臺灣博碩士論文加值系統

背景: Leucovorin與5-fluorouracil (5-FU)的合併使用為目前大腸直腸癌的標準化學治療方式。自2008年起，由於Leucovorin製造困難，藥品短缺問題持續惡化，在全球爆發了Leucovorin短缺危機。因此，許多醫療機構依當時美國NCCN指引提出的建議，在大腸直腸癌化學治療中進行低劑量Leucovorin的使用。短缺問題解除後，雖多數機構已將Leucovorin改回標準劑量，但仍有少數機構維持低劑量Leucovorin的使用。本研究目的是透過系統性文獻回顧與統合分析研究來比較低劑量和高劑量Leucovorin在大腸直腸癌治療的有效性與安全性。
方法:使用PubMed、Cochrane Library和Embase資料庫進行系統性文獻搜尋至2018年11月。並將各納入研究的結果使用隨機效應模式進行統合分析。在療效方面，評估低劑量Leucovorin和高劑量Leucovorin化療組合在大腸直腸癌治療的中位存活時間(median survival time)與腫瘤反應率(tumor response rate)。在安全性方面，評估各納入研究報導的血液學及非血液學毒性結果。
結果:本研究共納入8篇隨機對照試驗及4篇回溯性研究。經統合分析後發現，在中位存活時間，兩組並無顯著差異(SMD = -0.06; 95% CI -0.19 to 0.08)。在腫瘤反應率方面，雖使用高劑量Leucovorin，有較佳腫瘤反應率，但未達到統計顯著差異(OR = 0.81; 95% CI 0.55 to 1.18)。在副作用方面，除使用低劑量Leucovorin發生腹瀉機率較低外(OR = 0.65; 95% CI 0.49 to 0.86)，在其他血液學和非血液學方面毒性，兩組並無顯著差異。
結論: 使用低劑量Leucovorin在大腸直腸癌的化學治療中，與高劑量Leucovorin的療效相似外，在安全性方面，並無嚴重的副作用發生。因此，當Leucovorin短缺發生時，在大腸直腸癌化學治療中使用低劑量Leucovorin為一項可行的因應方式。

Aim: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- versus high-dose leucovorin in the treatment of colorectal cancer.
Methods: The PubMed, Embase, and Cochrane databases were searched for studies published before November 2018. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumor response rate. Secondary outcomes were hematologic and nonhematologic toxicities.
Results: Eight randomized controlled trials and 4 retrospective studies were reviewed. The pooled median survival time was similar between the 2 dose levels (standard mean difference: −0.06, 95% confidence interval [CI]: −0.19 to 0.08), but the remaining 3 studies that had not been pooled by meta-analysis showed a survival benefits trend in high-dose leucovorin. The pooled tumor response rate appeared comparatively higher in the high-dose leucovorin regimen (odds ratio = 0.81; 95% CI: 0.55 to 1.18). No statistically significant difference was found between the hematologic and nonhematologic toxicities of the 2 groups. However, there were fewer diarrhea events in the low-dose leucovorin regimen.
Conclusion: Low-dose leucovorin regimens are seemly feasible approaches for colorectal cancer and metastatic colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumor response rate.

致謝 i
縮寫表 iii
目錄 iv
中文摘要 vi
Abstract viii
第一章 緒論 1
壹、研究動機 1
貳、文獻回顧 4
一、大腸直腸癌流行病學與臨床治療現況 4
二、Leucovorin和Fluorouracil(5-FU)的合併使用 13
三、全球Leucovorin短缺問題 17
參、研究問題 20

第二章 研究方法與材料 22
壹、文獻納入與排除標準 22
一、研究族群 22
二、研究介入 22
三、研究結果 22
四、研究類型 23
貳、搜尋策略 24
一、使用電子資料庫 24
二、使用關鍵字 24
三、其他來源 24
參、文獻篩選 25
肆、文獻資料萃取 26
伍、文獻評讀 27
一、隨機對照試驗 (RCT) 27
二、非隨機對照試驗 (non-RCT) 27
陸、設定指標 28
柒、資料統計與分析 29
一、資料合併及異質性分析 29
二、敏感性分析 30

第三章 研究結果 31
壹、文獻搜尋 31
貳、文獻基本性質 32
參、文獻品質 35
一、隨機對照試驗 (RCT) 35
二、非隨機對照試驗 (non-RCT) 36
肆、療效指標療效指標 38
一、中位存活時間 (Median survival time) 38
二、腫瘤反應率 (Tumor response rate) 41
伍、安全性指標安全性指標 43
一、血液學毒性 (Hematological toxicity) 43
二、非血液學毒性 (non-Hematological toxicity) 46
陸、敏感性分析 50
一、研究介入合併標靶治療的影響 50
二、研究介入5-FU劑量差異的影響 52
三、研究介入中合併其他化療藥物的影響 53

