IORT im multimodalen. Salzburg, Austria

Transcription

1 Stellenwert der IORT im multimodalen Behandlungskonzept Felix Sedlmayer Salzburg, Austria

2 Definition IORT refers e to the delivery e of irradiation at at surgery. A large single dose of irradiation is delivered to a surgically defined area, while uninvolved and dose-limiting iti tissues are displaced. The final goal of IORT being enhanced locoregional tumor control. Gunderson LL, Willet CG, Harrison LB, Calvo FA 23/02/2016 Gemeinnützige Salzburger 2 Landeskliniken Intraoperative Betriebsges.m.b.H Irradiation

3 IORT : Hypofraktionierung par excellence! Klassische Argumente Visuelle Kontrolle des CTV Abschirmung / Exklusion von Normalgewebsstrukturen Vor onkoplastischen Manövern (Mamma!) Modern(er)e Argumente Effekte? 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H Pä Prävention der Tumorzellrepopulation zwischen OP/RT Guter Oxygenierungsstatus während OP Mögliche immunmodulatorische 3

4 Is there still a role for IORT in times of competing dose escalation strategies (IMRT, IGRT, VMAT, STX, p+, )? IORT is more than just the delivery of a single high dose at utmost precision Two-Target Model in Single-Dose RT: High dose radiation engages both tumor stem cells and the microvascular endothelium as a linked target system Transient microvascular dysfunction regulates the processing of stem cells DNA dsb, converting potentially repairable damage into lethal lesions (8-12 Gy treshhold dose) (Fuks 2007) Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 4

5 Micromilieu Cytokines in Wound Fluid Beletti et al. Wound Fluid triggers breast cancer cell proliferation (but not that of normal cells) Wound Fluid stimulates migration and invasion of breast cancer cells (but not of normal cells) Both these effects are counteracted by IORT Wound Fluid from IORT-treated patients display a different molecular profile from other WF

6 Clinical evidence for IORT Traditional Innovative Stomach Breast Rectum Pancreas Sarcomas Cervix H-N Lung Prostate IORT systematic literature review 2008 up-date CLINICAL RESULTS De Paoli, Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 6

7 IORT clinical data 2009 Papers Patients Pancreas Rectum Head and Neck Stomach Sarcoma Gynecologic Tumors Lung Breast Miscellanous /02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H

8 ISIORT Europe Registry 2013: Frequency and Indications of IORT Krengli et al, Transl Cancer Res n = 6, Zentren, Dateneingabe Esophagus 53 Stomach 65 Brain 34 Cervix-vagina 29 Head and neck 28 Uterine body 17 Ovary 16 Bowel 12 Lymphnodes 9 Kidney 8 Abdominal 8 Biliary tract 8 Lung - lung apex 6 Sacrum 6 Adrenal glands 6 Bladder 5 Spine 2 Testis 2 Anus 1

9 growing access due to mobile machines and dedicated units. Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 9

10 HIERARCHY OF EVIDENCE Meta- analysis RCTs Pooled danalysis Cohort/Case-control Case series Case reports Opinion of Experts 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 10

11 Pooled Analyses Pancreas Rectal cancer Sarcoma ( Kidney ) Breast 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 11

12 Radiother Oncol pat, 5 institutions Local Control Survival 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 12

13 Results of European pooled analysis of IORT-containing multi-modalitymodality treatment for locally advanced rectal cancer Kusters M, Valentini V, Calvo FA, Krempien R, Nieuwenhuijzen GA, Martijn H, Doglietto GB, Del Valle E, Roeder F, Buchler MW, van de Velde CJ, Rutten HJ. Ann Oncol patients with LARC who underwent multimodality treatment up to 2005 preoperative (chemo)radiotherapy ( Gy), intended radical surgery, IORT ( Gy) and adjuvant chemotherapy (act). uni- and multivariate analyses of risk factors for LR, DM and OS 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 13

14 Results of European pooled analysis of IORT-containing multi-modality treatment for locally advanced rectal cancer T3+, T4 Kusters M, Valentini V, Calvo FA, Krempien R, Nieuwenhuijzen GA, Martijn H, Doglietto GB, Del Valle E, Roeder F, Buchler MW, van de Velde CJ, Rutten HJ. Ann Oncol Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). 42% of the patients received adjuvant CT LR, DM and OS were 12.0%, 29.2% and 67.1% Risk factors associated with LR and DM were no downstaging, lymph node (LN) positivity, margin involvement, ct4 disease and no postoperative p CT

15 Limb-sparing management with surgical resection, external-beam and IORT boost for patients with primary Soft Tissue Sarcoma of the extremity Calvo F et al, Strahlenther Onkol patients (3 Spanish institutions), medfu 53 mths. Med Tumor size 10 cm (2-26), 43% Stage III 5-year local control (LC) was 82 %. The 5-year IOERT in-field control, DFS and OS were 86, 62 and 72 %, respectively. Risk factor for LC: R1- Resection (HR 5.20, p < 0.001). IOERT in-field control: incomplete resection and higher IOERT dose 12.5 Gy ( HR 0.32, p = 0.02) 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 15

