Limited-Stage Small Cell
Lung Carcinoma:
Overview with Focus on
Management
John M. Watkins, M.D.
Medical University of South Carolina
Department of Radiation Oncology
Background

Small Cell Lung Cancer

15-20% of primary lung neoplasms
• Decreasing incidence



Classically large, central mass
Rapid growth
High metastatic potential (liver, adrenals, bone,
bone marrow, brain).
Classification

WHO (old classification)




Oat cell
Intermediate cell
Combined oat cell (with SqCC or adenoCA)
WHO/IASLC (1999)



Classical SCLC (most common)
Large cell neuroendocrine
Combined small-cell (predominant SCLC with
areas of NSCLC)
Histopathology

Diagnosis by light microscopy often sufficient:




Small “blue” malignant cells
Sparse cytoplasm
Finely dispersed chromatin without nucleoli
High mitotic rate, necrosis common
Histopathology

Immunohistology

Epithelial
• keratin
• epithelial membrane Ag

Neuroendocrine*
• NSE
• chromogranin A
*Pre-requisite for dx of large cell neuroendocrine but not small-cell.
Genetic Features
p53: mutated in 75-90%
 9p LOH: 90%
 Rb: loss of transcripts (60%) or
abnormal gene product (40%)
 Telomerase: activated in 90%
 c-kit: up-regulated in 80-90%
 k-ras: mutation rare (unlike NSCLC)

Staging

VA Lung Study Group
Limited (60-70%): primary/nodal
disease confined to ipsilateral
hemithorax, within a single radiotherapy
port
 Extensive (30-40%): metastatic disease
outside the ipsilateral hemithorax


IASLC: Limited (M0) vs extensive (M1)
Lung Cancer 2002;37:271
Work-Up


H&P
Chest, liver, adrenal CT


Head MRI (or CT)



Adrenal 17% FN rate by CT
CNS mets in 20-30% overall; 15% detection in
asymptomatic pts
Bone Scan
+/- Marrow Bx

Involved in 15-30% at presentation, but solitary
metastatic focus in only 2-6%
Am J Roentgenol 1983;140:949
J Neurooncol 2000;48:243
Cancer 1989;63:763
Work-Up

Role of PET (and PET/CT)
Not presently reimbursable for staging
SCLC
 Small retrospective studies at present:

• 4-11% upstaged
• Management change in ~15%
• RT nodal coverage changed in 25%
Clin Lung Cancer 2008;9:30
Radiol Clin N Amer 2007;45:609
Work-Up

Tissue Diagnosis
Trans-Bronchial vs CT-Guided
Approach
 Core Biopsy vs FNA
 Pleural Effusion

Prognostic Factors



Performance Status
Weight Loss
Stage





Early Limited > Limited > Extensive
Within extensive, number of involved sites
LDH (elevated = adverse)
Gender (women>men)
Paraneoplastic syndrome (adverse)
Treatment Paradigm

Interventions
Surgery (early)
 Chemotherapy
 Radiotherapy
 Surgery (recent)

Outline

Background






Classification
Histopathology
Genetic Features
Staging Review
Work-Up
Prognostic Factors

Management




Early Studies
Chemotherapy
Radiotherapy
Surgery
SHAMELESS
PLUG
Limited Stage SCLC:
Early Role of Surgery

1960s: MRC (n=144, randomized)

Limited-Stage: Resection vs RT
• Minimal active chemotherapy at the time


Similar poor outcomes (1-yr surv ~20%)
Resection out of favor with improvements
in chemotherapy, advancements in
radiotherapy
Lancet 1973;2:63
Limited Stage SCLC:
Chemotherapy


Due to systemic nature of SCLC, chemotherapy
is considered an essential intervention
SCLC is very chemo-responsive, with response
rates 80-90% for limited stage; however, very
rarely sustained (median 6-8 months)



Upon recurrence, median survival 4 months
cCR ~50% in limited stg, ~15-25% extensive stg
cCR controversial prognostic indicator; pooled
European trial data suggests cCR and KPS were
independent predictive factors for survival >2yrs
Cancer 2000;89:523
Chemotherapy
Regimens

Cisplatin / Etoposide (EP)

Demonstrated equivalent survival to CAV (or
CEV) chemo or EP/CAV alternation in extensive
stage disease
• EP/RT superior survival to VEC/RT in limited-stage

Most clinicians favor EP in order to avoid
adriamycin-associated toxicities concurrent with
XRT
JCO 1992;10:282
JNCI 1991;83:855
JCO 2002;20:4665
Limited-Stage SCLC:
Radiotherapy

Why XRT?



