VMAT-SBRT: Beneficio clínico-dosimétrico en cáncer ... · • RTOG 0617: Recidiva ganglionar N1...
Transcript of VMAT-SBRT: Beneficio clínico-dosimétrico en cáncer ... · • RTOG 0617: Recidiva ganglionar N1...
VMAT-SBRT: Beneficio clínico-dosimétrico en cáncer broncopulmonar
Dr Enrique CHAJON
Département de Radiothérapie
Centre Eugène Marquis
Rennes, France
Cancer Broncopulmonar
CBCNP localmente avanzado no operable
• Eligibles
• CBNPC stado IIIA - IIIB
• No-resécable o no-opérable
• Derrame pleural: citología negativa
• Atelectasia (si T identificable en PET scan)
• VEMS > 1-1,2 l/s o 40-50%; DLCO > 40%
• RTOG 0617: Recidiva ganglionar N1 o N2
(primitivo T1-T2 N0 tratado con cirugía sin
RT o CT adyuvante)
• No-eligibles
• N3 supra clavicular, escaleno o hilio
contra lateral ?
• Linfangitis péri-tumoral
• Derrame pleural o pericárdico tumoral
3
RT + CT en que momento?
4
OS
PFS
LC
OS PFS
6
RT CT concomitante
• CT consolidación:
• GFPC 95-01
• RTOG 0617
• RT-CT concomitante:
• RTOG 9410
• Inducción:
• CALGB 8831
• Secuencial:
• Reservado a pacientes frágiles
Podemos ir mas lejos en la dosis de RT?
7
Lancet Oncol 2015; 16: 187–99
Radiochimiothérapie. RTOG 0617
J. Bradley et al., WCLC 2013, PL-03.05
•D
esi
gn
•O
bje
ctif
pri
nci
pa
l :
surv
ie g
lob
ale
2 cycles CT
CBNPC
Stade IIIA/IIIB
PS 0-1
VEMS>1,5 l ou >50%
Bras B
RT 74 Gy 7,5 sm + CT
Bras A
RT 60 Gy 6 sm + CT
N = 544
R
Stratification :
IMRT vs 3D
PS (0 vs 1)
Staging (avec ou sans Pet)
Histologie (épi vs non épi)
2 cycles CT
2 cycles CT
+ Cetuximab
Bras B
RT 74 Gy 7,5 sm + CT
+ Cetuximab
Bras C
RT 60 Gy 6 sm + CT
+ Cetuximab
2 cycles CT
+ Cetuximab
CT: Carboplatine AUC 2, Paclitaxel 45 mg/m2
Cetuximab 400 mg/m2 puis 250 mg/m2
ConsolidationRadio-Chimio conco
Lecciones del estudio RTOG 0617
Como optimizar la dosis RT ?
3D CRT vrs VMAT
Rousseau D, et al. Cancer Radiother 2012
SMART (SIMULTANEOUS MODULATED ACCELERATED RADIATION THERAPY).
V20=23 cc
V50=30 cc
2,2 Gy/fr
1,8 Gy/fr
Œsophage
Chajon E, BJR 2015
Disminuir la toxicidad mejora el radio beneficio -
toxicidad
Experiencia CEM
Jaksic N, et al, in press, datos CEM
PACIFIC Study DesignPhase 3, randomized, double-blind, placebo-controlled, multi-center, global study1,2
* Response Evaluation Criteria In Solid Tumors v1.1
APF12 = proportion of patients alive and progression-free at 12 months; BICR = blinded independent central review; DoR = duration of response; IV = intravenously; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; OS24 = number (%) of patients who are alive at 24 months; PFS = progression-free survival; PK = pharmacokinetics; QoL = quality of life; q2w = every 2 weeks; SoC = standard of care; TTDM = time to death or distant metastasis.
1. US National Institutes of Health. A global study to assess the effects of MEDI4736 following concurrent chemoradiation in patients with stage III unresectable non-small cell lung cancer (PACIFIC). ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT02125461. Accessed May 16, 2017.
2. Paz-Arez A, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC. Presented at: European Society for Medical Oncology (ESMO) Annual Meeting; September 8-12, 2017; Madrid, Spain.
Randomization 2:1
1–42 days post-CRT
Treatments of patients with stage III unresectable NSCLC who have not progressed following platinum-based concurrent chemoradiation
Patients randomized = 713
Co-primary Endpoints Secondary Endpoints
• OS
• PFS*
• OS24
• DoR (per BICR)
• ORR (per BICR)
• APF12 and APF18
• TTDM
• Safety and tolerability
• Health-related QoL
• PK and immunogenicity
Durvalumab IV 10 mg/kg q2w up to 12
months (N=476)Placebo IV q2w (N=237)
Stratification factors
1.Age at randomization (<65
vs ≥65 years of age)
2.Sex (male vs female)
3.Smoking history (smoker
vs non-smoker)
PACIFIC Study – PFS by BICR
BICR = blinded independent central review; PFS = progression-free survival.
