Neues zur neoadjuvanten Vorbehandlung beim Rektumkarzinom

Transcription

1 Neues zur neoadjuvanten Vorbehandlung beim Rektumkarzinom Prof. Dr. med. R. Fietkau Strahlenklinik

2 Disclosure I have the following potential confilct(s) of interest to report: Type of affiliation/ financial interest Receipt of grants/research supports Receit of honoraria or consultation fees: Participation in a company sponsored speaker s bureau: Name ov commercial company Roche Pierre Fabre Sanofi Pfizer 2

3 Rektumkarzinom: Kurzzeit RT versus Langzeit RT 3

4 Ngan et al Rectal-Ca: 5 x 5 Gy vs. RCT (50,4 Gy + 5-FU) 5 x 5Gy (N=163) RCT (N=163) Locoreg. recurrences 7,5% 4,4% p=0,24 (3 years) Lokoreg. recurr. distal 6/48 1/31 p=0,21 Survival 74% 70% p=0,62 (5 years) Late toxicity G3/G4 5,8% 8,2% p=0,53 4

5 Rektumkarzinom: RCT mit 5-FU versus 5-FU / Oxaliplatin 5

6 Sauer et al CAO/ARO/AIO-94 Rectal Cancer Study: adjuvant vs. neoadjuvant RCT Locoregional recurrence rate 6

7 Hofheinz et al Rektum - Karzinom : RCT mit 5-FU versus Capecitabine 7

8 Hofheinz et al Rektum - Karzinom : RCT mit 5-FU versus Capecitabine Overall Survival 8

9 Hofheinz et al Rektum - Karzinom : RCT mit 5-FU versus Capecitabine 9

10 CAO/ARO/AIO-04 KONTROLL-ARM: Radiotherapie : 28 x 1.8 Gy Chemotherapie: 5-Fluorouracil 1000 mg/m²/d Dauerinfusion RT-Woche d 1-5 d EXPERIMENTELLER ARM: 50.4 Gy Radiotherapie : 28 x 1.8 Gy 50.4 Gy Chemotherapie: 5-Fluorouracil 250 mg/m²/d Dauerinfusion Oxaliplatin 50 mg/m²/d d 1-14 d d 1 d 8 d 22 d O P E R A T I O N 5-FU: 500 mg/m 2 /d als Bolus über 2-5 min. (Tag 1-5), Wiederholung Tag 29, insgesamt 4 Kurse Folinsäure 400mg/m 2 ; 2h-Infusion Oxaliplatin 100mg/m²; 2h-Infusion 5-FU Infusion 2400 mg/m²; 46h-Infusion F S d 1 O X 5-FU-Infusion über 46 h Wiederholung d 15; insgesamt 8 Kurse 10

11 Rödel et al Rektum-Ca: Neoadjuvante RCT mit 5-FU/Ox vs. 5-FU (CAO/ARO/AIO-04) 11 5-FU/Ox/RT N=624 5-FU/RT N=606 Toxizität Grad ¾ RCT 23% 20% Diarrhoe Grad ¾ RCT 12% 8% RT-Unterbrechungen 10% 7% RT-Abbruch/ RCT 3% 3% CT inkomplett/rct 15% 21% Adjuvante CT Grad 3/4 36% 36% Adjuvante CT volle 42% 65% Dosis Adjuvante CT alle Zyklen 72% 77%

12 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin Disease free survival 12

13 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin Overall survival 13

14 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin Table 2. Intention-to-Treat Analysis of First Events for Primary Endpoint Disease-free Survival Fluorouracil and oxaliplatin group (n=613) Fluorouracil group (n=623) Macroscopically incomplete local resection 4 9 (R2) Locoregional recurrence (after R0/R1 resection) Distant Metastasis/Progression Death First Event for Disease-free Survival (Total)

15 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin 5-FU/Ox besser 15

16 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin 5-FU/Ox besser 16

17 Rödel et al. ASCO 2014 Rektum-Ca: neoadjuvante RT und adjuvante RT Vergleich 5-FU vs. 5-FU/Oxaliplatin 5-FU/Ox besser 17

18 nach Rödel et al Rektum-Ca: Phase-III-Studien 5-FU+Ox/RT vs. 5-FU/RT Cum.dose of preop. concurrent chemotherapy (planned) ACCORD 12/0405- Prodige 2 Cape mg/m 2 with or without STAR-01 NSAPB R-04 CAO/ARO/AIO-04 5-FU 8.550mg/m 2 with or without 5-FU 8.550mg/m 2, Cape mg/m 2 with or without 5-FU mg/m 2 versus Compliance with pre-op. CRT in Ox-groups Grade 3-4 Tox: pre-op. CRT Ox 360mg/m 2 RT: 87% Ox: 41% 25% vs. 11% (p<0,001) pcr rate 19% vs. 14% (p=0,09) Ox 360mg/m 2 RT: 84% Ox: 66% 24% vs. 8% (p<0,001) Ox 360mg/m 2 Ox 200mg/m 2 with 5-FU 7.000mg/m 2 not reported RT: 94% Ox: 85% 15% vs. 7% (p<0,001) (only grade 3-4 diarrhea) 16% (p=0.90) 21% vs. 19% (p=0,46) 23% vs. 20% 17% vs. 13% (p=0,04) 18

