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
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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.
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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
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
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.
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.
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,
Hand-foot skin reaction (HFS) and survivalComparison 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)
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.