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

25% Lung and bronchus

15% Breast

10% Colon and rectum

6% Ovary

6% Pancreas

4% Leukemia

Lung and bronchus32%

Prostate 10%

Colon and rectum 10%

Pancreas 5%

Leukemia 4%

Non-Hodgkin’s 4%lymphoma

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

Activated proto-oncogenes in lung cancer

Gene Chromosome

Activation SCLC (%) NSCLC (%)

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/Amplification

5-10 (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, LOH, mutation

<10 60-70

SMAD2 18q21 LOH, mutation <10 <10

SMAD4 18q21 LOH, mutation <10 <10

PTEN 10q23 HD, LOH, mutation

<10 <10

FHIT 3p14 HD, aberrant splicing

75 75

RASSF1 3p21 Methylation 80 30-40

Unbalanced translocation causing LOH in adenocarcinoma of the lung

Ogiwara H et al. Oncogene 27, 4788, 2008

7 cell lines and 3 primaries

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 CANCERHistological Types

Non-small cell lung cancer (85%) AdenocarcinomaSquamous cell carcinomaLarge 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

*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.

The incidence of NSCLC increased by over 26% between 1974 and 1998 The incidence of SCLC decreased approximately 9% between 1998 and 2001

0

10

20

30

40

50

60

70

1975 1980 1985 1990 1995 2000

Year of diagnosis

Inci

den

ce

rat

e*

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.

Initial evaluation:Chest x-ray

CT scanPET scan*

Peripheral tumor Central tumor

Options- Percutaneous fine needle aspiration- Bronchoscopy- Video-assisted thoracoscopy- Thoracotomy

Options- Sputum cytology- Bronchoscopy- Percutaneous fine

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: Evaluation and Diagnosis

Suspected lung cancer

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 andtransferrin. 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 (within a tolerable radiation field)

Extensive disease (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

Limited Disease (Janne et al. Cancer 2002)

Median survival SEER database

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

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

Eur J Cardiothorac Surg, 5:306;1991

pTN0M0 (n=63)

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

•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.

Risk of radiation esophagitis with CT-RT

(refs Choi 99; Hirota 01; Rusch 01; Senan 02; Vokes 02)

Fried et al. J. Clin. Oncol. 22,4837,2004

Early vs Late Radiotherapy for LD SCLC. Meta analysis

2 year survival 3 year survival

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 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

Irinotecan

Noda K et al. New Engl J Med 2002

cisplatin/irinotecan versus cisplatin/etoposide in SCLC ED

Japanese experience

Noda et al. NEJM 2002

Hanna et al. Proc. ASCO 2005, #1094

Randomized phase III study comparingIrinotecan/Cisplatin (IP) with Etoposide/Cisplatin (EP)

in patients with previously untreated, ED SCLC

Randomize

Cisplatin 30 mg/m2 d 1, 8

Irinotecan 65 mg/m2 d 1, 8

Q 21

Cisplatin 60 mg/m2 d 1

etoposide 120 mg/m2 d 1-3

Q 21

LBA 7004

N = 221

N = 110

IP vs EP in SCLC ED – US experience

Phase III study of oral Topotecan/Cisplatin versus Etoposide/Cisplatin (EP) as first-line

therapy in patients with ED SCLC

randomize

Cisplatin 60 mg/m2 d 5

Topotecan 1.7 mg/m2/d d 1-5

Q 21

Cisplatin 80 mg/m2 d 1

etoposide 100 mg/m2 d 1-3

Q 21

abstract 7003

Eckardt JR et al. J Clin Oncol 2005; 23: 621s

N = 389

N = 395

Eckardt JR et al. J Clin Oncol 2005; 23: 621s

Maintenance therapyunsuccesfull

• 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

SCLC

•Measurable disease

•LD or ED

•Response to FLT

•Off therapy >60 days

RANDOMIZE

Topotecan

1.5 mg/m2 daily x 5 q 3 wks

Cyclophosphamide 1000 mg/m2

Doxorubicin 45 mg/m2

Vincristine 2 mg

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 first line

No patients Response rate (%)

Response duration (mo)

Author

> 4.5 < 4.5

19 18

79 44

7 4

Postmus PE 1987

> 4.5 < 4.5

8 4

50 50

6 Giaccone G 1987

> 4.5 < 4.5

5 9

80 11

3 Vincent M 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 lastchemotherapy

> 2.6 mo. 9/17 53 0.016

< 2.6 mo. 2/16 12

Giaccone et al. J.Clin. Oncol. 6;1264,1988

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 DesignPCIPCI

20-30 Gy in20-30 Gy in5-12 fractions5-12 fractions

No PCINo PCI

RandomAny response

Stratification: Performance score and Institute

< 5 weeks

4-6 weeks

No responseChemotherapy

(4-6 cycles)

Slotman et al. NEJM 2007

(months)

0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

PCI

Control

1 year: 14.6% vs. 40.4%

HR: 0.27 (0.16-0.44) p<0.001

Symptomatic brain Symptomatic brain metastasesmetastases

(months)

0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

P=0.2699

Control

PCI

Extracranial progressionExtracranial progression

(months)

0 3 6 9 12 15 18 21 24 27

0

10

20

30

40

50

60

70

80

90

100

PCI

Control

6 months: 23.4% vs. 15.5%

HR: 0.76 (0.59-0.96) p=0.02

Failure-free survivalFailure-free survival

(months)

0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

PCIControl

1 year: 27.1% vs. 13.3%

HR: 0.68 (0.52-0.88) p=0.003

Overall survival

Summary 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