Lung cancer

Abstract

Lung cancer is the most common cause of cancer-related death in men, and the second most common one in women. The primary cause remains tobacco smoking, but there is an ongoing association with air pollution and specific carcinogens including radon, asbestos and coal fumes. The outcomes remain poor with fewer than one-in-five patients surviving 5 years after diagnosis. Lung cancer presents in several different ways; early recognition and diagnosis is essential to improve outcomes. Much of the work in general practice with patients who are suffering from lung cancer involves palliative care, and by managing patients well, GPs can have a big impact on patients’ last days of life.

Clinical case scenario

A 64-year-old man presents to the practice with a 2-week history of cough with worsening dyspnoea. He also has pain on inspiration over the right side of his chest and accompanying crackles on auscultation that prompt treatment with antibiotics. However, he returns 3 weeks later with persistent cough and chest signs. He is referred urgently for a chest X-ray, which reveals right lobar consolidation. A respiratory team referral under the 2-week wait is made with a request for a computersied tomography scan of the thorax. The scan confirms a mass suggestive of malignancy, and this is confirmed to be a small cell carcinoma after subsequent biopsy by the respiratory team.

He is initially managed with chemotherapy, but further scans reveal that the tumour has already metastasised to liver and bones. During subsequent months he experiences more severe pain and becomes less able to move easily around his home. The practice is able to liaise effectively with the local palliative care team to ensure a holistic package is arranged including a Macmillan nurse, regular visits from a district nurse and a detailed pain management programme from his GP. As he becomes weaker, the practice is able to provide personalised care and develops a close relationship with the patient until he passes away peacefully at home.

Presentation

Many patients when diagnosed with lung cancer are at an advanced stage of the disease. It is essential to refer patients promptly to secondary care when the symptoms are suggestive of lung cancer. The most common presentation is of cough not resolving or unresponsive to treatment. Cough is the presenting feature of lung cancer in 56% of patients, followed by chest pain in 37% of patients (Horn and Lovly, 2018). Other symptoms commonly observed include worsening dyspnoea, weight loss, vocal changes and haemoptysis, however, a broad range of symptoms can present. As a result of the non-specific nature of many symptoms, patients are often diagnosed at an advanced stage of disease (Maori et al., 2019).

Older patients in particular may present with very vague symptoms including malaise, fatigue and poor appetite. The risk of lung cancer increases with age, and over 85% of new diagnoses are in patients over 65 years in age (World Health Organisation WHO, 2014). In 2017 the incidence in males was 74 per 100 000 of the population, whereas in females the incidence was 66 per 100 000 (Office for National Statistics (ONS), 2017). A significant number of patients are diagnosed incidentally as a result of investigation for other conditions, with one 2015 study noting the proportion of patients so diagnosed to be as high as 53.9% (Quadrelli et al., 2015).

Patients with chronic obstructive pulmonary disease (COPD) present challenges to diagnosis, as there is significant overlap between the symptoms of COPD and lung cancer. Patients with COPD may, for example, have a chronic cough associated with chest pain and shortness of breath. In such patients, assessing any changes in the nature of the cough or asking about weight loss may be the key to correct diagnosis.

Prevention

The primary strategy for the prevention of lung cancer is smoking cessation, with the risk of lung cancer directly proportional to the number of years spent smoking cigarettes and the quantity of cigarettes smoked during that time (Powell et al., 2013). There is little evidence to suggest that dietary changes have any meaningful benefit in reducing the incidence of lung cancer.

Recent research has not supported the use of screening tests such as routine chest X-rays and computerised topography (CT) scans (National Institute for Health and Care Excellence (NICE), 2019). A further key measure in prevention of mesothelioma has been the introduction of national strategies to remove asbestos from buildings and the subsequent use of safer construction materials (Borasio et al., 2008).

