Lung Malignancy

The management guidelines for small-cell and non-small-cell lung cancers in this article are taken from the guidelines published by NICE in February 2005.¹ There is a separate article on Malignant Mesothelioma - a tumour of mesothelial cells which usually occurs in the pleura, but may also occur elsewhere, e.g. the peritoneum.

Approximately 95% of all primary lung tumours are bronchial carcinomas. Metastases in the lung are common and typical sites for the primary tumour include the kidney, prostate, breast, bone, gastrointestinal tract, cervix and ovary. Metastases usually develop in the parenchyma and are relatively asymptomatic even when metastases are extensive. Carcinoma of the stomach, pancreas and breast may involve mediastinal glands and spread along the lung lymphatics (lymphangitis carcinomatosa) causing progressive and severe breathlessness.

Primary bronchial cancers are classified as follows:²

• Small-cell lung cancers (SCLC), which account for about 17% of cases:
  • Also called oat-cell carcinoma and arises from Kulchitsky cells, which are part of the amine precursor uptake and decarboxylation (APUD) endocrine system. APUD cells manufacture polypeptides and amines which act as hormones or neurotransmitters
  • Rapidly growing and highly malignant; spread early and are almost always inoperable at presentation.
  • Responds to chemotherapy but the prognosis is poor.
• Non-small-cell lung cancers (NSCLC), which account for 80% of cases. The NSCLC are often grouped together when treatment is being considered. NSCLC include:^1,3
  • Squamous (42% of NSCLC):
    • Most present as obstructive lesions of the bronchus leading to infection.
    • Local spread is common but widespread metastases occur relatively late.
  • Adenocarcinoma (39% of NSCLC):
    • Arise from mucous cells in the bronchial epithelium.
    • Is the most common bronchial carcinoma associated with asbestos and is more common in non-smokers than other cell types.
    • Invasion of the pleura and the mediastinal lymph nodes is common.
    • Often metastasise to the brain and bones.
  • Large cell:
    • Are less-differentiated forms of squamous cell and adenocarcinomas.
    • Large cell carcinomas metastasise early.
  • Carcinoid tumours (7% of NSCLC)
  • Bronchoalveolar cell (4% of NSCLC):
    • Occurs either as a peripheral solitary nodule or as diffuse nodular lesions.

• Lung cancer is the most common cause of cancer death for men, who account for 60% of lung cancer cases.
• In women, lung cancer is the second most common cause of cancer death after breast cancer.

Risk factors

• Active or passive cigarette smoking is the major risk factor.⁴
• Increased age.
• People with chronic obstructive pulmonary disease.⁵
• People with a previous history of cancer (especially head and neck).⁵
• Industrial dust diseases, asbestos, chromium, arsenic, iron oxides and radiation.

• Initial symptoms and signs include:⁶
  • Cough
  • Dyspnoea
  • Weight loss
  • Chest pain
  • Haemoptysis
  • Bone pain
  • Finger clubbing
  • Fever
  • Weakness
  • Superior vena cava obstruction
  • Dysphagia
  • Headache
  • Nausea and vomiting
  • Hoarseness (recurrent laryngeal nerve involvement)
  • Wheezing and stridor
• Other presentations include recurrent or slowly resolving pneumonia, anorexia, hypertrophic pulmonary osteoarthropathy and supraclavicular or axillary lymphadenopathy.
• Chest signs: sometimes no signs; otherwise consolidation, collapse, pleural effusion.
• Metastatic disease: bone tenderness, hepatomegaly, confusion, fits, focal neurological deficit, cerebellar syndrome, proximal myopathy, peripheral neuropathy.

Other causes of a "coin lesion" (solitary, round, circumscribed shadow in the lung field on chest x-ray):

• Secondary malignancy
• Arteriovenous malformation
• Pulmonary hamartoma:
  • Rare, benign tumour
  • CT scan shows lobulated mass with flecks of calcification
  • Often excised to exclude malignancy
• Bronchial adenoma:
  • Rare, slow growing tumour
  • 90% are carcinoid tumours; 10% are cylindromas
  • Treatment is surgery
• Abscesses
• Granuloma, e.g. tuberculosis
• Encysted effusion (fluid, blood, pus)
• Cyst
• Foreign body
• Skin tumour (e.g. seborrhoeic wart)

• Consider immediate referral (acute admission or referral occurring within a few hours, or even more quickly if necessary) for patients with:
  • Signs of superior vena caval obstruction (swelling of the face/neck with fixed elevation of jugular venous pressure)
  • Stridor
• Refer urgently (to be seen within 2 weeks) patients with:
  • Persistent haemoptysis in smokers or ex-smokers aged 40 years and older (don't wait for chest x-ray result before referring).
  • A chest X-ray suggestive of lung cancer (including pleural effusion and slowly resolving consolidation).
  • A normal chest X-ray where there is a high suspicion of lung cancer.
  • A history of asbestos exposure and recent onset of chest pain, shortness of breath or unexplained systemic symptoms where a chest X-ray indicates pleural effusion, pleural mass or any suspicious lung pathology.