~80-90% eventual local failure with chemo alone
cCR may improve long-term survival… so add RT to boost
cCR rates
CALGB (Perry; n=399)




ChemoRT (cyc 1) vs ChemoRT (cyc 4) vs Chemo
Chemo = cyclophos/etoposide/vincristine q3wk x18mo
(adria replaced etoposide every other cycle after cycle 6)
RT = 40 Gy to primary, mediast, bilat s-clavs + 10 Gy
boost (also PCI to all pts, concurrent w/chemo)
Results: ChemoRT regimens improved cCR, FFF, OS
NEJM 1987;316:912
Limited-Stage SCLC:
Radiotherapy

META Analysis (Pignon, 13 randomized trials):


2103 evaluable patients, mdn survivor f/u 43 months
Improved survival of 5.4% at 3yrs for chemoRT over
chemo alone.
• Benefit more apparent in younger patients (RR 0.72 for age
<55y vs 1.07 for >70y)

Unable to discern benefit of “early” (w/in 60 days of
chemo start) vs “late” RT initiation, or sequential vs
concurrent.
NEJM 1992;327:1618
Limited-Stage SCLC:
Radiotherapy

Timing of XRT: JCOG 9104 (Takada):


231 pts w/LS-SCLC
Concurrent vs Sequential:
• Cis/Etopo q3-4wk x4cyc, 45 Gy @ 1.5 Gy/fx BID w/cyc 1 vs
after cyc 4

Trend improved survival for concurrent chemoRT
• Median Surv: 27.2 vs 19.7 months (p=0.097)
• Increased leukopenia in concurrent, similar esophagitis
JCO 2002;20:3054
Limited-Stage SCLC:
Radiotherapy

Timing of XRT: META Analysis (Huncharek):



1574 evaluable patients, 7 of 8 trials used platinum-based
chemo regimen (3 cisplatin-etoposide alone)
Evaluation of 1-, 2-, and 3-year overall survivals of patients
treated with early (cycle 1-2) vs late (>3 cycle, or sequential,
or split) radiotherapy concurrent with chemotherapy.
Outcome: Early initiation results in 50-60% relative
improvement in 3-year survival
Oncologist 2004;9:665
Limited-Stage SCLC:
Radiotherapy

Radiotherapy Dose / Fractionation

Present Acceptable Regimens
• Daily: 50 – 70 Gy @ 2 Gy/fx once daily
• BID: 45 Gy @ 1.5 Gy/fx twice daily
• Concomitant Boost: 61 Gy @ 1.8 Gy/fx,
BID over final 9 days
Limited-Stage SCLC:
Radiotherapy

Rationale:

Linear cell kill even at low doses
• No shoulder = minimal DNA repair capability

Pilot studies demonstrate efficacy &
tolerability of BID chemoRT
• 2y OS - 40%
• Gr 3 esophagitis: ~35-40%

Smaller fraction size should spare late
toxicity
Limited-Stage SCLC:
Radiotherapy
NEJM 1999;340:265
Limited-Stage SCLC:
Radiotherapy

Design:



Limited Stage SCLC
Chemotherapy: Cisplatin (60 mg/m2) + Etoposide (120
mg/m2), q3wks x 4 cycles
Radiotherapy: 45 Gy delivered @ 1.8 Gy/fx daily (5 wks)
versus 1.5 Gy/fx BID (3 wks)
• RT begins with cycle 1
• Fields: gross tumor, ipsi hilar, bilat mediast
• Ipsi S-clav only if clinically involved
• Inf border ~5cm below carina (or ipsi hilum); otherwise,
1-1.5cm to block edge
• Megavoltage linacs only (no Cobalt)
• PCI (whole brain) given 25 Gy @ 2.5 Gy/fx if cCR
Limited Stage SCLC:
BID vs Daily RT

