling time of small-cell lung cancer causes it to disseminate widely, and at diagnosis it is very rarely considered operable. However, the slower doubling times for squamous-cell cancers and adenocarcinomas, together with the relatively lesser tendency for the former to disseminate, makes surgery the best option whenever possible for the NSCLCs. A precise anatomical staging classification was first applied to lung cancer in 1973 and immediately demonstrated that the prognosis of NSCLC depended strongly on the extent (or stage) of the disease, and the introduction of the TNM staging system (T describing the primary tumour, N the extent of regional lymph node involvement, and M the absence or presence of metastases) encouraged an ordered assessment of investigations and selection of cases for surgery. On the basis of this experience, the system was modified in 1997 and again in 2009 using a much more extensive data set from centres around the world, and survival data is now based on more than 100 000 cases (Tables 3 and 4).

The following investigations form the basis for the diagnosis and staging of patients with lung cancer.

Radiological assessment

The value of the chest radiograph in the diagnosis and management of pulmonary neoplasm needs no emphasis. No initial examination is complete without a lateral radiograph, although many investigators move directly to a CT scan of the thorax and upper abdomen when faced with the likelihood of a new lung cancer.

The finding of a normal radiograph of the chest does not exclude bronchial carcinoma, as patients presenting with haemoptysis and a normal chest radiograph are sometimes found to have a central tumour on bronchoscopy. The rounded or ovoid shadow of a peripheral tumour is described in greater detail below; these are sometimes cavitated. The common appearance of a tumour arising from the main central airways (70% of all cases) is enlargement of one or other hilum. Even experienced observers sometimes have difficulty in deciding whether or not a hilar shadow is enlarged, and if there is any suspicion, investigation by CT and/or bronchoscopy should be pursued. Consolidation and collapse distal to the tumour may have occurred by the time that the patient presents, with the tumour itself often being obscured in the process. Collapse of the left lower lobe is often hard to identify, as is a tumour situated behind the heart. Apically located masses or superior sulcus tumours (Pancoast tumours) may be misdiagnosed as pleural caps, and often have a long history of pain in the distribution of the brachial nerve roots. Loss of the head of the first, second, or third rib is not unusual.

The mediastinum may be widened by enlarged nodes. Involvement of the phrenic nerve may lead to paralysis and elevation of the hemidiaphragm, which then moves paradoxically on sniffing. Tumour spreading to the pleura causes effusion, but such an abnormality may be secondary to infection beyond obstruction caused by a central tumour. The ribs and spine should be carefully examined for the presence of metastasis. Spread of tumour from mediastinal nodes peripherally along the lymphatics gives the appearance characteristic of lymphangitis carcinomatosa—bilateral hilar enlargement with streaky shadows fanning out into the lung fields on either side. Rarely, localized obstructive emphysema may be observed.

Sputum cytology

Cytological examination of sputum is a very useful noninvasive test for the diagnosis of malignant pulmonary disease. The positive incidence on a single sample is lower with tumours less than 2 cm in diameter (40%) and higher with larger masses (60%). Central tumour yields a higher proportion of positive results than peripheral lesions. The yield increases according to the number of specimens examined, and three consecutive morning specimens should be submitted in the first instance. The yield rose to 85% with four samples in a study of those in whom a diagnosis of lung cancer was made.

CT

Thoracic CT imaging is extremely important in the staging of lung cancer. It can identify the site, size, and extension of the primary tumour far more clearly than a conventional chest radiograph. It also frequently identifies mediastinal lymphadenopathy when posteroanterior and lateral chest radiographs fail to show any abnormality. It will also identify silent metastatic disease in the liver, adrenal glands and in abdominal lymph nodes. It is recommended that a CT is performed prior to considering bronchoscopy as the primary lesion may be shown to be poorly accessible to the bronchoscope and may be easier to sample by CT controlled transthoracic biopsy. The CT scan may also identify mediastinal involvement which can be directly sampled by bronchoscopic or ultrasound-guided techniques, or direct sampling towards an abdominal metastasis. These would both provide a diagnosis and also help stage the disease from a single procedure.

Mediastinal lymphadenopathy on CT is arbitrarily taken to be pathological if the glands are more than 10 mm in transverse diameter. However, previous infective conditions such as tuberculosis or an associated distal pneumonia can cause appearances indistinguishable from malignant enlargement. Thus, positive CT scans of the mediastinum must be confirmed by mediastinal lymph node biopsy to confirm tumour involvement. This is important because nearly 40% of lymph nodes deemed enlarged on CT criteria are found not to contain cancer when they are sampled, either by biopsy or at the time of surgery.

