臺灣博碩士論文加值系統

研究背景及目的：
近年來，國人乳癌發生率持續增加，所幸醫療技術的進步及各種抗癌藥物的發展，乳癌個案 5 年存活率可達八成以上。然而，癌症病人生命之延長並不一定代表有好的生活品質，因此有愈來越多癌症照護組織開始提倡及重視癌症病人治療後的心理問題，其中又以憂鬱症對癌症病人的影響較大，特別是在抗癌藥物治療的過程中更為顯著。而過去研究抗癌藥物治療與憂鬱相關性的文獻中，多半是討論因藥物引起的癌因性疲勞、嘔吐及掉髮等副作用所帶來的不適感及其可能進一步導致患者產生之憂鬱症。此外，以往的研究多以問卷收案的方式進行。因此，本研究試圖利用全民健保資料庫來探討不同抗癌用藥組合以及藥物本身與乳癌病人的憂鬱症副作用間是否有相關性，希望有助於醫生未來可以選擇較好的化療藥物治療，並能提早做好憂鬱症相關衛教或治療，以期減低乳癌病人接受抗癌藥物治療後之憂鬱症發生率。

方法：
本計畫利用衛生福利部之健保資料200萬人抽樣歸人檔進行回溯性世代研究。本研究先利用門診及住院檔找出於 2003-2012 年間新診斷為乳癌的病人 (ICD-9-CM 174)，且串聯重大傷病檔確認乳癌診斷之正確性，再進一步區分成單獨使用化療、及化療合併使用標靶藥物組別。針對結果變項憂鬱症，則以相關的ICD_9-CM疾病碼加以定義。之後則利用 Cox Proportional Hazards Model進行資料統計分析以探討不同抗癌藥物與憂鬱症間之相關性。本研究校正的可能干擾因子包括人口學資料(婚姻狀態、教育及年齡)以及臨床資料(是否接受放射治療/開刀、共病史、癌症期別、及憂鬱症發病前之用藥狀況)等。此外，本研究也嘗試針對年齡 (小於45歲、大於及等於45歲)、期別 (早、晚期)等變項進行次族群分析。
研究結果：
本回溯性世代研究共納入5781名乳癌患者。在單獨使用化療以及化療合併使用標靶藥物組之組間分析，於追蹤期間發生憂鬱症個案共有372人，單獨使用化療藥物的組別之十年累積發生率為6.25%；化療合併使用標靶藥物組之十年累積粗發生率為7.81%。在控制其他干擾變項後，化療合併使用標靶藥物組的風險為單用化療組的1.48倍(95%CI, 1.11-1.98)，並且達統計上的顯著意義。而單用化療藥物組之有無憂鬱症的組內分析，憂鬱症個案共有317人，暴露組之十年累積發生率為6.30%；非暴露組之十年累積粗發生率為6.01%。在控制其他干擾變項後，暴露組別的風險為非暴露組的1.04倍(95%CI, 0.78-1.38)，並未達統計上的顯著意義。

結論：
對於需要合併使用化療藥物及標靶治療的乳癌病人，可能會因為合併藥物治療導致之不適感較單獨使用化療藥物時來得高，而導致病人較大的身心負擔，並進而導致憂鬱症。因此建議乳癌病人可在接受抗癌藥物治療後採取相關的預防措施，以減少憂鬱症之風險。