• Chest x-ray:
  • May show a peripheral circular opacity, hilar enlargement, consolidation, pleural effusion or bony secondaries.
  • Urgent referral for a chest X-ray (the report should be returned within 5 days) is indicated when a patient presents with haemoptysis, or any of the following unexplained or persistent (lasting more than 3 weeks) symptoms or signs:⁵
    • Cough
    • Chest/shoulder pain
    • Dyspnoea
    • Weight loss
    • Chest signs
    • Hoarseness
    • Finger clubbing
    • Features suggestive of metastasis from a lung cancer (e.g. in brain, bone, liver or skin)
    • Cervical/supraclavicular lymphadenopathy
  • Urgent chest x-ray is also indicated for patients with underlying chronic respiratory problems with unexplained changes in existing symptoms.⁵
  • If the chest X-ray is normal but there is a high suspicion of lung cancer, patients should be offered urgent referral.
• Contrast-enhanced chest CT scan: to stage the tumour. The scan should also include the liver and adrenals. Chest CT should be performed before an intended fibreoptic bronchoscopy or any other biopsy procedure.
• Percutaneous transthoracic needle biopsy: for diagnosis of peripheral lesions and superficial lymph nodes.
• Bronchoscopy: to establish a histological diagnosis and assess operability. Should be performed on patients with central lesions.
• Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS–TBNA) is used to investigate mediastinal masses, predominantly in the context of staging of lung cancer.⁷
• Surgical biopsy should be performed for diagnosis where other less invasive methods of biopsy have not been successful or are not possible. Biopsies should be taken from metastases if this can be achieved more easily than from the primary site.
• An 18F-deoxyglucose positron emission tomography (FDG-PET) scan should be performed to investigate solitary pulmonary nodules in cases where a biopsy is not possible or has failed.
• Lung function tests.
• Cytology: sputum and pleural fluid. Sputum cytology is rarely indicated and should be reserved for the investigation of patients who have centrally placed nodules or masses and are unable to tolerate, or unwilling, to undergo bronchoscopy or other invasive tests.

Staging

• Follows the TNM classification:⁸
  • Tumour (T)
    • TX - Positive malignant cytology results, no lesion seen
    • T1 - Diameter smaller than or equal to 3 cm
    • T2:
      • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
      • Tumour with any of the following features of size or extent:
        • Over 3 cm in greatest dimension
        • Involves main bronchus
        • Over 2 cm distal to the carina
        • Invades the visceral pleura
    • T3:
      • Tumour of any size that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, mediastinal pleura, parietal pericardium.
      • Or tumour in the main bronchus < 2 cm distal to the carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung.
    • T4 - Invasion of mediastinal organs (e.g. oesophagus, trachea, great vessels, heart), malignant pleural effusion, or satellite nodules within the primary lobe
  • Regional lymph node involvement (N)
    • N0 - No lymph nodes involved
    • N1 - Ipsilateral bronchopulmonary or hilar nodes involved
    • N2 - Ipsilateral mediastinal or subcarinal nodes
    • N3 - Contralateral mediastinal, hilar, any supraclavicular nodes involved
  • Metastatic involvement (M)
    • M0 - No metastases
    • M1 - Metastases present
• Stage groupings:
  • IA - T1 N0 M0
  • IB - T2 N0 M0
  • IIA - T1 N1 M0
  • IIB - T2 N1 M0 or T3 N0 M0
  • IIIA - T1-3 N2 M0 or T3 N1 M0
  • IIIB - Any T4 or any N3 M0
  • IV - Any M1
• MRI should not routinely be performed to assess the stage of the primary tumour but should be performed, where necessary, to assess the extent of disease for patients with superior sulcus tumours.
• CT alone may not be reliable for the assessment of mediastinal and chest wall invasion. Ultrasound scan or MRI may be used but surgical assessment may be necessary.
• Patients who are staged as candidates for surgery or radical radiotherapy on CT should have an FDG-PET scan to look for involved intrathoracic lymph nodes and distant metastases.
• Histological/cytological investigation of lymph nodes should be performed to confirm N2/3 disease when FDG-PET scan is positive. If an FDG-PET scan for N2/N3 disease is negative, biopsy is not required even if the patient's nodes are enlarged on CT scan.
• An MRI or CT scan should be performed for patients with clinical signs or symptoms of brain metastasis.
• A radionuclide bone scan should be performed for suspected bone metastases.