Another advantage of CT is its ability to detect tumour invasion of the surrounding pleura and chest wall, although its ability to assess invasion of the mediastinum itself is poor and should not be used as a criterion of unresectability.

Bronchoscopy

Bronchoscopy, is frequently the definitive diagnostic method in lung cancer. About 70% of all lung cancers arise in a main bronchus, lobar, first-, or second-generation airways, and will be visible and within biopsy or cytological brush range. Bronchoscopy also yields valuable information regarding suitability for surgical resection. Attempts to resect are ill advised if the main carina is obviously involved, or unequivocally broad with splaying of the main bronchi and immobility on respiration, or where there is involvement of the trachea, unless confined to the right lateral wall. Histological confirmation is now obtainable in 85 to 90% of bronchoscopically visible lesions, and three or more biopsies of a visible endobronchial lesion should approach 95% accuracy. Endobronchial biopsies provide the highest sensitivity, followed by brushings and then washings.

Transbronchial and transoesophageal biopsy

Historically the mediastinum has been staged and malignant involvement of mediastinal nodes has been confirmed by surgical sampling by mediastinoscopy (for right paratracheal and subcarinal nodes) and/or anterior mediastinotomy for left-sided nodes. Although these techniques remain the ‘gold standard’, they have been to some extent replaced by minimally invasive techniques including transbronchial needle aspiration (TBNA) and transoesophageal endoscopic ultrasound (EUS), fine-needle aspiration, or biopsy. The use of TBNA in staging lung cancer is reported to be moderately sensitive and highly specific in diagnosing spread to mediastinal nodes accessible through the bronchial wall at fibre-optic bronchoscopy, in particular the paratracheal nodes and those around the carina. Often involvement of these structures causes widening of the carina, making targeting easy. The sensitivity can be improved by using an ultrasound-guided endoscope, allowing better identification of an abnormal node which can then be sampled under direct ultrasound vision. A recent meta analysis showed the sensitivity of blind TBNA in NSCLC was between 39 and 78%, but depended greatly on the prevalence of cancer in the lymph nodes. The specificity was 99%.

Use of the EUS technique via the oesophagus also has a high yield. It is currently performed by gastroenterologists and will sample nodes in the posterior mediastinum or the subaortic fossa, and also within the abdomen. When used as both a diagnostic tool and as a staging method, the yield is high and the specificity 100%.

Transbronchial biopsy of the lung parenchyma via the fibre-optic bronchoscope is now rarely used for peripheral tumours as direct sampling under CT or ultrasound control has superseded this technique. It remains useful for more diffuse lesions such as may be seen in adenocarcinoma, bronchoalveolar-cell carcinoma, and lymphangitis carcinomatosis.

Percutaneous needle biopsy

Percutaneous needle biopsy of an intrapulmonary mass may be carried out using a variety of cutting needles to obtain a core of tissue for both histology and cytology. The procedure can be performed under fluoroscopic, CT, or ultrasound control, but is best avoided in patients with poor respiratory function or with bleeding diatheses. Positive yields as high as 90% have been reported, with biopsy samples having a higher and more specific yield than cytological aspirates. It is a useful diagnostic method in patients for whom exploratory thoracotomy may be hazardous, or in attempts to determine whether a solid mass is a primary, secondary, or benign tumour. Pneumothorax occurs following about 25% of procedures, with some 2 to 4% requiring a chest drain. Small haemoptyses are a common complication.

Thoracoscopy

Visualization of the parietal and visceral pleura plays an important part in the diagnosis of effusions and pleural tumours. Biopsy of lesions can be carried out under direct vision, and absence of pleural tumour is important in decisions about resectability of a lung tumour. Thoracoscopy is inadvisable in the absence of effusion or pneumothorax, and is unsatisfactory in the presence of empyema or gross haemothorax. However, in otherwise operable tumours with a pleural effusion that is not bloodstained and without positive cytology or pleural biopsy, thoracoscopy may be a useful next step in determining operability. Video-assisted thoracoscopy (VATS) has extended this technique and will also permit inspection and sampling of suspicious mediastinal lymph nodes.

