1.

06c
September 28, 2017

LUNG CANCER
Dr. Lou Jorel Tia
Department of Internal Medicine

TOPIC OUTLINE  2012: 1.8 million new lung cancer cases diagnosed
I. Introduction o Unfortunately, 87% of patients diagnosed with lung cancer will
II. Signs & Symptoms die from their disease.
III. Epidemiology o There is a relative lack of variability in survival in different
IV. Risk Factors regions.
a. Smoking
 Lung cancer survival rates are poor
b. Radon
c. Asbestos o 1 in 7 lung cancer patients survives for 5 years after diagnosis
d. Air Pollutants o Survival rates are particularly poor for metastatic lung cancer
e. HIV o 5-year survival for metastatic lung cancer is only 4%
f. Genetic Predisposition
V. Diagnostic Tests
RISK FACTORS
a. Biopsy
- Lymph node biopsy Smoking
- Tumor biopsy  1929: Association between cigarette smoking and lung cancer was
b. Cytology first proposed (and has since been confirmed by many sources)
- Sputum cytology
 Worldwide: Tobacco use is the most important risk factor for lung
- Pleural Fluid cytology
VI. SCLC cancer, causing ~ 70% of global lung cancer deaths
VII. NSCLC  Even the differences in rates of lung cancer in men and women is
a. Subtypes thought to reflect historical differences in tobacco exposure.
b. Risk factors  Smoker vs Non-smoker
c. Staging o Lung cancer death risk is around 15 times higher in current
d. Incidence by stage
smokers (with no other habits) compared with never smokers.
e. Genetic alterations
VIII. Management o Lung cancer risk increases with both smoking duration and
a. Surgery amount, but is more dependent on duration than
b. Chemotherapy consumption.
c. Immunomodulators  Smoking one pack of cigarette a day for 40 years is more
d. Treatment algorithms hazardous than smoking two packs a day for 20 years.
o Lung cancer risk in smokers is indeed higher in those who start
SIGNS & SYMPTOMS smoking at a younger age.
 Based on location: what structures are impinged  Also associated with increased susceptibility to the
 Most people with lung cancer have symptoms at the time of carcinogenic effects of tobacco smoke in adolescents.
presentation. o Second-hand smoke is a risk factor for lung cancer.
 Those with cancer-related symptoms are likely to have more  Living with someone who smokes increases the risk by
advanced disease. around a quarter.
 Patients experiencing signs and symptoms are most likely to present  27% increased risk in women exposed to spousal and
with: environmental tobacco smoke.

Radon
 Naturally-occurring radioactive gas that increases lung cancer risk,
particularly amongst smokers.
 Exposure can occur in enclosed spaces such as mines and houses.
 Attributed to about 10% of lung cancer cases.

Asbestos
 Exposure to asbestos leads to a greater risk of lung cancer.
 Lung cancer mortality is higher in asbestos workers than in
individuals who have not been exposed.
 Attributed to about 9-15% of lung cancer cases.

Air Pollutants
 A number of lung cancers are caused by heavy exposure to air
pollutants and industrial carcinogens.
 Diesel exhaust, fumes, certain metals, silica, polycyclic aromatic
hydrocarbons and nitrogen oxides.
 Attributed to about 1-2% of lung cancer cases.
EPIDEMIOLOGY
 Males > Females HIV
 Most common cause of death from cancer worldwide.  HIV-infected individuals are known to be at an increased risk of lung
 Solid tumors with the highest mortality rate cancer.
 2012: 1.59 million lung cancer deaths
o In 2012, worldwide, more people died of lung cancer than of
colorectal, breast and prostate cancers combined.

1 of x [Transcriber 1, Transcriber 2, and so on...]

 Lung Cancer

Genetic Predisposition
 Lung cancer is 82% higher in people whose sibling has had lung
cancer.
 25-37% higher in those whose any of the parents has had the disease.
 The association is independent of any association with smoking.

