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Lung cancer 

Lung cancer
Chapter:
Lung cancer
Author(s):

S.G. Spiro

DOI:
10.1093/med/9780199204854.003.181901_update_003

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Screening—discussion of use of low-dose spiral CT in National Lung Screening Trial.

Clinical staging—enhanced discussion of use of PET scanning.

Prognosis and management—use of analysis of mutations within tumours to target therapy with, e.g. kinase inhibitors; discussion of stereotactic radiotherapy.

Updated on 29 May 2014. The previous version of this content can be found here.
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Essentials

Lung cancer remains the commonest killing cancer in both men and women in the developed world, and is increasingly common in developing countries, although as a result of decreased tobacco consumption in Western countries there has been a considerable reduction in the incidence amongst men over the last 20 years, and a slowing down in incidence in women over the last few years. Nevertheless, lung cancer in women is commoner than breast cancer in some Western countries. There are several important industrial associations with lung cancer, in particular asbestos, but tobacco remains by far the most important cause.

Pathology—there are four main cell types of lung cancer, of which adeno-, squamous and large cell varieties comprise non-small-cell lung cancer (NSCLC), with the more aggressive type—small cell—being regarded as a separate entity from the point of view of staging and treatment.

Clinical features—there are no particular presenting features that strongly suggest a new lung cancer, hence it is a disease that often presents late and with widespread metastatic disease. Symptoms and signs can be subdivided into (1) intrapulmonary symptoms—cough (most commonly), haemoptysis (most dramatically), wheeze, chest discomfort, and breathlessness (rare as a presenting feature); (2) extrapulmonary, intrathoracic symptoms and signs—Horner’s syndrome, vocal cord paralysis, superior vena caval obstruction, dysphagia; (3) extrathoracic, metastatic manifestations—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; and (4) paramalignant syndromes—syndrome of inappropriate secretion of antidiuretic hormone, ectopic ACTH syndrome, hypercalcaemia, neuromyopathies, finger clubbing, and hypertrophic pulmonary osteoarthropathy.

Lung cancerIncidental findings and screening—about 5% of lung cancers are found by chance on a chest radiograph performed for reason other than suspicion of cancer, and these tend to have a better prognosis. Screening of high-risk groups for lung cancer with low-dose spiral CT is attracting interest and randomized trials are beginning to be reported. The very large National Lung Screening Trial of 56,000 individuals in the USA has shown a 20% reduction in mortality from lung caner with three annual CT screens compared to a control group, and a 6.7% reduction in all-cause mortality.

Lung cancerClinical staging—accurate clinical staging is paramount for treatment decisions, especially for NSCLC, which may be resectable. Following a chest radiograph, a CT of the thorax and upper abdomen should be performed. Biopsy of the primary tumour (via a bronchoscope for centrally situated lesions and—using ultrasound guided systems—mediastinal lymph nodes, or by percutaneous image-guided needle, depending on best access) or of a metastasis is required, the latter providing a diagnosis and staging information at the same time. PET scanning, which depends on the uptake of a glucose analogue (fluorodeoxyglucose, FDG) by active tumour and its metastases, is recommended as the final staging test in those patients where resection or another curative treatment is contemplated. PET will change the clinical stage in about 30% of apparently resectable cases.

Lung cancerPrognosis and management—(1) NSCLC— ‘curative’ treatment by surgical resection can be applied to 10 to 15% of all cases, of whom about 35% survive at 5 years. Radical radiotherapy cures very few with locally advanced disease, although better results are claimed with the addition of chemotherapy. Newer techniques such as sterotactic radiotherapy, with tighter focus on the tumour, may increase the cure rate. In patients with advanced NSCLC and good performance status, survival at 1 year is 15 to 20% with supportive care alone, and 40% with chemotherapy. Emerging evidence of mutations within tumours has lead to better identification of those who may respond to targeted therapy, e.g. with kinase inhibitors or receptor antagonists, rather than cytotoxic chemotherapy. (2) Small-cell tumours—life expectancy of those with untreated disease is about 3.5 months for limited disease and 6 weeks for extensive disease. Chemotherapy remains the cornerstone of treatment: 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%. Patients achieving a complete response after chemotherapy should have prophylactic cranial irradiation. Median survival is around 18 months for limited disease and 9 months for extensive stage disease.