19 Rektumkarzinom: Adjuvant CT nach neoadjuvanter RCT 19

20 Bosset et al Rectal cancer: EORTC Studie 22921: Effect of adjuvant CT following chemoradiotherapy or radiotherapy T 3/4 < 75 years R RT RT 2 x 5- FU/Leucovorin RT RT 2 x 5- FU/Leucovorin O P E R A T I O N 4 x 5- FU/Leucovorin 4 x 5- FU/Leucovorin RT : 1,8 Gy 45 Gy CT : 5-FU-Bolus 350 mg/m² d 1 5 Folinsäure 20 mg/m² d

21 Bosset et al Rectal cancer: EORTC Studie 22921: Effect of adjuvant CT following chemoradiotherapy or radiotherapy 21

22 Hong et al Rektum-Ca: 5-FU/Oxaliplatin/Folsäure versus 5-FU/Folinsäure als adjuvante Chemotherapie nach neoadjuvanter RCT; Phase II-Studie (N=321) Disease Free - Survival 22

23 Rektum-Ca: Disease Free Survival nach 5-FU versus 5-FU/Oxaliplatin (3 Jahre) 5-FU / Ox 5-FU CAO/ARO/AIO-04 75,9% 71,2% PETACC 06 73,9% 74,5% Hong et al ,6% 62,9% ACCORD 12/0405- Prodige 2 72,7% 67,9% 23

24 Rectal cancer: Adjuvant chemotherapy How often was adjuvant chemotherapy used? CAO/ARO/AIO-94 adjuvant 72% neoadjuvant 81% Hong et al neoadjuvant 100% EORTC neoadjuvant 78% PETACC -06 neoadjuvant 66% 24 CAO/ARO/AIO-04 5-FU/Ox 81% 5-FU 82%

25 Rektumkarzinom: Induktion CT vor neoadjuvanter RCT 25

26 Francois et al. (J Clin Oncol 1999); N = 201 Rektum - Karzinom : Zeitpunkt der OP nach RT Stadium : T2 T3 Radiotherapie neoadjuvant : 13 * 3 Gy OP nach OP nach 1-2 Wochen 6-8 Wochen pathological 10,3 % 26% p = 0,005 down-staging Spinktererhalt 68% 76% p = 0,27 möglich 26

27 Tulchinsky et al Interval to Re-Staging N=132 patients (T3-4 or N+); 5-FU based CRT Gy; Surgery scheduled 6-8 weeks after CRT > 7 weeks p= weeks p=

28 Fernandez-Martos et al Rektumkarzinom: Induktions-CT + RCT +OP versus RCT + OP + CT(CAPOX) CT/RCT RCT + CT pcr (%) 14,3 13,5 Complete Study treatment Grad 3/4 Tox during CT Grad 3/4 Tox during RCT 91% 54% p<0, % 54% p=0,004 23% 29% p=0,381 28

29 Fernandez-Martos et al Rektumkarzinom: Induktions-CT + RCT + OP versus RCT + OP + CT (CAPOX) 29

30 30 Phase-II: CAO/ARO/AIO-12

31 Rektumkarzinom: Verzicht auf RT bei alleiniger neoadjuvanter CT 31

32 Boland et al Rektum Karzinom: alleinige neoadjuvante Chemotherapie 32

33 Rektumkarzinom: Verzicht auf OP 33

34 Maas et al Rectal cancer: Wait and See Policy following ccr after CRT Patients: 192 pts with ct3 and ct4 carcinomas; > 3 LN RCT with Capecitabine 21 pts with ccr (MR; biopsy; endoscopy) 1/20 pt with local recurrence (salvage sucessfully) Median follow-up: 25 months 34

35 Maas et al Rectal cancer: Functional outcome of surgery (pcr) versus wait and see strategy 35

36 Bujko et al Rectal cancer: RCT versus RT + local excision for ct1; ct2, borderline ct2/t3 Patients: N = 89 Therapy: 5 x 5 Gy + 4 Gy or 55,8 Gy + leucovorin/5-fu LE good responders: ypt0-1/r0/g1-2/ypn0 LO VO (N = 63; 70%) 36 no further therapy

37 Bujko et al Rectal cancer: local recurrences (2 years) Short course RT 11,8% p=0,04 RCT 6,2% (multivariate analysis) 37

38 Zusammenfassung: 1. Neoadjuvante RCT mit 5-Fu weiterhin der Standard im klin. Stadium II/III 2. Adjuvante CT mit 5-FU/Oxaliplatin bei Subgruppen (< 60 J.) nach neoadjuvanter RCT effektiv? 3. Neue Therapieansätze - neoadjuvante CT / RCT - Verzicht auf RT oder OP in selektionierten Fällen 38

39 Rektumkarzinom: Verzicht auf RT 39

40 Taylor et al Preoperative high-resolution MRI can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone a prospective, multicenter, european study 40

41 Taylor et al Preoperative high-resolution MRI can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone a prospective, multicenter, european study Problempunkte Nicht auswertbare Patienten 11.3% (52/477)* Nur absolute Angabe der lokalen Rezidivraten Anteil Stadium pl 40% (49/122) Anteil Stadium cl 46% (57/122) pt3/4 N0 3,4% (1/29) pn1 2,7% (1/36) pn2 12,5% (1/8) * Deutsche Rektum-Studie: (3%) 41