31st December 2024

Lung cancer

Epidemiology of lung cancer

Lung cancer is the third most common cancer in the UK. Risk factors are a mixture of non-modifiable – primarily age – and modifiable – primarily smoking (active and passive), exposure to occupational chemicals (asbestos, more rarely radon gas), and exposure to ionising radiation. A majority of cases are linked to smoking and considered largely preventable.

Pathology of lung cancer

Lung cancer has been classically divided into small cell and non-small cell types. Small cell lung cancers (SCLC) account for approximately 20% of all cases, whilst the majority are non-small cell lung cancers (NSCLC). ‘NSCLC’ is a blanket term comprising a variety of histological types including adenocarcinoma (approximately 40% of cases), squamous cell carcinoma (SCC, approximately 30%), large cell carcinoma, and other rarer histological types.

Adenocarcinoma of the lung is the most common histological type both overall and in non-smokers. Adenocarcinomas usually arise in the lung periphery. By comparison, SCCs typically arise centrally and cavitation may be another distinguishing feature. SCLCs are aggressive tumours arising from neuroendocrine cells, typically of the larger airways. SCLCs tend to carry a worse prognosis and a majority of patients already have distal metastases at the time of diagnosis (de novo metastatic disease).

Common sites of lung cancer metastasis include the adrenal glands, bone, brain, liver and other parts of the lung.

Presentation of lung cancer

Symptoms include cough, haemoptysis, dyspnoea, recurrent chest infection, chest pain, hoarse voice, and symptoms of metastatic disease. Presentation may be delayed, in part as symptoms may be dismissed as side effects or benign complications of smoking.

Two-week-wait referral criteria are outlined in the table below.

The various classical and/or emergency presentations of lung cancer depend on histological type, site within the lung, and disease stage at presentation:

• SCC classically causes hypercalcaemia secondary to parathyroid hormone-related protein (PTHrP) release. Hypercalcemia has a range of clinical manifestations (e.g. constipation, confusion, thirst, depression, renal stones). The typical ECG finding is a shortened QTc (corrected QT interval).
• Both adenocarcinoma and SCC are classically associated with hypertrophic pulmonary osteoarthropathy (HPOA), which manifests as digital clubbing and painful inflammation of the interphalangeal, metacarpophalangeal and metatarsophalangeal joints.
• SCLC may feature ectopic secretion of antidiuretic hormone (ADH) or adrenocorticotropic hormone (ACTH), giving rise to an SIADH (syndrome of inappropriate antidiuretic hormone secretion) or Cushing’s syndrome, respectively. Cushing’s syndrome can be differentiated from other causes of raised cortisol with several investigations. ACTH is raised, and cortisol levels remain high (i.e. are not suppressed) with both the low- and high-dose dexamethasone tests.
• SCLC may be associated with paraneoplastic Lambert Eaton myasthenic syndrome (LEMS), a progressive disease of the neuromuscular junction. It results in muscle weakness that improves with exercise (with proximal lower limb muscles affected first), cranial nerve palsies, autonomic dysfunction (e.g. constipation and dry mouth) and areflexia.  In 60% of patients, there is underlying SCLC, so screening for this is essential. Other less common underlying malignancies include NSCLC, lymphoproliferative disease and prostate cancer.
• Pancoast tumours (of the lung apex) may present with upper limb pain and weakness resulting from invasion of the brachial plexus and with an ipsilateral Horner’s syndrome resulting from compression of the thoracic sympathetic chain.
• Emergency presentations of lung cancer include superior vena cava obstruction (SVCO), of which lung cancer is the commonest cause, and metastatic spinal cord compression, which, if suspected, requires MRI of the whole spine to be performed.

Diagnosis of lung cancer

CXR is often the first-line investigation, but CT chest, abdomen and pelvis is the investigation of choice in all patients with suspected lung cancer. PET scan may also be done. Tissue to confirm the diagnosis may be obtained with endobronchial ultrasound (EBUS) or, if not accessible by EBUS, on CT-guided percutaneous biopsy or video-assisted thoracoscopic surgery (VATS).  Pleural fluid may additionally be aspirated and sent for cytology. Pleural tap results suggestive of malignancy are an exudate (protein >30 g/L) with high LDH, low pleural pH (<7.3) and low glucose (<3.4 mmol/l), and with lymphocytosis or blood in the sample.

Management of lung cancer

All patients with lung cancer should be counselled regarding smoking cessation and supported with the prescription of nicotine replacement therapy and referral to community cessation services.

Management of NSCLC

Early NSCLC: Radical lobectomy with lymph node sampling should be considered for all patients with early NSCLC. Lobectomy carries fewer short-term complications and better preserves lung function than a pneumonectomy.

