Transcript Chemoradiotherapy for Rectal cancer

Chemoradiotherapy
for Rectal cancer
Dr. A . Sun Myint
Lead Clinician GI Tumour Group
Clatterbridge Centre for Oncology
Association of Coloproctology of Great Britain and Ireland
M62 Coloproctology Course - March 23rd 2007
Background
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In the UK over 10,000 new rectal cancer
Five year survival 50% (NBOCAP-2006)
Nearly half will develop recurrences
At presentation 30% T3/T4 N + MO
Preoperative radiotherapy reduce LR
So far, no survival advantage
Treatment Options
Options
• Surgery
• Radiotherapy
• Chemotherapy
Improvements
TME / Training
Sub specialisation
Pre operative
Chemoradiotherapy
Post operative
Advance /metastatic
Adjuvant
New agents
Radiotherapy
Preoperative Radiotherapy
Short course or Long course?
• Short course
• Long course
Preoperative Radiotherapy
Short course or Long course?
• Short course - Mobile operable tumour
• Long course - Fixed / Tethered tumour
30%( MRI defined CRM +)
Preoperative Radiotherapy
Short course or Long course?
• Short course - Mobile operable tumour
• Long course - Fixed / Tethered tumour
( MRI defined CRM +)
Improving Outcomes
• Add chemotherapy to radiation
• Increase radiation dose
Chemo-radiotherapy
Concurrent Chemotherapy + RT
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5FU
5FU / FA
5FU infusion + Irino / Oxaliplatin
Capecitabine + Irino / Oxaliplatin+ EGFR
Capecitabine + Irino / Oxaliplatin+ VEGFR
Oxaliplatin is a radiosensitiser
in HT-29 xenograft models
Tumour volume
160
Control
120
Oxaliplatin 5mg/kg
80
Radiation only (5Gy)
40
Oxaliplatin + radiation
0
01
05
09
13
17
Days post-treatment
21
Blackstock A et al. Int J Rad Oncol Biol Phys 2000;16:92–94
Comparative tumor sterilization rate
by treatment modality
Treatment
modality
pCR + pMic
RO
EBRT alone
7.1% (26%)
40%
EBRT+ chemo
16.2% (31%)
60%
EBRT+ duplet
21% (60%)
90%
Is chemo-Radiotherapy
better than RT alone?
EORTC Rectal cancer trial
T3/T4 rectal cancer
n=1011
Pre-op RT
SURGERY
Pre-op
Chemo/RT
SURGERY
Pre-op RT
SURGERY
Adjuvant
Chemo
Pre-op
Chemo/RT
SURGERY
Adjuvant
Chemo
EORTC Rectal cancer trial
Local
recurrence
Pre-op
Chemo/RT
Pre-op RT
8.7%
17%
(p=0.0016)
Bossett al ASCO 2005
EORTC Rectal cancer trial
Adjuvant
Chemo
Survival
Bossett al ASCO 2005
67.2%
No Adjuvant
Chemo
63.2%
FFCD 9203- Rectal cancer trial
T3/T4 rectal cancer
n=733
Pre-op RT
SURGERY
Pre-op CRT
SURGERY
JP Gerard et al ASCO 2005
Ad Chemo
Ad Chemo
FFCD 9203- Rectal cancer trial
Pre-op
Chemo/RT
Local
recurrence
8.0%
JP Gerard et al ASCO 2005
Pre-op RT
16.5%
FFCD 9203- Rectal cancer trial
Adjuvant
Chemo
Survival
67%
JP Gerard et al ASCO 2005
No Adjuvant
Chemo
66%
Chemo RT vs. Radiotherapy
Local control in T3/T4 rectal cancer
Trials
Pre-op CRT
Pre-op RT
EORTC 22921
8.7%
17.1%
FFCD 9203
8%
16.5%
German-94
6%
Pre-operative
Radiotherapy better than
post op RT?
