lung cancer update

1

Lung Cancer Update

David M. Jackman, MD

Senior Physician, Lowe Center for Thoracic Oncology,

Dana-Farber Cancer Institute

Medical Director of Clinical Pathways, Dana-Farber Cancer Institute

Assistant Professor, Harvard Medical School

2

Titles: • Senior Physician, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute

• Medical Director of Clinical Pathways, Dana-Farber Cancer Institute

• Assistant Professor, Harvard Medical School

Education and Training:• MD: Brown Medical School

• Residency, Internal Medicine: Beth Israel Deaconess Medical Center, Boston, MA

• Fellowship, Medical Oncology: Dana-Farber/Massachusetts General Hospital, Boston, MA

Specialty: • Thoracic Oncology

• Clinical Pathways and Care Delivery

David Jackman, MD

3

• I have no financial disclosures.

Disclosures

4

• Epidemiology

• Clinical Presentation, Diagnosis, Staging

• Screening

• Overview of Lung Cancer Therapy

• Sample Questions

Agenda

5

Epidemiology

6

Practice Question 1

Which of the following statements is true about cancer?

A. Breast cancer is the most common cause of cancer death in women.

B. For former smokers, it takes ~ 10 years for the risk of lung cancer to decrease to that of a nonsmoker.

C. More than half of new lung cancers are already metastatic at the time of diagnosis.

D. Tumor grade (level of differentiation under the microscope) is a more important predictor than tumor stage (extent of disease on scans)

E. Small cell lung cancer is both more aggressive and more common than non-small cell lung cancer.

PresentationScreening Lung Cancer Therapy SummaryEpidemiology

7

Lung Cancer is the leading cause of cancer death


0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

Death

s p

er

year

131,880

52,98048,220 44,130

LUNG

CANCER

COLON

CANCER

PANCREATIC

CANCER

BREAST

CANCERData from Cancer statistics, 2021.

Siegel et al, Ca Cancer J Clin

8

Smoking is the leading risk factor for lung cancer

Cum

ula

tive r

isk (

%)

2

4

6

8

10

12

14

5545 65 75

Continuing cigarette smokersStopped age 60Stopped age 50Stopped age 40Stopped age 30Lifelong non-smokers

Peto et al, BMJ 2000; 321 (7257): 323-9

Age

• Risk is proportional to the

amount and duration of

tobacco smoking

• Cessation lowers risk, but

it never returns to that of a

lifelong non-smoker


9

Non-smokers account for 10-20% of lung cancer cases in the United States

Causes of lung cancer in non-smokersAdapted from American Cancer Society Facts & Figures 2006. Special

section Environmental Pollutants.


10

Stage is the most important prognostic factor

Stage

Goldstraw et al, JTO 2016

Stage at

Diagnosis*

15

22

55

*Stage unknown

in 8%

SEER 2000


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Impact of Lung Cancer Histology

15%

21%

34%

9%

17%

4%

Small Cell

Non-Small Cell

Squamous

Adenocarcinoma

Large

Cell

Other

NOS Small Cell Squamous Adenocarcinoma

Most Common

LocationCentral Central

Central or

Peripheral

Found in non-

smokers?Exceedingly Rare Rare Yes

Targetable

genomic

alterations

Extremely unlikely Unlikely

Possible,

especially in

nonsmokers

Classic

Paraneoplastic

Syndrome(s)

SIADH,

Cushings,

Lambert-Eaton

Hypercalcemia -

Adapted from Targeted Oncology, 11/20/17


Non-Small Cell

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Practice Question 1

Which of the following statements is true about cancer?

A. Breast cancer is the most common cause of cancer death in women.

B. For former smokers, it takes ~ 10 years for the risk of lung cancer to decrease to that of a nonsmoker.

C. More than half of new lung cancers are already metastatic at the time of diagnosis.

D. Tumor grade (level of differentiation under the microscope) is a more important predictor than tumor stage (extent of disease on scans)

E. Small cell lung cancer is both more aggressive and more common than non-small cell lung cancer.


13

Lung Cancer Screening

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According to current USPSTF Guidelines, low-dose CT screening for lung cancer is currently recommended for which of the following asymptomatic patients?