Positron emission tomography (PET) scanning

PET scanning, which depends on the uptake of a glucose analogue (fluorodeoxyglucose, FDG) by active tumour and its metastases, has gained wide acceptance as a test with much better characteristics than CT, especially for the mediastinum. It is now recommended as the final staging test in those where resection or another curative treatment is contemplated. Furthermore, the intensity of uptake of the FDG isotope reflects the aggression of the tumour: the higher the uptake, the likelier the disease is to spread and do badly following surgery. Because uptake of the PET isotope in malignant structures is based on tumour activity and not (as with CT) just lymph node size, its routine use as a preoperative staging tool has been shown to save about 20% of all thoractomies, which (if proceeded with) would have been futile and noncurative. However, PET scanning has a 10% false-positive rate, due to coexisting infection or inflammation, and a positive area of uptake should always be confirmed by sampling if that abnormal area would directly affect a management decision. A new generation of combined CT/PET scanners will provide the advantages of both techniques and outperform either test alone.

Lung function testing

The ability to climb one flight of stairs without breathlessness has been claimed to be a very good indication of fitness for resection, but formal evaluation of lung function is essential in all patients for whom surgery is being considered. Simple spirometry is usually adequate if the forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) are greater than 70% of predicted normal. If either value is less than 70% predicted, the gas transfer needs to be also 70% of predicted for the subject to withstand a pneumonectomy. If it is less, then differential lung function needs assessing using a ventilation perfusion scan to calculate the quality of performance of the remaining lung tissues. Simple formulae are available to predict the post operative lung function from these scans with reasonable accuracy. However, if the predictions are borderline for the resection intended, then an exercise test should be performed to calculate the maximum oxygen uptake and surgery only performed if this is more than 15 ml/kg per min. In general, the risks are greater for a pneumonectomy and worse for a right-sided operation. The surgeon needs to be given clear advice as to how extensive a resection an individual patient can tolerate safely, without becoming a respiratory cripple as a result of a curative pulmonary resection.

Other investigations

In general, the ability to identify small metastatic deposits is as unsatisfactory for lung carcinomas as for other solid tumours. The available techniques are relatively crude, and this partially explains the high extrathoracic relapse rate following so-called ‘curative’ resections for NSCLC. In patients with no symptoms other than those caused by their primary tumour, imaging scans of brain, liver, and bones are unhelpful if there is no clinical evidence of neurological, hepatic, or bony disease and normal biochemistry. CT brain scans have a high accuracy in detailing cerebral metastases in patients with neurological symptoms. In patients with a palpable liver and/or abnormal liver function tests, a liver CT scan or ultrasonography should be performed. CT scan of the upper abdomen identifies abnormalities of one or both adrenal glands in up to 10% of patients considered for surgery, and fine-needle aspiration of the adrenal gland should be performed if this remains the only contraindication to pulmonary resection. Bone scans have a high false-positive rate due to Paget’s disease, active arthritis, healing fractures, renal disease, and hyperparathyroidism. However, a bone scan should be ordered in patients with bone pain, local tenderness, or nonspecific symptoms of weight loss or malaise.

Biopsy or cytological aspiration of enlarged lymph nodes and skin metastases should be carried out whenever indicated. Indeed, some studies have shown that routine ultrasound scans of the scalene nodes and the supraclavicular fossae in subjects whose CT shows mediastinal nodal enlargement, will have identifiable nodes containing tumour in 30% of cases with ultrasound-guided fine-needle aspiration of the neck region. If an isolated hepatic or bony lesion identified with isotope or CT scanning appears to be the only contraindication to surgery, then this should be biopsied under radiological control.

Staging

The final procedure before thoracotomy, or other localized treatment such as radical radiotherapy, is assessment of the mediastinum, since this may be involved in up to 50% of patients with a peripheral, poorly differentiated tumour and in a much greater percentage of central lesions. If CT shows no other obvious site of disease and a PET scan only confirms uptake in the primary tumour and at no other distant site, then the surgeon can proceed directly to thoracotomy. If the CT and/or PET scan is abnormal at a distant site, or is not available, then mediastinal exploration should be performed by whatever technique is applicable. Increasingly this is by TBNA or EUS, proceeding to mediastinoscopy only if suspicious areas are not confirmed by these techniques. Similarly, isolated suspicious lesions in the liver, adrenal glands, etc should be biopsied as they both stage as inoperable and provide the cell-type diagnosis. Most patients with extrathoracic metastases will have abnormal nodes within their mediastinum.

