Lung Cancer

Question 1

Lung Cancer – Risk Factors

Leading cause of death from cancer in women and men

Answer 1

– Smoking tobacco (highest risk)
• 85% of lung ca in Canada is related to smoking
• Smokers are about 20 times more likely to develop lung cancer than non-smokers
– Second hand smoke (passive smoking)
• 20-30% increased risk of lung cancer in non-smokers who live with smokers
– Asbestos
– History of COPD, TB, lupus,
– Immunosuppression - HIV/AIDS or immunosuppressant medications
– Occupational exposure to certain chemicals
– Exposure to radiation (eg radiotherapy for lymphoma)
– Beta carotene* with smoking - used to think that it can help and rpevent cancer, but it does the opposite
– Outdoor air pollution

cannabis:
- uncertain, but cannabis smoke contains many same cancer causing subtsances as tobacco, typically u inhale more smoke and hold it in
e-cigs: uncertain, may be better than regular cigarettes

Question 2

Signs and Symptoms

Answer 2

• Cough
• Dyspnea
• Weight loss
• Chest pain
• Symptoms are more likely in patients who already have COPD
ddull nagging pain in chest

Question 3

Diagnosis

Answer 3

• Diagnostic procedures should be tailored to the individual patient and may include:
– Chest X ray included review of previous Xrays to identify any changes
– Chest CT or PET
– Bronchoscopy
– Sputum cytology from cough or bronchoscopy
– Biopsy – via bronchoscopy or fine needle or excisional or from surgery.

Question 4

Work Up

Answer 4

• Laboratory tests
• Consider bone scan
– to explore for bone metastases
• Consider CT or MRI head
– to explore for brain metastases
• CT chest/abdomen
– may also reveal adrenal or liver metastases
• Pulmonary Function Tests
– Implications for post op recovery and tolerance to radiation, capacity to breathe may be compromised
see if they can tolerate tx, radiation

Question 5

Screening for Lung Cancer

This is new

Answer 5

• The Canadian Task Force on Preventive Health Care (CTFPHC) recommends
screening for lung cancer with low-dose CT once each year for 3 years in
adults who:
– are 55-74 years of age (evidence shows that screening is most effective for
people in this age group)
– are current smokers or former smokers who quit in the last 15 years
– A minimum of 30 pack-year history of smoking
• Purpose is to identify lung cancer early when it is more treatable
• Evidence suggests screening reduces lung cancer mortality by 20 to 25%
• Screening program should include support to help people quit
smoking

Question 6

Lung Cancer Screening in Alberta

Answer 6

• An Alberta funded screening program for lung cancer just started in
Sept 2022.
– Two-year Pilot Project
– Offered in three primary care networks
• Mosaic, PLC Calgary
• O-day’min, RAH Edmonton
• Grande Prairie, GPRH
• Eligible Albertans are:
– 50-74 years old
– Current or previous long time tobacco cigarette users

Question 7

Lung Cancer
Can be divided into 2 histologic types:

Answer 7

Small Cell Lung Cancer
SCLC
12-15% of lung cancers

Non Small Cell Lung Cancer
NSCLC
≥80% of lung cancers

Question 8

NON-SMALL CELL LUNG CANCER (NSCLC)

3B –> advanced disease starting

Answer 8

Non-Small Cell Lung Cancer (NSCLC)
Stage 1:
• 23% of patients are diagnosed at stage 1
• 5 year survival is approximately 80%
Stage 4:
• 47% of patients are diagnosed at stage 4
• 5 year survival is approximately 10%

There is evidence to suggest that for smokers with early stage disease, 5 year
survival is approximately double if they quit smoking after diagnosis.
• NSCLC 70% vs 33%

big cause of mortality

Question 9

Types of NSCLC

“Non-Squamous” – This term is sometimes used to
describe adenocarcinoma but inclusive of other rare types
of NSCLC that are NOT squamous cell

this term is being used as more

Answer 9

Adenocarcinoma (Non-squamous)
• Approximately 50% of NSCLC - msot common
• Glandular cells (mucous making cells) on outer part of lung
• Most common type in non-smokers. However, number of cases is still higher in smokers because it such a huge risk factor

Squamous cell carcinoma (epidermoid)
• Approximately 35% of NSCLC
• Squamous cells that line the bronchi

OTHERS (15%)
• Adenosquamous carcinoma (mixed)
• Large cell carcinoma (large under microscope)

Question 10

Treatment of Early NSCLC

Answer 10

Stage I-IIIA Resectable Disease:Recommendation:
• Surgery
• Add Adjuvant Chemotherapy if
stage II or higher
• If positive margins, consider adding
adjuvant radiation or re-resecting
after adjuvant chem
can it be cut out?