Management

• Patients with lung cancer, in particular those with a better prognosis, should be encouraged to stop smoking.
• Surgical resection:
  • Treatment of choice for patients with stage I or stage II disease. Lobar resection is the procedure of choice. Patients with stage I or II who would not tolerate lobectomy because of co-morbid disease or pulmonary compromise should be considered for limited resection or radical radiotherapy.
  • All patients undergoing surgical resection should have systematic lymph node sampling to provide accurate pathological staging.
  • In patients with stage IIIA NSCLC, surgery alone is associated with a relatively poor prognosis.
  • Percutaneous radiofrequency ablation may be used in patients with small early stage lung cancer for whom surgery is not appropriate or who do not wish to undergo conventional surgery, and for patients with a small number of lung metastases.⁹
• Radiotherapy:
  • Radical radiotherapy is indicated for patients with stage I, II or III NSCLC who have good performance status and whose disease can be encompassed in a radiotherapy treatment volume without undue risk of normal tissue damage.
  • All patients should undergo pulmonary function tests (including lung volumes and transfer factor) before having radical radiotherapy.
  • Patients who have poor lung function but are otherwise suitable for radical radiotherapy should still be offered radiotherapy, provided the volume of irradiated lung is small.
• Chemotherapy:
  • Chemotherapy should be offered to patients with stage III or IV NSCLC and good performance status, to improve survival, disease control and quality of life.
  • Chemotherapy for advanced NSCLC should be a combination of a single third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) plus a platinum drug. Either carboplatin or cisplatin may be administered. Patients who are unable to tolerate a platinum combination may be offered single-agent chemotherapy with a third-generation drug. Docetaxel, gefitinib and erlotinib improve overall survival in patients with NSCLC.¹⁰
  • Docetaxel monotherapy should be considered if second-line treatment is appropriate for patients with locally advanced or metastatic NSCLC in whom relapse has occurred after previous chemotherapy.
  • Erlotinib:¹¹
    • Erlotinib is recommended, within its licensed indication, as an alternative to docetaxel as a second-line treatment option for patients with NSCLC.
    • Erlotinib is not recommended for the second-line treatment of locally advanced or metastatic NSCLC in patients for whom docetaxel is unsuitable (i.e. where there is intolerance of or contraindications to docetaxel) or for third-line treatment after docetaxel therapy.
• Combination therapy:
  • Postoperative radiotherapy should be considered after incomplete resection of the primary tumour for patients with NSCLC, with the aim of improving local control.
  • Adjuvant chemotherapy should be offered to NSCLC patients who have had a complete resection.
  • Patients with stage III NSCLC who are not suitable for surgery but are eligible for radical radiotherapy should be offered sequential chemotherapy and radical radiotherapy.
• Percutaneous radiofrequency ablation:
  • There is only limited evidence for the effectiveness of percutaneous radiofrequency ablation for the treatment of primary and secondary lung cancers.⁹

Staging

• Staging investigations include serum lactate dehydrogenase, liver function tests and serum sodium.¹
• Should be staged by a contrast-enhanced CT scan of the patient's chest, liver and adrenals and by selected imaging of any symptomatic area. Two-stage system of staging is used:
  • Limited stage disease: this includes patients with disease that:
    • Is confined to one hemithorax
    • Involves ipsilateral hilar lymph nodes
    • Involves ipsilateral and contralateral supraclavicular lymph nodes
    • Involves ipsilateral and contralateral mediastinal lymph nodes
    • Can be with or without ipsilateral pleural effusions, independent of cytology
  • Extensive stage disease: disease at sites beyond the definition of limited disease. This includes patients with:
    • Metastatic lesions in the contralateral lung
    • Distant metastatic involvement (e.g. brain, bone, liver or adrenals)

Management

• Patients with lung cancer, in particular those with a better prognosis, should be encouraged to stop smoking.
• All patients with SCLC should be offered:
  • Platinum-based chemotherapy.
  • Multi-drug regimens, because they are more effective and have a lower toxicity than single-agent regimens.
• Four to six cycles of chemotherapy should be offered to patients whose disease responds. Maintenance treatment is not recommended.
• Patients with limited-stage SCLC should be offered thoracic irradiation concurrently with the first or second cycle of chemotherapy or following completion of chemotherapy if there has been at least a good partial response within the thorax.
• For patients with extensive disease, thoracic irradiation should be considered following chemotherapy if there has been a complete response at distant sites and at least a good partial response within the thorax.
• Patients with limited disease and complete or good partial response after primary treatment should be offered prophylactic cranial irradiation.¹²
• Second-line chemotherapy should be offered to patients at relapse only if their disease responded to first-line chemotherapy. The benefits are less than those of first-line chemotherapy.