Treatment and prognosis of NSCLC

Lung cancer-non-small cell - non-technical article

Surgery

Surgery remains the single modality most likely to be curative in NSCLC. Before surgery the patient should have been carefully staged, and the chances of long-term survival will be greatly influenced by this. All patients with stage IIIB disease (Table 4) should not undergo thoracotomy, but those with stage I, II, and some with IIIA disease can be considered for resection. In general, patients with squamous-cell carcinomas have higher 5- and 10-year survival rates than those with adenocarcinoma and large-cell carcinomas, and the more differentiated the tumour the better is the prognosis. Table 5 summarizes survival data at 5 years for preoperatively staged NSCLC. Clearly, small peripheral lesions with no nodal disease (stage IA) fare best (up to 70% survival at 5 years), but the survival rate decreases with both size of tumour and increasing involvement of hilar and mediastinal nodes. Essentially the survival data is similar to that for a decade previously as used by Mountain in the setting of the updated TNM classification although it may change with the new, 2009, classification (Table 5).

About 15% of all patients who present with NSCLC eventually come to thoracotomy. Most of the others are excluded almost immediately because of clinically evident metastatic disease, radiological or bronchoscopic evidence of inoperability, general frailty and/or significant associated other illnesses, or inadequate lung function. Of those having a ‘curative’ resection, the overall survival rate at 5 years is approximately 25% and at 10 years it is 16 to 18%. Death from local or distant recurrence of the tumour is equally probable, highlighting the inadequacies of current staging techniques. However, the careful application of the TNM system and the advent of more sophisticated scanning equipment such as PET may lead to improvement.

Only very rarely is there an indication for palliative surgery, and resection should not be considered in the presence of intrathoracic or distant metastasis.

Advanced age is not a contraindication to surgery. About 45% of new patients with lung cancer are over 70 years of age and these individuals appear to tolerate lobectomy as well as younger patients, although the mortality for pneumonectomy (8–10%) is double that of those under 70. There is no evidence that tumours grow more slowly in elderly people, hence the disease is as likely to be the terminal event in older as in younger patients and resection should be encouraged in patients who are fit. Smokers should be persuaded to stop smoking before thoracotomy because continued smoking increases perioperative complications.

Video-assisted thoracoscopic resection of peripheral masses is currently reserved for those with inadequate lung function for lobectomy, as hilar and mediastinal node evaluation and dissection is not always possible. However, these lung sparing procedures may be more suitable for elderly subjects. The cure rates for segmentectomy by VATS is less good than by open thoracotomy and lobectomy with lymph node dissection.

Radiotherapy

Patients who are excluded from surgery because of adverse prognostic factors, advanced stage of tumour, or other coincidental disease constitute the largest group treated with radiotherapy. Although the usual aim of radiotherapy will be palliative, there will be a small group of patients in whom more aggressive therapy will be used in the hope of cure, or at least long-term survival, particularly in those who have refused surgery. Radiotherapy for lung cancer is limited by the comparative radiosensitivity of three critical normal tissues likely to be included in the radiation beam: normal lung, spinal cord, and the heart, each of which has a specific tolerance dose. Increased radiation dose leads to greater killing of tumour cells but may produce unwanted damage to normal cells. Radiation dose must be expressed not only in terms of total dose but also numbers of fractions and overall time. There is no clear evidence for an optimum radical (curative) radiation dose, but doses of 60 Gy (6000 rad) in 5 to 6 weeks are commonly given, with higher doses becoming more commonplace as the accuracy of dose delivery improves with the use of CT scanners, and even PET scanners, to set the fields, and confocal techniques allowing normal tissues to be increasingly spared.

Alternative to surgery

In some patients with a technically resectable tumour there may be medical contraindications for resection or the patient may refuse surgery. In general, the results of radical radiotherapy in these patients are inferior to the 5-year survival following surgery. The best result for radiotherapy was a 5-year survival rate of 22% for peripheral squamous-cell cancers, but other series record a 5-year survival rate of 6%.

Preoperative and/or postoperative radiotherapy

Preoperative radiotherapy has been given in a few uncontrolled studies, but there is no evidence that this approach improves survival. Two recent meta-analyses have shown no benefit from postoperative radiotherapy for stage I and II disease, and it is not clear whether or not it has any value in stage IIIA disease with nodal involvement, but benefit is likely to be small and it is not recommended.

Radical radiotherapy for locally advanced, inoperable disease

In otherwise fit patients with small-volume intrathoracic disease which is not resectable, usually because of mediastinal involvement, it is common practice to attempt to cure with radiotherapy. Results with daily single fractions are disappointing, even with doses of up to 60 Gy, with 5-year survival rates ranging from 5 to 17%.

Recently, continuous hyperfractionated accelerated radiotherapy (CHART), with a fraction every 8 h for 12 consecutive days to a total of 54 Gy, has been compared to conventional daily radiotherapy in NSCLC. CHART gave an absolute improvement in 2-year survival from 20% to 29%, with the greatest benefit (14% absolute improvement) in squamous-cell cancers. This appears a real advance in the provision of radiotherapy for locally advanced, inoperable tumours, but it has not proved to be a feasible technique for busy radiotherapy departments. A similar approach with no treatment at week-ends (CHARTWELL) may be as useful and seems to be effective.

Studies of combining radiotherapy with concurrent or sequential courses of chemotherapy have been compared to radiotherapy alone and shown a survival benefit. It also appears that concurrent chemotherapy may be better than the two treatment modalities given consecutively, although the toxicity for the concurrent approach is higher. Chemoradiotherapy is now regarded as the approach of choice for locally advanced, inoperable NSCLC.

Palliation

Radiotherapy can provide excellent palliation for many symptoms, with two of the most distressing, haemoptysis and cough, controlled in up to 80% of cases. Administration of two fractions (each of 8.5 Gy, 1 week apart) appears adequate. Dyspnoea from bronchial obstruction and dysphagia are relieved in most cases. The syndrome of superior vena caval obstruction is relieved in about 80% of sufferers, but usually requires a more conventional course of five to ten fractions of radiotherapy. Pain from bone secondaries can be relieved in more than 50% by a single fraction of 8 Gy, often given at the same time as a clinic visit. Brain metastases generally respond poorly to radiotherapy. A 48-h trial of dexamethasone, 4 mg orally four times daily, is recommended as initial management. If a worthwhile response follows the resolution of the oedema surrounding the metastases, then radiotherapy will consolidate this gain, after which steroids should be rapidly withdrawn. Spinal cord compression is a relatively common occurrence associated with vertebral body metastatic disease. Pain and bony tenderness often precede it and may be helpful in localizing the lesion. Responses to radiotherapy are usually incomplete and disappointing, often because of interruption of the vascular supply to the spinal cord by the tumour.

Chemotherapy

Several cytotoxic agents show activity against NSCLC, but much less frequently or dramatically than with small-cell tumours. However, combination chemotherapy can achieve impressive response rates; partial responses in 50% of patients with locally advanced disease and in 35% of those with advanced extrathoracic disease have been reported. The most active regimens include two agents: cisplatin or carboplatin, and gemcitabine or paclitaxel or vinorelbine. These ‘third-generation’ drugs have replaced the more toxic and often harder to give agents such as ifosfamide, mitomycin, or vindesine. A meta-analysis of 53 randomized controlled studies in which patients received or did not receive chemotherapy in addition to surgery, radiotherapy, or to best supportive care was published in 1995. This suggested a 5% advantage for the addition of chemotherapy to surgery (confidence intervals –1 to 7%), a smaller nonsignificant advantage for the addition of chemotherapy to radiotherapy, and—in those with advanced disease—a 10% improvement in survival at 1 year for the addition of chemotherapy to best supportive care. Subsequent trials of adjuvant chemotherapy following successful surgery versus no further treatment have confirmed a 5.2% increase in the 5-year postsurgery survival with the addition of chemotherapy, and patients should be offered this choice.

In advanced disease, which will affect up to 90% of all cases of NSCLC, chemotherapy only confers a survival advantage of 6 to 8 weeks compared to best supportive care alone, making evaluation of effects on quality of life important. A large trial of second-generation cytotoxic chemotherapy vs best supportive care showed no disadvantage in global health scores with chemotherapy, and modern third-generation combinations have been shown to improve quality of life, at least while the patient is responding and in remission. There is no particular regimen that stands out, but chemotherapy in advanced disease for patients with a good performance status will increase the median survival by 4 to 6 months and the 1-year survival from 18% untreated to 35 to 40%.

