Small cell lung

cancer

Prudhviraj masapu
Moderator : DrChandrasekar
 Introduction
• Most common cancer worldwide
– Estimated 1,600,000 new cases
– 1,380,000 deaths/year
– In the United States in 2011, approximately 28,000
patients were diagnosed with SCLC, constituting
approximately 13% of all lung cancer diagnoses

• The term lung cancer, or bronchogenic carcinoma,

refers to malignancies that originate in the
airways or pulmonary parenchyma.
 Small cell lung cancer
• Mostly caused by cigarette smoke. SCLC among all lung
cancer histologies has been decreasing, perhaps
because of smoking cessation and the proliferation of
low-tar cigarettes.
• Only 2% to 3% of patients with this malignancy are
never smokers
• Is a neuroendocrine tumor.
• Highly sensitive to chemotherapy and radiotherapy,
but recurrence is common.
• Exposure to asbestos, benzene, coal tar, and radon gas
• Improvement in 2- and 5-year survival in both
limited- and extensive-stage disease in recent
decades,
• The outcomes are still extremely poor, particularly
since the majority (approximately 60%) of patients
present with extensive-stage disease with an
expected 2-year survival of only 4%.
• Paradoxical combination of good response and
high relapse !!!
 Genetic Alterations Associated with Small
Cell Lung Cancer
Tumor Suppressor Genes  Protooncogenes 
RASSF1A  Myc 
FHIT  Bcl-2 
Retinoic acid receptor-beta  c-Kit 
p53  c-Met 
RB  IGF-1 
Telomeres TGF-B 
  G protein–coupled receptors
 Gross
Tumors are white-tan, soft, friable, and often
show extensive necrosis.
 Microscopic pathology
According to the World Health Organization lung
cancer classification of 1999-a malignant
epithelial tumor consisting
• one of the small, round, blue cell tumors (along
with neuroblastoma, rhabdomyosarcoma
• Scant cytoplasm.
• Ill-defined borders.
• Finely granular "salt and pepper" chromatin.
• Absent or inconspicuous nucleoli.
• Frequent nuclear molding.
• A high mitotic count. mitotic rate is
characteristically high, averaging 60 to 80 per 2
mm SQUARE
• Crush artifact is a frequent finding in small
transbronchial or mediastinal biopsy specimens
and can make pathologic interpretation difficult
 IHC
• pancytokeratin antibody such as AE1/AE3 is
useful to confirm if the tumor is a carcinoma
• Neuroendocrine differentiation can be
demonstrated using a panel of markers such as
CD56, chromogranin, and synaptophysin
• A high proliferation rate of 80% to 100% should
be seen with Ki-67.
• Thyroid transcription factor-1 (TTF-1) is positive
in 70% to 80%
• Grading criteria
Grade  Histology  Conventional Nomenclature 
Low-grade NE Ca <3 mitotic figures x 10 hpf Carcinoid tumor
Absent necrosis

Intermediate- >3 but <10 mitoses x 10 hpf Atypical carcinoid

grade NE Ca Necrosis

High-grade NE Ca    

Small cell type >10 mitoses x 10 hpf Small cell carcinoma

Necrosis
Large Cell NE Ca > 10 mitoses x10 hpf Large cell NE Ca
Necrosis
 Clinical Presentation
• Presenting symptoms in patients with SCLC can be constitutional,
pulmonary, the result of extrathoracic spread, or due to
paraneoplastic disorders.
• fatigue was the most common
• Hemoptysis was noted in 14%
• Superior vena cava obstruction is present at diagnosis in 10%
• SCLC is a rapidly growing and aggressive tumor.
• No more than 2% of SCLC present as a superior sulcus tumor

• Patients develop symptoms over a short period of time and are

usually diagnosed within 3 months from onset of symptoms.
 symptoms at presentation are worsening of
cough, shortness of breath and dyspnoea.

• Others- chest pain, hoarseness, malaise,

anorexia, weight loss, hemoptysis.

