place de la radiothérapie dans les cbpc métastatiques...murray et al (jco 1993) ct only possible...
TRANSCRIPT
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?