Management of complications—some complications of lung cancer require specific measures to alleviate symptoms: (1) vocal cord paralysis may be helped by injection of Teflon into the affected cord; (2) obstruction of the upper airway causing stridor, or of the lower major airways, is usually treated initially with radiotherapy; (3) malignant pleural effusion is treated with talc pleurodesis; (4) dexamethasone may control the symptoms of brain metastasis and, if so, this should be consolidated with radiotherapy, and (5) intravenous stenting can cause dramatic relief from superior vena caval obstruction.

The multidisciplinary team—the importance of the combined support to the patient and the family given by the family doctor, palliative care medical and nursing staff, and hospice organizations, and the hospital team cannot be overemphasized.

General epidemiology

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 35 000 deaths per year in England and Wales, with 70% 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%. The increasing incidence in women means that lung cancer is now the fourth commonest cancer in women worldwide and the second commonest cause of cancer death.

Lung cancerAge-standardized mortality rates for cancer show that in Europe lung cancer in men was by far the commonest cause of death. Hungary has the highest mortality (109.5 deaths per 100 000 population) with Poland (104.5) second, and Estonia third with 91.5 deaths per 100 000. For women, Denmark has the highest incidence (49.5), with Hungary (39.8) second and the UK (38.7) third. Within the UK there are much higher rates in Scotland and the North of England, reflecting smoking patterns. 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 18.19.1.1. 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.

Table 18.19.1.1 Death rate from lung cancer in males by smoking habits when last asked (British doctors’ study)

Tobacco use category

Death rate (age standardized per 100 000)

Nonsmokers

10

Ex-smokers

43

Continuing smokers

Any tobacco

104

Pipe and/or cigar only

58

Mixed

82

Cigarette smokers only

140

Number smoked per day

1–14

78

15–24

127

25 or more

251

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 Box 18.19.1.1.

Reproduced from Coggon D, Acheson ED (1983), with permission.

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 have disseminated at the time of diagnosis, even though most metastases may be too small to detect.

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, although this is changing as adenocarcinomas seem to be becoming commoner throughout the world. 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

Carcinoid tumours are described in Chapter 15.9.

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.

Lung cancerRecent 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. The responses to these targeted treatments in those with the EGFR mutation is striking and has led to pathologists examining all diagnostic biopsies for their presence. Targeted therapy is now the first line treatment for EGFR positive individuals, who broadly are Asian, women, and nonsmokers with an adenocarcinaoma.

Furthermore NSCLC harbours other “driver” mutations, which if “turned off” can be a highly effective antitumour therapy. These are found in particular in adenocarcinomas in multiple genes, including (in addition to EGFR) HER2, KRAS, BRAF, PIK3CA, ATK1, MEK1, ROS1 and ALK. Mutations within individual genes can be associated with primary drug resistance, primary drug sensitivity, or secondary drug resistance. The distinct tumour mutation profile of many Asian women has become a target for treatment (see below) as 90% of them may contain one of EGFR, HER2, ALK, ROS1, and KRAS, of which EGFR, HER2, ROS1, and ALK are treatable with kinase inhibitors.

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 (Fig. 18.19.1.1). 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 up to 98% of incidentally discovered nodules tend to be benign, making investigation problematic.

Fig. 18.19.1.1 The lung cancer growth curve and ability to detect a tumour during its natural history.

Fig. 18.19.1.1
The lung cancer growth curve and ability to detect a tumour during its natural history.

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 (Fig. 18.19.1.2). These patients tend to have a better prognosis (20–70% 5-year survival) than those with symptoms related to the primary tumour (12–35% 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 12 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 specific entity amongst the 20 most common eventual causes.

Fig. 18.19.1.2 Chest radiograph showing a chance finding of a right upper lobe mass (arrow) with a bulky right hilum.

Fig. 18.19.1.2
Chest radiograph showing a chance finding of a right upper lobe mass (arrow) with a bulky right hilum.

Clinical symptoms and signs 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 18.19.1.2).

Table 18.19.1.2 The presentation of lung cancer (frequency (%) of commoner symptoms/signs indicated)

Chest symptoms

Mediastinal involvement

Chest radiographic abnormalities

Paramalignant syndromes

Extrathoracic metastases

Haemoptysis (6–35)

Superior vena caval obstruction (0–4)

Peripheral nodule

Hypercalcaemia (0–10)

Bone pain (6–25)

Cough (8–75)

Left recurrent laryngeal nerve palsy (0–10)

Lobar/lung collapse

SIADH (0–50)

Neurological

Wheeze (0–10)

Diaphragmatic palsy (0–5)

Cavitating mass

SIACTH (0–5)

Jaundice

Stridor (0–2)

Pericardial effusion

Abnormal hilum

HPOA/clubbing (0–20)

Skin nodules

Pain (20–50)

Dysphagia

Pleural effusion

Lambert–Eaton syndrome (0–3)

Lymphadenopathy

Dyspnoea (3–60)

Lymphangitis

Cerebellar dysfunction

Weight loss (0–68)

Bone lesion

Neuropathies

Lethargy (0–10)

Wide mediastinum

SIACTH, syndrome of inappropriate ACTH; SIADH, syndrome of inappropriate antidiuretic hormone; HPOA, hypertrophic pulmonary osteoarthropathy.

Intrapulmonary symptoms

Lung cancerCough 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 (Figs. 18.19.1.318.19.1.7). A change in the cough habit, or a cough lasting more than 4 weeks, 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, especially if there is accompanying hoarseness. A recent awareness campaign which for three months in summer 2013 asked those in a UK region with a cough lasting more than three weeks to see their GP, resulted in 700 more primary lung cancers being found than in the corresponding period two years earlier.

Fig. 18.19.1.3 Cavitating squamous-cell lung cancer.

Fig. 18.19.1.3
Cavitating squamous-cell lung cancer.

Fig. 18.19.1.4 Chest radiograph showing a tumour in the right lower lobe behind the heart causing a double shadow for right heart border.

Fig. 18.19.1.4
Chest radiograph showing a tumour in the right lower lobe behind the heart causing a double shadow for right heart border.

Fig. 18.19.1.5 Chest radiograph showing a collapsed left upper lobe due to proximal tumour.

Fig. 18.19.1.5
Chest radiograph showing a collapsed left upper lobe due to proximal tumour.

Fig. 18.19.1.6 (a) Chest radiograph showing an ill-defined parenchymal mass (arrow) in the left upper lobe; (b): CT scan of the chest of the same patient as in (a), confirming a large central mass (arrow) encasing the left upper lobe bronchus.

Fig. 18.19.1.6
(a) Chest radiograph showing an ill-defined parenchymal mass (arrow) in the left upper lobe; (b): CT scan of the chest of the same patient as in (a), confirming a large central mass (arrow) encasing the left upper lobe bronchus.

Fig. 18.19.1.7 (a) Chest radiograph showing a right upper lobe tumour causing wheeze with bulky right paratracheal nodes (arrow); (b) CT scan of the chest of the same patient as in (a), showing grossly enlarged mediastinal pretracheal lymph nodes (arrow); (c) chest radiograph of the same patient as in (a), showing complete response after two courses of chemotherapy.

Fig. 18.19.1.7
(a) Chest radiograph showing a right upper lobe tumour causing wheeze with bulky right paratracheal nodes (arrow); (b) CT scan of the chest of the same patient as in (a), showing grossly enlarged mediastinal pretracheal lymph nodes (arrow); (c) chest radiograph of the same patient as in (a), showing complete response after two courses of chemotherapy.

Expectoration of sputum may be due to irritation of the tumour in a major airway or to infection occurring distal to partial bronchial obstruction, although this is more common in COPD. 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, or with streaks in their sputum, 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 (Fig. 18.19.1.7).

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 (Fig. 18.19.1.8). 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.

Fig. 18.19.1.8 Chest radiograph showing a large left upper lobe mass with a right rib metastasis (arrow) causing pain, which was the reason for presentation in this case.

Fig. 18.19.1.8
Chest radiograph showing a large left upper lobe mass with a right rib metastasis (arrow) causing pain, which was the reason for presentation in this case.

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 mid-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, with increased dyspnoea in those with pre-existing lung disease, e.g. COPD.

Dysphagia is due to compression of the mid-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, with increased dyspnoea in those with pre-existing lung disease, e.g. COPD.

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 (Figs. 18.19.1.818.19.1.11). 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.

Fig. 18.19.1.9 CT scan of the upper abdomen of the same patient as shown in Fig. 18.19.1.6, revealing a large necrotic liver metastasis (arrow).

Fig. 18.19.1.9
CT scan of the upper abdomen of the same patient as shown in Fig. 18.19.1.6, revealing a large necrotic liver metastasis (arrow).

Fig. 18.19.1.10 CT scan of the brain in patient presenting with vagueness. Note marked cerebral oedema around metastases (arrows), and midline shift.

Fig. 18.19.1.10
CT scan of the brain in patient presenting with vagueness. Note marked cerebral oedema around metastases (arrows), and midline shift.

