2. INCIDENCE AND ETIOLOGY
15-20% of lung cancer with decreasing incidence
SEER Database-Shows proportion of SCLC cases decreased in US from 17 to 13% in
last 30 yrs.
97% cases- TOBACCO Exposure
Indoor Radon exposure -2nd cause lf lung cancer in USA.
Other RISK FACTORS
Asbestos
Arsenic
Polyclinic Hydrocarbons
5. SMALL CELL Poorly
differentiated
cells,from NE cells
Male smokers Central Produce ADH or
ACTH
SCC Keartin pearls or
intercellular bridges
M.C tumor in male
smokers
Central May produce
Adenocarcinoma Glands or mucin M.C tumor in non
smokers and
females
Peripheral
Large Cell Poorly
differentiated large
cells
Smokers Central or
Peripheral
Poor prognosis
BAC Columnar cells –
grow along
preexisting alveoli
or bronchioles
Not related to
smoking
Peripheral Good prognosis
Carcinoid Tumor WD,arises from NE
cells
Not related to
smoking
Forms a polyp like
mass in bronchus
Good prognosis
Pathological Types Of Lung Cancer
6.
7. HISTOLOGY
SCLC-Arises from NE precursor cells
”Klutchisky cells”
According to WHO Classification of 1999-A
malignant epithelial tumor
Scanty cytoplasm
Ill defined borders
Fine granular salt and pepper chromatin
Absent or inconspicuous nucleoli
Frequent nuclear molding
High mitotic count
9. GENETIC ABNORMALITIES
P53 MUTATIONS-75 -98%
Loss of RB1 gene function at 13 q14
MYC family amplifications---Tumors with these amplification are sensitive with
Aurora Kinase inhibitors, evaluated in clinical trials
Activation of telomerase
Upregulation of wild type c-kit and its ligand stem cell factor
Loss Of PTEN
10. NSCLC vs SCLC
Generally cytology is reliable for diagnosis of NSCLC,but difficult in SCLC
IHC used are
SCLC- TTF_1 positive
CK 3,4 +ve
p63 –negative
NE Markers-Chromogranin, synaptophysin, NSE, Neural Cell adhesion
molecules
11. CLINICAL PRESENTATION
Typically arises in central airways, infiltrating the submucosa –narrowing the bronchial
lumen through extrinsic or endobrochial spread
M.C-Large hilar mass with bulky LAP
Causing Cough
Hemoptysis ,weight loss
Metastasis to –Liver
Adrenals
Brain
Bone and bone marrow
12. Clinical Features- Extrathoracic
Brain Metastasis
Approximately 50% of SCLC develop brain
metastasis during the course of their disease
Presentation varies
Discrete ICSOL
Leptomeningeal infiltration
Brain metastasis are symptomatic in 90% at
presentation.
13. Clinical Features-Extrathoracic
BONE-Commonly lytic lesions
No elevation in s.ALP or s.Ca2+
ADRENALS/LIVER
Usually asymptomatic
Elevation of transaminases
LUNGS
Lymphangitis carcinomatosa- Can cause dyspnoea
19. FDG PET
Helps in Staging work up
More accurate in detection of mediastinal
LN
Detects extrathoracic metastasis
Differentiates benign from malignant
Sensitivity-90%
Specificity-94%
20.
21. SMALL CELL CARCINOMA-STAGING
THE VALSG[Veteran’s Administration Lung Study Group] is the most commonly
used system
Devised by Zelen M in 1973
Depends on the ABILITY to encompass the entire tumor in a single Radiation
portal.
22. VALSG-LIMITED STAGE
Disease confined to one hemithorax,although
local extensions may be present
No extrathoracic metastasis except for possible
ipsilateral’supraclavicular nodes if they can be
same portal as the primary tumor
Primary tumor and regional nodeswhich can be
adequately treated and encompassed in every
portal.
