Post on 06-May-2018
1
Prof. Dr. med. R. Fietkau
StrahlenklinikUniversitätsklinikum Erlangen
Neoadjuvant chemoradiotherapy –Does it work without ?
2
- 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
3
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 ?
4
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)
5
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
6
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
7
Rectal Cancer: CRM and Nodal StatusEriksen et al. 2006; Surgery alone
(Cox regression analysis; adjusted for age; gender; tumor site)
8
Rektum – Karzinom: Anatomie und Chirurgie
9
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
10
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
11
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 ?
12
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
13
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)
14
Rectal cancer :Late toxicity following 5 X 5 Gy (Pollack et al. 2006)
15
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
16
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
17
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“
18
Rectal cancer: adjuvant vs. neoadjuvant RCT
Locoregional recurrence rate: (CAO/ARO/AIO-94)
19
Rectal Cancer: ARO-AIO-CAO-Study: DFS
20
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
21
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.
22
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
23
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)
24
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))
25
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
26
Rectal cancer: EORTC – Studie 22921
Effect of CT on locoregional recurrence rate(Bosset et al. 2006)
27
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
28
(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
29
(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
30
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%
31
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)
32
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)
33
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
34
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
35
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 ?
36
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 %
37
Rectal cancer: ARO/AIO/CAO-studyDistant metastases
38
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)
39
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
40
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
41
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)
42
Rectal Cancer: therapeutic strategy
NeoadjuvantRCT
OPERATION
Adjuvant Chemotherapy
RCT AdjuvantChemotherapy
43
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 %
44
Rectal cancer: RCT
(Rödel et al, 2005)
Neoadjuvante RCT
DFSand tumour regression
45
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
46
Rectal cancer: EORTC – Studie 22921: (Colette et al. 2008)Effect of adjuvant CT following chemoradiotherapy
or radiotherapy
47
Rectal cancer: EORTC – Studie 22921: (Colette et al. 2008)Effect of adjuvant CT following chemoradiotherapy
in ypN0 tumors
48
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
49
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
50
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
51
Strahlentherapie Rostock
Rostock: Warnemuende Entrance to the Baltic SEA
52
Erlangen: University in Frankonia