Lung Cancer

John C. Morris, M.D.

Professor
Division of Hematology-Oncology
Department of Internal Medicine
University of Cincinnati

February 3, 2018
• 1761- “Lung tumors” reported in coal miners in Silesia

• Prior to the 20th century a rare disease:

• 1878- 1% of cancers seen at autopsy at the University of Dresden, but by
1927 it accounted for 14% of cancers (Witschi H., 2001).
• Prior to 1930 lung cancer was a rare diagnosis in the U.S.

• 1986- Lung cancer surpassed breast cancer as the most

common fatal cancer in women

• Leading cause of cancer death in the U.S. with an expected

222,500 cases and 158,870 deaths in 2017 (Siegel RL, et al. 2017)
 Estimated Cancer Deaths

American Cancer Society, 2017

 Causes of Lung Cancer

• Tobacco • Beryllium
• Cigarettes • Cadmium
• Risk lower for other
tobacco products • Halomethyl ethers
• ?E-cigarettes? • Nickel fumes
• Asbestos • Vinyl chloride
• Radon gas • Aromatic hydrocarbons
• Air pollution • Genetic predisposition- Li-
• Chromium Fraumeni syndrome (p53-)
• Arsenic • Viruses- JSRV?, HPV?
• Diesel fumes • Diet?
 Smoking and Lung Cancer Risk
• WHO estimates 80-90% of lung cancer is smoking-related:
• 16-18% of smokers will develop lung cancer.
• Lung cancer risk is 15 to 30-fold higher for smokers than non-smokers.
• Passive smoking (2nd hand smoke) may increase risk by 16-24%.

• More than 60 known EPA-designated carcinogens are found in

cigarette smoke including: arsenic, benzene, benzo-[a]-pyrene,
cadmium, chromium, complex hydrocarbons, nicotine, plutonium,
polonium, radon, nitrosamines, etc.

• Greatest reduction in lung cancer risk occurs if you quit smoking by

age 30, but even quitting at age 50 results in a >60% risk reduction.

• Patients who already suffer from advanced lung cancer that quit
smoking have longer survivals.
 Lung Cancer in Non-smokers
• Greater percentage of non-smokers being diagnosed with
lung cancer (Sun S et al, 2007).

• Estimated ~10% of lung cancer in men and 22% of lung

cancer in women are in never smokers (Parkin DM et al,
2005; Bryant A et al, 2007). ~50% of lung cancers in Asian
women occur in non-smokers.

• Lung cancer in “never smokers” is the 7th leading cause of

cancer death worldwide.

• Typically adenocarcinomas.
 Lung Cancer Screening
• 1970-80’s: Negative studies
• MSKCC- Annual chest X-ray ±sputum cytology
• Johns Hopkins- Annual chest X-ray + cytology
• Mayo Clinic- Annual chest X-ray + cytology every 4 months.

• National Lung Screening Trial (NLST)

• Enrolled more than 53,000 asymptomatic current and former smokers (defined
as smoked >30 pack-years and smoked within the last 15 years) between the
ages of 55-74 years.
• Compared low-dose helical CT (LDCT) to chest X-ray for early detection of lung
cancer.
• Findings announced November 2010:
• 20% fewer lung cancer deaths in the LDCT screening group
• Overall 7% fewer deaths from any cause in LDCT screening group

• The NCCN, NCI, ACCP and ATS recommend screening based

on this study, although guidelines vary slightly between the
societies.
Lung Cancer
 Lung Cancer Histology

• Non-small Cell Lung Cancer (NSCLC): ~85-90%

• Squamous cell (epidermoid)
• Adenocarcinoma- currently the MC histology observed

• Small Cell Lung CA (SCLC): Dec'd from 20-25%

 10-15% since 1960’s
 Lung Cancer Pathology
Squamous Cell (epidermoid) Adenocarcinoma

Small Cell Lung Carcinoma

Signs and Symptoms of Lung Cancer
• Cough • Hoarseness
• Hemoptysis • Facial swelling
• Dyspnea • Arm pain
• Chest pain • Bone pain
• Wheezing
• lymphadenopathy
• Weight loss
• Ptosis
•
•
Anorexia
Fatigue
• Fever/pneumonia
• Neurological findings • Metabolic
abnormalities
• Paraneoplastic syndromes
• Digital “clubbing” • Asymptomatic
 Medical Evaluation of the Pt w/
Suspected Lung Cancer
• H&P
• Serum chemistries, LDH, LFTs, CBC with differential and
platelet count, routine coagulation studies.
• High resolution CT-scan of chest and upper abdomen with
contrast to include liver and adrenal glands
• Biopsy
• Positron emission tomography (PET)/CT
• Brain MRI
• Bone scan-has been replaced by PET/CT
• Pulmonary function testing (PFTs) if contemplating surgery
• Additional lung functions studies if PFTs marginal
 Lung Cancer: Tissue is the issue!

