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The Christie NHS Foundation Trust
Treatment of Limited stage (Stage I-III)
SCLC Dr David Cobben
Manchester Lung Cancer Group
Manchester Radiation Related Research Group
ESMO-The Christie Preceptorship programme on Lung Cancer
8th March 2019
The Christie NHS Foundation Trust
Conflict of Interest
• None
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Disclaimer
• Trained in the Netherlands as Radiation Oncologist
• 50% clinical work: lung cancer radiotherapy
• 50% research in lung radiotherapy (MR-linac)
• Work in tandem with medical oncologist
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Contents• Introduction
• Staging
• Elective Nodal vs Involved nodal irradiation
• RT techniques
• Treatment of Limited Stage SCLC (focus on stage III)
• Turrisi (Intergroup 0096)
• CONVERT
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Introduction
• Incidence of SCLC 10-15% of all lung cancer cases
• >95% are associated with tobacco exposure
• One third present with stage I-III disease (“limited”)
• Two thirds present with stage IV disease (“extensive”)
• Centrally located disease
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Introduction
• Rapid growth
• Excellent responses to CT and RT but few patients will
be long term survivors
• High risk of local relapse
• High risk of distant spread (brain)
• Overall 5 year overall survival is 10%
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Staging
Three staging systems
• Veterans Affairs Lung Cancer Study Group
(VALCSG) 1974
• International Association for the Study of Lung
Cancer (IASLC) 1989, 2018
• American Joint Committee on Cancer (AJCC)
2010
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VALG Staging: Limited Disease
Ahmad , BMJ 2018
•Unilateral tumour
•Unilateral hilar, mediastinal and SCF
nodes
•No extra-thoracic disease
(exception in uni-lateral SCF)
•Encompassing RT portal
1. Contralateral SCF nodes
2. Contralateral mediastinal nodes
3. Contralateral hilar nodes
4. Contralateral lung nodule
5. Malignant pleural effusion
6. Malignant pericardial effusionTurrisi
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IASLC Staging: Limited Disease
Ahmad , BMJ 2018
•Unilateral tumour
•Unilateral hilar, mediastinal and SCF
nodes
•Contralateral mediastinal and SCF
nodes
•Malignant pleural effusion
(cytology+/-)
•No extra-thoracic disease
(exception in uni-lateral SCF)
•Encompassing RT portal
1. Contralateral hilar nodes
2. Contralateral lung nodule
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AJCC Staging: Stages I-III
Ahmad , BMJ 2018
•Any T
•Any N
•M0
1. Contralateral lung nodule (Fig D)
2. T3/T4 with multiple lung nodules
(Fig E and F)
CONVERT Trial
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Which staging system to use?
ESMO guidelines , Annals of Oncol 2013
Nicholson J Thor Oncol 2015
• Be aware of different staging systems
• Suggest to use 8th edition of IASLC (as for NSCLC)
Better prognostic information for T and N
More precise nodal staging� conformal RT techniques
Especially in era of involved nodal instead of elective
nodal RT
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Which staging system to use?
Form IASLC 8th TNM edition
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Elective vs Involved Nodal RT
• Only affected nodes
• Safety margins (microscopic disease, b
breathing motion, etc) (Green)
• Affected nodes (Red)
• Surrounding stations (Purple)
• Safety margin (microscopic disease,
breathing motion, etc) (Green)
Treatment Volume also impacts surrounding Organs:
Acute and late side effects (e.g.):
-Oesophagitis-Oesophageal fistula
-Pneumonitis-Pulmonary Fibrosis
-Pericarditis-Myocardial infarction
Radiotherapy technique also impacts surrounding Organs
Elective nodal RT:Turrisi trail
Involved nodal RT:CONVERT trial
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RT techniques2D 3D IMRT
Era <1995 >1995 “Now”
Diagnostic Imaging CT CT CT
Pre-treatment
Imaging
Fluoroscopy CT CT
Contouring No Contouring of
tumour, nodes,
OARS in 3D
Contouring of
tumour, nodes,
OARS in 3D
Shaping of dose Lead blocks Leafs Leafs , segments
“Conformality” Poor Better Best
Dose to surrounding
organs
High dose to
surrounding
organs
Less dose to
surrounding
organs
Less dose to
surrounding
organs
Imaging on linear
accelerator
Electronic
Portal Image
Cone-beam CT Cone beam CT
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2D
Rodin J Thor Onc 2015
• Fluoroscopy (correlating anatomical landmarks related to CT)
• No contouring
• Lead blocks
• Poorly shaped
• High dose to surrounding organs
• Portal Imaging during treatment
Turrisi trial
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IMRT
Rodin J Thor Onc 2015
• Planning CT, capturing 4D motion
• Contouring on CT in 3D of Tumour, Nodes and OARS
• Planning: software: influencing the dose to T, N and OARS
• Leafs and segments
• Nicely shaped (conformal)
• Lower dose to surrounding organs
• CB-CT during treatment
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Current evidence in stage I-III SCLC
• Chemo-RT >CT (Pignon, Warde)
• Early RT >late RT (Fried , Cochrane review)
• Concurrent chemo-RT >sequential CTRT (Takada)
• Best survival results achieved with early BD concurrent chemo
RT (Turrisi, Jeremic, Faivre-Finn)
• PCI improves survival - 6% @ 3 years (Auperin)
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• Cisplatin is the best radiosensitiser and has higher response rate�Cisplatin plays a major role in the treatment of LS-SCLC
• Cisplatin-Etoposide can be delivered at full dose with thoracic RT with an acceptable toxicity profile
• No change in systemic therapy in last 20 years
� No role for anthracyclines/pemetrexed/irinotecan
� No role for chemotherapy dose intensification
� No role for targeted agents
Systemic treatment in stage I-III SCLC
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What is the SOC for Stage I-III SCLC?