In general practice, smoking cessation groups can be organised within practices and patients may be signposted to existing local or national groups. Nicotine replacement therapies including patches, lozenges, sprays or tablets, may be prescribed. These therapies are generally well tolerated, but patients should be warned about possible skin or nasal irritation, insomnia and vivid dreams. Varencicline (champix) has the strongest evidence base for smoking reduction and is safe for most patients apart from those with chronic kidney disease, pregnant or breastfeeding patients and children under age 18. Bupropion, originally an antidepressant, may also be useful, although care must be taken in prescribing for patients with bipolar disorder, eating disorders and epilepsy (NICE, 2019).

Diagnosis

GPs should have a low index of suspicion for lung cancer, particularly in smokers. A full and detailed history is helpful, considering particularly the social history with a full smoking and occupational history.

It is particularly helpful to ask about the duration of any cough and whether any blood has been expectorated. Asking specifically about changes in the nature of the cough is essential in patients with COPD. Typically, patients present with a history of a persistent cough, not responding to antibiotics, or a cough they notice sounds different. Patients should be asked about chest pain, worsening dyspnoea and voice changes. When asking about dyspnoea, ask about patients’ baseline respiratory effort and any changes to this, including, for example, reduced exercise tolerance or nocturnal dyspnoea. Some patients may have been treated for several chest infections across different primary care settings and a thorough past medical history is needed to establish this fact, particularly when patients are new to the practice. In addition to smoking history, an occupational history with reference to potential asbestos exposure is essential. This includes patients who have worked as plumbers, in shipbuilding or in manufacturing.

A full respiratory examination should be carried out, noting areas of persistently reduced breath sounds or crepitations, enlarged lymph nodes and any changes in weight. Also note any new neurological features such as Horner’s syndrome or any change in sensation over the face or arms. An urgent chest X-ray is needed for patients over 40 years in age and with finger clubbing, supraclavicular lymphadenopathy, persistent cervical lymphadenopathy or chest signs consistent with lung cancer. Unexplained thrombocytosis is also an indication for an urgent chest X-ray. Unexplained hyponatraemia and hypercalcaemia warrant further investigation in view of the associated paraneoplastic syndromes (Broadus et al., 1988). Similarly, normocytic anaemia may be indicative of underlying malignancy. NICE guidelines advise an urgent chest X-ray within 2 weeks for patients aged over 40 years and with a greater than 3-week history of two or more unexplained suspicious symptoms. These include: unexplained cough, fatigue, shortness of breath, chest pain, weight loss or appetite loss. Appetite loss is a more recent addition to the guidelines, and is included because many of the symptoms are not well-described by more elderly patients.

If the patient has smoked in the past, NICE guidelines advise that only one of these symptoms is required for a chest X-ray to be necessary. The indications for an urgent chest X-ray are shown in Box 1. An X-ray with features suggestive of lung cancer is shown in the image.

Box 1.

Indications for an urgent chest X-ray in smokers aged over 40 years.

3-week history of:

• Cough

• Fatigue

• Shortness of breath

• Chest pain

• Weight loss

• Appetite loss with no apparent alternative explanation.

One symptom should trigger an X-ray in smokers or those with asbestos exposure, whereas two symptoms are needed for non-smokers.

Source: NICE (2019)

The Scottish Intercollegiate Guidelines Network (SIGN) encourages all patients with a presentation suggestive of lung cancer to have a chest X-ray, including patients with change in cough or new cough, dyspnoea, chest/shoulder pain, loss of appetite, weight loss, chest signs, hoarseness or fatigue in a smoker aged over 40 years (SIGN, 2014). Practitioners in Scotland are encouraged to use the Scottish Referral Guidelines for Suspected Cancer (2019).

Current NICE guidelines suggest referral to the respiratory team, using the 2-week rule, of all patients with any chest X-ray findings suspicious of cancer or patients aged 40 years and over with unexplained haemoptysis. A normal chest X-ray should not preclude a patient from being referred with a possible diagnosis of lung cancer. X-ray findings may be ambiguous, and patients with smaller tumours can have normal chest X-ray scans. As such, patients presenting with a clinical picture highly suggestive of lung cancer should still be referred under the 2-week rule for a lung cancer assessment. NICE guidelines for 2-week rule referrals are illustrated in Box 2 (NICE, 2019).

