臺灣博碩士論文加值系統

腫瘤產生的骨骼轉移好發於乳癌患者。已有研究指出抗骨吸收藥物可以降低癌症的復發機率，然而抗骨吸收藥物對於癌症患者的骨骼相關事件、無疾病惡化與整體存活時間的影響，研究報導比較侷限。本研究目的在於分析來自於某醫學中心之乳癌癌症登記病患資料，比較病患投予第一代與第二代雙磷酸鹽類藥物或單株抗體藥物，是否有無延長無疾病惡化與整體存活時間的影響。
本研究利用回溯性方法，收集並分析來自高雄某私立醫學中心從2000年1月到2014年12月的乳癌癌症登記病患資料。本研究收案條件為診斷為乳癌併發骨轉移的患者且接受過雙磷酸鹽類藥物或單株抗體藥物Denosumab。雙磷酸鹽類藥物包含了第一代的Clodronate與Pamidronate以及第二代的Zoledronic acid，共有444位患者納入本研究之分析。本研究統計分析使用獨立樣本t檢定(Student''s t-test)、單因子變異數分析(one-way ANOVA)、卡方適合度檢定(chi-square Goodness of Fit Test)、邏輯斯回歸(Logistic Regression)探討使用不同藥物治療之病人間各重要變項之差異，並使用存活分析進一步探討病人的存活率。
研究結果指出接受第一代雙磷酸鹽類藥物與新藥物治療病患的無疾病惡化存活時間(Progression Free Survival, PFS)沒有達到顯著差異(p=0.062)。但仍能看出接受新藥物治療病患的PFS確實有存活延長的趨勢。接受第一代雙磷酸鹽類藥物病患的整體存活時間(Overall Survival, OS)與接受新藥物的病患具有統計上的顯著差異(p<0.001)。接受Zoledronic acid與Denosumab的新藥治療對於OS有較佳的存活情形。
本研究證實新藥物包含第二代雙磷酸鹽類Zoledronic acid與單株抗體Denosumab可以有意義的延長病患存活時間。但是在PFS的比較上，與Zoledronic acid沒有達到統計上的差異。這結果可能的原因是因為Denosumab上市時間較晚，統計時接受治療的病人數較少的關係。隨著未來更多資料的取得，將更有機會可進一步分析對於Zoledronic acid與Denosumab在病人存活時間上的效果。

Bone metastases are common in breast cancer. While antiresorptive agents has been shown to effectively reduce cancer relapse, the effect of antiresorptive agents on skeletal-related events, overall survival and progression-free survival time has been rarely studied. This study aims to analyze the effects of first and second generation bisphosphonates and a monoclonal antibody drug on the prevention of overall survival and progression-free survival time based on clinical data from a medical center.
We collected data from a private medical center in Kaohsiung between January 2000 and December 2014 in a retrospective way. A total of 444 patients diagnosed with breast cancer and prescribed bisphosphonates and an antibody drug of Denosumab were included in this study. The bisphosphonates considered in this study include the first generation drugs of Clodronate and Pamidronate and the second generation drug of Zoledronic acid. Student''s t-test and chi-square Goodness of Fit Test were applied to evaluate the significance of factors. The logistic regression model was applied to calculate the odds ratios.
Our results show that there is no significant difference in the survival time between the first generation bisphosphonates and new drugs (p=0.062). However, the progression-free survival time of patients using new drugs has been significantly prolonged. The overall survival time of patients using the first generation of bisphosphonates is significantly different (p<0.001) from that of patients using new drugs. The overall survival time also benefits from the use of new drugs including the Zoledronic acid and Denosumab.
This study confirms that the new drugs of a second generation bisphosphonate Zoledronic acid and an antibody drug Denosumab significantly increase the therapeutic effects of prolonged survival time of patients. Although a few benefits have been shown in this study, there is no significant difference of survival time observed in this study between patients using Zoledronic acid and the new single-body antibody drug Denosumab. This could be due to the small sample size of patients using Denosumab as it came to market late. With more data available, the effects of Zoledronic acid and Denosumab on survival time could be further analyzed with higher confidence.

