Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemoradiotherapy for locally advanced rectal cancer: safety results of a randomized phase III trial R.-D. Hofheinz, F. Wenz, S. Post, A. Matzdorff, S. Laechelt, L. Mueller, H. Link, M. Moehler, I. Burkholder, A. Hochhaus

Background Capecitabine, an oral 5-fluorouracil (5-FU) derivative, has been shown to be an effective alternative to intravenous 5-FU / leucovorin in the adjuvant treatment of stage III colon cancer. Twelves et al. N Engl J Med 2005 Capecitabine 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 Capecitabine has radiosensitizing properties. Several phase I and II trials investigated combined modality therapy using capecitabine in the perioperative treatment of rectal cancer. e.g. Dunst et al. J Clin Oncol 2002 The present phase-III trial compares capecitabine with standard 5-FU in the perioperative treatment of locally advanced rectal cancer.

Study design The study was designed as a two-arm, two-strata multicenter, randomized, open phase III trial . (arm A: Cape, arm B: 5-FU, stratum [S] I: adjuvant, S II: neoadjuvant). Primary aim was to determine whether 5- year overall survival rate (SR5) was noninferior in arm A (Cape) vs arm B (5-FU) with noninferior margin of 12.5% H0: Capecitabin is inferior to 5-FU (i.e. SR5Cape< SR55-FU - 12.5%) vs H1: Capecitabin is not inferior to 5-FU (i.e. SR5Cape ≥ SR55-FU - 12.5%) It is assumed that SR55-FU=57.5%. Sample size calculation is performed with β=80%, α=5% and a drop-out rate of 5%. Therefore, a total of 372 evaluable patients (186 per arm) was required to evaluate noninferiority of maximal 12.5% with a follow-up time of 4 years.

Main inclusion & exclusion criteria Patients aged 18 years Histologically proven rectal cancer (0 – 16 cm ab ano) No distant metastases ECOG status 0-1 Leucocytes > 3,500/µl, thrombocytes > 100,000/µl, hemoglobin > 10g/dl. Adequate liver and renal function (bilirubin < 2mg/dl, creatinine < 2mg/dl) Pts to be treated in SI (adjuvant stratum) Total mesorectal resection performed (R0-resection) Tumor stages pT3/4 Nx or pTxN0 M0 Pts to be treated in SII (neoadjuvant stratum) uT3/4 Nx or uN+

Treatment regimen Arm A Arm B Chemoradiotherapy: 50.4 Gy + Cape 1,650 mg/m² days 1-38 plus five 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] four cycles of bolus 5-FU 500mg/m² d 1-5, rep. d 29 S I: 2 x 5-FU > CRT > 2 x 5-FU (450mg/m² cycle 4 & 5) 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

Treatment regimen Adjuvant stratum S I Arm A Arm B week 1 5 9 13 17 21 Capecitabine 2,500mg/m² (during radiotherapy 1,650mg/m²) week 1 5 9 13 17 21 5-FU 500mg/m² 5-FU 450mg/m² Radiotherapy 50.4 Gy Arm B

Treatment regimen Neodjuvant stratum S II Arm A Arm B Surgery Capecitabine 2,500mg/m² (during radiotherapy 1,650mg/m²) week 5 10 16 20 24 28 Surgery 5-FU 500mg/m² Radiotherapy 50.4 Gy Arm B

Patient recruitment (n=392)

Baseline characteristics Capecitabine (N=197) 5-FU (N=195) Age (yrs) N 197 195 Median 64.6 64.0 [Min, Max] [29.6, 84.8] [32.8, 86.3] Sex N 191 188 Male 124 (64.9%) 125 (66.5%) Female 67 (35.1%) 63 (33.5%) WHO N 183 175 120 (65.6%) 96 (54.8%) 1 60 (32.8%) 78 (44.6%) 2 3 (1.6%) 1 (0.6%) UICC N 194 II 29 (14.7%) 24 (12.4%) III T1-3 154 (78.2%) 156 (80.4%) III T4 14 (7.1%) 14 (7.2%)

Baseline characteristics Adjuvant stratum Capecitabine (N=115) 5-FU T status 115 0, 1, 2 22 (19.1%) 32 (27.8%) 3, 4, X 93 (80.9%) 83 (72.2%) N status 114 0, X 42 (36.5%) 30 (26.3%) 1, 2, 3 73 (63.5%) 84 (73.7%)

Baseline characteristics Neoadjuvant stratum Capecitabine (N=81) 5-FU (N=80) T status 80 76 1, 2 8.8% 5.3% 3, 4, X 91.2% 94.7% N status 75 0, X 48.0% 52.0% 1, 2, 3

Duration of treatment Percentage of pts receiving schedules cycles Capecitabine ADJUVANT NEOADJUVANT 5-FU ADJUVANT NEOADJUVANT

Toxicity (I) CTC grades 1 – 4, observed in more than 10 pts Capecitabin (N=197) 5-FU (N=195) p-value 2 Total 1 1/2 3/4 Hemoglobin 62 58 - 52 49 2 0.32 Leukocytes 50 47 3 68 16 0.047 Platelets 23 32 29 1 0.19 Creatinine 5 0.45 Bilirubin 8 6 0.10 GGT 7 0.57 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.