• Hemoptysis and postobstructive pneumonia are

relatively uncommon due to the submucosal
growth pattern of the tumor.
• Spread to the mediastinal lymph nodes is a
hallmark of SCLC, and syndromes resulting
from mass effect are commonly seen.
• Most patients with SCLC have metastases at
diagnosis
• Brain metastases can be detected in at least
18% of patients at diagnosis
Paraneoplastic syndrome
• SCLC accounts for approximately 75% of the tumors
associated with the syndrome of inappropriate
antidiuretic hormone (SIADH).
• Tolvaptan, an oral vasopressin V2-receptor antagonist,
has been shown to significantly improve serum sodium
in patients with SIADH over a 4- and 30-day period
• Increased serum levels of adrenocorticotropic
hormone can be detected in up to 50% of patients with
lung cancer, but Cushing syndrome develops in only 5%
of patients with SCLC
• Paraneoplastic neurologic disorders seen in patients with SCLC include
sensory, sensorimotor, and autoimmune neuropathies and
encephalomyelitis
• Symptoms may precede the diagnosis by many months and are often
the presenting complaint
• Subacute peripheral sensory neuropathy associated with the anti-Hu
antibody may be the most frequent paraneoplastic neurologic disorder
seen in those with SCLC
• Less common is the Lambert-Eaton syndrome, characterized by
proximal muscle weakness
• The occurrence and severity of the neurologic symptoms is unrelated to
tumor bulk and usually does not resolve with antineoplastic therapy.
 Staging

Staging Systems
• American Joint Committee on Cancer (AJCC)
Tumor, Node, and Metastasis (TNM). 8th
edition
• Veterans Administration Lung Study Group
(VALG).
• International Association for the Study of Lung
Cancer (IASLC).
• Limited-stage disease : SCLC is confined to the
hemithorax of origin, the mediastinum, or the
supraclavicular nodes, which can be encompassed
within a tolerable radiation therapy port.

• Extensive-stage disease : SCLC has spread beyond the

supraclavicular areas and is too widespread to be
included within the definition of LD. Patients with
distant metastases (M1) are always considered to have
ED.
• Patients with pleural effusion, massive pulmonary
tumor, and contralateral supraclavicular nodes
have been both included within and excluded from
LD by various groups BUT STILL continued in LD
• Analyses of two large cooperative group
databases, which included over 4,000 patients,
showed that the survival of individuals with an
isolated effusion was similar to that of patients
with extensive disease
 T-descriptor
Every cm counts…
Proposed (TNM 8th) Previous (TNM 7th)
Up to 1 cm: T1a T1a
>1-2 cm: T1b T1a
>2-3 cm: T1c T1b
>3-4 cm: T2a T2a
>4-5 cm: T2b T2a
>5-7 cm: T3 T2b
>7 cm: T4 T3
Rami-Porta R, J Thoracic Oncol, 2015
International Association for the Study of Lung Cancer, 2015
T – Primary Tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without evidence
of main bronchus
T1a(mi) Mininally invasive adenocarcinoma
T1a Tumour 1 cm or less in greatest diameter
T1b Tumour more than 1 cm but not more than 2 cm
T1c Tumour more than 2 cm but not more than 3 cm
T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features:
Involves main bronchus (without involving the carina), invades visceral pleura, associated with
atelectasis or obstructive pneumonitis that extends to the hilar region
T2a Tumour more than 3 cm but not more than 4 cm
T2b Tumour more than 4 cm but not more than 5 cm
T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following:
chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s) in the
same lobe as the primary
T4 Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina;
separate tumour nodule(s) in a different ipsilateral lobe to that of the primary

International Association for the Study of Lung Cancer, 2015

 N-descriptor
No changes in the TNM 8th Edition…

Exploratory subgrouping (for future validation)

- N1a: Single N1
- N1b: Multiple N1
- N2a1: Single N2 (skip metastasis)
- N2a2: Single N2 + N1
- N2b: Multiple N2

Asamura H et al. J Thoracic Oncol, 2015, in press

International Association for the Study of Lung Cancer, 2015
 M-descriptor
• M1a: as it is
• M1b: single metastasis in a single organ
• M1c: multiple metastases in a single organ or
in several organs

