Neoadjuvant Therapy for Rectal Cancer is Overrated Joon H. Lee, Research Resident University of Colorado 8/31/2009
Objectives Brief overview of staging rectal cancer Current guidelines for evaluation and treatment of rectal cancer Data without benefit for five-year survival (5YSR) Benefit of neoadjuvant therapy Conclusions
Staging: American Joint Committee on Cancer (AJCC) Meredith et al. Surg Clin of N Amer. 2009
Stage-based Survival Meredith et al. Surg Clin of N Amer. 2009
Diagnostic Evaluation Establishing locoregional involvement with transrectal ultrasound Possible role of MRI to evaluate mesorectal node involvement Evaluation of distant metastases by CT scan Still controversial role of combined PET/CT for evaluation of distant metastases Meredith et al. Surg Clin of N Amer. 2009
Treatment Standard of Care Neoadjuvant Chemotherapy: 5-fluorouracil (5-FU), leucovorin, & oxaliplatin (FOLFOX) Neoadjuvant Radiotherapy: External beam radiation (XBR) no consensus on dose but 28 fractions, total 50.4 Gy used often Surgical resection: Low anterior resection (LAR), abdominal perineal resection (APR), local excision Fry et al. Sabiston Textbook of Surgery. 2007
German Rectal Cancer Study Group Randomized controlled trial (RCT) of preop vs. postop chemoradiotherapy Multicenter (26) trial with n=823, 421 in preop arm; 1 Endpoint of overall survival 50.4 Gy XBR and 5-FU Median follow-up 46 months Overall 5 YSR of 76% vs 74% (p=0.80) Sauer et al. NEJM. 2004
Cochrane Database Review 2007 Review of preoperative radiotherapy for localized resectable adenocarcinoma of rectum 20 randomized controlled studies Included studies with other included therapies if uniformly applied to both arms 19 studies failed to show significant overall survival benefit Wong et al. Cochrane Database Sys Rev. 2007
Wong et al. Cochrane Database Sys Rev. 2007
Wong et al. Cochrane Database Sys Rev. 2007. Colorectal Cancer Collaborative Group. Lancet. 2001
5 Year Survival Benefit Prospective randomized multicenter trial with preoperative XBR (25 Gy over one week) versus surgery alone N=1168, 583 radiotherapy vs 585 control Local recurrence 11% vs 27% in control Overall 5 YSR 58% in experimental arm vs 48% in control Swedish Rectal Cancer Trial. NEJM. 1997
Swedish Rectal Cancer Trial Swedish Rectal Cancer Trial. NEJM. 1997
Discrepancies Exist There is no evidence of control of postoperative adjuvant therapies A local recurrence rate of 27% in the control arm is exorbitantly high Surgeons in neither arms performed total mesenteric excision (TME) Why is this study different from all other studies? Swedish Rectal Cancer Trial. NEJM. 1997
Total Mesenteric Excision In conjunction with either low anterior resection or abdominal perineal resection No blunt dissection of the mesorectum during rectal resection Careful sharp dissection, direct visualization, and care in preservation of autonomic nerves Avoid violation of tumor package, (i.e. mesorectal envelope) Reported local recurrence rate of 6 % without neoadjuvant therapy with n=301 Heald. Eur J Cancer. 1995
Dutch Colorectal Cancer Group Randomized multi-center controlled trial, n=1805; 897 preoperative XBR and TME, 908 TME alone Statistically significant increase in blood loss (p<0.001) and perineal complications (26% vs 18% p=0.05) in XBR group Kapiteijn et al. NEJM. 2001.
Kapiteijn et al. NEJM. 2001.
E Kapiteijn et al. Overall 2 year survival rate was 82% in experimental arm and 81.8% in control; Hazard ratio 1.02 No significant differences in distant and overall recurrence Significant decrease in local recurrence: 2.4% in neoadjuvant arm versus 8.2% (p<0.001) Kapiteijn et al. NEJM. 2001.
Local Recurrence & Survival Med Res Coun RC WP. Br J Surg. 1984 GA Higgins. Cancer. 1986 A Gerard. Ann Surg. 1988 M Buyse. JAMA. 1988 JA Reis Neto. Dis Colon Rectum. 1989 O Dahl. Cancer. 1990 PA Goldberg. Eur J Cancer. 1994 PJ Marsh. Dis Colon Rectum. 1994 B Cedermark. Cancer. 1995 Med Res Coun RC WP. Lancet. 1996 Stockholm CCSG. Ann Surg Onc. 1996 S Petersen. Chirug. 1998 NP Nguyen. Am J Clin Onc. 2000 MW Onaitis. Ann Surg Onc. 2001 MW Onaitis. Ann Surg. 2001 K Tankel. Am J Surg. 2002 PJ Allen. J Gastrointest Sug. 2003 JP Gerard. J Clin Onc. 2006 KC Peeters. Ann Surg. 2007 S Tsujinaka. Int J Colorectal Dis. 2008 GJ Chang. Cancer. 2009 HY Cheung. Surg Endosc. 2009 D Sebag-Montefiore. Lancet. 2009
Management of Local Recurrence Locally recurrent rectal cancer has 5 YSR of 22-31% and local control of 50-71% Degrades quality of life; 1 symptom: Pain Surgery remains mainstay of treatment: APR, total pelvic exenteration, abdominosacral resection Multimodality therapy: Surgery, XBR, chemotherapy (again, FOLFOX), intraoperative radiotherapy Moriya. Japan J Clin Onc. 2006
Management of Local Recurrence Is there a survival benefit with combined modalities? A debate for another day. Moriya. Japan J Clin Onc. 2006
Conclusions No evidence of benefit of neoadjuvant therapies in 5 year survival rate Local recurrences are troubling but do not appear to impact overall survival Neoadjuvant chemoradiotherapy is overrated
Conclusions (continued) Buy a Swedish car, not a Swedish operation
Tack själv (Thank You in Swedish)
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