DIAGNOSTIC TESTS
 Imaging techniques that are used to locate a suspicious mass in the
lungs or other parts of the body (staging) include:
o X-rays: Incidental findings of mass
o CT scans: Preferred, can see the dimension, location, etc
o PET scans: Costly, done for Lymphoma
o PET-CT scans
o MRI
 Samples collected using a range of procedures are used to
determine whether a suspicious mass is actually lung cancer. Figure 1. Bronchoscopy
 Examination of a biopsy using histology is the only way to make a
definitive diagnosis of lung cancer. Tumor biopsy: Surgical biopsy
 Samples can be collected from the lymph nodes to assess whether  Thoracotomy: A cut is made between the ribs and a tumor sample is
the tumor has spread (staging). removed.
 Routine laboratory tests (e.g. blood counts, clinical chemistry) are  Performed while the patient is under general anesthetic.
not currently used to diagnose lung cancer but to inform of the  Thoracoscopy
patient’s general health. o Alternative method to conventional surgical biopsy
o Uses a camera and small instruments to obtain lung tissue
Biopsy o Less invasive procedure 9only two small cuts are made) and
recovery is faster.
 Removal of a small amount of tissue for examination under a
microscope.
 May also be used for other investigations such as molecular testing. Cytology
 Tissue biopsies can be collected from:  Cytology sampling is an option in patients who are unable to undergo
o The tumor itself invasive diagnostic procedures.
o The lymph nodes  Cytology samples are often fluid that contain cells extracted from the
 Biopsies from metastases may be collected if a sample cannot be body.
obtained by other methods, and the metastases are easily accessible.  Samples collected for analysis: Sputum or Pleural Fluid
 Fine needle aspirate containing tumor cells can also be acquired via
Lymph node biopsy minimally invasive procedure using thin hollow needle.
 Inconclusive
 Used to diagnose and stage the tumor
 Invasive procedures are needed to biopsy mediastinal and hilar
lymph nodes. Sputum cytology
 Mediastinoscopy: medially-located mass  Sputum coughed up from the lungs is collected and examined under
 Endobronchial ultrasonography the microscope to check for cells with abnormal morphology shed
 Transbronchial needle aspiration from the tumor.
 Least invasive diagnostic test that can be performed in patients with
suspected lung cancer.
Tumor biopsy: Bronchoscopy
 Limited use only:
 Bronchoscopy is used to find tumors in the larger airways of the o Difficulties in obtaining enough cells if the tumor is not centrally
lungs located.
 During this procedure, a biopsy can then be performed to obtain o Can detect lung cancer in only about 60% of cases.
tumor samples. o Not be used to rule out a diagnosis of lung cancer if the result is
 A long thin tube, called a bronchoscope, is passed through the mouth negative.
or nose into the airways.
 A small brush, needle or tongs can be inserted to collect tissue
Pleural fluid cytology
samples.
 Conventional bronchoscopy: Detects 30-50% of lung cancers  Source: Pleural fluid in pleural effusion
 Bronchoscopy using ultrasound: Detects around 95% of lung  A needle is inserted between the ribs to drain the pleural fluid, which
cancers is removed and analysed.
 Patients with pleural effusion: 60-80% of cancers can be detected by
this procedure.
Tumor biopsy: Needle aspiration
 Core biopsy: A biopsy needle is used to remove one or more small
SMALL CELL LUNG CARCINOMA (SCLC)
cylinders (cores) of tumor tissue
 This procedure may be used when bronchoscopy fails.  10-15% of all lung cancers worldwide
 For peripherally-located masses  Named for the size of the cancer cells when seen under the
microscope
 Very aggressive
 Other names: oat cell cancer, oat cell carcinoma, small cell
undifferentiated carcinoma
 Often starts in the bronchi near the center of the chest and tends to
spread quickly to other parts of the body
 Very rare to occur in a never smoker

2 of 6 Marj
 Lung Cancer

NON-SMALL CELL LUNG CARCINOMA (NSCLC)

 85-90% of all lung cancers worldwide

Subtypes
 ADENOCARCINOMA: most common etiology in non-smokers, more
peripheral (chest pain)
 LARGE CELL CARCINOMA: medial or central
 SQUAMOUS CELL CARCINOMA: central ( cough, hemoptysis)

Risk Factors
 Current/former smoker
 Female Incidence by stage
 Younger age  Majority of patients with lung cancer are diagnosed at Stage III or
Stage IV
TNM Classification of Lung cancer  Stage at time of diagnosis in UK lung cancer patients, 2003 to 2006
 Describes tumor size, nodal involvement and metastasis o Stage IV: 36%
o Stage III: 32%
o Stage II: 7%
o Stage I: 15%
o Unknown: 11%

