@fifimcdrmh [email protected]
Small Cell Lung Cancer18th ESO-ESMO Masterclass 2019
Dr Fiona McDonald
Consultant Thoracic Clinical Oncologist
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Disclosures
Consulting fees: Astra Zeneca
Speaker fees: Astra Zeneca, Elekta
Research grants: Elekta, MSD, Varian, Accuray
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Objectives
SACT in Stage IV Disease
Thoracic RT & PCI in Stage IV Disease
Management of Stage I-III Disease
Introduction to Small Cell Lung Cancer
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Introduction to Small Cell Lung Cancer
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What is the scale and cause of the problem?
Leading cause of cancer-related mortality worldwide:– In males lung cancer-related deaths exceed prostate cancer-related
deaths
– In females lung cancer-related deaths exceed breast cancer-related deaths
– Worldwide every year more people die from lung cancer than from prostate, breast and colon cancer combined together
75% of cases: Principle risk factor is smoking
10-25% of cases: Never smokers
More common in Asia and women
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How is the pathological diagnosis & disease extent evaluated?
AdenocarcinomaSquamous cell
carcinoma
Small cell carcinoma 10-15%
Other
Consider:– Accessibility of disease
– Invasiveness of procedure
– Local clinical expertise
– Efficiency
Endoscopic biopsy:– EBUS-TBNA
– EUS-FNA
Percutaneous biopsy:– CT or US guided
Surgical biopsy:– VATS
– Mediastinoscopy
Other
Govindan et al JCO 2006;
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Consider:– Primary tumour (T stage)
– Local lymph nodes (N stage)
– Metastatic disease (M stage)
CT chest / abdomen
(PET CT scan)
(Brain imaging)– MRI (or contrast CT)
IV
III
I-II
How is the pathological diagnosis & disease extent evaluated?
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What is the stage?
Veteran Staging: Limited & ExtensiveIASLC 8th Lung TNM Staging
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What is the prognosis?
Surveillance Epidemiology & End Results Database, USA;
5 Year Overall Survival Rates
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Management of Stage I-III Disease
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77 year old female
Presented with clubbing, cough & weight loss
PMH: Hypertension, NIDDM
DH: Amlodipine, Metformin
PS: 2
Ex smoker: Prior 50 PYH, stopped 5 years ago
Case: Presentation
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Case: Investigations
CT: T2b N3 (bilateral hilar & SCF LNs) M0 LUL
PET: SUV max 9.5
MRI Brain: No intracranial disease
Path: Bx L SCF Small Cell
LFTs: FEV1 0.9 43% FVC 2.1 66%% TLCO 54%
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Case: What treatment would you recommend?
– Sequential radical CRT +/- PCI
– Concurrent radical CRT (daily RT)+/- PCI
– Concurrent radical CRT (twice daily RT) +/- PCI
– Radical radiotherapy +/- PCI
– Palliative radiotherapy +/- PCI
– Palliative SACT +/- PCIDo not duplicate or d
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CRT Superior to Chemotherapy Alone
Meta-Analysis of 13 randomised trials2140 patients
3 year survival 8.9 % CT alone vs 14.3% CRT
Thoracic RT benefited younger group of patientsRR of death CRT as compared with CT alone0.72 for patients <55 years old (0.56-0.93) 1.07 for patients >70 years old (0.70-1.64)
LimitationsDated RT techniques (2D)Response to treatment assessed on CXR
14% reduction in risk of death, p = 0.001
Pignon et al NEJM 1992;