目錄
摘要 i
Abstract iii
致謝 v
表目錄 viii
圖目錄 ix
第一章 緒論 1
第一節 研究背景與動機 1
第二節 研究目的 4
第三節 名詞解釋 5
第二章 文獻探討 7
第一節 乳癌治療概論 7
第二節 乳癌發生骨轉移的探討 12
第三節 雙磷酸鹽類藥物概論 15
第四節 單株抗體Denosumab於骨轉移治療概論 19
第三章 研究方法 21
第一節 研究設計 21
第二節 研究架構 22
第三節 研究對象 23
第四節 資料處理與統計方法 24
第四章 研究結果分析與討論 26
第一節 基本資料分析 26
第二節 無惡化存活時間、整體存活時間結果 43
第三節 討論……………………………………………………………………51

第五章 結論與建議 55
第一節 研究限制 55
第二節 結論與建議 56
參考文獻 58
附件 人體試驗/研究同意證明書…………...…………………………………...66
表目錄
表一 癌症治療雙磷酸鹽類藥物差異比較表.................................................18
表二 第一代雙磷酸鹽類藥物與新藥物之病患描述性統計分析 26
表三 第一代、第二代雙磷酸鹽類與單株抗體藥物之病患描述性統計分析 28
表四 第二代雙磷酸鹽類藥物與單株抗體藥物之病患描述性統計分析 30
表五 是否接受過放射治療之病患描述性統計分析 32
表六 乳癌復發與否之病患描述性統計分析 34
表七 癌症是否轉移之病患描述性統計分析 36
表八 存活與否之病患描述性統計分析 38
表九 第一代雙磷酸鹽類藥物與新藥物之病患變項分析 40
表十 第二代雙磷酸鹽類藥物與單株抗體藥物之病患變項分析 42




圖目錄
圖一 研究架構圖……………………………..…………………………………….22
圖二 第一代雙磷酸鹽類藥物與新藥物之病患無惡化存活時間變化…………...44
圖三 第二代雙磷酸鹽類藥物與單株抗體藥物之病患無惡化存活時間變化…...46
圖四 第一代雙磷酸鹽類藥物與新藥物之病患整體存活時間變化…..………….48
圖五 第二代雙磷酸鹽類藥物與單株抗體藥物之病患整體存活時間變化……...50

參考文獻
1.中華民國 102 年癌症登記報告. 2013:68.
www.hpa.gov.tw/File/Attach/5191/File_6166.pdf
2.Rordorf T, Hassan AA, Azim H, Alexandru E, Er O, Gokmen E, et al. Bone health in breast cancer patients: a comprehensive statement by CECOG/SAKK Intergroup. Breast. 2014;23(5):511-25. doi: 10.1016/j.breast.2014.05.023. PubMed PMID: 24986766.
3.Irelli A, Cocciolone V, Cannita K, Zugaro L, Di Staso M, Lanfiuti Baldi P, et al. Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer. Bone. 2016;87:169-75. doi: 10.1016/j.bone.2016.04.006. PubMed PMID: 27091227.
4.Van Acker HH, Anguille S, Willemen Y, Smits EL, Van Tendeloo VF. Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2016;158:24-40. doi: 10.1016/j.pharmthera.2015.11.008. PubMed PMID: 26617219.
5.Neville-Webbe HL, Gnant M, Coleman RE. Potential anticancer properties of bisphosphonates. Semin Oncol. 2010;37 Suppl 1:S53-65. doi: 10.1053/j.seminoncol.2010.06.008. PubMed PMID: 20682373.
6.Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015;26(2):313-20. doi: 10.1093/annonc/mdu544. PubMed PMID: 25403582.
7.Gul G, Sendur MA, Aksoy S, Sever AR, Altundag K. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr Med Res Opin. 2016;32(1):133-45. doi: 10.1185/03007995.2015.1105795. PubMed PMID: 26451465.