German pre op. vs. post operative
chemoradiotherapy for rectal cancer
Preoperative
Chemo-RT
Surgery
Surgery
Post operative
Chemo-RT
Sauer et al N Engl J Med (2004) 351;17 1731-01740
German pre op. vs. post operative
chemoradiotherapy for rectal cancer
Pre op
Local
recurrence
Survival
Post op
n=405
n=394
6%
13%
P=0.0006
76%
74%
P=0.08
Sauer et al N Engl J Med (2004) 351;17 1731-01740
German pre op. vs. post operative
chemoradiotherapy for rectal cancer
Pre op
Acute
Toxicity
Late
Toxicity
Post op
n=405
n=394
27%
40%
P=0.001
14%
24%
P=0.01
Sauer et al N Engl J Med (2004) 351;17 1731-01740
Newer agents for
chemoradiotherapy
Chemoradiotherapy
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5FU bolus
5FU+ FA
Infusional 5FU
Capecitabine
Irinotecan +Cape
Oxaliplatin +Cape
Triplet therapy
R
A
D
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O
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H
E
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A
P
Y
NWCCOG 1+ RICE
CORE/ SOCRATES
Ir/Oxali + MdG+ VEGF
Pre-operative
5-FU chemoradiation:
• 5-FU-based chemoradiation has become part of
standard pre-operative therapy for rectal cancer
– effective downstaging
– 10–30% pCR rates
• Protracted infusion of 5-FU with postoperative
radiotherapy
improves survival versus bolus
1
5-FU
1O’Connell
MJ et al. N Engl J Med 1994;331:502–7
Infused versus bolus 5-FU during
pelvic radiation
Overall survival (%)
Infused 5-FU (n=328)
100
Bolus 5-FU (n=332)
80
60
Log rank p=0.005
Cox model p=0.01
40
20
0
0
1
2
3
4
Years after randomisation
O’Connell MJ et al. N Engl J Med 1994;331:502–7
Capecitabine + radiation
capecitabine plus radiotherapy
• Infused 5-FU is cumbersome and inconvenient
for patients
• Oral capecitabine simplifies chemoradiation and
is highly appealing to patients
• Potential for enhanced therapeutic ratio
– capecitabine generates 5-FU preferentially
in
1
tumour via thymidine phosphorylase (TP)
– radiotherapy further upregulates TP in tumour
1Miwa
2Sawada
2
M et al. Eur J Cancer 1998;34:1274–81
N et al. Clin Cancer Res 1999;5:2948–53
Irradiation upregulates TP
TP (units/mg protein)
5Gy
25
2.5Gy
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20
Control
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15
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10
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5
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0
0
*p<0.05
3
6
9
12
15
Days after X-ray irradiation
18
21
Sawada N et al. Clin Cancer Res 1999;5:2948–53
capecitabine enhances activity of
radiation in WiDr xenografts,
Tumour
inhibition (%)
120
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100
80
60
40
20
0
*p<0.05
Sawada N et al. Clin Cancer Res 1999;5:2948–53
Capecitabine chemoradiation:
• Oral capecitabine is replacing 5-FU in
chemoradiation
– capecitabine is highly effective and well
tolerated in combination with radiotherapy
– capecitabine simplifies chemoradiation and is
highly appealing to patients and clinicians alike
Chemoradiation in rectal cancer:
German phase II study (n=68)
Day
1
8
15
22
29
35
50.4Gy radiotherapy
1.8Gy / fraction
825mg/m2
twice daily
Continuous (days 1–37)
• Male / female (%)63 / 37
• Median age
65 years
• ECOG 0/1 (%)
54 / 41
• T3 / T4 (%)48 / 52 (57% N1–3)
Dunst J et al. Proc Am Soc Clin Oncol 2003;22:277 (Abst 1113)
capecitabine
chemoradiation:efficacy
Patients (%)
1
2
Dunst study
Lin study
Down staging
79
73
pRR
80
87
pCR
5
20
1Dunst
2Lin
J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282)
E et al. Proc Am Soc Clin Oncol 2003;22:287 (Abst 1152)
capecitabine chemoradiation:
Toxicity
Patients (%)
80
• No grade 4 adverse events
60
Grade 1/2
40
Grade 3
20
0
Diarrhoea
Local
erythema
Pain
Hand-foot
syndrome
Nausea
Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282)
NSABP R-04
rectal cancer trial
