1. www.OncologyEducation.ca 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

2. www.OncologyEducation.ca Thank you for downloading this update. Please feel free to use it for educational purposes. Please acknowledge OncologyEducation.ca and Dr. Scott Berry when using these slides.

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

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

5. www.OncologyEducation.ca Study Design Arm AChemoradiotherapy 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 BChemoradiotherapy 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. www.OncologyEducation.ca Study Design

7. www.OncologyEducation.ca RESULTS % of Patients Receiving All Scheduled Cycles Cape5FU Adjuvant Group 77.6%80.0% Neoadjuvant Group 45.7%40.0%

8. www.OncologyEducation.ca RESULTS Cape5FUp-value 5 Yr DFS 67.8%54.1%P=0.035 5 Yr OS 75.7%66.6% P<0.001 (non-inferiority) P=0.053 (exploratory for superiority Distant Mets (%) 18.9%27.7%P=0.0367 Local Recurrence (%) 6.1%7.2%p = 0.7795

9. www.OncologyEducation.ca 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) Comparison (  ² test) Clinical stagingPathohistology T statusp = 0.5p = 0.07 N statusp = 0.7p = 0.09

10. www.OncologyEducation.ca Hand-foot skin reaction (HFS) Comparison of 3-y DFS and 5-y OS Capecitabine Any grade HFS n = 62 Capecitabine No HFS n = 135 5-FU All patients n = 195 3-y DFS83.2% 1 71.4%66.6% 95%-CI (%)71.0 – 90.662.6 – 78.459.1 – 73.0 5-y OS91.4% 2 68.0%66.6% 95%-CI (%)80.5 – 96.356.6 – 77.057.7 – 74.0 1 Test for superiority: p = 0.031 versus Cape no-HFS (n = 135) & p = 0.004 versus remaining population (n = 330) 2 Test for superiority: p = 0.001 versus Cape no-HFS (n = 135) & p < 0.0001 versus remaining population (n = 330)

11. www.OncologyEducation.ca TOXICITY Capecitabine n = 197 5-FU n = 195 p-value Total 1 1/23/4Total1/23/4 Hemoglobin6258–524920.32 Leukocytes504736850160.047 Platelets23 –322910.19 GGT55–76–0.57 Bilirubin8612110.10 1 CTC-grade is missing in some pts. 2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.

12. www.OncologyEducation.ca TOXICITY Capecitabine n = 197 5-FU n = 195 p-value Total1/23/4Total1/23/4 Nausea363323230–0.69 Vomiting141119810.39 Diarrhea1048317857640.07 Mucositis12111171520.34 Stomatitis88–1211–0.37 Abdominal pain 231911411–0.17 Proctitis312611091< 0.001 1 CTC-grade is missing in some pts. 2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.

13. www.OncologyEducation.ca Diarrhea Capecitabine n = 197 5-FU n = 195 p-value Diarrhea47430.72 Capecitabine n = 197 5-FU n = 195 p-value Diarrhea8862< 0.001 Cycles without radiotherapy Cycles with radiotherapy

14. www.OncologyEducation.ca TOXICITY Capecitabine n = 197 5-FU n = 195 p-value Total1/23/4Total1/23/4 Fatigue5550–292720.002 Anorexia13 –6510.16 Alopecia44–1110–0.07 Hand-foot skin reaction 6256433–< 0.001 Radiation dermatitis29222353210.41 Thrombosis / Embolism 102711520.83 1 CTC-grade is missing in some pts. 2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.

15. www.OncologyEducation.ca 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. www.OncologyEducation.ca 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