Small Cell Lung Cancer

Treatment guidelines

By
Osama Elzaafarany, MD
Assistant lecturer of clinical oncology
Medical research Institute
Alexandria University, Egypt.
July 2014
Incidence

• Approximately 15% of bronchogenic

carcinomas.
• In the year 2013, an estimated 31.000 new
cases will be diagnosed at USA.
• Nearly all cases are attributed to cigarette
smoking. Smoking cessation: reduce
risk of death in SCLC by 50%
according to ESMO guidelines

‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013.
CA Cancer J Clin. 2013 Jan;63(1):11-30.
 Natural history & prognosis:

 Small-cell lung cancer (SCLC) originates from

neuroendocrine-cell precursors.
 Rapid doubling time, high growth fraction.
 Early development of widespread
metastases.
 High response rates to both chemotherapy and
radiotherapy.
 SCLC is the most common solid tumor associated
with paraneoplastic syndromes: SIADH, ACTH
production syndrome, and Eaton-Lambert
syndrome.
 Usually relapses within two years despite
treatment (2ys DFS~10%), and most of
patients die from recurrent disease.
 Development of treatment resistance in patients with
metastatic disease.
 Without treatment: median survival from
diagnosis is 2 - 4 months.
 ~ 30 % presented by limited disease.
 10-15% of patients present with brain
metastases and 2 year incidence after chemo-
RT is 50–80%.
 Median survival after recurrence ~ 4 ms.
 Limited Extens.
stage stage
MS ~ 20 ms ~ 12 ms

5-ys OS ~ 25 % ~ 10 %

Response to treat. ~ 90 % ~ 70 %

Complete Response ~ 50 % ~ 20 %

 Brain mets: 50 %.
 Bone Mets: 40 %.
 Liver mets: 25 %.
 Staging:

Veterans Administration Lung Study Group:

• Limited stage (LS):
disease confined to one hemithorax and
regional nodes (historically defined as fitting into
a single radiation port)
• Extensive stage (ES):
any disease not meeting limited stage criteria
AJCC TNM staging system:
Limited stage:
 Stage I-III.
 Exclude:
• T3-4 with multiple lung nodules.
• T3-4 with tumor/nodal volume that does not fit in
tolerable radiation plan.
Extensive stage:
 Stage IV.
 T3-4 with multiple lung nodules.
 T3-4 with tumor/nodal volume that does not fit
in tolerable
 Standard of care

Limited stage Advanced stage

CCRTx PCI
CTx

• CTx:
25Gy/10 Fx
Cis-VP16
X 4 cycles.
• RTx:
45Gy/3w; (1.5Gy BID).
Start Rtx. With or
cycle 1-2 of CTx. 60-70Gy: (2Gy/Fx).
 Evidence based medicine

Line of treatment Evidence

Why Cisplatin-VP16 ? Phase III trial from Norway.
Why not CEV? JCO, 2002

Is the concurrent CTx-RTx Japanese Oncology Group trial,

better than the sequential ? Phase III, JCO, 2002.

Why 45Gy/ 1.5Gy BID? ECOG/RTOG trial,

NEGM, 1999.

PCI benefit? Meta-analysis, NEGM, 1999

• Head to head trial of Cis-Vepsid VS CAV
failed to show survival advantage.

• But, it seems that Cis-VP16 is better

tolerated and has good responses.

• NCCN recommend Cis-VP16 as the

standard of care.
 Benefit of RTx:

CTx alone VS CTx-RTx.

was shown in a 2 meta-analyses:
(Pinon et al, NEGM, 1992).
(warde et al, JCO, 1992):

5 % improvement of 2-ys OS
 Cis-VP16
VS
CEV

MS 2-ys OS 5-ys OS
Cis-VP16 15 ms 14% 5% P=0.0004
CEV 10 ms 6% 2%

No statistical difference in toxicity

Limited disease Extensive disease

Overall survival
Japanese Clinical Oncology Group trial-9104
JCO, 2002.

Concurrent 4 X EP + RTx.
with first-second cycle of CTx.
231 pts.
Limited stage
Sequential 4 X EP then RTx.

“RTx was 45Gy/3ws;

1.5Gy BID.”

Results:
• Significant increase of MS with concurrent arm.
• Increase haematologic toxicity with concurrent arm.
MS 5-ys OS Sever esophagitis
Concurrent 27 ms 24 % 9%
Sequential 20 ms 18 % 4%
 ECOG/RTOG trial, NEGM-1999
Intergroup 0096

Twice daily 45Gy/ 1.5Gy BID

412 pts. With concurrent

Limited stage Cis-Vepsid
Once daily 45Gy/ 1.8 Gy daily

– RTx to begin with 1st CTx cycle

– PCI given for all patients with clinical CR after completion; (25
Gy/10).