Eligibility






SCLC limited to one hemithorax +/- ipsi s-clav
No pleural effusion (regardless of cytology)
Bone scan, bilat BM bx neg
Labs: plt (>100k), WBC (>4k), Cr (<1.5)
FEV1: >1L
Stratification



ECOG 0-1 vs 2
Gender
Wt loss past 6 mo (<5% vs >5%)
Limited Stage SCLC:
BID vs Daily RT

Enrollment





No Major differences
Majority ECOG PS 0-1
Rare s-clav at pres’n
Majority whites
Majority <5% wt loss
Limited Stage SCLC:
BID vs Daily RT

Toxicity

Higher Gr 3
esophagitis for BID,
o/w no diff
Limited Stage SCLC:
BID vs Daily RT

Clinical Response Rate

No difference between BID /
QD
Limited Stage SCLC:
BID vs Daily RT

Outcomes

At mdn f/u 8y (min 5y)
• 5y OS

26% BID vs
Patterns of Failure
• Thoracic failure
~35% BID vs ~50% QD
• Local + Distant
~5% BID vs ~25% QD

Subgroup Analysis
• Worse PS & male
gender assoc with
worse px
16% QD
Limited Stage SCLC:
BID vs Daily RT

Issues:
 Increased toxicity
• Requirement of elective mediastinal nodal radiotherapy?
• Identifiable factors associated with severe esophagitis?

Suboptimal local control
• Was 45 Gy in daily fractionation a sufficient comparative
arm?
• Increased thoracic failures in QD arm
• Reduction of thoracic failure is primary benefit of XRT;
with chemo alone, ~90% local failure!!
• Benefit of higher dose?
• Benefit of increased dose intensification?
• Other treatment-related factors impacting loco-regional
control in BID group?
Limited Stage SCLC:
RT Volume

Role of Elective Nodal RT (De Ruysscher)


Phase II Study (prospective)
RT Targets: Primary Tumor & +LNs (by CT)
• 45 Gy @ 1.5 Gy BID (w/cyc 1-2)
• Carbo/etopo chemo x5cyc