If ineligible for surgery, radical radiotherapy may be considered. This includes stereotactic ablative radiotherapy (SABR), a particularly precise type of radiotherapy appropriate for smaller tumours, which restricts damage to nearby structures.

Eligibility for surgery should be determined through assessment of operative risk. The following factors should be taken into consideration:

• Performance status
• Presence of comorbidities
• Global risk score to estimate risk of operative mortality
• Cardiac investigations – ECG and echocardiography are usually required; exercise stress testing for reversible myocardial ischaemia may be required depending on the presence of cardiac symptoms and risk factors
• Lung function tests – FEV1 and TLCO (transfer factor of the lung for carbon monoxide) should be measured in all patients, and postoperative dyspnoea should be predicted

Following surgery, adjuvant chemotherapy (a cisplatin-based combination regimen) is offered to those with adequate performance status, depending on staging. Neoadjuvant chemotherapy is only available as part of a clinical trial.

Locally advanced NSCLC: Locally advanced disease involving mediastinal lymph nodes is also potentially curable, and surgery with chemoradiotherapy should be considered. If this is not an option, radical radiotherapy is an alternative.

If operable, lobectomy with lymph node dissection should be offered if technically feasible and if the patient is suitably fit (see above for eligibility criteria). Patients may be offered either neoadjuvant or adjuvant chemotherapy.

Patients whose tumours are inoperable should receive concurrent platinum-based chemotherapy and radiotherapy (radical chemoradiotherapy) as a non-surgical treatment pathway, and this may be followed by durvalumab (an anti-PD-L1 [programmed death-ligand 1] immune checkpoint inhibitor) in PD-L1-positive patients. Pneumonitis secondary to radiotherapy ± durvalumab is the main adverse event.

Metastatic NSCLC: This is incurable, and any treatment has palliative intent. Three modalities of treatment exist:

1. Targeted therapy, chosen based on the presence of specific mutations. Examples include:
   • Tyrosine kinase inhibitors (TKI) – may be offered first line in inoperable locally advanced or metastatic NSCLC with proven mutations. Examples include erlotinib, gefitinib and afatinib, all for tumours with epidermal growth factor (EGFR) mutations. An EGFR-TKI can be used alongside chemotherapy if the patient is fit enough to tolerate it.
   • Crizotinib – with a mutation of the anaplastic lymphoma kinase (ALK) gene. This is a second-line option for patients who have had platinum-based chemotherapy.
2. Immune checkpoint inhibitors (immunotherapy) – for those with no targetable mutation, but with proven PD-L1 expression, e.g. pembrolizumab.
3. Chemotherapy – histology-specific chemotherapy, usually including a platinum-based drug, may be given to those fit for treatment who have no targetable mutation and with a contraindication to immunotherapy.

Management of SCLC

Very early SCLC: SCLC is usually advanced at presentation and only a minority of patients with very early disease qualify for surgical resection aimed at cure. As in NSCLC, extensive work-up is required to ensure fitness for surgery (see above for eligibility criteria). In the minority of patients with SCLC who do proceed to surgical resection, nodal dissection should be performed and adjuvant chemotherapy offered.

Locally advanced SCLC: Nodal disease may be treated curatively with radical chemoradiotherapy.

Metastatic SCLC: Chemotherapy is the mainstay. A platinum-based drug (carboplatin/cisplatin) and etoposide are usually first line. Patients may be eligible for combination with immunotherapy. Atezolizumab is a type of immunotherapy (PDL-1 inhibitor) licensed for extensive small cell lung cancer.