A. A 42 year-old nonsmoking former naval midshipmen with a history of asbestos

exposure

B. A 56 year-old non-smoker whose father had died of lung cancer at age 64.

C. A 76 year-old who had smoked 1 pack per day for 30 years (from age 16-46).

D. A 70 year-old who had smoked 1 pack per day for 30 years (from age 35-65).

E. A frail 84 year-old with Class III CHF who has continued to smoke 2 packs per day

since age 14.

Practice Question 2


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ABCs of Lung Cancer Screening


BenefitAudience Calendar

• Asymptomatic adults, and

• Aged 55 to 80 years, and

• Heavy and recent

smoking history:

• > 20 pack-years, and

• Currently smoke or

quit smoking within

the past 15 years.

• Annual Low-Dose Chest

CT

• Screening should be

discontinued once a person

has not smoked for 15

years or develops a health

problem that substantially

limits life expectancy or the

ability or willingness to have

curative lung surgery.

NLST (NEJM 2011. 365: 395-409):

• 20% decrease in lung cancer

mortality

• 6.7% decrease in all cause

mortality

NELSON (de Koning et al, WCLC

2018):

• 26% decrease in lung cancer

mortality

USPSTF: Grade B

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Follow-up of Radiographic Findings

Setting Guidelines

Screening of an asymptomatic patient LUNG-RADS1

Incidental finding on a scan performed for another

reason

Fleishner Guidelines2

Radiographic study performed as part of evaluation

of a symptomatic patient

Aggressive follow-up

1. LUNG-RADS: American College of Radiology. https://www.acr.org/-/media/ACR/Files/RADS/Lung-

RADS/LungRADSAssessmentCategoriesv1-1.pdf

2. Fleishner Guidelines: MacMahon et al, Radiology 2017.

https://pubs.rsna.org/doi/10.1148/radiol.2017161659


https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/LungRADSAssessmentCategoriesv1-1.pdf


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Screening Follow-up: LUNG-RADS

Category Definition

Risk of

Malignancy

Estimated

Population

Prevalence Recommended Follow-Up

Category 0 (incomplete)

• prior CT studies were performed, but are not available for comparison

• Part or all of lungs cannot be evaluated

N/A 1%

Comparison with prior studies

before assignment of Lung-

RADS classification

Category 1: Negative

• no lung nodules

• lung nodule(s) with specific findings favoring benign nodule(s): complete, central,

and/or popcorn calcification; calcification in concentric rings; fat-containing nodules

<1%

90%

Continue annual screening with

LDCT

Category 2: Benign appearance or behavior

• solid nodule(s)

• <6 mm at baseline

• new nodule <4 mm

• subsolid nodule(s)

• <6 mm on baseline screening

• ground glass nodule(s)

• <30 mm (Version 1.1 change previously 20 mm)

• ≥30 mm and unchanged or slowly growing (Version 1.1 change previously 20

mm)

• category 3 or 4 nodules that are unchanged for ≥3 months

< 1%

Continue annual screening with

LDCT

From 2019 LUNG-RADS from ACR


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Category DefinitionRisk of

Malignancy

Estimated

Population

Prevalance

Recommended

Follow-Up

Category 3: Probably Benign

• Solid nodule(s)

• ≥6 mm to <8 mm at baseline, OR

• new nodule 4 mm to <6 mm

• Part solid nodule(s)

• ≥6 mm total diameter with solid component <6 mm, OR

• new <6 mm total diameter

• Non-solid nodule(s)

• (GGN) ≥30 mm on baseline CT or new

1-2% 5%

6-month follow-up

with LDCT

Category 4A: Suspicious

• Solid nodule(s)

• ≥8 mm to <15 mm at baseline, OR

• growing nodule(s) <8 mm, OR

• new nodule 6 mm to <8 mm

• Part solid nodule(s)

• ≥6 mm total diameter with solid component ≥6 mm to <8 mm, OR

• With a new or growing <4 mm solid component

• Endobronchial nodule

5-15% 2%

• 3-month follow-up

with LDCT

• PET/CT may be

used if there is a

≥8 mm solid

component

Screening Follow-up: LUNG-RADS From 2019 LUNG-RADS from ACR


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Category DefinitionRisk of

Malignancy

Estimated

Population

Prevalence

Recommended Follow-Up

Category 4B, Very Suspicious

• Solid nodule(s)

