Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy

1. Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer: Long term results of a randomized phase III trial R. Hofheinz, F. Wenz, S. Post, A. Matzdorff, S. Laechelt, J. Hartmann, L. Müller, H. Link, M. H. Moehler, E. Kettner, E. Fritz, U. Hieber, H. W. Lindemann, M. Grunewald, S. Kremers, C. Constantin, M. Hipp, D. Gencer, I. Burkholder, A. Hochhaus, on behalf of the German MARGIT study group

2. Background • Capecitabine (Cape), an oral fluoropyrimidine derivative, has been shown to be equieffective with 5-fluorouracil (5-FU) / leucovorin in the adjuvant treatment of stage III colon cancer. [Twelves et al. N Engl J Med 2005] • Cape was non-inferior to infusional 5-FU in combination with oxaliplatin as first-line treatment for metastatic colorectal cancer.[Cassidy et al. J Clin Oncol 2008] • Cape has radiosensitizing properties. Several phase I and II trials investigated combined modality treatment using Cape in the perioperative treatment of rectal cancer. [e.g. Dunst et al. J Clin Oncol 2002] • The present phase-III trial sought to compare Cape with 5-FU in the perioperative treatment of locally advanced rectal cancer.

3. Study design • Primary aim To determine whether 5-year overall survival rate (SR5) was non-inferior in arm A (Cape) vs. arm B (5-FU) with non-inferior margin of 12.5%. • Assumption: SR55-FU = 57.5%. Sample size calculation performed with β = 20%, α = 5% and a drop-out rate of 5%. • Study was designed as a two-arm, two-strata multicenter, randomized, open phase III trial. • N = 372 evaluable patients (186 per arm) required to evaluate non-inferiority with a follow-up time of 4 years.

4. Main inclusion & exclusion criteria • Patients ≥18 years • Histologically proven rectal cancer (0 – 16 cm ab ano) • No distant metastases • Adequate hematological parameters: Leukocytes > 3,500/µl, thrombocytes > 100,000/µl, hemoglobin > 10g/dl. • Adequate liver & renal function Patients treated in adjuvant stratum • Total mesorectal resection performed (R0-resection) • Tumor stages pT3/4 Nany M0 or pTany N+ M0 Patients treated in neoadjuvant stratum • uT3/4 uNany M0 or uTany uN+ M0 (staging with EUS) • Total mesorectal excision mandatory

5. Treatment regimen 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 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. Treatment regimen Adjuvant stratum S I Arm A Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day) Radiotherapy 50.4 Gy Week 1 5 9 13 17 21 Radiotherapy 50.4 Gy 5-FU 500mg/m² day 1 – 5 (during radiotherapy 225 mg/m²/day) Arm B

7. Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day) Surgery Radiotherapy 50.4Gy Week 1 5 10 16 20 24 28 Radiotherapy 50.4Gy Surgery 5-FU 500mg/m² day 1 – 5 (during radiotherapy 1000 mg/m² d 1 – 5, d 29 – 33) Treatment regimen Neodjuvant stratum S I Arm A Arm B

8. Patients recruitment (n = 392) 2007

9. Baseline characteristics

10. Adjuvant stratum – % of patients receiving schedules cycles

11. Neoadjuvant stratum – % of patients receiving schedules cycles

12. Hematological and liver toxicity – NCI-CTC grades (v. 2.0)

13. Gastrointestinal Toxicity – NCI-CTC grades (v. 2.0)

14. Diarrhea – NCI-CTC grades (v. 2.0) Cycles without radiotherapy Cycles with radiotherapy (Cycle 3 in adjuvant strata & cycle 1 in neoadjuvant strata)

15. Other Toxicity – NCI-CTC grades (v. 2.0)

16. Neoadjuvant stratum – CONSORT diagram Randomized n = 161 5-Fluorouracil, n = 80 Capecitabine, n = 81 Informed consent withdrawn, n = 1 Refused port implantation, n = 1 Protocol violation (sigma CA), n = 1 Primary resection, n = 2 No start (worsening renal function), n = 1 Commenced RChT, n = 78 Commenced RChT, n = 77 No surgery (refusal, n = 2; PD, n = 1) No surgery (pCR n = 1, PD n = 1) Died during RChT (accident, n = 1; heart attack, n = 1) Surgery, n = 75 Surgery, n = 73 Deep anterior resection, n = 58 Abdominoperineal resection, n = 16 Not resectable, n = 1 Deep anterior resection, n = 53 Abdominoperineal resection, n = 19 Local excision, n = 1 Died ≤ 30 days post surgery, n = 3 Died ≤ 30 days post surgery, n = 1

17. Neoadjuvant stratumComparison Arm A & Arm B pCR: pathological complete remission

18. Neoadjuvant stratumComparison Arm A & Arm B

19. Neoadjuvant stratum – 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)

20. Disease related events

21. Disease free survival (DFS)Secondary endpoint (Median Follow-up 52 mon.)

22. Overall survival (OS)Primary endpoint (Median Follow-up 52 mon.)

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

24. 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.