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Prof. Dr. med. R. Fietkau

StrahlenklinikUniversitätsklinikum Erlangen

Neoadjuvant chemoradiotherapy –Does it work without ?

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- Reduction der local recurrences- Reduction der distant metastases

- Improvement of prognosis

- Quality of life:- Sphincter preservation- low late toxicity- acepptable acute toxizcity

Rectal Cancer: Objectives of Therapy

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Neoadjuvant chemoradiotherapy –Does it work without ?

Questions

- If surgery is optimal: Do we need radiotherapy / chemoradiotherapy at all ?

- What is the better choice: 5 * 5 Gy or long term radiochemotherapy ?

- Is intensification of chemotherapy during radiochemotherapy necessary ?

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Local recurrence rate (5 years)Peeters Quirke Lippinger

UICC-Stage N = 908 N = 675 N = 16983

I 1,7 % 6 % 10.4%

II 7,2 % 12% 14.3%

III 20.6 % 25% 19.7%

IV 26.9 %

Rektum – Karzinom: Surgery alone (TME + CRT (CRM +))

(Peeters et al. 2007; Quirke et al. 2006; Lippinger et al. 2006)

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ARO/AIO/CAO Rectal Cancer Study: Locoregional recurrence rate following surgery alone N = 46

5 – year rate:29.6 +/- 7.8 %(pUICC II/III)

Fietkau et al. Int J Radiat Oncol Biol Phys 2007

0,00 20,00 40,00 60,00 80,00

Time in months

0

10

20

30

40

Cum

ulat

ive in

cden

ce o

f loc

oreg

iona

l rec

urre

nces

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Rectal Cancer: Circumferential Resection Margin(CRM) and local recurrence rate

Local recurrence *

CRM + CRM - p

Quirke et al. 2006 31 % 14% < 0,001Birbeck et al. 2002 38 % 10 % < 0,0001Wibe et al. 2002 22 % 5 % < 0,001Nagtegaal et al. 2002 16 % 6 % 0,0007Peeters et al. 2007 23.5% 8.7 %

* Different follow up times andcalculation processes

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Rectal Cancer: CRM and Nodal StatusEriksen et al. 2006; Surgery alone

(Cox regression analysis; adjusted for age; gender; tumor site)

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Rektum – Karzinom: Anatomie und Chirurgie

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Rectal Cancer: Quality of Surgery and Effect of Radiotherapy

Locoregional Recurrence Rate (3 years)

Plane of Surgery OP±RCT RT-OP HR

Muscularis propria plane (12,6%) 29% 9% 2.76

Intramesorectal plane (34,1%) 12% 6% 2.02

Mesorectal plane (53,2%) 6% 1% 4.47

Quirke et al. 2006 ASCO, N = 1119

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Rectal cancer: If surgery is optimal: Do we needradiotherapy / chemoradiotherapy at all ?

Be aware: only in 50 – 60 % surgery is optimal

We need RT but selection is necessary:

Stage III patients; CRM + patients;

CRM – Patients: exact analysis is necessary to define the patients with a high risk of recurrence

The effect of RT is best if surgery is best

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Neoadjuvant chemoradiotherapy –Does it work without ?

Problems

- If surgery is optimal: Do we need radiotherapy / chemoradiotherapy at all ?

- What is the better choice: 5 * 5 Gy or long term radiochemotherapy ?

- Is intensification of chemotherapy during radiochemotherapy necessary ?

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Rectal Cancer: Effect of preoperativeRadiotherapy (5 x 5 Gy)

Locol recurrence rate (5-years)

RT + OP OP P

0 – 5 cm 10,7% 12,0% 0.122

5 – 10 cm 3,7% 13,7% 0.001

>10.1 cm 3,7% 6,2% 0.122

All 5.8 % 11.4 % 0.001

Peeters et al. 2007

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Locol Recurrence Rate (5-years)

