SMALL CELL LUNG CANCER

(SCLC) and TKIs in NSCLC

G. Giaccone
Chief Medical Oncology Branch
National Cancer Institute
Bethesda, Maryland
 U.S. Cancer Mortality: Men

CA Cancer J Clin 2006

 U.S. Cancer Mortality: Women

CA Cancer J Clin 2006

 Worldwide Prevalence of Lung
Cancer
• According to WHO, >1.2 million new cases of lung and bronchial
cancer diagnosed each year worldwide, and approximately 1.1
million deaths annually
– Lung/bronchial cancer single largest cause of cancer deaths in US,
accounting for 32% of cancer deaths in men and 25% in women in
20041
– In Europe, about 400,000 new cases of lung and bronchial cancer
diagnosed each year,2 with 341,800 deaths (about 20% for all cancers)
reported in 20043

1. American Cancer Society

(http://www.cancer.org/docroot/pro/content/pro_1_1_Cancer_
Statistics_2004_presentation.asp)
2. Bray F, et al. Eur J Cancer. 2002;38:99-166.
3. Boyle P, Ferlay J. Ann Oncol. 2005;16:481-488.
 Lung Cancer Demographics
 Second most frequently diagnosed cancer in the
United States
– ~12% of all new diagnoses
– ~173,770 individual cases in 2004
– Median age at diagnosis is approximately 70 years
– Over 1/3 of all diagnoses are made in patients over
75 years of age
 Leading cause of cancer deaths in the
United States
– ~160,440 patients will die in 2004
– 32% and 25% of all cancer deaths in American men and
women, respectively
Jemal et al. CA Cancer J Clin. 2004;54:8.
SEER Cancer Statistics Review, 1975-2001. At: http://seer.cancer.gov/csr/1975_2001/. Accessed October 22, 2004.
 Estimated Cancer Death Rates
in the United States 2004
Men 290,890 Women 272,810

Lung and bronchus 32% 25% Lung and bronchus

Prostate 10% 15% Breast
Colon and rectum 10% 10% Colon and rectum
Pancreas 5% 6% Ovary
Leukemia 4% 6% Pancreas
Non-Hodgkin’s 4% 4% Leukemia
lymphoma

Jemal et al. CA Cancer J Clin. 2004;54:8.

 Activated proto-oncogenes in
lung cancer
Gene Chromosom Activation SCLC (%) NSCLC (%)
e
MYC 8q24 Amplification 90 25
MYCN 2p24 Amplification 25
MYCL 1p34 Amplification 25
KRAS 12p12 Mutation <1 20-40
HRAS 11p15 Mutation <10
NRAS 1p13
ERBB2 17q12 Amplification <1 <10
EGFR 7p11.2 Mutation/Am 5-10
plification (mutation)
 Inactivated tumor suppressor
genes in lung cancer
gene chromosome Activation SCLC (%) NSCLC (%)

TP53 17p13 LOH, mutation 90 50

RB1 13q14 LOH, mutation 90 15

CDKN2A 9q21 HD, methylation, <10 60-70

LOH, mutation
SMAD2 18q21 LOH, mutation <10 <10

SMAD4 18q21 LOH, mutation <10 <10

PTEN 10q23 HD, LOH, <10 <10

mutation
FHIT 3p14 HD, aberrant 75 75
splicing
RASSF1 3p21 Methylation 80 30-40
Unbalanced translocation causing LOH
in adenocarcinoma of the lung

7 cell lines and 3 primaries

Ogiwara H et al. Oncogene 27, 4788, 2008

 Select gene mutations in
NSCLC
• P53 50-70%
• Kras 20% (30% adenocarcinoma)
• P16 29% (adenocarcinoma)
• EGFR 10-30% (20% adenocarcinoma)
• LKB1 26% (34% adenocarcinoma)
• NTRK 10% pulmonary NE tumors
• EML-4-ALK 6.7%
• PIK3CA 1.6%
• MEK1 1%
TK and relative hazard to develop
metastases in early NSCLC

