IOT Institut d’Oncologie

Thoracique

Cecile Le Péchoux, 12ème Biennale Monégasque de

Cancérologie, 2016

Place de la radiothérapie dans les CBPC métastatiques

CBPC metastatique

Rapid doubling time, early development of widespread metastases

Over 2/3 of patients with SCLC have metastatic disease,

Backbone treatment is Platinum/etoposide based chemotherapy: 4-6 cycles

What about radiation?

ESMO guidelines SCLC.Ann Onc 2011, 2013; NCCN 2015

CBPC: Rationel pour un

Traitement Local

M0 SCLC patients : do they exist ? Landmark study of the NCIC

CT

M0 (and oligometastatic) SCLC patients can be divided into 3 groups according to the presence or absence of drug-resistant tumor and its location.

Murray et al (JCO 1993)

CT only possible Importance of RT

to eradicate resistant clones TRT improves LC,

but high rate of failure

PET-CT may contribute to select patients that may benefit from local treatment

Possibly more patients with lower metastatic burden modern imaging such as PET-CT and brain MRI ~ 20% pts upstaged from LD to ED

~ 8% downstaged

Use of 8th TNM classification..

Brink, 2004; Kalemkerian 2011, NCCN Guidelines 2015, ESM0 guidelines 2013

Treatment issues:

Local treatment of primary tumor

MA on the role of TRT: Metastatic pts have been probably included

Thoracic primary tumor is the most heterogeneous portion of the neoplasm

Most probable sanctuary of drug-resistant cells

Strong rationale to combine TRT to CT

Rationale for RT in SCLC metastatic patients Response Rate and Survival after Second line chemotherapy

• RR: 10% in resistant disease

(i.e. progression-free interval <3 months)

• RR: 20-25% in sensitive disease (interval >3

months).

• And Survival Poor MS ~ 4-5 months

SCLC ESMO guidelines 2013 and NCCN Guidelines 2015

Thoracic Radiotherapy in Extensive disease

Randomized study evaluating the role of TRT (54 Gy with 2 daily

fractions of 1.5 Gy) among patients with local CR or PR and extra-thoracic CR to chemotherapy

Serie of 210 pts

Jeremic et al. Role of RT in the combined-modality treatment of patients with ED SCLC: A randomized study. J

Clin Oncol 1999

Thoracic Radiotherapy in Extensive disease

Randomized study evluating the role of TRT (54 Gy with 2 daily

fractions of 1.5 Gy) among patients with extra-thoracic CR to chemotherapy and local CR or PR

Results (Groups 1 & 2)

CT-RT CT alone p

N patients 55 pts 54 pts

Median Time to LR 30 mo 22 mo NS

5-yr LRecurFree SR 20% 8.1% 0,062

Median Survival 17 mo 11 mo Sign

5-yr Survival 9.1% 3.7% 0,041

Jeremic et al. Role of RT in the combined-modality treatment of patients with ED SCLC: A randomized study. J

Clin Oncol 1999

ES-SCLC, WHO 0-2 4-6 platinum-based

chemotherapy

CREST Trial Design

Any response

TRT (30Gy in 10fx)

RANDOMIZE

PCI PCI

Stratification:

Institute

Presence of intrathoracic disease

Kindly provided by Ben Slotman ASCO 2014, Lancet 2014

No TRT 498 pts from 2009 to 2012

Study powered to detect a

10%

improvement in 1 yr OS from

randomisation

Control arm:27%

Study powered to detect a 10%

improvement in 1 yr OS

Slotman et al, CREST trial Lancet 2014

TRT No TRT p

1yr OS 33% 28% 0,066

1,5 yr OS 16% 9% 0,03

2 yr OS 13% 3% 0,04

Study powered to detect a 10%

improvement in 1 yr OS from

randomisation

Control arm: 27%

Impact on treatment failure

Slotman 2014, 2015

44% 79%

Overall survival Pts with residual intrathoracic disease (n=434)

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24

Months

Surv

ival P

robabili

ty

Thoracic RT

No Thoracic RT

215 184 132 94 59 35 22 15 11

219 188 138 82 50 26 14 5 4

Thoracic RT

No Thoracic RT

12 months OS - Thoracic RT : 32.5 ( 95% CI: 26.7 - 39.6 )

12 months OS - No Thoracic RT : 25.9 ( 95% CI: 20.6 - 32.6 )

HR= 0.81 ( 95% CI: 0.66 - 1 )

log-rank p-value 0.044

HR =0.81 (95%CI 0.66-1.00)

P<0.05

1 Yr Survival TRT: 32,5%

1 Yr Survival no TRT: 25,9%

Slotman IASLC 2015

Amélioration significative

SG dans ce sous groupe

de pts

Toxicité RTT de consolidation acceptable

Less acute grade 3 and 4 toxic events in CT than

in CTRT group (P < .00001).

