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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Study Design
N=392
Resectable Stage II/II
Rectal Cancer
Primary Outcome: 5 Yr OS (non-inferiority)
Mar 2002-July2005
Post-Op
Treatment
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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
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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
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Study Design
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RESULTS
% of Patients
Receiving All Scheduled Cycles
Cape
5FU
Adjuvant Group
77.6%
80.0%
Neoadjuvant
Group
45.7%
40.0%
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RESULTS
5 Yr DFS
Cape
5FU
p-value
67.8%
54.1%
P=0.035
P<0.001
(non-inferiority)
P=0.053
(exploratory for superiority
5 Yr OS
75.7%
66.6%
Distant Mets
(%)
18.9%
27.7%
P=0.0367
Local
Recurrence (%)
6.1%
7.2%
p = 0.7795
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Neoadjuvant Group – Trend of
Improved Downstaging with
Capecitabine
Comparison (² test)
Clinical staging
Pathohistology
T status
p = 0.5
p = 0.07
N status
p = 0.7
p = 0.09
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)
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Hand-foot skin reaction (HFS)
Comparison of 3-y DFS and 5-y OS
3-y DFS
95%-CI (%)
5-y OS
95%-CI (%)
1
2
Capecitabine
Any grade HFS
Capecitabine
No HFS
5-FU
All patients
n = 62
n = 135
n = 195
83.2%1
71.4%
66.6%
71.0 – 90.6
62.6 – 78.4
59.1 – 73.0
91.4%2
68.0%
66.6%
80.5 – 96.3
56.6 – 77.0
57.7 – 74.0
Test for superiority: p = 0.031 versus Cape no-HFS (n = 135) & p = 0.004 versus remaining population (n = 330)
Test for superiority: p = 0.001 versus Cape no-HFS (n = 135) & p < 0.0001 versus remaining population (n = 330)
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TOXICITY
Capecitabine
5-FU
n = 197
n = 195
p-value
Total1
1/2
3/4
Total
1/2
3/4
Hemoglobin
62
58
–
52
49
2
0.32
Leukocytes
50
47
3
68
50
16
0.047
Platelets
23
23
–
32
29
1
0.19
GGT
5
5
–
7
6
–
0.57
Bilirubin
8
6
1
2
1
1
0.10
1 CTC-grade
2
is missing in some pts.
p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
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TOXICITY
Capecitabine
5-FU
n = 197
n = 195
p-value
Total
36
1/2
33
3/4
2
Total
32
1/2
30
3/4
–
0.69
Vomiting
14
11
1
9
8
1
0.39
Diarrhea
104
83
17
85
76
4
0.07
Mucositis
12
11
1
17
15
2
0.34
Stomatitis
8
8
–
12
11
–
0.37
Abdominal
pain
23
19
1
14
11
–
0.17
Proctitis
31
26
1
10
9
1
< 0.001
Nausea
1
2
CTC-grade is missing in some pts.
p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
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Diarrhea
Cycles without radiotherapy
Diarrhea
Capecitabine
5-FU
p-value
n = 197
n = 195
47
43
0.72
Capecitabine
5-FU
p-value
n = 197
n = 195
88
62
Cycles with radiotherapy
Diarrhea
< 0.001
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TOXICITY
Capecitabine
5-FU
n = 197
n = 195
p-value
Total
1/2
3/4
Total
1/2
3/4
Fatigue
55
50
–
29
27
2
0.002
Anorexia
13
13
–
6
5
1
0.16
Alopecia
4
4
–
11
10
–
0.07
Hand-foot skin
reaction
62
56
4
3
3
–
< 0.001
Radiation dermatitis
29
22
2
35
32
1
0.41
Thrombosis /
Embolism
10
2
7
11
5
2
0.83
1 CTC-grade
2
is missing in some pts.
p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
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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.
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Bottom Line For
Canadian Medical Oncologists
• Many Canadian oncologists have
already started using capecitabine as
the systemic therapy component of neoadjuvant 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
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