1. TME trial TME radiotherapy 5 x 5 Gy TME alone randomisation n = 1861 resectable rectal carcinoma if CRM+: 50 GY

2. MRC CR 07: 5x5 Gy vs. postop CRT 5x5 Gy Surgery Pathology CRM -veCRM +veCRM -veCRM +ve Surgery Pathology nothing45Gy + 5 FU chemotherapy as per local protocol

3. My belief in 2002: 5x5 Gy for all Never heard of tailored treatment More insight: subgroup analyses Mainly hypothesis generating

4. Local Recurrence TME study p < 0.001 5.6% 10.9% 5 10 15 20 246 TME RT+TME 2.4% 8.2% Peeters et al., Ann Surg 2007

5. 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

6. 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 ITNM IITNM III 10 20 30

7. But better in MRC CR 07! pre-op (n=674) postop (n=676) pNNT TNM I0%3%ns33 TNM II2%8%sign16 TNM III9%17%sign12

8. On basis of this: tailored treatment Stage I TME Stage IIshort-term RT + TME Stage III short-term RT + TME Fixed T4 long-term RT + TME Do we need it for all heights?

9. LAR vs APR LAR APR p<0.001p=0.15 10.1% 14.0% 4.5% 9.3% 246246 10 20 10 20 years since surgery

10. TME trial: Distance to anal verge 246 10 20 246 5 - 10 cm10 - 15 cm 6.2% TME 3.7% RT 10 20 13.7% TME 3.7% RT p<0.0001p=0.12 NNT 10NNT 40

11. Again other results in MRC CR 07: pre-op (n=674) postop (n=676) pNNT 0-5 cm6%10%sign25 5-10 cm5%10%sign20 10-15 cm1%16%sign7 Selection because of Dutch results?

12. 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

13. 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

14. On basis of this: tailored treatment Stage I TME, possible role TEM Stage IIshort-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?

15. Stage I TME Stage IIshort-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

16. Few cells, still effective p = 0.0008 RR=82% 5 10 15 20 246 6.1% TME 1.1% RT+TME Years since surgery Local recurrence rate update of Marijnen et al., IJROBP 2003 CRM > 10 mm

17. Circumferential resection margins Margin determined by lymph node Margin determined by tumor

18. CRM en prognosis Local Metastases Survival n Margin < 1 mm16.437.669.7120 1.1 - 2.0 mm14.921.084.8 53 2.1 - 5.0 mm10.317.287.0139 5.1 - 10 mm 6.0 8.291.2155 > 10 mm 2.410.992.8189 p-value 0.0007 < 0.0001 < 0.0001 Nagtegaal, Am. J. Surg. Pathol 2002

19. CRM > 1 mm n = 1089 CRM < 1 mm n = 227 246 10 20 30 15.5% RT 23.3% TME p = 0.16 RR=33% 246 10 20 30 p = 0.001 RR=59% 9.1% TME 3.7% RT update Marijnen et al., IJROBP 2003 5x5 Gy does not compensate for positive margins!

20. MRC CR 07 pre-op (n=674) postop (n=676) p CRM -ve3%10%sign CRM +ve16%23%ns