Muller-Tidow C et al. Cancer Res 65 1778, 2005

 LUNG CANCER
Histological Types

 Non-small cell lung cancer (85%)

Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma

 Small cell lung cancer (15%)

 SCLC
 Mostly caused by cigarette smoke
 Kills approximately 30,000 people each year
in the US
 Is a neuroendocrine tumor
 Highly sensitive to chemotherapy and
radiotherapy, but recurrence is common
 SCLC

• Epidemiology
• Diagnosis and Staging
• Biology
• Treatment
 Epidemiology of SCLC

• SEER database
1978-1998
• Decrease SCLC
– 1986 17.4%
– 1998 13.8%
 NSCLC: United States Incidence
Over 3 Decades
70
60
Incidence rate*

50
40
30
20
10
0
1975 1980 1985 1990 1995 2000
Year of diagnosis
 The incidence of NSCLC increased by over 26% between 1974 and 1998
 The incidence of SCLC decreased approximately 9% between 1998 and 2001

*Rates are per 100,000 and are age-adjusted to the 2000 US standard population.
SEER Cancer Statistics Review, 1975-2001. At: http://seer.cancer.gov/csr/1975_2001/. Accessed October 22, 2004.
SCLC biopsy specimen
 Neural enzymes, peptides and
transmitters may be stored in the
dense core neurosecretory
granules associated with SCLC.
 Lung Cancer: Common Signs and
Symptoms
 Symptoms related to the primary tumor
– Cough, hemoptysis, wheeze and stridor, dyspnea,
and/or pneumonitis
 Symptoms related to metastases
– Bone pain, abdominal pain, headache, weakness,
and/or confusion
 Generalized symptoms
– Fatigue, malaise, and/or loss of appetite

American Society of Clinical Oncology. At: http://asco.org/ac/1,1003,_12-002611-00_18-0026183-00_19-00-00_20-

001,00.asp. Accessed October 26, 2004.
Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925.
 Lung Cancer: Evaluation and
Diagnosis
Suspected lung cancer

Initial evaluation:
Peripheral tumor Chest x-ray Central tumor
CT scan
PET scan*
Options Options
- Percutaneous fine needle aspiration - Sputum cytology
- Bronchoscopy - Bronchoscopy
- Video-assisted thoracoscopy - Percutaneous fine
- Thoracotomy needle aspiration
- Thoracotomy

*Some metastases visible by CT scan only.

CT = computed tomography; PET = positron emission tomography.
Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925.
Rivera et al. Chest. 2003;123(suppl):129S.
Lung cancer: chest X-ray
Lung cancer: chest CT-scan
Lung cancer: bronchoscopy
 Staging of SCLC
• Physical examination
• Serum chemistries and whole blood cell
counts
• CT scan of chest and upper abdomen
– US upper abdomen
• FDG PET scan
– Bone scan
• CT or MRI of the brain
• Bone marrow biopsy (optional)
SCLC metastasis.
•Liver (27%)
•Bone (41%)
•Adrenals (31%)
•Brain (14%)
•Lymph nodes, mediastinal
(80%)
SCLC carcinogenesis.

•Initiated by tobacco smoke

carcinogens.
•Is SCLC derived from
neuroendocrine Kulchitsky cells or
stem cells?
SCLC cell lines.
Bone marrow aspirates were obtained
from patients and mononuclear cells
collected.
Lymph node aspirates and other solid
tumors were mechanically dissociated
and cell suspensions obtained by mincing
and passing through 60 gauge steel
mesh.
The cells were cultured in a serum free
medium containing selenium, IGF-I and
transferrin. SCLC cells grew as
suspension cultures.
SCLC cell lines.

•Over a 20 year period, NCI established

113 SCLC and 110 NSCLC continuous
human cell lines.
A subset of SCLC is variant SCLC, which
has low levels of DDC, BB and NSE.
Phelps et al., J. Cell Bioc. Supp.
24:32(1996).
SCLC molecular abnormalities.

