1. John C. Morris, M.D. Professor
Lung Cancer
John C. Morris, M.D. Professor
Division of Hematology-Oncology Department of Internal Medicine University of Cincinnati
February 3, 2018

2. 1761- “Lung tumors” reported in coal miners in Silesia
Prior to the 20th century a rare disease:
% of cancers seen at autopsy at the University of Dresden, but by 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)

3. Estimated Cancer Deaths
American Cancer Society, 2017

4. Causes of Lung Cancer Tobacco Asbestos Radon gas Air pollution
Cigarettes
Risk lower for other tobacco products
?E-cigarettes?
Asbestos
Radon gas
Air pollution
Chromium
Arsenic
Diesel fumes
Beryllium
Cadmium
Halomethyl ethers
Nickel fumes
Vinyl chloride
Aromatic hydrocarbons
Genetic predisposition- Li- Fraumeni syndrome (p53-)
Viruses- JSRV?, HPV?
Diet?

5. 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.

6. 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.

7. 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 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.

8. Lung Cancer

9. 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

10. Lung Cancer Pathology Squamous Cell (epidermoid) Adenocarcinoma
Small Cell Lung Carcinoma

11. Signs and Symptoms of Lung Cancer
Cough
Hemoptysis
Dyspnea
Chest pain
Wheezing
Weight loss
Anorexia
Fatigue
Neurological findings
Paraneoplastic syndromes
Digital “clubbing”
Hoarseness
Facial swelling
Arm pain
Bone pain
lymphadenopathy
Ptosis
Fever/pneumonia
Metabolic abnormalities
Asymptomatic

12. 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

13. 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 %
Bone marrow biopsy/aspirate (SCLC)- not recommended
Open biopsy or resection specimen

14. Spread of Lung Cancer Lymphatic spread Direct tumor extension
Blood-borne spread

15. 8th AJCC/IASLC Staging Classification for Lung Cancer
Detterbeck FC, et al. Chest, 2017

16. Lung Cancer Stage and Survival

17. Non-small Cell Lung Cancer: Stage at Diagnosis
Stage I 10%
Stage II 20%
Stage IV 40%
Stage IIIA 15%
Stage IIIB 15%
Ettinger, et al. Oncology. 1996;10:

18. Treatment of Lung Cancer
Surgery
Radiation
Chemotherapy
Antineoplastic agents
Targeted therapies
Immunotherapy

19. VATS Procedure vs. Standard Thorocotomy

20. 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).

21. Chemotherapy Benefit by Stage in Completely Resected NSCLC Patients
No. deaths/ No. patients
HR for overall 5-Yr. survival (Chemotherapy vs. Control)
Category
Stage IA
104/347
1.40 ( )*
Stage IB
Stage II
515/1371
893/1616
0.93 ( )
P = .04
0.83 ( )
Stage III
878/1247
0.83 ( )
0.5
Chemotherapy Better
1.0
Observation Better
2.5
Pignon JP, et al. J Clin Oncol. 2008; 26:

22. 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

23. By the mid-2000’s we had reached a plateau for chemotherapy in advanced NSCLC
1.0
0.8
0.6
0.4
0.2
0.0
ECOG 1594
cisplatin/paclitaxel cisplatin/gemcitabine cisplatin/docetaxel carboplatin/paclitaxel
Patient Survival (%)
0 5
10 15
Months
Schiller JH, et al. N Engl J Med. 2002

24. 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 %
2-year survival %
Significant treatment associated side effects
Unsuccessful strategies:
Single agent chemotherapy
Multi-drug chemotherapy regimens
Non-platinum based chemotherapy
High-dose chemotherapy
Frasci et al. J Clin Oncol. 1999;17:
Kelly et al. Clin Cancer Res. 2000;6:

25. Selecting Chemotherapy by Molecular Analysis
Non-squamous* (n = 1252)
Squamous (n = 473)
HR=0.844
(95% CI: 0.71–0.98)
p=0.011
HR=1.229
(95% CI: 1.00–1.51)
p=0.051
Survival Probability
Pemetrexed + cisplatin
Survival Probability
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.

26. 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

27. “Driver mutations” in Adenocarcinoma of the Lung
Harris T. Disc Med; 2010.

28. 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:

29. Response of EGFR mutated adenocarcinoma to erlotinib.
Pan M et al. Nat Clin Pract Oncol 4: 603–607, 2007.

30. l(f Health..

31. EGFR Resistance and 3rd Generation TKIs
Osimertinib (Targrisso®)

32. 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.

33. 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

34. Immunotherapy of Lung Cancer: PD-1/PD-L1 Checkpoint Blockade

35. 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

36. PD-L1 Identifies NSCLC Patients Most Likely to Benefit From Pembrolizumab
Staining
Intensity 0+ 1+ 2+ 3+
PD-L1
Positivity, % 2
100
PD-L1 Negative
PD-L1 Positive
*Clinical trial assay.
Gandhi L, et al. AACR Abstract CT105.

37. Week 12
Baseline
Week 4

38. 2nd-line treatment in NSCLC
CheckMate 057: Nivolumab vs. Docetaxel as
2nd-line treatment in NSCLC

39. KEYNOTE: Pembrolizumab vs
KEYNOTE: Pembrolizumab vs. Platinum-based Chemotherapy as 1st-line Treatment in Advanced NSCLC
Reck M, et al. N Engl J Med 2016; 375:

40. PD-1/PD-L1 Blockade Immune-Mediated Toxicities
Occasional (5-20%)
Infusion reactions
Endocrinopathies: thyroid, adrenal, hypophysitis
Fatigue
Rash: maculopapular and
pruritus
Topical treatments
Diarrhea/colitis
Infrequent (<5%)
Pneumonitis
Other Grade 3/4 toxicities uncommon:
Initiate steroids early, taper
slowly
Central nervous system
Blistering rash
Kidney
Hepatitis/liver enzyme abnormalities
1. Topalian SL, et al. N Engl J Med. 2012;366: Patnaik A, et al. ASCO Abstract 2512.
3. Brahmer JR, et al. N Engl J Med. 2012;366: Herbst RS, et al. ASCO Abstract 3000.

41. 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
Smoking  SCLC

42. 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

43. SCLC Median Survival Very-limited disease ~5 years Limited disease
18-24 months
Extensive disease
~10 months
SCLC without treatment < 8 weeks

44. 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.

45. 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.

46. 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.

47. 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