With chemotherapy on a plateau for NSCLC, new data is emerging on so-called targeted therapy. As described previously, mutations in EGFR have been identified in lung cancer, and overexpression of EGFR and its ligands in NSCLC has made it a target for treatment. Two oral inhibitors of EGFR, gefitinib and erlotinib, have been studied in detail, mainly in patients with advanced disease. Studies assessing different doses of gefitinib in patients previously treated and relapsed after chemotherapy showed tumour activity, responses and improvements in quality of life. However, a trial of gefitinib vs placebo in patients who had relapsed following chemotherapy showed only trends to better survival with the active treatment, although a similar trial of erlotinib did show both a survival advantage (2 months) and an improvement in quality of life in previously treated patients with advanced relapsed disease. Neither gefitinib nor erlotinib has been shown to be of added value when given at the start of treatment, concurrently with chemotherapy. The best responses in patients with pretreated advanced disease have been in women, of Asian origin, never smokers, and with adenocarcinoma. Other targeted therapies are in preparation and this approach may become of increasing value in the future.

Treatment and prognosis of small-cell lung cancer

Small-cell lung cancer is separated from the other types of lung cancer because of its very different biological and clinical features. It has an explosive growth pattern, such that the TNM staging classification makes no impact on prognosis or survival, almost certainly because careful staging puts most patients into the inoperable category. However, simple staging has some prognostic impact and those with limited disease (tumour confined to one hemithorax and the ipsilateral supraclavicular fossa) fare better than those with extensive disease (involvement of any site outside the hemithorax). The life expectancy of those with untreated small-cell lung cancer is about 3.5 months for limited disease and 6 weeks for extensive disease.

Lung cancer-small cell - non-technical article

Prognostic factors

Multivariate analyses of large patient populations show that routine biochemical values such as serum sodium, albumin, and alkaline phosphatase allow separation of prognostic subgroups. In addition, performance status and extent of disease are important influences. For instance a good performance status and normal biochemical values (i.e. a good prognostic category) has a 2-year survival rate of 20%, yet a correspondingly low performance status with one or more abnormal biochemical parameters (poor prognosis) has virtually no 2-year survivors. Women tend to do better than men and those under 60 better than those over 60 years of age. These factors are helpful both for stratification within clinical studies and for identifying those patients likely to do well with chemotherapy and those for whom intensive potentially toxic chemotherapy would appear inappropriate. Survival beyond 5 years (cure) is achieved in 4 to 12% of patients with limited disease and in hardly anyone with extensive disease at diagnosis. Most studies of long-term survival report late deaths due to other cancers, including NSCLCs in up to 30% of these long-term survivors.

Surgery

Very occasionally patient with small-cell lung cancer can be surgically cured, usually those presenting with a peripheral tumour and no evidence of local spread or metastasis despite extensive staging investigations. These patients are rare, but nevertheless have a 5-year survival rate in the region of 30 to 40%.

Radiotherapy

Radiotherapy has an important role in palliation of symptoms that may develop after relapse following chemotherapy. Chest irradiation also significantly decreases the rate of recurrence at the primary tumour site and in the mediastinum. A total dose of 40 to 50 Gy is usually given. Two meta-analyses on the value of adding radiotherapy to chemotherapy have shown a 5% advantage at 3 years for the addition of radiotherapy. The optimal timing of radiotherapy in relation to chemotherapy is not clear, and studies looking at giving it early (within the first 30 days of starting chemotherapy) or late (at the end of chemotherapy) have been inconclusive, but the most important factor in efficacy seems to be ensuring the prescribed chemotherapy is achieved. In several studies the additional toxicity of radiotherapy has prevented planned chemotherapy, with disadvantageous effects on survival.

Cranial irradiation

Cranial metastases are common, with 10% of patients in remission developing them as their first site of relapse. Prophylactic cranial irradiation given at the end of chemotherapy will delay the presentation of cerebral metastases and also reduce their overall incidence. This is important, as the development of cerebral disease is associated with severe morbidity, often making it difficult for the sufferer to live at home. A meta-analysis looking at the effects of prophylactic cranial irradiation on survival showed that the cumulative incidence of brain relapse was halved and the risk of death reduced by 16%, with this survival benefit being maintained after 6 years, hence it is now recommended that patients achieving a complete response after chemotherapy should have prophylactic cranial irradiation.

