Download Small Cell Lung Cancer

Small Cell Lung Cancer
Bruce E. Johnson, M.D.
Professor of Medicine
Harvard Medical School
Chief Clinical Research Officer
Dana-Farber Cancer Institute
DISCLOSURES
Off-Label Usage
• Temozolomide
Financial Relationships with Relevant Commercial
Interests
• Consultant AstraZeneca, Bristol-Myers Squibb, Chugai, Genentech
BioOncology, Pfizer, Sanofi-Aventis, Ariad, GE Health care, Millenium
• Stockholder/Ownership Interest: KEW
Resolution
• Reviewed and found to be unbiased.
SMALL CELL LUNG CANCER
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Pathology and molecular pathogenesis
Presentation
Staging
Treatment
Prophylactic cranial irradiation
Relapsed small cell lung cancer
SMALL CELL LUNG CANCER-2014
 The Recalcitrant Cancer Research Act of 2012 (H.R. 733)
requires the National Cancer Institute (NCI) to “develop
scientific frameworks” that will assist in making “progress
against recalcitrant or deadly cancers.” Small cell lung cancer
(SCLC) is a recalcitrant cancer as defined by its five-year
relative survival rate of less than 7 percent and the loss of
approximately 30,000 lives per year. While it is true that the
outcomes for the other common forms of lung cancer
(squamous cell and adenocarcinoma) need to be greatly
improved, each of the three major types of cancer that
originate in the lung present very dif ferent problems,
requiring dif ferent solutions.
http://deainfo.nci.nih.gov/advisory/ctac/workgroup/SCLC/SCLCCongressionalResponse
EPIDEMIOLOGY
Moolgavkar et al JNCI 2012
EPIDEMIOLOGY
• The Median Prevalence of Cigarette Smoking across the
United States is 18.1% (20.5% for men and 15.8% for
women)
• The Prevalence Ranged from 10.6% in Utah to 28.3% in
Kentucky in 2012.
• Massachusetts has 18.2% of Adults Smoking Cigarettes
in 2011(9th)
http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm#state
EPIDEMIOLOGY
Cancer Death Rates* Among
Men, US, 1930 - 2010
Cancer Death Rates* Among
Women, US, 1930 - 2010
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data 1960 – 2010, US Mortality Volumes 1930 – 1959.
National Cancer Center for Health Statistics, Centers for Disease Control and Prevention.
American Cancer Society Statistics 2014
EPIDEMIOLOGY
• 224,210 men and women (116,000 men and 108,210
women) will be diagnosed at a median age of 70
• 159,260 men and women will die of cancer of the lung and
bronchus in 2014
• The overall 5-year relative survival for 2002-2008 from 18
SEER geographic areas was 15.9%
• The percentage with localized disease at time of presentation
is 15%, regional is 22%, and distant is 56% (6% is unstaged)
http://seer.cancer.gov/statfacts/html/lungb.html#survival
PATHOLOGY AND MOLECULAR
PATHOGENESIS
 Non-Small Cell Lung Cancer
87%
 Small Cell Carcinoma
13%

Small Cell Carcinoma
> 90%

Variant (Combined Small Cell Carcinoma) < 10%
Travis WD, et al. World Health Organisation Classification of Tumors. Pathology and Genetics of Tumors
of the Lung, Pleura, Thymus and Heart. 4th ed. WHO: Geneva, Switzerland; 2004.
PATHOLOGY AND MOLECULAR
PATHOGENESIS: SMOKING
 Small cell lung cancer is the most closely linked with
cigarette smoking.
 > 97% of patients have a history of cigarette smoking.
 Squamous cell carcinoma and large cell carcinoma are
intermediately linked with cigarette smoking.
 Approximately 80% of patients have a history of cigarette smoking.
 Adenocarcinoma is least closely linked to cigarette smoking.
 70% of patients have a history of cigarette smoking.
 Pulmonary carcinoid tumors are not associated with cigarette
smoking
SMALL CELL LUNG CANCER
PATHOLOGY AND MOLECULAR
PATHOGENESIS
 Markers of neuroendocrine dif ferentiation

Chromogrannin A

Synaptophysin

CD56 or Neural Cell Adhesion Molecule
(NCAM)
Travis WD, et al. World Health Organisation Classification of Tumors. Pathology and Genetics of Tumors
of the Lung, Pleura, Thymus and Heart. 4th ed. WHO: Geneva, Switzerland; 2004.