Box 2.

Patients who require referral under the 2-week rule.

• Chest X-ray findings suggestive of lung cancer

• Aged > 40 years and presenting with unexplained haemoptysis

• Clinical picture highly suggestive of lung cancer

Source: NICE (2019)

Patients with significant exposure to asbestos are at risk of developing mesotheliomas. As a result, NICE guidelines suggest urgent referral for a chest X-ray of patients with a history of exposure and one of the symptoms discussed above, a history of finger clubbing or chest signs compatible with pleural disease (NICE, 2019).

Local guidelines may vary, but it is often helpful to simultaneously arrange a CT scan of the thorax should the chest X-ray findings suggest a mesothelioma. In some local authorities, radiologists interpreting chest X-rays may suggest further imaging; this may lead to more rapid diagnosis. This will typically be followed in secondary care by a bronchoscopy or biopsy depending on the location of the tumour on imaging.

It is essential not to neglect other causes of cough or hoarseness in particular, and to arrange an urgent 2-week wait referral to the ear, nose and throat (ENT) department if symptoms persist. ENT referral should be considered where the chest X-ray is normal and the symptoms are more in keeping with upper respiratory tract pathology (NICE, 2019).

On diagnosis of a malignancy, further evaluation is needed for metastatic spread including a CT scan. Further assessment for malignant spread is by assessment of the patient’s general condition, paying particular attention to the forced expiratory volume and other lung function tests, as these may determine a patient’s suitability for surgical intervention. A multi-disciplinary team meeting will involve respiratory specialists, oncologists, radiologists, specialist nurses and occupational therapists with close involvement of the patient to decide on appropriate treatment.

Types of lung cancer

There are several types of lung cancer, all of which have a poor prognosis. Differentiating between the forms of malignancy is helpful in deciding on treatment strategy.

Small cell cancer

Small cell cancer presents in the central airways and progressively involves the submucosa. Over 70% of patients have significant metastases at diagnosis. Metastases commonly involve the liver, adrenal glands, bone, and brain. Patients present with symptoms described previously, which may be non-specific. Haemoptysis may be a presenting feature (Cancer Research UK, 2015).

Presenting in the lung, small cell cancer is referred to as oat cell cancer. It originates from neuro-endocrine cells in the bronchus, and as a result may present with paraneoplastic syndromes such as that of inappropriate anti-diuretic hormone secretion. This is characterised by unsuppressed antidiuretic hormone causing an unrelenting increase in solute-free water being returned to the venous circulation from the renal tubules. This causes hyponatraemia and intracellular swelling with consequences such as cerebral oedema and symptoms associated with hyponatraemia. These symptoms are non-specific and include: anorexia, nausea, muscle aches, seizures, delirium, confusion and ultimately reduced conscious level. Diagnosis is made by identifying a low serum sodium level with decreased osmolality and a high urine sodium level with no signs of organ failure or other cause of hyponatraemia. Patients presenting with this should be referred for management in secondary care with close attention to fluid balance (Maori et al., 2019).

A further condition associated with small cell lung cancer is Lambert–Eaton myesthenic syndrome, which occurs as a result of auto-immune destruction of the presynaptic membranes of the neuro-muscular junctions. The weakness predominantly affects the lower limbs and bulbar muscles, and may be relieved by exercise. The patient presents with hyporeflexia and there are often autonomic symptoms including dry eyes and mouth, constipation or excessive sweating. The condition responds to treatment of the underlying malignancy (Mareskaand Gutmann, 2004).

Patients with small cell carcinoma may also present with features consistent with ectopic adreno-corticotropic hormone production. This leads to excessive cortisol production with Cushingoid features including rapid weight gain with central obesity, muscle and bone weakness, diabetes mellitus, osteoporosis, infertility and impotence (Nieman and Ilias, 2005).

