Small Cell Lung Cancer

Palak Desai, MD
 Natural History of SCLC
SCLC is distinguished from NSCLC by its rapid
doubling time, high growth fraction, and the
early development of widespread metastases
Although considered highly responsive to
chemotherapy and radiotherapy, SCLC usually
relapses within two years despite treatment
Overall, only three to eight percent of all
patients with SCLC (10 to 13 percent of those
with limited disease) survive beyond five years
 SCLC Histology
SCLC is a “small blue round cell tumor” from neuroendocrine cells
Classifications:
oat cell (lymphocyte-like), fusiform, polygonal
OR classical, large cell neuroendocrine, combined SCLC/NSCLC

Immunohisto tests:
TTF1+ (adeno & SCLC)
Keratin, epithelial membrane
Antigen

Most SCLCs stain positively for markers

Of neuroendocrine differentiation, including
Chromogranin A, neuron-specific enolase,
Neural cell adhesion molecule (NCAM; CD56),
And synaptophysin
 Clinical Presentation of SCLC
Smokers (almost exclusively)

Cough 75%

Hemoptysis in 50%

Dyspnea and chest pain 40%

Constitutional symptoms 10 to 15%

Clubbing 16 to 29%

pneumonia, weight loss

 SCLC Paraneoplastic Syndromes
SIADH

ectopic ACTH production- Cushing’s syndrome

Eaton-Lambert Myasthenic syndrome

 proximal muscle weakness that improves on repetition
(“facilitation”)

Hypercalcemia

Peripheral Neuropathy
SCLC Staging
SCLC Staging
SCLC Staging
Where does SCLC metastasize to?

Brain (30%)

Adrenal (20-40%)

Liver (25%)

Lung

Skeleton (35%)
 Prognostic Factors
The host factors of poor performance status and weight loss
Stage (limited versus extensive).
In extensive disease, the number of organ sites involved is
inversely related to prognosis
Metastatic involvement of the central nervous system, the
marrow, or the liver is unfavorable compared to other sites,
although these variables are confounded by the number of
sites of involvement.
In most trials, women fare better than men, although the
reasons for this are not known.
The presence of paraneoplastic syndromes is generally
unfavorable
 Survival
Limited Stage:
 Median OS: 14-24 months
 5-yr OS: 20%

Extensive Stage:
 MedianOS: 6-11 months
 5-yr OS: 2%
Workup
 Limited vs. Extensive stage
Limited stage Extensive stage

Incidence 1 out of 3 people with 2 out of 3 people with

SCLC SCLC

Spread Only in one lung and To other lung, to lymph

perhaps in lymph nodes nodes on the other side
on the same side of the of the chest, or to
chest distant organs

Area confined to an area Wide spread

Treatment chemo-radiation ± PCI Chemotherapy ± PCI

Lung Cancer (small cell) Overview. American cancer society. http://

www.cancer.org/cancer/lungcancer-smallcell/overviewguide/lung-cancer-small-cell-overvie
w-staging
 First Line Therapy
During the 1970s CAV (cyclophosphamide, adriamycin,
and vincristine) was the standard regimen
In the 1980s several phase III clinical trials
demonstrated that EP (Etoposide + Platinum) was
equivalent to CAV
 CAV vs EP
Sundstrom et al, 2002
 436 patients were randomized to chemotherapy with EP (n = 218) or CEV
(n = 218).
 Patients were stratified according to extent of disease (limited disease
[LD], n = 214; extensive disease [ED], n = 222).
 The EP group received five courses of etoposide 100 mg/m(2)
intravenously (IV) and cisplatin 75 mg/m(2) IV on day 1, followed by oral
etoposide 200 mg/m(2) daily on days 2 to 4.
 The CEV group received five courses of epirubicin 50 mg/m(2),
cyclophosphamide 1,000 mg/m(2), and vincristine 2 mg, all IV on day 1.