• Sputum cytology
• Bronchoscopy
• Lavage
• Brushings
• Forceps biopsy
• Transbronchial biopsy
• Fine needle aspiration (FNA) biopsy
• Endobronchial ultrasound (EBUS) FNA
• Accuracy for mediastinal LN- 84-96.3%
• Bone marrow biopsy/aspirate (SCLC)- not recommended
• Open biopsy or resection specimen
 Spread of Lung Cancer
Lymphatic spread
Direct tumor
extension

Blood-borne
spread
8th AJCC/IASLC Staging Classification for Lung Cancer

Detterbeck FC, et al. Chest, 2017

Lung Cancer Stage and Survival
 Non-small Cell Lung Cancer: Stage at Diagnosis

Stage I 10%
Stage IV 40% Stage II 20%

Stage IIIA 15%

Stage IIIB 15%

Ettinger, et al. Oncology. 1996;10:81-111.

 Treatment of Lung Cancer
• Surgery

• Radiation

• Chemotherapy
• Antineoplastic agents
• Targeted therapies
• Immunotherapy
VATS Procedure vs. Standard Thorocotomy
 Radiation Therapy for Lung Cancer
• Radiation therapy (RT) is usually used in combination with chemotherapy
to treat patients with locally advanced (stage III, positive resection
margins), but potentially curable NSCLC.

• RT improves local tumor control of tumor, but as a single modality has a

marginal effect on survival.

• It is used to treat certain complications of lung cancer (bronchial

obstruction, brain metastases, bone metastases).
• Increasing use of stereotactic body RT (SBRT) for resectable patients with
major contraindications to surgery (i.e. severe COPD, extreme age).
• As part of the primary treatment of SCLC in combination with
chemotherapy and as prophylactic cranial irradiation (PCI).
 Chemotherapy Benefit by Stage in Completely Resected
NSCLC Patients

No. deaths/ HR for overall 5-Yr. survival

Category No. patients (Chemotherapy vs. Control)

Stage IA 104/347 1.40 (0.95-2.06)*

Stage IB 515/1371 0.93 (0.78-1.10)

P = .04
Stage II 893/1616 0.83 (0.73-0.95)

Stage III 878/1247 0.83 (0.72-0.94)

0.5 1.0 1.5 2.0 2.5

Chemotherapy Better Observation Better

Pignon JP, et al. J Clin Oncol. 2008; 26:3552-9.

 Drug Therapy for Lung Cancer

1970’s-1990’s: First Generation-

• Alkylating agents, antimetabolities, antitumor antibiotics- Cyclophosphamide,
nitrosoureas, methotrexate, doxorubicin
• Platinum-doublets- Carboplatin or cisplatin combined with etoposide, docetaxel,
gemcitabine, paclitaxel, pemetrexed, vinblastine or vinorelbine.

2000’s: Second Generation- Targeted therapy

• Tyrosine kinase inhibitors: gefitinib, erlotinib, afatinib, omersitanib
• Monoclonal antibodies: bevacizumab
2010’s: Third Generation- Immunotherapy
• Negative-immune checkpoint blockade: nivolumab, pembrolizumab, atezolizumab (anti-
PD-1/PD-L1 monoclonal antibodies) and combinations
By the mid-2000’s we had reached a plateau for
chemotherapy in advanced NSCLC

1.0 ECOG 1594

cisplatin/paclitaxel
Patient Survival (%)

0.8 cisplatin/gemcitabine
cisplatin/docetaxel
0.6 carboplatin/paclitaxel

0.4

0.2

0.0
0 5 10 15 20 25 30
Months
Schiller JH, et al. N Engl J Med. 2002
 Chemotherapy in Advanced NSCLC
• By 2000’s:
• Overall response rates were 15-25%
• Time to progression- 4-6 months
• Median survival- 8-9 months compared to 5-6 months for
untreated patients
• 1-year survival- 20-25%
• 2-year survival- 10-15%
• Significant treatment associated side effects
• Unsuccessful strategies:
• Single agent chemotherapy
• Multi-drug chemotherapy regimens
• Non-platinum based chemotherapy
• High-dose chemotherapy

