Lung Cancer

Question 1

Who gets lung cancer?

Answer 1

Age, peak 75-90
Sex, M>F
Lower socioeconomic status
Smoking history
——–duration, intensity, when stopped

Question 2

What are other aetiological factors for lung cancer apart from smoking and passive smoking?

Answer 2

Asbestos – exposure (plumbers, ship-builders, carriage workers, carpenters, etc) – risk up to x2
Radon – e.g. silver miners in Germany late 19th century; 1950s uranium mining in Colorado
Indoor cooking fumes – wood smoke, frying fats
Chronic lung diseases (COPD, fibrosis)
Immunodeficiency
Familial/ genetic – several loci identified

Question 3

What is the pathogenesis of lung cancer?

Answer 3

Lung cancer may arise from all differentiated and undifferentiated cells
The interaction between inhaled carcinogens and the epithelium of upper and lower airways leads to the formation of DNA adducts: pieces of DNA covalently bound to a cancer-causing chemical
If DNA adducts persist or are misrepaired, they result in a mutation and can cause genomic alterations. These are key events in lung cancer pathogenesis, especially if they occur in critical oncogenes and tumour suppressor genes.

Question 4

What are the different types of lung cancer?

Answer 4

Squamous cell carcinoma (~30% of cases).
– previously the most common
– originating from bronchial epithelium; centrally located

Adenocarcinoma (~40%)
– most common from 1980s onwards – low tar cigarettes, inhaled more deeply / retained longer
– originating from mucus-producing glandular tissue; more peripherally-locate

Large cell lung cancer (~15%)
heterogenous group, undifferentiated

Small cell lung cancer (~15%)
originate from pulmonary neuroendocrine cells
highly malignant

Question 5

Mutations in what genes are important for directed treatments?

Answer 5

epidermal growth factor receptor (EGFR) tyrosine kinase
15-30% of adenocarcinoma
more so in women, Asian ethnicity, never-smokers

anaplastic lymphoma kinase (ALK) tyrosine kinase
2-7% of non-small cell lung cancer
especially in younger patients and never smokers

c-ROS oncogene 1 (ROS1) receptor tyrosine kinase
1-2% of non-small cell lung cancer
especially in younger patients and never smokers

BRAF (downstream cell-cycle signalling mediator)
1-3% of non-small cell lung cancer
especially in smokers

Question 6

What are the key symptoms of lung cancer?

Answer 6

Cough
Weight loss
Breathlessness
Fatigue
Chest pain
Haemoptysis
Or frequently asymptomatic

Question 7

What are the key symptoms of lung cancer?

Answer 7

Cough
Weight loss
Breathlessness
Fatigue
Chest pain
Haemoptysis
Or frequently asymptomatic

Coughing up blood
Repeated respiratory infection

Question 8

What are features of advanced/ metastatic disease?

Answer 8

Neurological features:
focal weakness, seizures, spinal cord compression

Bone pain

Paraneoplastic syndromes
clubbing, hypercalaemia, hyponatraemia, Cushing’s

Question 9

What are common sites of lung cancer metastases?

Answer 9

Bones
Liver
Brain
Lymph nodes
Adrenal glands

Question 10

What are signs of lung cancer?*

Answer 10

Clubbing
Cachexia
Horner’s syndrome
Superior vena cava obstruction (Pemberton’s sign)

Question 11

What is the diagnostic strategy for lung cancer?

Answer 11

Establish most likely diagnosis
Establish fitness for investigation and treatment
Confirm diagnosis
—–specific type of cancer if considering systemic treatment
Confirm staging

Question 12

Who is art of the lung cancer MDT?

Answer 12

Respiratory
Radiology
Pathology
Thoracic surgery
Oncology
Palliative care

Question 13

Look at chest Xray and staging CT of chest and abdomen**

Question 14

What is an example of definitive imaging for staging?**

Answer 14

PET-CT (fluorodeoxyglucose)

Question 15

How is type of biopsy chosen?

Answer 15

Choose method based on accessibility, availability and impact on staging

Question 16

What are the types of biopsy?*

Answer 16

CT-guided lung biopsy
To access peripheral lung tumours

Bronchoscopy
for tumours of central airway
where tissue staging not important

Endobronchial ultrasound and transbronchial-needle aspiration of mediastinal lymph nodes (EBUS [TBNA])
To stage mediastinum +/- achieve tissue diagnosis

Question 17

How does staging work??