 In addition, LD patients received thoracic radiotherapy concurrent with

chemotherapy cycle 3, and those achieving complete remission during the
treatment period received prophylactic cranial irradiation.
Sundstrom et al, JCO 2002
 CAV vs EP
The 2- and 5-year survival rates in the EP arm
(14% and 5%, P =.0004) were significantly
higher compared with those in the CEV arm
(6% and 2%).
Among LD patients, median survival time was
14.5 months versus 9.7 months in the EP and
CEV arms, respectively (P =.001).
The 2- and 5-year survival rates of 25% and
10% in the EP arm compared with 8% and 3%
in the CEV arm (P =.0001).
For ED patients, there was no significant
survival difference between the treatment
arms.
Quality-of-life assessments revealed no major
differences between the randomized groups.
 Carboplatin vs Cisplatin
In clinical practice, carboplatin is frequently substituted
for cisplatin to reduse the risk of emesis, neuropathy,
and nephropathy.
The use of carboplatin carries a greater risk of
myelosuppression
Randomized trials have suggested similar efficacy of
cisplatin and carboplatin in patients with small cell lung
cancer
 Carboplatin vs Cisplatin
Rossi et al, 2012– Meta-analysis
 Four eligible trials with 663 patients (328 assigned to cisplatin and 335 to
carboplatin) were included in the analysis.
 Median OS was 9.6 months for cisplatin and 9.4 months for carboplatin
(hazard ratio [HR], 1.08; 95% CI, 0.92 to 1.27; P = .37).
 There was no evidence of treatment difference between the cisplatin and
carboplatin arms according to sex, stage, performance status, or age.
 Median PFS was 5.5 and 5.3 months for cisplatin and carboplatin,
respectively (HR, 1.10; 95% CI, 0.94 to 1.29; P = .25).
 ORR was 67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to
1.16; P = .83).
 Toxicity profile was significantly different for each of the arms:
hematologic toxicity was higher with carboplatin, and nonhematologic
toxicity was higher with cisplatin.

Rossi et al, JCO 2012

Carboplatin vs Cisplatin
Other Chemotherapy
Combinations
 Irinotecan

Irinotecan and a platinum agent has

provided the greatest challenge to EP
Small phase III trial performed in
Japan reported that patients with
extensive stage SCLC who were
treated with Irinotecan plus cisplatin
experienced a median survival of 12.8
months compared to 9.4 months for
patients treated with EP (P= 0.002)
In addition, the 2 year survival was
19.5% in the irinotecan plus cisplatin
group vs 5.2% in the EP group

Noda et al, NEJM 2002

 Irinotecan
Hanna et al, 2006
 The primary objective was to compare overall survival in
extensive-disease SCLC patients randomly assigned to
receive IP (n = 221) or EP (n = 110).
 Patients were randomly assigned in 2:1 ratio to:
 cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV
on days 1 and 8 every 21 days
 cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV
on days 1 to 3 every 21 days for at least four cycles, until
progressive disease, or until intolerable toxicity resulted.

Hanna et al, JCO 2006

 Irinotecan- Hanna et al

There was no significant

difference in:
 response rates (48% v 43.6%)
 median time to progression
(4.1 v 4.6 months)
 overall survival (median
survival time, 9.3 months v
10.2 months; P = .74).
 Irinotecan
SWOG S0124
 North American Trial
 651 patients
 Patients were randomly assigned:
 IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60
mg/m(2) day 1, every 4 weeks)
 EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80
mg/m(2) day 1, every 3 weeks).

Lara et al, JCO, 2009

 SWOG S0124
Response rates with IP and EP were
60% and 57%, respectively (P = .
56).
Median progression-free survival
for IP and EP was 5.8 and 5.2
months, respectively (P = .07).
Median overall survival for IP and
EP was 9.9 and 9.1 months,
respectively (P = .71).
Severe diarrhea was more common
with IP (19% v 3%); severe
neutropenia and thrombocytopenia
were higher with EP versus IP (68%
v 33% and 15% v 4%, respectively)
 Irinotecan + Carboplatin
Hermes et al
 Randomized phase III trial
 209 patients
 Patients with ED SCLC were randomly assigned to receive either
 (IC)--carboplatin (AUC= 4) and irinotecan (175 mg/m2) intravenously
both on day 1
 (EC) consisted of carboplatin as in IC and etoposide (120 mg/m(2)/d)
orally on days 1 through 5. Courses were repeated every 3 weeks with
four cycles planned.
 Doses were reduced by one third in patients with a WHO
performance status (PS) of 3 to 4 and/or age older than 70 years.
 Primary end point was overall survival (OS). Secondary end points
were quality of life (QOL) and complete response (CR) rate.

Hermes et al, JCO 2008

 Irinotecan + Carboplatin
OS was inferior in the EC
group (hazard ratio = 1.41;
95% CI, 1.06 to 1.87; P = .02).

Median survival time was 8.5

months for IC compared with
7.1 months for EC.

One-year survival rate was

34% for IC and 24% for EC.

