Posicionamiento tecnológico y clínico de la RIO frente a los avances

Radioterapia Intraoperatoria: Posicionamiento tecnológico y clínico

Prof. Felipe A. Calvo

Departamento de Oncología

Hospital General Universitario Gregorio Marañón 1995-2014

VIII Jornadas InternacionalesHospital 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…

• 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: “5 top” temas selectos

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







Productivity &

Relevance

694 PubMed > 1.300, 300 IF 104 PubMed 277,856 IF

1997 2007 2010

1999 Textbook1rst edition

2011 Textbook2nd edition

Historical Perspective

Events

80’s 90´s 21rst1905 Barcelona

1965 Kyoto

1978 Washington

98 Foundation ISIORT

MiniaturizedLA

ISIORT-Europe GEC-ESTRO

Collaboration

ISIORT–Europe Registry

IORT TPSpatent

>50 mini-LINACS IORT

82 Europe

Phase III breast cancer IEO/TargitElectrons / Low X-rays

European pooled-analysis pancreas / rectum / breast / sarcomas

RTOG Phase I-II

Phase III rectal French

NCI Phase III

Systematic literature reviews

Data

Experimental animal normal tissues tolerance studies

Implantation & Learning curve Initial results, toxicity & indicationsselection

Technological optimization long-term results

collaborative science

Productivity &

Relevance

694 PubMed > 1.300, 300 IF 104 PubMed 277,856 IF

1997 2007 2010

1999 Textbook1rst edition

2011 Textbook2nd edition

Historical Perspective

Events

80’s 90´s 21rst1905 Barcelona

1965 Kyoto

1978 Washington

98 Foundation ISIORT

MiniaturizedLA

ISIORT-Europe GEC-ESTRO

Collaboration

ISIORT–Europe Registry

IORT TPSpatent

>50 mini-LINACS IORT

82 Europe

Phase III breast cancer IEO/TargitElectrons / Low X-rays

European pooled-analysis pancreas / rectum / breast / sarcomas

RTOG Phase I-II

Phase III rectal French

NCI Phase III

Systematic literature reviews

Data

Experimental animal normal tissues tolerance studies

Local therapy

Local tumor control promotion

Dose–escalation (improvement)

Dose–de–escalation (equivalence)

Survival

Contribución académica: oncología multidisciplinar

• Intensificación topográfica

• Radioterapia dosis-densa y dosis-intensa (tiempo de tratamiento acortado)







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%).

• 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%)

Bibliometric Analysis of Intraoperative Radiotherapy (IORT)

Top ten quantity citation index journals

207 journals

IORT clinical publications: methodology







• Tecnológica/Dosimétrica

• Estrategia radioterápica: intensificación/equivalencia

• Entorno intra-hospitalario: gestión

• Entorno extra-hospitalario: I + D+ i

Estructura: versatilidad clínica

Fundaments: Technology

Electron beams

Brachytherapy

Low energy X-Rays






“To IORT or not to IORT…”

IORT/DOSE

(COMPONENT)

ESCALATION (Anticipated boost + EBRT)

(EBRT-CT + Delayed boost)

EQUIVALENCE (boost + ½ EBRT)

DE-ESCALATION ( boost alone )

Disease Models for Dose–escalation: Results

• 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 is a precise anticipated RT boost

IORT Results: Locally advanced unresectable pancreatic cancer3 decades… a summary

1981-2005, 23 Institutions, 862 patients

8-16 months median survival time (12 months)

50-100% pain relieve effect (80%)

1978-2001, 150 patients, MGH-Boston

13 months MST, 8 long-term survival

<6 cm ᴓ applicator 17% 3-y OS

2011

2005

IORT Results: Locally advanced unresectable pancreatic cancer3 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


OS @ 5-y 36%-48% (DFS 28%)

R PTSLC

(in-field)

DFS

(mo)

IORT

(20Gy+40Gy)

15 68% 20

no IORT

(50Gy-55Gy)

20 22% 38

Acute enteritis 1 vs 12,

chronic enteritis 2 vs 7,

fistula 0 vs 6 (significant)

1988

2011

In-field failure 20%-60% (32%)