16 Limb-sparing management with surgical resection, external-beam and IORT boost for patients with primary Soft Tissue Sarcoma of the extremity Calvo F et al, Strahlenther Onkol 2014.IOERT dose 12.5 Gy increases the rate of IOERT in field control, but DFS remains modest, given the high risk of distant metastases..intensified local treatment needs to be tested in the context of more efficient concurrent, neo- and adjuvant systemic therapy. 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 16

17 IOERT in limited stage breast cancer I/II Radiother Oncol Pat., 7 Institutions, 10 Gy (D max) IOERT- Boost Gy WBI Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 17

18 Results Total FUP: med mths ( In-Brust Recurrences: n = 16 (1.44%) Perce entage local control rate Local Control 100,0 95,0 90,0 85,0 80,0 75,0 72,4 mths: actuarial 99.2 % 70,0 0,00 20,00 40,00 60,00 80,00 100,00 120,00 Survival time [months] 8 Out Quadrant Recurrences 8 In Quadrant Recurrences Local In-Breast Controlrate total 98.5 % actuarial after 72.4 Mths 992% 99.2 Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 18

19 Independent risk factors for IBTR favours local control favours not local control No Hormonal Therapy Hormone receptor status positive Grading < G3 Age > 60 50<= Age < 60 0,001 0,010 0,100 1,000 10, ,000 Hazard ratio 40<= Age < Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 19

20 Generating Level I IIA evidences Breakthrough Breast IORT? ELIOT, Targit: Focus: replacing EBRT shortening of treatment SFN, Montpellier: augmenting EBRT HIOB: Synthesis of both aspects 20

21 Was heißt das : 20 Gy IORT. Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 21

22 % der Bio-Äquivalenzdosis : Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 22

23 % der Bio-Äquivalenzdosis : S U R G E R Y Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 23

24 % der Bio-Äquivalenzdosis : S U R G E R Y I O R T Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 24

25 kv versus Elektronen: Bio-Äquivalenzdosis ab Schnittrand (%): 100% S U R G E R Y 25% Orthovolt Ot ot I O R T <10% Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite 25

26 kv versus Elektronen: Bio-Äquivalenzdosis ab Schnittrand (%): 100% S U R G E R Y 25% Orthovolt Ot ot I O R T <10% 100% Landeskrankenhaus Salzburg Universitätsklinikum der PMU Elektronen Seite 26

27 kv versus Elektronen: BED von ED 20 Gy ~ 70 Gy frakt. RT (ED 2 Gy) S U R G E R Y 70 Gy I O R T 6,3 Gy Orthovolt Ot ot Landeskrankenhaus Salzburg Universitätsklinikum der PMU Seite Gy Elektronen

28 IORT as APBI? Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 28

29 intraoperative PBI ELIOT intraop. PBI Elektronen 21 Gy vs. WBI + ext. Boost rand. Äquivalenzstudie prim Endpunkt: In-Brustrezidive (IBTR) Äquivalenzbeweis: i 5-LRR 7.5% 75% 1305 (651 ELIOT/ 654 Standard) Alter: Lj TARGIT intraop. PBI 50-KV Orthovolt 21 Gy vs. WBI +/- ext. Boost rand. Nicht-Unterlegenheitsstudie prim. Endpunkt: In-Brustrezidive (IBTR) Beweis: eis Differenz in der LRR < 2.5% 3442 (1721 TARGIT/ 1730 Standard) Alter: > 45 Lj T1-2 (max. 2.5 cm), N0/+ T , N0-1 (2) Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 29

30 Results ELIOT/Standard FUP: Median 5.8 years (4.1 77) 7.7) TARGIT/Standard FUP: Median 2.4 Jahre (12-52 months) LRR: 4.4% /vs. 0.4% (p<0.0001) LRR-IQ: 2.5%/vs. 0.4% (p=0.0003) LRR-OQ: 1.9%/vs. 0% (p=0.0001) LRR : 3.3% ( ) /vs. 1.3% ( ) (abs. Diff. 2%) p=0.042 Targit expected LR at ten years Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 30

31 Summary An overall, available data on IORT shown a favourable impact on local control and, in selected dtumor sites, in OS (in CMT) However, despite the several thousand of Pts treated, limited levels of evidence are available in supporting recommendations Technological og ca advances allow an extension on IORT-clinical activity with the possibility to prove its efficacy in Well designed clinical trials (as in breast cancer) 23/02/2016 Gemeinnützige Salzburger Landeskliniken Betriebsges.m.b.H 31