RT + OP OP P

CRM +1 19.7% 23.5% 0,39

CRM -1 3.4% 8.7% 0,001

CRM + 2 16 % 31%CRM - 2 4% 14%

Peeters et al. 20071, Quirke et al. 2006 2

Rectal Cancer: Effect of preoperativeRadiotherapy (5 x 5 Gy)

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Rectal cancer :Late toxicity following 5 X 5 Gy (Pollack et al. 2006)

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Sphincter function and 5 x 5 Gy

(Pollack et al. DCR 2006)

OP 5 x 5 Gy / OPN = 43 N = 21

Fecal incontinence 26 % 57 % p = 0,01Gas incontinence 17 % 71 % p = 0,03Soiling 16 % 38 % p = 0,04Stool frequency / week 10 20 p = 0,02

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Rectal cancer : Adjuvant and neoadjuvant RCT

5- FU 5- FU 5- FU 5- FU 5- FU 5- FU 5 x 1000 mg/m² 5 x 1000 mg/m² 5 x 500 mg/m²

( Protokoll CAO / ARO / AIO 1994 )RANDOMISATION

Arm I : OP

Arm II :

5- FU 5- FU 5- FU 5- FU 5- FU 5- FU 5 x 1000 mg/m² 5 x 1000 mg/m² 5 x 500 mg/m²

RT : 50,4 Gy + 5,4 Gy Boost

OPRT : 50,4 Gy

0 2 4 6 8 10 12 14 16 18 20 22 Wochen

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Rectal Cancer: ARO-AIO-CAO-Study:Downsizing by neoadjuvant RCT

Pathological Stage:Präoperative RCT Postoperative RCT

0 8 % -I 26 % 18 %II 29 % 29 %III 25 % 40 %IV 6 % 7 %

unbekannt 6 % 6 %

p = 0,001„D

owns

izin

g“

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Rectal cancer: adjuvant vs. neoadjuvant RCT

Locoregional recurrence rate: (CAO/ARO/AIO-94)

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Rectal Cancer: ARO-AIO-CAO-Study: DFS

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Rectal Cancer: ARO-AIO-CAO-Study:Acute toxicity (WHO 3/4)

Präop. RCT Postop. RCT

Diarrhoe 11 % 18 % 0,03

Hematology 5 % 8 % 0,24

Skin 11 % 16 % 0,06

All 27 % 39 % 0,002

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Rectal Cancer: ARO-AIO-CAO-Study:Perioperative complications: Intention to treat Analyse

Insufficience of anastomosis

Postop. Bleeding

Delayed Heeling

Ileus

Fistula

Postop. RCT

12,0 %

3,0 %

6.0 %

2,0 %

3,0 %

Preop. RCT

10,0 %

2,0 %

4,0 %

3,0 %

1,0 %

n.s.

n.s.

n.s.

n.s.

n.s.

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Rectal Cancer: ARO-AIO-CAO-Study:Late toxicity (WHO 3/4)

Präop. RCT Postop. RCT

GastrointestinaleToxicity 9 % 16 % 0,05Anastomosis 4 % 12 % 0,004

Bladder 2 % 4 % 0,19

All 14 % 24 % 0,009

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Rectal cancer:Sphincter Function following RCT

Stuhlfrequenz

2,82,80

1

2

3

4

5

6

Mit RCT ohne RCT

Stuh

lfreq

uenz

Anz

ahl/d

(Pietsch et al. IJCD 2007; CUK Rostock)

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Rectal cancer: Sphincter Function following RCT

67%64%

33%28%

33%32%

33%40%

58%56%

0% 10% 20% 30% 40% 50% 60% 70%

Warnzeit >15 min

fraktionierteEvakuation

eingeschr.Diskrimination

Veränderung derLebensgewohnheiten

Zufriedenheit mitKontinenz

ohne RCT

mit RCT

(Pietsch et al. IJCD 2007; CUK Rostock))

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Rectal Cancer: EORTC – Study 22921

R

OPERATION

T 3/4< 75 Jahre

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 –5

Folinic acid 20 mg/m² d 1 - 5

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Rectal cancer: EORTC – Studie 22921

Effect of CT on locoregional recurrence rate(Bosset et al. 2006)