• ≥ 15 mm at baseline, OR

• new or growing, and ≥8 mm

• subsolid nodule(s)

• solid component ≥8 mm, OR

• new or growing ≥4 mm solid component

>15% 2%

For 4B and 4X:

• Chest CT with or without

contrast, as appropriate

• PET-CT and/or tissue

sampling depending on

the probability of

malignancy and

comorbidities (PET-CT if

solid component ≥8 mm)

• For new large nodules that

develop on an annual

repeat screening CT, a 1

month LDCT may be

recommended to address

potentially infectious or

inflammatory conditions.

Category 4X, Very Suspicious

• category 3 or 4 nodules with additional features or imaging findings that increase

the suspicion of malignancy

• includes:

• spiculation

• ground glass nodule(s) that double in size in 1 year

• enlarged regional lymph nodes

>15% 2%

Category S: Other - Modifier may add on to category 0‐4 coding

• Clinically Significant or Potentially Clinically Significant Findings (non lung cancer)N/A 10%

• As appropriate to the

specific finding

Screening Follow-up: LUNG-RADSFrom 2019 LUNG-RADS from ACR


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According to current USPSTF Guidelines, low-dose CT screening for lung cancer is currently recommended for which of the following asymptomatic patients?

A. A 42 year-old nonsmoking former naval midshipmen with a history of asbestos

exposure

B. A 56 year-old non-smoker whose father had died of lung cancer at age 64.

C. A 76 year-old who had smoked 1 pack per day for 30 years (from age 16-46).

D. A 70 year-old who had smoked 1 pack per day for 30 years (from age 35-65).

E. A frail 84 year-old with Class III CHF who has continued to smoke 2 packs per day

since age 14.

Practice Question 2


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Clinical Presentation,

Diagnosis,

and Staging

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A 68 year-old man with ongoing tobacco use (1ppd x 50 years) presents with worsening shortness of breath over 2 months time, along with hoarseness. CT angiogram is negative for pulmonary embolus, but it does show a large left hilar mass, along with subcarinal and left supraclavicular adenopathy and concerns for lesions in the liver and left adrenal. Serum chemistries are notable for a sodium of 124.

What is the most likely cause of hyponatremia?

Practice Question 3

A. DehydrationB. Psychogenic polydipsiaC. Syndrome of inappropriate andidiuretic hormone (SIADH)D. Laboratory error


23

Clinical Presentation of Lung Cancer:


Lungs

Brain

Liver

Adrenals

Bones

Lymph Nodes

Generalized Symptoms

Symptoms related to local destruction, obstruction, or replacement

Paraneoplastic Syndromes

• Fatigue

• Weight loss

• Night sweats

• Cough

• Shortness of breath

• Hemoptysis

• SVC Syndrome

• Focal bone pain

• Fracture

• Cord Compression

• Focal CNS symptoms

• Seizure

• Altered Mental Status

• SIADH

• Paraneoplastic Cushings

• Hypercalcemia

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CT chest with IV contrast

Lung Cancer Staging:

Mediastinal Nodes

• Mediastinal staging:

• For potentially resectable

patients

• For patients with locally

advanced disease

• How:

• Mediastinoscopy

• Bronchoscopy/EBUS

• Lymph node dissection at

the time of surgery

Lungs

Lymph Nodes

Brain MRI with gad (preferred), or

CT head with IV contrast

PET/CT (preferred), or

Bone scanBones

Liver

Adrenals

Brain


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Lung Cancer Diagnosis:

ENDS

❑ Safe, timely, accurate diagnosis

❑ Obtain sufficient tissue for subsequent

biomarker studies, clinical trial eligibility

❑ Confirm spread (when applicable)

MEANS

❑ CT-guided biopsy

❑ Bronchoscopy/EBUS

❑ Mediastinoscopy

❑ Thoracentesis, other drainage

❑ Surgical procedure

❑ Other

Additional Information:

❑ Bone biopsies are usually inadequate for biomarker studies, trial eligibility. The

decalcification process that bone biopsies undergo denatures DNA.