IORT Results: breast cancer (anticipated boost) 3 decades… a summary

1997-2009, 2.301 patients, 16 Institutions

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

89% OS @ 10-years (MFT 73 moths)

Local recurrence (in-breast) 0-4% (1,8%)

2011

2007

1,4% in-breast recurrence (8/16 in-quadrant)

IORT Results: breast cancer (anticipated boost) 3 decades… a summary

1998-2005

300 patients

20Gy boost + 50Gy whole-breast

1,0% in-quadrant

2004-2007, 211 premenopausal pts (46% adjuvant CT)

12Gy boost + hypofractionated RT (2,85Gy x 13f)

Maximal acute toxicity skin toxicity 67% G1, 28% G2, 4% G3

2010

2008

1,7% local recurrences @ 5-years (in-breast)

0% in-breast recurrence

1109 pts ISIORT-Europe

MFT 72 months

99,2% local control

Grade 3 (p = 0.03)

IORT Results: colo-rectal recurrent cancer Mayo Clinic3 decades… a summary

1981-2008, Mayo Clinic (>25 years experience)

607 patients (rectal 70%), recurrent 45% previous RT, R0 85%

Survival affected by Rstatus, CT, before/after 1997

2011

LC 68% @ 5-y, 30% OS

Central-control vs prior EBRT (18% vs 14%), R0/R+(11% vs 9%)

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 Adversidadfactor

Compensaciónriesgo

Ginecológico1 61 69 42 No EBRT Para-aórtico

Recto1 60 44 39 No EBRTR1

Fragmentación

Sarcoma 2 103 64 52 No EBRTR1

Fragmentación Grado Histológico

Renal3 98 72 43 RecurrenteN+

R1

1, HGUGM2 HGUGM, HRyC, CUN3 HGUGM, CUN, MGH, Heidelberg







• Breast cancer


iORT is a precise delayed RT boost

Opportunity to select the boost for post-neoadjuvant adversity

IORT Results: pancreatic cancer post-resected 3 decades… a summary


9-19 months MST (16 mo)

1985-2006, 270 patients,

Gemelli, San Rafaelle, Marañón, Heildelberg, Paracelsus

OS 5-y 18% (preoperative CRT NST 30 MO vs 20 MO)

2011

9%-55% local recurrence

2009

Local control @ 5-y 23% (T3-4, R2, N+)

IORT Results: pancreatic cancer post-resected 3 decades… a summary

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

2008

60 pts resected

1995-2010

29 non-IOERT pts

vs

31 IOERT pts

Pancreatology 2014

pN+ exclusive for LRR

1994 – 2006

290 patients preop RT (70% CRT)

,

(distal, R+, 48% outside IORT field)

67% cancer-specific survival @ 5-years

1989 – 2005

605 patients Catharina, Marañón, Gemelli, Heidelberg

68% OS @ 5-y (male,>70 years,no-downstaging,N+,R+,CT)

“Seed and soil” adjuvant chemotherapy on LC

Prognostic index model

IORT Results: Locally advanced rectal cancer 3 decades… a summary

12% local recurrence @ 5-y (downstaged,N+,R+,adjuvant CT)

2009

13% local recurrence, 5% presacral,

2010

1993 – 2001 / 7 French institutions

2000 – 2009 publications, 15 articles (quality selection)

1755 patients

10% reduction in LR over the IORT area

IORT Results: Locally advanced rectal cancer 3 decades… a summary

R PTS LC OS Complications

IORT (1Gv) 73 91% 70% 29%

no IORT 69 92% 74% 19%

“Technical feasibility for future phase III trials”

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

2011

2011

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 +







• Breast cancer


iORT is a precise exclusive RT boost

Disease Model for Dose–escalation

• Breast cancer: dose de-escalation 21 Gy

• Cardiac protection + single day RT

Out-trial patients ELIOT

Adverse features:

21 Gy IOeRT alone

21 Gy single – ELIOT(out trial)

Leonardi MC: Rad Onc 2012

1.9% / 7.4% / 7.7% 2.2% / 0.7% / 1.3%

N=1808

573/468/767

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

2010

LC influenced by age,size-N,Cerb+++,grade,perineural

“Suitable”

