Prof. Dr. med. R. Fietkau

Strahlenklinik

Neues zur neoadjuvantenVorbehandlung

beim Rektumkarzinom

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Disclosure

I have the following potential confilct(s) of interest to report:

Type of affiliation/ Name ov commercialfinancial interest company

Receipt of grants/researchsupports

Receit of honoraria or consultationfees:

Participation in a companysponsored speaker‘s bureau:

RochePierre FabreSanofi

Pfizer

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Rektumkarzinom:

Kurzzeit RT versus

Langzeit RT

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Rectal-Ca: 5 x 5 Gy vs. RCT (50,4 Gy + 5-FU)

5 x 5Gy(N=163)

RCT (N=163)

Locoreg. recurrences(3 years)

7,5% 4,4% p=0,24

Lokoreg. recurr. distal 6/48 1/31 p=0,21Survival(5 years)

74% 70% p=0,62

Late toxicity G3/G4 5,8% 8,2% p=0,53

Ngan et al. 2012

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Rektumkarzinom:

RCT mit 5-FU

versus

5-FU / Oxaliplatin

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CAO/ARO/AIO-94 Rectal Cancer Study: adjuvant vs. neoadjuvant RCT

Locoregional recurrence rate

Sauer et al. 2012

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Rektum - Karzinom : RCT mit 5-FU versus Capecitabine

Hofheinz et al. 2012

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Rektum - Karzinom : RCT mit 5-FU versus Capecitabine

Hofheinz et al. 2012

Overall Survival

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Rektum - Karzinom : RCT mit 5-FU versus Capecitabine

Hofheinz et al. 2012

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CAO/ARO/AIO-04

OPERATION

5-FU: 500 mg/m2/d als Bolus über 2-5 min. (Tag 1-5), Wiederholung Tag 29, insgesamt 4 Kurse

Chemotherapie:5-Fluorouracil 1000 mg/m²/d Dauerinfusion

1.+5. RT-Woche d 1-5

KONTROLL-ARM:

1 2 3 5 6 4

d 29-33

50.4 Gy:Radiotherapie 28 x 1.8 Gy

Chemotherapie:5-Fluorouracil 250 mg/m²/d

Dauerinfusion

Oxaliplatin 50 mg/m²/d

d 1

d 1-14

d 8 d 22 d 29

EXPERIMENTELLER ARM:

d 22-35

1 2 3 5 6 4

:Radiotherapie 28 x 1.8 Gy 50.4 Gy

Folinsäure 400mg/m2; 2h-Infusion Oxaliplatin 100mg/m²; 2h-Infusion 5-FU Infusion 2400 mg/m²; 46h-Infusion

d 1

5-FU-Infusion über 46 h

Wiederholung d 15; insgesamt 8 Kurse

OX

FS

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Rektum-Ca: Neoadjuvante RCT mit 5-FU/Ox vs. 5-FU (CAO/ARO/AIO-04)

5-FU/Ox/RTN=624

5-FU/RTN=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 volleDosis

42% 65%

Adjuvante CT alle Zyklen

72% 77%

Rödel et al. 2012

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Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Disease free survival

Rödel et al. ASCO 2014

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Rödel et al. ASCO 2014

Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Overall survival

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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

(R2)

4 9

Locoregional recurrence (after R0/R1 resection) 12 23

Distant Metastasis/Progression 107 140

Death 36 26

First Event for Disease-free Survival (Total) 159 198

Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Rödel et al. ASCO 2014

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Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Rödel et al. ASCO 2014

5-FU/Ox besser

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Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Rödel et al. ASCO 2014

5-FU/Ox besser

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Rektum-Ca: neoadjuvante RT und adjuvante RTVergleich 5-FU vs. 5-FU/Oxaliplatin

Rödel et al. ASCO 2014

5-FU/Ox besser

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ACCORD 12/0405-Prodige 2

STAR-01 NSAPB R-04 CAO/ARO/AIO-04

Cum.dose of pre-op. concurrentchemotherapy(planned)

Cape 40.000mg/m2

with or without

Ox 360mg/m2

5-FU 8.550mg/m2

with or without

Ox 360mg/m2

5-FU 8.550mg/m2, Cape 40.000mg/m2

with or without

Ox 360mg/m2

5-FU 10.000mg/m2

versus

Ox 200mg/m2

with5-FU 7.000mg/m2

Compliance withpre-op. CRT in Ox-groups

RT: 87%Ox: 41%

RT: 84%Ox: 66%

not reported RT: 94%Ox: 85%

Grade 3-4 Tox: pre-op. CRT

25% vs. 11%(p<0,001)

24% vs. 8%(p<0,001)

15% vs. 7%(p<0,001) (onlygrade 3-4diarrhea)