Fig. 18.19.1.11 CT (A) and PET (B) scan of the abdomen showing a solitary mass in the right anterior abdominal wall (arrows) in a patient with a lung tumour. The mass is PET positive.

Fig. 18.19.1.11
CT (A) and PET (B) scan of the abdomen showing a solitary mass in the right anterior abdominal wall (arrows) in a patient with a lung tumour. The mass is PET positive.

Lung cancerBony 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. Bone lesions are usually confirmed when a PET scan is done for staging purposes, and isotope scans are now rarely performed.

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 may become grossly enlarged with an irregular margin.

Metastases to the brain may be the presenting symptom in lung cancer in 4% of patients and may be encountered at some time in the illness in 30% (Fig. 18.19.1.10). The symptoms simulate those of any expanding brain tumour.

The adrenal glands are involved in 15 to 20% of patients, rarely producing symptoms and found on a staging CT. 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 (Fig. 18.19.1.11).

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 typical radiographic appearances are shown in Fig. 18.19.1.12. 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.

Fig. 18.19.1.12 Radiograph of the ankle showing new periosteal growth due to hypertrophic pulmonary osteopathy.

Fig. 18.19.1.12
Radiograph of the ankle showing new periosteal growth due to hypertrophic pulmonary osteopathy.

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.

Investigations 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 (Table 18.19.1.3 and Table 18.19.1.4).

Table 18.19.1.3 International Association for the Study of Lung Cancer staging project: TNM classification

cTNM clinical classification

Primary tumour (T-factor)

TX

Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualised by imaging or bronohoscopy

TO

No evidence of primary tumour

Tis

Carcinoma in situ

T1

Tumour <3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)

T1a

Tumour <2 cm in greatest dimension

T1b

Tumour:>2 cm but not >3 cm in greatest dimension

T2

Tumour >3 cm but not >7 cm; or tumour with any of the following features:

Involves main bronchus, >2 cm distal to the carina

Invades visceral pleura

Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a

Tumour >3 cm but not >5 cm in greatest dimension

T2b

Tumour >5 cm but not >7 cm in greatest dimension

T3

Tumour more than 7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumour in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe

T4

Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe

Regional lymph nodes (N-factor)

NX

Regional lymph nodes cannot be assessed

NO

No regional lymph node metastasis

N1

Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3

Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M-factor)

MX

Distant metastasis cannot be assessed

MO

No distant metastasis

M1

Distant metastasis

M1a

Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial) effusion

M1b

Distant metastasis

Table 18.19.1.4 International Association for the Study of Lung Cancer staging project: stage grouping

Occult carcinoma

TX NO MO

Stage 0

Tis NO MO

Stage IA

T1a, b NO MO

Stage IB

T2a NO MO

Stage IIA

T1a, b N1 MO

T2a N1 MO

T2b NO MO

Stage IIB

T2b N1 MO

T3 NO MO

Stage IIIA

T1, T2 N2 MO

T3 N1, N2 MO

T4 NO, N1 MO

Stage IIIB

T4 N2 MO

Any T N3 MO

Stage IV

Any T Any N M1

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 (see Figs. 18.19.1.218.19.1.8). Anything suspicious will lead to the radiologist suggesting 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—ideally with endobronchial ultrasound to examine the lymph nodes—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 (see Fig. 18.19.1.4). Apically located masses or superior sulcus tumours (Pancoast tumours) may be misdiagnosed as pleural caps, and often have a history of several months 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 (see Fig. 18.19.1.8). 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

Lung cancerAlthough it is recommended that patients suspected of having lung cancer should be referred for a chest X-ray, we know from screening studies that CT is about four times better at identifying new lung cancers than the conventional chest radiograph. CT it is not yet regarded as the first choice investigation, but this may change in the next few years. Nevertheless, 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.

Lung cancerMediastinal lymphadenopathy on CT is arbitrarily taken to be pathological if a gland is 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. PET scanning (see below) is often performed as a final staging test before a lymph node is biopsied: this will confirm abnormality by an increased uptake (SUV) and/or it may identify an occult metastasis that might be more accessible to biopsy and downstage the patient, thus changing management.

