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

Colorectal cancer is number three in cancer mortality

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

Results 1st Line Therapy of Advanced CRC CR/PR TTP (mon) OS (mon) 5-FU/FA Bolus 15-20% 4-6 11-12 5-FUInf / ± FA 20-30% 7 10-15 5-FU Prodrugs ± FA 20-35% 7 10-15 5-FU/ FA/ Mitomycin 50% 8 15 5-FUBolus/Inf/ FA/ Irinotecan 40-50% 6-8 15-17.5 5-FUInf / FA/ Oxaliplatin 50-55% 7-9 16-19.5

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)

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

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

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

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

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

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;84:299-304

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

TEGAFIRI is an effective alternative regimen for the management of recurrent or metastatic colorectal cancer Tzu-Chi Hsu Oncol Lett 2015;9:1059-64

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

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

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

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.

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 2017 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,

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

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

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

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%)

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)

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)

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)

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

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%)

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

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

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

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

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

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