Background and Objectives:
In recent years, the incidence of breast cancer in Taiwan has continuously increased. Fortunately, with the advancement of medical technology and the development of various anticancer drugs, the 5-year survival rate of breast cancer cases has improved to more than 80%. However, the prolonged life of cancer patients does not necessarily represent a good quality of life. As a result, more and more cancer care organizations have begun to advocate and emphasize the importance of psychological problems of cancer patients after treatment. Among them, depression has a greater impact on cancer patients, especially in the course of anticancer drug treatment. In the past, literature report on the correlation between anticancer drug treatment and depression has mostly discussed various discomforts caused by drug-induced side effects such as cancer-induced fatigue, vomiting, and hair loss, which may further lead to depression in patients. Moreover, the method of studies usually is through questionnaire collection. Therefore, this study aimed to use the National Health Insurance Research Database to explore whether there are correlations between different anticancer drug combinations and depression side effects of the drugs among breast cancer patients. It is hoped that this study will help physicians in the future selection of better chemotherapy regimens, and provision of early antidepressant treatment or depression-related education to reduce the incidence of depression after receiving anti-cancer treatment among breast cancer patients.

Methods:
This study used the 2 million National Health Insurance Research Database of the Ministry of Health and Welfare to conduct a retrospective cohort study. This study employed both outpatient and inpatient data files to find patients with newly diagnosed breast cancer from 2003 through 2012 (ICD-9-CM 174). The diagnosis of breast cancer was confirmed by using a series of major catastrophic illness files. We further divided breast cancer patients into patients who used chemotherapy alone, use of chemotherapy combined with target drugs. The outcome, i.e., depression, was defined by using relevant ICD-9-CM codes. We then used the Cox Proportional Hazards Model for analyzing the association between various anti-cancer drugs and the risk of depression after receiving anti-cancer drugs. Possible confounding factors, including demographic data (marital status, education and age) and clinical data (e.g., the receipt of radiation therapy/surgery or not, history of comorbidities, stage of cancer, medication use before the onset of depression) were also controlled for. In addition, we performed subgroup analysis by stratifying on age (less than 45 years old vs greater than or equal to 45 years old), and cancer stage (early vs late stage).

Results:
This retrospective cohort study included a total of 5,781 breast cancer patients. In the analysis between patients receiving chemotherapy alone and patients receiving both chemotherapy and target therapy, there were a total of 372 cases of depression identified during the study period. The 10-year cumulative incidence of depression among patients who received chemotherapy alone was 6.25%; whereas the incidence was 7.81% among those receiving both chemotherapy and target therapy. After controlling for potential confounders, the risk of depression in the combined chemotherapy and target therapy group was 1.48 times (95% CI, 1.11-1.98) that of the chemotherapy alone group. As for the analysis of the risk of depression among patients receiving chemotherapy alone, a total of 317 depression cases were identified. The 10-year cumulative incidence of depression was 6.30% for patients receiving chemotherapy; whereas the incidence was 6.01% for those who did not receive chemotheraoy. After controlling for potential confounders, the risk in the chemotherapy alone group was 1.04 times (95% CI, 0.78-1.38) that of the group who did not receive chemotherapy.

Conclusions:
For breast cancer patients who require the use of both chemotherapeutic drugs and target therapy, the discomforts caused by the treatment may be greater than chemotherapy alone, which then result in greater psychological burden on the patients and subsequently lead to depression. Therefore, it is recommended that relevant preventive measures should be taken to reduce the risk of depression after receiving anti-cancer treatment in patients with breast cancer.

誌謝 i
中文摘要 ii
英文摘要 (Abstract) iv
目錄 vi
圖表目次 viii
第一章 緒論 1
第一節 研究背景及動機 1
第二節 研究目的 4
第二章 文獻探討 5
第一節 乳癌與憂鬱症之相關流行病學研究 5
第二節 乳癌患者用藥情況與憂鬱症之相關性研究 9
第三章 利用全民健康保險資料之研究設計與方法 13
第一節 研究架構及流程圖 13
第二節 研究對象 15
第三節 研究設計 17
第四節 變項定義 19
第五節 分析方法及工具 23
第四章 研究結果 28
第一節 以全民健康保險資料庫之乳癌病人為研究對象之描述性統計 28
第二節 以全民健康保險資料庫之乳癌病人為研究對象之存活分析 36
第三節 次族群分析 48
第五章 討論 66
第一節 乳癌病人在使用不同藥物組合與憂鬱症之相關性 66
第二節 研究優勢 69
第三節 研究限制 70
第六章 結論 73
參考文獻 74
附錄一、Dartmouth-Manitoba (D-M)’s CCI 之 ICD 9 定義[73] 80
附錄二、HER2受體與賀爾蒙治療次族群分析--------------------------------------------82
附錄三、以一年為追蹤期限之次族群分析-------------------------------83

