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Flashcards in Lung cancer Deck (38)
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1

Epidemiology of lung cancer

 

  • 9.2% of new cancer diagnosis in 2018, but high mortality rate 18.9% due to common late stage diagnosis 
  • Incidence rate of lung cancer decreased in males by 32% but increased in females by 72% 
  • Only 15% of all lung cancer cases are diagnosed at an early stage
  • Majority present with distant metastasis at diagnosis with a 5 year survival rate of about 4%

2

Risk factors of lung cancer

RR of lung cancer in longterm smokers = 10-30x higher than non-smokers

  • smoking/tobacco. most potent carcignogen of cigarette smoke = polycyclic aromatic hydrocarbons (PAHs)
  • occupation (miners, heavy metal workers)
  • second hand smoke
  • family history
  • radon gas
  • ageing
  • other illnesses e.g. COPD, TB
  • pulmonary fibrosis 
  • pollution
  • exposure to radiation 

Lung cancer prevalence in never-smokers is higher in Asian countries, particularly in women, associated with EGFR mutation. probably due to inhalation of cooking oil vapour and domestic coal use.

3

Screening of lung cancer

Currently nil recommended. 

Previous trial of annual low dose CT scans; very high false positive rate. 

4

Staging of lung cancer

 

  • Mediastinal staging is important
    • PET good for mediastinal lymph node. not commended for confirmed stage 4 disease on CT scan 
  • Bronchoscopy or endoscopic USG (EBUS)
    • Provide sampling
    • Local evaluation for intervention (stent) 
    • Local resection/cryotherapy 
  • Tumour specimen can be obtained by; cytology, bronchoscopy, transthoracic needle aspiration biopsy, mediastinoscopy, thoracoscopy, thoracentesis. 
  • lymph node is important. drainage of lymph node determines stage of IIa-IIIc

5

Describe role of imaging in diagnosis and staging of lung cancer

 

  • PET scan sensitive (91%) and specificity (86%) for mediastinal LNs. (not applicable for confirmed stage IV disease)
    • Useful pre-operative to avoid futile thoracotomy
    • Also to exclude distant metastasis
  • CT scan sensitive (75%) and specificity (66%) for mediastinal LNs.
  • Mediastinal LNs sampling is necessary for all patients with enlarged or abnormal nodes detected by CT or PET scan.
  • M1A: pleural effusion, tumor in contra-lateral lung , pleural or pericardial nodule 
  • Positive prognostic factors: stage of disease, good performance status (most cancers), lack of substantial weight loss and female sex.

6

Mx of stage 1 & 2 lung cancer

 

Stage 1: 

  • Surgery if medically fit 
  • Non surgical candidate: Stereotactic surgery effective treatment option ( only for T1 or T2, N0)
  • 5 year survival: 60-80%

 

Stage 2

  • Surgery if medically fit
  • Non surgical candidate: Radiotherapy (conventional fractionated radiotherapy)
  • 5 year survival: 40-50%

 

Types of mx: 

  • Surgery: lobectomy is preferred and draining LNs resection is recommended for all tumours >2cm, or tumours <2cm with solid appearance on CT. 
  • Stereotactic radiotherapy effective alternative for node negative non-bulky tumour
  • Adjuvant chemotherapy: in stage II and IIIA disease. (stage IB controversial). Normally cisplatin based combination treatment

7

Mx of Stage III lung cancer

Multidisciplinary assessment is crucial. most controversial

 

Non-bulky stage IIIA

  • Optimal treatment is local approach
  • Surgery +/- radiotherapy + chemotherapy 
  • 5 year survival: 36%

 

Bulky IIIA and IIIB ​

  • NO surgery 
  • Chemo-Radiotherapy (CRT) better survival c.f. RT alone 
  • 5 year survival: 20%

 

8

Mx of stage III non small cell lung cancer

  • occasionally resectable if no bulky mediastinal or contralateral LNs
  • In appropriately staged & fit patients; concurrent radiotherapy + platinum based chemotherapy (e.g. cisplatin-etoposide, cisplatin-vinorelbine)
    • 6weeks RT + concurrent chemo
    • cure rate 20-30%
  • Durvalumab (PD-L1) for 12 months post chemoradiotherapy improves DFS 