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Best Outcomes with Twice Daily Fractionation
Turrisi et al NEJM 1999;
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Concurrent Better Than Sequential
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Time (months)
Takada et al JCO 2002;
P=0.097
Concurrent CRT MS 27 mths
Sequential CRT MS 19 mths
RT 45 Gy in 30# bd 3w
Cisplatin Etoposide4 cycles
Q3w sequential armQ4w concurrent arm
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Early RT Better Than Late RT
Fried et al JCO 2004;
7 RCTs: Advantage of ‘Early RT’ commencing in first 9 weeks of chemotherapy
2 Year OS
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CONVERT: Twice daily vs Once daily to 66 Gy with Modern RT
Faivre-Finn et al Lancet Oncol 2017;
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Time (months)
---- Once Daily---- Twice Daily
547 patients8 countries75 centres
PS 0-2No age limit
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Organ at risk Arm N Median (Range)
Lung V5 (%) BDOD
246234
56.2 (7.2-88.5)
60.8 (7.0-91.6)
Lung V20 (%) BDOD
252240
23.2 (0.1-35.4)
28.8 (8.0-40.5)
Heart (% total dose)
BDOD
240229
2.0 (0-45.3)1.4 (0-36.2)
Spinal cord (max dose, Gy)
BDOD
251241
32.0 (1.3-45.8)
41.7 (1.3-52.6)
Oesophagus (max dose, Gy)
BDOD
248236
45.7 (0.7-64.4)
65.9 (2.2-71.7)
Oesophagus V35 (%)
BDOD
246230
34.0 (0-76.5)38.8 (0-
82.8)
Arm BD (n=254) OD (n=256) p
AE (grade) 1-2
n (%)
3
n (%)
4
n (%)
5
n (%)
1-2
n (%)
3
n (%)
4
n (%)
5
n (%)
Oesophagitis 159
(62·6)
46
(18·1)
1
(0·4)
- 135
(52·7)
47
(18·4)
- - 0·85
Pneumonitis 51
(20·1)
3
(1·2)
1
(0·4)
1
(0·4)
49
(19·1)
3
(1·2)
1
(0·4)
2
(0·8)*
0·70
CONVERT: OAR Doses & Acute Toxicity
Faivre-Finn et al Lancet Oncol 2017;
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Setting the Standard in the Modern Era
Courtesy of Corinne Faivre-Finn;
SW
OG 971
3
SW
OG 022
2
NCCTG 892
052
CALGB 923
5
RTOG 960
9
ECOG 259
6
INT00
96QD
INT00
96BID
CONVERT Q
D
CONVERT B
ID
0
10
20
30
40
Me
dia
n S
urv
iva
l (m
on
ths
)
CT alone
sCRT
cCRT
BD cCRT
CONVERT BD
5 year survival (%)
<10
10-15
20-25
25
34
Med
ian
Su
rviv
al
(Mo
nth
s)
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Prophylactic Cranial Irradiation
Auperin et al NEJM 1999; Le Pechoux et al Lancet Oncol 2009;
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Time (Years) Time (Years)
Inci
de
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of
Bra
in M
eta
sta
ses
Standard dose 25 Gy 10#
5% increase in OS at 3 years (p=0.01)
Major risk of spread to brain-50 to 60%
PCI can reduce the risk of spread by 50%
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Chemo-Radiotherapy:
cis-/carboplatin + etoposide
4 cycles
Biomaterial for translational research:
Consolidation vs observation:
induction maintenance
max 1 year
combination nivolumab
nivolumab/ipilimumab
observation
Screening:
LD SCLCPCI
Tumour
evaluation:
PD
off
Voluntary re-biopsy:
→ FFPE block
yes
noR
• • •
3 6 9 3 6 9 1812
after randomisation
RT (Thoracic Radiotherapy): CT scans for tumour assessment
accelerated schedule preferred - up to 18 months: every 9 weeks
start: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks
day 1 of chemo cycle 2 - years 3 & 4: every 6 months
- at 5 years
0Week
Serum
At progression:
Whole blood Whole bloodWhole blood
RT
RT
from start of chemotherapy
-2
CT
Serum SerumSerum
FDG-PET-CT
or CT
Brain MRI
or CT
Biopsy:
FFPE block
or slides
27 ∙∙∙
CT • • •
14 16
Multicentre, open label, randomized phase II trial
Primary Endpoints: PFS and OS Sample Size:260 patients
STIMULI: Potential Role of IO?
