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!