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Radioterapia Intraoperatoria:
Posicionamiento tecnológico y clínico
Prof. Felipe A. Calvo
Departamento de Oncología
Hospital General Universitario Gregorio Marañón 1995-2014
VIII Jornadas Internacionales
Hospital Universitario Ramon y Cajal, Junio 2014
Dedicado a los Dres. Hugo Marsiglia y Alfredo Ramos,
impulsores incansables de la formación avanzada en Oncología Radioterápica
“Latido a latido, lección a lección, paciente a paciente, residente a residente…”
Radioterapia Intraoperatoria: en el tablero de los avances tecnológicos
Posicionamiento…. Clínico…
Estructura: “5 top” temas selectos
• Definición y descripción: los fundamentos…
• Perspectiva histórica: oncología evolutiva…
• Entorno académico: práctica clínica innovada…
• Versatilidad asistencial: los mimbres hospitalarios…
• Posicionamiento bio-tecnológico: reto y fugacidad…
Argumentos para escépticos…
3 decadas… un resumen
Es radioterapia…
Es radioterapia precisa…
Es un componente de RT super-precisa para intensificar dosis…
Es una alternativa eficiente para RT subintensificada equivalente …
Añade un margen radiobiológico de seguridad al quirúrgico…
No interfiere con el tratamiento sistémico…
Fundamentos: Definición
Radioterapia durante cirugía de cancer
Protección de tejidos normales ( desplazamiento temporal)
Mínima carga tumoral (estado post–resección)
Fundamentos: Descripción
Radioterapia guiada por la visión
Radioterapia guiada por el tacto
Radioterapia guiada por la cirugía
Estructura: “5 top” temas selectos
• Definición y descripción: los fundamentos…
• Perspectiva histórica: oncología evolutiva…
• Entorno académico: práctica clínica innovada…
• Versatilidad asistencial: los mimbres hospitalarios…
• Posicionamiento bio-tecnológico: reto y fugacidad…
Historical Perspective
Phase III breast cancer IEO/Targit
Electrons / Low X-rays
Phase III rectal French
Data
NCI Phase III
European pooled-analysis pancreas / rectum / breast / sarcomas
RTOG Phase I-II
Systematic literature reviews
Experimental animal normal tissues tolerance studies
1905 Barcelona
1965 Kyoto
1978 Washington
90´s
80’s
82 Europe
Events
Productivity
&
Relevance
Miniaturized
LA
21rst
98 Foundation
ISIORT
ISIORT–Europe
Registry
ISIORT-Europe
GEC-ESTRO
Collaboration
1997
IORT TPS
patent
>50 miniLINACS IORT
2007
2010
694 PubMed > 1.300, 300 IF
104 PubMed 277,856 IF
1999 Textbook
1rst edition
2011 Textbook
2nd edition
Historical Perspective
Phase III breast cancer IEO/Targit
Electrons / Low X-rays
Phase III rectal French
Data
NCI Phase III
European pooled-analysis pancreas / rectum / breast / sarcomas
RTOG Phase I-II
Systematic literature reviews
Experimental animal normal tissues tolerance studies
1905 Barcelona
1965 Kyoto
1978 Washington
90´s
80’s
82 Europe
Events
98 Foundation
ISIORT
ISIORT–Europe
Registry
ISIORT-Europe
GEC-ESTRO
Collaboration
Implantation & Learning curve
Productivity
&
Relevance
Miniaturized
LA
21rst
Initial results, toxicity & indications
selection
IORT TPS
patent
>50 miniLINACS IORT
Technological optimization
long-term results
collaborative science
1997
2007
2010
694 PubMed > 1.300, 300 IF
104 PubMed 277,856 IF
1999 Textbook
1rst edition
2011 Textbook
2nd edition
Contribución académica: oncología multidisciplinar
Local therapy
Local tumor control promotion
Dose–escalation (improvement)
Dose–de–escalation (equivalence)
Survival
• Intensificación topográfica
• Radioterapia dosis-densa y dosis-intensa (tiempo de tratamiento acortado)
Estructura: “5 top” temas selectos
• Definición y descripción: los fundamentos…
• Perspectiva histórica: oncología evolutiva…
• Entorno académico: práctica clínica innovada…
• Versatilidad asistencial: los mimbres hospitalarios…
• Posicionamiento bio-tecnológico: reto y fugacidad…
Bibliometric Analysis of Intraoperative Radiotherapy (IORT)
Strahlenther Onkol accepted 2014
• Pubmed Data Review From 1997 to 2012
• 858 IORT papers from 207 journals;
281 medical institutions from 32 countries.