9

Describe immunotherapy in lung cancer

 

stage III non small cell lung cancer: Durvalumab (immunotherapy)

durvalumab 10mg/kg, 2 weekly, for a year compare with placebo

significantly improved progression free survival 

now standard of care

10

Mx of stage 4 non small cell lung cancer

 

  • incurable but new therapies available 
  • Immunotherapy = first line or second line for patients without actionable mutation 
  • Performance status (PBS restrict most drug for performance status 2 or less) is important 
  • Radiotherapy has role in palliation of symptoms and also for brain metastasis 
  • Median survival 4-5 month with best supportive care without systemic treatment
  • New driver MEK, BRAF and HER2 emerging 

 

1. Non-squamous carcinoma: test for actionable mutations +/- PD-L1

  • Epidermal Growth Factor Receptor (EGFR) (15%)
    • non-smokers, young Asian females, adenocarcinoma
    • Mx: oral tyrosine kinase inhibitors (gefitinib, erlotinib, afatinib). more effective than chemo as first line. SE: acne like rash, diarrhoea.
    • EGFR inhibitor resistance: 60% due to T790M resistance mutation -> mx with 3rd generation EGFR TKI (osimertinib)
  • Anaplastic lymphoma Kinase (ALK) gene rearrangement (5%)
    • fusion oncogene of EML4-ALK. 5% lung adenocarcinomas. more common in non smokers, young pts
    • detected by FISH/IHC
    • Mx: inhibitors of ALK phosphorylation (crizotinib, alectinib, lorlatinib). superior to chemo.
  • ROS 1 (2%)
    • lung adenocarcinomas. more common in non-smokers, young pts. 
    • Mx: inhibitors of ALK phosphorylation (crizotinib, lorlatinib)
  • If no driver mutation, test for PDL-1 status (high vs low)
    • PD-L1 <1%: chemoimmunotherapy (platinum doublet + PD-L1 inhibitor)
    • PD-L1 1-49%: PD-1 inhibitor +/- chemotherapy
    • PD-L1 >50%: single agent PD-L1 inhibitor 

2. Squamous carcinoma: test for PDL-1 status

 

 

11

Describe metastatic non small cell lung cancer landscape of mutations

KRAS 22%

EGFR 17%

EML4-ALK 7%

 

These genetic alterations drive signaling pathways ->  cell proliferation.

Molecularly targeted therapies interrupting these pathways lead to significant therapeutic benefit 

12

Describe lung cancer classification 

1. Lung cancer -> 85% non small cell lung cancer, 15% small cell lung cancer

2. non small cell lung cancer -> 70% non squamous, 30% squamous. 

3. non-squamous lung cancer -> 90% adenocarcinoma (mixed subtypes, lepidic, acinar, papillary, micropapillary, solid), 10% large-cell carcinoma (large-cell neuroendocrine carcinoma)

 

i.e. 

  • adenocarcinoma: 40%
  • squamous cell: 20%
  • small cell: 13%
  • large cell: 7%
  • other: 20% (bronchoalveolar, carcinoid) 

 

13

What would you test for in advance stage III (not suitable for chemoradiotherapy) or stage IV non small cell lung cancer?

If non-squamous: test for actionable mutations (EGFR, ALK rearrangement, ROS 1). If -ve, then test for PDL-1 status (high vs low)

If squamous: test for PDL-1 status

14

Mx of EGFR mutant stage IV NSCLC

- mutant common in which demographic

- 1st generation

- 3rd generation; when to use 

- SE 

EGFR mutations: 

  • 40% of Asian patients, 5-15 % in unselected western population
  • More common in Adenocarcinoma, younger women, never smokers

1st generation EGFR inhibitor e.g. erlotinib, however develop invariable resistance 

  • Evidence: improve PFS compare with chemotherapy due cross over) 
  • SE: Acneiform rash (80%) mx with topical or oral antibiotics (tetracyclines), topical steroids; skin care and sun protection. Diarrhoea, Ocular changes, Alopecia, Nail changes, Pulmonary toxicity

3rd generation EGFR inhibitor eg. osimertinib, can be used if resistance developed against 1st generation 

