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