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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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N=392Resectable Stage II/II
Rectal CancerPrimary Outcome: 5 Yr OS (non-inferiority)
Study Design
Mar 2002-July2005Post-Op
Treatment
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N=392Resectable Stage II/II
Rectal CancerPrimary Outcome: 5 Yr OS (non-inferiority)
Study Design
Post July 2005
After Publication of Sauer TrialNeoadjuvant
TreatmentArms 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
Cape 5FU p-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
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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 staging Pathohistology
T status p = 0.5 p = 0.07
N status p = 0.7 p = 0.09
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Hand-foot skin reaction (HFS) Comparison of 3-y DFS and 5-y OS
CapecitabineAny grade HFS
n = 62
CapecitabineNo HFS
n = 135
5-FUAll patients
n = 195
3-y DFS 83.2%1 71.4% 66.6%
95%-CI (%) 71.0 – 90.6 62.6 – 78.4 59.1 – 73.0
5-y OS 91.4%2 68.0% 66.6%
95%-CI (%) 80.5 – 96.3 56.6 – 77.0 57.7 – 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)
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TOXICITY
Capecitabinen = 197
5-FU 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 is missing in some pts.2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.
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TOXICITY
Capecitabinen = 197
5-FU n = 195
p-value
Total 1/2 3/4 Total 1/2 3/4
Nausea 36 33 2 32 30 – 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 < 0.0011 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.
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Diarrhea
Capecitabinen = 197
5-FU n = 195
p-value
Diarrhea 47 43 0.72
Capecitabinen = 197
5-FU n = 195
p-value
Diarrhea 88 62 < 0.001
Cycles without radiotherapy
Cycles with radiotherapy
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TOXICITY
Capecitabinen = 197
5-FU 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 is missing in some pts.2 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 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