ICL 3.7: Lung Cancer Diagnosis and Management Flashcards
how much mortality is caused by lung cancer?
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
which cancers are most lethal for men vs. women?
men: lung > prostate > colorectal
women: lung > breast > colorectal
lung cancer remains the top cancer killer
how does lung cancer develop?
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….
what causes cancer?
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
how is cigarette smoke associated with lung cancer?
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
- toxic substances that directly kill cells and induce inflammation
how is radon associated with lung cancer?
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
which occupational exposures can cause lung cancer?
- asbestos
- arsenic
- indoor cooking fires, roofing fumes
what is the new potential risks that could lead to lung cancer?
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
how is cell turnover effected in lung cancer?
increased airway epithelial cell death rate due to
- recurring exposure to cytotoxins in cigarette smoke
- 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!
what is the genetic predisposition of lung cancer?
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
how does ineffective immune surveillance contribute to the development of lung cancer?
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
what are some of the causes of ineffective immune system function?
- Age; immune function declines with age
- AIDS (lung cancer is most common cancer cause of death)
- therapeutic immunosuppresion (e.g. lung transplant patients)
- the cell with driver mutation also acquires a mutation that enables secretion of a protein that inhibits T-cells at checkpoint
who is effected by cancer in non-smokers?
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
how have we tried to prevent lung cancer since the 1960s?
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
how is the FDA trying to regulate cigarettes?
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
how do you treat nicotine addicted patients?
- identify, counsel, and treat patients with nicotine addiction
- offer FDA-approved Nicotine replacement therapy (NRT)
- nicotine receptor agonist (vareniclin [Chantix])
- adrenergic/dopamine reuptake inhibitor: Bupropion (Zyban, Wellbutrin)
- nicotine replacement: patch, gum, inhalation
what are the rates of tobacco use in the US?
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
what is the argument for nicotine e-cigarettes as nicotine replacement therapy?
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
what is the problem with vaping THC products?
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
at what government level is THC legalized?
THC products legalized by states but not federal government!
the states are poorly equipped to regulate and are not prepared for health hazards…
what are the 5 categories of symptoms associated with advanced lung cancer?
- local symptoms: cough, hemoptysis, obstructive pneumonia
- constitutional: weight loss fever
- local invasion: Impingement or invasion of nerve, pleural/pericardial fluid
- distant metastasis; bone pain, headache, pleural effusion
- paraneoplastic; SIADH, neurological symptoms, hypercalcemia
what are the causes of morbidity in lung cancer?
- 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
- 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
- metastases –> bone pain, brain mets (seizures, pain, loss of function)
how do you approach the management of a lung cancer patient?
- history and PE
- diagnostic testing/biopsy as required to establish diagnosis
- tissue diagnosis
- staging workup
- stage established
- multidisciplinary discussion and treatment planning; smoking cessation counseling
how are treatment decisions individualized?
treatment decisions are individualized, based on:
- stage at presentation: earlier the stage, the better chance for cure.
- SCLC vs NSCLC: different staging and management
- tumor-cell biology factors: driver mutations, immune checkpoint inhibitor secretor, tumor mutation burden, etc.
- patient-specific factors: overall health/performance status, age, co-morbidities, PFTs, wishes
what is the multidisciplinary approach to lung cancer treatment?
- surgery if early
- radiation teatment
- systemic therapy: chemotherapy, targeted molecular agents, immunotherapy, etc.
what are the 3 goals of lung cancer treatment?
- cure; feasible if early stage, overall health/performance status permissive
- control disease/maintain QoL; if later stage and/or health non-permissive
- palliation of symptoms; late stage, poor health, and/or intolerant of any treatment
what are the least invasive diagnostic procedures?
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)
what is the non-small cell TNM staging of lung cancer?
T = tumor size or anatomic extent
N = number of lymph nodes involved or levels of locoregional nodes involved
M = metastases beyond locoregional site
what is the purpose of staging lung cancer?
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
what are the categories of T in the staging?
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
what are the categories of N in the staging?
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
what are the categories of M in the staging?
wM0 = no distant metastasis
M1 = distant metastasis
how does malignant pleural effusion effect lung cancer staging?
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.
what are some of the benign causes of pleural fluid in lung cancer?
- obstruction of central airway
- obstruction of central pulmonary artery
so you have to actually confirm that pleural effusion contains malignant cells
what testing do you do to stage cancer?
- FDG PET/CT scan for uptake inside/outside chest
- bronchoscopy –> if suspicious PET/CT + lymph nodes to obtain sample for path
- brain MRI with contrast for mets because head CT relatively insensitive
what are the treatment options for each stage of NSCLC lung cancer?
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
what is direct vs. indirect DNA damage?
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
what is the role of radiation in NSCLC treatment?
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
what is SBRT?
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
what are the uses of SBRT?
- used to cure Stage 1 or focused recurrence
- alternative option for patients who are unable/unwilling to undergo surgical tx
- aggressive local therapy in the setting of metastatic disease
- palliation of pain, dyspnea, bleeding, etc.
what are the indications to do emergency radiation therapy
- vena cava syndrome
- bronchial obstruction
- myelocompression
- bronchial obstructions
- tumor bleeding
what is the chemotherapy regimen done prior to surgical resection of stage IIIA NSCLC?
platinum-based
so this is chemo that is neo-adjuvant meaning it’s done before surgery
what is the chemotherapy regimen done prior to surgical resection of stage IIIB NSCLC?
these are concurrent chemo-radiation regiments because stage IIIB and IV you can no longer do surgery
- 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
- consolidation
two additional 3-week “cycles” of standard dose chemotherapy
how do you treat metastatic NSCLC?
- traditional treatment = platinum based radiation with paclitaxel or gemcitabine (squamous) or pemetrexed (adeno)
- gene-targeted = tyrosin kinase inhibitors and immunomodulators
TKI = EGFR kinase inhibitors and ALK kinase inhibitors
immunomodulators = PD-1 and PD-L1 inhibitors
what are the advances in treatment to approaches to treating lung cancer?
it used to just be giving cytotoxic drugs
now we have gene targeted therapy and immune modulation therapy!!
why is it important to identify which known cancer genes are altered in each tumor?
because there are effective gene targeting
treatments
erlotinib, afatinib, osimertibin* therapy targets EGFR gene
crizotinib therapy targets RET, ALK, and ROS genes
what are PD-1 and PD-L1 antibodies?
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!!
when would you use PD-L1 inhibitors as first line therapy?
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
what are the adverse effects of PD-1 and PD-L1 antibodies?
immune mediated:
1. pneumonitis*; treat with high dose corticosteroids like prednisone
- 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%
what is the survival of untreated small cell lung cancer?
local disease typically 12 to 15 weeks
advanced disease 6 to 9 weeks
how does small cell differ from non-small cell when it comes to treatment?
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
how would you treat limited disease small cell lung cancer?
this means the disease confined to a single radiation port
radiotherapy plus cisplatin based chemotherapy can be potentially curative (5%)
how would you treat extensive disease small cell lung cancer?
this means the disease is beyond a single radiation port
treat with chemotherapy +/- radiotherapy
rarely cured….
what is the first line chemo for small cell lung cancer?
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
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
C. most electronic nicotine delivery systems
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?
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
stereotactic body radiation therapy (SBRT) might be used for treatment of lung cancer with which stage characteristics?
attempted cure of stage IA lung cancer
use SBRT in patients who don’t qualify for surgery because surgery is slight better
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
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