第四章 討論討論 55
壹、研究結果總結 55
貳、低劑量Leucovorin在胃癌治療的爭議 56
參、不同化療給藥方式的影響 57
肆、併用藥品的影響 58
伍、標靶治療的影響 59
陸、異質性分析 60
柒、研究限制 62

第五章 結論與展望 63

參考文獻 64

圖表 70

1.NCCN Clinical Practice in Oncology：Colon cancer V.1.2019.
2.Mini, E., et al., Enhancement of the antitumor effects of 5-fluorouracil by folinic acid. Pharmacology & Therapeutics, 1990. 47(1): p. 1-19.
3.Hayes, M.S., et al., Lessons from the leucovorin shortages between 2009 and 2012 in a medicare advantage population: where do we go from here? Am Health Drug Benefits, 2014. 7(5): p. 264-70.
4.NCCN Clinical Practice in Oncology：Colon cancer V.1.2012.
.
5.Reynolds, J., et al., High- versus low-dose leucovorin in the modified FOLFOX6 regimen for first-line treatment of metastatic colorectal cancer. J Oncol Pharm Pract, 2017. 23(3): p. 173-178.
6.Shank, B.R., et al., Effects of the leucovorin shortage: Pilot study investigating cost, efficacy, and toxicity comparison of low fixed-dose versus body surface area-adjusted leucovorin dosing in patients with resectable colon or metastatic colorectal cancer. J Oncol Pharm Pract, 2017. 23(3): p. 163-172.
7.Budai, B., et al., The use of high dose d,l-leucovorin in first-line bevacizumab+mFOLFIRI treatment of patients with metastatic colorectal cancer may enhance the antiangiogenic effect of bevacizumab. Angiogenesis, 2013. 16(1): p. 113-21.
8.Group., U.S.C.S.W. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999-2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. 2018; Available from: www.cdc.gov/cancer/dataviz.
9.衛生福利部國民健康署. 中華民國105年癌症登記報告. 2018; Available from: https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=269&pid=10227.
10.Surveillance, E., and End Results (SEER) Program. SEER*Stat database: Incidence-SEER 9 Regs Research data with Delay-adjustment, Malignant only, Nov 2015 Sub (1975-2013) ,Katrina/Rita Population Adjustment.-Linked To County Attributes-Total US, 1969-2014 Counties. 2016; Available from: https://seer.cancer.gov/data/seerstat/nov2015/.
11.National Cancer Institute: Surveillance, E., and End Results (SEER) Program. Annual Report to the Nation 2018: National Cancer Statistics. 2018; Available from: https://seer.cancer.gov/report_to_nation/statistics.html.
12.Miguel A Rodriguez-Bigas, M., Axel Grothey, MD. Overview of the management of primary colon cancer. 2019 Mar.; Available from: www.uptodate.com.
13.Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.
14.NCCN Clinical Practice in Oncology：Rectal cancer V.1.2019.
15.Kuipers, E.J., et al., Colorectal cancer. Nat Rev Dis Primers, 2015. 1: p. 15065.
16.Petrelli, F., et al., Timing of Adjuvant Chemotherapy and Survival in Colorectal, Gastric, and Pancreatic Cancer. A Systematic Review and Meta-Analysis. Cancers (Basel), 2019. 11(4).
17.Jeffrey W Clark, M., Axel Grothey, MD. Systemic chemotherapy for metastatic colorectal cancer: General principles. 2019 Mar.; Available from: www.uptodate.com.
18.Wolmark, N., et al., Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst, 1988. 80(1): p. 30-6.
19.Goodwin, R.A. and T.R. Asmis, Overview of systemic therapy for colorectal cancer. Clin Colon Rectal Surg, 2009. 22(4): p. 251-6.
20.Wolmark, N., et al., The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol, 1993. 11(10): p. 1879-87.
21.Wu, C., Systemic Therapy for Colon Cancer. Surg Oncol Clin N Am, 2018. 27(2): p. 235-242.
22.Rougier, P., et al., Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. The Lancet, 1998. 352(9138): p. 1407-1412.
23.Van Cutsem, E., et al., Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol, 2009. 27(19): p. 3117-25.
24.de Gramont, A., et al., Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol, 2000. 18(16): p. 2938-47.
25.Andre, T., et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med, 2004. 350(23): p. 2343-51.
26.Twelves, C., et al., Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med, 2005. 352(26): p. 2696-704.
27.Schmoll, H.J., et al., Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol, 2007. 25(1): p. 102-9.
28.Cassidy, J., et al., Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol, 2008. 26(12): p. 2006-12.
29.Porschen, R., et al., Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol, 2007. 25(27): p. 4217-23.
30.Diaz-Rubio, E., et al., Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol, 2007. 25(27): p. 4224-30.
31.Giantonio, B.J., et al., Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol, 2007. 25(12): p. 1539-44.
32.Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 2004. 350(23): p. 2335-42.
33.Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med, 2009. 360(14): p. 1408-17.
34.Douillard, J.Y., et al., Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 2013. 369(11): p. 1023-34.
35.de Gramont, A., et al., Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol, 1997. 15(2): p. 808-15.