1. Frasci et al. J Clin Oncol. 1999;17:2316-2325

2. Kelly et al. Clin Cancer Res. 2000;6:3474-3479.
 Selecting Chemotherapy by Molecular Analysis

Non-squamous* (n = 1252) Squamous (n = 473)

HR=0.844 HR=1.229
(95% CI: 0.71–0.98) (95% CI: 1.00–1.51)
p=0.011 p=0.051

Survival Probability
Survival Probability

Pemetrexed + cisplatin Gemcitabine + cisplatin

Gemcitabine + cisplatin Pemetrexed + cisplatin

Survival Time (months) Survival Time (months)

*Non-squamous- adenocarcinoma, large cell carcinoma, and other/indeterminate histology.

Scagliotti, et al. J Clin Oncol 2008.

 Drug Therapy for Lung Cancer

1970’s-1990’s: First Generation-

• Alkylating agents, antimetabolities, antitumor antibiotics- Cyclophosphamide,
nitrosoureas, methotrexate, doxorubicin
• Platinum-doublets- Carboplatin or cisplatin combined with etoposide, docetaxel,
gemcitabine, paclitaxel, pemetrexed, vinblastine or vinorelbine.

2000’s: Second Generation- Targeted therapy

• EGFR tyrosine kinase inhibitors: gefitinib, erlotinib, afatinib, omersitanib
• ALK inhibitors: crizotinib, ceritinib, alectinib
• Monoclonal antibodies: bevacizumab (anti-VEGF)
2010’: Third Generation- Immunotherapy
• Immune checkpoint blockade: nivolumab, pembrolizumab, atezolizumab (anti-PD-1/PD-
L1 monoclonal antibodies) and combinations
“Driver mutations” in Adenocarcinoma of the Lung

Harris T. Disc Med; 2010.

 Structure of the EGFR-ATP Binding Site
• Exons 18–21 = tyrosine
kinase domain.

• Mutations more frequent

in adenocarcinomas,
younger patients,
women, non-smokers,
and Asians.

• Mutations allow
gefitinib, erlotinib, and
afatinib to preferentially
bind and inactivate
EGFR.

Lynch TJ, et al. N Engl J Med. 2004; 350:2129-39.

Response of EGFR mutated adenocarcinoma
to erlotinib.

Pan M et al. Nat Clin Pract Oncol 4: 603–607, 2007.

l(f Health..
EGFR Resistance and 3rd Generation TKIs

Osimertinib (Targrisso®)
 Targeted Agents for Lung Cancer
• EGFR sensitizing mutations (11-17%)
• Gefitinib (Iressa®), erlotinib (Tarceva®), afatinib (Gilotrif®)
• T790M+ Resistance- osimertinib (Targrisso®)

• EML-4/ALK and ROS-1 translocations (3-6%)

• Crizotinib (Xalkori®), ceritinib (Zykaydia®), alectinib (Alcensa®).

• BRAF (V600E) mutations (1-4%)

• Vemurafenib (Zelboraf®), Debrafinib (Tafinlar®) ±Trametinib (Mekanist®)

• HER-2/neu overexpression (1-3%)

• Trastuzumab (Herceptin®), pertuzumab (Perjeta®), ado-trastuzumab
emtansine (Kadcyla®)- Not approved for lung cancer.
 Drug Therapy for Lung Cancer

1970’s-1990’s: First Generation-

• Alkylating agents, antimetabolities, antitumor antibiotics- Cyclophosphamide,
nitrosoureas, methotrexate, doxorubicin
• Platinum-doublets- Carboplatin or cisplatin combined with etoposide, docetaxel,
gemcitabine, paclitaxel, pemetrexed, vinblastine or vinorelbine.

2000’s: Second Generation- Targeted therapy

• Tyrosine kinase inhibitors: gefitinib, erlotinib, afatinib, omersitanib
• Monoclonal antibodies: bevacizumab
Today: Third Generation- Immunotherapy
• Negative-immune checkpoint blockade: nivolumab, pembrolizumab, atezolizumab (anti-
PD-1/PD-L1 monoclonal antibodies) and chemoimmunotherapy combinations
Immunotherapy of Lung Cancer: PD-1/PD-L1 Checkpoint Blockade
 Immunotherapy: Checkpoint Inhibitors in
Lung Cancer
• Nivolumab (Opdivo®)
• Administered I.V. every 2 weeks
• No testing for PD-L1 expression on the tumor required for
use in lung cancer
• 2nd-line treatment

• Pembrolizumab (Keytruda®)
• Administered I.V. every 3 weeks
• Testing for PD-L1 expression on the tumor required for use
in lung cancer
• Approved for 1st-line treatment
 PD-L1 Identifies NSCLC Patients Most Likely to Benefit
From Pembrolizumab

Staining 0+ 1+ 2+ 3+
Intensity
PD-L1 0 2 100 100
Positivity, %

PD-L1 Negative PD-L1 Positive

*Clinical trial assay.