CR was seen in 18 IC patients

compared with seven EC
patients (P = .02).
There were no statistically significant differences in
hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea
was more common in the IC group. QOL differences
were small, with a trend toward prolonged palliation
with the IC regimen.
 Many Drugs Have Failed In the
First Line Setting
Data reviewed from 52 first
line phase III trials between
1980 and 2006
Including 10,262 patients

110 Chemotherapy arms

NO difference in
outcomes/survival

Oze et al, Plos One 2009

 Thoracic Radiotherapy
in Limited Disease

Pignon et a, 1992
 Meta-analysis comparing
chemotherapy alone with
chemotherapy combined with
thoracic radiotherapy
 13 trials and 2140 patients with
limited disease

Pignon et al, NEJM, 1992

 The relative risk of death in the combined-
therapy group as compared with the
chemotherapy group was 0.86 (95 percent
confidence interval, 0.78 to 0.94; P = 0.001),
corresponding to a 14 percent reduction in
the mortality rate.
 The benefit in terms of overall survival at
three years (+/- SD) was 5.4 +/- 1.4 percent.
 Indirect comparison of early with late
radiotherapy and of sequential with non-
sequential radiotherapy did not reveal any
optimal time for treatment.
 There was a trend toward a larger reduction
in mortality among younger patients: the
relative risk of death in the combined-
therapy as compared with the chemotherapy
group ranged from 0.72 for patients less than
55 years old (95 percent confidence interval,
0.56 to 0.93) to 1.07 (0.70 to 1.64) for
patients over 70.
 Response Rates
In patients with limited stage disease, response rates of 70%
to 90% are expected after treatment with EP + thoracic
radiotherapy
In extensive stage disease, response rates of 60% to 70% can
be achieved with chemotherapy alone
Unfortunately median survival rates are only 14 to 20 months
for limited stage disease and 9 to 11 months for patients with
extensive stage disease
After appropriate treatment, the 2 year survival rate is
approximately 40% for limited stage disease and 5% in those
with extensive stage disease

Chute et al, JCO 1999

 Adding a 3rd agent?
Many strategies have been evaluated in an effort to
improve on the standard treatment for extensive stage
disease, including the addition of a third agent to
standard 2-drug regimens
In 2 trials, the addition of ifosfamide or
cyclophosphamide + an anthracycline to EP showed
modest survival advantage for patients with extensive
disease.
 Adding Ifosfamide
Loehrer et al, JCO 1995
 Patients were randomized to receive
 cisplatin (20 mg/m2) plus etoposide (100 mg/m2) (VP) both given
intravenously (i.v.) on days 1 to 4
 cisplatin (20 mg/m2), ifosfamide (1.2 g/m2), and etoposide (75 mg/m2) (VIP)
all given i.v. on days 1 to 4. Cycles were repeated every 3 weeks for four
cycles.
 Objective responses were observed in 55 of 82 (67%) and 59 of 81 (73%)
assessable patients treated with VP and VIP, respectively (difference not
significant).
 The difference in the median time to progression was statistically
different (P = .039).
 The median survival times on VP and VIP were 7.3 months and 9.0
months, respectively (P = .045) with 2-year survival rates of 5% versus
13%, respectively.
 EP + Cyclophosphamide and
Anthracycline
Pujol et al, 2001
 Phase III trial by French Federation of Cancer Institutes
 patients were randomly assigned to receive either
 EP (n = 109; etoposide at a dose of 100 mg/m(2) on days 1-3
plus cisplatin at 100 mg/m(2) on day 2)
 PCDE (n = 117; etoposide and cisplatin given as in EP plus
cyclophosphamide at 400 mg/m(2) on days 1-3 and 4'-
epidoxorubicin at 40 mg/m(2) on day 1) every 4 weeks.
 Both groups received a total of six cycles

Pujol et al, J Natl Cancer Inst, 2001

 EP + Cyclophosphamide and
Anthracycline
Pujol et al, 2001
 Patients in the PCDE arm had a statistically significant higher
frequency of combined complete plus partial responses
compared with those in the EP arm (21% plus 55% versus 13%
plus 48%, respectively; P =.02).
 Patients in the PCDE arm survived longer than those in the
EP arm (1-year survival rate: 40% and 29%, respectively;
median survival: 10.5 and 9.3 months, respectively; log-rank
P =.0067).
 relative risk of death for patients in the PCDE arm compared
with those in the EP arm was 0.70 (95% confidence interval =
0.51 to 0.95); the disease also progressed more slowly in
patients in the PCDE arm.
 Safety
 Hematologic toxicity was higher in the PCDE arm (22% with
documented infections compared with 8% in the EP arm; P
=.0038), and the toxicity-related death rate was 9% in the
PCDE arm versus 5.5% in the EP arm (P =.22). The global
health status showed similar improvement in both arms
during treatment.