• Topics:
1)Clinical 671, (78%)
a) Cancer outcome results 548 (64%) b) toxicity 123 (14%))
2)Physics and/or technology 153 (18%)
3)Radiobiology 34 (4%).
Bibliometric Analysis of Intraoperative Radiotherapy (IORT)
• Median impact factor of IORT publications of the last 15 years has
increased progressively:
1997-2001 (348 articles; 2.396);
2002-2006 (322 articles; 3.135)
(p=0.006)
2007-2012 (188; 3.798)
• Superior median impact factor was related to:
breast cancer (134 publications; 3.791)
soft tissue sarcoma (65 publications; 3.284)
colorectal (148 publications; 3.166)
pancreas cancer (158 publications; 2.907).
Bibliometric Analysis of Intraoperative Radiotherapy (IORT)
• The articles by journal distribution in the 3 more frequent:
International Journal of Radiation Oncology Biology and Physics 11 (13%)
Annals of Oncology 32 (4%)
Radiotherapy and Oncology 32 (4%).
• The most frequent geographical origin of publications were:
European (392; 46%)
USA (276; 32%)
Japan (121;14%)
Top ten
quantity citation index journals
207 journals
IORT clinical publications: methodology
Estructura: “5 top” temas selectos
• Definición y descripción: los fundamentos…
• Perspectiva histórica: oncología evolutiva…
• Entorno académico: práctica clínica innovada…
• Versatilidad asistencial: los mimbres hospitalarios…
• Posicionamiento bio-tecnológico: reto y fugacidad…
Estructura: versatilidad clínica
• Tecnológica/Dosimétrica
• Estrategia radioterápica: intensificación/equivalencia
• Entorno intra-hospitalario: gestión
• Entorno extra-hospitalario: I + D+ i
Fundaments: Technology
Electron beams
Brachytherapy
Low energy X-Rays
Estructura: versatilidad clínica
• Tecnológica/Dosimétrica
• Estrategia radioterápica: intensificación/equivalencia
• Entorno intra-hospitalario: gestión
• Entorno extra-hospitalario: I + D+ i
“To IORT or not to IORT…”
ESCALATION (Anticipated boost + EBRT)
(EBRT-CT + Delayed boost)
IORT/DOSE
(COMPONENT)
EQUIVALENCE (boost + ½ EBRT)
DE-ESCALATION ( boost alone )
Disease Models for Dose–escalation: Results
iORT is a precise anticipated RT boost
• Pancreatic cancer (unresectable)
• Pancreatic cancer (border-line / resectable)
• Gastro-esophageal cancer
• Locally advanced rectal cancer
• Soft tissue sarcomas
• Breast cancer
• Mono-oligotopic recurrent cancer
IORT Results: Locally advanced unresectable pancreatic cancer
3 decades… a summary
1981-2005, 23 Institutions, 862 patients
8-16 months median survival time (12 months)
50-100% pain relieve effect (80%)
2011
2005
1978-2001, 150 patients, MGH-Boston
13 months MST, 8 long-term survival
<6 cm ᴓ applicator 17% 3-y OS
IORT Results: Locally advanced unresectable pancreatic cancer
3 decades… a summary
2000-2006, 870 patients, 34 Institutions
21% investigational protocol,44% EBRT
76% concomitant gemcinabine, 75% IORT dose>25Gy
2011
2000-2006, 144 patients, 34 institutions
Local control 51%, 2 years
EBRT 50 Gy + IORT= LC 71%
Survival CT 18% vs 0% 2 years
2011
IORT Results: Soft tissue sarcomas
3 decades… a summary
180-185, 35 patients, NCI-Bethesda
PTS
LC
(in-field)
DFS
(mo)
IORT
(20Gy+40Gy)
15
68%
20
no IORT
(50Gy-55Gy)
20
22%
38
R
1988
Acute enteritis 1 vs 12,
chronic enteritis 2 vs 7,
fistula 0 vs 6 (significant)
1988-2008, 1173 patients, 18 Institutions
In-field failure 20%-60% (32%)
OS @ 5-y 36%-48% (DFS 28%)
2011
IORT Results: breast cancer (anticipated boost)
1997-2009, 2.301 patients, 16 Institutions