References

• Cancer Research UK. Lung cancer [Internet]. cancerresearchuk.org. 2022 [cited 17 April 2022]. Available from: https://www.cancerresearchuk.org/about-cancer/lung-cancer
• Cassidy J, Bissett D, Spence RAJ, Payne M, Morris-Stiff G. Oxford Handbook of Oncology (4 ed.) [Internet]. Oxford University Press. [cited 2022 Apr 17]. Available from: https://oxfordmedicine.com/view/10.1093/med/9780199689842.001.0001/med-9780199689842
• Lim E, Baldwin D, Beckles M, Duffy J, Entwisle J, Faivre-Finn C, et al. Guidelines on the radical management of patients with lung cancer. Thorax. 2010 Oct 1;65(Suppl 3):iii1–27
• Midthun D. Overview of the initial treatment and prognosis of lung cancer [Internet]. Lilenbaum R and Schild S, editors. UpToDate. 2022 [cited 17 April 2022]. Available from: https://www.uptodate.com/contents/overview-of-the-initial-treatment-and-prognosis-of-lung-cancer
• National Institute for Health and Care Excellence. Lung and pleural cancers – recognition and referral [Internet]. Cks.nice.org.uk. 2022 [cited 17 April 2022]. Available from: https://cks.nice.org.uk/topics/lung-pleural-cancers-recognition-referral/
• Gundepalli SG, Tadi P. Lung Pancoast Tumor. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
• NICE. Lung and pleural cancers – recognition and referral [Internet]. 2021 [cited 2023 Aug 17]. Available from: https://cks.nice.org.uk/topics/lung-pleural-cancers-recognition-referral/
• Stages of lung cancer | Cancer Research UK [Internet]. [cited 2023 Aug 14]. Available from: https://www.cancerresearchuk.org/about-cancer/lung-cancer/stages-types/stages
• Treatment | Lung cancer: diagnosis and management  | Guidance | NICE [Internet]. [cited 2023 Aug 14]. Available from: https://www.nice.org.uk/guidance/ng122/chapter/Treatment#assessing-people-with-non-small-cell-lung-cancer-for-treatment-with-curative-intent
• Adjei AA, Wang F. BMJ Best Practice Non small cell lung cancer. 2022 Oct 25;
• Targeted and immunotherapy treatment for lung cancer | Cancer Research UK [Internet]. [cited 2023 Aug 14]. Available from: https://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment/immunotherapy-targeted
• Treatment options for small cell lung cancer (SCLC) | Lung cancer | Cancer Research UK [Internet]. [cited 2023 Aug 14]. Available from: https://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment/small-cell-lung-cancer
• Meador CB. BMJ Best Practice Small cell lung cancer. 2023 Jun 13;
• Aggarwal K. Superior vena cava syndrome [Internet]. [cited 2023 Aug 14]. Available from: https://bestpractice.bmj.com/topics/en-gb/848/aetiology
• El-Feky M, Gaillard F. Squamous cell carcinoma of the lung. Radiopaedia.org. Radiopaedia.org; 2005
• Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003 May 1;67(9):1959–66.
• Part 10.1: Life-Threatening Electrolyte Abnormalities. Circulation. 2005 Nov 28;112(24_suppl):IV-121-IV–125.
• QT Interval • LITFL • ECG Library Basics [Internet]. [cited 2023 Aug 14]. Available from: https://litfl.com/qt-interval-ecg-library/
• Cushings – Zero To Finals [Internet]. [cited 2023 Aug 14]. Available from: https://zerotofinals.com/medicine/endocrinology/cushings/
• Pleural Fluid Interpretation | Transduate vs Exudate | Geeky Medics [Internet]. [cited 2023 Aug 14]. Available from: https://geekymedics.com/pleural-fluid-interpretation/#:~:text=Results%20generally%20are%20not%20diagnostic%2C%20but%20most%20transudates,effusions%20are%20associated%20with%20empyema%20or%20pulmonary%20embolism
• Chorin E, Rosso R, Viskin S. Electrocardiographic Manifestations of Calcium Abnormalities. Ann Noninvasive Electrocardiol. 2016 Jan;21(1):7-9. doi: 10.1111/anec.12316. Epub 2015 Nov 2. PMID: 26524386; PMCID: PMC6931435.
• Jayarangaiah A, Lui F, Theetha Kariyanna P. Lambert-Eaton Myasthenic Syndrome. [Updated 2023 Oct 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507891/
• Maconachie R, Mercer T, Navani N, McVeigh G. Lung cancer: diagnosis and management: summary of updated NICE guidance BMJ 2019; 364 :l1049 doi:10.1136/bmj.l1049
• Higuchi M, Takagi H, Ozaki Y, Inoue T, Watanabe Y, Yamaura T, Fukuhara M, Muto S, Okabe N, Matsumura Y, Hasegawa T, Osugi J, Hoshino M, Shio Y, Suzuki H. Comparison of surgical outcomes after pneumonectomy and pulmonary function-preserving surgery for non-small cell lung cancer. Fukushima J Med Sci. 2018 Apr 17;64(1):30-37. doi: 10.5387/fms.2017-10. Epub 2018 Feb 20. PMID: 29459574; PMCID: PMC5956088
• Lung Expert Advisory Group Members. Lung Cancer Clinical Guidelines [Internet]. 2018 May [cited 2024 Jan 11]. Available from: https://www.northerncanceralliance.nhs.uk/wp-content/uploads/2018/11/Lung-Clinical-Guidelines-v13.2-2.pdf
• Miura, Y., Mouri, A., Kaira, K., Yamaguchi, O., Shiono, A., Hashimoto, K., Nishihara, F., Shinomiya, S., Akagami, T., Murayama, Y., Abe, T., Noda, S.-e., Kato, S., Kobayashi, K. and Kagamu, H. (2020), Chemoradiotherapy followed by durvalumab in patients with unresectable advanced non-small cell lung cancer: Management of adverse events. Thorac Cancer, 11: 1280-1287. https://doi.org/10.1111/1759-7714.13394