23% vs. 20%

pCR rate 19% vs. 14% (p=0,09)

16% (p=0.90) 21% vs. 19% (p=0,46)

17% vs. 13% (p=0,04)

Rektum-Ca: Phase-III-Studien 5-FU+Ox/RT vs. 5-FU/RT

nach Rödel et al. 2012

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Rektumkarzinom:

Adjuvant CT

nach neoadjuvanter RCT

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Rectal cancer: EORTC – Studie 22921:Effect of adjuvant CT following

chemoradiotherapy or radiotherapy

R

OPERAT ION

T 3/4< 75 years

RT

RT 2 x 5-FU/Leucovorin

RT

RT 2 x 5-FU/Leucovorin

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 – 5Folinsäure 20 mg/m² d 1 - 5

Bosset et al. 2007

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Rectal cancer: EORTC – Studie 22921: Effect of adjuvant CT following

chemoradiotherapy or radiotherapy

Bosset et al. 2014

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Rektum-Ca: 5-FU/Oxaliplatin/Folsäure versus5-FU/Folinsäure als adjuvante Chemotherapie

nach neoadjuvanter RCT; Phase II-Studie (N=321)

Hong et al. 2014

Disease Free - Survival

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5-FU / Ox 5-FUCAO/ARO/AIO-04 75,9% 71,2%PETACC – 06 73,9% 74,5%Hong et al. 2014 71,6% 62,9%ACCORD 12/0405-Prodige 2

72,7% 67,9%

Rektum-Ca: „Disease Free Survival“ nach 5-FU versus 5-FU/Oxaliplatin (3 Jahre)

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Rectal cancer: Adjuvant chemotherapy

How often was adjuvant chemotherapy used?

CAO/ARO/AIO-94 • adjuvant 72%• neoadjuvant 81%

Hong et al. 2014 • neoadjuvant 100%

EORTC 22921 • neoadjuvant 78%

PETACC -06 • neoadjuvant 66%

CAO/ARO/AIO-04 • 5-FU/Ox 81%• 5-FU 82%

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Rektumkarzinom:

Induktion CT

vor neoadjuvanter RCT

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Rektum - Karzinom : Zeitpunkt der OP nach RT

Stadium : T2 – T3Radiotherapie : 13 * 3 Gy neoadjuvant

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

Francois et al. (J Clin Oncol 1999); N = 201

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Interval to Re-Staging

Tulchinsky et al. 2008

> 7 weeks

≤ 7 weeksp=0.05

p=0.03

N=132 patients (T3-4 or N+); 5-FU based CRT 45-50.4 Gy;Surgery scheduled 6-8 weeks after CRT

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Rektumkarzinom: Induktions-CT + RCT +OP versus RCT + OP + CT(CAPOX)

Fernandez-Martos et al. 2010

CT/RCT RCT+ CT

pCR (%) 14,3 13,5Complete Study treatment 91% 54% p<0,000

01Grad 3/4 Tox during CT

14% 54% p=0,004

Grad 3/4 Tox during RCT

23% 29% p=0,381

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Rektumkarzinom: Induktions-CT + RCT + OP versus RCT + OP + CT (CAPOX)

Fernandez-Martos et al. 2010

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Phase-II: CAO/ARO/AIO-12

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Rektumkarzinom:

Verzicht auf RT

bei alleiniger neoadjuvanter

CT

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Rektum – Karzinom: alleinige neoadjuvante Chemotherapie

Boland et al. 2014

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Rektumkarzinom:

Verzicht auf OP

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Rectal cancer: Wait and See Policyfollowing cCR after CRT

Maas et al. 2011

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

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Rectal cancer: Functional outcome of surgery (pCR) versus wait and see strategy

Maas et al. 2011

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Rectal cancer: RCT versus RT + local excision for cT1; cT2, borderline cT2/T3

Bujko et al. 2013

Patients: N = 89Therapy: 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%)

no further therapy

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Short course RT11,8% p=0,04

RCT 6,2% (multivariateanalysis)

Bujko et al. 2013

Rectal cancer: local recurrences (2 years)

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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

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Rektumkarzinom:

Verzicht auf RT

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Taylor et al. 2011

Preoperative high-resolution MRI can identify goodprognosis stage I, II, and III rectal cancer best managed bysurgery alone – a prospective, multicenter, european study

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Taylor et al. 2011

Preoperative high-resolution MRI can identify goodprognosis stage I, II, and III rectal cancer best managed bysurgery alone – a prospective, multicenter, european study

Problempunkte

Nicht auswertbare Patienten 11.3% (52/477)*Nur absolute Angabe der lokalen RezidivratenAnteil 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%)