Local recurrence (in-breast) 0-4% (1,8%)
2011
Median follow-up 25-109 months (70 mo)
1998-2005, 1.231 patients, ISIORT-Europe, 10Gy boost
Salzburg, Montpellier, Gemelli, San F. Neri, IEO, Münster
1,4% in-breast recurrence (8/16 in-quadrant)
2007
89% OS @ 10-years (MFT 73 moths)
3 decades… a summary
IORT Results: breast cancer (anticipated boost)
1998-2005
300 patients
20Gy boost + 50Gy whole-breast
1,7% local recurrences @ 5-years (in-breast)
2010
1,0% in-quadrant
2004-2007, 211 premenopausal pts (46% adjuvant CT)
12Gy boost + hypofractionated RT (2,85Gy x 13f)
0% in-breast recurrence
Maximal acute toxicity skin toxicity 67% G1, 28% G2, 4% G3
2008
3 decades… a summary
1109 pts ISIORT-Europe
MFT 72 months
99,2% local control
Grade 3 (p = 0.03)
IORT Results: colo-rectal recurrent cancer Mayo Clinic
3 decades… a summary
1981-2008, Mayo Clinic (>25 years experience)
607 patients (rectal 70%), recurrent 45% previous RT, R0 85%
LC 68% @ 5-y, 30% OS
Central-control vs prior EBRT (18% vs 14%), R0/R+(11% vs 9%)
Survival affected by Rstatus, CT, before/after 1997
2011
Oligo-recurrencia cáncer ginecológico
Oligo-recurrencia cáncer rectal y renal
Radioterapia Intraoperatoria:
Resultados en oligo-recurrencia: actualización 1984-2014
Cáncer
N
CL %
SV 5 años
Adversidad
factor
Compensación
riesgo
Ginecológico1
61
69
42
No EBRT
Para-aórtico
Recto1
60
44
39
No EBRT
R1
Fragmentación
Sarcoma 2
103
64
52
No EBRT
R1
Fragmentación
Grado
Histológico
Renal3
98
72
43
Recurrente
N+
R1
1, HGUGM
2
3
HGUGM, HRyC, CUN
HGUGM, CUN, MGH, Heidelberg
Disease Models for Dose–escalation: Results
iORT is a precise delayed RT boost
Opportunity to select the boost for post-neoadjuvant adversity
• Pancreatic cancer (unresectable)
• Pancreatic cancer (border-line / resectable)
• Gastro-esophageal cancer
• Locally advanced rectal cancer
• Soft tissue sarcomas
• Breast cancer
• Mono-oligotopic recurrent cancer
IORT Results: pancreatic cancer post-resected
1985-2009, 778 patients, 23 Institutions
9-19 months MST (16 mo)
9%-55% local recurrence
2011
1985-2006, 270 patients,
Gemelli, San Rafaelle, Marañón, Heildelberg, Paracelsus
Local control @ 5-y 23% (T3-4, R2, N+)
OS 5-y 18% (preoperative CRT NST 30 MO vs 20 MO)
2009
3 decades… a summary
IORT Results: pancreatic cancer post-resected
2008
1984-2002, 14 Journal articles, 789 patients
Palliative surgery + IORT
0-3% OS @ 5-years
Curative surgery + IORT
6-22% OS @ 5years
Curative surgery + IORT + EBRT
7-27% OS @ 5-years
3 decades… a summary
60 pts resected
1995-2010
29 non-IOERT pts
vs
31 IOERT pts
Pancreatology 2014
pN+ exclusive for LRR
IORT Results: Locally advanced rectal cancer
1994 – 2006
290 patients preop RT (70% CRT)
13% local recurrence, 5% presacral,
,
(distal, R+, 48% outside IORT field)
2009
67% cancer-specific survival @ 5-years
1989 – 2005
605 patients Catharina, Marañón, Gemelli, Heidelberg
12% local recurrence @ 5-y (downstaged,N+,R+,adjuvant CT)
68% OS @ 5-y (male,>70 years,no-downstaging,N+,R+,CT)
“Seed and soil” adjuvant chemotherapy on LC
2010
Prognostic index model
3 decades… a summary
IORT Results: Locally advanced rectal cancer
3 decades… a summary
1993 – 2001 / 7 French institutions
R
2011
PTS
LC
OS
Complications
IORT (1Gv)
73
91%
70%
29%
no IORT
69
92%
74%
19%
“Technical feasibility for future phase III trials”
2000 – 2009 publications, 15 articles (quality selection)
1755 patients
