Lung Cancer: Recognition, Staging and Treatment by Cell Type

Introduction

Lung cancer is the third commonest cancer in the UK and by a wide margin the commonest cause of cancer death, accounting for around 35,000 deaths a year - more than breast, prostate and bowel cancer combined.³ Around 48,000 people are diagnosed each year.

The dominant clinical problem is late presentation. Symptoms are non-specific and easily attributed to smoking, COPD or ageing, and by the time most patients present the disease is advanced: fewer than a third are diagnosed at a stage where curative treatment is possible. This is why the referral thresholds are deliberately low and why a national screening programme has been introduced.

Risk factors

• Smoking - responsible for around 85% of cases, with a 15 to 30-fold increase in risk. Risk is related to duration more than intensity, falls after cessation but never returns to that of a never-smoker.
• Second-hand smoke - raising risk by around 25% in non-smoking partners of smokers
• Radon - naturally occurring radioactive gas seeping from granite bedrock, and the second commonest cause overall and the commonest in never-smokers. Highest exposures in the UK are in Devon, Cornwall and parts of Scotland.
• Asbestos - and note that asbestos and smoking act multiplicatively rather than additively
• Other occupational carcinogens - arsenic, chromium, nickel, cadmium, silica, diesel exhaust and polycyclic aromatic hydrocarbons
• Air pollution - particulate matter, now classified as a definite human carcinogen
• Pre-existing lung disease - COPD and idiopathic pulmonary fibrosis both increase risk independently of smoking
• Previous radiotherapy to the chest, for example for lymphoma or breast cancer
• Family history and, increasingly recognised, inherited susceptibility
• HIV infection - roughly doubling the risk

Types of lung cancer

The primary division is between small cell and non-small cell lung cancer, because it determines the entire treatment approach.

Clinical features

Local effects of the tumour

• Cough - the commonest presenting symptom, or a change in a longstanding smoker's cough
• Haemoptysis - usually small volume, and a symptom that should always be investigated
• Breathlessness - from airway obstruction, collapse, effusion or lymphangitis
• Chest pain - dull and persistent, or pleuritic with chest wall invasion
• Recurrent or slowly resolving chest infection, especially in the same lobe - suggesting post-obstructive pneumonia
• Monophonic wheeze or stridor - a fixed sound from a single obstructed airway, quite unlike the polyphonic wheeze of asthma

Local invasion and regional spread

Metastatic disease

• Bone - pain, pathological fracture, spinal cord compression and hypercalcaemia
• Brain - headache, seizures, focal neurological deficit, personality change and confusion
• Liver - hepatomegaly, right upper quadrant pain, jaundice and deranged liver function
• Adrenal glands - usually asymptomatic and found on staging CT
• Skin and subcutaneous nodules

Constitutional and general signs

• Weight loss, anorexia and fatigue
• Finger clubbing - present in around a third, most often with non-small cell disease
• Hypertrophic pulmonary osteoarthropathy - clubbing with painful, swollen wrists and ankles from periosteal new bone formation; a classic association with adenocarcinoma
• Cachexia, anaemia and thrombocytosis
• Thrombophlebitis migrans (Trousseau sign) and unprovoked venous thromboembolism

Paraneoplastic syndromes

These are effects of the tumour that are not caused by its mass or by metastasis, and they may be the presenting feature. They are examined frequently because each points to a particular cell type.

Referral and investigation

Who to refer, and how fast

NICE NG12 sets deliberately low thresholds, because early symptoms are so easily dismissed.¹

• Offer an urgent chest X-ray (within 2 weeks) to people aged 40 and over with two or more of the following unexplained symptoms, or one or more if they have ever smoked: cough, fatigue, breathlessness, chest pain, weight loss or appetite loss
• Consider an urgent chest X-ray in people aged 40 and over with any of: persistent or recurrent chest infection, finger clubbing, supraclavicular or persistent cervical lymphadenopathy, chest signs consistent with lung cancer, or thrombocytosis
• Refer on a suspected cancer pathway (seen within 2 weeks) if the chest X-ray suggests lung cancer, or if the person is aged 40 or over with unexplained haemoptysis
• A normal chest X-ray does not exclude lung cancer. Around one in five is missed on the plain film. If clinical suspicion remains, refer or arrange a CT anyway - this is one of the most common causes of delayed diagnosis.

Establishing the diagnosis and stage

1. Chest X-ray - looking for a mass, hilar enlargement, collapse, effusion, cavitation or a raised hemidiaphragm
2. Contrast-enhanced CT of the chest, abdomen and pelvis - the standard staging investigation, covering the liver and adrenals
3. PET-CT - where treatment with curative intent is being considered, to detect occult nodal and distant disease that would change the plan
4. Brain imaging (contrast MRI preferred) - for stage III disease, for all patients with small cell lung cancer, and where there are neurological symptoms
5. Tissue diagnosis - by the least invasive route that gives adequate material and stages the patient at the same time

Other investigations

• Bloods - FBC (anaemia, thrombocytosis), U&Es (hyponatraemia of SIADH), calcium, LFTs including ALP, and clotting
• Lung function tests - FEV1 and TLCO to assess fitness for surgery or radical radiotherapy, with a cardiopulmonary exercise test in borderline cases
• Performance status (WHO or ECOG, 0 to 4) - as important as stage in determining what treatment a patient can tolerate
• Molecular and immunohistochemical testing on NSCLC tissue - EGFR, ALK, ROS1, BRAF, KRAS G12C and other drivers, plus PD-L1 expression. This is now essential rather than optional, because it determines first-line treatment in advanced disease.