EXTENSIVE STAGE
Disease exceeding the above boundaries
Organs within a curative radiation portal cannot
safely tolerate curative radiation doses
So Malignant pleural effusion,B/L pulmonary
involvement,cardiac tamponade are included in
extensive disease
70% of all SCLC
32. <5% Of patients present
in very early stage
All standard evaluation
must be considered
befre surgery
Negative pathological
mediastinal staging is
mandatory prior to
surgery
All node negative
patients should undergo
adjuvant chemotherapy
alone
Node positive patients
should undergo adjuvant
chemoradiotherapy
35. NCDB STUDY
CONCLUSION
In this population based analysis, patients with
T1-T2 NoMo SCLC treated with SBRT regimens
incorporating chemotherapy had comparable
survival outcomes to concurrent
chemoradiotherapy using standard
fractionation.
Addition of Chemotherapy significant
improved OS independent of RT regimen
delivered and it is being underutilised in SBRT
patients
Treatment paradigms of T1-T2NoMO SCLC
using SBRT warrant further exploration and
should incorporate chemotherapy as clinically
tolerated
Materials and Methods
Accural from 2004-2015
T1-T2 No patients treated with a curative
intent with SBRT [BED10
of 72-180Gy in <_10 fractions]
OR
CFRT [Delivered daily or or twice daily,45-
70Gy]
With or without Chemotherapy
Chemotherapy must have been initiated
within 21 days prior to RT administration
or up to 14 days after completion of RT
42. The Meta analysis by Pignon et.al examined the question of timing of thoracic
irradiation(sequential,alternation,and concurrent) and no statistically significant
differences were found.
However,3/4 trials that showed a significant survival advantage for combined
modality treatment used a concurrent or alternating scheme
where as
Seven out of nine trials that did not show a survival advantage used a
sequential plan
45. CONCLUSION: SAFER TO TREAT THE POST
CHEMOTHERAPY VOLUME
CONCLUSION:SAFER TO TREAT THE POST CHEMOTHERAPY VOLUME
46. DOSE,TIME AND FRACTIONATION
SCLC is highly radiosensitive,suggesting that hyperfractionation could be
employed to reduce late normal tissue toxicity
Since it has high proliferation rate,arguing for accelerated treatment to
counteract repoplulation
50. CONCLUSIONS
Study powered to show superiority of RT OD if 2 yr OS was 12% higher than RT
BID, which it did not
2YR OS rate :51% for OD vs 56% for BD; absolute difference of 5.3%
No significant difference in mOS for RT OS vs BD
25 months for OD vs 30 months for BD
Similar toxicity between groups
51.
52. CONTINUOUS AF
SCHEMES
CONTINUOUS AF IS TOO
TOXIC FOR DAILY USE
CURRENT NCCN RECOMMENDS
60-70GY IF OPTING FOR DAILY
TRTEATMENT,BUT DOES NOT
VOICE A PREFERENCE RELATIVE
TO THE BID REGIMEN
54. Concept of chemo radiation package was discussed by Peters and Withers in
relation to head and neck cancers
Similar to this, delay in RT leads to tumor repopulation in LSCLC owing to its
aggressive behaviour.
This concept has been statistically evaluated by De Ruyscher et.al from
Netherlands and Overall treatment time could be a major determinant of tumor
outcome in LSCLC
Performed a systematic review and identified SIX Phase III RCT like Turrisi
et.al,Murray et.al etc –SER was the most important predictor of outcome.
Significant 5 YR OS in short SER Arms and more when SER <30 DAYS
56. CONCURRENT VS SEQUENTIAL CCT
Generally accepted that concurrent CRT is better
than sequential CRT
To evaluate the optimal timing of Thoracic RT
TAKADA ET.AL,2002
Cis /Etoposide -4 cycles
TRT-Dose of 45 Gy/15 days,BD at 1.5Gy/#
Delivered on D2 of 1st Ct in CRT arm and after
4th cycle in sequential arm
57. IMPORTANCE OF TIMING OF TRT IN THE COMBINED MODALITY
TREATMENT OF LSCLC,Murray et.al
308 patients
CT: CAV alternating with EP Q3 weekly 3 cycles
RT: 40Gy/15#/ 3weeks to the primary site
Early Thoracic Irradiation-Within 1st cycle of EP
Late Thoracic Irradiation-With last cycle of EP
After completion of CT+RT,patients without progressive disease will receive
PCI 25Gy/10#
58. RESULTS
EARLY THORACIC IRRADIATION
Leads to better PFS and OS
LATE TI:Higher risk of Brain metastasis
Complete remission rate:Not significantly different between two treatment arms
Early administration of Thoracic Irradiation in the combined modality therapy of
LSCLC is superior to late or consolidative RT.