10% reduction in LR over the IORT area
2011
Safety
Primary
Recurrent
Acute *
0,7% - 22%
2% - 20%
Late
11% - 30%
5,4% - 74%
Efficacy (LR 5y)
6% - 12%
32% - 46%
* Except incontinence evaluation
335 pts
1995-2010
MFT 72 months
IOERT in-field control 96%
R & O accepted 2014
125 pts
2005-2010
44 (35%) laparoscopic IOERT
Median hospital stay 0.02
Median blood transfusion 0.01
J Cancer Res Clin Oncol 2014
CRM < 2 mm
CRM +
Disease Models for Dose–escalation: Results
iORT is a precise exclusive RT boost
• Pancreatic cancer (unresectable)
• Pancreatic cancer (border-line / resectable)
• Gastro-esophageal cancer
• Locally advanced rectal cancer
• Soft tissue sarcomas
• Breast cancer
• Mono-oligotopic recurrent cancer
Disease Model for Dose–escalation
Out-trial patients ELIOT
• Breast cancer: dose de-escalation 21 Gy
• Cardiac protection + single day RT
Adverse features:
21 Gy IOeRT alone
21 Gy single – ELIOT(out trial)
1.9% / 7.4% / 7.7%
2.2% / 0.7% / 1.3%
N=1808
573/468/767
Leonardi MC: Rad Onc 2012
IORT alone Result: Breast cancer (De-escalation studies)
3 decades… a summary
2000-2008, 1.822 patients, IEO-Milan, T<2,5cm
21Gy alone, MFT 36 months
1,3% in-breast ipsilateral,2,3% in-quadrant,89 OS @ 10-y
LC influenced by age,size-N,Cerb+++,grade,perineural
2010
“Suitable”
1.5% at 5-y
“Good”
1.9% at 5-y
ELIOT
Randomized Clinical Trial
T< 2.5 cm
R
BCS +
BCS +
Conventional RT
(50 + 10 Gy / 6 weeks)
IOeRT
(21 Gy / 1 day)
B
IOeRT 21 Gy - ELIOT
EBRT
RL– 5 y
ELIOT
p
4 (0.4%)
21 (2.5%)
0.0003
0
14 (1.9%)
0.0001
TOTAL
LOCAL
4 (0.4%)
35 (4.4%)
<0.0001
Relapse
Axilar/gang
2 (0.3%)
9 (1%)
0.03
LRR
6 (0.8%)
44 (5.4%)
<0.0001
Contralateral
13 (1.7%)
8 (1.1%)
0.34
Metastases
35 (4.8%)
33 (5.1%)
0.94
New 1º ipsi
Veronesi U.: Lancet 2013
91 pts
15-20 Gy + CT
Postop RT + CT
73 vs 71 % LC
Results for sceptics…
3 decades… a summary
IORT…
Is radiotherapy… feasible and tolerable
Is precise radiotherapy… able to be planned and registered
Is a precise component of RT for dose-escalation…
50Gy + 10/15Gy IORT LC >90% R0
50Gy + 10/15Gy IORT LC >60% R1/2
Is an efficient alternative for RT dose-de-escalation…
20-21Gy LC >95% R0
Adds a radiobiological safety margin to surgical resection…
Does not interferes with systemic therapy…
Estructura: versatilidad clínica
• Tecnológica/Dosimétrica
• Estrategia radioterápica: intensificación/equivalencia
• Entorno intra-hospitalario: gestión
• Entorno extra-hospitalario: I + D+ i
Estructura: versatilidad clínica
Entorno intra-hospitalario: gestión
• Visibilidad OR en los equipos quirúrgicos
• Relación preferente (selecta, “entre iguales”) cirujanos I + D + i
• Comité de Tumores: programación anticipada de indicación RT
• Acreditación Cum Laude de coordinación multiprofesional
• Quirófano adicional
• Cultura de la interdisciplinariedad (sesiones de evaluación RIO)
Estructura: versatilidad clínica
• Tecnológica/Dosimétrica
• Estrategia radioterápica: intensificación/equivalencia
• Entorno intra-hospitalario: gestión
• Entorno extra-hospitalario: I + D+ i
Organizative & Collaborative projects
3 decades… a summary
ISIORT –Europe registry
ISIORT-Europe / GEC-ESTRO joint meetings
Montpellier 2007, Porto 2009, London 2011, Vienna 2013
Pooled analysis projects USA-Europe-(Japan)
ISIORT 2014 Cologne (German Breast Cancer Conference)
September 2014
Estructura: “5 top” temas selectos
• Definición y descripción: los fundamentos…