❑ If there appears to be only a single site of spread, it should be biopsied to confirm or rule

out metastasis.


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Paraneoplastic SyndromesDisease Paraneoplastic Syndrome Mechanism

Squamous NSCLC Hypercalcemia PTHrP

Small cell lung cancer Syndrome of inappropriate antidiuretic

hormone (SIADH)

Anti-diuretic hormone

(aka arginine vasopressin)

Cushing syndrome Ectopic ACTH

Lambert-Eaton Ab against voltage-gated calcium

channels

Thymoma Myasthenia gravis Ab against nicotinic acetylcholine

receptors

Pure red cell aplasia Suspect IgG against erythroblasts,

epo


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A 68 year-old man with ongoing tobacco use (1ppd x 50 years) presents with worsening shortness of breath over 2 months time, along with hoarseness. CT angiogram is negative for pulmonary embolus, but it does show a large left hilar mass, along with subcarinal and left supraclavicular adenopathy and concerns for lesions in the liver and left adrenal. Serum chemistries are notable for a sodium of 124.

What is the most likely cause of hyponatremia?

Practice Question 3

A. DehydrationB. Psychogenic polydipsiaC. Syndrome of inappropriate andidiuretic hormone (SIADH)D. Laboratory error


28

Overview of Therapy

For Lung Cancer

29

A 66 year-old woman currently on therapy for her stage IV non-small cell lung cancer presents to her local ED with several days of worsening shortness of breath, dry cough, and low-grade fevers. CT chest is concerning for pneumonitis. Which of the following could be an explanation for these findings?

Practice Question 4

A. Alectinib (ALK inhibitor)-related pneumonitisB. Docetaxel-related pneumonitisC. Pembrolizumab (immunotherapy)-related pneumonitisD. SARS CoV2 infectionE. All of the above


30

Overview of Therapy for Lung Cancer

NSCLC

SCLC

Stage I

Stage II

Stage III

Stage IV

Limited

Extensive

Stage Stage Description Therapy

Limited to one lung +/- regional nodes,

in a feasible radiation portChemoradiotherapy

Anything beyond limited stage Palliative systemic therapy

Contralateral/distant spread and/or

malignant effusionPalliative systemic therapy

Even larger lung mass, and/or

mediastinum or supraclavicular nodesMultidisciplinary Therapy

Larger lung mass, and/or local/hilar

nodes

Resection +/- adjuvant

systemic therapy

Small lung mass, no spread Resection


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Overview of Therapy for Lung Cancer

NSCLC

SCLC

Stage I

Stage II

Stage III

Stage IV

Limited

Extensive

Stage Stage Description Therapy

Limited to one lung +/- regional nodes,

in a feasible radiation portChemoradiotherapy

Anything beyond limited stage Palliative systemic therapy

Contralateral/distant spread and/or

malignant effusionPalliative systemic therapy

Even larger lung mass, and/or

mediastinum or supraclavicular nodesMultidisciplinary Therapy

Larger lung mass, and/or local/hilar

nodes

Resection +/- adjuvant

systemic therapy

Small lung mass, no spread Resection


Genomically

Targeted Therapy

Chemotherapy +

Immunotherapy

Immunotherapy +

Immunotherapy

Chemotherapy

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Role of Radiation in Lung Cancer


The Role of Radiation in Lung CancerCurative

• Early-stage: alternative to

surgery in poor operative

candidates

• Locally advanced: with

chemotherapy as a

neoadjuvant (pre-operative)

or definitive strategy

Palliative

• To address an urgent

symptom. e.g.: cord

compression, SVC

syndrome, airway or

esophageal obstruction

• To palliate: e.g., bone

metastasis

• Brain metastases

Other

• Prophylactic cranial

irradiation (small cell)

• Consolidative chest radiation

(small cell)

• Oligo-progressive disease,

particularly for patients on

targeted tx or immunotherapy

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FDA Approvals for Lung Cancer


Landmark Approvals:

• 2004: The first targeted agents (gefitinib, erlotinib) are

approved for non-small cell lung cancer

• 2015: The first immunotherapy agent (nivolumab,

pembrolizumab) approved in non-small cell lung cancer

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FDA Approvals for Lung Cancer