•Allelic loss (3p, 4p, 4q, 5q, 8p, 9p,

10q, 13q, 17p, 22q)
•Microsatellite instabilities (35%)
• MYC overexpression (30%)
•Stem cell factor, c-kit
overexpression (30%)
•Bombesin/ Gastrin releasing
peptide (BB/GRP), GRP receptor,
IGF-I receptor
Chromosome losses in SCLC
include:
3p loss is an early event and
5q, 13q and 17p loss occurs later.
SCLC molecular abnormalities.

•P53 inactivation (90%)

•Rb inactivation (90%) but not
p16.
•FHIT inactivation (75%)
•BCL2 expression (85%)
 Small cell lung carcinoma
 Rapid growth and early metastases
 Staged in limited vs extensive disease (based on possibility of
chest radiation in one field)
– Limited disease:
 stage I : resection followed by adjuvant chemotherapy; 5y 35-45%
 Stage II-III : chemoradiation, PCI in CR; 5y 20-25%
– Extensive disease:
 Chemotherapy : response 50-70%, 5y <5%
 Prognostic factors for survival

19 mo 10 mo 7 mo 2 mo
 Staging of small cell lung cancer

Limited disease Extensive disease

(within a tolerable radiation field) (distant metastases)
DEFINITION OF DISEASE EXTENSION

• Very-limited disease: confined to one

hemithorax without mediastinal lymph
node involvement.
• Limited disease: confined to one
hemithorax including the contralateral
lymph nodes (all within radiation field).
• Extensive disease: beyond these
bounderies.
 survival of SCLC
marginally improvement of survival in 2 decades

Median survival SEER database

Limited Disease (Janne et al. Extensive Disease (Chute et al. J

Clin Oncol 1999)
Median survivals in SCLC

• Very-limited disease ~5 years

• Limited disease 18-24 months
• Extensive disease 10 months

• SCLC without treatment < 3 months

Combination chemotherapy.
Active combinations include:
cyclophosphamide, doxorubicin, VP-
16(CDE),
C, doxorubicin, vincristine (CAV),
E, cisplatin (EP),
VP-16, ifosfamide, P (VIP), and
I, carboplatin, VP-16 (ICE).
Approach to very-limited
disease

Surgery followed by
chemotherapy
Survival of patients with SCLC according
to lymph node involvement

pTN0M0 (n=63)
pTN1M0 (n=51)
pTN2M0 (n=32)

Eur J Cardiothorac Surg, 5:306;1991

About half of patients with very-
limited disease may be cured with
combined-modality approach that
includes surgical resection and
adjuvant chemotherapy
 preoperative SCLC
• 1 randomized study
• 328 patients (N2 excluded)
• 5 courses CAV q 3 wks + radiotherapy thorax
and brain + thoracotomy
• randomized if > PR
• 217 responders (90 CR, 127 PR)
• 146 randomized

Lad T et al. Chest 1994; 106: 320S

-resection rate 83%
-19% complete
resection
-9% only NSCLC as
residual disease

median survival
-all 12 months;
-randomized 16
months

Lad T et al. Chest 1994; 106: 320S

Approach to limited disease
 Limited Disease - SCLC

• treatment has a small but definitively curative intent

( 5y survival: 10 – 25 % )
• combination chemotherapy is the backbone of treat-
ment

• thoracic radiotherapy significantly improves long

term survival

• early thoracic radiotherapy gives better results than

late radiotherapy
 limited disease - SCLC
• cisplatin and etoposide are most easily combined
within concurrent chemoradiation protocols (Turrisi
et al )
• BID radiotherapy gives better local control and
better long term survival than QD (5y survival %:
26% Turrisi et al, NEJM 99 )

• PCI significantly improves survival by 4-5 % at 5

years when given to complete responders (Auperin
et al )
A meta-analysis of thoracic RT in LD-SCLC

12 phase III studies

Pignon et al NEJM 1992

 SCLC - Meta-analysis of PCI
From 7 randomised trials of PCI vs no-PCI

Patients 987 (140 patients had ED-SCLC)