 These findings have not been uniformly observed, and the

addition of an alkylating agent, with or without
anthracycline, significantly increases hematologic toxicity
when compared to EP alone
 The addition of paclitaxel to either cisplatin or
carboplatin plus etoposide yielded promising results in
phase II trials but did not improve overall survival, and
was associated with unacceptable toxicity in a
subsequent phase III study
Maintenance chemotherapy has not been shown to
prolong survival as well

Neill et al, JCO 2005, Zhou et al, Plos One 2013

Simon et al, Crit Rev Oncol Hematol, 2004
 Outcomes of 1st line platinum-
based combination

I.K. Demedts et al Eur Respir J 2010

 Thoracic Radiotherapy for ES
Most patients with extensive stage small-cell lung cancer (ES-SCLC)
who undergo chemotherapy, and prophylactic cranial irradiation,
have persistent intrathoracic disease.
Phase 3 randomized controlled trial at 42 hospitals, 498 patients

Patients with WHO performance score 0–2 and confirmed ES-SCLC

who responded to chemotherapy.
They were randomly assigned (1:1) to receive either thoracic
radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy.
All underwent prophylactic cranial irradiation. The primary
endpoint was overall survival at 1 year in the intention-to-treat
population. Secondary endpoints included progression-free survival

Slotman et al, Lancet 2015

Overall survival at 1 year was not
significantly different between groups:
33% (95% CI 27–39) for the thoracic
radiotherapy group versus 28% (95% CI
22–34) for the control group (hazard ratio
[HR] 0·84, 95% CI 0·69–1·01; p=0·066).
However, in a secondary analysis, 2-year
overall survival was 13% (95% CI 9–19)
versus 3% (95% CI 2–8; p=0·004).
Progression was less likely in the thoracic
radiotherapy group than in the control
group (HR 0·73, 95% CI 0·61–0·87;
p=0·001).
At 6 months, progression-free survival
was 24% (95% CI 19–30) versus 7% (95% CI
4–11; p=0·001).

Slotman et al, Lancet 2015

 Second Line Therapy
Although SCLC is very responsive to initial treatment, most patients
relapse with relatively resistant disease
These patients have a median survival of only 4 to 5 months when
treated with further chemotherapy
Second line and third line chemotherapy provides significant palliation
in many patients, although the likelihood of response is highly
dependent on the time from initial therapy to relapse
 If the interval is less than 3 months, response to most agents is poor (<10%)
 If interval is more than 3 months, then the expected response rates are
approximately 25%

If patients relapse more than 6 months after first line treatment, then
treatment with their original regimen is recommended
 Topotecan
Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV)
were evaluated in a randomized, multicenter study of patients with
small-cell lung cancer (SCLC) who had relapsed at least 60 days after
completion of first-line therapy.
Patients received either
 topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21
days (n = 107)
 CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and
vincristine 2 mg) infused on day 1 every 21 days (n = 104).

Eligibility included the following:

 bidimensionally measurable disease
 ECOG performance status of less than or equal to 2
 and adequate marrow, liver, and renal function.

Von Pawel et al, JCO 1999

Response rate was:
 26 of 107 patients (24.3%) treated with topotecan
 19 of 104 patients (18.3%) treated with CAV (P = .285).
 Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .
552).

Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795).

The proportion of patients who experienced symptom improvement was greater in

the topotecan group than in the CAV group for four of eight symptoms evaluated,
including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with
daily activity (P< or =.043).
Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV
courses (P<.001).
Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with
topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of
CAV courses, respectively (P<.001 for both).
Nonhematologic toxicities were generally grade 1 to 2 for both regimens.