The following list is a brief outline of certain aspects of palliative care for patients with lung cancer. Guidance is also provided in the British National Formulary.¹³

• Breathlessness:
  • Strong opiate, e.g. morphine or diamorphine.
  • Non-drug interventions based on psychosocial support, breathing control and coping strategies should be considered.
• Bronchial obstruction:
  • Radiotherapy.
  • Debulking bronchoscopic procedures (for large airway obstruction).
  • Cryotherapy is effective for treating malignant endobronchial obstruction.¹⁴
  • Photodynamic therapy is effective for treating advanced bronchial carcinoma¹⁵ and is also effective for localised inoperable endobronchial cancer.¹⁶
  • Patients with extrinsic compression may be considered for treatment with stents.
• Pleural effusion:
  • Pleural aspiration or drainage should be performed.
  • Patients who benefit symptomatically from aspiration or drainage of fluid should be offered talc pleurodesis for longer-term benefit.
• Haemoptysis if distressing:
  • Radiotherapy.
  • Debulking bronchoscopic procedures should be considered for the relief of bleeding due to an endobronchial tumour within a large airway.
• Cough:
  • Opioids (e.g. codeine, morphine).
  • Radiotherapy.
• Chest pain:
  • Radiotherapy.
• Troublesome hoarseness due to recurrent laryngeal nerve palsy:
  • Refer to an ear, nose and throat specialist for advice.
• Superior vena obstruction:
  • Chemotherapy and radiotherapy according to the stage of disease and performance status.
  • Stent insertion should be considered for the immediate relief of severe symptoms of superior vena caval obstruction or following failure of earlier treatments.¹⁷
• Bone pain:
  • For patients with bone metastasis requiring palliation and who have not been helped by standard analgesic treatments, single-fraction radiotherapy should be considered.
• Cerebral metastases:
  • Corticosteroids and radiotherapy should be considered.
• Spinal cord compression:
  • Is a medical emergency and immediate treatment (within 24 hours), with corticosteroids, radiotherapy and surgery where appropriate, is recommended.
  • Patients with spinal cord compression should have an early referral to an oncology. physiotherapist and an occupational therapist for assessment, treatment and rehabilitation.

Local

• Recurrent laryngeal palsy, phrenic nerve palsy, Horner's syndrome, Pancoast's syndrome
• Cardiovascular: superior vena cava obstruction, pericarditis, atrial fibrillation
• Rib erosion

Metastatic

• Brain: confusion, fits, focal neurological deficit, cerebellar syndrome
• Bone: bone pain, hypercalcaemia
• Liver: hepatomegaly
• Adrenals: Addison's disease

Non-metastatic⁶

• Endocrine: inappropriate antidiuretic hormone (ADH) secretion, non-metastatic hypercalcaemia, Cushing's syndrome, gynaecomastia, hypoglycaemia, hyperthyroidism
• Neuromuscular: subacute sensory neuropathy, mononeuritis multiplex, myasthenic syndrome (Lambert-Eaton syndrome), encephalomyelitis, necrotising myelopathy, polymyopathy, motor neurone disease
• Skeletal: hypertrophic pulmonary osteoarthropathy (joint stiffness and severe pain in the wrists and ankles, sometimes with gynaecomastia. Is usually associated with clubbing of the fingers. May regress after resection of the lung tumour)
• Renal: glomerulonephritis, nephrotic syndrome
• Collagen/vascular: dermatomyositis, polymyositis, vasculitis, systemic lupus erythematosus, endocarditis
• Cutaneous: acquired hypertrichosis languinosa, erythema gyratum repens, erythema multiforme, tylosis, erythroderma, exfoliative dermatitis, acanthosis nigricans, thrombophlebitis migrans, pruritus, urticaria, dermatomyositis
• Haematological: anaemia, thrombocytosis, thrombocytopenic purpura, disseminated intravascular coagulation

• Survival rates for lung cancer are very poor.
• A study in USA comparing 5-year survival of smokers and non-smokers with NSCLC found survival rates of:³
  • Stage 1: never-smokers 62%; smokers 75%
  • Stage II: never smokers 46%; smokers 53%
  • Stage III disease: never smokers 36%; smokers 41%
  • The 5-year survival rate was significantly lower in patients who had a smoking history of > 20 pack-years.
• The median survival of patients with small cell lung cancer who are treated with multiple agent chemotherapy and multimodality therapy are:¹⁸
  • For limited disease, 20 months with a 2-year survival rate of 45% and a 5-year survival rate of 20%.
  • For extensive disease, 12 months with a 2-year survival rate of 4.6%.

• Actively discourage smoking and encourage smoking cessation.
• Prevent occupational exposure to carcinogens.