59. EARLY VS LATE THORACIC RT
• Reduce chances of systemic metastasis
• Reduce chances of appearance of chemoresistant.
• Lower probability of radioresistance
• Diminished accelerated repopulation
Early better:
• Allows shrinkage of portals to a reduced tumor volume
• Reversible resistances
Late Better:
63. Definition
70% of all SCLC
Organs within a curative radiation portal cannot safely tolerate curative radiation
doses
So Malignant pleural effusion,B/L pulmonary involvement,cardiac tamponade are
included in extensive disease
66. EVOLUTION OF CHEMOTHERAPY REGIMENS
Sensitivity of SCLC to chemotherapy agents was recognised over50 yrs ago
Livingston et.al developed the CAV combination followed sequentially by thoracic
and brain irradiation. There was significant improvement in ORR,CR and MS in
both LS and ES SCLC. With these, CAV became the standard chemotherapy
regimen.
EP regimen was first explored in the late 1970’s
Three RCT compared EP to CAV which showed less myelosuppression with EP
and when combined with radiation, there was less esophagitis and interstitial
pneumonitis
67. In the largest trial by Sundstorm, EP regimen produced a better mOS [15
months v 10 months] and 5 yr [10 %vs 3%] for patients with LS disease
With these studies EP became the standard first line chemotherapy
68. Chemo-Controversy
Cisplatin-Important side effect is
nephrotoxicity-so hyperhydration is
preventive, but problematic in elderly
So alternative is Etoposide +Carboplatin
Studied in HCOG –Demonstrated to be as
effective and with lesser toxicity profiles
So Carboplatin can be a good alternative,
especially in who cant tolerate Cisplatin
ETOPOSIDE
Intravenously or Orally?
Studies demonstrated that oral
formulation
Less effective and Inferior survival
69. ALTERNATIVES TO PLATIN/ETOPOSIDE-IRINOTECAN
SWOG
Found no significant difference
Population based polymorphisms in UDP-
UGT1A1,the enzyme responsible for
detoxifying the active metabolite of
Irinotecan,may account for the difference
in the study
In Japanese PH III Trial
Cisplatin +Irinotecan>EP arm
Significantly more effective
Longer mOS[12.8vs 9.4months]
Higher 2 yr OS rate[19 vs 5%]
Hematological toxicity less pronounced
CONFLICTING RESULTS
70. Alternatives to Platin/Etoposide-Topotecan and Belotecan
Combination of Topotecan +Cisplatin was
studied in PH III trials
Demonstrated similar tolerability with
identical RR,mOS and 1 yr OS
Increased hematological toxicity
Belotecan
New Camptothecin analogue
Shown activity in PH II trials
PhIII trials are running
71. STRATEGIES
Alternating cycles of Combination Chemotherapy Regimens
Tried due to recognition of clonal heterogeneity within a tumor and intolerability of
treatment regimens containing more than four drugs-No Substantial benefit
TRIPLET CHEMOTHERAPY
Resulted in more toxicity with no improvement in survival
Maintenance Therapy
Not recommended due to lack of significant benefit
DOSE INTENSIFICATION
Four RCT have concluded that intensive multidrug weekly regimens results in more
toxicity without improving outcome
73. CHEMOTHERAPY
Combination of Etoposide with a platinum based agent is still the standard of
care in ES-SCLC since 1980’s
SWOG study was conducted to study on feascibity of replacement of Irinotecan
with Etoposide-No significant survival advantage
Carboplatin can be a reasonable substitute based on the RCT combining the 2