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, which is described in detail in Chapter 18.3.3, is frequently the definitive diagnostic method in lung cancer. About 60–70% 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.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound needle aspiration biopsy (EUS-FNA)

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 are being increasingly replaced by minimally invasive techniques including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), where fine needle aspiration or biopsy is performed with a catheter containing an ultrasound probe placed within a fibreoptic bronchosope, and endoscopic ultrasound needle aspiration or core-biopsy (EUS-FNA), via a similar catheter placed within an endoscope in the oesophagus. 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%. Incorporating the ultrasound guided system allows access to the upper and lower paratracheal nodes, the subcarinal nodes and some hilar nodes. The EUS allows direct sampling of the left paratracheal nodes, aorto-pulmonary window, sub-carinal, and para-oesophageal nodes, i.e. a more extensive field than accessible at open mediastinoscopy. Both these procedures are safe and often done in conjunction after a PET scan localizes potential tumour containing nodes. The sensitivity of these techniques is much greater with the use of the ultrasound probe, approaching 90% in studies with disease prevalences of 61–68%.

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 transthoracic 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, bullae adjacent to the tumour 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 lung tissues likely to remain after a planned resection. 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, and much greater than for a lobectomy. 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 staging algorithm investigations for NSCLC are summarized in Fig. 18.19.1.13. 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 those with 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, this should be assessed and biopsied. If a CT is abnormal in the mediastinum and PET 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 biopsies of 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. However, most patients with extrathoracic metastases will have abnormal nodes within their mediastinum.

Fig. 18.19.1.13 Staging algorithm for non-small-cell lung cancer.

Fig. 18.19.1.13
Staging algorithm for non-small-cell lung cancer.

Treatment and prognosis of NSCLC

Surgery

Surgery remains the single modality most likely to be curative in NSCLC. Before surgery the patient should have been carefully staged (Fig. 18.19.1.13), and the chances of long-term survival will be greatly influenced by this. All patients with stage IIIB disease (Table 18.19.1.4) 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 18.19.1.5 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. The 5-year survival curves for a more recent series of 3211 patients from Norway, operated upon between 1993 and 2002, are shown in Fig. 18.19.1.14 for survival by pathological stage and for extent of resection. 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 18.19.1.5).

Table 18.19.1.5 5-year post surgical survival rates in NSCLC by clinical (C) and pathological post operative (P) stage: studies of >2000 patients

Pfannschmidt

Goya

Naruke

Stage

C stage

P stage

C stage

P stage

C stage

P stage

IA

68.5

72.0

79.5

70.8

79.0

IB

66.6

49.9

60.1

44.0

59.7

IIA

55.4

48.7

59.9

41.1

56.9

IIB

49.0

40.6

42.2

35.5

45.0

IIIA

35.8

35.9

29.8

22.6

23.6

IIIB

35.4

28

19.3

18.5

16.5

IV

Not defined

20.8

20

5.1

Data expressed as percentage.

From Potton E and Spiro SG, in Thoracic Malignancies, 2009.

Fig. 18.19.1.14 Left panel: Kaplan–Meier survival curves according to surgical procedure for patients resected for lung cancer diagnosed between 1993 and 2002 in Norway. Right panel: same population showing survival by stage.

Fig. 18.19.1.14
Left panel: Kaplan–Meier survival curves according to surgical procedure for patients resected for lung cancer diagnosed between 1993 and 2002 in Norway. Right panel: same population showing survival by stage.

(from Thorax 2006; 61, 40, with permission.)

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 extrapulmonary disease 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 was initially reserved for those with inadequate lung function for lobectomy, as hilar and mediastinal node evaluation and dissection is not always possible. However, as experience has developed, it is being used more and more for lobectomy, as well as exploration of the draining hilar and mediastinal nodes. Advantages include less post-operative pain and shorter inpatient stays. The survival data shows no differences between a VATS lobectomy and a lobectomy by thoracotomy. However, a wedge resection confers a worse 5-year survival than anatomical segmentectomy. These lung sparing procedures may be more suitable for elderly subjects.

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. The increasing availability of stereotactic body radiotherapy has allowed small masses, usually less than 3 cm in diameter, to be precisely positioned for radiotherapy, allowing larger than conventional doses to be given to a reduced volume of lung, and avoiding exposure of normal lung to adverse effects. There are no randomized trials of stereotactic body radiotherapy against conventional fields and doses, but the early 2-year survival is encouraging at 45–77%, with hardly any progression seen and very little pulmonary toxicity.

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%.

In 1997 continuous hyperfractionated accelerated radiotherapy (CHART), with a fraction every 8 h for 12 consecutive days to a total of 54 Gy, was 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.

