ICL 3.7: Lung Cancer Diagnosis and Management

Question 1

how much mortality is caused by lung cancer?

Answer 1

160,000 deaths each year in the United States and 1/4 of all deaths due to cancer

non–small-cell lung cancer (NSCLC) is 85% of cases

adenocarcinoma (60%), squamous cell carcinoma (20%), and large cell carcinoma (5%)

small-cell lung cancer (SCLC) - 15% of cases

Question 2

which cancers are most lethal for men vs. women?

Answer 2

men: lung > prostate > colorectal
women: lung > breast > colorectal

lung cancer remains the top cancer killer

Question 3

how does lung cancer develop?

Answer 3

normally, each lung comprises trillions of cells of different tissue types in a highly organized structure

a lung cancer is born when a certain set of genes mutates in a single airway epithelial cell

that cell then replicates in uncontrolled fashion, disrupts the lung organization and harms the host

filling the breathing space isn’t what actually kills people….

Question 4

what causes cancer?

Answer 4

carcinogens like cigarette smoke increase the rate of DNA adducts and or DNA strand breakage

toxins in cigarette smoke also increase cell death and inflammation which increased airway epithelial cell (AEC) (and DNA) replication rate

these increase replication rate which is even more compounded with old age which is bad because with faster replication, there are more errors

the carcinogens and toxins also cause higher rates of promutations which are bulky adducts added onto the nucleotide bases that aren’t removed by nucleotide excision repair prior to DNA replication –> so then the replication machinery mis-reads the base with the bulky adduct on it and inserts the incorrect nucleotide and you get a mutation in the daughter strand!!

mutations can effect cell cycle control genes, apoptosis control genes, and key immune regulatory genes

Question 5

how is cigarette smoke associated with lung cancer?

Answer 5

this is the major avoidable etiologic agent is an addictive product made and promoted for consumption by an industry

80-85% of cases caused by cigarette smoke inhalation

second hand smoke also associated with lung cancer risk

cigarette smoke components that contribute to cancer include:
1. thousands of carcinogens
Reactive oxygen species in actively combusting tobacco smoke

2. toxic substances that directly kill cells and induce inflammation

Question 6

how is radon associated with lung cancer?

Answer 6

second most common avoidable cause of lung cancer (10% of cases)

noble (chemically inert) radioactive gas resulting from radioactive decay of uranium deep in earth crust

after passing through crust (because chemically inert) decays into charged alpha emitters (e.g. polonium)

when inhaled, the alpha particles may damage airway epithelial DNA

Question 7

which occupational exposures can cause lung cancer?

Answer 7

1. asbestos
2. arsenic
3. indoor cooking fires, roofing fumes

Question 8

what is the new potential risks that could lead to lung cancer?

Answer 8

inhalation of combusting cannabis

Δ 9 -tetrahydrocannabinol (THC), like nicotine, produces addiction

documented carcinogens in combusted cannabis

risk for lung cancer 2-6-fold increase in heavy marijuana smokers

Question 9

how is cell turnover effected in lung cancer?

Answer 9

increased airway epithelial cell death rate due to

1. recurring exposure to cytotoxins in cigarette smoke
2. chronic inflammation and cytotoxins from macrophages and lymphocytes like COPD/chronic bronchitis or pulmonary fibrosis

there’s also increased airway epithelial stem cell replication rate in response to increased death rate –> increasing age multiples this effect!

Question 10

what is the genetic predisposition of lung cancer?

Answer 10

85-90% of heavy smokers do not develop lung cancer so clearly there’s got to be some genetics involved too

over ten lung cancer risk variants significantly associated based on GWAS, each with low effect

nicotine receptor variants and telomerase variants are some of the non-familial things that we think are associated with lung cancer

there’s also a very small familial component = Li-Froumeni syndrome

Question 11

how does ineffective immune surveillance contribute to the development of lung cancer?

Answer 11

if an airway epithelial cell acquires driver mutation and multiple other mutations then the mutated protein products should be recognized as non-self but if the intrinsic and/or adaptive immune system function is sub-optimal then tumor cells proliferate faster than immune system can recognize and kill them

Question 12

what are some of the causes of ineffective immune system function?

Answer 12

1. Age; immune function declines with age
2. AIDS (lung cancer is most common cancer cause of death)
3. therapeutic immunosuppresion (e.g. lung transplant patients)
4. the cell with driver mutation also acquires a mutation that enables secretion of a protein that inhibits T-cells at checkpoint

Question 13

who is effected by cancer in non-smokers?