  • T790 mutation is most common mechanism of resistance.
  • oral, third-generation, irreversible EGFR-TKI that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations.
  • Works post progression to erlotinb/gefinitib (need to have confirm T790 mutation) APPROVED
  • Also shows improve PFS as first line treatment NOT-APROVED
  • Excellent CNS penetration, less skin toxicity

15

Describe molecularly targeted therapy for ALK rearrangement in metastatic NSCLC

- role of ALK

- % of NSCLC

- demographic

- examples & SE of ALK targeted therapy 

 

  • ALK = novel receptor tyrosine kinase where chromosomal translocation a/w 60% anaplastic large-cell lymphomas –hence “ALK”
  • NSCLC a/w the novel EML4-ALK fusion oncogene (Inversion in chromosome 2 that fuses EML4 gene with ALK gene)
  • Ix with IHC + FISH 
  • 2-7%NSCLC
  • Frequently Asian, Adenocarcinoma, 50-60% men, never or lightsmokers
  • ALK TKIs have shown significant ORR and PFS advantages as well as survival advantage c.f. other mx
  • Alectinib (a new ALK TKI): first line treatment. longer PFS than crizotinib. better CNS penetration, less toxic than crizotinib (older ALK TKI). 
  • SE of Crizotinib: Visual changes, Neutropenia, ltered bowel habit, Pulmonary toxicity, Fluid retention, Hepatotoxicity, Bradycardia, prolonged QT, Fatigue, Cytochrome p450 interactions 

16

Mx of ROA-1 rearrangement metastatic NSCLC

 

 

  • chromosomal rearrangements of the gene encoding ROS1 proto-oncogene 
  • 1% of subgroup of non–small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. 
  • Crizotinib targets ROS 1 ( in addition to ALK and MET kinase) with 72% response rate
  • Mx with crizotinib: has marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. (PBS listed) 

17

Describe immunotherapy in NSCLC

 

  • PDL-1 is biomarker for predicting response and first line approval is based on PDL-1 expression for single agent pembrolizumab.
  • Every patient without actionable mutation (e.g. ALK rearrangement, EGFR, ROS-1) should have PDL1 check as baseline test. 
  • recent trial; synergistic effect with chemotherapy -> excellent result even in PDL-1 negative patients when used in combination. 
  • Most patients will have immunotherapy either as 1st line for high PDL-1, or low PDL-1 who are 'fit'. 2nd line setting, if not eligible first line. 

18

Chemotherapy Mx of stage IV NSCLC 

- indications

 

Currently used for:

  • Patient with low (<50) PDL1 with squamous cell NSCLCA
  • Patient who is not suitable candidate for immunotherapy 
  • Immunotherapy is contraindicated
  • Maintenance treatment after 4 cycles of platinum doublet; with pemetrexed was generally well tolerated. No benefit in squamous pathologies.  

19

Mx of limited stage small cell lung cancer

Limited stage = All disease within one radiation field (i.e. ipsilateral lung and hilar/mediastinal LNs)

curable 20-30% with concurrent chemoradiotherapy

 

  • Platinum (cisplatin or carboplatin) with etoposide is recommended.
  • Classified according to radiotherapy field (limited vs extensive)
  • Radiotherapy recommended for limited stage from cycle 2 onwards.
  • URGENT assessment with CT staging including brain (MRI preferred)
  • Prophylactic brain radiotherapy (can progress rapidly and once progressed, hard to recover)

20

Clinical characteristics of small cell lung cancer

- in regards to smoking, chemotherapy, metastasis & others

  • Strongly associated with smoking 
  • Very chemotherapy sensitive tumour, but rapid progression 
  • Early to metastasise, high mitotic rate -> Chemo & radiosensitive
  • Classically bulky lymphadenopathy
  • Occasional present with variety of paraneoplastic syndrome
  • CNS metastasis is frequent (MRI brain/CT recommended)
  • Doesn’t cause clubbing

21

Mx of extensive stage small cell lung cancer

generally incurable but do expect excellent response with chemoradiotherapy. even in very unwell pts. 

