The evidence supporting this protocol is provided by two phase III randomised controlled trials, the NSABP R-04 trialr and the German study by Hofheinz et al.r
NSABP R-04 trialr
Between July 2004 and August 2010, a total of 1608 patients with clinical stage II or III rectal cancer were randomised to receive radiation therapy with one of the following concurrent chemotherapy regimens: continuous IV infusion (CIV) 5-FU (225 mg/m2/day for 5 days a week), with or without oxaliplatin (OX) (50 mg/m2/week); oral capecitabine 825 mg/m2 BD/day for 5 days a week), with or without oxaliplatin (OX) (50 mg/m2/week).
The end points were complete pathologic response (pCR), sphincter-saving surgery (SSS), and surgical downstaging (SD).
Hofheinz et alr
A total of 401 patients with stage II or III locally advanced rectal caner (LARC) were enrolled into this two-arm, two-strata randomised phase III trial (arm A: capecitabine, arm B: 5FU; stratum I: adjuvant , SII: neoadjuvant). Arm A: CRT: 50.4 Gy + Cape 825 mg/m2 BD d1-38 daily plus 5 cycles of cape 1250 mg/m2 BD d1-14 q21days (SI: 2 x Cape, CRT, 3x Cape; SII: CRT, TME surgery, 5 x cape). Arm B: CRT: 50.4Gy + 5FU 225 mg/m2/day CIV plus 4 cycles of bolus 5FU 500 mg/m2 d1-5 q28days (SI: 2x5FU, CRT, 2x5FU; SII: CRT, TME surgery, 4 x 5FU).
The primary endpoint was overall survival (OS) and secondary endpoints were disease-free survival (DFS) and safety.
Efficacy
NSABP R-04 trialr
Interim results presented at ASCO 2011 showed that there were no significant differences in the pCR, SSS, or SD between 5-FU and capecitabine regimens or between the regimens, with or without oxaliplatin. The primary end-point, overall survival is yet to be reported.
Hofheinz et alr
Regarding duration of treatment, 78% (Cape) and 80% (5FU) completed all scheduled treatment cycles in SI, and 46% (Cape) and 40% (5FU) in neoadjuvant stratum SII. In SII, a total of 38% (Cape) and 43% (5FU) did not continue chemotherapy after tumour resection. At a median follow-up of 52 months, the local recurrence rate was equal (cape 6%, 5FU 7%; p=0.665), while significantly less patients developed distant metastases in the capecitabine arm (19% v 28%; p=0.037).
Kaplan-meier estimates of (A) overall survival (B) disease-free survivalr
(A)
© Lancet Oncology 2012
(B)
© Lancet Oncology 2012
Toxicity
Patients receiving capecitabine had more hand-foot skin reactions (HFS), fatigue, and proctitis, while leukopenia was more frequent with fluorouracil. The rate of diarrhoea was significantly greater in the capecitabine arm compared to the fluorouracil arm during chemoradiation.r
Toxicityr
(all grades) |
Capecitabine
n=197 |
Fluorouracil
n=195 |
p-value |
Haemoglobin |
62 |
52 |
0.29 |
Leukocytes |
50 |
68 |
0.04 |
Platelets |
23 |
32 |
0.18 |
Nausea |
36 |
32 |
0.63 |
Vomiting |
14 |
9 |
0.30 |
Diarrhoea |
104 |
85 |
0.07 |
Mucositis |
12 |
17 |
0.32 |
Stomatitis |
8 |
12 |
0.35 |
Abdominal pain |
23 |
14 |
0.13 |
Proctitis |
31 |
10 |
< 0.001 |
Fatigue |
55 |
29 |
0.002 |
Anorexia |
13 |
6 |
0.10 |
Alopecia |
4 |
11 |
0.06 |
Hand-foot skin reaction |
62 |
3 |
<0.001 |
Radiation dermatitis |
29 |
35 |
0.39 |
adapted from Hofheinz et al. 2012