Hand-foot skin reaction Toxicity (II) CTC grades 1 – 4, observed in more than 10 pts Capecitabin (N=197) 5-FU (N=195) p- value 2 Total 1 1/2 3/4 Fatigue 55 50 - 29 27 2 0.002 Anorexia 13 6 5 1 0.16 Alopecia 4 11 10 0.07 Hand-foot skin reaction 62 56 3 <0.001 Radiation dermatitis 22 35 32 0.41 Thrombosis/Embolism 7 0.83 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.

Toxicity (III) CTC grades 1 – 4, observed in more than 10 pts Capecitabin (N=197) 5-FU (N=195) p- value 2 Total 1 1/2 3/4 Nausea 36 33 2 32 30 - 0.69 Vomiting 14 11 1 9 8 0.39 Diarrhea 104 83 17 85 76 4 0.07 Mucositis 12 15 0.34 Stomatitis 0.37 Abdominal pain 23 19 0.17 Proctitis 31 26 10 <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.

Diarrhea Toxicity CTC-grade 1-4, only in cycles without radiotherapy Capecitabin (N=197) 5-FU (N=195) p-value Diarrhea 47 43 0.72 Toxicity CTC-grade 1-4 only in cycles with radiotherapy (Cycle 3 in adjuvant strata & cycle 1 in neoadjuvant strata) Capecitabin (N=197) 5-FU (N=195) p-value Diarrhea 88 62 <0.001

Downstaging Neoadjuvant stratum S II Capecitabine (N=81) 5-FU (N=80) pre-op post.-op post-op T status 80 69 76 0, 1, 2 8.8% 53.6% 5.3% 40.6% 3, 4, X 91.2% 46.4% 94.7% 59.4% N status 75 68 0, X 48.0% 73.5% 52.0% 55.1% 1, 2, 3 26.5% 44.9%

Downstaging in S II Comparison Arm A & Arm B Pre-OP Post-OP T status p=0.5 p=0.17 N status p=0.7 p=0.03 p-values resulted from exact two-sided Chi-square test Patients receiving capecitabine exhibited a significantly lower rate of N-positive tumors (p=0.03) a by trend improved T-downstaging (defined as ypT0-2) (p=0.17)

T-Downstaging in S II Transition matrix – Capecitabine 50.7 % 46.4% Capecitabine (N=69) post-op T status 1 2 3 4 pre-op T status - 1.4% 4.3% 10.1% 5.8% 26.1% 40.6% improvement no change deterioration 50.7 % 46.4% 2.9 %

T-Downstaging in S II Transition matrix – 5-FU 41.1 % 57.4 % 1.5 % 5-FU (N=68) post-op T status 1 2 3 4 pre-op T status - 1.5% 4.4% 2.9% 26.5% 51.5% improvement no change deterioration 41.1 % 57.4 % 1.5 %

Disease free survival Preliminary data Log-rank: p=0.303

Disease free survival rates Preliminary data 1-year [95% CI] 2-year 3-year [95% CI] 4-year 5-year [95% CI] Capecitabine (N=197) 93.2% [89.3,97.2] 82.7% [75.8,90.1] 76.3% [67.9,85.7] 63.5% [51.6,78.1] 54.3% [40.2,73.3] 5-FU (N=195) 93.1% [89.0,97.4] 79.2% [71.9,87.2] 64.5% [54.8,75.8] 56.9% [45.9,70.6] 43.5% [29.0,65.1] Median follow-up: Arm A (Cape): 1.60 years [95% CI: 1.19,1.92] Arm B (5-FU): 1.66 years [95% CI: 1.25,2.14]

Conclusions Both treatment regimens were well tolerated. Patients receiving capecitabine reported more all grade hand-foot skin reactions, proctitis, and fatigue, while leukopenia was more frequently observed with 5-FU. Patients receiving capecitabine in the neo-adjuvant stratum exhibited a significantly lower rate of N-positive tumors and a trend in improved T-down-staging (defined as ypT0-2 tumors) at the price of a higher rate of diarrhea during chemoradiotherapy. Median follow-up is still short. The preliminary 3-year disease-free survival rates are: Capecitabine 76.3% and 5-fluorouracil 64.5%. Data on the primary endpoint are expected for 2010.