Objectives
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DFS
recurrence rate
pCR
safety
capecitabine continuously
throughout
radiotherapy (50.4Gy*)
Resectable rectal
cancer, stage II–III
n=1600
5-FU continuous
infusion throughout
radiotherapy (50.4Gy*)
*Plus 5.4Gy for fixed tumours
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R
G
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Y
Chemoradiation using
Oxaliplatin combination
capecitabine/oxaliplatin
chemoradiation
Patients (%)
Glynne-Jones
(n=16)
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2
Rödel
(n=31)
pCR
31
19
pT1 / 2N0
19
23
R0
88
94
R1
12
6
Resection margin
1Glynne-Jones
R et al. Proc Am Soc Clin Oncol 2003;22:292 (Abst 1174)
2Rödel C et al. J Clin Oncol 2003;21:3098–104
CORE: European study
Day
1
8
15
22
29
Radiotherapy
45Gy / 25 fractions
capecitabine
825mg/m twice daily
Monday to Friday
2
Oxaliplatin
50mg/m
weekly
2
 CORE: Capecitabine, Oxaliplatin, Radiotherapy and Excision
Chemoradiotherapy using
Irinotecan combination
RICE - NWCCOG study
Day
1
8
15
22
29
Radiotherapy
45Gy / 25 fractions
capecitabine
825mg/m twice daily
Monday to Friday
2
IRINOTECAN
60mg/m2 weekly
S. Gollins, S.Myint, E. Levine et al Proc Am Soc Clin Oncol 2006;24:617s (Abst 13519)
Chemoradiotherapy
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5FU bolus
5FU+ FA
Infusional 5FU
Capecitabine
Irinotecan +Cape
Oxaliplatin +Cape
Triplet therapy
R
A
D
I
O
T
H
E
R
A
P
Y
NWCCOG 1+ RICE
CORE/ SOCRATES
Ir/ Oxali + cape+ EGF
ARISTOTLE
Reducing Toxicity from CRT
Toxicity
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Chemoradiotherapy is more toxic than
radiotherapy alone
To reduce toxicity:Preoperative rather than post op
Radiation volume
Dose, fractionation and time
Radiation techniques
Are there any other options to
reduce toxicity
from chemoradiation?
Improving Outcomes
• Add chemotherapy to radiation
• Increase radiation dose
Increasing Radiation dose
• External Beam ( 45 Gy /25# /35)
• EBRT +Boost ( 50.4Gy/28#/38)
• EBRT + Contact RT boost (60-80Gy)
• EBRT + Contact HDR boost
Papillon Technique
Radical contact radiotherapy
Lyon R96-02 Trial
Results
EBRT
Clinical CR
( 2% )
Path CR/micro (34%)
Sphincter
(44%)
EBRT+ boost
(24%)
(57%)p=.027
(76%)p=.004
JP Gerard et al. J Clin Oncol 2004 :22 2404-2409
Lyon R96-02 Trial
Results
EBRT
LR
Morbidity
LR Survival
3%
43%
88%
EBRT + Boost
1%
38%
92%
JP Gerard et al J Clin Oncol 2004 :22 2404-2409
HDR Rectal
Brachytherapy
20mm
5mm
Pre op HDR Brachytherapy
Pathology
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T0N0
Micro
Residual
N+
29%
37%
34%
31%
• T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst:
1062
Pre op HDR Brachytherapy
Results
• Median FU 37months
• 5years Local recurrence
DFS
OS
CSS
• Toxicity G3
3%
65%
74%
84%
1% (30% CRT)
T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst: 1062
Comparative tumor sterilization rate
by treatment modality
TREATMENT
pCR
(pMic)
RO
EBRT alone
7.1% (26%)
40%
CT+ EBRT
13% (31%)
60%
EBRT+contact
21% (60%)
NA
HDR alone
29% (66%)
97%
CT+EBRT+
HDR boost
40%? (80%)
100?
Treatment Options
• Surgery
T1/T2/T3 / N+
(clear CRM)
• Pre op chemo RT
r CRM <1mm
(sphincter preservation)
• Post op chemo RT
p CRM<1mm
(node +ive)
• Radical RT
T1/T2/ N0
Conclusions-1
• All cases with rectal cancer should be
discussed at the MDT
• MRI scan is essential for pre operative
assessment
• Pre operative chemoradiotherapy offers
better local control than pre operative
radiotherapy alone
Conclusions-2
• Pre operative chemoradiotherapy is more
effective and less toxic than post operative
chemoradiotherapy
• Nearly half the patients with rectal cancer
will develop recurrences; however no DFS
or overall survival benefit has been shown
with adjuvant chemotherapy in any of the
trials published so far.
It is important to
contribute to clinical
trials