Answer 17

TNM based on characteristics

Question 18

How else is staging assessed?

Answer 18

Early vs locally-advanced vs metastatic

Question 19

What are the determinants of treatment?

Answer 19

Patient fitness
Cancer histology
Cancer stage
Patient preference
Health service factors

Question 20

How is patient fitness assessed using the WHO performance status?

Answer 20

0 – Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)
2 – Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours)
3 – Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours)
4 – Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
5 – Death

Radical treatment usually restricted to PS 0-2

Comorbidity + lung function also very important

Question 21

What is the standard of care for early stage disease?

Answer 21

Surgical resection is standard of care for early stage disease
Lobectomy + lymphadenectomy usual approach
Sublobar resection if stage 1 (≤3 𝑐𝑚)

Question 22

What are the different types of surgical resection?

Answer 22

Wedge resection
Segmental resection
Lobectomy
Pneumonectomy

Question 23

What is an alternative to surgery for early stage disease?

Answer 23

Radical radiotherapy

Particularly if comorbidity
Stereotactic ablative body radiotherapy (SABR)
—–Technique of choice
——High-precision targeting, multiple convergent beams

Question 24

What is the treatment for early stage disease?

Answer 24

Surgery or radiotherapy with curative intent

Question 25

What is the treatment for locally advanced disease (involving thoracic lymph nodes)?

Answer 25

Surgery + adjuvant chemotherapy
Radiotherapy + chemotherapy +/- immunotherapy

Question 26

What is the treatment for metastatic disease?

Answer 26

With targetable mutation (e.g. EFGR, ALK, ROS-1): tyrosine kinase inhibitor
No mutation, PDL-1 positive: immunotherapy alone
No mutation, PDL-1 negative: ‘standard’ chemotherapy + immunotherapy
Palliative care, alone or with the above

Question 27

Describe the systemic treatment that is oncogene directed?

Answer 27

First line for metastatic NSCLC with mutation

NICE-approved,
EGFR: erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib
ALK: crizotinib, ceritinib, alectinib, brigatinib, lorlatinib
ROS-1: crizotinib, entrectinib

Efficacy
improvements in progression-free survival, but not necessarily overall survival vs standard chemotherapy:
e.g. erlotinib PFS 14 vs 5 months, OS 23 vs 29 months compared to chemo (OPTIMAL trial)
e.g. crizotinib PFS 8 vs 3 months, OS 20 vs 23 months

Side effects
generally well-tolerated (tablets)
rash, diarrhoea, and (uncommonly) pneumonitis

Question 28

Describe the systemic treatment that is immunotherapy?***

Answer 28

First line for metastatic NSCLC with no mutation (and PDL1 ≥50%)

NICE-approved,
Pembrolizumab, atezolizumab, nivolumab

Efficacy
improvements in progression-free survival and overall survival vs standard chemotherapy:
e.g. pembrolizumab PFS 10 vs 6 months, OS >30 vs 14 months (KEYNOTE-024 trial)
[32% alive at 5 years]

Side effects
generally well-tolerated
Immune-related side-effects in 10-15% (thyroid, skin, bowel, lung, liver)

Question 29

Describe the systemic treatment that is cytotoxic chemotherapy?

Answer 29

First line for metastatic NSCLC with no mutation and PDL1 ≤50% (in combination with immunotherapy)

Long established
Target any rapidly dividing cells
Platiunum-based regimens, e.g. carboplatin, cisplatin, paclitaxel, pemetrexed

Efficacy,
when used alone (old data, pre-2000) modest improvements in overall survival vs best supportive care:
e.g. 29 vs 20% one year survival in clinical trials
with pembrolizumab (Keynote 189), a lot better (23% 2y survival vs 5% for standard chemo alone)

Side effects
Frequent: fatigue, nausea, bone marrow suppression, nephrotoxicity
Quality of life poorly evaluated in trials; no evidence for improvement

Question 30

Describe how palliative and supportive care works?

Answer 30

Should be offered as standard to all patients with advanced stage disease

Symptom control, psychological support, education, practical and financial support, planning for end of life

Lung cancer specialist nurses key

Evidence for survival as well as symptomatic benefit: Temer et al. N Engl J Med. 2010;363:733
151 patients, new diagnosis NSCLC in USA
Standard oncology care +/- early palliative care
At 12 weeks:
Improved quality of life
Lower depression scores
Median survival 11.6 v 8.9 months