• Perspectiva histórica: oncología evolutiva…
• Entorno académico: práctica clínica innovada…
• Versatilidad asistencial: los mimbres hospitalarios…
• Posicionamiento bio-tecnológico: reto y fugacidad…
Radioterapia Intraoperatoria: avances tecnológicos
Posicionamiento…. Clínico…
> 20% RT
> 40% IOERT
Oligocancer
Surgical margins
Topography LR
RT progress
Radioterapia Intraoperatoria: avances tecnológicos
Posicionamiento…. Bio-modelos-outcome…
From physical dose outcome analysis…
Physical dose
EBRT
Physical dose
IORT
+
Physical
dose total
=
To biomodeling dose-dense IOERT containing results:
pooled sarcoma data
BED
RT
BED
IORT
+
Polo et al. ASTRO 2012
BED
total
=
Radioterapia Intraoperatoria: avances tecnológicos
Posicionamiento…. Tecno-modelos-guiado/seguridad…
The past, The present, the future
The Past
The present
3 decades… a summary
The future
Tissue tolerance knowledge
Standardization procedures (Surgery + Radiotherapy)
Patient transportation
The past, the present, the future
The past
The Present
3 decades… a summary
The future
Miniaturized IORT dedicated technology
IOERT TPS, real-time radio-surgical navigation
Dose-escalation vs Dose-de-escalation alternatives trials
The past, The present, the future
The past
The present
3 decades… a summary
The Future
Tailored / individualized oncology & IORT
Nomogram guided IORT
Molecular guided IORT
“Making friends”: IMRT/IGRT + IORT (super-hypofrationated RT)
Posicionamiento clínico: entorno de avances tecnológicos
• Definición y descripción: los fundamentos…
Alianza quirurgica = exacto-precisión y protección de tejidos normales
• Perspectiva histórica: oncología evolutiva…
3 decadas consolidadas de control local y supervivencia
• Entorno académico: práctica clínica innovada…
Éxito en estrategias de boost anticipado, retrasado y exclusivo (modelos)
• Versatilidad asistencial: los mimbres hospitalarios…
Incorporable al 40% de la práctica clínica radioterápica
• Posicionamiento bio-tecnológico: reto y fugacidad…
Hibridos SBRT-IGRT-IMRT e hipofraccionamiento; externalizar I+D+i
IORT Results: Polivalent indications
3 decades… a summary
Cancer sites not reviewed
• Gastric cancer
Fu et al. Int J Radiat Oncol Biol Phys 2008;72:1488-94
Drognitz et al. Int J Radiat Oncol Biol Phys 2008; 70:715-721
EBRT vs EBRT+IORT 46 vs 57% 3-y
• Head and neck cancer
Most et al. Laryngoscope 2008;118:69-74
Mauricci et al. Head Neck 2008;30:701-8
Perry et al. Int J Radiat Oncol Biol Phys 2010;76:1140-6
Zeidan et al. Int J Radiat Oncol Biol Phys 2011;April 20
• Renal cell carcinoma
Hallemeier et al. Int J Radiat Oncol Biol Phys 2011;April 20
Central recurrence 9%, LR 27%, 5-y
• Cervix cancer
Giordia et al. Eur J Surg Oncol 2011;37:442-7
Survival CRT + IORT 49% 5-y
• Lung cancer
Torre W et al. Thorac Cardiovasc Surg 2009;57:353-7
Local in-field recurrence 34%
• Prostate cancer
Saracino et al. Int J Radiat Oncol Biol Phys 2008;71:1049-56
Rocco et al. BJU Int. 2009;104:1624-30
Krengli et al. Int J Radiat Oncol Biol Phys. 2010;76:1073-7
• Pediatric solid tummors
Kunieda et al. Jpn J Clin Oncol 2008;38:562-6
Rich et al. J Pediatr Surg 2011;46:97-102
Stauder et al. J Pediatr Hematol Oncol 2010;33:350-5
Local control 50% 5-y (recurrent)
• Cholangiocarcinoma
Kaiser et al. Hepatogastroenterology 2008;55:1951-4
Survival 23 mo vs 9 mo, 42% vs 0% 2-y
• Bone sarcomas
Calvo et al. Intraoperative Irradiation 2nd 2011
Survival 57% @ 25-y