drugs with etoposide
No significant OS difference between the two arms with better toxicity
profiles in the carboplatin arm
No clinical trial has been able to establish role of maintenance therapy as
standard of care option after first line treatment of SCLC
74. ADDITION OF IMMUNE CHECK POINT INHIBITORS TO
CHEMOTHERAPY
ATEZOLIZUMAB
Anti PDL-1 Moncolonal antibody
78. SUMMARY
IM power 133-1st study in over 20yrs to
show a clinically meaningful improvement
in OS over the current standard of care in
1L ES-SCLC
Shows improvement in mOS and mPFS
Data suggest that Atezoluzumab plus
carboplatin and Etoposide is a new
standard of care in the first line treatment
of ES-SCLC
82. INTERIM ANALYSIS
DURVALUMAB WITH PLATINUM ETOPOSIDE WAS ASSOCIATED WITH
SIGNIFICANT IMOROVEMENT IN OS
mOS was 13 vs 10.3 months with 34% of the patienst alive at 18 months
85. PCI in SCLC ,after obtaining CR or PR with CRT or Chemotherapy
RATIONALE
• 10-14% pts have detectable brain metastasis at presentation
• At the time of death at least one third (35-40%) have brain metastasis
• Approximately 50 % have brain metastasis when sent for post-mortem
• Frequency of brain metastasis increases, as survival time increases
• With improvements in survival after chemotherapy or chemo-radiation,
recurrence in the CNS an increasing problem affecting 50% of pts at 2 yrs
• Pts with ESSCLC more likely to develop brain mets than LSSCLC (69% vs 47%)
86. OBJECTIVES
• To prevent the clinical manifestations of previously present but occult CNS
disease, as SCLC pts are at high risk of developing brain metastasis
• To prevent the morbidity associated with clinically evident brain metastasis, and
conferring the patients a better quality of life
• Now known to improve survival to a significant degree, in addition to it’s
established role in preventing the morbidity associated with brain metastasis
87. QUESTIONS
Does it increase survival?
Is it applicable in only limited stage or in extensive stage as well?
Optimum Dose of PCI
Late Neurotoxicity
Benefit in Older age >70yrs
88. Does it Increase Survival ?
RCT in early 1980’s and 1990’s ,suggested of improved survival in PCI ,but not
statistically significant
Meta analysis of 7 RCT[1977-1995]
987 patients[85% LS and 15% ES]
Randomisation to PCI or Observation following response to Chemotherapy or
CRT
PCI regimens varied from 24/12 # to40 Gy/20#
Benefits consistent irrespective of age,P.S, stage and type of induction
chemotherapy,but no relation found with timing of PCI and survival
89. SCLC -META ANALYSIS OF PCI VS NO PCI
Auperin et.al
Patients 987 (140 patients had
ED-SCLC)
Overall survival benefit +5% (95% CI:
1 -10%)
3 year survival 20 vs 15%
Incidence of brain metastasis 33 vs
59%
90. ANALYSIS
Forest Plot and KM curve showing an
absolute benefit of 5.4% at 3 years in
favour of PCI in LS-SCLC
91. IS THE BENEFIT OF PCI SAME IN ES –SCLC AS WELL?
EORTC study
Pts with ES-SCLC who had response to
systemic chemotherapy underwent 5 to 12
fractions of 20 to 30 Gy with no further
therapy
Primary End point-Time to symptomatic
brain metastasis
Secondary endpoint-OS
92.
93. Dose Fractionation Issues in PCI in SCLC
• Multi-institutional Intergroup trial: (720 patients)
Standard dose PCI (25 Gy in 10 daily fractions) vs High dose PCI (36 Gy in 18 daily
fractions or 24 twice daily fractions)
• At 2 yrs. No significant difference in incidence of brain mets.