1. Paz-Arez A, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC. Presented at: European Society for Medical Oncology (ESMO) Annual Meeting; September 8-12, 2017; Madrid, Spain.
PF
S p
rob
ab
ility
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomization (months)
Placebo
Durvalumab
Stratified hazard ratio,
0.52 (95% CI, 0.42–0.65)
Two-sided P<0.0001
476 377 301 264 159 86 44 21 4
237 163 106 87 52 28 15 4 3
1
0
No. At Risk
Durvalumab
Placebo
Durvalumab
(N=476)
Placebo
(N=237)
Median PFS, months (95% CI) 16.8 (13.0–18.1) 5.6 (4.6–7.8)
12-month PFS rate, % (95% CI) 55.9 (51.0–60.4) 35.3 (29.0–41.7)
18-month PFS rate, % (95% CI) 44.2 (37.7–50.5) 27.0 (19.9–34.5)
PACIFIC Study – Time to Death or Distant Metastasis by BICR (ITT)
BICR = blinded independent central review; ITT = intent-to-treat; NR = not reached.
1. Paz-Arez A, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC. Presented at: European Society for Medical Oncology (ESMO) Annual Meeting; September 8-12, 2017; Madrid, Spain.
Months (95% CI) Durvalumab Placebo
Median time 23.2 (23.2-NR) 14.6 (10.6-18.6)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1 3 6 9 12 15 18 21 24 27 30
Pro
ba
bil
ity
of
de
ath
or
dis
tan
t m
eta
sta
sis
Hazard ratio, 0.52 (95% CI, 0.39–0.69)
Two-sided P<0.0001
Time from randomization (months)
Placebo
Durvalumab
No. At Risk
Durvalumab
Placebo
476 407 336 288 173 91 46 22 4 1 0
237 184 129 106 63 32 16 5 4 0 0
Y en SBRT?
• No invasivo
• BED optima
• Hipo fraccionamiento
• Numero reducido de sesiones
(3-10)
•Alta eficacidad
•Poco toxico
Efficace pour les histologies radiorésistents
20
Am J Clin Oncol 2013;36:589-595 IJROBP 2012;82:940-945
Cancer du Rein Sarcome
21
Realizable en el paciente fragil
Analyse systématique de donnés de la littérature (non opérables)
• 45 articles (3641 pts non opérables)
• 86% stades I
Solda et al. Radiother Oncol 2013
Control local à 2ans: 91% Survie Globale à 2ans: 70%
SBRT: Patients opérables
23
SBRT
Surgery
Experience Rennes
SFRO 2017
SBRT: QoL
24
Drug-Radiotherapy combinations
Chemotherapy: cisplatin,
5-FU, temozolomide, taxanes,
etc…
VEGF inhibition: bevacizumab, cediranib
EGFR inhibition: cetuximab, panitumumab,
gefitinib, erlotinib, AZD9291…
mTOR inhibition:
everolimus, temsirolimus,
rapamycin…
PIK3 inhibition: BKM
120…
AKT inhibition: nelfinavir,
XL765…
MEK inhibition: AZD6244…
c-MET inhibition: ficlatuzumab…
PARP inhibition: olaparib…
ATR inhibition: AZD6738…
CTLA-4 blockade: ipilimumab, tremelimumab…
PD-1 blockade: nivolumab, lambrolizumab,
pembrolizumab, AMP-224…
PDL-1 blockade: atezolizumab, MEDI4736…
Hypoxic Modifiers: nimorazole,
tirapazamin, metformin
ALK inhibition: crizotinib…
Optimisation des thérapies ciblés (EGFR, ALK …..)
26IJROBP 2014;88:892-898
Effet immunomodulateur
DNAdouble-strandbreaks
Reassortment of tumor cells intoradiosensitivephases of the
cell cycle (G2/M)
Reoxygenationof hypoxic areas
Repair of sublethal DNA
damage
Repopulation of surviving tumor
cells
Killing of cancer cells.
Release of cancer cell antigens
Cancer Ag présentation (dendritic cells/APCs)
Priming and activation (APCs
& T cell)
Trafficking of T cellsto tumors (CTLs)
Infiltration of T cellsinto tumors (CTLs)
Recognition of cancer cells by T cells (CTLs,
cancer cells) CANCER
Lymph node
Blood
vessel
SBRT et immunothérapia
• 98 patients
28
Extra-cérébrale
Lan
cet O
nco
l2
01
7; 1
8: 8
95
–9
03
Translational Researche
Vanpouille-Box C, et al. Nature Comm 2017
Breast cancer cells
Patient-derived TP53/KRAS-mutated lung adenocarcinoma xenograft
Conclusion
• La VMAT y la SBRT han demostrado su beneficio dosimétrico
• EL impacto clínico es significativo:
• en la administración de dosis eficaces
• y en la reducción de la toxicidad
• Su alta eficiencia y precisión la hacen una de las técnicas de elección en combinación con IGRT para mejorar los resultados en NSCLC
Muchas gracias por su atención!