Genomic alterations in lung cancer associated with an

FDA-approved targeted therapy

Mutations EGFR

BRAF V600E

KRAS G12C

MET exon 14

Fusions/Rearrangements ALK

ROS1

NTRK

RET

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Toxicities with Targeted Therapies

PresentationScreening Lung Cancer Therapy Other Thoracic TumorsEpidemiology

Gene Agent CYP3A4?1 Selected Common Side Effects2 Selected Serious Side Effects2

EGFR 1st gen:

• erlotinib

• gefitinib

2nd gen:

• afatinib

• dacomitinib

3rd gen:

• osimertinib

Y

Y

N

Y

Y

Rash, skin dryness, diarrhea Pneumonitis/Interstitial lung disease,

hepatotoxicity, nephrotoxicity, severe

rash/mucositis, severe diarrhea.

Osimertinib: Cardiotoxicity

ALK 1st gen:

• crizotinib

2nd gen

• alectinib

• brigatinib

• ceritinib

3rd gen:

• lorlatinib

Y

Y

Y

Y

Y

Fatigue, diarrhea, nausea, visual

changes.

Crizotinib: hypogonadism

Pneumonitis, hepatotoxicity

Lorlatinib: CNS / cognitive changes

ROS1 crizotinib Y Fatigue, diarrhea, nausea, visual

changes. Hypogonadism

Pneumonitis, hepatotoxicity

BRAF Dabrafenib+trametinib Y Fever, nausea. Hepatotoxicity, cardiotoxicity. Basal cell CA

NTRK entrectonib

larotrectinib

Y

Y

Hepatotoxicity, fatigue, nausea -

MET capmatinib Y Edema, nausea, nephrotoxicity Interstitial lung disease, hepatotoxicity

RET selpercatinib Y Dry mouth, diarrhea, hepatotoxicity Hepatotoxicity, hypertension

1. Collated from www.drugs.com. 2. This is not a comprehensive list of toxicities. For more information, see prescribing info for each agent.

http://www.drugs.com/

36

• Side effects can occur at any point in treatment course

• Can get immune-mediated toxicity of essentially any system

• Some severe but rare side effects include: pneumonitis,

hepatotoxicity, CNS toxicity, cardiotoxicity, SJS

• For severe toxicity: consult, hospitalization, steroids,

immunomodulators

Considerations with immunotherapy


37

A 66 year-old woman currently on therapy for her stage IV non-small cell lung cancer presents to her local ED with several days of worsening shortness of breath, dry cough, and low-grade fevers. CT chest is concerning for pneumonitis. Which of the following could be an explanation for these findings?

Practice Question 4

A. Alectinib (ALK inhibitor)-related pneumonitisB. Docetaxel-related pneumonitisC. Pembrolizumab (immunotherapy)-related pneumonitisD. SARS CoV2 infectionE. All of the above


38

Cancer statistics, 2020.

Siegel et al, Ca Cancer

J Clin

39

• Stage is the most important predictor of outcome

• Small cell lung cancer is the most likely to be associated

with smoking and with paraneoplastic syndromes (esp

SIADH)

• Lung cancer screening: in smokers heavy (> 20 pk-yrs)

and recent (quit within the last 15 years)

• Staging: Chest CT w/ contrast, PET/CT, Brain MRI

Take Home Points, Test Prep version


40

• Staging: Brain imaging needs IV contrast

• The importance of adequate tissue for diagnosis and

testing (core > FNA, non-bone > bone)

• Many targeted therapies – metabolized via CYP3A4 –

drug interactions

• Lung Cancer Screening

Take Home Points, Clinical Practice Version


41

• Cancer statistics, 2020. Siegel et al, Ca Cancer J Clin

• www.drugs.com

• LUNG-RADS: American College of Radiology.

https://www.acr.org/-/media/ACR/Files/RADS/Lung-

RADS/LungRADSAssessmentCategoriesv1-1.pdf

• Fleishner Guidelines: MacMahon et al, Radiology 2017.


References

http://www.drugs.com/

https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/LungRADSAssessmentCategoriesv1-1.pdf


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