Answer 13

15-20% of lung cancer is in non-smokers and we have no idea why it happens

predominantly women, and asian –> some evidence for hormonal contribution, not consistent

predominantly adenocarcinoma so it’s more likely to have EGF receptor mutation or ALK1 or ROS1 translocation; less likely to have KRAS mutation

Question 14

how have we tried to prevent lung cancer since the 1960s?

Answer 14

percentage of smokers in the US population decreased 1965-2015 from 42.4% of the adult population in 1965 to <15% (13.7%) in 2018

lung cancer incidence decreasing in men and plateauing in women

remaining smoker group is enriched for variants in nicotine receptor gene

Question 15

how is the FDA trying to regulate cigarettes?

Answer 15

cigarette smoke contains nicotine, a highly addictive substance

FDA is moving to regulate and reduce nicotine in cigarettes and regulate electronic nicotine delivery systems (ENDS) or e-cigarettes

Question 16

how do you treat nicotine addicted patients?

Answer 16

1. identify, counsel, and treat patients with nicotine addiction
2. offer FDA-approved Nicotine replacement therapy (NRT)
   - nicotine receptor agonist (vareniclin [Chantix])
   - adrenergic/dopamine reuptake inhibitor: Bupropion (Zyban, Wellbutrin)
   - nicotine replacement: patch, gum, inhalation

Question 17

what are the rates of tobacco use in the US?

Answer 17

approximately 20% of U.S. adults used any tobacco product

cigarette smoking reached an all-time low (13.7%)

e-cigarette and smokeless tobacco product use prevalence increased –> marked increase in prevalence of e-cigarette use among adolescents

Question 18

what is the argument for nicotine e-cigarettes as nicotine replacement therapy?

Answer 18

e-cigarettes are at least 95% less harmful to health than tobacco smoking

e-cigarettes more effective for smoking cessation than current FDA-approved nicotine replacement therapy when accompanied by behavioral support

e-cigarette group more likely than nicotine-replacement group to use assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants])

also, reduced cough and phlegm production

Question 19

what is the problem with vaping THC products?

Answer 19

vaping products containing THC reported by 84% of cases

the issue is the addition of Vitamin E as diluting solution to cheat the consumer is implicated as primary cause of respiratory failure

some cases were associated with acute exogenous lipoid pneumonia (ELP) while others were caused by eosinophilic pneumonia and ARDS

Question 20

at what government level is THC legalized?

Answer 20

THC products legalized by states but not federal government!

the states are poorly equipped to regulate and are not prepared for health hazards…

Question 21

what are the 5 categories of symptoms associated with advanced lung cancer?

Answer 21

1. local symptoms: cough, hemoptysis, obstructive pneumonia
2. constitutional: weight loss fever
3. local invasion: Impingement or invasion of nerve, pleural/pericardial fluid
4. distant metastasis; bone pain, headache, pleural effusion
5. paraneoplastic; SIADH, neurological symptoms, hypercalcemia

Question 22

what are the causes of morbidity in lung cancer?

Answer 22

1. proximal cancers: sub-types squamous, small cell –> less prevalent today due to advent of filtered cigarettes 60 years ago

they cause obstruction of major airways which leads to collapsed lungs; may be associated with effusion due to increased vacuum that draws fluid in from lymphatics

they also invade the major vessels and can cause massive hemoptysis and thrombosis

2. distal cancers: sub-type adenocarcinoma –> more prevalent today because carcinogens in filtered smoke delivered more peripherally

they cause effusion of fluid into pleural space; decreased oxygenation, pain, shortness of breath

they can also invade the chest leading to pain

3. metastases –> bone pain, brain mets (seizures, pain, loss of function)

Question 23

how do you approach the management of a lung cancer patient?

Answer 23

1. history and PE
2. diagnostic testing/biopsy as required to establish diagnosis
3. tissue diagnosis
4. staging workup
5. stage established
6. multidisciplinary discussion and treatment planning; smoking cessation counseling

Question 24

how are treatment decisions individualized?

Answer 24

treatment decisions are individualized, based on:

1. stage at presentation: earlier the stage, the better chance for cure.
2. SCLC vs NSCLC: different staging and management
3. tumor-cell biology factors: driver mutations, immune checkpoint inhibitor secretor, tumor mutation burden, etc.
4. patient-specific factors: overall health/performance status, age, co-morbidities, PFTs, wishes

Question 25

what is the multidisciplinary approach to lung cancer treatment?

Answer 25

1. surgery if early
2. radiation teatment
3. systemic therapy: chemotherapy, targeted molecular agents, immunotherapy, etc.

Question 26

what are the 3 goals of lung cancer treatment?

Answer 26

1. cure; feasible if early stage, overall health/performance status permissive
2. control disease/maintain QoL; if later stage and/or health non-permissive
3. palliation of symptoms; late stage, poor health, and/or intolerant of any treatment

Question 27

what are the least invasive diagnostic procedures?