Squamous cell carcinoma

Squamous cell carcinomas present in similar ways to other types of lung cancer. Patients may also present in slightly unconventional ways with vocal changes as a result of local spread of the tumour resulting in laryngeal damage leading to vocal damage in addition to dysphagia as a result of oesophageal damage.

Squamous cell carcinomas are more strongly associated with smoking than other malignancies. It most often arises in central bronchi with spread to local lymph nodes and cavitations may be seen on X-ray (Kenfield et al., 2007).

There may also be secretion of parathyroid-related protein (PTHrP) leading to hypercalcaemia, which may be the first sign of a malignancy. Hypercalcaemia may present with thirst, muscle weakness, loss of appetite, confusion, constipation, abdominal pain, and depression. Patients with a significant hypercalcaemia require admission for IV rehydration (Broadus et al., 1988).

Adenocarcinomas

Adenocarcinomas are the most common form of lung cancer, accounting for over 50% of cases (WHO, 2014). They are more likely to be seen peripherally in the lungs and have a weaker association with cigarette smoking than other forms of lung cancer, with a relative risk (ratio of the probability of cancer in smokers to non-smokers) of 2.4, whereas the relative risk for small cell carcinoma is as high as 21.7 (Yun et al., 2005). It is a slower-growing malignancy, but tends to metastasise earlier, arising from type 2 pneumocytes. Other features associated with this include secretion of PTHrP in a similar manner to that seen in squamous cell tumours. Approximately 1% of patients suffer from hypertrophic pulmonary osteoarthropathy, presenting with a triad of distal clubbing, arthritis, and bilateral symmetrical periosteal formation (Sandler et al., 2007).

Large cell carcinomas

Large cell cancers form a heterogenous group of malignancies that lack any distinctive cytogenetic features of small or squamous cell carcinomas. The malignancy originates from epithelial cells and is essentially a diagnosis of exclusion, comprising 5–10% of all lung malignancies (Kenfield et al., 2007).

Mesotheliomas

Mesotheliomas are malignancies arising in the pleural space. The presentation may be indolent with non-specific symptoms over time. Patients may also present with lung collapse or pneumothorax in addition to a pleural effusion present on chest X-ray. They typically follow exposure to asbestos, and this exposure in combination with cigarette smoking greatly increases the risk of mesothelioma. There is typically a 20 to 40 year time lag between exposure and diagnosis (Borassio et al., 2008). Patients often present with a pleural effusion on examination and on chest X-ray. The prognosis is poor with no effective curative treatment available and a median survival of just 2 years from diagnosis (O’Reilly et al., 2007).

Pancoast tumours

Pancoast tumours are typically non-small cell cancers originating from epithelial cells that present as an apical lung cancer with ipsilateral Horner’s syndrome. There is invasion of the cervical sympathetic plexus. In addition, there may be brachial plexus invasion at C8 to T2 leading to arm and shoulder pain. As a result of unilateral recurrent nerve palsy, other features include hoarseness and a bovine cough. They may be rapidly growing so that neurological features precede the clinical features of cough and shortness of breath.

Treatment and prognosis

Treatment and prognosis depend heavily on the type of cancer. Small cell cancer has a particularly poor prognosis as a result of the high risk of relapse despite treatment. The 10-year survival rate remains 3.5%, with a slightly better outcome for women. Treatment initially involves combination chemotherapy with etoposide and cisplatin or carboplatin. There may be a role for radiotherapy, particularly cranial irradiation, which can alleviate symptoms associated with brain metastases such as headache or seizures. As a GP it is important to explain to patients the potential side effects and challenges of radiotherapy, including fatigue and weight loss (Maori et al., 2019).