Turrisi et al. N Engl J Med 1999
Once Daily Thoracic Irradiation
D1 D3
RT 45Gy/33D/25F
Twice Daily Thoracic Irradiation
RT 45Gy/19D/30F
Lim
ited
Sta
ge S
mall C
ell
Lu
ng
Can
cer
CR→→→→PCI
If<CR
→→→→ No PCI
Registration
Randomisation
Restage
Chemotherapy (PE)
Radiotherapy
D22 D24 D43 D45 D64 D66
D1 D3 D22 D24 D43 D45 D64 D66
Intergroup 0096 TrialOS
Toxicity
5yr: 26% vs16%
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Is Timing of Thoracic RT with chemo important?
•7 RCTs
•Advantage of early (<9 weeks) radiotherapy
•2 yr % •NNT for benefit •p
•All (1524)
•Platinum
•Platinum +•BDRT
+5.2 [0.6-9.7] 20 0.03
+9.8 [3.8-15.9] 10 0.001
+16.7 [9.4-26] 6 0.001
•Fried et al. J Clin Oncol 2004
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CONVERT multinational, phase III randomised study
RT 45Gy/30F/19D
Lim
ited
Sta
ge S
mall C
ell
SD,PR,CR→→→→PCI
If<SD→→→→ no PCI
Registration
Randomisation
RestageChemotherapy
Radiotherapy
D1 D3 D22 D24 D43 D45 D64 D66
Twice-daily (BD) thoracic RT
D1 D3 D22 D24 D43 D45 D64 D66
RT 66Gy/33F/45D
Once-daily (OD) thoracic RT
Stratification factorsCentreNo. of cycles chemo: 4 vs.6 PS: 0,1 vs. 2
RTP after randomisationRT started on D22 cycle 13DCRT or IMRTNo ENIQA programme
Chemotherapy4 to 6 cycles Cisplatin 25mg/m2 D1-3 or75mg/m2 D1Etoposide 100mg/m2 D1-3
547 patients
8 countries
75 centres
PS 0-2
No age limit
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Overall survival
Median follow-up: 45 months
Overall survival(n=543)
BD OD Log-rank
Median(months)
30 (24-34) 25 (21-31)
p=0.14
1-year 83% (78-87) 76% (71-81)
2-year 56% (50-62) 51% (45-57)
3-year 43% (37-49) 39% (33-45)
5-year 34% (27-41) 31% (25-37)
Primary objective-overall survival Trial hypothesis
Expected survival BD arm 44%Projected survival OD arm 56%
(5) (1) (17) (30) (22) (13) (3)(3) (1) (27) (29) (25) (19) (3)
HR=1.18 with 95% CI 0.95-1.45 p=0.14
0
20
40
60
80
100
Aliv
e (
%)
273 224 151 92 54 25 6 2BD270 202 134 88 46 21 7 3OD
Number at risk
0 1 2 3 4 5 6 7Years from randomisation
OD
BD
Overall survival
Faivre-Finn. Lancet Oncol 2017
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CONVERT: Toxicity
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)
•Faivre-Finn. Lancet Oncol 2017
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CONVERT: How to interpret the results
• Survival in both arms was higher than previously reported (BD vs OD): CONVERT 2YOS 56% and 51% (ns) vs Turrisi 47% vs 41% CONVERT 5Y OS 34 and 31 % (ns) vs Turrisi 26% vs 16% (sign)
• Radiation-related toxicities were lower than expected likely due to the use of modern RT techniques (3D and IMRT) and involved instead of elective nodal RT
• No difference in grade 3/4 acute oesophagitis (BD vs OD)
• CONVERT 19% vs 19% (ns) Turissi 27 vs 11% (sign)Grade 3/4 acute
radiation pneumonitis was rare (2.5% BD, 2.2% OD)
• 45Gy in 30 # BD should continue to be regarded as standard of carebecause CONVERT is not an equivalence trial
• OD RT did not result in a superior survival or better toxicity than BD RT
• Therefore the control arm of the study should be considered SOC
Faivre-Finn. Lancet Oncol 2017
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CONVERT data: other questions that can be answered
Unique data set
• Outcome related to QA vs non-QA compliant centres
• Outcome related to high vs low volume centres
• Predictive value of PET-CT staging on outcome
• Effect of CB-CT changes on survival
• Impact of heart-dose on survival
• Impact of prophylactic use of anti-biotics
• PCI and patterns of relapse
• Translational: Predictive value of circulating tumour cells at baselineRadiobiology
• Survey on impact of CONVERT on clinical practice
• Outcome in Stage I-II patients (Salem et al JAMA Oncology Dec 2018)
•Faivre-Finn. Lancet Oncol 2017Faivre-Finnn Clinical Oncology 2017
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Future areas of research
• Dose escalation with Bi-daily radiotherapy
• CTC’s to identify treatment other options
• Targeted agents
•Faivre-Finn. Lancet Oncol 2017
Faivre-Finnn Clinical Oncology 2017
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Conclusions
• Be aware of the different staging systems: trials and communication with colleagues.
• The treatment volume AND RT technique impactthe side effects
• Early, concurrent chemo-radiotherapy, bi-daily is the standard of care
• More results awaited from CONVERT trial (e.g. CTC’s)
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Questions?