1. JHSGR Neoadjuvant Therapy For Rectal Cancer Dr Chris TL Cheng Princess Margaret Hospital

2. Neoadjuvant Therapy for Rectal Cancer Background Benefits of neoadjuvant therapy Selection Criteria Staging & CRM Multidisciplinary Team (MDT) approach

3. Background During the 1990s, TME and postoperative adjuvant chemoradiotherapy (CRT) for locally advanced rectal tumors was the gold standard treatment regimen High Local recurrence (LR) rates despite the use of adjuvant CRT investigators decided to test neoadjuvant radiotherapy (RT) or CRT investigators decided to test neoadjuvant radiotherapy (RT) or CRT

4. Short course pre-op RT Local recurrence Survival Swedish (1997) rectal cancer trial (pre-TME) 27% to 11% (p<0.001) 5-yr survival 48% to 58% (p=0.004) Dutch TME trial (2001) 8.2% to 2.4% (p<0.001) No difference

5. Pre-op radiotherapy Swedish rectal cancer trial (1997) Pre TME era, n=1168 Pre TME era, n=1168 Short course pre-op RT Short course pre-op RT Significant reduction of local recurrence from 27% to 11% (p<0.001), and in all Dukes stage Significant reduction of local recurrence from 27% to 11% (p<0.001), and in all Dukes stage Improved 5-year survival from 48% to 58% (p=0.004) Improved 5-year survival from 48% to 58% (p=0.004) Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336: 980–7.

6. Pre-op radiotherapy Dutch colorectal cancer group (2001) TME trial Post TME era, n=1805 Post TME era, n=1805 Short course pre-op RT Short course pre-op RT Significant reduction of local recurrence from 8.2% to 2.4% (p<0.001) Significant reduction of local recurrence from 8.2% to 2.4% (p<0.001) No difference in overall survival No difference in overall survival Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–46.

7. Pre-op radiotherapy UK Medical Research Council (MRC CR07) & National Cancer Institute of Canada trial (NCIC-CTG C016) Local recurrence at 3 years Local recurrence at 3 years Pre-op short course RT: 4.4% Selective Post-op adjuvant chemoRT: 10.6% Relative risk reduction 61% (p<0.0001) No difference in overall survival No difference in overall survival Sebag-Montefiore D et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20.

8. Short course preop RT on local recurrence Relative risk reduction in LR 57%

9. Neoadjuvant RT Vs Neoadjuvant ChemoRT Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006041. DOI: 10.1002/14651858.CD006041.pub2 Chemotherapy in addition to neoadjuvant RT improves complete response

10. German rectal cancer study group Neoadjuvant CRT Vs Adjuvant CRT Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731– 40. Overall SurvivalLocal Recurrence

11. Neoadjuvant CRT has less toxicities Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731– 40.

12. Neoadjuvant ChemoRT is recommended for locally advanced rectal cancer Local recurrence for locally advanced CA rectum TME only TME + adjuvant chemoRT Neoadjuvant RT + TME Neoadjuvant chemoRT + TME Reduction in local recurrence

13. Advantages of neoadjuvant CRT apply to virgin, well-oxygenated tissue more profound reduction of local recurrence compared with postoperative CRT more profound reduction of local recurrence compared with postoperative CRT downstage the tumor downstage the tumor make radical resection or sphincter preserving surgery feasible make radical resection or sphincter preserving surgery feasible

14. Selection Criteria -T 3-4 -N +ve -Predicted CRM ≤ 2mm Accurate pre-op staging is important for neoadjuvant therapy consideration Accurate pre-op staging is important for neoadjuvant therapy consideration

15. Meta-analysis on T and N staging No accurate investigation for LN EUS is operator dependent, cannot pass stenotic tumor, and can only detect mesorectal lymph nodes Bipat et al. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging--a meta-analysis. Radiology 2004 Sep;232(3):773-83. T N

16. CRM (circumferential resection margin) the distance from the edge of the tumor to the margin of the resected specimen a credible surrogate marker for local recurrence (LR) The prognostic value of CRM involvement is independent of TNM classification. CRM ≤ 2mm consider margin positive

17. MRI for CRM MRI recommended for CRM assessment MERCURY (Magnetic resonance imaging and rectal cancer european equivalence) study group MRI and histopathologic assessments of tumor spread equivalent to within 0.5 mm MRI and histopathologic assessments of tumor spread equivalent to within 0.5 mm Accurate measurement of the depth of extramural tumor spread Accurate measurement of the depth of extramural tumor spread Mercury Study Group. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007 Apr;243(1):132-9.

18. Multidisciplinary Team Multidisciplinary Team Surgeons Pathologists Radiologists Oncologists

19. Multidisciplinary team (MDT) Discussion at the MDT meeting Increases the proportion of patients receiving neoadjuvant treatment Increases the proportion of patients receiving neoadjuvant treatment Improves local cancer control Improves local cancer control Improves 5-year survival Improves 5-year survival Palmer G et al. Preoperative tumour staging with multidisciplinary team assessment improves the outcome in locally advanced primary rectal cancer. Colorectal Dis. 2010 Oct 19 ePub

20. Radiologists: Standardized MRI reporting by specialist gasterointestinal radiologists

21. Oncologists Long Vs Short Scheme CRT Short scheme Long scheme Intensity 5 fractions of 500 cGy 4,500 to 5,060 cGy daily during 4 weeks Time before OT 3-4 days 4-6 weeks Aim Reduce local recurrence Downstage tumour and secure threatened CRM

22. Chemotherapy Addition of chemotherapy to RT improves complete pathologic remission up to 38% Xeloda (Capecitabine): oral route 5-FU + Irinotecan/Oxaliplatin + RT Downstaging 67-84% Downstaging 67-84% Biological agents Bevacizumab/Cetuximab Bevacizumab/Cetuximab

23. Pathologists Quirke’s detailed reporting system for rectal specimen Completeness of mesorectal excision Completeness of mesorectal excision Surgical audit Surgical audit MRI audit MRI audit Quirke P. Training and quality assurance for rectal cancer: 20 years of data is enough. Lancet Oncol 2003;4:695–702. Quirke P, Durdey P, Dixon MF, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996 –9.

24. Re-staging after neoadjuvant CRT After RT, both EUS and MRI offered poor diagnostic performance in the assessment of T and N stages Mezzi G. et al. Endoscopic ultrasound and magnetic resonance imaging for re- staging rectal cancer after radiotherapy. World J Gastroenterol. 2009 Nov 28;15(44):5563-7.

25. Optimal time for operation 4-6 weeks is optimal Allows RT-induced tissue swelling or local inflammation to subside. Allows RT-induced tissue swelling or local inflammation to subside. Allows time for tumor regression, which may improve resectability and possibility of sphincter preservation. Allows time for tumor regression, which may improve resectability and possibility of sphincter preservation. 1)Lim S-BM et al. Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers. Ann Surg 2008; 248:243–251. 2)Veenhof AA et al. Preoperative radiation therapy for locally advanced rectal cancer: a comparison between two different time intervals to surgery. Int J Colorectal Dis. 2007;22:507–513

26. Conclusion For locally advanced rectal cancer: Neoadjuvant ChemoRT Neoadjuvant ChemoRT Accurate pre-op staging Accurate pre-op staging Multidisciplinary team (MDT) approach Multidisciplinary team (MDT) approach

27. Thank you!