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 Lung cancers are classified into two main categories:

• Small-cell lung cancers (SCLC), which account for about 20% of cases.
• Non-small-cell lung cancers (NSCLC), which account for the other 80%. These include:¹
  • Squamous (35% of cases)
  • Adenocarcinoma (27%)
  • Large cell (10%).

The non-small cell lung cancers (NSCLC) are often grouped together when treatment is being considered. Malignant mesothelioma is a tumour of mesothelial cells which usually occurs in the pleura, but may also occur elsewhere, e.g. the peritoneum. Information about malignant mesothelium is included at the end of this article.

• 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.²
• Increased age.
• Industrial dust diseases, asbestos, chromium, arsenic, iron oxides and radiation.

• Initial symptoms and signs include:³
  • Cough
  • Dyspnoea
  • Weight loss
  • Chest pain
  • Haemoptysis
  • Bone pain
  • Finger clubbing
  • Fever
  • Weakness
  • Superior vena cava obstruction
  • Dysphagia
  • 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" in the lung field include:

• Secondary malignancy.
• Arteriovenous malformation
• Pulmonary hamartoma: rare, benign tumour. CT scan: 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).

• Patients should be offered an urgent referral while awaiting the result of a chest X-ray, for patients with persistent haemoptysis who are smokers/ex-smokers and older than 40 years.
• Emergency referral should be considered for patients with signs of superior vena caval obstruction (swelling of the face/neck with fixed elevation of jugular venous pressure) or stridor.

• 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.
• Chest x-ray:
  • May show a peripheral circular opacity, hilar enlargement, consolidation, pleural effusion or bony secondaries. Urgent referral for a chest X-ray is indicated when a patient presents with haemoptysis, or any of the following unexplained or persistent (lasting more than 3 weeks) symptoms or signs:
    • 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.
  • 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.
• 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.
• Radionuclide bone scan: for suspected bone metastases.

Staging

• Follows the TNM classification:⁴
  • Tumour (T)
    • TX - Positive malignant cytology results, no lesion seen
    • T1 - Diameter smaller than or equal to 3 cm
    • T2 - Diameter larger than 3 cm
    • T3 - Extension to pleura, chest wall, diaphragm, pericardium, within 2 cm of carina, or total atelectasis
    • 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. 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.

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.⁵
• 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 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.
• 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.⁶

Staging

• 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.⁷
• 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 Formulary⁸.

• 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.⁹
  • Photodynamic therapy is effective for treating advanced bronchial carcinoma¹⁰ and is also effective for localised inoperable endobronchial cancer.¹¹
  • 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.¹²
• 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 for symptomatic treatment.
• 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.

Non-metastatic³

• Endocrine: inappropriate ADH secretion, non-metastatic hypercalcaemia, Cushing syndrome, gynaecomastia, hyperthyroidism
• Neuromuscular: subacute sensory neuropathy, mononeuritis multiplex, Lambert-Eaton syndrome, encephalomyelitis, necrotising myelopathy
• Skeletal: hypertrophic osteoarthropathy, clubbing
• Renal: glomerulonephritis, nephrotic syndrome
• Collagen/vascular: dermatomyositis, polymyositis, vasculitis, systemic lupus erythematosus
• Cutaneous: acquired hypertrichosis languinosa, erythema gyratum repens, erythema multiforme, tylosis, erythroderma, exfoliative dermatitis, acanthosis nigricans, thrombophlebitis migrans, pruritus, urticaria
• Anaemia, thrombocytosis, thrombocytopenic purpura, disseminated intravascular coagulation.

• Survival rates for lung cancer are very poor.
• One-year survival for lung cancer patients diagnosed between 1993-1995 were 21.4% for men and 21.8% for women; five-year survival rates were 5.5% for both men and women.¹³

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

• Tumour of mesothelial cells which usually occurs in the pleura (80-90% of all cases), but also other sites, including the peritoneum and pericardium.
• Three times more common in men than women. Often presents between the ages of 40 and 70 years.
• Because of the widespread use of asbestos until the end of the 1970's the incidence of pleural mesothelioma has risen for some decades and is expected to peak between 2010 and 2020.¹⁴
• It is associated with occupational exposure to asbestos but the relationship is complex. 90% report previous exposure to asbestos, but only 20% of patients have pulmonary asbestosis. The latent period between exposure and development of the tumour may be up to 45 years.¹⁵

Clinical features

• Chest discomfort, pleuritic pain, dyspnoea, weight loss, fatigue, fever, sweats, finger clubbing, recurrent pleural effusions.
• If the tumour has metastasised there may be lymphadenopathy, hepatomegaly, bone pain/tenderness, abdominal pain/obstruction (peritoneal malignant mesothelioma).
• Examination of the chest often reveals a pleural effusion.

Investigations

• Chest x-ray: pleural thickening/effusion.
• There is debate as to whether MRI scan of the chest or laparoscopic thoracoscopy is the best method for assessing the extent of the disease.
• Bloody pleural fluid.
• Diagnosis is made on histology, following a pleural biopsy or at post-mortem.

Staging

• Stage I: Confined inside the capsule of the parietal pleura: ipsilateral pleura, lung, pericardium, and diaphragm
• Stage II: All of stage I with intrathoracic (N1 or N2) lymph nodes
• Stage III: Local extension of disease into the following: chest wall or mediastinum; heart or through the diaphragm, peritoneum; with or without extrathoracic or contralateral (N3) lymph node involvement
• Stage IV: Distant metastases.

Management

• Symptomatic; as cure is only possible with surgery for extremely localized (stage 1) mesothelioma. Traditional treatment modalities (surgery, radiotherapy, and chemotherapy) have evolved slowly, and there has been little improvement in establishing effective treatments.¹⁵
• Extrapleural pneumonectomy may lengthen time to recurrence.
• Pleurectomy and decortication may provide palliative relief from pain and pleural effusions (operative mortality 6-30% and less than 2% respectively).
• Studies of chemotherapy have shown poor results but promising results have been achieved with pemetrexed and raltitrexed in combination with cisplatin and other combinations, including cisplatin and gemcitabine. Single-agent therapy with vinorelbine may provide useful palliation with low toxicity.¹⁶
• Radiation therapy can also help pain, but neither DXR or chemotherapy currently improves survival.
• Industrial compensation may be appropriate.

Prognosis

• Difficult to assess because of considerable variation in "time to diagnosis".
• Depends on patient age, staging information, histology and general "performance status" at diagnosis, but is generally very poor (>650 deaths/yr in the UK).
• Median survival is 11 months. It is almost always fatal.