8.Zheng GZ, Chang B, Lin FX, Xie D, Hu QX, Yu GY, et al. Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours. Eur J Cancer Care (Engl). 2016. doi: 10.1111/ecc.12541. PubMed PMID: 27430483.
9.Gomez Garcia S, Clemons M, Amir E. Rethinking end-points for bone-targeted therapy in advanced cancer. Eur J Cancer. 2016;63:105-9. doi: 10.1016/j.ejca.2016.05.014. PubMed PMID: 27299662.
10.Breast Cancer Treatment (PDQ(R)): Health Professional Version. PDQ Cancer Information Summaries. Bethesda (MD)2002.
11.Buga S, Sarria JE. The management of pain in metastatic bone disease. Cancer Control. 2012;19(2):154-66. PubMed PMID: 22487978.
12.Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165-76. doi: 10.1053/ctrv.2000.0210. PubMed PMID: 11417967.
13.Kostenuik PJ. Revisiting the seed and soil theory of bone metastasis: new tools, same answer. J Musculoskelet Neuronal Interact. 2004;4(4):375-6. PubMed PMID: 15758267.
14.Hagberg KW, Taylor A, Hernandez RK, Jick S. Incidence of bone metastases in breast cancer patients in the United Kingdom: results of a multi-database linkage study using the general practice research database. Cancer Epidemiol. 2013;37(3):240-6. doi: 10.1016/j.canep.2013.01.006. PubMed PMID: 23416031.
15.McCartan DP, Prichard RS, MacDermott RJ, Rothwell J, Geraghty J, Evoy D, et al. Role of bone scan in addition to CT in patients with breast cancer selected for systemic staging. Br J Surg. 2016;103(7):839-44. doi: 10.1002/bjs.10124. PubMed PMID: 27004443.
16.Diel IJ. Prognostic factors for skeletal relapse in breast cancer. Cancer Treat Rev. 2001;27(3):153-7; discussion 9-64. doi: 10.1053/ctrv.2000.0209. PubMed PMID: 11417965.
17.Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat. 2000;59(3):271-8. PubMed PMID: 10832597.
18.Wu SG, Sun JY, Yang LC, Tang LY, Wang X, Chen XT, et al. Patterns of distant metastasis in Chinese women according to breast cancer subtypes. Oncotarget. 2016;7(30):47975-84. doi: 10.18632/oncotarget.10099. PubMed PMID: 27322074; PubMed Central PMCID: PMCPMC5216993.
19.Oster G, Lamerato L, Glass AG, Richert-Boe KE, Lopez A, Chung K, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer. 2013;21(12):3279-86. doi: 10.1007/s00520-013-1887-3. PubMed PMID: 23884473.
20.Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004;100(12):2613-21. doi: 10.1002/cncr.20308. PubMed PMID: 15197804.
21.Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-82. PubMed PMID: 15173273.
22.Coleman RE. Bisphosphonates: clinical experience. Oncologist. 2004;9 Suppl 4:14-27. doi: 10.1634/theoncologist.9-90004-14. PubMed PMID: 15459426.
23.Hansen-Algenstaedt N, Joscheck C, Wolfram L, Schaefer C, Muller I, Bottcher A, et al. Sequential changes in vessel formation and micro-vascular function during bone repair. Acta Orthop. 2006;77(3):429-39. doi: 10.1080/17453670610046361. PubMed PMID: 16819682.
24.Green JR. Bisphosphonates: preclinical review. Oncologist. 2004;9 Suppl 4:3-13. doi: 10.1634/theoncologist.9-90004-3. PubMed PMID: 15459425.
25.Iwamoto J, Takeda T, Katsumata T, Tanaka T, Ichimura S, Toyama Y. Effect of etidronate on bone in orchidectomized and sciatic neurectomized adult rats. Bone. 2002;30(2):360-7. PubMed PMID: 11856643.
26.Hering F, Rodrigues PR, Lipay M. Clodronate for treatment of bone metastases in hormone refractory prostate cancer. Int Braz J Urol. 2003;29(3):228-33. PubMed PMID: 15745526.