Lung cancerChemotherapy and targeted therapy

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. Chemotherapy became a routine treatment for inoperable NSCLC about 20 years ago after a meta-analysis of 53 randomized controlled studies in which patients did or did not receive chemotherapy in addition to surgery, radiotherapy, or to best supportive care. 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. The agents used in these early trials were more toxic than the newer, currently available agents and the associated deleterious effects on quality of life have dramatically improved. Also it emerged that different combinations of drugs are more effective for different cell types of NSCLC. The optimal initial chemotherapy for squamous cell NSCLC is carboplatin or cisplatin, plus one of gemcitabine, vinorelbine, or paclitaxel. A large study of these agents compared to cisplatin and pemetrexed, showed superior survival for the latter doublet for adenocarcinomas, and this had become the initial treatment of choice. However, the routine assessment for EGFR and other mutations has changed this (see below).

The use of chemotherapy as an adjuvant following successful surgery has shown a 5.2% increase in the 5-year post surgery survival for patients with at least Stage II disease, and this should be offered to those who have recovered well and within 60 days of their surgery.

In advanced disease, which will affect up to 90% of all cases of NSCLC, chemotherapy confers an important survival advantage compared to best supportive care alone. In general, studies of palliative chemotherapy have shown a quality of life benefit, at least over the first few months after treatment is complete. There is no particular regimen that stands out, but chemotherapy in advanced disease, chosen on their cell-type, 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%. More recent clinical trials have shown a differential effect of chemotherapy in that adenocarcinomas have a higher response rate and survival with pemetrexed plus a second agent, whilst squamous cell tumours respond better to platinum containing doublets. Hence the importance of establishing the cell type in NSCLC prior to planning therapy.

The rapid evolution of molecular biology and the ability to identify the presence of mutations in small biopsy tissue samples has lead to a drive for targeted therapy based on inhibition of the “driver” mutant gene. The first important mutation discovered—and now routinely sought for—was EGFR, and overexpression of EGFR and its ligands in NSCLC has made it a target for treatment. Two oral inhibitors of EGFR, gefitinib and erlotinib, are in current use. Patients who harbour EGFR mutations have approximately a 70% better response rate and prolonged progression-free survival and improved quality of life on an EGFR tyrosine kinase inhibitor (TKI) than with conventional chemotherapy. Conversely, patients whose tumours are wild-type for EGFR display minimal responses to EGFR TKI, and do best with first line chemotherapy. With this approach the overall survival of patients with EGFR mutant tumours treated first line with TKIs is about 27–30 months. By comparison the overall survival of patients with metastatic unselected NSCLC on first-line chemotherapy is 10–12 months. Similar observations have been made for patients with tumours harbouring ALK fusions, which can now be treated with the ALK TKI crizotinib. Other targeted therapies are in preparation and this approach may become of increasing importance 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.

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 (Fig. 18.19.1.15). 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.

Fig. 18.19.1.15 Survival in small-cell lung cancer by prognostic factors (G, good; Im intermediate; P, poor) compared to full staging (L, limited; E, extensive disease).

Fig. 18.19.1.15
Survival in small-cell lung cancer by prognostic factors (G, good; Im intermediate; P, poor) compared to full staging (L, limited; E, extensive disease).

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. 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. There is no established second line treatment at relapse, although if remission has been achieved for a year or longer, restarting the same chemotherapy regimen can be effective in some cases.

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 (see Chapter 18.17). 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 in Chapter 31.1, 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. A large study of 53 454 individuals has been published. The National Lung Screening Trial (NLST) randomized current and ex-smokers to three annual low-dose CT scans in the screened group, whereas the control group had a chest radiograph. The trial has shown a 20% reduction in mortality for the CT-screened arm, with 247 deaths from lung cancer per 100 000 person-years in the screened arm versus 309 in the controls. This represents an overall reduction in all cause death rate of 6.7%. A study of this magnitude is unlikely to ever be repeated and its impact will seriously affect thinking regarding screening for lung cancer. However, the study was expensive, there is no cost effectiveness data as yet, and there is data to suggest that the high risk individual for lung cancer is elderly, poorly educated and risk averse, and unlikely to participate in a screening trial. More information is needed. However, other randomized trails, smaller than NLST, are in progress and will report soon, and although low-dose CT may become an important 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 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. In the NLST, 24.2% of CT-screened individuals had positive scans, of which 96.4% were false positive. 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. The mechanism and management of the general symptoms of the carcinoid syndrome are described in Chapter 15.9.

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