| 摘要: | 研究背景與目的：近年來，由於乳癌治療方式的進步，婦女的乳癌死亡率顯著下降。然而隨著乳癌病人的存活率越高，後續其他非癌症死亡率則有增加的趨勢，其中心血管疾病是乳癌倖存者的主要死因。心血管疾病風險較高與乳癌的治療方式所造成的心臟毒性副作用有關，其中化學治療所造成的影響甚鉅。?環類藥物是常見的乳癌化學治療藥物，過去研究指出?環類藥物會導致心臟衰竭等不良心血管事件，然而大多以歐美病人為主，關於亞洲病人的討論較少；且現有研究對於心臟衰竭的發生率在不同研究中有所差異，故本研究的目的為探討台灣乳癌倖存者接受化療後發生心臟衰竭的風險。
研究方法：本研究為一回顧性世代研究，暴露組為使用化學治療的乳癌病人，對照組為無使用化學治療的乳癌病人。研究資料來源為台北醫學大學三院(北醫附醫 ;萬芳醫院 ;雙和醫院)臨床資料庫，於2000/01/01-2019/12/31期間ICD主診斷碼為乳癌的病人。此資料庫包含乳癌病人之門診 ;住院 ;用藥 ;院內癌症登記等資訊。排除掉男性 ;2018年後診斷乳癌 ;有心臟衰竭病史的乳癌病人後，暴露組使用傾向分數以1：1進行配對，每組各1169人。暴露組進一步以三種分組定義進行分析，分別為(1)使用化療的藥物種類(?環類 ;?環類+紫杉醇類 ;紫杉醇類 ;其他化療藥物) ;(2)以?環類藥物之平均累績劑量分為高低劑量兩組以及(3)?環類藥物是否合併使用賀癌平藥物分為兩組(?環類+賀癌平 ;?環類)，來比較發生心臟衰竭的風險與發生率。同時將依照藥物暴露時間分成兩年(短期) ;五年(中期) ;八年(長期)三個時間點來比較藥物暴露時間長短對於心臟衰竭的影響。
結果：在完整追蹤時間的存活分析中，化療暴露組罹患心臟衰竭的風險，在校正了共病(糖尿病 ;高血壓 ;高血脂) ;乳癌分期 ;乳癌診斷年齡後，相較於無化療對照組，化療組罹患心臟衰竭的風險有增加的趨勢，但未達統計顯著差異(HR=1.37, 95%CI=0.75-2.50)。但在暴露五年 ;暴露八年時，校正了共病 ;乳癌分期 ;乳癌診斷年齡後，相較於無化療對照組，化療組罹患心臟衰竭的風險顯著增加(暴露五年HR=2.21, 95%CI=1.08-4.50；暴露八年HR=2.06, 95%CI=1.09-3.90)。將暴露組依照使用化療的藥物種類分組，結果顯示在暴露八年時，校正了共病 ;乳癌分期 ;乳癌診斷年齡後，相較於無化療對照組，?環類組罹患心臟衰竭的風險顯著增加(HR=2.26, 95%CI=1.02-4.98)。將化療暴露組依據?環類藥物之平均累績劑量分為高劑量組 ;低劑量組，其結果發現不論暴露時間長短，在校正共病 ;乳癌分期後，相較於無化療對照組，高劑量組罹患心臟衰竭的風險皆顯著增加(兩年HR=4.85, 95%CI=1.20-19.61；五年HR=3.11, 95%CI=1.21-7.95；八年HR=3.11, 95%CI=1.21-7.95)。低劑量組則是在暴露八年時顯示於校正共病 ;乳癌分期後，其罹患心臟衰竭的風險顯著增加(HR=2.50, 95%CI=1.08-5.75)。將?環類藥物是否合併使用賀癌平分為兩組的結果顯示，校正共病後，暴露五年時?環類組相較於無化療對照組，其罹患心臟衰竭的風險顯著增加(HR=2.18, 95%CI=1.01-4.71)。?環類+賀癌平組則是在暴露兩年時，在校正共病後，其罹患心臟衰竭的風險有增加趨勢，為邊緣性顯著(HR=3.79, 95%CI=0.94-15.23, P=0.061)。
結論：在校正共病後，本篇研究顯示心臟衰竭的風險與化療藥物種類 ;?環類藥物劑量和是否合併使用賀癌平藥物有關。結果強調了在進行化學治療時偵測心臟毒性的重要性。
Background and Purpose: Breast cancer mortality among women has declined significantly in recent years due to advances in breast cancer treatment. However, as the survival rate of breast cancer patients increased, the subsequent non-cancer mortality tended to increase, and cardiovascular disease was the main cause of death for breast cancer survivors. Higher risk of cardiovascular disease linked to cardiotoxic side effects of breast cancer treatment modalities, with chemotherapy having a major impact. Anthracyclines are common chemotherapeutic drugs for breast cancer, and studies have shown that anthracyclines can lead to adverse cardiovascular events such as heart failure (HF). However, most of them were focused on Caucasians, and there were few discussions about Asian patients. In addition, the incidence of heart failure varied among different studies. Therefore, this study aimed to determine the risk of heart failure associated with chemotherapy in breast cancer survivors in Taiwan.