Stage II-IIIA Non-Resectable Disease
• Concurrent radiation + chemo (Chemoradiation)
• Intense, focused radiation followed by adjuvant chemotherapy
• Neoadjuvant chemotherapy, surgery, +/- adjuvant radiation (Make it a bit smaller)
NOTE: IF stage IIIA and good response from concurrent radiation + chemotherapy then give:
Durvalumab

Stage I-IIIA, ECOG 3-4 (PoorPS)
Palliative radiation

Question 11

Adjuvant (or Neoadjuvant) Chemotherapy

Answer 11

For adjuvant or neoadjuvant use a “PLATINUM DOUBLET” (platinum + another drug)
Cisplatin 80 mg/m2 DAY 1 and
Vinorelbine 30mg/m2 DAY 1, 8, 15,22
Repeat every 21 days for 4cycles

Cisplatin 75 mg/m2 DAY 1
and Pemetrexed 500 mg/m2
DAY 1
Repeat every 21 days for 4 cycles

Cisplatin 75 mg/m2 DAY 1
and Gemcitabine 1250
mg/m2 Day 1 & 8
Repeat every 21 days for 4 cycles

Carboplatin AUC 6 day 1
and Paclitaxel 200 mg/m2
DAY 1
Repeat every 21 days for 4 cycles

Smoking Cessation?

Question 12

Cisplatin

Answer 12

• MOA
– similar to bifunctional alkylating agents
– Covalently binds to DNA and disrupts DNA function
• Side Effects
– Ototoxicity (30%)
• Can manifest as tinnitus or hearing loss
– Nephrotoxicity (30%)
• Can manifest as elevated SCr, hypokalemia, hypomagnesemia
• Often requires extra hydration (IV per and post hydration) and supplementation of potassium and
magnesium in the IV fluid
Waste elextroyltes
Need tons of hydration
Always get magnesium, potassium if coming in low with that too

• Dose reduce if renal impairment
– Bone marrow suppression
– Nausea and vomiting (highly emetogenic, 90%)
• BIG BAG PUKEY DRUG 9/10 will through up if no prophylaxis
• Requires multiple antinauseants to prevent acute and delayed nausea and vomiting

Question 13

Carboplatin

Answer 13

• Analog of cisplatin
• Dosed based on Calvert formula
– Dose (mg) = AUC x (CrCl in mls/min + 25)
• Benefit of carboplatin over cisplatin is that it is less ototoxic and nephrotoxic

– Often used for patients that can’t tolerate cisplatin (example have renal insufficiency)
• Side Effects:
– Substantially more myelosuppression (bone marrow) as compared to cisplatin
– Anemia (70%), Neutropenia (18%), Thrombocytopenia (25%)

Question 14

Vinorelbine

Answer 14

• MOA
– Semi-synthetic vinca alkaloid
– Inhibits cell growth by binding to tubulin on mitotic microtubules
• Side Effects
– Bone marrow suppression
• Anemia (approx. 80%) severe neutropenia (approx. 30%)
– Changes in bowel habits (Central neuropathy messes with bowels_
• Constipation (approx. 35%) (neuro-toxicity related)
• Diarrhea (appox. 15%)
– Sensory neuropathy (approx. 25%)
– Alopecia
• Hair thinning (total hair loss is uncommon)

Question 15

Pemetrexed

Answer 15

• Antifolate antimetabolite
– Primarily inhibits thymidylate synthase which leads to reduced thymidine
for DNA synthesis
• Side effects
– Bone Marrow Suppression
• Anemia, neutropenia, thrombocytopenia
– Diarrhea
– Mucositis -bad mouth sores
– Fatigue
– Skin rash
• Risk is reduced if patient is pretreated with a corticosteroid tx with dex (might alredy be giving it anywayf for anti-nausea)

Question 16

Pemetrexed – Side Effect Prevention

Answer 16

Pemetrexed is like methotrexate
- Inhibits dihydrofolate reductase (DHFR)
- Required for purines synthesis

• Side effects of bone marrow suppression, diarrhea, mucositis are reduced if patient has supplementation of folic acid and Vitamin B12.
– Folic Acid 0.4 mg po daily starting 1 week before first dose and continuing until 3 weeks after the last dose
– Vitamin B12 1000 mcg IM q9weeks with first injection 1 week before
the first dose and ending 3 weeks after the last dose

Methotrexate like drug
Less myelosupp,, mucositis diarrhea with folic acid and vit b12
Prefered to start it before chemo, 1 wk before pemetrexed