Eberhardt W et al. J Thoracic Oncol, 2015, in press

International Association for the Study of Lung Cancer, 2015
N – Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene or supraclavicular lymph node(s)

M – Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastases in one or several organs

International Association for the Study of Lung Cancer, 2015

STAGE T N M
Occult TX N0 M0
0 Tis N0 M0
IA1 T1a(mi)/T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a-T2b N1 M0
T3 N0 M0
IIIA T1a-T2b N2 M0
T3 N1 M0
T4 N0/N1 M0
IIIB T1a-T2b N3 M0
T3/T4 N2 M0
IIIC T3/T4 N3 M0
IVA Any T Any N M1a/M1b
IVB Any T Any N M1c

International Association for the Study of Lung Cancer, 2015

8th Edition of the TNM Classification for Lung
Cancer
N0 N1 N2 N3 M1 M1 M1c
a b
T1a IA1 IIB IIIA IIIB IVA IVA IVB
T1b IA2 IIB IIIA IIIB IVA IVA IVB
T1c IA3 IIB IIIA IIIB IVA IVA IVB
T2a IB IIB IIIA IIIB IVA IVA IVB
T2b IIA IIB IIIA IIIB IVA IVA IVB
T3 IIB IIIA IIIB IIIC IVA IVA IVB
T4 IIIA IIIA IIIB IIIC IVA IVA IVB

International Association for the Study of Lung Cancer, 2015

 Survival
• Limited disease :16-24 months
• Extensive disease: 6-12 months
• Without treatment SCLC: 2 to 4 months
 Investigative Workup
• To establish diagnosis:
– FOB
– FNAC
• To stage the disease:
– CXR
– USG
– CT Chest, abdomen(liver, adrenals)
– MRI Brain/CT Brain
– PET/Bone scan- For patients with limited-stage disease, bone scan and bone
marrow aspiration or biopsy are indicated if the lactic dehydrogenase is
elevated, and thoracentesis is indicated if pleural effusion is present.
• Blood investigations
– Hemogram
– Biochemistry : RFT, LFT
– S.LDH
Unilateral iliac crest bone marrow aspiration and biopsy are still a routine part of staging for
many oncologists and should be performed in limited-stage patients with elevations of serum
lactate dehydrogenase (LDH

. Carcinoembryonic antigen (CEA) has been found to predict outcome in SCLC in multiple series
 Treatment
Limited-stage disease -CT+ Thoracic RT(preferred)
-Combination CT
-Lobectomy+/- mediastinal node
dissection or sampling followed by CT or CRT

-Prophylactic cranial irradiation

Extensive-stage disease -Combination CT(preferred)
-Radiotherapy
- Prophylactic cranial irradiation
Recurrent disease - Chemotherapy
- Palliation therapy
 Chemotherapy
• Chemotherapy improves the survival of patients
with limited-stage disease or extensive-stage
disease , but it is curative in only a minority of
patients.
• With incorporation of current chemotherapy
regimens into the treatment program, however,
survival is prolonged, with at least a fourfold to
fivefold improvement in median survival compared
with patients who are given no therapy.
• The combination of platinum and etoposide is the most widely used
standard chemotherapeutic regimen.

• Adjuvant chemotherapy is recommended for those who have

undergone surgical resection.

• No consistent survival benefit has resulted from- 1.platinum versus

nonplatinum combinations 2.increased dose intensity or dose
density
3. altered mode of administration (e.g., alternating or sequential
administration) of various chemotherapeutic agents
4.maintenance chemotherapy.
• Relapsed SCLC: Topotecan
 Radiation therapy
Curative:
– With Chemotherapy in localized SCLC
Palliative:
– For palliation of symptoms due to primary growth
– In SVCO
– For palliation of bone mets
– For palliation of brain mets
Preventive:
– For prophylactic cranial irradiation
• SCLC is highly radiosensitive and thoracic
radiation therapy improves survival of patients
with LD and ED tumors.
• For LD :45 Gy ,1.5Gy /#,in 3 weeks twice daily
61.2 Gy in 5 weeks RTOG 0239
60-70 Gy once daily regimen
• GTV + 1.5 cm
• Ipsilateral hilar region+mediastinum
( from thoracic inlet and includes subcarinal region)
• If Subcarinal involvement (+), inferior border is 5
cm below carina
• No contralateral hilar region and supraclavicular
lymphatics are included within RT portal if not
involved.
 Chemotherapy and radiation therapy

• Combined-modality treatment with etoposide and cisplatin with

thoracic radiation therapy is the most widely used treatment for
patients with limited-stage disease SCLC.
• Fried et.al early start of radiotherapy
• Evidence (combined modality treatment):
Survival
– Mature results of prospective randomized trials suggest that combined-
modality therapy produces a modest but significant improvement in
survival of 5% at 3 years compared with chemotherapy alone.
– Clinical trials have consistently achieved median survivals of 18 to 24
months and 40% to 50% 2-year survival rates with less than a 3%
treatment-related mortality.
A meta-analysis of thoracic RT in LD-SCLC

12 phase III studies

Pignon et al NEJM 1992

 Concurrent vs Sequential CCT
• accepted that concurrent
chemoradiation is better than
sequential chemoradiation.
• Takada et al (2002): JCOG
– Used CE
– RT dose 45 Gy in 30# @ 1.5 Gy per
fraction bid over 3 weeks
– Median survival improved from 19
months to 27 months
Length of treatment:
•  The optimal duration of chemotherapy for
patients with LD SCLC is not clearly defined
• No improvement exists in survival after the
duration of drug administration exceeds 3 to 6
months.
• Maintenance chemotherapy does not prolong
survival for patients with LD SCLC
• Dose and timing.
 The optimal dose and timing of TRT remains
controversial.
– Multiple clinical trials and meta-analyses with the
weight of evidence suggesting a small benefit to
early TRT .
– In an analysis of four trials, the completion of
therapy in less than 30 days was associated with
an improved 5-year survival rate .
– Both once-daily and twice-daily chest radiation
schedules have been used in regimens with
etoposide and cisplatin.
– Esophagitis was increased with twice-daily
treatment.
– Twice-daily radiation therapy has not been broadly
adopted. Once-daily fractions to higher doses of
greater than 60 Gy are feasible and commonly
used; their clinical benefits are yet to be defined in
phase III trials.
 Prophylactic cranial irradiation

• Patients who have achieved a complete remission

can be considered for administration of PCI.
• Patients whose cancer can be controlled outside
the brain have a 60% actuarial risk of developing
central nervous system (CNS) metastases within 2
to 3 years after starting treatment
• The risk of developing CNS metastases can be
reduced by more than 50% by the administration
of PCI.
• Not performed in patients with poor
performance status or impaired
neurocognitive functioning.
• Dose: 25 Gy /10#
Role of PCI:
• A meta-analysis of seven randomized trials evaluating the value of PCI in
patients in complete remission reported improvement in brain recurrence,
disease-free survival, and OS with the addition of PCI. The 3-year OS was
improved from 15% to 20% with PCI.

• A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete

remission after chemoradiation therapy demonstrated that standard-dose
PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses
of brain radiation.

• Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that

doses higher than 25 Gy in 10 daily fractions do not improve long-term
survival.
 SCLC - Meta-analysis of PCI
From 7 randomised trials of PCI vs no-PCI

Patients 987 (140 patients had ED-SCLC)

Chemo- & RT schemes various

Overall survival benefit +5% (95% CI: 1 -10%)

3 year survival 21 vs 15%

Incidence of brain mets 33 vs 59%

Auperin et al. NEJM 1999

 Very limited stage disease
• Stage I(T1-2,N0) , mediastinal staging to be
ruled out for involved mediastinal nodes
before resection
• Lobectomy is preferred
• Adjuvant RT(without nodal mets) or
chemoRT(with nodal mets) is recommended.
SCLC metastasis.
• Liver (27%)
• Bone (41%)
• Adrenals (31%)
• Brain (14%)
• Lymph nodes mediastinal (80%)
 Prognostic factors
• Poor performance status
• Extensive stage disease
• Weight loss
• Raised LDH
 Follow up

1-2 years 3-5 years >5 years

3-4 months Every 6 months annually

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