At median f/u 18 months, isolated nodal failure in
3/27 (11%)
• All ipsilat supraclav! None mediastinum
• Grade 3 esophagitis in 8/27 (30%)
• “The safety of selective nodal RT… should not be
extrapolated to patients with LD-SCLC until more data
are available”
Radiother Oncol 2006;80:307
Limited Stage SCLC:
Esophagitis
Predictors of Severe Acute Esophagitis from
Twice-Daily Thoracic Radiotherapy and
Concurrent Chemotherapy for
Small-Cell Lung Cancer
John M. Watkins, M.D.
Medical University of South Carolina
Department of Radiation Oncology
Charleston, South Carolina, U.S.A.
Oral presentation at the 90th Annual Meeting of the American Radium Society, Laguna Niguel,
California: 3 May 2008. Manuscript submitted to Int J Radiat Oncol Biol Phys, 13 Jun 2008.
Objectives
In SCLC patients undergoing twice-daily RT
with concurrent platinum-based
chemotherapy, describe:
– Severe Acute Esophagitis (RTOG Grade >3)
Incidence
Treatment Delays (attributable to toxicity)
Associated Factors (Patient-, Tumor-, Treatment-,
and Dosimetric-Related)
Design
Retrospective cohort descriptive series
– Medical University of South Carolina
– Ralph H. Johnson Veterans’ Affairs Medical
Center (Charleston, SC)
Design
Inclusion Criteria:
– Limited- or Extensive-Stage SCLC
– Concurrent chemoRT with twice-daily RT at 1.5
Gy per fraction
– Completion of >42 Gy
– CT-based treatment planning (3D
reconstruction)
– Treatment conducted at MUSC
Design
Exclusion Criteria:
– Treatment break >5 days (unless due to
esophageal toxicity)
Machine maintenance, holidays considered treatment
breaks
– RT at another institution/facility
– Insufficient post-chemoRT follow-up
Minimum 3 months post chemoRT completion
Methods
Retrospective analysis of QA Database
– June 1999 through June 2007
Definitions
– Severe Acute Esophagitis: RTOG Grade >3
Grade 3: Severe odynophagia requiring feeding
tube, intravenous fluids, hyperalimentation, +/>15% weight loss
Grade 4: Complete esophageal obstruction,
ulceration, fistula, or perforation
Grade 5: Death due to esophagitis
http://www.rtog.org/members/toxicity/acute.html
Methods
Definitions & Statistics
– Stepwise univariate logistic regression analyses of
potential associated factors
– Secondary multivariate analysis for significant &
marginally significant factors (multiple logistic
regression model)
Methods
Definitions & Statistics
– Variables analyzed:
Age (</>65yrs,
continuous)
Gender
Race
Tobacco Use (Active)
Tumor Site
Tumor Size (Max;
</>3cm,
continuous)
Number of beams
Elective mediastinal
irradiation
Days RT start to
completion
Esophageal volume
Mean esophageal dose
Esophageal Dosimetry
(Relative Volume)
– Area Under Curve
– Dose Thresholds
(V5V45)
Study Population
Patient Characteristics
– 48 patients included; median post-RT survivor
follow-up 25.8 months (range 2.7-83.0)
n
%
Age
Median 63.5 yrs
(Range) (47-82)
% >70 yrs
14 29.2
Gender
Male
64.6%
31 64.6
White
89.6%
43 89.6
Race
Active Tobacco
Use
19 39.6
Study Population
Tumor Characteristics
n
Primary Tumor
Location*
Right
Left
Primary Tumor
Size$
Median 4.5cm
(Range) (1-11)
%
22 51.2
21 48.8
n
%
Hilar Lymph Nodes
Ipsilateral
41
Bilateral
3
85.4
6.3
Mediastinal Lymph
Nodes
Ipsilateral 26
Bilateral 8
54.2
16.7
Supraclavicular
Lymph Nodes
Ipsilateral
12.5
6
*Of 43 patients, excluding 2 mediastinal primaries and 3 with indeterminate
location by records.
$By maximal dimension, of 41 patients with recorded data.
Study Population
Radiotherapy Characteristics
n
%
RT Days
RT Delay
RT Dose Completed
Median
(Range)
2
(1-10)
45 Gy
(42-51)
%
Number of
Beams
Median 22 days
(Range) (18-34)
Median
(Range)
>4 days
n
23
47.9
7
14.6
3 16
4 22
5 9
6* 1
Field Volume$
IL Mediast
BL Mediast
IL SClav
BL SClav
8
6
3
2
33.3
45.8
18.8
2.1
16.7
12.5
6.3
4.2
*Initiated RT with AP/PA, changed at ~9 Gy to 6-field.
$IL=ipsilateral, BL=bilateral, Mediast=mediastinum, SClav=supraclavicular.
Study Population
Chemotherapy Characteristics
n
Regimen*
CE
CbE
%
12 12.2
36 87.8
Cycles*
Median
4
(Range) (2-6)
>4 cycles
36 87.8
*Of 41 pts with chemo data; CE=cisplatin/etoposide; CbE=
carboplatin/etoposide. Prior to concurrent therapy, one patient received paclitaxel
with CbE for 3 cycles and another changed from CbE after 1 cycle of CE.
Study Population
Dosimetric Characteristics
– 47 patients with contoured esophageal
volumes and mean/maximal esophageal
doses
Esophagus
n=47
Volume
Median
(Range)