Chemotherapy

Small-cell lung cancer is much more sensitive to cytotoxic chemotherapy than the NSCLC tumours, with a much higher response rate for several cytotoxic drugs. In the late 1970s there was a very rapid improvement in median survival, and subsequent studies using combinations of three and four drugs brought longer response times, but responses have subsequently reached a plateau. Nevertheless, with modern combination cytotoxic treatment, which is usually given as an outpatient procedure every 3 weeks, the median survival has been extended to 14 to 18 months for limited disease and to 9 to 12 months for extensive disease. Most combinations include etoposide, cisplatin or carboplatin, cyclophosphamide, doxorubicin, and vincristine. There is no outstanding regimen, although etoposide and carboplatin is favoured by most. Modern regimens would be expected to achieve a complete response rate (i.e. disappearance of all measurable disease) in 40 to 50% of cases and a partial response rate (>50% reduction in tumour bulk) in a further 40%, giving a total response rate of 80 to 85%. All these regimens have side effects: most patients will experience some nausea and vomiting, and life-threatening septicaemia occurs in 1 to 4%, but treatment-related deaths are uncommon.

Much effort has been applied during the last 25 years to improve the median and long-term survival of patients with small-cell lung cancer, without any notable success. In general, those patients likely to do better are those who present with limited disease and a good performance status. Patients with extensive disease tend to have a universally bad prognosis and very few survive beyond 2 years. However, some metastatic sites (bone and bone marrow) are not as sinister as others (brain or liver), and the occasional patient with extensive disease does well with chemotherapy, but in general treatment is offered in this circumstance for palliation and not in the hope of cure. Studies assessing the quality of life in patients presenting with small-cell lung cancer have shown that over 70% have important symptoms such as weight loss, malaise, bone pain, dyspnoea, and haemoptysis. Most of these patients have extensive disease, but after 3 months of chemotherapy symptoms can be relieved in 60 to 70% of sufferers, making chemotherapy worthwhile, with symptomatic benefits far outweighing the potential side-effects. Ten per cent of small-cell lung cancer patients present with superior vena caval obstruction: this responds as well as any presentation to chemotherapy.

Intensity of treatment

Intensifying the dosage or the frequency of administration of cytotoxic agents has been thoroughly explored without real benefit on median survival. Small advantages are occasionally seen, but these have to be balanced by the increased toxicity resulting from a more aggressive approach. Attempts to overcome or delay the emergence of cell resistance to chemotherapy have involved alternating combinations of drugs, but these more complicated regimens have not been rewarding either. Similarly, the use of colony growth stimulation factors to allow higher or more frequent doses of drugs has not added to survival. Other studies with very high dose schedules and bone marrow harvesting and reinfusion have been unsuccessful.

Duration of treatment

Toxicity of chemotherapy increases with the number of courses given. It is now apparent that most of the tumour response to chemotherapy occurs within the first two or three cycles. Studies attempting to minimize the duration of chemotherapy without adversely affecting survival have shown that six courses of combination chemotherapy is optimal (with a course every 3 weeks), with no benefit from maintenance regimens.

General management of patients with lung cancer

There are certain complications which require specific measures to alleviate symptoms.

Patients who seem likely to survive for 6 months or more and who have vocal cord paralysis are considerably helped by an injection of PTFE (Teflon) into the affected cord, which restores voice production in a high percentage of cases and reduces the risk of aspiration.

Obstruction of the upper airway causing stridor, or of the lower major airways, is usually treated initially with radiotherapy. Should this complication recur or be unsuitable for radiotherapy, then it can sometimes be treated by laser photocoagulation administered either via a fibre-optic bronchoscope or under general anaesthetic via a rigid instrument. This is most suitable as a palliative treatment in central tumours occluding large airways: removal of considerable quantities of tumour can be achieved in a single treatment session with the rigid instrument. Trials are in progress assessing the additional benefits of endobronchial radiotherapy (brachytherapy) using iridium or caesium wires delivered via the fibre-optic bronchoscope. This procedure irradiates endobronchial tumour to a circumferential depth of about 1 cm, and will often produce a further remission. It is used where further external-beam radiotherapy cannot be given because of the risk of exceeding normal tissue tolerance. Infection distal to tumour requires antibiotic therapy and, where appropriate, oxygen therapy and bronchodilators. Severe, recurrent haemoptysis may be controlled by radiotherapy or laser.

Malignant pleural effusion recurs after aspiration unless the pleural space is obliterated. Chemical pleurodesis can be induced by intrapleural instillation of a number of agents, or by the more invasive procedure of talc pleurodesis. However, the increasing availability of VATS makes a talc pleurodesis preferable in all reasonably fit patients who can undergo a general anaesthetic. In general a pleurodesis is recommended early in management, before embarking on chemotherapy in NSCLC. In small-cell lung cancer it is worthwhile to give chemotherapy first as it is likely to gain control.

