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Small Cell Lung Cancer

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
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
 ectopic ACTH production- Cushing’s syndrome
 Eaton-Lambert Myasthenic syndrome
 proximal muscle weakness that improves on repetition
 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
 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
 Limited Stage:
 Median OS: 14-24 months
 5-yr OS: 20%
 Extensive Stage:
 MedianOS: 6-11 months
 5-yr OS: 2%
Limited vs. Extensive stage
Limited stage
Extensive stage
1 out of 3 people with
2 out of 3 people with
Only in one lung and
perhaps in lymph nodes
on the same side of the
To other lung, to lymph
nodes on the other side
of the chest, or to
distant organs
confined to an area
Wide spread
chemo-radiation ± PCI
Chemotherapy ± PCI
Lung Cancer (small cell) Overview. American cancer society.
http://www.cancer.org/cancer/lungcancer-smallcell/overviewguide/lung-cancer-small-celloverview-staging Accesed july 9,2014
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
 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
 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
 Quality-of-life assessments revealed no
major differences between the randomized
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
 Randomized trials have suggested similar efficacy of
cisplatin and carboplatin in patients with small cell lung
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
 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
 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
 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).
 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
 (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
 Primary end point was overall survival (OS). Secondary end
points were quality of life (QOL) and complete response (CR)
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
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 combinedtherapy 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 nonsequential 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 combinedtherapy 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
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
 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
 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; logrank 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.
 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 platinumbased combination
I.K. Demedts et al Eur Respir J 2010
Thoracic Radiotherapy for ES
 Most patients with extensive stage small-cell lung cancer (ESSCLC) 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
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, 2year 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
 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 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 =
 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 (logrank 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 treatmentfree 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
 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;
 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
Future Treatment Strategies
 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
 Primary endpoints are overall survival and progression-free
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
 when available, archived tumor tissue was assessed
retrospectively for DLL3 expression by
 Single-agent activity in recurrent/refractory SCLC
 Comparable responses in second and third line
 Responses and survival improved vs. historical approved
 First biomarker-directed therapy in SCLC
 Manageable safety profile
 Results justify further clinical development
 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 EDSCLC 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