39.3 cc
(10.3-123)
Dose
Mean
19.7 Gy
(Range) (5.3-30.8)
Maximum
45.6 Gy
(Range) (27.1-51.4)
Study Population
Dosimetric Characteristics
– 38 patients with dose-volume histograms.
Relative Volume
V5
V10
V15
V20
V25
V30
V35
V40
V45
Median
Range
58.8%
54.5%
52%
47.2%
45.8%
40.8%
37%
33%
8%
(28-90%)
(25-84%)
(3-81%)
(0.5-79%)
(0-78%)
(0-77%)
(0-75.5%)
(0-73%)
(0-58%)
Results
Acute Toxicities
– All 48 patients evaluable
RTOG Grade
<2
3
Esophageal
37
11
(77.1%) (22.9%)
Pulmonary
46
(95.8%)
1
(2.1%)
4-5
0
(0%)
1
(2.1%)
Results
Univariate Analysis
OR
p-value
95% CI
OR
p-value
95% CI
Gender
0.353
0.1388
0.0889-1.402
1.543
0.5514
0.370-6.426
0.083-8.251
Mediastinal
Coverage
Race
0.825
0.8699
Age*
1.027
0.4718
0.955-1.104
RT Time
0.953
0.7065
0.743-1.222
Age >65
1.971
0.3280
0.506-7.682
Dose
0.888
0.9938
0 - >100
Tobacco Use
0.492
0.3471
0.112-2.157
Esophageal
Volume
0.987
0.5223
0.949-1.027
Tumor Laterality
1.5
0.7388
0.138-16.269
Tumor Size
1.204
0.1865
0.914-1.584
Mean Esophageal
Dose
1.003
0.0017
1.001-1.005
Tumor Size
>3cm
5.474
0.1291
0.609-49.710
Maximal
Esophageal Dose
1.000
0.7152
0.998-1.003
Number of
Beams
0.880
0.7989
0.328-2.359
RV-AUC*#
1.304
0.0037
1.090-1.559
*Continuous variable. #RV-AUC=Relative Volume-Area Under Curve.
Results
Multivariate Analysis
– Only RV-AUC remained significant:
RV-AUC
OR
p-value
95% CI
1.303
0.0037
1.090-1.559
Results
Association of Relative Volume by
Absolute Dose Threshold
Grade 0-2 Grade 3
p-value
OR*
95% CI
V5
0.49
0.72
0.0052
3.179456
1.390-7.275
V10
0.43
0.67
0.0038
3.497436
1.471-8.317
0% vs 48%
V15
0.41
0.65
0.004
3.691932
1.488-9.157
for V15
V20
0.375
0.62
0.0039
3.098413
1.417-6.777
</>50%
V25
0.345
0.59
0.0042
2.935947
1.383-6.231
V30
0.33
0.57
0.0053
2.310791
1.266-4.217
V35
0.305
0.551
0.0043
2.349635
1.292-4.274
V40
0.275
0.525
0.004
2.469511
1.318-4.629
V45
0.06
0.115
0.1192
1.474251
0.896-2.426
*Odds ratio for a change of 10% (of patients experiencing grade 3 toxicity).
Conclusions
Twice-daily thoracic radiotherapy at 1.5 Gy
per fraction with concurrent chemotherapy is
associated with ~25% risk of severe acute
esophagitis (RTOG grade 3).
Relative volume dosimetric parameters were
statistically significantly associated with
grade 3 toxicity.
– V15 as suggested surrogate within present series.
Limited Stage SCLC:
Fractionation
Survival Comparison of Dose-Optimized
Once Versus Twice-Daily Radiotherapy
with Concurrent Chemotherapy for
Limited Stage Small-Cell Lung Cancer
John A. Fortney, M.D.
Medical University of South Carolina
Department of Radiation Oncology
Charleston, South Carolina, U.S.A.
Poster presentation at the 90th Annual Meeting of the American Radium Society, Laguna Niguel,
California: 3 May 2008. Manuscript in progress for submission to Lung Cancer.
Methods
Single institution retrospective cohort comparison of
limited-stage SCLC patients treated with curative-intent
concurrent chemoradiotherapy.
Compare toxicity and survival outcomes of BID RT to 45
Gy at 1.5 Gy per fraction vs QD RT to >59 Gy at 1.8-2 Gy
per fraction.
Overall survival comparison between the two RT cohorts
(log-rank test).
Patients received all RT at a single institution with
concurrent platinum-based chemotherapy.
Results
Between 1994 and 2007:
– 72 limited-stage SCLC patients were identified for inclusion into the
present study
55 treated with twice-daily (BID) RT
17 treated with once-daily (QD) RT
– Treatment groups balanced by patient, tumor, and treatment
characteristics.
Results
At a median survivor follow-up of 22.9 months (range 5.7-84.9), 40
patients have died.
Estimated 1-, 2-, and 3-year overall survivals for the entire population at
were 76.4%, 46.0%, and 38.9%, respectively, with a median survival of
22.7 months.
– No statistically significant difference in overall survival was detected
between the BID and QD cohorts (median 22.7 vs 22.2 months,
respectively; p=0.603 by log rank). No difference DSS, FFF, LRFFF.
Conclusions
The present retrospective cohort comparison did
not detect a statistically significant difference in
overall survival, disease-specific survival, freedom
from failure, or loco-regional freedom from failure
between patients receiving BID RT to 45 Gy vs QD
RT to >59 Gy with concurrent chemotherapy.
While BID RT remains a proven standard, further
prospective study of higher-dose and/or doseintensified RT is warranted.
Limited Stage SCLC:
BID vs Daily RT