Gandhi L, et al. AACR 2014. Abstract CT105.

Baseline Week 4 Week 12
CheckMate 057: Nivolumab vs. Docetaxel as
2nd-line treatment in NSCLC
KEYNOTE: Pembrolizumab vs. Platinum-based Chemotherapy as
1st-line Treatment in Advanced NSCLC

Reck M, et al. N Engl J Med 2016; 375:1823-1833.

 PD-1/PD-L1 Blockade Immune-Mediated
Toxicities

Occasional (5-20%) • Infusion reactions

• Fatigue • Endocrinopathies: thyroid,
• Rash: maculopapular and adrenal, hypophysitis
pruritus Infrequent (<5%)
• Topical treatments • Pneumonitis
• Diarrhea/colitis • Other Grade 3/4 toxicities
• Initiate steroids early, taper uncommon:
slowly • Central nervous system
• Hepatitis/liver enzyme • Blistering rash
abnormalities • Kidney
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 2. Patnaik A, et al. ASCO 2012. Abstract 2512.
3. Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465. 4. Herbst RS, et al. ASCO 2013. Abstract 3000.
 Small Cell Lung Cancer
 Associated with heavy smoking.

 SCLC is distinguished from NSCLC by its

rapid doubling time, high growth fraction, and
early development of widespread metastases

 Considered highly responsive to chemotherapy and radiotherapy,

SCLC usually relapses within two years despite treatment

 Overall, only 3% percent of all patients with SCLC (10-15% percent

of those with limited disease) survive beyond five years
 SCLC Staging

• Common (VA Lung Study Group)-

• “Very limited” stage- Rare and defined as
AJCC/ISLAC T1-2N0M0
• Limited stage- Can be encompassed in a single
radiation field: primary lesion/hemithorax/hilum,
mediastinal and ipsilateral supraclavicular lymph
nodes excluding a pleural effusion
• Extensive stage- Anything else or a pleural
effusion

• AJCC (TNM)- now being promulgated

 SCLC Median Survival

 Very-limited disease ~5 years

 Limited disease 18-24 months

 Extensive disease ~10 months

 SCLC without treatment < 8 weeks

 Treatment of Limited Stage SCLC

 In addition to chemotherapy, there is a significant role for radiation

therapy (XRT) in the treatment of LS-SCLC.
 Local tumor progression occurs in up to 80 % of such patients
treated with chemotherapy alone.
 High local recurrence rate can be significantly reduced by the
addition of thoracic XRT.
 Survival is improved when thoracic XRT is added to chemotherapy
compared with chemotherapy alone
 Prophylactic cranial irradiation (PCI)- Indicated for patients with a
complete or partial response to their chemotherapy treatment.
 Treatment of Limited Stage SCLC

 Current standard of care for patients with LS-SCLC:

 Four cycles of combination chemotherapy (typically
cisplatin/carboplatin plus etoposide [EP]) + concurrent
thoracic radiotherapy during the chemotherapy
treatment.
 Prophylactic cranial irradiation (PCI)
 Generally recommended for patients with a complete
response or significant tumor regression at the
completion of chemotherapy.
 Treatment of Extensive Stage SCLC
 The majority of patients with SCLC have extensive stage
disease.
 Definition - tumor that includes distant metastases,
malignant pericardial or pleural effusions, and/or
contralateral supraclavicular or contralateral hilar lymph
node involvement.
 Primary therapeutic modality is systemic chemotherapy-
Usually etoposide/cisplatin or carboplatin.
 Good response to chemotherapy- XRT may add
additional benefit.
 Paraneoplastic syndromes
• Lambert-Eaton: myesthenia-like syndrome
• Limbic encephalitis
• Cerebellar degeneration
• Hypercalcemia - very rare with SCLC, most often
with SQUAMOUS CELL CARCINOMA
• Cushing’s syndrome- due to ectopic ACTH
secretion, NOT cortisol
• SIADH
• Hypertrophic pulmonary osteoarthropathy