Staging

Non-small cell lung cancer is staged with the TNM system, which drives the treatment decision:

• T - size of the primary and what it invades
• N - nodal involvement, from N0 (none) through N1 (ipsilateral hilar), N2 (ipsilateral mediastinal) to N3 (contralateral or supraclavicular)
• M - metastases, including separate tumour nodules and malignant pleural or pericardial effusion
• Stages I and II are potentially curable by surgery; stage III is locally advanced and usually treated with chemoradiotherapy; stage IV is metastatic and treated systemically

Small cell lung cancer is also formally staged by TNM, but the practical division remains:

• Limited stage - confined to one hemithorax and encompassable within a single tolerable radiotherapy field. Treated with concurrent chemoradiotherapy with curative intent.
• Extensive stage - beyond that, in around two thirds of patients at diagnosis. Treated with chemotherapy plus immunotherapy.

Management

Every patient should be discussed at a lung cancer multidisciplinary team meeting and allocated a lung cancer nurse specialist, who is consistently one of the most valued parts of care from the patient's point of view.

Non-small cell lung cancer

• Surgery - lobectomy is the standard operation for stage I and II disease in a patient fit enough, with pneumonectomy, segmentectomy or wedge resection in selected cases. Increasingly performed by VATS or robotically. Fitness is assessed with lung function, exercise testing and cardiac risk.
• Stereotactic ablative radiotherapy (SABR) - highly conformal radiotherapy delivered in a few fractions, for early-stage disease in patients unfit for surgery. Local control rates approach those of surgery.
• Adjuvant chemotherapy after resection of stage II or III disease, and adjuvant targeted therapy or immunotherapy in selected molecular subgroups
• Concurrent chemoradiotherapy for stage III disease, followed by durvalumab consolidation
• Stage IV disease - guided by molecular testing: a targeted tyrosine kinase inhibitor where a driver mutation is present (for example osimertinib for EGFR, alectinib for ALK), immunotherapy such as pembrolizumab alone where PD-L1 expression is high, or chemotherapy combined with immunotherapy where it is not

Small cell lung cancer

• Chemotherapy is the backbone - platinum (cisplatin or carboplatin) with etoposide. SCLC is strikingly chemosensitive initially, with high response rates, but almost always relapses.
• Concurrent chemoradiotherapy for limited-stage disease, given with curative intent
• Chemotherapy plus immunotherapy (atezolizumab or durvalumab) for extensive-stage disease
• Prophylactic cranial irradiation - offered to patients responding to treatment, because brain metastases are so common and the blood-brain barrier limits chemotherapy penetration
• Surgery has almost no role, because the disease has usually disseminated by diagnosis

Palliative and supportive care

• Early specialist palliative care referral - in advanced lung cancer this improves quality of life and mood, and in a landmark trial was associated with longer survival despite less aggressive end-of-life treatment
• Palliative radiotherapy - for haemoptysis, chest pain, bone pain, SVC obstruction and brain metastases
• Endobronchial treatment - stenting, debulking or brachytherapy for major airway obstruction
• Pleural procedures - talc pleurodesis or an indwelling pleural catheter for a recurrent malignant effusion
• Symptom control - opioids for pain and for breathlessness, steroids for raised intracranial pressure and SVC obstruction, and antiemetics
• Smoking cessation - beneficial even after diagnosis, improving treatment tolerance, surgical outcomes and survival
• Nutritional and psychological support, and attention to benefits and financial advice

Complications

• Malignant pleural effusion - occurring in around 15% and defining stage IV disease
• Post-obstructive pneumonia and lung abscess
• Superior vena cava obstruction
• Metastatic spinal cord compression and pathological fracture
• Brain metastases - present in around 10% at diagnosis in NSCLC and far more in SCLC
• Hypercalcaemia and hyponatraemia
• Venous thromboembolism - substantially increased, and often the first clue to an occult cancer
• Massive haemoptysis
• Cachexia and malnutrition
• Treatment complications - neutropenic sepsis, radiation pneumonitis and oesophagitis, and the immune-related toxicities of checkpoint inhibitors, which can affect any organ and include colitis, hepatitis, pneumonitis, thyroiditis and hypophysitis
• Depression and anxiety - very common, and compounded by the stigma many patients feel about a smoking-related cancer

Red flags

Prognosis

Overall survival remains poor. Around 40% of patients survive one year and only about 16 to 20% survive five years, largely because of late presentation - but the figures conceal an enormous range.

• Stage I NSCLC treated surgically - five-year survival of around 65 to 80%
• Stage III NSCLC - around 15 to 25% at five years with chemoradiotherapy
• Stage IV NSCLC - historically a median survival of under a year, but transformed in molecularly selected subgroups, where targeted therapy has produced median survivals of several years and durable responses to immunotherapy are now well documented
• Limited-stage SCLC - median survival around 15 to 20 months, with a minority cured by chemoradiotherapy
• Extensive-stage SCLC - median survival around 8 to 13 months, improved somewhat by the addition of immunotherapy

Prognosis depends on stage, histology, molecular subtype, performance status and weight loss. Performance status in particular is often decisive: a patient with stage IV disease who is fully active may tolerate treatment that would be unthinkable for someone confined to bed for more than half the day, whatever the stage.

The single most important message remains preventive. Smoking cessation reduces risk substantially within 10 to 15 years and improves outcomes even after diagnosis, and the Targeted Lung Health Check programme offers the first realistic prospect of shifting the stage distribution at diagnosis, which is what would change these survival figures most.