(5-fluorouracil 5-FU) [ ] FOLFOXIRI FOLFOXIRI. [DOI] /j.issn

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1 FOLFOXIRI 21 [ ] FOLFOXIRI 21 FOLFOXIRI 150mg/m 2 d 1 85mg/m 2 d 1 200mg/m 2 d mg/m 2 48h %(9/21) 8 (38.1%) 1 (4.8%)3 4.8%(1 ) % 93.4% % 14 (66.7%) 6 (28.6%) 1 (4.8%) 3 (14.3%) R0 21 (ORR) (DCR) % FOLFOXIRI FOLFOXIRI [ ] FOLFOXIRI [ ] R [ ] A [ ] (2016) [DOI] /j.issn Evaluation of efficacy and safety of modified infusion of fluorouracil, leucovorin, oxaliplatin, and irinotecan (mfolfoxiri) in treatment of metastatic colorectal cancer: a retrospective study of 21 cases WANG Xi-cheng, WEI Qing, GAO Jing, LI Yan-yan, CAO Yan-shuo, SHEN Lin * Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing , China * Corresponding author, lin100@medmail.com.cn [Abstract] Objective To evaluate the safety and preliminary efficacy of mfolfoxiri (the combination of irinotecan, oxaliplatin and 5-fluorouracil with reducing dosages) in first-line treatment for Chinese patients with unresectable metastatic colorectal cancer (mcrc). Methods A total of 21 patients received mfolfoxiri treatment: irinotecan 150mg/m 2 on day 1, oxaliplatin 85mg/m 2 on day 1, leucovorin 200mg/m 2 on day 1, and 5-fluorouracil (5-FU) 2800mg/m 2 in a 48-h continuous infusion starting on day 1. The regimen was repeated every 2 weeks. Result All the 21 patients were evaluated for efficacy of the aforesaid therapeutic regimen, and the incidence of toxic effects. No death occurred in association with the treatment. The total rate of grade 3 to 4 adverse events was 42.9% (9/21) including 38.1% (8 cases) with grade 3 neutropenia and 4.8% (1 case) suffering from grade 3 anemia. One of 21 patients (4.8%) showed grade 4 neutropenia accompanied by fever. The delivered relative doseintensityof irinotecan, oxaliplatin and 5-FU during the entire treatment course were 93.4%, 98.5% and 97.6%, respectively of planned dosage. In the intention-to-treat analysis for treatment activity, 14 patients showed remission, 6 stability, and 1 with progression of the disease. The overall response rate was 66.7%, and the disease control rate was 95.2%. Three patients (15.8%) with residual liver metastases were radically resected after mfolfoxiri chemotherapy. Conclusions This mfolfoxiri project has manageable toxicity and is well tolerated in Chinese patients. The safety profile appears to be improved compared with standard FOLFOXIRI regimen. In addition, the antitumor activity and preliminary efficacy seem to be maintained. [Key words] colorectal cancer; FOLFOXIRI; chemotherapy; objective response rate [ ] [ ] ( ) [ ] lin100@medmail.com.cn 50 [1-2] [3] [4-6] (5-fluorouracil 5-FU)

2 Med J Chin PLA, Vol. 41, No. 3, March 1, (irinotecan) (oxaliplatin) [7-9] (5-FU ) [10] +5-FU/ (leucovorin LV) +5-FU/ LV 5-FU [11-15] 2 FOLFOXIRI (5-FU ) (objective response rate ORR) 58.1%~69.0% (progression free survival PFS) 10.4~11.0 (overall survival OS) 22.5~26.5 [16-17] FOLFOXIRI PFS OS [18-19] FOLFOXIRI FOLFOXIRI ~75 (ECOG) 2 RECIST 1.1 : Kras Braf DNA PCR PCR 2 [20] UGT1A1 DNA PCR UGT1A1* 28 UGT1A1* 6 PCR [21] 1.3 FOLFOXIRI 1 150mg/m 2 250ml 0.9% 1h 85mg/m 2 5% 250ml 200mg/m 2 5% 250ml 2h 5-FU 2800mg/m h mg 2h 2mg NCI CTC /L /L 3d % % FU 15% (CEA) CT CT/MRI 6~ (NCI-CTC) [22] 1 RESIST SPSS 19.0 χ 2 Fisher PFS 1 P<0.05