Question 17

Gemcitabine

Answer 17

• MOA – pyrimidine analog. Active metabolites are incorporated into DNA leading to inhibition of DNA synthesis and induction of apoptosis
• Toxicities
– Bone Marrow Suppression (anemia, neutropenia, thrombocytopenia)
• Monitor CBC
– Elevated liver enzymes
• Monitor LFTs
– Pulmonary toxicity, not for ppl with lots of lung fxn decline
• Rare but can be severe
• Monitor for progressive dyspnea, hypoxemia, cough

Question 18

Durvalumab

Answer 18

• Durvalumab is indicated in patients that:
– Have stage IIIA NSCLC, and
– Have received concurrent chemotherapy + radiation, and
– Had a good response to treatment (no progression)
Consolidate response to platnum double, could hold response much longer

• Duvalumab in an Immune Checkpoint Inhibitor
– PD-L1 blocking Monoclonal Antibody
– 10mg/kg (up to 750mg) IV every 2 weeks OR 20mg/kg (up to 1500
mg) IV every 4 weeks
– Approximate cost is $12,000 per 1500mg dose

Question 19

Treatment of NSCLC – Advanced or Metastatic Disease
• Advanced (Stage IIIB, IIIC) or Metastatic Disease (Stage IV)

Answer 19

– Goals of Care:
• Extension of life, Quality of life, Palliation
Trying to delay progression
– Treatment options:
• Radiation therapy alone (poor ECOG)
• Chemotherapy +/- Radiation
– Platinum Doublet (example Cisplatin or Carboplatin + Pemetrexed)
• Targeted oral therapies:
– Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs)
– Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors (ALK TKIs)
– ROS1 (ROS1 TKIs)
• Immune Checkpoint Inhibitors:
– Pembrolizumab (+/- Chemotherapy)
– Nivolumab +/- Ipilimumab and Chemotherapy
– Atezolizumab

ECOG 3-4, hard to give really intense tx, may get radiation
ECOG up to 2 still have more options

Question 20

Pharmacogenetics - Refresher

• Ethics and Responsibility:
– Remember our goals:
• Maximize survival, extension of life, quality of life
• Minimize toxicities
– Does the evidence support that this is the best therapy for this specific patient OR
Does the evidence support that this therapy has reduced toxicity for this specific
patient?
– Do the recommendations of pCODR or provincial drug plans support cost
effectiveness for the patient?

Answer 20

• Predictive biomarker
– indicative of therapeutic efficacy because there is an interaction between
the biomarker and therapy on patient outcome
• Prognostic biomarker
– Indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumour aggressiveness
• Pathologic evaluation includes molecular diagnostic studies to determine whether certain gene alterations are present
Genetic changes that tell us this is a pretty bad disease

• Pathology
– In lung cancer, there are many genetic mutations and molecular targets that can
be identified through PCR, FISH (fluorescence in situ hybridization), NGS (next generation sequencing)
– IHC (immunohistochemistry) can detect presence of PD-L1 in tissue

Question 21

DNA related Predictive Biomarkers for Advanced/Metastatic
NSCLC Adenocarcinoma (non-squamous)

Answer 21

Sensitizing EGFR gene mutations 15%
• Common “sensitizing” mutations are deletion exon 19 (exon 19del) or point mutation in exon 21 (L858R)
• Predicts for benefit from EGFR tyrosine kinase inhibitors (osimertinib, afatinib, gefitinib, erlotinib)
can target inside of the ECFR

ALK (anaplastic lymphoma kinase) fusion oncogenes
5%
• Predicts for benefit from ALK tyrosine kinase inhibitors (brigatinib, alectinib)

ROS1 rearrangement positive 2%
• Predicts for benefit from ROS1 tyrosine kinase inhibitors (entrectinib, crizotinib)

BRAF V600E point mutations 2% • Predicts for benefit from combination BRAF inhibitor + MEK
Inhibitors (Dabrafenib + Trametinib, however, this is not covered in Alberta for NSCLC….. Yet?)

KRAS mutations 25% • If KRAS mutation present, then very unlikely alterations with EGFR, ALK, ROS1 exist (ie they don’t overlap)
• REMEMBER from colon cancer: EGFR targets not beneficial
• KRAS mutation is also a POOR PROGNOSTIC MARKER

Question 22

EGFR Mutation Positive

Answer 22

• Sensitizing EGFR Mutations
– Most common mutations are deletion exon
19 (exon 19del) or point mutation in exon 21
(L858R).
– T790M mutation is less common and tends
to be an acquired mutation while on
treatment
– EGFR sensitizing mutations are found in
approximately 10% of Caucasian patients
with NSCLC and up to 50% of Asian patients
with NSCLC
– EGFR mutations are more common in neversmokers and females