Patients must be fully informed of the side effects of chemotherapy, particularly including vomiting and nausea, which over time may lead to dehydration. There may be neurological side effects including weakness and paraesthesia. Patients may suffer from hair loss. The risk of neutropenic sepsis remains high, and patients should be encouraged to seek help early in the event of a fever. Local guidelines may vary, however, it is important for patients to have a clear point of contact for action should neutropenic sepsis be suspected, whether that be direct access to the oncology team or use of the 111 service out of hours.

Recent developments have included the development of immunotherapies for small cell cancer including nivolumab and atezolizumab, which have been shown to improve survival rates in certain patient groups. Patients must still be monitored closely for signs of a relapse, and in this event an aggressive combination of four chemotherapy medications may be used (Maori et al., 2019). The treatment options continue to evolve and liaising with colleagues in secondary care remains essential.

Treatment of squamous cell carcinoma depends on the stage of the malignancy. Patients with stage 1 or 2 malignancies may be offered curative surgery to remove the malignancy with adjuvant chemotherapy, whereas patients with later-stage disease will be offered palliative chemotherapy, often with cisplatin or carboplatin. In these stages patient survival rates remain low (Sandler, 2007).

Treatment of adenocarcinomas depends upon the stage of the malignancy, in addition to the condition of the patient. Stage 1, 2 and 3a malignancies are removed surgically using a pneumonectomy or lobectomy if the patient is able to tolerate the surgery. If the patient is unable to tolerate the surgery, or has a stage 4 malignancy, platinum-based chemotherapy involving cisplatin or carboplatin is first line. There is some role for radiotherapy as an adjuvant to surgery and chemotherapy (Sandler, 2007).

Mesothelioma treatment remains challenging, as the malignancy is resistant to chemotherapy and radiotherapy. Surgical options are limited with pleurectomies not showing good results and pneumonectomies presenting with serious complications. Chemotherapy often is the only option with cisplatin-based chemotherapy demonstrated to improve survival rates from 10 to 13.3 months in one case series (Panou et al., 2015).

Complications

Superior vena cava obstruction affects 3% of patients who suffer from lung cancer, with the other major cause being lymphoma. It occurs due to infiltration of the vessel wall, a clot within the superior vena cava or extrinsic pressure as a result of a mass. The presentation is with worsening shortness of breath, possibly with stridor in addition to obvious facial swelling and corneal injection. Other symptoms include a headache, which becomes worse on stooping, as well as visual disturbances and dizziness with a high risk of collapse. If suspected, examination findings may include non-pulsatile distension of the neck veins and dilated collateral veins over the chest wall. Patients with this condition should be immediately referred for an oncology opinion, as there is a 70% response rate to palliative radiotherapy. High-dose dexamethasone may also be started while awaiting review in secondary care (WHO, 2014).

Although pain commonly occurs in the context of lung cancer, pain which suddenly becomes more severe may indicate a possible fracture, so orthopaedic involvement is indicated. Patients with lung cancer remain at risk of spinal cord compression as a result of vertebral fractures, and any patient presenting with back pain should be fully evaluated for any neurological signs. These include leg weakness, urinary or faecal incontinence, numbness and paraesthesia. Urgent referral to secondary care should take place when any neurological complications arise.

Similarly, dyspnoea may be a sign of an underlying complication, such as a pleural effusion or pulmonary embolism. Identifying patients with potentially treatable conditions such as effusions is essential in adding months to patient’s lives. Therefore, patients should be examined thoroughly and investigations arranged, when if there is a sudden change in the patient’s symptoms.

Confusional states may arise as a result of the metabolic abnormalities discussed earlier, however, brain metastases may lead to gradual onset confusion in addition to seizures associated with focal neurological deficits and loss of consciousness. An urgent CT scan should be requested and there may be a role for radiotherapy. Confusional states may be exacerbated by worsening dehydration as patients become less able to tolerate fluids, exacerbating hyponatraemia and hypercalcaemia. It is essential in these circumstances to assess each patient individually, as some may benefit from brief hospital admissions for rehydration, whereas others clearly will not and may not wish to spend the last days of their lives in hospital.

