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JHSGR Neoadjuvant Therapy For Rectal Cancer Dr Chris TL Cheng Princess Margaret Hospital Neoadjuvant Therapy for Rectal Cancer Background Benefits of neoadjuvant therapy Selection Criteria Staging & CRM Multidisciplinary Team (MDT) approach 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 Short course pre-op RT Local recurrence Swedish (1997) 27% to 11% rectal cancer trial (p<0.001) (pre-TME) Dutch TME trial 8.2% to 2.4% (2001) (p<0.001) Survival 5-yr survival 48% to 58% (p=0.004) No difference Pre-op radiotherapy UK Medical Research Council (MRC CR07) & National Cancer Institute of Canada trial (NCIC-CTG C016) 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 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. Short course preop RT on local recurrence Relative risk reduction in LR 57% Neoadjuvant RT Vs Neoadjuvant ChemoRT Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation Chemotherapy addition to neoadjuvant versus radiation alone in for stage II and III resectable rectal cancer. Cochrane Database of Systematic Reviews 2009, Issue 1.response Art. No.: CD006041. DOI: RT improves complete 10.1002/14651858.CD006041.pub2 German rectal cancer study group Neoadjuvant CRT Vs Adjuvant CRT Local Recurrence Overall Survival Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731– 40. 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. Local recurrence for locally advanced CA rectum TME only TME + adjuvant chemoRT Neoadjuvant RT + TME Neoadjuvant chemoRT + TME Reduction in local recurrence Neoadjuvant ChemoRT is recommended for locally advanced rectal cancer Advantages of neoadjuvant CRT apply to virgin, well-oxygenated tissue more profound reduction of local recurrence compared with postoperative CRT downstage the tumor make radical resection or sphincter preserving surgery feasible Selection Criteria - T 3-4 - N +ve - Predicted CRM ≤ 2mm Accurate pre-op staging is important for neoadjuvant therapy consideration Meta-analysis on T and N staging T N 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. 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 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 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. Surgeons Radiologists Multidisciplinary Team Oncologists Pathologists Multidisciplinary team (MDT) Discussion at the MDT meeting Increases the proportion of patients receiving neoadjuvant treatment Improves local cancer control 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 Radiologists: Standardized MRI reporting by specialist gasterointestinal radiologists Oncologists Long Vs Short Scheme CRT Short scheme Intensity 5 fractions of 500 cGy Long scheme 4,500 to 5,060 cGy daily during 4 weeks Time before OT Aim 3-4 days 4-6 weeks Reduce local recurrence Downstage tumour and secure threatened CRM 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% Biological agents Bevacizumab/Cetuximab Pathologists Quirke’s detailed reporting system for rectal specimen Completeness of mesorectal excision Surgical 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. 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 restaging rectal cancer after radiotherapy. World J Gastroenterol. 2009 Nov 28;15(44):5563-7. Optimal time for operation 4-6 weeks is optimal Allows RT-induced tissue swelling or local inflammation to subside. 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 Conclusion For locally advanced rectal cancer: Neoadjuvant ChemoRT Accurate pre-op staging Multidisciplinary team (MDT) approach Thank you!