36.Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47.
37.Longley, D.B., D.P. Harkin, and P.G. Johnston, 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 2003. 3(5): p. 330-8.
38.Diasio, R.B. and B.E. Harris, Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet, 1989. 16(4): p. 215-37.
39.Nadal, J.C., et al., In vivo potentiation of 5-fluorouracil by leucovorin in murine colon carcinoma. Biomed Pharmacother, 1988. 42(6): p. 387-93.
40.Park, J.G., et al., Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. J Natl Cancer Inst, 1988. 80(19): p. 1560-4.
41.Mini, E., B.A. Moroson, and J.R. Bertino, Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells: enhancement by leucovorin. Cancer Treat Rep, 1987. 71(4): p. 381-9.
42.Parchure, M., R.Y. Ambaye, and S.V. Gokhale, Combination of anticancer agents with folic acid in the treatment of murine leukaemia P388. Chemotherapy, 1984. 30(2): p. 119-24.
43.Straw, J.A., D. Szapary, and W.T. Wynn, Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res, 1984. 44(7): p. 3114-9.
44.Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet, 2000. 355(9215): p. 1588-96.
45.Madajewicz, S., et al., Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. 1984. 44(10): p. 4667-4669.
46.Machover, D., et al., Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol, 1986. 4(5): p. 685-96.
47.Machover, D., et al., Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep, 1982. 66(10): p. 1803-7.
48.Erlichman, C., et al., A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol, 1988. 6(3): p. 469-75.
49.O''Connell, M.J., A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. A Mayo Clinic/North Central Cancer Treatment Group study. Cancer, 1989. 63(6 Suppl): p. 1026-30.
50.Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol, 1992. 10(6): p. 896-903.
51.Thirion, P., et al., Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol, 2004. 22(18): p. 3766-75.
52.McBride, A., et al., National survey on the effect of oncology drug shortages on cancer care. Am J Health Syst Pharm, 2013. 70(7): p. 609-17.
53.Services, U.S.D.O.H.A.H., Common Terminology Criteria for Adverse Events (CTCAE). 2017.
54.Liberati, A., et al., The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. PLOS Medicine, 2009. 6(7): p. e1000100.
55.Julian PT Higgins, J.S., Matthew J Page, Jonathan AC Sterne Revised Cochrane risk of bias tool for randomized trials (RoB 2.0). 2016.
56.Sterne, J.A., et al., ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ, 2016. 355.
57.DerSimonian, R. and N. Laird, Meta-analysis in clinical trials. Control Clin Trials, 1986. 7(3): p. 177-88.
58.Green, J.P.H.a.S., Cochrane Handbook for Systematic Reviews of Interventions. 2011.
59.Jager, E., et al., Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol, 1996. 14(8): p. 2274-9.
60.Labianca, R., et al., High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a ''GISCAD'' phase III study. Italian Group for the Study of Digestive Tract Cancer. Ann Oncol, 1997. 8(2): p. 169-74.
61.Maroun, J.A., et al., Retrospective comparative analysis of 5FU + low-dose folinic acid vs. 5FU + high-dose folinic acid in the treatment of metastatic colorectal cancer. The Ottawa experience. Am J Clin Oncol, 1997. 20(4): p. 387-92.
62.Petrelli, N., et al., The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol, 1989. 7(10): p. 1419-26.
63.Poon, M.A., et al., Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol, 1991. 9(11): p. 1967-72.
64.Sugano, K., et al., [Early phase II trial of l-leucovorin and 5-fluorouracil in advanced colorectal cancer. l-Leucovorin and 5-FU Study Group]. Gan To Kagaku Ryoho, 1995. 22(5): p. 627-37.
65.Ychou, M., et al., A prospective randomized study comparing high- and low-dose leucovorin combined with same-dose 5-fluorouracil in advanced colorectal cancer. Am J Clin Oncol, 1998. 21(3): p. 233-6.
66.Sasaki, T., et al., [A randomized early phase II study of l-leucovorin and 5-fluorouracil in gastric cancer. l-Leucovorin and 5-FU Study Group]. Gan To Kagaku Ryoho, 1995. 22(4): p. 521-9.
67.Jeong, J., et al., Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer. Ann Oncol, 2008. 19(6): p. 1135-40.
68.Im, C.K., et al., A phase II study of paclitaxel combined with infusional 5-fluorouracil and low-dose leucovorin for advanced gastric cancer. Cancer Chemother Pharmacol, 2008. 61(2): p. 315-21.
69.Jeung, H.C., et al., A phase II study of infusional 5-fluorouracil and low-dose leucovorin with docetaxel for advanced gastric cancer. Oncology, 2006. 70(1): p. 63-70.
70.Buroker, T.R., et al., Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol, 1994. 12(1): p. 14-20.
71.Haller, D.G., et al., Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol, 2005. 23(34): p. 8671-8.
72.Bennouna, J., et al., Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol, 2013. 14(1): p. 29-37.