End of life care

The role of the GP in end of life care often involves development of a close relationship with the patient and awareness of changes in the patient’s condition as they arise. Pain is a common problem, often as a result of bony metastases, leading to severe discomfort throughout the whole body. Bony pain may initially respond well to non-steroidal anti-inflammatory drugs, but may later require opiates. There is often a role for palliative radiotherapy. Pain may also affect the chest wall as the tumour begins to invade and create pressure on the intercostal nerves.

As the cancer progresses, the pain may become more severe, to the point where the patient requires opioid analgesia. At this point regular morphine sulphate is likely to be of benefit, often with oral morphine solution. As the patient becomes less able to tolerate oral forms of analgesia, it is usually essential to use a syringe driver to administer medication, including diamorphine, subcutaneously. The dose should be started as an equivalent to the patient’s requirement of oral medication and may be titrated upwards until adequate analgesic control is established, with as required medication as a minimum. A further option is to use transcutaneous patches to deliver opiate analgesics including fentanyl and buprenorphine. Many patients with lung cancer become increasingly breathless as they reach the end of their lives, with the cause usually multi-factorial. Restrictive causes include respiratory muscle weakness, fibrosis and reduced respiratory effort as a result of chest wall pain. If no cause is identified, there may be a role for morphine-based analgesia. The sensation of dyspnoea may lead to worsening agitation as the patient becomes more distressed. In this situation benzodiazepines such as midazolam may be of benefit.

Nausea and vomiting are a common problem in the palliative care of patients, often as a result of strong opiate medication in addition to the ongoing malignancy and associated metabolic abnormalities. During the final stages of life, it is vital to control these symptoms using anti-emetics, potentially through a syringe driver. Cyclizine or levopromazine are both highly effective.

During the later stages of the illness, it is essential to consider the patient in a holistic context. There may be a large grieving family and GPs are often a vital resource of reassurance and support. Families often appreciate having a named GP they are able to contact in the event of problems and the relationships developed remain close even after the patient has passed away. The role of district nurses in providing regular visits is essential, and ensures that patients receive continuity of care. Many practices have palliative care leads and maintain up-to-date lists of patients with palliative care needs.

GPs also work in the context of a wider team where they are able to draw on support from specialist nurses, often associated with organisations such as Macmillan Cancer Support. Oncologists are able to offer advice during emergencies and hospital-based palliative care teams may also visit regularly to ensure the patient is supported. Regular visits may also be carried out by occupational therapists to ensure that patients’ homes are adequately supported for their condition.

Patients should be made aware of other sources of support, particularly that offered through the disability living allowance. There may be a need to supply supporting evidence and this should be done promptly to ensure patients receive the support required. It may be helpful to ask patients about their religious beliefs and sensitively encourage them to seek spiritual support. Organisations such as Maggie’s cancer care are also a valuable resource for counselling and bereavement management.

GPs are able to access a good range of resources related to palliative care including the RCGP palliative care online toolkit, which contains clinical resources and guidelines for both clinicians and patients. It has been developed in collaboration with other organisations, including Macmillan and Marie Curie, and involves a patient-centred approach (RCGP, 2020).

KEY POINTS

Lung cancer remains an extremely common form of cancer; survival outcomes are usually poor with smoking cessation the primary preventive strategy

Prompt, appropriate referral by GPs of patients with suspected lung cancer according to clear guidelines is essential to achieve earlier diagnosis

GPs should have a low index of suspicion for lung cancer, particularly in smokers; a full and detailed history of symptoms, smoking and occupation is essential to guide referral

A normal chest X-ray should not preclude referral for suspected lung cancer, as patients with smaller tumours can have normal chest X-rays

Treatment of lung cancer depends on the disease type and staging

Patients must be managed holistically with exploration of wider social contexts as well as symptoms and signs suggestive of disease progression

Footnotes

ORCID iD

Dr Michael Bryant

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