(29% in standard arm vs 23% with high dose)
• No significant diff. In survival between the 2 groups
(42% in standard dose arm vs 36 % with high dose)
• Increased incidence of chronic neurotoxicity at 1 yr. after PCI in
the 36 Gy cohort (p=0.02)
• These results established 25 Gy in 10 daily fractions (2.5 Gy/fraction) as standard
dose of PCI in small cell lung cancer
94. Does It Cause Neurotoxicity? And ways to Reduce
• Neurocognitive toxicity partly related to radiation induced injury to neural progenitor cells in the
hippocampus (inverse relationship between radiation dose to the hippocampus and performance
on neuropsychological testing)
• RTOG 0933 Study: Hippocampus sparing cranial irradiation to reduce the incidence of
neurocognitive toxicity, as the hippocampus is rarely affected by BM but displays the major site
of learning, memory and spatial information .
• Exploring IMRT for PCI, the mean doses to the hippocampus could be reduced by 81-87% to
doses of 0.49-0.73 Gy with preserved target volume coverage and homogeneity.
• Neuroprotective drugs ? Under exploration
95. GUIDING PRINCIPLES
LS SCLC with CR or PR: PCI
ES SCLC:
PCI recommended for all pts who had complete response
Dose: 25Gy/10F
20Gy/5 F (selected ES SCLC)
Higher doses: increased toxicity and mortality(RTOG 0212)
Most common S/E : fatigue, headache, nausea and vomiting.
Pt not receiving PCI :brain imaging for surveillance of metastasis
96. PLANNING OF PCI
-0.5 cm below the orbital roof
-1 cm below and 1 cm in front of the
lower most portion of the temporal
fossa
-1 cm away from the extreme
edges of the calvaria
97. SUMMARY
• High propensity for SCLC to develop Brain Metastasis
PCI significantly lowers the incidence of BM, in patients achieving good
response to induction chemotherapy
• No evidence of serious morbidity associated with PCI, if given after
completion of all chemotherapy and in moderate fraction size
• Meta-analysis confirmed the survival benefit in both limited and extensive SCLC
pts in complete remission (5% improvement in 3 yr survival)
• Although different dose fractionation regimes are in practice, 25 Gy in 10
fractions and 36 Gy in 18 fractions are within the standard of care.
• Dose of 30 Gy in 15 fractions clearly suboptimal
• Optimal fraction size 2.5 to 3 Gy to avoid late neuro toxicity
• Timing of PCI: Should start as early as feasible after completing
chemotherapy
• Objective psychometric testing should be done, if feasible before and after PCI
to asses neuro-cognitive morbidity
• Little data on use of PCI in pts >70 yrs of age
98. ROLE OF THORACIC RT IN ES-SCLC
Thoracic tumor progression is a major cause of morbidity in patients with ES-
SCLC
Even after chemotherapy,75-90% of the pts have resistant intrathoracic disease
and approximately 90% develop intrathoracic progression in the first year
Consolidative Thoracic RT is beneficial in patients who have Cr or pR to
chemotherapy,especially with residual disease and low bulk extrathoracic disease
102. DUTCH STUDY
Primary End pint-OS at 1 year
Also anlysed mOS at OS at 2yrs
Secondary End point-Intrathoracic
control,pattern of failure ,PFS
103.
104. RESULTS
OS AT 1 YR was not significant between the two groups[33% vs 28%]
In a secondary analysis
2 YR OS-13% vs 3%
At 6 months,PFS was 24% vs 7%
106. AIM
To investigate the prognostic importance
of number and site of metastasis of
patients included in CREST Study
Eligible Patients
>18 yrs
WHO PS 0-2
ES-SCLC
Any response after platinum based
chemotherapy
Patients with leptomningeal,brain or
pleural metastasis were excluded
107.
108. CREST UPDATE
RESULTS
PFS was superior in the absence of bone
metastasis and showed a favourable trend
in the absence of liver metastasis
In patients without liver metastasis, those
receiving TRT had significantly longer PFS
compared to those who didn’t receive TRT
109. PLANNING OF RT
Principles:
Adequate coverage of the 1° tumor : 1.5 – 2 cm
Adequate margins to account for respiratory motion
Adequate coverage of draining nodes (1st echelon) : 1 cm
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 SCF unless involved.
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.