Chemo- & RT schemes various

Overall survival benefit +5% (95% CI: 1 -10%)

3 year survival 20 vs 15%

Incidence of brain metas 33 vs 59%

Auperin et al. NEJM 1999

 Risk of radiation esophagitis with CT-RT

• With once-daily RT: <5% acute Grade 3-4 esophagitis

• With concurrent chemo-RT: 25-52% acute G3-4 esophagitis

• Risk of acute high-grade esophagitis associated with a length

of irradiated organ of >10 cm

• Risk of late toxicity associated with >50 Gy delivered to >32%

of the esophageal volume & when any portion of esophageal
circumference receives >80 Gy.

• Use of involved-fields significantly reduces the length of

irradiated esophagus.
(refs Choi 99; Hirota 01; Rusch 01; Senan 02; Vokes 02)
Early vs Late Radiotherapy for LD
SCLC. Meta analysis

2 year survival 3 year survival

Fried et al. J. Clin. Oncol. 22,4837

,2004
 SCLC LD Standard of treatment

Cisplatin 80 mg/m2 d1
Etoposide 120 mg/m2 d1-3
Q3wk x 4
Thoracic Radiotherapy 45 Gy
1.5 Gy/fraction bid 3 wk

Turrisi et al. NEJM 1999

Approach to SCLC ED
Standard of treatment for SCLC ED

• Cisplatin or Carboplatin plus Etoposide

– Median survival approx. 11 months
– 5 year survival approx 0%

• No improvement achieved by
– Alternating chemotherapy
– Maintenance chemotherapy
– Novel agents (taxanes, topo 1 inhibitors)
– Biologicals
 Irinotecan
Irinotecan plus cisplatin compared with etoposide plus
cisplatin for extensive stage small cell lung cancer

• irinotecan 60 mg/m2 d 1,8,15; cisplatin 60 mg/m2 d 1 q 4

weeks
• etoposide 100 mg/m2 d 1,2,3; cisplatin 80 mg/m2 d 1 q 3
weeks
• 154 patients (planned 230)
• median survival IP 12.8 months; EP 9.4 months
• at 2 years 19.5% versus 5.2% alive

Noda K et al. New Engl J Med 2002

 cisplatin/irinotecan versus
cisplatin/etoposide in SCLC ED
Japanese experience

Noda et al. NEJM 2002

LBA 7004
Randomized phase III study comparing
Irinotecan/Cisplatin (IP) with Etoposide/Cisplatin (EP)
in patients with previously untreated, ED SCLC

R Cisplatin 30 mg/m2 d 1, 8
a N = 221
n Irinotecan 65 mg/m d 1, 8 2

d Q 21
o
m Cisplatin 60 mg/m2 d 1
i etoposide 120 mg/m2 d 1-3 N = 110
z Q 21
e
Hanna et al. Proc. ASCO 2005, #
1094
IP vs EP in SCLC ED – US experience
abstract
7003
Phase III study of oral Topotecan/Cisplatin
versus Etoposide/Cisplatin (EP) as first-line
therapy in patients with ED SCLC
r Cisplatin 60 mg/m2 d 5
a N = 389
n Topotecan 1.7 mg/m /d d 1-5 2

d Q 21
o
m Cisplatin 80 mg/m2 d 1
i etoposide 100 mg/m2 d 1-3 N = 395
z Q 21
e
Eckardt JR et al. J Clin Oncol 2005; 23: 621s
Eckardt JR et al. J Clin Oncol 2005; 23: 621s
 Maintenance therapy
unsuccesfull
• Chemotherapy
• Biologicals:
– Interferons
– Marimastat
– Vaccination
– ZD6474 (VEGFR and EGFR inhibitor)
Second line therapies