Question 23

EGFR Tyrosine Kinase Inhibitor

Answer 23

– Erlotinib & Gefitinib (first generation), Afatinib (second generation), Osimertinib (third
generation)
– All EGFR TKIs have efficacy in exon 19del or exon 21 (L858R). However…….
• Only osimertinib has evidence of activity against T790M mutation (patients will be switched to
osimertinib if they develop this mutation while on Erlotinib, Gefitinib, or Afatinib)
– FLAURA trial, 2020: osimertinib superior efficacy (longer overall survival) as
compared to Gefitinib and Erlotinib (with common EGFR mutations).
• Osimertinib now funded for FIRST LINE treatment of EGFR sensitizing mutation
positive NSCLC in Alberta
– **Osimertinib has better penetration to brain (passes BBB) as compared to previous
EGFR TKIs
Just gonna talk about osimertinibi
Pt lived longer, better survival

Question 24

EGFR TKI – Side Effects

Answer 24

• Fatigue – common (20-50%)
• Rash – very common (approximately 50%)
– Papulopustular, acneform, erythematous (look like acne)
– Usually on face, neck and upper torso
– Onset is usually within the first 2 weeks of treatment
– Worsened by sun exposure
• Diarrhea – very common (approximately 60-90%)
– Treat with loperamide
• Hepatic dysfunction or Increase in Liver Transaminases (10%)
– Monitor liver enzymes
• Interstitial lung disease (approximately 1%)

Question 25

ALK Gene Rearrangements

Answer 25

• ALK is a receptor tyrosine kinase that can
be rearranged in NSCLC, resulting in
dysregulation and inappropriate signaling
through the ALK kinase domain.
• ALK inhibitors used/funded in Alberta:
– Alectinib, Brigatinib

Question 26

ALK TKI Side Effects

• End in nibs

Answer 26

• GI Toxicities
– Diarrhea, up to 50% with brigatinib
– Constipation, up to 35% with alectinib
– Nausea/Vomiting 30% with brigatinib

• Hepatotoxicity or elevation in transaminases and/or bilirubin
– Monitor liver enzymes and bilirubin
• Hyperglycemia with Brigatinib
– New or worsening, up to 67% of patients
– Can be up to grade 3
– Initiate appropriate antihyperglycemic medication
Hyperglycemia, diabetes pt need a lot o=ore insulin

• Myalgia with Alectinib (30%)

• Symptomatic Bradycardia
– HR < 50 bpm has been reported
– Monitor HR and BP
• Can cause QTc prolongation
– 5-6% (quite high)

• Hypertension with Brigatinib (up to 30%)
– Can be up to grade 3
– Treat appropriately

• CK elevation (creatinine kinase elevation)
– Reported in up to 75% of patients
– Can be severe with muscle pain & weakness
Check for sore muscles

Question 27

ROS1 Gene Rearrangments

Answer 27

• ROS1 encodes a large
transmembrane receptor and is a
proto-oncogene.
• Gene rearrangement
(development of oncogene) leads
to dysregulation and
inappropriate signaling.
• ROS1 Tyrosine Kinase Inhibitors
funded in Alberta:
– Entrectinib
– Crizotinib

Question 28

ROS1 TKI Side Effects

Answer 28

• Vision Disorders
– Entrectinib 20%, Crizotinib up to 60%
– Double vision, impaired vision, floaters, diplopia,
– Median onset is 7-13 days
– Caution with driving
– Usually mild and usually improves with time. So
can usually continue treatment. However, if
severe vision loss, must discontinue.
- Vision AE go away usually after 1-2 wks

• Cognitive Disorders (Entrectinib)
– Dizziness, headache, changes in balance,
confusion
• Neuropathy, up to 20%
– Neuralgia, paresthesia, sensory disturbance

• GI issues
– Diarrhea (up to 60%)

• Hepatic issues
– ALT & AST elevation
– Hepatic failure (rare)

• Bradycardia
– Symptmatic with HR<50 consider hold or dose reduction
• QT prolongation (2-3%)

Question 29

TKI Drug Interactions

Answer 29

• Erlotinib, Gefitinib, Osimertinib, Entrectinib, Crizotinib, Alectinib, Brigatinib =
Major CYP 3A4 Substrate
– Avoid grapefruit juice
– Monitor INR for patients on warfarin
– Consider implications if coadministered with 3A4 inhibitors or inducers
• Inhibitors – more toxicities
• Inducers – reduced efficacy
• Gefitinib, Erlotinib, Entrectinib = pH dependent absorption
– Avoid PPIs, H2 antagonists??
• QTc prolongation
– Chronic therapy!