Answer 27

transthoracic fine needle aspirate

endobronchial ultrasound (EBUS) needle aspirate can be done if there’s extension of the tumor into the mediastinum and the lymph nodes of the mediastinum)

Question 28

what is the non-small cell TNM staging of lung cancer?

Answer 28

T = tumor size or anatomic extent

N = number of lymph nodes involved or levels of locoregional nodes involved

M = metastases beyond locoregional site

Question 29

what is the purpose of staging lung cancer?

Answer 29

to compare people in the same stages in clinical trials

it’s also critical to minimize confounding effects when assessing new drugs/treatments and providing patient with accurate prognosis

periodic re-evaluation of staging criteria takes into account new empiric information

Question 30

what are the categories of T in the staging?

Answer 30

T1a = <1 cm
T1b =  1-2 cm
T1c =  2-3 cm

T2a = 2-4 cm
T2b = 4-5 cm

T3 = 5-7 cm 
T4 = 7+ cm

the size of the tumor has a huge effect on the outcome of the cancer! the bigger the worse

Question 31

what are the categories of N in the staging?

Answer 31

N0: no involvement of lymph nodes

N1: ipsilateral hilar, inter-lobar, lobar (stations 10-12)

N2: ipsilateral mediastinal (Stations 2, 4), and/or subcarinal (station 7)

N3: supraclavicular (station 1), and/or contralateral mediastinal or hilar (stations 2, 4)

between N0-N3 each change associated with big effect on prognosis

the clinical determination of the lymph stage is worse than the pathologic

Question 32

what are the categories of M in the staging?

Answer 32

wM0 = no distant metastasis

M1 = distant metastasis

Question 33

how does malignant pleural effusion effect lung cancer staging?

Answer 33

first you need to confirm that pleural effusion contains malignant cells and if yes then it’s automatically an M1 which means it’s stage 4…

malignant cells typically arise through obstruction and back flow of lymphatics or direct extension of tumor

treatment: intermittent thoracentesis, or placement of a tunneled chest tube with bag for intermittent drainage.

Question 34

what are some of the benign causes of pleural fluid in lung cancer?

Answer 34

1. obstruction of central airway
2. obstruction of central pulmonary artery

so you have to actually confirm that pleural effusion contains malignant cells

Question 35

what testing do you do to stage cancer?

Answer 35

1. FDG PET/CT scan for uptake inside/outside chest
2. bronchoscopy –> if suspicious PET/CT + lymph nodes to obtain sample for path
3. brain MRI with contrast for mets because head CT relatively insensitive

Question 36

what are the treatment options for each stage of NSCLC lung cancer?

Answer 36

Stage 1A: surgery alone! (or SBRT for non-surgery candidate

Stages 1B, IIA, IIB; surgery + adjuvant (post surgery) chemo

Stage IIIA; neoadjuvant chemo (pre-surgery) +/- RT then Surgery

Stage IIIB: chemo + RT

Stage IV: chemotherapy, including gene targeting and/or immune modulation when appropriate; supportive care

Question 37

what is direct vs. indirect DNA damage?

Answer 37

biologic effects of radiation are from DNA damage

direct DNA damage is when an electron interacts with DNA

indirect DNA damage is when an electron interacts with water to produce a hydroxyl radical which in turn damages the DNA

Question 38

what is the role of radiation in NSCLC treatment?

Answer 38

definitive therapy (+/- concurrent chemo) with curative intent

early stage lung cancer do stereotactic beam radiation therapy to focus high energy on the cancer from many different angles (SBRT)

stage III lung cancers do radiation with a wider field with lower intensity

Question 39

what is SBRT?

Answer 39

Stereotactic Body Radiotherapy

it’s high-intensity beams of radiation delivered with surgical precision

there’s Rreal-time image guidance (including motion control, tumor-tracking)

used to cure Stage 1 or focused recurrence –> it’s also an alternative option for patients who are unable/unwilling to undergo surgical tx

Question 40

what are the uses of SBRT?

Answer 40

1. used to cure Stage 1 or focused recurrence
2. alternative option for patients who are unable/unwilling to undergo surgical tx
3. aggressive local therapy in the setting of metastatic disease
4. palliation of pain, dyspnea, bleeding, etc.

Question 41

what are the indications to do emergency radiation therapy

Answer 41

1. vena cava syndrome
2. bronchial obstruction
3. myelocompression
4. bronchial obstructions
5. tumor bleeding

Question 42

what is the chemotherapy regimen done prior to surgical resection of stage IIIA NSCLC?

Answer 42

platinum-based

so this is chemo that is neo-adjuvant meaning it’s done before surgery

Question 43

what is the chemotherapy regimen done prior to surgical resection of stage IIIB NSCLC?