Dexamethasone, 4 to 16 mg orally daily, may control the symptoms of brain metastasis and, if so, this should be consolidated with radiotherapy to prevent severe steroid-induced myopathy, especially in patients who show a good symptomatic response to the steroids.

Prednisolone, 20 mg orally daily, is often used to improve the sense of well-being, as are blood transfusion or hyperalimentation.

Palliative care is described here (palliative care), but the importance of the combined support to the patient and the family given by the family doctor, palliative care medical and nursing staff, hospice organizations, and the hospital team cannot be overemphasized.

Prevention and screening

Lung cancer is a preventable disease which in 80% of cases is due to smoking, particularly of cigarettes. Strenuous efforts must be made to persuade people not to start smoking, to establish more effective methods of enabling people to stop, and to promote further research into effective health education. The promotion of cigarettes with low tar, nicotine, and carbon monoxide contents may have made a small contribution to prevention, but low-tar cigarettes are not a substitute for giving up smoking. Penal taxation by governments may help, as will smoke-free public places.

The identification of occupational hazards and implementation of appropriate measures to safeguard the health of employees are clearly important preventive measures, even although the number at risk is very small.

Screening of normal but high-risk populations with chest radiography and/or sputum cytology has been shown to have no effect on the mortality from lung cancer, even though more cancers are discovered. However, new studies of various populations using low-dose spiral CT have identified lung cancers in 1.4 to 2.7% of subjects in prevalence screens, the great majority having stage I disease, which is about 4 to 6 times what one would pick up by chest radiography. The older the subjects screened, the greater the smoking history and the presence of airways obstruction, the higher the incidence of occult lung cancers. As yet there are no randomized controlled trials of low-dose CT vs a control group to assess the effect of this modality on mortality, but at least one large study of 50 000 individuals has closed to recruitment. However, although low-dose CT may be a possible method of identifying lung cancers early, it has its problems and limitations. It will only pick up peripheral tumours, i.e. adenocarcinomas in the lung parenchyma, and not central, mainly squamous tumours. Small-cell cancers appear to grow too rapidly to be found by screening and will present with symptoms. Depending on where in the world the study is performed, many subjects will be found to have benign nodules that require follow up according to radiological algorithms which require repeated scans. The incidence of nodules varies from 15 to 40%, which is a potentially huge burden for imaging departments. Clearly, if low dose CT is found to identify stage I tumours and studies show an improvement in mortality, then this expensive technique will have to be considered as part of the preventive approach to smokers and ex-smokers who are fit enough to be likely to survive for 5 years or more, making screening in them worthwhile.

Other primary lung tumours

The slow-growing intrabronchial lesions previously grouped under the heading of bronchial adenoma have now been reclassified into bronchial carcinoids, adenoid cystic tumours, and mucoepidermoid tumours. They are not related to cigarette smoking, and tend to be diagnosed at a younger age than carcinoma of the bronchus.

True bronchial adenomas derived from bronchial glands are rare. These tumours were once thought to be benign, but they are potentially and often frankly malignant, being capable not only of destructive local growth but also of metastasis to regional lymph nodes in about one-third of patients, and to distant organs, particularly liver and brain, in about 10%. They are occasionally located in the trachea.

The most common symptoms of bronchial carcinoids are cough, haemoptysis, and recurrent pneumonia, although not infrequently the lesion is discovered on routine radiographic examination before symptoms develop. In the few cases that have extensive liver secondaries, there may be the classical symptom pattern of intermittent cyanotic flushings, intestinal cramps and diarrhoea, bronchoconstriction, and cardiovascular lesions. The radiographic appearances are those of a solitary nodule, pulmonary collapse, or obstructive hyperinflation. As most of the tumours occur in main stem or proximal portions of lobar bronchi, bronchoscopy is usually the definitive diagnostic measure. The tumour appears as a white or pink polypoid or lobulated mass, with the bronchial mucosa appearing to be intact. Biopsy may be followed by brisk haemoptysis.

Surgical resection is the treatment of choice. In the absence of regional spread or distant metastases 5-year survival prospects are excellent, but if there is involvement of regional nodes, survival rates fall to 70%. Some aggressive carcinoid tumours carry a much worse prognosis. 

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