Treatment of Limited stage (Stage I-III) SCLC...Contralateral lung nodule 5. Malignant pleural effusion Turrisi 6. Malignant pericardial effusion The Christie NHS Foundation Trust

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


Conflict of Interest

• None


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


Contents• Introduction

• Staging

• Elective Nodal vs Involved nodal irradiation

• RT techniques

• Treatment of Limited Stage SCLC (focus on stage III)

• Turrisi (Intergroup 0096)

• CONVERT


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


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%


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


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


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


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


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


Which staging system to use?

Form IASLC 8th TNM edition


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


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


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


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


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)


• 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


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%


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


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


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


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


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


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


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


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)


Questions?

Documents

Treatment of Limited stage (Stage I-III) SCLC...Contralateral lung nodule 5. Malignant pleural effusion Turrisi 6. Malignant pericardial effusion The Christie NHS Foundation Trust