GENOMIC ANALYSES OF 152 SMALL-CELL
LUNG CANCERS
 Pe ife r et al Nature Ge netics 201 2 44:1104 and Rud in et al Nature
Ge netics Nat Ge netics 201 2 44:1111
UPDATE ON SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
PRESENTATION
Local
Systemic
Symptom or Sign
Percentage
Symptom or Sign
Percentage
Cough
50%
Weight loss
50%
Dyspnea
40%
Weakness
40%
Chest pain
35%
Anorexia
30%
Hemoptysis
20%
Paraneoplastic
syndrome
15%
Hoarseness
10%
Fever
10%
PRESENTATION OF PARANEOPLASTIC
SYNDROMES
Syndrome
Protein
Hyponatremia of Malignancy
Arginine Vasopressin and
Atrial Natriuretic Peptide
Parathyroid Hormone Related
Peptide
Hypercalcemia of Malignancy
Ectopic ACTH Syndrome
Acromegaly
Adrenocorticotrophic
Hormone
Growth Hormone Releasing
Hormone
Pts with SCLC
15%
<1%
3%
<1%
SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
SMALL CELL LUNG CANCER: STAGING
 The staging classification for these patients is a simple twostage Veterans Administration Lung Study Group System,
updated in 1989 by International Association for the Study of
Lung Cancer.
 Limited stage: Disease confined to 1 hemithorax with regional lymph
nodes including either ipsilateral or bilateral hilar, mediastinal, and
supraclavicular lymph node metastases and without ipsilateral pleural
effusion that fit within a tolerable chest radiation field
 IASLC now recommends staging them using TNM; stage I-III and IV is
roughly equivalent to limited or extensive stage disease.1
 Extensive stage: Disease beyond these boundaries
1 Va l l i er s et a l . J o u r n a l o f T h o r a c ic O n c o l o g y. 2 0 0 9 ; 4 : 10 4 9 - 10 5 9
SMALL CELL LUNG CANCER: METASTATIC
SITES
 Bone-35%
 Liver-25%
 Bone marrow-20%
 Brain-20%
 Extrathoracic lymph nodes-5%
 Subcutaneous masses-5%
SMALL CELL LUNG CANCER:
PROGNOSTIC FACTORS
Factors Consistently Reported
Factors Inconsistently Reported
Good performance status
Normal serum sodium
Limited stage disease
Younger age
Female gender
Absence of liver or brain mets
Caucasian
Normal liver function tests
SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment: Limited stage and extensive stage
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
Pre-treatment
2 Years after Treatment
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
BID
PE
PE
PE
PE
BID
PE
PE
PE
PCI
PE
Cisplatin - 80; Etoposide - 100 / Q 21 days in sequential,
Q 28 days in concurrent. PCI: 24 Gy 1.5 Gy BID to 45 Gy
Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060.
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060.
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
BID
PE
PE
PE
PE
PCI
QD
PE
PE
PE
PE
Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 Gy
Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271.
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271.
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
 Patients with limited stage SCLC should be treated with
concurrent chest radiotherapy with etoposide plus cisplatin.
These patients lived longer than patients treated with
chemotherapy alone.
 The chest radiotherapy should start with cycle 1 or 2.
 The chest radiotherapy should be given twice daily over 3
weeks.
 An ongoing trial comparing etoposide cisplatin plus 45 Gy
given twice daily over 3 weeks versus 70 Gy once daily in 2 Gy
fractions (NCT00632853).
SMALL CELL LUNG CANCER:
LIMITED STAGE SMALL CELL LUNG CANCER
 Patients with a solitary pulmonary nodule and a diagnosis of
SCLC should undergo evaluation for resection (2-3%).
 Patients should have mediastinoscopy because 20% will have
positive lymph nodes.
 Patients should be treated with adjuvant chemotherapy
following resection.
Strand TE, et al. Thorax. 2006;61(8):710-715.
SURGERY FOR SCLC
Surgery vs. no surgery for NO disease
Surgery vs. no surgery for N1 disease
Schreiber D, et al. Cancer. 2010;116(5):1350-1357.
SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment: Limited stage and extensive stage
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
SMALL CELL LUNG CANCER: IRINOTECAN FOR
EXTENSIVE STAGE SMALL CELL LUNG CANCER
 651 patients with extensive stage SCLC
 Randomized to 4 cycles of irinotecan 60 mg/m2 IV on days 1 ,
8, and 15 plus cisplatin 60 mg/m2 on day 1 on 28 day cycle
versus etoposide 100 mg/m2 on days 1 , 2, and 3 plus
cisplatin 80 mg/m2 on day 1 every 3 weeks
 Followed for response, time to progression, and survival
Lara PN JR, et al. J Clin Oncol. 2009;27(15):2530-2535.
SMALL CELL LUNG CANCER: IRINOTECAN FOR
EXTENSIVE STAGE SMALL CELL LUNG CANCER
Lara PN, JR, et al. J Clin Oncol. 2009;27(15):2530-2535.