Ongoing investigations:

CALGB 30610 

CONVERT
• Cis/Etopo (25/75 mg/m2, d1-3) q4wk x4-6cyc
• RT: init d22 (cyc 1)
• 45 Gy BID vs 66 Gy QD
• Accrual Target: 532
Oncologist 2007;12:1096
Limited Stage SCLC:
BID vs Daily RT
Oncologist 2007;12:1096
Limited-Stage SCLC:
Role of Surgery
Limited Stage SCLC:
Role of Surgery

Renewed interest in resection for
solitary pulmonary nodule (SPN)
SCLC
4-12% of SPNs
 ~4% of SCLC presents as SPN, more
likely to be variant histology


Impressive survival in pooled analysis of
resected SPN SCLC: 5y OS 40-53%

Majority received post-rsxn chemotherapy
Chest 1992;101:225
Limited Stage SCLC:
Role of Surgery

Mayo Clinic (n=77)
Pneumonectomy (2), bilobectomy (3),
lobectomy (28), sublobectomy (34), hilar
bx (10)
 Mediastinal LND (50), sampling (19)
 At mdn f/u 19mo, 5y OS 38% for stage I-II
 Post-op chemo (3) or chemoRT (40)

Mayo Clin Proc 2006;81:619
Limited Stage SCLC:
Role of Surgery

Induction ChemoRsxn (n=260, review
of 9 trials)
Chemo Response ~90%
 60% of pts went to resection

• Complete resection in 80% of these (50%
overall)
pCR in 10% (majority with some residual)
 5yr OS ~70% for pT1N0 disease

Comp Text Thorac Oncol W&W;Baltimore 1996:439
Limited Stage SCLC:
Role of Surgery

Induction ChemoRsxn (n=328,
LCSG)

CAV x 5cyc, then re-stage & randomize:
• Resection + RT & PCI
• RT & PCI

66% response; 146 pts randomized:
• 70 rsxn (58 attempted rsxn, 54 completed)
• 76 no rsxn

No difference survival (2yr OS ~20%)
Chest 1994;106;(6 suppl):320S
A bit about PCI…
Role of Prophylactic Cranial
XRT

Incidence of CNS Mets




~50% for all SCLC; as high as 80% at 5y post-Tx
Elective PCI (WBRT) decreases risk to <5%
Meta Analysis showed 5% survival benefit @ 3y
Typical dose 30-35 Gy @ 2-2.5 Gy/fx
• Ongoing RTOG 0212 trial comparing:
• 25 Gy @ 2.5 Gy/fx daily
• 36 Gy @ 2 Gy/fx daily
• 36 Gy @ 1.5 Gy/fx BID
Prophylactic Cranial
Irradiation

Meta analysis demonstrated ~5% OS
benefit at 3y in pts with CR
Prophylactic Cranial
Irradiation

Survival Benefit: 3y OS 20% PCI vs 15% no PCI
NEJM 1999;341:476
Prophylactic Cranial
Irradiation

Survival Benefit: 3y OS 20% PCI vs 15% no PCI
NEJM 1999;341:476