1. 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

2. 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.

3. 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 %) vs H1: Capecitabin is not inferior to 5-FU (i.e. SR5Cape ≥ SR55-FU %) 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.

4. 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+

5. 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 [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

6. 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
5-FU
500mg/m²
5-FU
450mg/m²
Radiotherapy 50.4 Gy
Arm B

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

8. Patient recruitment (n=392)

9. 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%)

10. 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%)

11. 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

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

13. 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.

14. 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.

15. 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.

16. 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

17. 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%

18. 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)

19. 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 %

20. 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 %

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

22. 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): years [95% CI: 1.19,1.92]
Arm B (5-FU): years [95% CI: 1.25,2.14]

23. 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.