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Back to the Case: Treatment
Concurrent radical chemoradiotherapy
Cisplatin & Etoposide 4 cycles
– Cisplatin & Vinorelbine 3 cycles
– ABC motion management with MDIB
– IMRT
– Lung V20 35% MLD 18.5 Gy
– Daily CBCT image verification
– 45 Gy 30# bd with cycles 2 & 3
– Completed July 2018
– Grade 1 fatigue, Grade 1 cough, Grade 2 oesophagitis
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Case: Outcome
Oct 2018
Jan 2019
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SACT in Stage IV Disease
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First-Line: Cisplatin Etoposide Chemotherapy
Pujol et al Br J Cancer 2000; Mascaux et al Lung Cancer 2000;
Cisplatin Containing Regimen Better
Non- Cisplatin Containing Regimen Better
Cisplatin contating regimen associated with significantreduction of risk of death
at 1 year OR 0.8 p=0.002
Addition of Etoposide also associated with improved outcome in meta-analysis
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First-Line: Cisplatin vs Carboplatin
Rossi et al JCO 2012;
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Time (Months)
4 eligible trials with total of 663 patients (329 cisplatin, 334 carboplatin)
Haematological toxicity higher with carboplatin
Non-haematological toxicity higher with cisplatin
Cisplatin mOS 9.6 mCarboplatin mOS 9.4 m
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Second Line: Cisplatin Etoposide & Irinotecan vsTopotecan for sensitive relapsed disease
Goto et al Lancet Oncol 2016;
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Time (Weeks)
TopotecanCombination
HR 0.67 p=0.079
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Second Line: Topotecan vs BSC
O’Brien et al JCO 2006;
TopotecanBest Supportive Care
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Time (Weeks)
HR 0.64 p=0.01
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Emerging Role of IO …….
Lawrence et al Nature 2013;
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First-line atezolizumab plus chemotherapy in extensive-stage SCLC: Trial design
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Ov
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Time (Months)
First-line atezolizumab plus chemotherapy in extensive-stage SCLC: OS
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Pro
gre
ssio
n F
ree
Su
rviv
al
Time (Months)
First-line atezolizumab plus chemotherapy in extensive-stage SCLC: PFS
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First-line atezolizumab plus chemotherapy in extensive-stage SCLC: Toxicity
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Thoracic RT & PCI in Stage IV Disease
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Prophylactic Cranial Irradiation
Slotman et al NEJM 2007;
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Time (Months) Time (Months)
Inci
de
nce
of
Bra
in M
eta
sta
ses
Risk of BMs at 1 year:15% in irradiation group
40% in control group
mOS:6.7 m in irradiation group
5.4 m in control group
Note: 75 year age limit
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Takahasi et al Lancet Oncol 2017;
Prophylactic Cranial Irradiation
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Time (Months) Time (Months)
Inci
de
nce
of
Bra
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eta
sta
ses
PCINo PCI
HR 1.27P= 0.094
MRI at baseline, 3-month intervals up to 12 months & at 18 & 24 months after enrolment.
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Consolidation Thoracic Radiotherapy
Jeremic et al JCO 1999;
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Time (Months)
mOS 17 vs 11 months5-year OS 9.1% v 3.7%
P = 0.041).
54 Gy 36#
Intra-thoracic CRExtra-thoracic CR
Intra-thoracic PRExtra-thoracic CR
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Slotman et al Lancet Oncol 2014;
CREST: Consolidation Thoracic Radiotherapy
OS at 1 year33% TRT
28% Control p=0·066
TRT Control
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CREST: Consolidation Thoracic Radiotherapy
Slotman et al Lung Cancer 2017;
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2013
Due out 2019
Clinical Practice Guidelines
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Take home messages
cCRT with Twice Daily RT is the SOC for Localised Disease +/- PCI
Cisplatin & Etoposide Form the Basis of SACT for Advanced Disease
Consider PCI & TRT in Chemotherapy Responders with Advanced Disease
There is an Emerging Role of Immunotherapy ……
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Thank you
@fifimcdrmh [email protected]
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