Answer 43

these are concurrent chemo-radiation regiments because stage IIIB and IV you can no longer do surgery

1. induction

radiotherapy combined with low dose weekly cisplatin or carboplatin based chemotherapy which takes advantage of synergy between chemo and RT, but need lower doses to reduce toxicity

2. consolidation

two additional 3-week “cycles” of standard dose chemotherapy

Question 44

how do you treat metastatic NSCLC?

Answer 44

1. traditional treatment = platinum based radiation with paclitaxel or gemcitabine (squamous) or pemetrexed (adeno)
2. gene-targeted = tyrosin kinase inhibitors and immunomodulators

TKI = EGFR kinase inhibitors and ALK kinase inhibitors

immunomodulators = PD-1 and PD-L1 inhibitors

Question 45

what are the advances in treatment to approaches to treating lung cancer?

Answer 45

it used to just be giving cytotoxic drugs

now we have gene targeted therapy and immune modulation therapy!!

Question 46

why is it important to identify which known cancer genes are altered in each tumor?

Answer 46

because there are effective gene targeting
treatments

erlotinib, afatinib, osimertibin* therapy targets EGFR gene

crizotinib therapy targets RET, ALK, and ROS genes

Question 47

what are PD-1 and PD-L1 antibodies?

Answer 47

tumor cell is secreting PD1 ligand and it binds to PD1 receptor on killer T cell

now the T cell is inactivated and no longer recognizes the tumor cell as foreign

so if you give the antibody to PD1 or the ligand the T cells wake up and start killing the tumor cells!!

Question 48

when would you use PD-L1 inhibitors as first line therapy?

Answer 48

you must have 50% or more PD-L1 expressing cells to use immunotherapy as first line therapy if there’s no other targetable mutations

so use pembrolizumab immunotherapy over platinum based chemotherapy! better survival

Question 49

what are the adverse effects of PD-1 and PD-L1 antibodies?

Answer 49

immune mediated:
1. pneumonitis*; treat with high dose corticosteroids like prednisone

2. endocrinopathies

other adverse effects: fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea

severe infusion reactions: rigors, chills, wheezing, pruritis, flushing, rash – 0.2%

Question 50

what is the survival of untreated small cell lung cancer?

Answer 50

local disease typically 12 to 15 weeks

advanced disease 6 to 9 weeks

Question 51

how does small cell differ from non-small cell when it comes to treatment?

Answer 51

SCLC exquisitely sensitive to both chemotherapy and radiotherapy so this is first-line

resistant disease usually develops

no effective gene targeted therapy but immunmodulation does help to some degree

Question 52

how would you treat limited disease small cell lung cancer?

Answer 52

this means the disease confined to a single radiation port

radiotherapy plus cisplatin based chemotherapy can be potentially curative (5%)

Question 53

how would you treat extensive disease small cell lung cancer?

Answer 53

this means the disease is beyond a single radiation port

treat with chemotherapy +/- radiotherapy

rarely cured….

Question 54

what is the first line chemo for small cell lung cancer?

Answer 54

Cisplatin or Carboplatin and Etoposide

repeat every three weeks for 4 cycles for limited stage and 4-6 cycles for extensive-stage disease

NSCLC = carbiplatinum or penetrexib

Question 55

which of the following is not known to contribute individual variation in lung cancer risk?

A. complex genetic predisposition

B. indoor radon

C. most electronic nicotine delivery systems

D. age

Answer 55

C. most electronic nicotine delivery systems

Question 56

at what clinical stages of lung cancer may patients be considered for surgical removal of lung cancer according to standard of care as long as their overall health will allow for it to be done safely?

Answer 56

stages I-IIIA

stage I benefits the most

stage II offer surgery with chemo after the surgery

stage IIIA consider neo-adjuvant therapy before surgery

more advanced stages have more comorbities

Question 57

stereotactic body radiation therapy (SBRT) might be used for treatment of lung cancer with which stage characteristics?

Answer 57

attempted cure of stage IA lung cancer

use SBRT in patients who don’t qualify for surgery because surgery is slight better

Question 58

which of the following is correct regarding a 60 year old woman who is a heavy smoker, 8 cm L upper lobe mass, atelectasis, pleural effusion by CXR after presenting to the ER with 3 months of progressive chest pain, cough, hemoptysis and 30 pound weight loss after working vigorous factory job for 10 hour shifts and even now climbs apartment stairs with only small SOB

Answer 58

late stage because 8cm mass

she’s not a candidate for SBRT and she’s no longer a candidate for surgical removal after placement of chest tube

so ideally she would’ve been offered annual LDCT screening when she became 50 years old