Genetic alterations and tumor growth

 Oncogenic driver mutations
o KRAS 25%
o EGFR sensitizing 17% (with drugs available to target this)
o ALK 8% (with drugs available to target this)
o EGFR other 4%
o HER2 3%
o BRAF 2%
o PIK3CA 0.8%
o MET 0.7%
Stage I
o NRAS 0.7%
 Earliest stage of disease o MEK 0.1%
 Stage IA o No identified mutations arrangements 36%
o < 3 cm o Two or more genes 3%
o Cancer has not spread to any lymph nodes  Molecular abnormalities in oncogenic drivers affect signaling
 Stage IB pathways that regulate biological processes such as cell growth,
o > 3 cm but < 5 cm survival, proliferation, and migration, as well as angiogenesis, leading
o Cancer has not spread to any lymph nodes to cancer development and maintenance.
 Signaling pathways are often interconnected, with cross-talk
Stage IIA between pathways driving tumor growth
 Slightly larger and/or have spread to the lymph nodes or invaded
nearby structures KRAS in NSCLC
 Tumor < 5 cm and cancer has spread to regional lymph nodes, OR  RAS family of proteins are responsible for the activation of signaling
 Tumor > 5 cm but < 7 cm and cancer has not spread to any lymph pathways that regulate:
nodes o Cell proliferation
o Survival
Stage IIIA o Differentiation
 Larger and/or have spread further within the thorax  Mutations in RAS genes occur in around 30%of all human cancers
 Tumor of any size that invades the heart and cancer has spread to (KRAS is the most commonly mutated family member)
regional lymph nodes, OR  In most cases, KRAS mutations are found in tumors wild type for
 Cancer has spread to lymph nodes in center of the chest and the EGFR and ALK
lungs AND > 7 cm OR tumor in the main bronchus OR tumor  KRAS mutations define a distinct molecular subgroup of NSCLC
directly invades diaphragm  KRAS is the most common mutation in NSCLC
Stage IV  Role as a prognostic or predictive biomarker is still unclear
 Currently, there are no anti-KRAS therapies approved for NSCLC
 Tumor of any size
 MEK-targeted therapies are being investigated for KRAS-mutated
 Have metastasized either within the chest or to distant areas of
patients (MEK is frequently activated in tumors with KRAS
the body
mutations)
 Common sites of distant metastasis: brain, bones, liver, and adrenal
glands
ALK rearrangements and EGFR mutations NSCLC
 Targeted therapies exist for EGFR mutations and ALK
rearrangements
 These alterations are routinely tested in NSCLC to ensure patients
are identified and receive appropriate therapy.

Categories

3 of 6 Marj
 Lung Cancer

 Serve as predictive biomarkers in NSCLC  Chemotherapy drugs are often administered in combination, usually
o Predictive biomarker: A molecule that will indicate how a tumor as doublets.
may respond to treatment. Combination Acronym Combination Acronym
 Testing for these rearrangement and mutation is recommended Cisplatin + Cis-Pem Carboplatin + Pem-Carbo
 ALK rearrangements more common in: Pemetrexed Pem-Cis Pemetrexed Pem-CP
o Younger onset of disease Pem-Carb
o Never/minimal smokers Cisplatin + Cis-Pac Carboplatin + Carbo-Pac
o Adenocarcinoma Paclitaxel Paclitaxel
 EGFR mutations Cisplatin + Cis-Gem Carboplatin + Gem-Carbo
o Activating mutations in the first four exons of the tyrosine kinase Gemcitabine Gem-Cis Gemcitabine
domain Gem-Cisplat
 Classical activating mutations Cisplatin + Doc-Cis Carboplatin + Carbo-Doc
 90% are deletions in exon 19 or an L858R point mutation Docetaxel Docetaxel
on exon 21 (seen in the PH) Cisplatin + Vin-Cis Carboplatin + Vin-Carbo
 Others: G719 point mutation on exon 18 or Vinorelbine Vinorelbine VP
duplication/insertion on exon 20 Cisplatin + Cis-Etop Carboplatin + Carbo-Etop
o Lead to constitutive (Ligand-independent) activation of the Etoposide Etoposide
tyrosine kinase domain which results in Gemcitabine + Gem-Doc Gemcitabine + Gem-Vin
 Proliferation Docetaxel Vinorelbine
 Invasion/metastasis NOTE: Pemetrexed- for Adenocarcinoma
 Angiogenesis
Vinorelbine- survival benefit in addition to Cisplatin for early
 Inhibition of apoptosis
stage lung cancer
o More commonly seen in:
 Adenocarcinoma  Chemotherapy can be used either before or after surgery.
 Women  NEOADJUVANT CHEMOTHERAPY
 Never smokers o Used to shrink the tumor before surgery, making it easier to
 Asian populations (Around 1 in 3 patients with NSCLC can be remove, potentially with more conservative surgery
detected) o Also offers an early opportunity to treat micrometastasis
 ADJUVANT CHEMOTHERAPY
o Used after surgery with the aim of killing any cancer cells that
NSCLC MANAGEMENT/THERAPIES
may be left in the body after treatment
 Three main categories of treatment:  CHEMORADIATION
o Surgery o Chemotherapy in combination with radiotherapy concurrently or
o Radiotherapy sequentially
o Anticancer drugs o Radiosensitization: Chemotherapy enhancing the effectiveness of
 These treatments are given alone or in combination depending on the radiotherapy when given simultaneously
stage of the disease.
Immune System in Cancer Regulation
Surgery
 Immunomodulators: newest drugs for cancer
 Techniques used to excise lung tumors:  Cancer cells considered foreign (Genetic Mutations)  Destroyed by
o Pneumonectomy: very aggressive type T cells
o Sleeve resection  TCR binds to MHC (cancer antigen)  CD28 in T cell binds to B7
o Lobectomy  Cancer Immunoevasion
o Sub-lobar resection o Can evade immune response by upregulation of CTLA4 & PDL1
 Newer less invasive techniques for surgery (i.e video-assisted o CTLA4
thoracoscopy) have reached post-operative mortality and morbidity  Naturally-occurring and functions to control the immune
 Standard treatment of choice for patients with Stage I-II NSCLC response
 Higher affinity than CD28
Chemotherapy/Anticancer drugs  Binds to B7  inactivation of T cell, interleukin production
Class of drug Generic Name ESMO NCCN o PDL1: Program Death Ligand 1
Platinum agents Carboplatin √ √  Found in the MHC
Alkylating agents Cisplatin √ √  PD1: Program Death 1 found in T cells
Alkylating agents Fosfamide x √  Immune Checkpoint Blockade
Taxanes/ o Block CTLA4 receptors
Docetaxel √ √
Mitotic Inhibitors
o Inhibit binding of PDL1 and PD1
Paclitaxel √ √
o Unopposed T cell activation
Vinca alkaloid/ Mitotic Inhibitor Vinorelbine √ √
o Monoclonal antibodies
Topoisomerase Inhibitors Etoposide √ √  CTLA4 inhibitors: ipilimumab, tremelimumab
Irinotecan x √  PD1 inhibitor: Pembrolizumab, Nivolumab
Anti-metabolites Gemcitabine √ √  PDL1 inhibitor: Durvaluma
Pemetrexed √ √
Anti-tumor antibiotic Mitomycin C x √