 

1. cisplatin/caboplatin and etoposide 4 cycles

2. consolidative chest radiotherapy in selected patient + brain radiotherapy

3. Immunotherapy: PD-1 +/- CTLA4 inhibitors 

22

Describe mesothelioma

- risk factors

- histological subtypes

- outline of mx

- median survival

 

  • Mesothelioma common pleural malignancy directly related to asbestos exposure (long latency of 30-40yrs) + tobacco 
  • Three main histological subtype: Epithelioid more common but sarcomatoid worse survival 
  • Px: usually pleural +/- peritoneal 
  • generally incurable
  • Mx: 
    • radical treatment: extrapleural pneumonectomy. a/w high morbidity 
    • 1st line = Palliative intent chemotherapy (cisplatin and pemetrexed) 
      • palliative chemo improves survival 
    • addition of bevacizumab significantly improves overall survival in malignant metastatic pleural mesothelioma 
    • May respond to PD-1 inhibitor 
  • Median survival is 12.1 month 

23

 

62 year old female with incidental lung nodule (1.8cm). Biopsy adenocarcinoma of lung. 

Mx if fit & healthy. 

Mx if unfit for surgery e.g. pulmonary fibrosis, COPD

1. fit & healthy -> lobectomy

2. unfit for surgery -> Stereotactic Body Radiation Therapy (SBRT)

24

 

62 year old female with SOB. FDG scan: several LNs and primary. No distant metastasis. ECOG 1. No CI to immunotherapy

Mx if biopsy showed:

a. adenocarcinoma/squamous cell with high PDL1 (>50)

b. adenocarcinoma with low PDL-1 (<50)

c. squamous cell with low PDL-1 (<50)

a. adenocarcinoma/squamous cell with high PDL1 (>50): single agent pembrolizumab

b. adenocarcinoma with low PDL-1 (<50): ABCP (atezolizumab, bevacizumab, carboplatin & paclitaxel if accessible)

c. squamous cell with low PDL-1 (<50): Platinum doublet chemotherapy

25

 

62 year old male Fit, EX smoker. Presented with cough. No other PMx. Biopsy shows adenocarcinoma. Staging T3N2, not surgical candidate. Lung function good for radical dose radiotherapy

Best management? 

Completed definitive chemoradiotherapy

Followed by 1 year of durvalumab (anti PD-L1 antibody)

26

Types of lung cancer

1. small cell lung cancer

2. non small cell lung cancer: large cell, adenocarcinoma, and squamous cell cancer

 

27

Mx of early stage non small cell lung cancer

  • Early stage; Lobectomy if FEV1 & DLCO suitable 
  • If not surgical candidate, stereotactic body radiation for small tumours and conventional radiation for large tumours
  • Adjuvant radiation if positive tumour margins on resected localised lung cancer
  • Adjuvant cisplatin-based chemotherapy is standard treatment of all resected stage II and III lung cancer.

 

Lobectomy +/- adjuvant radiotherapy if positive margin 

Lobectomy +/- chemotherapy if stage II/III

28

If you have hilar nodal disease, what stage non small cell lung cancer is it? 

Once you have hilar lymph node, at least stage II

 

Stages I and II are differentiated by hilar nodal metastatic disease (present in some patients with stage II cancer, but not present in stage I) and also by the size and invasiveness of the primary tumor into adjacent structures. 

29

Screening for recurrence post mx in early stage non small cell lung cancer

  • early-stage disease remain at risk for both distant and local recurrence
  • pts with smoking histories also at risk for developing a second primary lung cancer, head & neck cancers
  • history, physical examination, and chest CT Q6 months for the first 2 years and then annually
  • Smoking cessation; the risk steadily declines beginning 5 years after quitting, but it never quite reaches the incidence found in nonsmokers.

30

Mx of locally advanced non small cell lung cancer

  • Locally advanced = clinically detectable lymphadenopathy in the mediastinum or by a primary tumor that invades into local structures, such as the mediastinum, heart, trachea, esophagus, or great vessels.
  • surgical therapy with curative intent +/- neoadjuvant or adjuvant chemotherapy or radiation treatment. previously considered incurable. e.g. 
    • including satellite nodules in another ipsilateral lobe
    • isolated tumour nodule in contralateral lung
    • limited ipsilateral mediastinal node involvement
    • a single node station and non bulky disease
  • If bulky/multistation (widespread multistinal or hilar lymph node involvement) mediastinal LN: combined platinum-based chemo + radiotherapy. however recurrence rate is very high (70-90%) after chemoradio treatment.