1. Both Xeliri and Tegafiri combined with bevacizumab are effective regimen for management of recurrent or metastatic colorectal cancer 以Xeloda或Uracil-tegafur 和irinotecan併用bevacizumab 是治療再發或轉移大腸癌的有效方式
Tzu-Chi Hsu1,2, Ming-Jen Chen1
Division of colon and rectal surgery, Department of Surgery, Mackay Memorial Hospital1; Department of surgery, Taipei Medical University2; Taipei, Taiwan
許自齊1,2 陳明仁1 台北馬偕紀念醫院外科部大腸直腸外科1;
台北醫學大學外科部2

2. Colorectal cancer is number three in cancer mortality

3. Conventional FU/LV-Based Palliative Therapy for Colorectal Cancer
Improvement in Overall Survival
 6 months compared to BSC
Abrogation of Tumor-Related Symptoms
in 40% for a duration > 9 months
Benefit in Terms of Quality of Life
Prolongation of the asymptomatic phase by 2-9 months compared to BSC
Cost-Effectiveness of Treatment
Costs per gained year of life:
US $10,000
Scheithauer, BMJ 93
Hafstrom, Cancer 94
Beretta, Proc ASCO 97
Glimelius, Ann Oncol 93
Nordic GI Group, JCO 92
Glimelius, Ann Oncol 93
Allen-Mersh, Lancet 94
Glimelius, Ann Oncol 95

4. Results 1st Line Therapy of Advanced CRC
CR/PR TTP (mon) OS (mon)
5-FU/FA Bolus 15-20%
5-FUInf / ± FA 20-30%
5-FU Prodrugs ± FA %
5-FU/ FA/ Mitomycin 50% 8 15
5-FUBolus/Inf/ FA/ Irinotecan 40-50%
5-FUInf / FA/ Oxaliplatin %

5. Advancing overall survival in mCRC
1960s Best supportive care
1970–1980s 5-FU
1990s 5-FU/LV
IFL
FOLFOX
FOLFOX/FOLFIRI sequence
IFL + bevacizumab
Oxaliplatinfluoropyrimidine + bevacizumab
Oxaliplatinfluoropyrimidine + VEGF + EGFR Inhibition ? 6 12 18 24 30
Median overall survival (months)

6. Real-life experience of Regorafenib in metastatic colorectal cancer treatment
Tzu-Chi Hsu, MD, FACS, FACRS
Attending Surgeon of Colon and Rectal
Surgery, Taipei Mackay Memorial Hospital;
Professor of Surgery, Taipei Medical
University;
Professor of surgery, Mackay Medical college
Taipei, Taiwan

7. Curative and palliative treatment strategies in cancer treatment
Survival
Palliative Therapy
Curative Therapy
Time 7

8. Irinotecan in the treatment of metastatic colorectal cancer
Irinotecan in the treatment of metastatic colorectal cancer *Approved by DOH in 1999

9. Bevacizumab in the treatment of metastatic colorectal cancer
Bevacizumab in the treatment of metastatic colorectal cancer *Approved by DOH in May 2005

10. VEGF Inhibitors Y Y PlGF VEGF-B VEGF-C, VEGF-D VEGF-A Bevacizumab
Ramucirumab Y
Ziv-aflibercept
(VEGF trap)
Sunitinib
Sorafenib
Lenvatinib
Regorafenib
VEGF-R1
(Flt-1)
Migration
Invasion
Survival
VEGF-R2
(KDR/Flk-1)
Proliferation
Survival
Permeability
VEGF-R3
(Flt-4)
Lymphangiogenesis
Functions
Slide credit: clinicaloptions.com

11. An open-label safety study of first-line bevacizumab in combination with standard chemotherapy in Chinese patients with metastatic colorectal cancer treated in an expanded access program in Taiwan
Lee KD, Chen HH, Wang HM, Tsao CJ, Hsu TC, Chiou CF, Su WC, Wang JY
Oncology 2013;84:

12. Taiwan Experience: UFUR and LV as 1st Therapy for mCRC
Jpn J Clin Oncol 2000;30(11)510–514

13. TEGAFIRI is an effective alternative regimen for the management of recurrent or metastatic colorectal cancer
Tzu-Chi Hsu
Oncol Lett 2015;9:

14. Figure 3. Overall survival of each Dukes’ stage in the further study group
Dukes’ — Dukes’B Dukes’C －-－ Dukes’D

15. Figure 4. Progression free survival of each Dukes’ stage in the further study group
Dukes’ — Dukes’B Dukes’C －-－ Dukes’D

16. Background
Many patients with metastases or recurrences from colorectal cancer have been proven to respond well to chemotherapy
It has been suggested that multiple drugs together with biologics result in a better response than therapy with only chemotherapeutic agents

17. Aim
To evaluate a single surgeon’s experience of response rate of combination chemotherapy with biologic avastin
Employing irinotecan and oral capecitabine or uracil-tegafur (UFUR) with leucovorin, together with bevacizumab for patients with recurrent or metastatic colorectal cancer.

18. Study period: January 2009 to March 2017, Number of patients: 140
Materials and methods
Study period: January 2009 to March 2017,
Number of patients: 140
Study period: January 2009 to March 2017,
Number of patients: 140
All the patients were followed until September or death.
No.
regimen
frequency
Fluorouracil + A 15
Uracil-Tegafur 300mg/m2 or Capecitabine 900mg/m2,
Bevacizumab 5mg/kg
Every 2 weeks
FOLFIRI + A 18
Irinotecan 150mg/m2, 5-FU 1500mg/m2,
TEGAFIRI + A 36
Uracil-Tegafur 300mg/m2,
Irinotecan 150mg/m2,
XELIRI + A 71
Capecitabine 900mg/m2,

19. Both Xeliri and tegafiri combination with bevacizumab are effective regimen for the management of recurrent or metastatic colorectal cancer
Patient characteristic chart
DFS OS
Treatment cycle (median, mean)
Adverse events

20. Patient characteristic
Fluorouracil + A
FOLFIRI + A
TEGAFIRI + A
XELIRI + A
Total
n=15
n=18
n=36
n=71
N=140 n %
p-value
Gender
0.2299
Female 6 40 12
66.67 14
38.89 30
42.25 62
44.29
Male 9 60
33.33 22
61.11 41
57.75 78
55.71
Age (meta with CT confirm)
0.0007
mean, sd
73.41
11.73
11.26
64.43
9.78
61.44
12.18
63.02
12.05
Primary tumor site
0.0003
Colon 10 16
44.44
84.51 98 70
Rectum 5 20
55.56 11
15.49 42
Pathological differentiation
0.0068
well differentiated 1
6.67 4
22.22
1.41
4.29
moderately differentiated 50 31
86.11 58
81.69
108
77.14
poorly differentiated 2
13.33 3
8.33
12.68 18
12.86
unknown
5.56
4.23 8
5.71
ECOG PS 15
100 36 71
140

21. Patient characteristic
Fluorouracil + A
FOLFIRI + A
TEGAFIRI + A
XELIRI + A
Total
n=15
n=18
n=36
n=71
N=140 n %
p-value
RAS type
0.3029
mutaion 6
54.55 10
58.82 13
39.39 24
36.36 53
41.73
wild type 5
45.45 7
41.18 20
60.61 42
63.64 74
58.27
Previous adjuvant CT
0.0045 No 12 80
66.67 16
44.44 55
77.46 95
67.86
Yes 3
33.33
55.56
22.54 45
32.14
Lesion of metastatic site
0.5938
Liver and Lung 2
13.33
11.11 1
2.86 8
11.27
9.35
Liver only 40 9
25.71 27
38.03 44
31.65
Lung only
16.67
17.14
14.39
Other(single)
38.89 11
15.49 29
20.86
multiple (with Lung)
6.67
5.56
2.82
3.6
multiple(with Liver) 4
11.43
12.68 15
10.79
mutiple(>=2)
14.29
8.45
Surgical resection of metastatic disease
0.0905
86.67 18
100 26
72.22
112
80.58
27.78
19.42