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Rectal cancer: 5x5 Gy vs. RCT

(Bujko et al, 2004)

n = 316

resectableRectal cancerT3/T4

RT: 5 x 5 Gy + OP

RCT: 1,8 50,4 Gy + OP2 courses 5FU/LV

R

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(Bujko et al, 2004)

5 x 5 Gy RCT

Tu-lenght (postop.) 45 mm 26 mm p < 0,001

pCR 1 % 16 % p < 0,001

R1 13 % 4 % p = 0,017

Rectal cancer: 5x5 Gy vs. RCT

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(Bujko et al, 2004, 2006)

5 x 5 Gy RCT

LRR (4 years) 9% 14% p = 0,17

M1 (4 years) 31,4% 34,6% p = 0,8

Rectal cancer: 5x5 Gy vs. RCT

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Rectal Cancer: ARO-AIO-CAO-Study: Effect of adequate RT on locoregional recurrence rate

Fietkau et al. Int J Radiat Oncol BiolPhys 2007

0 20 40 60 80

Months

0

10

20

30

40

Cum

ulat

ive

inci

denc

e of

loco

rgio

nal r

ecur

renc

es

(%)

RT indicated not givenRT not adequateRT adequate

P < 0.0001

6.8+/- 1.4%

21.2+/-5.6%

29.6+/-7.8%

Adequate RT:

Reduction of RT- dose < 15%

Prolongation of duration of RT> 15%

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Rectal Cancer: Complete neoadjuvant RCT

CAO/AIO/ARO-Study: 89 % (RT)(Fietkau et al. 2007)

EORTC-Study 22921: 82 % (CT)(Bosset et al. 2006) 95 % (RT)

Polnish Study: 69 % (RCT)(Buijko et al. 2004/2006)

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Rectal cancer: adjuvant vs. neoadjuvant RCT

Preoperat. RCT Postoperat. RCT

Before randomization„APR necessary“ 116 78

Sphincter preserved 45/116 (39 %) 15/78 (19 %)

p = 0,004

(CAO/ARO/AIO-94)

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Rectal cancer: 5x5 Gy vs. RCT

(Fietkau, BJC Letter to the editor 2007)

5 x 5 Gy (N = 155) 50,4 Gy + CT (N = 157)

Primary sphincter preserved N = 95 N = 91(Bujko et al. 2004)

No late permanent stoma N = 66 N = 76(Bujko et al. 2006)

New stoma or stoma N = 29/95 N = 15/91not reversed (30,5 %) (16,4 %)

p = 0,024

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What is the better choice: 5 * 5 Gy or long term radiochemotherapy ?

- There is no clear answer today:

- 5 x 5 Gy may be sufficient in T2/T3 tumours in themiddle rectum

- but

- 5x 5 Gy has only minor effect:

- CRM + tumours („T4 tumours“)

- Tumours in the lower rectum (0 – 5 cm)

- If sphincter preservation is wanted

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Neoadjuvant chemoradiotherapy –Does it work without ?

Problems

- If surgery is optimal: Do we need radiotherapy / chemoradiotherapy at all ?

- What is the better choice: 5 * 5 Gy or long term radiochemotherapy ?

- Is intensification of chemotherapy duringradiochemotherapy necessary ?

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Rectal Cancer: ARO/AIO/CAO-studyEffect of RCT and Stage on local recurrences

(Fietkau et al, 2007)

Local recurrence rate (5 years) and adequate RCT

UICC-Stage N = 553

pCR 0 %I 2,4 %II 3,8 %III 11.3 % IV 22.9 %

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Rectal cancer: ARO/AIO/CAO-studyDistant metastases

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Local recurrence (RT) distant metastases(CT)

GITSG 1985 11 % 26 %

Krook 1991 13 % 29 %

O´Connell 1994 8 % 31 %Tepper 1997 11 % 28 %ARO/AIO/CAO 12 % (adj.) 32 %

6 % (neoadj.) 32 %SRCT 1997 11 % (neoadj.) 24 %NRCT 2001 5,8 % (neoadj.)

