tme trial tme radiotherapy 5 x 5 gy tme alone randomisation n = 1861 resectable rectal carcinoma if...
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TME trial
TME
radiotherapy5 x 5 Gy
TME alone
randomisationn = 1861
resectablerectal carcinoma
if CRM+: 50 GY
MRC CR 07: 5x5 Gy vs. postop CRT
5x5 Gy
Surgery
Pathology
CRM -ve CRM +ve CRM -ve CRM +ve
Surgery
Pathology
nothing 45Gy + 5 FU
chemotherapy as per local protocol
My belief in 2002:
5x5 Gy for all
Never heard of tailored treatment
More insight:
subgroup analyses
Mainly hypothesis generating
Local Recurrence TME study
p < 0.001
5.6%
10.9%
5
10
15
20
2 4 6
TME
RT+TME2.4%
8.2%
Peeters et al., Ann Surg 2007
Radiotherapy before TME:Is it beneficial?
Local recurrence from 10.9% to 5.6%
When you treat 100 patients:
89.1 would never get recurrence: unnecessary
5.6 still get recurrence: unnecessary
5.3 recurrence prevented
To save 1 patient a local recurrence, you treat 100 / 5.3= 19 unnecessary
And it gets even worse......
0.4% vs 1.7% p = 0.09
NNT 77
10.6% vs 20.6% p < 0.001
NNT 10
5.3% vs 7.2% p = 0.33
NNT 53
TNM I TNM II TNM III
10
20
30
But better in MRC CR 07!
pre-op(n=674)
postop(n=676)
p NNT
TNM I 0% 3% ns 33
TNM II 2% 8% sign 16
TNM III 9% 17% sign 12
On basis of this:tailored treatment
Stage I TME
Stage II short-term RT + TME
Stage III short-term RT + TME
Fixed T4 long-term RT + TME
Do we need it for all heights?
LAR vs APR LAR APR
p<0.001 p=0.15
10.1%
14.0%
4.5% 9.3%
2 4 6 2 4 6
10
20
10
20
years since surgery years since surgery
TME trial: Distance to anal verge
2 4 6
10
20
2 4 6
5 - 10 cm 10 - 15 cm
6.2% TME
3.7% RT
10
20
13.7% TME
3.7% RT
p<0.0001 p=0.12
NNT 10 NNT 40
Again other results in MRC CR 07:
pre-op(n=674)
postop(n=676)
p NNT
0-5 cm 6% 10% sign 25
5-10 cm 5% 10% sign 20
10-15 cm 1% 16% sign 7Selection because of Dutch
results?
Abandon RT for high tumors?
Too few LR in proximal tumours (> 10 cm)
No significant effect of RT in proximal tumours
Side effects: incontinence and sexual function
Keep RT for high tumors ?
Subgroup analyses are hazardous: use with caution
Discrepancy with Swedish study for low tumors
Discrepancy with German study for high tumors
Very effective in MRC CR 07 study
Tumour distance from anal verge NOT standardized
On basis of this: tailored treatment
Stage I TME, possible role TEM
Stage II short-term RT + TME
Stage III short-term RT + TME
Fixed T4 long term RT + TME
RT for high tumors may be omitted in selected cases
But how to define a high tumor?
Stage I TME
Stage II short-term RT + TME
Stage III short-term RT + TME
Fixed T4 long term RT + TME
RT for high tumors may be omitted in selected cases
And what about T3 tumors?
On basis of this: tailored treatment
Few cells, still effective
p = 0.0008
RR=82%
5
10
15
20
2 4 6
6.1% TME
1.1% RT+TME
Years since surgery
Loca
l re
curr
en
ce r
ate
update of Marijnen et al., IJROBP 2003
CRM > 10 mm
Circumferential resection margins
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
T
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
CRMCRM
mucosa
m. propria
perirectal fat
inked margin
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
T
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1BCircumferential margin determined by a positive lymph node (LN)
T
LN
CRM
mucosa
m. propria
perirectal fat
inked margin
mucosa
m. propria
perirectal fat
inked margin
Figure 1BCircumferential margin determined by a positive lymph node (LN)
T
LN
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
T
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
CRMCRM
mucosa
m. propria
perirectal fat
inked margin
mucosa
m. propria
perirectal fat
inked margin
Figure 1ACircumferential margin determined by the tumor (T)
T
CRM
mucosa
m. propria
perirectal fat
inked margin
Figure 1BCircumferential margin determined by a positive lymph node (LN)
T
LN
CRM
mucosa
m. propria
perirectal fat
inked margin
mucosa
m. propria
perirectal fat
inked margin
Figure 1BCircumferential margin determined by a positive lymph node (LN)
T
LN
Margin determined by lymph node
Margin determined by tumor
CRM en prognosis
Local Metastases Survival n
Margin
< 1 mm 16.4 37.6 69.7 120
1.1 - 2.0 mm 14.9 21.0 84.8 53
2.1 - 5.0 mm 10.3 17.2 87.0 139
5.1 - 10 mm 6.0 8.2 91.2 155
> 10 mm 2.4 10.9 92.8 189
p-value 0.0007 < 0.0001 < 0.0001
Nagtegaal, Am. J. Surg. Pathol 2002
CRM > 1 mmn = 1089
CRM < 1 mmn = 227
2 4 6
10
20
30
15.5% RT
23.3% TME p = 0.16
RR=33%
2 4 6
10
20
30p = 0.001
RR=59%
9.1% TME
3.7% RT
update Marijnen et al., IJROBP 2003
5x5 Gy does not compensate for positive margins!
MRC CR 07
pre-op(n=674)
postop(n=676)
p
CRM -ve 3% 10% sign
CRM +ve 16% 23% ns