22. Patient characteristic
Patients in flurouracil with avastin group are older
More patients with colon cancer in the xeliri with avastin group than tegafiri with avastin group (84.51% vs 44.44%)
More patients had previous adjuvant chemotherapy in xeliri with avastin group than tegafiri with avastin group (77.46% vs 44.44%)
Xeliri with avastin group and tegafiri with avastin group had similar rate of metastasectomy (22.54% vs 27.78%)

23. PFS N=140 MST (month)=12.26 (10.52, 14.10) regimen n MST 95% CI
Fluorouracil + A 15
10.52
6.69
22.13
FOLFIRI + A 18
8.00
3.67
15.18
TEGAFIRI + A 36
11.02
8.39
16.82
XELIRI + A 71
14.10
11.25
16.33
N=140
MST (month)=12.26 (10.52, 14.10)

24. OS N=140 MST (month)=24.33 (19.74, 30.10) regimen n MST 95% CI
Fluorouracil + A 15
17.48
6.69
33.54
FOLFIRI + A 18
20.52
8.79
26.82
TEGAFIRI + A 36
27.70
22.26
37.74
XELIRI + A 71
22.16
17.31
30.92
MST (month)=24.33 (19.74, 30.10)

25. PFS and OS
Progression free survival is highest in xeliri with avastin group(14.10 m) followed by tegafiri with avastin group (11.02 m), lowest in folfiri with avastin group (8.00 m)
Overall survival is highest in tegafiri with avastin group (27.70 m), followed by xeliri with avastin group (22.16 m), lowest in fluorouracil with avastin group (17.48 m)

26. Treatment Cycle mean sd median range Fluorouracil + A n=15 11.67 5.69
5-22
FOLFIRI + A
n=18
12.06
7.67
12.5
2-30
TegaFIRI + A
n=36
14.14
9.01 13
2-35
XeLIRI + A
n=71
14.89
9.35 14
1-55
Total
N=140
13.99
8.74

27. AE AE Fluorouracil + A FOLFIRI + A TEGAFIRI + A XELIRI + A Total
Abdominal pain
2(3%)
2(1%)
Colon perforation
1(1%)
Diarrhea
3(8%)
6(8%)
9(6%)
Dysuria
1(7%)
Fatigue
1(3%)
Hand and foot syndrome
2(13%)
3(4%)
6(4%)
Insomnia
1(6%)
3(%)
Itching of skin
Lost body weight
Nausea
2(6%)
5(4%)
Oral ulcer
5(7%)
8(6%)
Poor appetite
7(19%)
12(17%)
19(14%)
Severe hand and foot syndrome
Shoulder pain
Stomatitis
Vomiting
6(40%)
2(11%)
18(50%)
38(54%)
64(46%)

28. Treatment cycle and AE
No significance difference in treatment cycle among groups
One patient in the xeliri with avastin group developed colon perforation
Xeliri with avastin group and tegafiri with avastin group had similar rate of diarrhea, hand and foot syndrome, and poor appetite
Xeliri with avastin group had slightly higher rate of oral ulcer than tegafiri with avastin group

29. Advantages of the combination therapy as out patient
Do not require admission
Over all injection time is shorter
Do not require additional apparatus for
injection
Tolerated reasonably well for most of
patients
Hematological and non-hematological
side effect are fewer

30. Disadvantages of the combination therapy as out patient
No way to be sure the patients are following
the instructions to take oral medications
Nausea and vomiting associated with
injection of Campto might interfere with
the desire to take oral medications
Vomiting and diarrhea associated with
injection of Campto might decrease the
amount of actual intake of oral medications

31. Conclusion Multiple agents together with biologics
might offer long term survival in patients with
metastatic or recurrent colorectal cancer
Combination chemotherapy of irinotecan and capecitabine or irinotecan and tegafur-uracil together with bevacizumab are viable options with acceptable result for recurrent or metastatic colorectal cancer

32. Conclusion
Both xeliri and tegafiri together with bevacizumab as out patient is advantageous because of no requirement for admission, shorter injection time, no requirement for additional apparatus for injection, good tolerance by most patients, and acceptable hematological and non-hematological side effects
Further study is necessary to determine the best combination of the chemotherapeutic agents with bevacizumab

33. No needs of port A for infusion
Advantages of the combination therapy as out patient
No admission
No infusor
Oral drugs
No needs of port A for infusion