圖表目次
表 1、常見憂鬱疾病診斷表 6
表 2、乳癌之常見抗癌藥品 8
表 3、常用抗癌藥物與精神相關副作用之比例 9
表 4、常見憂鬱疾病診斷及ICD-9-CM code對照表 13
表 5、健保資料乳癌病人之不同抗癌藥物分組之基本變項分析 27
表 6、健保資料乳癌病人之不同抗癌藥物分組之基本變項分析 (續) 29
表 7、發生憂鬱症之乳癌病人變項分析 30
表 8、健保資料乳癌病人之組間存活分析 (Survival analysis) 32
表 9、健保資料乳癌病人之單用化療組之組內存活分析 (Survival analysis) 35
圖 1、全民健康保險之乳癌病人資料研究架構圖 10
圖 2、全民健康保險之乳癌病人資料研究流程圖 11
圖 3、健保資料乳癌病人之組間分析之累積發生率曲線 26
圖 4、健保資料乳癌病人之單用化療組內分析之累積發生率曲線 26
圖 5、健保資料乳癌病人之組間分析之總結果存活曲線 (Survival curve) 38
圖 6、健保資料乳癌病人之單用化療組之組內分析之總結果存活曲線(Survival curve) 38
圖 7、健保資料乳癌病人之組間分析之主要結果存活曲線 (Survival curve) 39
圖 8、健保資料乳癌病人之組間分析之次要結果存活曲線 (Survival curve) 39
圖 9、健保資料乳癌病人之單用化療組之組內分析之主要結果存活曲線 (Survival curve) 40
圖 10、健保資料乳癌病人之單用化療組之組內分析之次要結果存活曲線 (Survival curve) 40
圖 11、組間次族群分析之存活曲線 (Survival curve) (小於45歲) 42
圖 12、組間次族群分析之存活曲線 (Survival curve) (大於45歲) 42
圖 13、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (小於45歲) 43
圖 14、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (大於45歲) 43
圖 15、組間次族群分析之存活曲線 (Survival curve) (停經前) 45
圖 16、組間次族群分析之存活曲線 (Survival curve) (停經後) 45
圖 17、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (停經前) 46
圖 18、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (停經後) 46
圖 19、組間次族群分析之存活曲線 (Survival curve) (早期乳癌) 48
圖 20、組間次族群分析之存活曲線 (Survival curve) (晚期乳癌) 48
圖 21、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (早期乳癌) 49
圖 22、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (晚期乳癌) 49
圖 23、組間次族群分析之存活曲線 (Survival curve) (非精神專科診斷) 51
圖 24、組間次族群分析之存活曲線 (Survival curve) (精神專科診斷) 51
圖 25、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (非精神專科診斷) 52
圖 26、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (精神專科診斷) 52
圖 27、組間次族群分析之存活曲線 (Survival curve) (賀爾蒙治療) 54
圖 28、組間次族群分析之存活曲線 (Survival curve) (無賀爾蒙治療) 54
圖 29、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (賀爾蒙治療) 55
圖 30、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (無賀爾蒙治療) 55
圖 31、組間次族群分析之存活曲線 (Survival curve) (一年以前有憂鬱史) 57
圖 32、組間次族群分析之存活曲線 (Survival curve) (一年以前無憂鬱史) 57
圖 33、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (一年以前有憂鬱史) 58
圖 34、單獨使用化療藥物組之組內次族群分析之存活曲線 (Survival curve) (一年以前無憂鬱史) 58

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