3 (66.7%) 7 (33.3%) 50(43~61) 1 12 (57.1%) ECOG=1 9 ECOG=0 20 (95.2%) (1~9) 1 (n=21) Tab. 1 Baseline characteristics of patients (n=21) Characteristics Number of patients [n(%)] Sex Male 14(66.7) Female 7(33.3) ECOG performance status 0 8(38.0) 1 13(61.9) Primary Colon 15(71.4) Rectum 6(28.6) Number of metastatic sites Single 0(0) Multiple 21(100) Metastases Synchronous 20(95.2) Metachronous 1(4.8) Site of disease Liver 20(95.2) Lung 2(9.5) Other 4(19.0) Previous chemotherapy Adjuvant 0(0) Palliative 0(0) Previous radiotherapy 0(0) Baseline CEA(ng/ml) (57.1) >100 9(42.9) Differentiation High-median 15(71.4) Low 6(28.6) ( 2 3) 98.5% 93.4% 5-Fu 97.6% (7.8%) 2 1 (4.8%) 1 (4.8%) (n=8 38.1%) 3 2 (102 ) Tab. 2 Maximum toxicity per cycle (102 cycles) Adverse event (%) NCI-CTC grade(%) Diarrhea Neurotoxicity 18.6 Thrombocytopenia 1.0 Neutropenia Anemia Nausea/vomiting Tab. 3 Maximumtoxicityof21patients Adverse event NCI-CTC Grade(%) Diarrhea Alopecia Neurotoxicity 38.1 Thrombocytopenia 4.8 Neutropenia Anemia Nausea/vomiting Cutaneous 33.3 indicates no data available 9 (42.9%) 11 (10.7%) (26.5%) (G-CSF) UGT1A1*28 UGT1A1*6 [23-24] 10 UGT1A1*6 UGT1A1* UGT1A1* Kras Braf 21 RECIST 1.1 CR 14 (66.7%) PR 7 6 (28.6%) SD 1 (4.8%) 6 (28.6%) R0 3 (14.3%) R0 1 (4.8%) R1 2 PFS 5.3 (1.1~8.9 ) 21 Kras Braf 7 (33.3%) Kras 3

4 Med J Chin PLA, Vol. 41, No. 3, March 1, (14.3%) Braf Kras Braf ORR 81.8% Kras Braf ORR 50.0%( 4) 4 Kras/Braf FOLFOXIRI [n(%)] Tab. 4 Preliminary efficacy of FOLFOXIRI stratified by Kras/Braf status [n(%)] Kras PR SD PD ORR 10(Mutated) 5(50.0) 4(40.0) 1(10.0) (Wild) 9(81.8) 2(18.2) 0(0) 81.8 PR. Partial remission; SD. Stable diseases; PD. Progressive of diseases; ORR. Objective response rate 3 NCCN ESMO FOLFOXIRI [25-26] ORR OS [27] FOLFOXIRI %~5.8% %~27.7% %~49.0% [18-19] ( ) FOLFOXIRI Kras/Braf FOLFOXIRI FOLFOXIRI 5-Fu 21 ( 2 3) %~50.0% %~27.7% %~5.8% [18-19] % 3 5-FU 1 2 UGT1A1*28 UGT1A1*28 [28-31] FOLFOXIRI UGT1A1*28 UGT1A1*28 FOLFOXIRI ORR 66.7% (diseases control rate DCR) 95.2% [18-19] [32] FOLFOXIRI ORR 65.9% 6 (28.6%) R0 3 (14.3%) R0 1 (4.8%) R1 2 Braf [33-37] Braf FOLFOXIRI [38-42] Kras/Braf ORR 81.8% Kras/Braf ORR 50.0% Kras/Braf FOLFOXIRI Kras [43-45] EGFR [46-48] Kras/Braf FOLFOXIRI OS OS PFS 5.3 [16-19,42] PFS (95.2%) 3 (9/ %) (carcino-embryonic antigen CEA) 100ng/ml( 1) FOLFOXIRI FOLFOXIRI

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