Dr Fiona McDonald...Leading cause of cancer-related mortality worldwide: – In males lung cancer-related deaths exceed prostate cancer-related deaths – In females lung cancer-related

@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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Inci

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of

Bra

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sta

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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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Time (Months)

First-line atezolizumab plus chemotherapy in extensive-stage SCLC: OS


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Pro

gre

ssio

n F

ree

Su

rviv

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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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Slotman et al NEJM 2007;

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Inci

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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;


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Inci

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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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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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Documents

Dr Fiona McDonald...Leading cause of cancer-related mortality worldwide: – In males lung cancer-related deaths exceed prostate cancer-related deaths – In females lung cancer-related