Rectal cancer : Results of randomized studies following RT/RCT (UICC II/III)

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Rctal Cancer : Neoadj. RCT with Oxaliplatin

Aschele, 2005

⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪RT ⎢⎢⎢

ORAL

INFUSIONAL

Machiels, 2005

Oxalip 5-Fu pCR

260 350 14%

360 225 28%

Cap 200 1650 19%

260 1300 27%

250 1650 13%

Absolut/mg/m2 mg/m2

Gerard, 2003

Rödel, 2003

Glynne-Jones,2005

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Rektumkarzinom : Neoadj. RCT with Irinotecan

Klautke, 2005

Gollins, 2005

⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪ ⎢⎪⎪⎪⎪RT ⎢⎢⎢

Klautke, 2006ORAL

INFUSIONAL

Mehta, 2003

Hofheinz, 2005

CPT11 5-Fu pCR

200 200 32%

240 250 24%

Cap 240 1500 18%

240 1650 20%

250 1000 21%

Absolut/mg/m2 mg/m2

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Rectal cancer: Neoadjuvante RCT vs. intes. neoadj. RCT

Mitchell Klautke Saueret al, 2005 et al, 2005 et al, 2004

CT 5Fu/CPT11 5Fu/CPT11 5Fu

LRR 0% 7% 6%

M1 23% 24% (14% R0) 36%

(Klautke, Fietkau 2007)

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Rectal Cancer: therapeutic strategy

NeoadjuvantRCT

OPERATION

Adjuvant Chemotherapy

RCT AdjuvantChemotherapy

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Rectal cancer: Adjuvant chemotherapy

How often was adjuvant chemotherapy used ?

CAO / AIO / ARO-Studie:Adjuvant 72 %Neoadjuvant 81 %

Fietkau et al. 2006:Neoadjuvant 68 %

EORTC 22921:Neoadjuvant 78 %

Polish study:5 * 5 Gy 47 %Neoadjuvant 31 %

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Rectal cancer: RCT

(Rödel et al, 2005)

Neoadjuvante RCT

DFSand tumour regression

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Rectal cancer: Effect of ypN-category on DFS:(STR. Rostock; N = 95; 11.97 – 6.2004; M0 R0)

Time in months

100806040200

Dis

ease

free

sur

viva

l1,00

,80

,60

,40

,20

0,00

ypN category

ypN2

ypN1

ypN0

Fietkau et al. 2006

P < 0.001

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Rectal cancer: EORTC – Studie 22921: (Colette et al. 2008)Effect of adjuvant CT following chemoradiotherapy

or radiotherapy

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Rectal cancer: EORTC – Studie 22921: (Colette et al. 2008)Effect of adjuvant CT following chemoradiotherapy

in ypN0 tumors

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Is intensification of chemotherapy duringradiochemotherapy necessary ?

-Local control is depending on stage (UICC III and IV)-Distant metastases are not influenced by conventionalRCT with 5 – FU- The compliance to adjuvant CT following neoadjuvantRCT is 60 - 80%-The pCR rate is higher following intensified RCT compared to 5-FU RCT-Selection for adjuvant therapy by the help of responseto neoadjuvant RCT may be possible- This concept is investigated in the running German study

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Rectal cancer :neoadj. RCT versus intens. neoadj. RCT

Rectal cancerUICC II / III R

5 - FURCT:5 – FU

RCT:5-FU/Oxal

Design of the current study of the German Rectal Cancer Group

FolFOX

OP

OP

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Neoadjuvant chemoradiotherapy –Does it work without ?

- If surgery is optimal: Do we need radiotherapy / chemoradiotherapy at all ?Yes; in selected patients.

- What is the better choice: 5 * 5 Gy or long term radiochemotherapy ?It depends on the situation.

- Is intensification of chemotherapy during radiochemotherapy necessary ?An open question

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Strahlentherapie Rostock

Rostock: Warnemuende Entrance to the Baltic SEA

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Erlangen: University in Frankonia