Authors: Hofheinz et al Reviewed By: Scott Berry Date posted: June 2011

1. Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer:Long term results of a randomized phase III trial Authors: Hofheinz et al Reviewed By: Scott Berry Date posted: June 2011

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3. Study Design N=392 Resectable Stage II/II Rectal Cancer Primary Outcome: 5 Yr OS (non-inferiority) Mar 2002-July2005 Post-Op Treatment

4. Study Design N=392 Resectable Stage II/II Rectal Cancer Primary Outcome: 5 Yr OS (non-inferiority) Post July 2005 After Publication of Sauer Trial Neoadjuvant Treatment Arms Added

5. Study Design Arm A Chemoradiotherapy 50.4 Gy + Cape 1,650 mg/m² days 1 – 38 plus 5 cycles of Cape 2,500 mg/m² d 1 – 14, rep. d 22 S I: 2 x Cape  CRT  3 x Cape S II: CRT  TME surgery (4 – 6 weeks after CRT)  Cape x 5 Arm B Chemoradiotherapy 50.4 Gy + 5-FU 225 mg/m² c.i. daily [S I] or 5-FU 1,000 mg/m² c.i. d 1 – 5 and 29 – 33 [S II] plus 4 cycles of bolus 5-FU 500mg/m² d 1 – 5, rep. d 29 S I: 2 x 5-FU  CRT  2 x 5-FU S II: CRT  TME surgery (4 – 6 weeks after CRT)  5-FU x 4 Cape: capecitabine; CRT: chemoradiotherapy; TME: total mesorectal excision; 5-FU: 5-fluorouracil

6. Study Design

7. RESULTS % of Patients Receiving All Scheduled Cycles

8. RESULTS

9. Neoadjuvant Group – Trend of Improved Downstaging with Capecitabine Patients receiving capecitabine exhibited • less ypN-positive tumors (p = 0.09) • improved T-downstaging (i.e. ypT0 – 2) (p = 0.07) • more pCR (ypT0 ypN0): 13.2 % vs. 5.4% (p = 0.16)

10. Hand-foot skin reaction (HFS) Comparison of 3-y DFS and 5-y OS

11. TOXICITY

12. TOXICITY

13. Diarrhea Cycles without radiotherapy Cycles with radiotherapy

14. TOXICITY

15. Author’s Conclusions • Both treatment regimens were well tolerated. Cape patients had more all grade HFS, proctitis, diarrhea and fatigue, while alopecia and leukopenia were more frequently observed with 5-FU. • In the neo-adjuvant stratum Cape led by trend to improved downstaging and a numerical higher rate of pCR. • Cape was non-inferior to 5-FU regarding 5-year survival. • Exploratory test for superiority was borderline significant. • 3-year DFS was significantly better with Cape. • HFS indicated superior 3-year DFS and 5-year OS. • Capecitabine may replace 5-FU in the perioperative treatment of locally advanced rectal cancer.

16. Bottom Line For Canadian Medical Oncologists • Many Canadian oncologists have already started using capecitabine as the systemic therapy component of neo-adjuvant and adjuvant therapy of rectal cancer based on • Extrapolation from adjuvant colon cancer trials for the chemotherapy component • Based on the results of phase II trials, population based outcome studies and interim results of phase III trials for the chemorads component • This results of this study affirm that practice