No difference in late grade 3 and grade 4 toxicities between CTRT and CT.

Jeremic Study

Jeremic J Clin Oncol 1999; Slotman Lancet 2014

CREST Trial In pts with M1 disease with any response after

CT,TRT led to a significant improvement in PFS (P<0.001) nearly 50% reduction in the risk of intrathoracic progression

(P<0.001), significant difference in OS and PFS in patients who had residual

intrathoracic disease after CT

Conclusion: Consolidation RT to pts with good response or partial response to CT. Ongoing analysis

Still more than 40% of pts had local recurrence after TRT Higher dose to thorax Treatment of other metastatic sites?...

Treatment issues: Role of radiation for extra-cranial metastases

SCHEMA RTOG 0937

S

T

R

A

T

I

F

Y

1. CR vs PR to

ChT

2. 1 vs 2-4

metastatic

lesions

3. <65 vs >65

years

R

A

N

D

O

M

I

Z

E

Arm 1:

-PCI (25 Gy/10 fr)

Arm 2:

-PCI

-RT –Chest and

metastatic lesions

(45 Gy/15 fr

or 30-40 Gy/10 fr)

Required sample size: 154 pts

Statistical hypothesis: 1-yr survival 30% improved to 45%

Activated in 2010 Gore Elisabeth, Coordinator

RTOG 0937 Closed to accrual based on planned interim analysis (86/97

patients analysed) with MFU 9 mo

MF 9 mo, Observed OS exceeded predicted OS. Consolidative RT to thorax and extracranial mets delayed progression, did not improve OS

Control Arm

PCI arm

Investigational Arm

PCI + consolidation extra cranial RT

N patients 42 pts 44 pts

1 yr Survival 60.1% 50.8% (p=0,21)

1 yr rate of

any progress 79.6% 75%

Gr 4 and 5

toxicities 1 1/1

Gore E, ASTRO 2015

Irradiation prophylactique cérébrale (IPC)

Risque de rechute cérébrale : problème majeur

dans les CPC

45% à 2 ans chez des pts mis en RC

Chimiothérapie peu efficace comme prophylaxie

d ’une dissémination cérébrale (barrière

cérébro-méningée) mais efficace sur lésions

objectivables (RO : 70 %)

SM après découverte de métastases cérébrales

(MC) malgré traitement : 4.5 mois

Arriagada et al, JNCI 1995

PCI increases survival in responders

461 224 103 61 44 34 23 19 15

526 276 139 101 66 52 40 29 17

0,00

0,10

0,20

0,30

0,40

0,50

0,60

0,70

0,80

0,90

1,00

0 12 24 36 48 60 72 84 96

M onths since random izationAt risk

No PCI

PCI

Overall Survival3 yrs OS: 15.3% versus 20.7% in the PCI group

(p=0.01)

Auperin et al, NEJM 1999 Slotman et al, NEJM 2007

Metaanalysis of Aupérin et al

85% LD SCLC, 15% ED SCLC

Phase III EORTC study.

Slotman et al

100% ED SCLC

Seto, ASCO 2014

Control Arm PCI Arm p

Median

OS

5,4 mo 6,7mo <0,003

MA No PCI PCI p

Median OS 5,3 mo 5,9 mo =0,01

Slotman, NEJM 2007 Aupérin, NEJM 1999

Survie à 1 an: IPC ou pas d’IPC

Treatment algorythm for SCLC

*if no confirmation of solitary metastasis is obtained, RT may be added after 1st response evaluation and

may be omitted in case of obvious metastatic involvement

** or concomitant CTRT

Combined

CT-RT

SCLC ESMO guidelines 2011,2013

**

+ TRT in case of

extra thoracic response

and thoracic PR Proposition: changement standard

Take home message Etoposide and platinum remains the backbone of 1st

line treatment

As in non metastatic SCLC, progress in the outcome of

M1 patients

better integration of CT and RT: EP+ TRT+PCI in

responders (good and partial response) sequentially

after 4-6 cycles of CT with low toxicity

• PCI to responders, Japanese final results awaited

Need to pursue clinical trials in SCLC+++

Use the new TNM classification!

Merci de votre attention

Questions?