AMRUBICIN FOR EXTENSIVE STAGE SCLC
 282 patients with extensive stage SCLC
 Randomized to 4 cycles of irinotecan 60 mg/m 2 IV on days 1 ,
8, and 15 plus cisplatin 60 mg/m 2 on day 1 on 28 day cycle
versus amrubicin 40 mg/m 2 on days 1 , 2, and 3 plus cisplatin
60 mg/m 2 on day 1 every 3 weeks
 Followed for response, time to progression, and survival
Satouchi M, et al. J Clin Oncol. 2014;32:1262
AMRUBICIN FOR EXTENSIVE STAGE SCLC
Satouchi M, et al. J Clin Oncol. 2014;32:1262
SMALL CELL LUNG CANCER: STRATEGIES FOR
EXTENSIVE STAGE SMALL CELL LUNG CANCER
 140 limited and extensive stage patients treated with
transplant doses of ifosfamide, carboplatin and etoposide (Tx)
versus standard doses of the same drugs 1
 724 patients with limited and extensive stage treated with
etoposide and cisplatin +/- thalidomide 2
 795 patients given topotecan 1 .0 mg/m2 IV days 1-5 plus
cisplatin 75 mg/m2 IV day 1 versus etoposide 100 mg/m2 IV
days 1-3 plus cisplatin 3
1.
2.
3.
Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8):533-541.
Lee SM, et al. J Natl Cancer Inst. 2009;101(15):1049-1057.
Fink TH et al. J Thoracic Oncol. 2012 Sep;7(9):1432
SMALL CELL LUNG CANCER:
EXTENSIVE STAGE SMALL CELL LUNG CANCER
 Patients with extensive stage SCLC should be treated with 2
drugs which produce moderate myelosuppression. Etoposide /
cisplatin remains the standard treatment.
 Patients with SCLC treated with intensive chemotherapy
(adding paclitaxel or autologous transplant doses) do not live
longer than patients treated with standard doses.
SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment: Limited stage and extensive stage
 Prophylactic and therapeutic cranial irradiation
 Relapsed small cell lung cancer
SMALL CELL LUNG CANCER:
PROPHYLACTIC CRANIAL IRRADIATION FOR
LIMITED AND EXTENSIVE STAGE
Survival for Limited and
Extensive Stage
N = 987
Auperin et al. N Engl J Med. 1999;341-476.
38
Survival for Extensive Stage
N = 286
Slotman B, et al. N Engl J Med. 2007;357:664
SMALL CELL LUNG CANCER:
PROPHYLACTIC CRANIAL IRRADIATION FOR
EXTENSIVE STAGE
Patient with ES SCLC with response to first-line platinum
doublet chemotherapy were randomized to either PCI
(25Gy/10 fractions) or observation (Obs) alone.
The patients were required to prove the absence of BM by
MRI prior to enrollment
The study was terminated because of futility when 163 were
entered and there were 111 death
The median OS was 10.1 and 15.1 months for PCI (n=84) and
Obs (n=79), respectively (HR=1 .38, 95%CI= 0.95-2.01;
stratified log-rank test, P=0.091).
Seto et al. ASCO 2014 #7503
39
SMALL CELL LUNG CANCER:
DOSE OF PROPHYLACTIC CRANIAL
IRRADIATION
40
Le Pechoux C, et al. Lancet Oncol 2009;10:467.
SMALL CELL LUNG CANCER:
PROPHYLACTIC CRANIAL IRRADIATION
 Patients with SCLC have a 60-80% actuarial risk of developing
brain metastases within 2 years after the start of treatment.
 PCI has been shown to prolong survival for patients with both
limited and extensive SCLC with a response to chemotherapy.
 PCI (2500 cGy) administered at the time of complete
remission can reduce the chance of developing brain
metastases by 50-67%.
Arrigada R, et al. J Natl Cancer Inst. 1995;87(3):183-190. Auperin A, et al. N Engl J Med. 1999;341(7):476484. Slotman B, et al. N Engl J Med. 2007;357(7):664-672. Le Pechoux C, et al. Lancet Oncol
2009;10:467
SMALL CELL LUNG CANCER:
STEREOTACTIC RADIOSURGERY AFTER RT
51 Pts with SCLC Rx with PCI (16) or WBRT (35)
Median 18 Gy (range 10-24)
Proportion Surviving
42
Harris et al. Int J Radiat Oncol Biol Phys epub 2012
SMALL CELL LUNG CANCER: LONG-TERM OUTCOME
OF PATIENT WITH LIMITED STAGE SCLC
Jänne PA, et al. Cancer.