1.5% at 5-y

“Good”

1.9% at 5-y

ELIOT

T< 2.5 cm

BCS +IOeRT

(21 Gy / 1 day)

R

Randomized Clinical Trial

BCS +Conventional RT

(50 + 10 Gy / 6 weeks)

B

IOeRT 21 Gy - ELIOT

EBRT ELIOT p

RL– 5 y 4 (0.4%) 21 (2.5%) 0.0003

New 1º ipsi 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

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…






• 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)


Entorno intra-hospitalario: gestión






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







Radioterapia Intraoperatoria: avances tecnológicos

Posicionamiento…. Clínico…

http://www.ajedrez32.com/wp-content/uploads/2008/12/salvapantallas-5.bmp

> 20% RT

> 40% IOERT

Oligocancer

Surgical margins

Topography LR

RT progress


Posicionamiento…. Bio-modelos-outcome…


Physical dose

EBRT

Physical dose

IORT

Physical

dose total

+ =

From physical dose outcome analysis…

BED

RT

BED

IORT

BED

total

+ =

To biomodeling dose-dense IOERT containing results:

pooled sarcoma data

Polo et al. ASTRO 2012


Posicionamiento…. Tecno-modelos-guiado/seguridad…


The past, The present, the future 3 decades… a summary

Tissue tolerance knowledge

Standardization procedures (Surgery + Radiotherapy)

Patient transportation

The Past The present The future

The past, the present, the future 3 decades… a summary

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, the future 3 decades… a summary

Tailored / individualized oncology & IORT

Nomogram guided IORT

Molecular guided IORT

“Making friends”: IMRT/IGRT + IORT (super-hypofrationated RT)

The past The present The Future


Alianza quirurgica = exacto-precisión y protección de tejidos normales


3 decadas consolidadas de control local y supervivencia


Éxito en estrategias de boost anticipado, retrasado y exclusivo (modelos)


Incorporable al 40% de la práctica clínica radioterápica


Hibridos SBRT-IGRT-IMRT e hipofraccionamiento; externalizar I+D+i

Posicionamiento clínico: entorno de avances tecnológicos


Cancer sites not reviewed

• Gastric cancer Fu et al. Int J Radiat Oncol Biol Phys 2008;72:1488-94Drognitz et al. Int J Radiat Oncol Biol Phys 2008; 70:715-721

• Head and neck cancerMost et al. Laryngoscope 2008;118:69-74Mauricci et al. Head Neck 2008;30:701-8Perry et al. Int J Radiat Oncol Biol Phys 2010;76:1140-6Zeidan et al. Int J Radiat Oncol Biol Phys 2011;April 20

• Prostate cancerSaracino et al. Int J Radiat Oncol Biol Phys 2008;71:1049-56Rocco et al. BJU Int. 2009;104:1624-30Krengli et al. Int J Radiat Oncol Biol Phys. 2010;76:1073-7

• Pediatric solid tummorsKunieda et al. Jpn J Clin Oncol 2008;38:562-6Rich et al. J Pediatr Surg 2011;46:97-102Stauder et al. J Pediatr Hematol Oncol 2010;33:350-5

• Renal cell carcinomaHallemeier et al. Int J Radiat Oncol Biol Phys 2011;April 20

• Cervix cancerGiordia et al. Eur J Surg Oncol 2011;37:442-7

• Lung cancerTorre W et al. Thorac Cardiovasc Surg 2009;57:353-7

• CholangiocarcinomaKaiser et al. Hepatogastroenterology 2008;55:1951-4

• Bone sarcomas Calvo et al. Intraoperative Irradiation 2nd 2011

IORT Results: Polivalent indications 3 decades… a summary

EBRT vs EBRT+IORT 46 vs 57% 3-y

Local in-field recurrence 34%

Local control 50% 5-y (recurrent)

Central recurrence 9%, LR 27%, 5-y

Survival 23 mo vs 9 mo, 42% vs 0% 2-y

Survival CRT + IORT 49% 5-y

Survival 57% @ 25-y

Documents

Posicionamiento tecnológico y clínico de la RIO frente a los avances