• response to first-line therapy > 60%

• > 95 % relapse after first-line treatment

• second-line treatment often considered as

indicated as part of palliation
Phase III study comparing
topotecan vs. CAV as second line
therapy in patients with sensitive
relapse small cell lung cancer
R
SCLC Topotecan
A
•Measurable 1.5 mg/m2 daily x 5 q 3 wks
N
disease
D
•LD or ED O Cyclophosphamide 1000 mg/m2
•Response to FLT M Doxorubicin 45 mg/m2

•Off therapy >60

I Vincristine 2 mg
days Z
E
Second line chemotherapy for
SCLC. Symptom improvement
Symptom Topotecan (%) CAV (%) P value

Dyspnea 27.9 6.6 0.002

Cough 24.6 14.8

Chest pain 25.0 17.1

Hemoptysis 26.7 33.3

Anorexia 32.1 15.8 0.042

Insomnia 33.3 18.9

Hoarseness 32.5 13.2 0.043

Fatigue 2.9 9.2 0.032

Daily activity 26.9 11.1 0.023

Second line chemotherapy for
SCLC: reinduction chemotherapy.
Time after No patients Response Response Author
first line rate (%) duration (mo)

> 4.5 19 79 7 Postmus PE

< 4.5 18 44 4 1987

> 4.5 8 50 6 Giaccone G

< 4.5 4 50 1987

> 4.5 5 80 3 Vincent M

< 4.5 9 11 1988

Sensitive RR 61%
Refractory RR 35%
 Second line chemotherapy for
SCLC: influence of interval and
response to first-line treatment
response RR (%) p

response 1st-line Y 10/24 42 0.044

N 0/7 0

period since last > 2.6 mo. 9/17 53 0.016

chemotherapy
< 2.6 mo. 2/16 12

Giaccon
e et al. J
 Background: Brain
metastases (BM) in SCLC
• High incidence: 18% at diagnosis; 80% at 2 years
• Major impact on physical and psychological functioning
• Poor response to systemic therapy and brain radiotherapy
• Prophylactic cranial irradiation (PCI) improves survival in patients in
complete remission (Auperin et al., 1999)

Does PCI have a role in patients with

ED-SCLC after chemotherapy?
Study Design
PCI
No response 20-30 Gy in
Chemotherapy 5-12 fractions
(4-6 cycles) Any response Random

< 5 weeks No PCI

4-6 weeks

Stratification: Performance score and Institute

Slotman et al. NEJM 2007

Symptomatic brain
metastases
100

90

80 1 year: 14.6% vs. 40.4%

70
HR: 0.27 (0.16-0.44) p<0.001
60

50

40
Control
30

20
PCI
10

0 (months)
0 4 8 12 16 20 24 28 32 36
Extracranial progression
100
Control
90

80 PCI
70

60

50 P=0.2699
40

30

20

10

0 (months)
0 4 8 12 16 20 24 28 32 36
Failure-free survival
100

90

80 6 months: 23.4% vs. 15.5%

70
HR: 0.76 (0.59-0.96) p=0.02
60 PCI
50

40

30

20

10 Control
0 (months)
0 3 6 9 12 15 18 21 24 27
Overall survival
100

90

80 1 year: 27.1% vs. 13.3%

70
HR: 0.68 (0.52-0.88) p=0.003
60

50

40

30

20 PCI
10 Control
0 (months)
0 4 8 12 16 20 24 28 32 36
Summary
• PCI significantly reduces the risk of symptomatic brain
metastases (p<0.001; HR = 0.27; 14.6 vs. 40.4% at 1 yr)

• No difference for the time to extra-cranial progression

• PCI significantly prolongs failure-free survival and overall

survival (Overall survival: p=0.003; HR = 0.68 ; 27.1 vs. 13.3% at 1 yr)

• PCI is well tolerated and does not adversely influence

QoL/global health status
 Treatment of SCLC : state of
the art
• Limided Disease
 Concomitant early radiotherapy for limited disease SCLC
 Cisplatin-etoposide best tested
 PCI for complete responders
 Surgery rarely used
• Extensive Disease
 Platinum-based chemotherapy
 Second-line therapy with topotecan
 PCI for responders