1. นายแพทย์ธราธร ตุงคะสมิต นายแพทย์ชำนาญการพิเศษ โรงพยาบาลมะเร็งอุดรธานี
Acute toxicities of concurrent chemoradiation with 5-fluorouracil versus capecitabine in locally advanced rectal cancer
นายแพทย์ธราธร ตุงคะสมิต
นายแพทย์ชำนาญการพิเศษ
โรงพยาบาลมะเร็งอุดรธานี
Journal of Thai Association of Radiation Oncology
Vol.22 No.1 January – June 2016

2. Introduction Concurrent chemoradiation (CCRT) Standard of care
Locally advanced rectal cancer
Stage T3, T4 or positive pelvic lymph node
Local control
Reduce tumor size
Improve resectability
Overall outcome of treatment

3. Introduction German study group
Preoperative (pre-op) versus postoperative (post-op) CCRT
Better local control rate & toxicities in pre-op group
Intravenous fluorouracil (5-FU) ; standard chemotherapy for CCRT
Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:

4. Introduction Capecitabine
Oral form 5-FU
NSABP R-04 : CCRT with capecitabine versus 5-FU
Pathologic complete response rate (pCR)
Tumor down-staging
sphincter preservation rate
Similar efficacy
O'Connell MJ, et al. Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04. J Clin Oncol 2014; 32(18):

5. Introduction Hofheinz et al. RCT non-inferiority trial
Compare CCRT capecitabine versus 5-FU
Pre-op & post-op CCRT
Non-inferior overall survival
Hofheinz RD, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, noninferiority, phase 3 trial. Lancet Oncol 2012; 13: 579–88.

6. Objective
Evaluated and compared acute toxicities during course of CCRT either preoperative or adjuvant postoperative in locally advanced rectal cancer using oral capecitabine versus intravenous 5-FU

7. Multicenter randomized study 7 radiation therapeutic cancer centers
Material and methods
Multicenter randomized study
7 radiation therapeutic cancer centers
วชิระฯ, ราชวิถี, เชียงใหม่, ลำปาง, สงขลาฯ, ชลบุรี และอุดรธานี
January 2015 – October 2015
53 locally advanced rectal cancer patients
24 pts in 5-FU
29 pts in Capecitabine

8. Locally advanced stage CA Rectum
Eligible criteria
Age >18
Locally advanced stage CA Rectum
T3-T4
Node positive
No distant metastasis
Preoperative or postoperative CCRT
No contraindication for chemotherapy
No active severe underlying disease

9. 5-FU Capecitabine Chemotherapy Dose 1,000 mg/m2
Intravenous continuous drip
day 1-5 and day of RT
Capecitabine
Dose 825 mg/m2 bid
During RT day

10. Whole pelvis RT RT technique Upper border : L5 - S1 Lower border :
obturator foramen or 2-3 cm tumor inferiorly
Lateral border :
1.5 – 2 cm lateral pelvic brim
Anterior border :
posterior pubic symphysis (T3) or anterior pubic symphysis (T4)
Posterior border :
whole sacral bone

11. Conventional fractionation (1.8 - 2 Gy/day) 5 fractions / week
RT technique
Dose 45 – 50.4 Gy
Conventional fractionation ( Gy/day)
5 fractions / week
Total treatment time 5-6 weeks

12. Acute treatment related toxicities were scored and recorded based on
Physical exam and lab tests every week during CCRT by radiation oncologists
Acute treatment related toxicities were scored and recorded based on
Radiation Therapy Oncology Group (RTOG) criteria
National Cancer Institute Common Toxicity Criteria (CTCAE) version 4.03

13. : Compare the acute toxicities between 2 groups
Statistical analysis
Primary endpoint
: Compare the acute toxicities between 2 groups
Different in the severity of toxicities between described as percentage
Compared using Chi-square test
Two-tailed p-value < 0.05
SPSS IBM V.20

14. Whole Pelvis RT 45 – 50.4 Gy Enrolled (N = 53) 5-FU (n=24)
Capecitabine (n=29)
Pre-op CCRT 10
Post-op CCRT 14
Pre-op CCRT 15
Post-op CCRT 14
Whole Pelvis RT 45 – 50.4 Gy
Neutropenia (severe) 3
Complete
(n=21)
Complete
(n=29)

15. Patients characteristics
5-fluorouracil
(n=24)
Capecitebine
(n=29)
p-value
Age (years)
- Median
- Range 57
26-71 59
44-86
0.088
Gender:
- Male
- Female 13 11 14 15
0.785
Treatment:
- Preoperative
- Postoperative 10
0.583

16. Acute non-hematologic toxicities
5-fluorouracil (n=24)
Capecitabine (n=29)
p-value
Grade 1
Grade 2
Grade 3 - 4
Dermatitis
29.2
20.8
41.4
6.9
0.289
Diarrhea
50.0
33.3
8.3
48.3
27.6
0.212
Genitourinary
16.7
4.2
0.372
Hand-foot syndrome
17.2
3.4
0.327

17. Grade 1-2 non-hematologic toxicities

18. Acute hematologic toxicities
Toxicities (n)
5-fluorouracil (n=24)
Capecitabine (n=29)
p-value
Grade 1
Grade 2
Grade 3 - 4
Hemoglobin 1 4 2
0.673
Leucopenia 3
0.085

19. Acute hematologic toxicities
n =29
Hemoblogin
Neutropenia

20. Acute toxicities between treatment groups in capecitabine
Preoperative (n=15)
Postoperative (n=14)
p-value
Grade 1
Grade 2
Grade 3 - 4
Dermatitis
33.3
13.3
50.0
0.127
Diarrhea
73.3
20.0
21.4
35.7
0.054
Genitourinary
0.383
Hand-foot syndrome
6.67
0.273

21. Discussion
Ramani et al. report acute toxicity gr 3 in capecitabine group
4% for diarrhea
1% for neutropenia
Whereas in this study reported no gr 3 acute toxicities in capecitabine arm
Ramani VS, Sun MA, Montazeri A, Wong H. Preoperative chemoradiotherapy for rectal cancer: A comparison between intravenous 5-fluorouracil and oral capecitabine. Colorectal Dis 2010; 12(suppl2):

22. Discussion
Acute toxicities in postop CCRT would more frequent than preop CCRT
14 in 29 cases treated with postop CCRT with capecitabine
All grade acute toxicities were comparable to preop CCRT with capecitabine
No sever grade of acute toxicities

23. Discussion 5-FU : more acute diarrhea and leucopenia
Capecitabine : more HFS
Hofheinz, et al. showed significant in term of leucopenia in 5-FU arm and HFS & fatigue in capecitabine arm
All different results showed no statistical significant
Lancet Oncol, 2012 Jun;13(6): doi: /S (12)70116-X. Epub 2012 Apr 13.

24. Conclusion
This report showed that the acute toxicities of CCRT with capecitabine in locally advanced rectal cancer are comparable to the standard infusion 5-FU.