Von Pawel et al, JCO 1999

 Oral Topotecan
O’Brien et al, 2006
 randomly assigned patients with relapsed SCLC not
considered as candidates for standard intravenous therapy
to best supportive care (BSC) alone (n = 70) or oral
topotecan (2.3 mg/m2/d, days 1 through 5, every 21 days)
plus BSC (topotecan; n = 71).
 Primary end point was overall survival

O’Brien et al, JCO 2006

 Oral Topotecan

OS was prolonged in the topotecan

group 26 weeks vs 14 weeks (log-rank
P = .0104).
Median survival with BSC was 13.9
weeks (95% CI, 11.1 to 18.6) and with
topotecan, 25.9 weeks (95% CI, 18.3
to 31.6).
Statistical significance for survival was
maintained in a subgroup of patients
with a short treatment-free interval (<
or = 60 days).
Response to topotecan was 7% partial
and 44% stable disease.
Patients on topotecan had slower quality of life deterioration and
greater symptom control.
Principal toxicities with topotecan were hematological: grade 4
neutropenia, 33%; grade 4 thrombocytopenia, 7%; and grade 3/4
anemia, 25%.
Comparing topotecan with Best Supportive Care, infection grade 2
was 14% versus 12% and sepsis 4% versus 1%; other grade 3/4
events included vomiting 3% versus 0, diarrhea 6% versus 0,
dyspnea 3% versus 9%, and pain 3% versus 6%.
Toxic deaths occurred in four patients (6%) in the topotecan arm.
All cause mortality within 30 days of random assignment was 13%
on BSC and 7% on topotecan.
 Prophylactic Cranial Irradiation
EORTC Study
 Patients between the ages of 18 and 75 years with
extensive stage small-cell lung cancer were randomly
assigned to undergo prophylactic cranial irradiation
(irradiation group) or receive no further therapy (control
group).
 The primary end point was the time to symptomatic brain
metastases. CT or MRI of the brain was performed when
any predefined key symptom suggestive of brain
metastases was present.
 The two groups (each with 143 patients) were well
balanced regarding baseline characteristics.

Slotman et al, NEJM 2007

 Prophylactic Cranial Irradiation
 Patients in the irradiation group had a
lower risk of symptomatic brain
metastases (hazard ratio, 0.27; 95%
confidence interval [CI], 0.16 to 0.44;
P<0.001).
 The cumulative risk of brain metastases
within 1 year was 14.6% in the
irradiation group (95% CI, 8.3 to 20.9)
and 40.4% in the control group (95% CI,
32.1 to 48.6).

Slotman et al, NEJM 2007

• Irradiation was associated with an
increase in median disease-free
survival from 12.0 weeks to 14.7
weeks and a median overall
survival from 5.4 months to 6.7
months after randomization.

• The 1-year survival rate was 27.1%

(95% CI, 19.4 to 35.5) in the
irradiation group and 13.3% (95%
CI, 8.1 to 19.9) in the control
group.
QOL
Future Treatment Strategies
 Immunotherapy
Checkmate 451 (ASCO 2016)
 Ipilumumab and Nivolumab as second line and maintenance
therapy in patients with extensive stage disease
 Adult pts with ED-SCLC who achieve stable disease or
better after first-line PT-DC and have ECOG performance
status 0–1 are eligible.
 Pts with active central nervous system metastases,
autoimmune disease, or toxicities attributed to prior
anticancer therapy not resolved to grade ≤ 1 were
ineligible.
 Primary endpoints are overall survival and progression-free
survival.
Study Design
Checkmate 032
 Delta-Like Protein 3 (DLL3)
An atypical inhibitory Notch Ligand

Induced by the key neuroendocrine

transcription factor, ASCL-1
Aberrant cell surface expression in
>80% of small cell lung and large
cell neuroendocrine cancers
 On both cancer stem and tumor
cells, but not normal adult tissues

Not prognostic, and does not

predict response to chemo
Patients with progressive SCLC after at least 1 previous
systemic therapy were eligible.
Efficacy was assessed by the investigator via RECIST and
toxicity
when available, archived tumor tissue was assessed
retrospectively for DLL3 expression by
immunohistochemistry.
Single-agent activity in recurrent/refractory SCLC
 Comparable responses in second and third line
 Responses and survival improved vs. historical approved
treatments

First biomarker-directed therapy in SCLC

Manageable safety profile

Results justify further clinical development

 Summary
Most SCLC pts present with ED-SCLC.

Initial response rates are high, but disease often rapidly

recurs or progresses. While 50-70% of patients with ED-SCLC
respond to first line platinum-based doublet chemotherapy,
all patients ultimately relapse, most within the first year.
Outcomes with second-line treatment are poor.

Sadly not much has changed in the past decade in regards

to first line therapy, but new treatments such as
immunotherapy and antibody-drug conjugates show
promising results in the second line setting.
Thank you