4 of 6 Marj
 Lung Cancer

Stage I-II NSCLC  Unresectable disease: With comorbities or patient’s refusal

o Stage I: Radiotherapy
o Stage II: Radiotherapy, Chemoradiation

Stage III NSCLC

Figure 2. Recommended treatment options for patients with Stage I-II NSCLC
 Surgery is the standard treatment of choice for patients with Stage
I-II NSCLC
 Complete removal of Stage I and II disease results in a 5-year OS rate
of about 60-80%
Figure 5. Recommended treatment options for patients with Stage III NSCLC

Figure 6. Treatment algorithm for patients with Stage IIIA and IIIB diseases

Figure 3. Treatment algorithm for patients with resectable disease Stage IV NSCLC
 Often not candidates for curative surgery
 Adjuvant chemotherapy  Surgery is used in select cases: Treatment of local complications such
o Stage IB as spinal cord compression, abscess
o Stage IIA/IIB  Radiation is not beneficial
 Adjuvant radiotherapy  Mainstay treatment: platinum-based chemotherapy or targeted
o Stage I and II NSCLC with an incomplete resection therapy
o Stage IA NSCLC with positive margins after surgery (surgery did  Choice of treatment based on molecular profile of the cancer:
not successfully remove all cancerous tissue) o No EGFR mutations or ALK rearrangements: Chemotherapy as
treatment of choice
o EGFR mutations
o ALK rearrangements
 Histology also important for treatment options.

Figure 4. Treatment algorithm for patients with unresectable disease

Figure 7. Treatment algorithm for patients without EGFR mutations/ALK
rearrangements (First line)

5 of 6 Marj
 Lung Cancer

 Patients with metastatic/advanced NSCLC without EGFR mutations or Transers’ Message

ALK rearrangements: platinum-based doublet chemotherapy (1st
line).
 Non-squamous histology and a PS 0-1: Chemotherapy + Bevacizumab
o Not be used in patients with predominantly SCC due to increased
risk of hemorrhage
o Monoclonal antibody which targets VEGF to inhibit angiogenesis

Figure 8. Treatment algorithm for patients without EGFR mutations/ALK

rearrangements (Second line)

LET’S GO BATCH 2019! 100% PROMOTION! #2019KAKAYANIN

#ROADTOCLERKSHIP

Figure 9. Treatment algorithm for patients with EGFR mutations/ALK

rearrangements (First line)

Figure 10. Treatment algorithm for patients with EGFR mutations/ALK

rearrangements (Second line)

Figure 11. Treatment algorithm for patients with ALK rearrangements

6 of 6 Marj