 Median survival= 23 ms with twice daily VS 19 ms with

once daily RTx. P=0.04

 5-Year OS = 26% for twice daily VS 16% in once daily .

 Higher incidence of G3-4 esophagitis with twice daily
 Criticism of Intergroup 0096 trial:
“45Gy BID not biologically = 45Gy once daily.”

being tested in
an ongoing
randomized
phase III trial
(Cancer and
Leukemia Group
B [CALGB]
30610/RTOG
0538).
 Prophylactic cranial irradiation
(PCI)
• Meta-analysis: (Auperin et al, NEGM,
1999):
 25 % decrease in 3-ys incidence of brain mets.
 Benefit was similar in both limited and
extensive stage SCLC.
Indications:
• CR or PR to CCRTx.
• Limited or extensive stage.
ESMO-2013 guidelines when there is no progression after CCRTx.
• Recommended dose:
• 25Gy/10 Fx; (NCCN, ESMO guidelines).
• 30Gy/10 Fx
Do not give doses > 30Gy
Do not give > 3Gy/Fx.
• Do not give PCI:
• Low PS.
• Age > 60 ys.
• Impaired nuero-cognitive functions.
• With CTx.
 Surgery in SCLC
• Only 5% of cases.
• For Stage I: (T1-2 + N0).
• Biopsy to confirm –ve mediastinal LNs.
• Type: lobectomy.
• Adjuvant CTx is recommended after complete
excision. (if –ve LNs.), add RTx to chemo If +ve LNs.
• 5 years OS= 40-60%.
• Most data are retrospective.
• Only one retrospective study by LCSG (chest, 1994)
show no OS benefit, but this study had only 19% of
patients with stage I !!
 Irinotecan
• Irino-cis VS Cis-VP16:
 Survival benefit in a Japanese phase III trial:
13 ms vs 9.5 ms (NEGM, 2002).
 Failed to show survival benefit in 2 phase III
American trials.
 PFS improved in a meta-analysis, J Thoracic
Oncology, 2010 (not used individual pts data).

• More GI toxicity.
 Role of maintenance therapy:

• Phase III trial, JCO, 2001.

• Adding Topotecan after 4-6 cycles of Cis-VP16.
• No survival benefit.
• Minor prolongation of the duration of response.
• Increase of cumulative toxicity.
 Dose intensity:

• No survival benefit in randomized trials.

• Excessive treatment-related mortality.
• Meta-analysis, JCO, 1991:
 Compare standard VS dose-intense CTx.
 CAV and Cis-VP16.
 Small insignificant increase in median survival in
extensive disease.
 Avastin
• Limited Stage:
 Phase II.
 Irino-Carbo-Avatin.
 Closed early dt increase T-E fistula.

• Extensive disease:
 Phase II, SALUTE trial, JCO-2011.
 Add to Cis/Carbo-VP16
 PFS = 5.5 ms.
 Ongoing phase III trial of add Avastin to
CTx.
 Topotecan as second line
• Topotecan VS CAV:
 Phase III trial, JCO, 1999.
 Same survival.
 Less toxicity with Topotecan.
• Topotecan VS BSC:
 Phase III trial, JCO, 2006.
 Oral.
 Improved OS (26 ws VS 14 ws).
• NCCN guidelines:
 Category 1: relapse > 3 ms.
 Category 2A: relapse < 3 ms.
 Similar toxicity of Oral and IV forms.
 Amrucibin

• Active relapsed and refractory SCLC (2nd line).

• Associated with common G 3-4 toxicity;
(Neutropenia).
• phase III trial, JCO, 2011 (abstract):
 Compared to Toptecan as second line.
 No difference in OS.
When treating metastatic disease:

 Better to give Carbo-VP16.

 4-6 cycles.
 If CR of metastatic site, consider
RTx to thorax: (ongoing CREST trial).
 SCLC in elderly patients:
• Under-presented in clinical trials.
• Similar prognosis as stage-matched younger
pts.
• Attention to support body systems.
• VP16 as single agent is inferior to combination
CTx.
• Prefered: 4 X Carbo-VP16
 Better results.
 Declining renal function with aging.
 AUC = 5.
 Radiotherapy
• High-dose volume to GTV + 1.5 cm margin.
• Include ipsilateral hilum, and bilateral mediastinum from
thoracic inlet to subcarinal region (5 cm below carina or
adequate margin on subcarinal disease).
• Exclude contralateral hilum or SCV unlessinvolved.
• If RT is preceded by chemotherapy, target volumes
should be defined on the RT planning CT scan.
However, the prechemotherapy originally involved lymph
node regions should be included.
Localized disease: