Small Cell Carcinoma of Lung

1. Management of Small Cell Management of Small Cell
Carcinoma of LungCarcinoma of Lung
Moderator: Dr R Kapoor
Department of Radiotherapy
PGIMER
Chandigarh

2. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
IntroductionIntroduction
Accounts for approximately 20 -15% of all lung
cancers.
30,000 new cases occur in the United States
each year.
Important Biological and Clinical differences from
NSCLC.
Paradoxical combination of good response and
high relapse !!!

3. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Classification: WHO 1999Classification: WHO 1999
Primary epithelial lung cancers
Small Cell (Oat Cell Type) Non Small Cell type
●Squamous Cell carcinomas
●Adenocarcinomas
●Adenosquamous Carcinomas
●Large Cell Carcinoma
●Carcinoma with pleomorphic or sarcomatoid elements
●Carcinoid tumors
●Carcinoma of salivary gland type
Source: Brambilla et al The new World Health Organization classification of lung tumours Eur Respir J 2001;
18:1059-1068
“SCLC presents a proliferation of small cells
(<4 lymphocytes in diameter) with unique
and strict morphological features....”

4. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Relevant AnatomyRelevant Anatomy
Pair of air filled sacs
supplied by dual
vascular system.
The central location of
these tumors allows
easy access to the
mediastinal contents.

5. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Nodal AnatomyNodal Anatomy
Mediastinal Hilar
0%
20%
40%
60%
80%
100%
Data from Autopsy Series Kunz et al 1985

6. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Nodal DrainageNodal Drainage

7. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
EpidemiologyEpidemiology
Accounts for 10 -20% of all lung
cancers in males.
10-30% in women.
In India accounts for ~ 15% of
all lung cancers.
Commonly in a middle aged
smoker (5
th
- 6
th
decade in India)

8. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Cell of OriginCell of Origin
Believed to of neuroendocrine origin
Differs from Atypical Carcinoid in:
Higher mitotic rate
Fewer markers of neuroendocrine differentiation
Weak /no staining with markers: Synaptophysin and
chromogranin
SCLC occupies the most high grade portion of the spectrum SCLC occupies the most high grade portion of the spectrum
with max metastatic potentialwith max metastatic potential
Carcinoid Atypical Carcinoid SCLC

9. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
EtiologyEtiology
Incidence patterns mirror the
change in smoking patterns
in society
Lag period of 20 -50 yrs
noted.
Cause of up to 90% of cases
diagnosed.
Interaction with other
environmental carcinogens
possible e.g. Asbestos
Data from Annual Report to the Nation on the Status of Cancer,
1973-1996, With a Special Section on Lung Cancer and
Tobacco Smoking Wingo et al JNCI Journal of the National
Cancer Institute 1999 91(8):675-690;

10. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Clinical Features: Thoracic DiseaseClinical Features: Thoracic Disease
Local Symptoms Cough
Dyspnea
Chest Pain
Mediastinal InvolvementHoarseness
Retrosternal Chest pain
Vocal Cord Palsy
Horner's Syndrome
Superior Vena Caval Syndrome
Hemoptysis
Post obstructive Wheezing

11. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Hemaotogenous MetastasisHemaotogenous Metastasis
Limited Stage Extensive Stage
0%
10%
20%
30%
40%
50%
60%
70%
80%
38%
74%
32%
26%
31%
56%
14%
16%
32%
37%
8%
17%
Liver Adrenal Bone
Kidney Brain Pancreas
SCLC is
characterized by
it's propensity to
spread
systemically.
Usually
hematogenous
metastasis is the
norm.

12. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Clinical Features: Extrathoracic Clinical Features: Extrathoracic
Brain Metastasis:
Approximately 50% of SCLC
patients develop brain
metastases during the course of
their disease.
Presentation varies:
Discreet ICSOL(s)
Leptomeningeal infiltration
Unlike other metastasis Brain
mets are symptomatic in 90% at
presentation

13. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Clinical Features: Extrathoracic Clinical Features: Extrathoracic
Other Common sites of Metastasis:
Bone:
Commonly lytic lesions
Pain: Less as compared to lesions in NSCLC
No elevationNo elevation in Serum ALP or Ca
2+
.
Adrenals / Liver:
Clinically asymptomatic mets.
However elevation in hepatic transaminases
common.
Lungs:
Lymphangitis carcinomatosa: Cause of dyspnea

14. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Paraneoplastic SyndromesParaneoplastic Syndromes
Cancer Cachexia
Endocrinological Syndromes
Neurological Syndromes
Musculoskeletal Syndromes
Dermatological Syndromes
Hematological and Vascular
●SIADH
●Cushing Syndrome
●Gynecomastia / Galactorrhea
●Hyperthyroidism
●Acromegaly
●Eaton Lambert Syndrome
●Cerebellar Degeneration
●Opsoclonus-Myoclonus Syndrome
●Cancer associated Retinopathy
●Stiff Man Syndrome
●Hypertrophic Pulm. Osteoarthopathy
●Dermatomyositis
●Polymyositis
●Acanthosis Nigricans
●Bazex disease
●Erythema gyratum repens
●Scleroderma
●Anemia
●ITP
●Marantic Endocarditis
●Trousseau's Syndrome

15. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Tit-bits on some syndromesTit-bits on some syndromes
SCLC is the most common cause of SIADH.
MC presents with Hyponatremia
Diagnostic triad of :
Euvolemia
Hyperosmalar Urine
Hypoosmolar Blood
In patients with SCLC, approximately 5% develop
Cushing's syndrome – MC malignancy associated with
Cushing's Syndrome
Most lung neoplasms produce large amounts of ACTH
precursors – SCLC convert these into active ACTH
(ectopic)!!

16. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Neurological SyndromesNeurological Syndromes
Overall SCLC is the most common cause.
Origin – Autoimmune?
Antibodies to substances produced by tumors.
Several Types of Auto antibodies characterized:
Anti-HU (Sensory Neuropathy, Encephalomyelitis)
Anti-Yo (Cerebellar Degeneration)
Anti-Ri (Opsoclonus Myoclonus Syndrome)
Anti-VGCC (Lambert Eaton Syndrome)
Anti-Amphiphisin (Stiff Man Syndrome)

17. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Neurological Syndromes..Neurological Syndromes..
Lambert Eaton Syndrome:
Proximal weakness associated with
aches & stiffness.
Autonomic dysfunction – dry mouth
Ptosis and opthalmoplegia milder
than MG.
LEMS is usually diagnosed prior to
any clinical manifestation of the
tumor (2-5 yrs lag period).
2 times commoner in males
MC in ages 50 - 70 yrs.
MG
LEMS

18. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Neurological SyndromesNeurological Syndromes
Paraneoplastic cerebellar degeneration:
Abrupt onset of cerebellar symptoms
Loss of Purkinje cells.
Associated with encephalomyelitis
Sensory neuropathy:
Pseudo-obstruction of the bowel – best
characterized sensory neuropathy
Usually associated with SCLC.

19. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Investigative WorkupInvestigative Workup
To establish diagnosis:
FOB
FNAC
To stage the disease:
CXR
USG
CT
MRI /PET/Bone scan
To assess suitability for treatment:
Hemogram
Biochemistry : RFT

20. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Evolution of pathological classificationEvolution of pathological classification
Kryberg et alWHO WHO IASLC WHO
1962 1967 1981 1988 1999
Oat cellLymphocyte LikeOat Cell Small Cell Cancer Small Cell Cancer
Polygonal Intermediate
Polygonal Fusiform Mixed small / large cell
Others Combined Combined small / large cellCombined small / large cell
Intermediate category removed due to difficulty in identification
Intermediate category proposed to indicate a continuum from SCLC to NSCLC

21. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Gross PathologyGross Pathology
MC perihilar location (2/3
rd
) (<5%
peripheral)
Situated in a peribronchial location
Infiltration of the bronchial
submucosa and peribronchial
tissue
Bronchial obstructionBronchial obstruction: Due to
circumferential bronchial
compression.

22. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Microscopic pathologyMicroscopic pathology
Proliferation of small cell ( < 4
lymphocytes in diameter.
Finely granular "salt and pepper"
chromatin
Frequent nuclear molding
High mitotic counts
AzzopardiAzzopardi effecteffect: hemotoxyphilic
DNA crusting of the vessel walls.

23. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Combined SCLCCombined SCLC
Defined when at least 10%10% of the tumor bulk is made of an
associated non-small cell component.
Any cases showing at least 10% of SCLC is also diagnosed as
SCLC combined, even if the tumor has a heterogeneous
sarcomatous component
Therapeutic significance??! Possible better prognosis of the
combined variant as per recent literature.
Previous categories of mixed SCLC and intermediate SCLC
have been dropped as they were difficult to identify and had
little prognostic significance.

24. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Chest X raysChest X rays
Pleural
Effusion
Phrenic
Nerve palsy
Mass
Collapse

25. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
RadiologyRadiology
RADIOGRAPHIC FEATURE SQ. CELL (%) ADENOCA (%) SCC (%) LARGE CELL (%)
Nodule ≤4 cm 14 46 21 18
Peripheral location 29 65 26 61
Central location 64 5 74 42
Hilar/perihilar mass 40 17 78 32
Hilar adenopathy 38 19 61 32
Mediastinal adenopathy 5 9 14 10
Miller WE: Roentgenographic manifestations of lung cancer. In Strauss MJ (ed): Lung Cancer: Clinical Diagnosis and
Treatments, 2nd ed. New York, Grune and Stratton, 1983.

26. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
CT scanCT scan
Mass
Pleural
Effusion
Node
Necrosis
Mediastinal
Shift

27. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
StagingStaging
The VALSG (Veterans' Administration Lung Study
Group) is the most commonly used system
Devised by Zelen M in 1973
Depends on the ABILITY to safely encompass
the entire tumor in a single Radiation portal.
Untreated LD patients (median survival: 15.7
weeks) survived significantly longer than ED
patients (5.0 weeks).

28. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
VALSG DefinitionVALSG Definition
Limited disease patients are characterized by
Disease confined to one hemithorax, although local
extensions may be present;
No extrathoracic metastases except for possible
ipsilateral, supraclavicular nodes if they can be included in
the same portal as the primary tumor; and
Primary tumor and regional nodes which can be
adequately treated and totally encompassed in every
portal.
Extensive disease patients are inoperable patients who
cannot be classified as having limited disease.

29. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
VALSG vs ISALC : LDVALSG vs ISALC : LD
Point VALSG Definition ISALC Definition
Limitation
Local Extensions
Regional Nodes
√ One Hemithorax √ One Hemithorax
¿? Allows if can be encompassed
in one RT portal
X Does not define
X Nodes not defined but includ-
ed if encompassed in one RT
portal
√ Both ipsilateral and contralat-
eral mediastinal and hilar nodes
included in the definition
Supraclavicular
Nodes
√ Only ipsilateral allowed √ Both ipsilateral and contralat-
eral allowed
Ipsilateral pleural
effusion
X Not defined ? Allowed ? √ Allowed irrespective of cytologi-
cal positivity

30. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Controversies in StagingControversies in Staging
VALSG staging system devised in the pre-CCT era.
With the advent of modern imaging techniques reliance on
surgical staging of mediastinum probably not necessary
Certain factors fail to predict a poor prognosis with
modern therapy:
Ipsilateral Pleural effusion
Mediastinal adenopathy
Contralateral Supraclavicular adenopathy

31. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Prognostic FactorsPrognostic Factors
Performance status (ECOG 3 or 4)
Older age (> 65 years)
Metastatic sites: Liver, Bone marrow and bone
Cushing's Syndrome
Continued tobacco use during therapy
Increased pretreatment LDH (> 2 times increase)
CNS paraneoplastic syndromes (anti-HU antibody)
High VEGF/ bcl-2 / p -glycoprotein (MDR) expression

32. Management of SCLCManagement of SCLC

33. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Treatment OutlineTreatment Outline
SCLCSCLC
Stage
Localized Disease Extensive Disease
Radiation Therapy (Curative intent ?)
+
Systemic Combination Chemotherapy
Systemic Combination Chemotherapy
+
Palliative Radiation
+
Palliative Care and Support

34. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Radiation SensitivityRadiation Sensitivity
Source: Radiation Biology of Lung Cancer; Sullivan et al JCB supp24

35. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Radiation BiologyRadiation Biology
Group Example n
IClassic SCLC 0.76 -1.241.0-2.0
IILarge Cell / Variant SCLC0.76-1.54.6-17.7
IIIAdenocarciniomas 1.0-1.41.2-6.8
D
0
(Gy)
Low D
0
& SF
2Gy values imply the high radiosensitivity
n (extrapolation number) is also low – Implies that the capacity
to repair sublethal damage is limited
Low dose per fraction radiation schedules have potential here.
However due to the propensity of disseminated disease
sensitivity ≠ curability

36. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Role of Radiation therapyRole of 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

37. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Dose Time FractionationDose Time Fractionation
Principle:
Alleviate the symptoms arising due to the tumor
quickly.
Integrated with Chemotherapy with minimal delay
Intent of treatment decides the TDF issues
In patient with LD, good PFS and good response to
CCT
– 30 Gy in 10# with PCI
In patient with ED or LD with poor response:
–Poor PFS: 600 - 800 cGy in SF
–Good PFS: 20 Gy in 5 #

38. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Planning RT for Localized SCLCPlanning RT for Localized SCLC
Principles:
Adequate coverage of the 1° tumor : 1.5 – 2 cm
Adequate margins to account for respiratory
motion
Adequate coverage of draining nodes (1
st
echelon)
: 1 cm
Ensuring volume irradiated doesn't receive doses
exceeding tolerance.
Dose:
30 Gy/10 # in 2 weeks preferred in our institution
Energy : Co
60
or 4-6 MV photons

39. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Palliative RadiotherapyPalliative Radiotherapy
Principles:
Use high dose per fraction to achieve greatest cell kill in
shortest possible time.
Use smaller number of fractions to reduce burden on
facility, patient and relatives.
Use simple AP – PA portal for quick, accurate and
comfortable setup
Further boost RT can be tailored individually depending
upon the patients response and performance status.
Dose schedules:
30 Gy in 10#
20 Gy in 5#
800 cGy in 1 #

40. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Manual MarkingManual Marking
Upper lobe tumors:
Superior border is kept at the SSN
Medial border extends 3 cm across the midline on
the opposite side
A field of 12 x 12 is usually used.
Lower lobe tumors:
Superior border is kept at the level of the nipple.
Supraclavicular field:
A separate supraclavicular field can be placed with
a gap of 0.5 cm

41. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Guidelines for RT planningGuidelines for RT planning
Upper lobe tumors:
Ipsilateral SCF should be treated
Inferior margins kept 5-6 cm below the carina
Mediastinum should be taken into the field with 1 cm
margins
A margin of 2 cm given around the primary tumor
Lower lobe tumors:
Lower border should encompass the lower border of
mediastinum down to the level of the diaphragm
Gross mediastinal adenopathy is taken into the field but
SCF can be avoided

42. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Portal arrangementsPortal arrangements
Upper Lobe
Middle Lobe
Lower lobe

43. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Critical organs and dosesCritical organs and doses
TD 5/5 Volumes & Tolerance (Gy)
Organ whole
Lung 45 30 17.5
Heart 60 45 40
Esophagus 60 58 55
Spinal cord 50 50 47
Brachial plexus 62 61 60
1/3
rd
2/3
rd

44. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Results of Thoracic RTResults of Thoracic RT
Landmark trial by the MRC in UK(Miller et al
1969):
144 patients selected fit for radical Sx or RT
Mean survival was 23.5 weeks for Sx and 43
weeks for RT (p = 0.03)
5 yr survival 1% in the Sx group and 5% in the
radiation alone group
Sole survivor in the Sx arm had received RT.

45. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
ResultsResults

46. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Effect of palliative RTEffect of palliative RT
Symptom Frequency Improved Complete Relief
Cough 61 – 93 % 56 -65% 30 – 54%
Hemoptysis 31 – 47% 81 -86% 74 -82%
Dyspnea 50 – 54% - 37 -40%
Pain 42 – 57% 65- 74% 50 -52%
Atelectasis23 – 26% - 60 -62%
Hoarseness 20 - 25% - 50 -52%
Dysphagia 5 – 10% - -

47. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Changing Paradigms of RChanging Paradigms of R
x x
Paradigm 1 : Surgery as Standard Treatment
Paradigm 2 : Thoracic radiation better than Surgery
Paradigm 3 : Thoracic Irradiation with adjuvant Chemotherapy
Paradigm 4 : Combination chemotherapy with adjuvant Radiotherapy
Paradigm 5 : Integrated Chemotherapy and Radiation therapy

48. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
RT resultsRT results
2 yr survival 2 yr local control

49. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Is TRT needed?Is TRT needed?
Warde et al (JCO, 1992):
11 RCTs (published) included
Total patients 1911
Looked at 2 yr survival, local control and toxicity
Found that:
Overall benefit of adjuvant RT on OS is 5%
LC rate improved by 25.3%
1.2% increased chance of death due to Rx related
toxicities

50. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Is TRT neededIs TRT needed
Pignon metanalysis (NEJM , 1992):
Used updated patient data from investigators
Based on 2140 patients
Assessed 3 yr survival rates and prognostic
factors for survival
14% reduction in the mortality rates at 3 yrs
Absolute benefit in OS of 5.4%
Twice as better local control (48% vs 23%)
Survival difference greater for patients aged < 50
yrs.

51. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Is TRT neededIs TRT needed
Both meta-analysis have conclusively proved:
Addition of thoracic RT improves the OS by
approximately 5%
Reduces the risk of intrathoracic failures by 30% -
60%.
In addition both meta-analyses used trials prior to
the CE era so a more effective therapy has not
been evaluated.
The increased incidence of toxicity related deaths
is significantly reduced with modern Rx.
ConclusionConclusion: Addition Thoracic Radiation is definitely indicated in
Limited Stage SCLC both to improve LC and OS

52. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
?? Controversies ???? Controversies ??
Ideal treatment volume?Ideal treatment volume?
TDF issuesTDF issues
Sequencing with CCTSequencing with CCT
Role of PCIRole of PCI

53. Ideal VolumeIdeal Volume

54. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Deciding the treatment volumeDeciding the treatment volume
Controversies
How much of mediastinal / hilar nodes to be
taken ?
Whether supraclavicular nodes are to included?
Whether volume of irradiation is to pre-CCT
volume or post CCT volume?
Optimum portal design?

55. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Intrathoracic Volume IncorporationIntrathoracic Volume Incorporation
Perez et al : Reported on results of
SECSG on treatment of SCLC
using thoracic RT (1981)
69% of patients treated with
inadequate portals had intra
thoracic failures (w.r.t. 32.5%
treated with adequate portals)
Inadequate portals → failure to
include contralateral hilum or
mediastinum
Data from While J et al
Impact of Radiation
therapy quality control in
LC in SCLC
ConclusionConclusion: Failure to include opposite mediastinal and hilar nodes in
the treatment volume can lead to significant intrathoracic failures

56. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Post CCT or Pre CCT volume?Post CCT or Pre CCT volume?
21/5/1977
6/7/1977
26/8/1977
11/10/1977
26/10/1977

57. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Pre CCT vs Post CCT volumePre CCT vs Post CCT volume
Patients treated to the post-CCT tumor volume have equivalent
survival
51 weeks survival with pre CCT vol w.r.t. 46 weeks survival with
post CCT vol (SWOG study ; Kies et al JCO 1987)
Patients treated to pre CCT volumen will have same local control
rates
More than 80% of local failures were within the post CCT
irradiated volume (Brodin et al Acta Oncologica 1990)
Patients treated to the pre-CCT volume can have significant
pulmonary toxicity if they survive
Double incidence of pnuemonitis and leucopenia in patients
treated to pre-CCT volumes.(SWOG study ; Kies et al JCO 1987)
Some studies have found a lower CR rate in patients treated to pre
CCT volume (? artifact)
ConclusionConclusion: It is safe to irradiate only the post CCT volume.

58. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Portal DesignPortal Design
Simple AP – PA fileds are gold standard for irradiation of
SCLC
Customizing fields not usual as:
Most of the tumors are situated centrally so majority of
peripheral lung parenchyma can be avoided.
Customizing field apertures may result in tumor miss
Majority of major protocol violations in the study by white
et al were due to inappropiate shielding
Difficulty in compensating for complex respiratory motion
Customization probably too time consuming an effort for
patients who are unlikely to be cured
ConclusionConclusion: Customized portal designing is unlikely to add to control

59. Time, Dose & FractionationTime, Dose & Fractionation

60. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Dose and Fractionation of RadiationDose and Fractionation of Radiation
Dose, time and fractionation choice depend upon:
Tumor size and bulk
Nature of symptoms
Severity of symptoms
Patient performance status
Expected survival
Possibility of complications
Logistical factors
Patient supportive care available

61. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Dose of RadiotherapyDose of Radiotherapy
NCI reported a clear dose response:
25 Gy in 10 #
37.5 Gy in 15 #
Higher dose associated with a significant gain in
PFS
Arrigada et al did a trial on LD with 3 dose
schedules given by split course:
45 Gy: 5 yr survival 16%
55 Gy: 5 yr survival 16%
65 Gy: 5 yr survival 20% (p = N.S.)

62. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Altered Fractionation Altered Fractionation
Group Radiation protocol CCT Survival
36% 18% (5 yr)
52% 26% (5yr)
66%34% (3 yr))
65% 29% (3 yr)
Local
Control
Turrisi et
al (1999)
ECOG /
RTOG /
SWOG
45 Gy in 25 # in 5 weeks (n= 206)
with concurrent CCT in 1
st
week
4 x EP D1 -D3
x 3weekly
45 Gy in 30# over 3 weeks giving 2
fractions /day (n = 216) with concur-
rent CCT
4 x EP D1 -D3
x 3weekly
Bonner et
al (2000)
50.4 Gy in 28# over 5½ weeks with 2
cycles concurrent EP (n = 132)
3 x EP (NA) >
1 x EP (Adj)
48 Gy in 32 # over 3 weeks with 2
fractions per day and gap of 2 weeks
after 1
st
16#s (n = 130)
3 x EP (NA) >
1 x EP (Adj)
ConclusionConclusion: Altered fractionation with split course is not effective

63. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Continuous AF schemesContinuous AF schemes
ConclusionConclusion: Sadly Continuous AF is too toxic for routine use !!!

64. Sequencing with CCTSequencing with CCT

65. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Sequencing with CCTSequencing with CCT
Several techniques of sequencing possible:
Concurrent
Sequential
Alternating
Controversies that exist are:
Is concurrent better than the other models
What is the ideal time of giving RT with CCT

66. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
CRT protocolsCRT protocols
Concurrent:
Radiation is started along with 1
st
CCT cycle typically
between the D1 or D2 of CCT.
CCT administered as scheduled.
Weekly chemoradiation is not used as full therapeutic
doses of CCT need to be delivered.
Sequential:
RT is administered after completion of 3 -4 cycles of
chemotherapy. CCT is not delivered during RT
Additional cycles of CCT may be given after RT
Alternating:
RT is usually given in a split course and CCT is
administered between the treatment breaks.

67. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Concurrent vs Sequential CCTConcurrent vs Sequential CCT
Generally 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

68. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Why not Concurrent CRT?Why not Concurrent CRT?
Controversy still exists about relative superiority of CCRT
Impairment in delivery of both modalities a frequent
problem
Most of patients will present with ED
Even patients with LD will have:
Poor performance scores
Bulky disease
Poor pulmonary functions
Several co-morbidities
Incompliance with an aggressive regimen
CCRT has a high in treatment mortality ( 7 -10%) in
various series

69. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Alternating ChemoradiationAlternating Chemoradiation
Popularized in the 1980s due
to the toxicity of then
available CCT agents
precluding concomitant /
sequential approach
Largest trial by Gregor et al
(ECOG/LCCG)1997 (n = 349)
Poor local control and severe
acute hematotoxicity in the
study arm
Most patients failed within the
portal
ConclusionConclusion: Alternate CRT is inferior to sequential CRT

70. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Early vs Late Thoracic RTEarly vs Late Thoracic RT
Early betterEarly better:
Reduce chances of systemic metastasis
Reduce chances of appearance of chemoresistant
clones
Lower probability of radioresistance
Diminished accelerated repopulation
Late BetterLate Better:
Allows shrinkage of portals to a reduced tumor volume
Reversible resistance (Kinetic and epigenetic
resistance.)

71. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Timing of RTTiming of RT

72. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Timing of RTTiming of RT
Two meta-analyses have also been published on this
topic:
Fried et al:
Defined late RT as after 9 weeks after starting CCT
OS benefit of 5% at 2 yrs with early RT (p = 0.03)
Benefit with the use of Platinum based regimens only and with
the use of hyperfractionated regimens
Cochrane review:
Early RT defined as that started within 30 days of CCT
No significant benefit at 2 or 3 yrs with the use of early or late
CCT
But found a significant advantage in 5 yrs survival with the
use of early thoracic radiotherapy with the use of cisplatin
based CCT ; OR of 0.62 (p = 0.02)

73. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Timing of RTTiming of RT
ConclusionConclusion: Early Start of RT does lead to a better outcome

74. Role of PCIRole of PCI

75. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Role of PCIRole of PCI
Dr Heine Hansen suggested possible role of PCI
in 1973 extrapolating experience from Leukemias
Role believed to exist as:
SCLC has aggressive behavior like leukemia
It is very chemosensitive
Development of new CCT regimens in 70's lead to
increased expectations of cure
Development of brain mets was thought to be the most
important cause of failures if chemotherapy was to be
successful.
BBB was expected to be a impediment for disease
eradication from the CNS (sanctuary)

76. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Benefit from PCIBenefit from PCI
In order for PCI to be integrated with the regimen
it should fulfill certain basic requirements:
Solitary CNS relapse should be a significant
clinical problem
Systemic control should be maintained for a
prolonged period of time
Side effects from PCI should not overcome any
survival benefit
PCI should be effective in eliminating sub clinical
metastatic disease in the CNS
Demonstrable survival benefit should be present

77. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Meta-analysisMeta-analysis
A meta-analysis was
published in BMC by
Meert et al (2001)
12 trials included; 1547
patients
5 trials evaluated the
role of PCI in patients
who had attained CR
5 trials included only LD
stages

78. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Toxicity of PCIToxicity of PCI
Long term neurological toxicity difficult to evaluate
Jhosnson et al reported on 20 patients with
median F/U of 6 yrs
15 of 20 patients had some neurological
complaints and abanormalities
Another study by Laukkanen et al reported
memory loss in 60% of long term survivors of
SCLC who had received PCI

79. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Practice GuidelinesPractice Guidelines
PCI should be given in:
Patients with LD stage with radiological CR
Documented absence of brain mets ( pre PCI CT)
Good performance status to merit further treatment
Dose of PCI:
20 - 24 Gy in 10 – 12 # is the recommended dose schedule
Timing:
Should be administered 2-3 weeks after completion of
chemotherapy
How given:
Parallel opposing fields with energy of 4-6 MV / Co
60

80. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
SummarySummary
Ideal RT volume:
Incorporate B/L mediastinal nodes
Post CCT volume can be irradiated safely
Extensive portal customizations can backfire
TDF issues:
Conventional once daily RT is of choice
Integration with CCT:
Early start of RT is better
Concomitant CRT is more effective but also highly toxic
Role of PCI:
Can improve survival in small subgroup of patients

81. ChemotherapyChemotherapy

82. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
ChemotherapyChemotherapy
The chemosensitivity of SCLC was first identified
50 years ago with the recognition that CCNU
could effect tumor regression in 50% patients
Several agents have single agent activity
However:
Complete remissions are relatively infrequent
Remission durations tend to be brief
Combination therapy is known to produce superior
survival**

83. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Single Agent ChemotherapySingle Agent Chemotherapy
Drug Dose ORR SurvivalToxicity
Cyclophosphamide 12 -23% 17 weeks Myelosuppression
Ifosfamide
50% 43 weeks
Doxorubuicin
50% 26 weeks
Vincristine 40-50% Peripheral neuropathy
Vindesine 20-33%
Vinorelbine 10-20%
Cisplatin
5-30%
Carboplatin 60-80% Thrombocytopenia
Etoposide
20-50%
Teniposide
30-50%
Paclitaxel 30% 43 weeks
Irinotecan 47% Life threatening diarrrhea
Topotecan 40% 20-25 weeks
Gemcitabine 27% 12 months
1- 1.1g/m
2
1.2- 1.5 g/m
2
Transient confusion, hem-
orrhagic cystitis
60-75 mg/m
2
Cardio-pulmonary toxicity,
additive effect with RT
1.5 mg/m
2
3-4 mg/m
2
25-30 mg/m
2
60-120 mg/m
2
Nephrotoxicity, emesis,
neurotoxicity
300-400 mg/m
2
300-400 mg/m
2
Nausea, myelosuppres-
sion
300 mg/m
2
Nausea, myelosuppres-
sion
250 mg/m
2
100 mg/m
2
1.5-2 mg/m
2
1g/m
2

84. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Standard CCT regimensStandard CCT regimens
Regimen Drugs Dose Frequency
EP
Cisplatin
3 weekly
Etoposide
EP (oral)
Cisplatin
4 weekly
Etoposide oral 50 mg PO D1 – 21
CE
Carboplatin
4 weekly
Etoposide
IE
Irinotecan
4 weekly
Etoposide
CAV
Cyclophosphamide
3 weeklyAdriamycin
Vincristine
CAE
Cisplatin
3 weeklyAdriamycin
Etoposide
ICE Ifosfamide 3 weekly
Cisplatin
Etoposide
V- ICE
Vincristine 1 mg D15 4 weekly
Ifosfamide
Carboplatin
Etoposide
25 mg/m
2
D1 – 3
100 -120 mg /m
2
D 1- 3
100 mg/m
2
D1
300 mg/m
2
D1
120 mg/m
2
D 1 – 3
70 mg/m
2
D1, 8, 15
80 mg/m
2
D1 – 3
1 g /m
2
D1
40 mg/m
2
D1
1 mg /m
2
D1
50 mg/m
2
D1
45 mg/m
2
D1
50 mg/m
2
D1 – 5
1.2 g/m
2
D1 – 4
20 mg/m
2
D1 – 4
75 mg/m
2
D1 – 4
5000 mg/m
2
D1
300 mg/m
2
D1
120 mg/m
2
D 1,2 Oral 240 mg/m
2
D3

85. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Cisplatin based CCTCisplatin based CCT
CE is considered standard regimen.
CR rates
20-45% in LD
10-25% in ED
ORR 60- 70%
Median survival 10 – 12 months
Carboplatin is equivalent in therapeutic efficacy as shown
by a HCOG study (Median survival 11.8 months with ORR
of 70 -80%)

86. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Alternative CCT regimensAlternative CCT regimens
Single agent Topotecan:
One phase III trial reported by Shiller et al compared
Topotecan to CAV (n = 188)
Same ORR (21% & 15%) and survival (5.8 & 5.5 mo)
Better symptom control – however greater hematological
toxicity
However it has also been shown in a RCT by same author
that 4 cycles of Topotecan after 4 cycles of PE is not
superior to observation.
ConclusionConclusion: Single agent Topotecan fails to improve results over those
obtained by PE regimen in SCLC when used as 1
st
line approach

87. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Alternative ChemotherapyAlternative Chemotherapy

88. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Combination CCTCombination CCT
Active regimens yield objective response rates in the
range of 80% to 90%
Complete remissions occurring in 30 to 50% of patients
Median survival:
7 to 9 months in extensive-stage patients (3 yr OS ~
1%)
20 months in patients with limited disease.(3 yr OS ~
20%)
Best survival is achieved in good performance status
patients who present with limited-stage disease and who
receive combined modality therapy with chemotherapy
plus thoracic radiotherapy.

89. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Toxicity of CCTToxicity of CCT
Most common complication is severe
myelosuppression, which occurs in 25% to 30%
Rates increased to 75% with CRT
Cyclophosphamide-based therapy associated with
the highest incidence of neutropenia
Cisplatin plus etoposide generally represents the
least myelosuppressive regimen
Late complications (heard of but not seen!!)
Pulmonary fibrosis
Cardiac toxicity

90. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
More intensive CCTMore intensive CCT
The concept of MDTI
is analogous to that of
TCP/NTCP
It defines the
maximum tolerated
dose intensity
dose intensity refers to
dose in mg/m
2
/week
The plateauing of the
curve is important

91. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Alternative StrategiesAlternative Strategies
Dose intensification
Weekly Chemotherapy
Alternating Chemotherapy

92. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Dose intensificationDose intensification
Trial YearRegimen ORR Comments
63% 29.3 weeks79%
CAV standard53% 34.7 weeks40%
31% 41 weeksNA
CEV standard42% 58 weeksNA
CAV standard38% 55 weeksNA
Ihde et al EP standard 85% 12 months2%
EP escalated 81% 11 months25%
Median
Survival
Toxici-
ties
Jhonson et al
(SECSG) (n = )
1987
00%
CAV escalated
(65%)
Hong et al (n =
353))
1989
00%
CAV escalated
(Cyclo 2g)
In LD stage only
and established
superiority of CEV
1994
00%
Escalated by giv-
ing for 5 days
ConclusionConclusion: Dose intensification by 25 – 50% over the standard doses
fails to improve the survival but increases toxicity significantly

93. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Weekly ChemotherapyWeekly Chemotherapy
Trial YearRegimen ORR Comments
1994Weekly ID /CE 82% 10.8 mo ↑↑
81% 10.6 mo
1999CODE NA
CAV/EP standard NA
1994CODE + G-CSF 84% 12 months 19%
CAV/ EP Standard77% 11 months 8%
Median
Survival
Toxici-
ties
Souhami et al
(CRC UK) (n =
438)
Dose intensity
relatively more in
3 weekly armCAV/ EP alt 3 week-
ly
NCI / SWOG
(n = 219)
9% mortality in the
CODE arm.
NCI / SWOG
(n = 227)
3% patients in
CODE arm died
due to toxicity
ConclusionConclusion: Dose intensification by giving weekly CCT fails to improve
the survival but increases toxicity significantly

94. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Alternating CCTAlternating CCT
3 major trials have appeared:
Fukuoka et al (JNCI 1991)
Roth et al -SECSG (JCO 1992)
Evans et al – NCI (AIM 1987)
All the 3 trials failed to show any significant advantage of
alternate CAV/EP vs EP alone but did show that CAV
alone was inferior. (OS with CAV/EP 16.8 mo, EP alone
11.6 mo and CAV 8.0 mo)
ConclusionConclusion: Alternating non cross resistant CCT regimens failed to
improve results as compared to standard regimens

95. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Chemotherapy for recurrenceChemotherapy for recurrence
Selected patients may be treated provided:
Good performance status
Symptomatic relapse
Local control maintained
Time of relapse > 6 months
Desires further treatment
Response rates:
Vinorelbine: 14%
Irinotecan: 33%
Topotecan: 19%
Paclitaxel: 25%

96. SVCO in SCLCSVCO in SCLC

97. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
SVCOSVCO
Seen in 6-10% patients at presentation
60 -70% of the patients are non ambulatory with
poor performance scores
60- 70% have extensive disease
60 -70% have extrathoracic extension of disease
80% patients have moderate to severe SVCO
20% will die within 2 weeks of presentation

98. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Management of SVCOManagement of SVCO
Principle:
SVCO is a oncologic urgency but a medical
emergency.
The 1
st
goal is hemodynamic stabilization of the
patient to allow the patient to lie down in the
treatment couch.
Radiotherapy should be given in large doses per
fraction as:
Fast debulking is needed
Most patients have poor general condition – cant
tolerate fractionated regimens
Patients are suitable for palliative treatment alone.

99. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Management of SVCOManagement of SVCO
Step 1: Initial workup
Patient should be nursed in a sitting position as most have
orthopnea with Type I hypoxia
Anxiety allayed through proper explanation and medications
To alleviate respiratory distress:
Moist O
2
inhalation – high flow
Nebulization with β agonists + Steroids: Reduces
bronchospasm
Injectable Deriphyllin: Reduces bronchospasm
Injectable loop diuretics: Reduce edema, promotes diuresis
and relieves pulmonary congestion
Injectable steroids: Reduces airway edema.
Injectable antibiotics: In event of fever of significant cough

100. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Management of SVCOManagement of SVCO
Step 2: Monitoring
Regular checking of
Pulse
BP
Respiratory rates
Arterial O2 saturation (where available)
Patient assessment:
Reduction in edema
Ability to lie down
Reduced respiratory distress
Biochemical and hematological evaluation
Radiological assessment of disease as permitted by
patient's condition

101. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Management of SVCOManagement of SVCO
Further management in the event of the HP S/O
SCLC can be:
Chemotherapy
Radiotherapy
Chemotherapy can be used initially in patients who
are:
Young
Good performance status
Good response to medical therapy
XRT planned as a adjuvant in the subsequent
treatment.

102. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Radiotherapy in SVCORadiotherapy in SVCO
Position: Supine with head turned to opposite side
Superior border: Encompasses the ipsilateral SCF upto the
crico-thyroid junction
Inferior border: Taken 2 -4 cm below the carina
Medial border: 1 cm beyond the mediastinal shadow on
opposite side
Lateral border: 1.5 -2 cm margin from the lateral most
extent of tumor
Doses:
800 cGy in single fraction
2000 cGy in 5 fractions
3000 cGy in 10 fractions – least commonly used

103. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Response to RTResponse to RT

104. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Radiotherapy in SVCORadiotherapy in SVCO
Radiotherapy alone can result in:
●Immediate subjective improvement (< 3 d) in
60% patients of SCLC
●Early improvement in 90% patients
●70% patients will respond to RT alone
●Addition of CCT doesn't improve response or
survival
●CCT by itself results in a slight delay in
response

105. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Investigational AgentsInvestigational Agents
Matrix Metalloproteinase Inhibitors (Marimastat)
Important in cancer cell invasion, metastasis, and
angiogenesis.
Two phase III studies
NCI and EORTC
No difference in survival
Adversely impacted the quality of life
Tyrosine Kinase Inhibitors: (Imatinib mesylate)
Phase II study
19 patients treated : No observed responses !!

106. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Other agentsOther agents
Antibody based therapy
Anti sense BCL-2 oligonucleotide (Genasense)
BCL-2 inhibits apoptosis and might contribute to
chemotherapy resistance.
Anti sense oligonucleotides inhibit the translation of mRNA
Rudin treated 12 patients with refractory SCLC
No objective responses were observed
2 of the 12 patients had stable disease.

107. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Follow up GoalsFollow up Goals
To detect symptomatic*symptomatic* progression of disease.
Gathering outcomeoutcome data
Providing reassurance and psychological support.

108. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Follow up GoalsFollow up Goals
To detect symptomatic*symptomatic* progression of disease.
Gathering outcomeoutcome data
Providing reassurance and psychological support.

109. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Follow Up ProtocolFollow Up Protocol
History and Physical Examination*:
Every 3 months for 1 -2 years
Every 6 months for the next 5 years
Annually thereafter
Investigations Suggested:
Chest X-rays
Other expensive investigations are not cost
effective.

110. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
Follow up: Other IssuesFollow up: Other Issues
Detection of residual disease is not required after
complete radiological response to 1° therapy –
due to lack of effective R
x
in this scenario.
Smoking cessation useful in the small subset who
get complete response:
Can potentially delay recurrence
Can reduce 2
nd
cancers

111. Management of Small Cell Lung Cancers. Moderator: Dr Rakesh Kapoor
ConclusionsConclusions
Despite its sensitivity to radiation SCLC is
extremely frustrating to treat
The systemic nature of disease and fast growth
make it one of the most aggressive malignancies
known
Radiation therapy is an important part of the
therapeutic armamentarium
Systemic combination chemotherapy is the
mainstay of treatment but ineffective in the long
run.

112. Thank Thank
YouYou