2002;95(7):1528-1538.
Govindan R, et al. J Clin Oncol.
43
2006;24(28):4543-4544.
SMALL CELL LUNG CANCER: LONG-TERM
OUTCOME OF PATIENTS WITH EXTENSIVE
STAGE SCLC
Chute JP, et al, J Clin Oncol.
1999;17(6):1794-1801.
Oze I, et al. PLoS One.
2009;4(11):e7835.
SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment: Limited stage and extensive stage
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
SMALL CELL LUNG CANCER:
TOPOTECAN FOR RELAPSED DISEASE
71 Rx 2.3 mg/m2/day PO
Topotecan days 1-5 vs 70 Placebo
O’Brien ME, et al. J Clin Oncol. 2006;24:5441
211 Rx 1.5 mg/m Topotecan IV
on days 1-5 vs CAV
46
von Pawel et al. J Clin Oncol. 1999;17:658.
TOPOTECAN VERSUS AMRUBICIN FOR
RELAPSED SCLC
Eligibility Criteria
• Small Cell Lung Cancer (SCLC)
• Extensive or Limited Disease
• Sensitive or refractory disease
(Progression ≥ 90 or <90 days after
completion of 1st line chemotherapy,
Response to 1st line chemo)
• 1 prior chemotherapy regimen
• ECOG performance status 0-1
• Stratified: Sensitive/Refractory;
Extensive/Limited
R
A
N
D
O
M
I
Z
E
2
to
1
Amrubicin IV
40 mg/m2
1x daily on
d 1-3 q 3 w
Topotecan IV
1.5 mg/m2
1x daily on
d 1-5 q 3 w
• Primary endpoint: Overall Survival
• Secondary endpoints: ORR, PFS, TTP, LCSS, quality of life, safety, sparse PK
• Analyses: Interim (deaths = 294), Final (deaths = 490)
[97.5% power: 6.0 vs. 8.7 months (HR: 0.69)]
Von Pawel WCLC 2011
#O01.02
TOPOTECAN VERSUS AMRUBICIN FOR
RELAPSED SCLC
1. 0
0.9
Survival Probability
0. 8
N/Events
Median OS
95% CI
Amrubicin
424/336
7.5 months
6.8 – 8.5
Topotecan
213/175
7.8 months
6.6 – 8.5
0. 7
• Third-line therapy was comparable
(46.5% topotecan vs. 47.4% amrubicin)
0.6
0. 5
0. 4
0. 3
0. 2
0. 0
.
0.01
1
0
0
.
# at risk
Amrubicin
Topotecan
HR=0.880
95% CI [0.733, 1.057]
P-value*=0.1701
3
6
9
12
15
18
21
24
27
30
33
17
4
7
1
3
1
1
0
0
0
Time (months)
343
164
250
122
109
77
94
43
50
22
32
8
* Unstratified log-rank test
TOPOTECAN VERSUS AMRUBICIN FOR
RELAPSED SCLC
Survival Probability
1.0
Sensitive Patients
0.9
0.8
Amrubicin
0.7
60.6
Median OS
95% CI
225/168
9.2 months
8.5-10.6
117/89
9.9 months
8.5-11.5
Topotecan
0.5
0.4
0.3
HR=0.936
95% CI [0.724, 1.211]
P-value*=0.6164
0.2
0.1
0.0
Survival Probability
N/Events
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
Time (months)
21
24
27
30
33
N/Events
Median OS
95% CI
Amrubicin
199/168
6.2 months
5.5-6.7
Topotecan
96/86
5.7 months
4.1-7.0
Refractory Patients
HR=0.766
95% CI [0.589, 0.997]
P-value*=0.0469
0
3
6
9
12
Time (months)
15
18
21
24
* Unstratified log-rank test
27
Von Pawel WCLC 2011
#O01.02
TEMOZOLOMIDE FOR RELAPSED SCLC
 Previously treated patients with sensitive relapse SCLC (48) or
refractory SCLC (16).
 24 had brain metastases including 13 with target lesions
assessable by RECIST
 Treated with 21/28 days of 75 mg/m2 of temozolomide
 Followed for toxicity, response, time to progression, and
survival
Pietanza et al. Clin Cancer Res 2012; 18:1138
50
TEMOZOLOMIDE FOR RELAPSED SCLC
4 of 13 Brain Mets had CR
and 1 had a PR (38%RR)
51
Pietanza et al. Clin Cancer Res 2012; 18:1138
UPDATE ON SMALL CELL LUNG CANCER
 Pathology and molecular pathogenesis
 Presentation
 Staging
 Treatment: Limited stage and extensive stage
 Prophylactic cranial irradiation
 Relapsed small cell lung cancer
52