27.Rodrigues P, Hering F, Campagnari JC. Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients. Prostate Cancer Prostatic Dis. 2004;7(4):350-4. doi: 10.1038/sj.pcan.4500752. PubMed PMID: 15534620.
28.Santangelo A, Testai M, Barbagallo P, Manuele S, Di Stefano A, Tomarchio M, et al. The use of bisphosphonates in palliative treatment of bone metastases in a terminally ill, oncological elderly population. Arch Gerontol Geriatr. 2006;43(2):187-92. doi: 10.1016/j.archger.2005.10.006. PubMed PMID: 16325938.
29.Menssen HD, Sakalova A, Fontana A, Herrmann Z, Boewer C, Facon T, et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol. 2002;20(9):2353-9. doi: 10.1200/JCO.2002.02.032. PubMed PMID: 11981007.
30.Body JJ. Is ibandronate effective in multiple myeloma? Eur J Haematol. 2003;71(6):470-1; author reply 1-2. PubMed PMID: 14703700.
31.Body JJ, Diel IJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol. 2003;14(9):1399-405. PubMed PMID: 12954579.
32.Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003;21(23):4277-84. doi: 10.1200/JCO.2003.05.147. PubMed PMID: 14581438.
33.Wang RF, Zhang CL, Zhu SL, Zhu M. A comparative study of samarium-153-ethylenediaminetetramethylene phosphonic acid with pamidronate disodium in the treatment of patients with painful metastatic bone cancer. Med Princ Pract. 2003;12(2):97-101. doi: 69120. PubMed PMID: 12634464.
34.Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996;335(24):1785-91. doi: 10.1056/NEJM199612123352401. PubMed PMID: 8965890.
35.Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. 2004;90(6):1133-7. doi: 10.1038/sj.bjc.6601663. PubMed PMID: 15026791; PubMed Central PMCID: PMCPMC2409647.
36.Tripathy D, Lichinitzer M, Lazarev A, MacLachlan SA, Apffelstaedt J, Budde M, et al. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol. 2004;15(5):743-50. PubMed PMID: 15111341.
37.Rosen LS, Gordon DH, Dugan W, Jr., Major P, Eisenberg PD, Provencher L, et al. breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100(1):36-43. doi: 10.1002/cncr.11892. PubMed PMID: 14692022.
38.Cramer JA, Gold DT, Silverman SL, Lewiecki EM. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18(8):1023-31. doi: 10.1007/s00198-006-0322-8. PubMed PMID: 17308956.
39.Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98(8):1735-44. doi: 10.1002/cncr.11701. PubMed PMID: 14534891.
40.Fulfaro F, Leto G, Badalamenti G, Arcara C, Cicero G, Valerio MR, et al. The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers. J Chemother. 2005;17(5):555-9. doi: 10.1179/joc.2005.17.5.555. PubMed PMID: 16323446.
41.Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol. 2006;17(6):986-9. doi: 10.1093/annonc/mdl041. PubMed PMID: 16533874.
42.Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2005;23(15):3314-21. doi: 10.1200/JCO.2005.05.116. PubMed PMID: 15738536.
43.Wardley A, Davidson N, Barrett-Lee P, Hong A, Mansi J, Dodwell D, et al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer. 2005;92(10):1869-76. doi: 10.1038/sj.bjc.6602551. PubMed PMID: 15870721; PubMed Central PMCID: PMCPMC2361764.
44.Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7(5):377-87. PubMed PMID: 11693896.
45.XGEVA中文仿單.9. www1.ndmctsgh.edu.tw/pharm/pic/medinsert/005XGE01.pdf
46.Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-9. doi: 10.1200/JCO.2010.29.7101. PubMed PMID: 21060033.
47.Pulido C, Vendrell I, Ferreira AR, Casimiro S, Mansinho A, Alho I, et al. Bone metastasis risk factors in breast cancer. Ecancermedicalscience. 2017;11:715. doi: 10.3332/ecancer.2017.715. PubMed PMID: 28194227; PubMed Central PMCID: PMCPMC5295847.
48.Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. PubMed PMID: 26040499.