Methods: This is a retrospective cohort study. The exposed group were breast cancer patients who took chemotherapy, and the control group were breast cancer patients without chemotherapy. The patients who diagnosed breast cancer by ICD from 2000/01/01 to 2019/12/31 were collected from Taipei Medical University Clinical Research Database (TMUCRD), which contained information on breast cancer patients’ outpatient clinics, hospitalizations, medications, and in-hospital cancer registration. Males, breast cancer patients diagnosed before 2018, and patients were a history of HF before breast cancer diagnosis were excluded. After propensity score matching with 1:1 ratio, and exposed group and the control group had 1169 patients respectively. Patients in exposed group were divided for further analysis according to three definitions (1) types of drugs used in chemotherapy (anthracycline-based, taxane+anthracycline-based, taxane-based, and others regimen); (2) high- and low-dose group based on mean anthracycline cumulative dose; (3) anthracyclines with and without trastuzumab (anthracycline+trastuzumab, anthracycline); to compare the risk and the incidence of HF. To analysis the association of chemotherapy exposure time and the risk of HF, the chemotherapy exposure time was set to two years(short-term), five years(mid-term), and eight years(long-term).
Results: In the complete follow-up time, the risk of HF in the exposed group was higher than that in the control group after adjusting for comorbidities (diabetes, hypertension, hyperlipidemia), breast cancer stage, and age at breast cancer diagnosis, but the difference was not statistically significant (HR=1.37, 95%CI=0.75-2.50). However, after adjusting for comorbidities, breast cancer stage, and age, the risk of heart failure was significantly higher in the 5-year and 8-year chemotherapy exposure groups than in the control group, respectively (5-year, HR=2.21, 95%CI=1.08-4.50; 8-year , HR=2.06, 95%CI=1.09-3.90). In subgroup analysis based on chemotherapy drug, the risk of HF was significantly higher in the 8-year anthracycline-based regimen group than in the control group after adjusting the comorbidities, breast cancer stages, and age (HR=2.26, 95%CI=1.02-4.98). When analyzing high and low anthracycline doses, the results showed a significantly increased risk of HF in the high-dose group compared with no-chemotherapy group, regardless of the duration of chemotherapy exposure, after adjusting the comorbidities, and breast cancer stages (2-year, HR=4.85, 95%CI=1.20-19.61; 5-year, HR=3.11, 95%CI=1.21-7.95; 8-year, HR=3.11, 95%CI=1.21-7.95). In the low-dose group, after eight years of exposure, the risk of HF was significantly increased after adjusting for comorbidity and breast cancer stage (HR=2.50, 95%CI=1.08-5.75). In subgroup analysis based on anthracycline with/without trastuzumab, the results indicated that the anthracycline group had a significantly increased risk of HF compared to no-chemotherapy group when exposed 5 years, after adjusting the comorbidities (HR=2.18, 95%CI=1.01-4.71). The anthracycline+trastuzumab group had an increased risk of HF compared to no-chemotherapy group when exposed 2 years, after adjusting the comorbidities, but it reached a borderline significant (HR=3.79, 95%CI=0.94-15.23, P=0.061).
Conclusions: After adjusting for comorbidities, the study showed that the risk of HF was associated with the type of chemotherapy drugs, the dose of anthracyclines, and whether trastuzumab drugs were used in combination. The result emphasized the importance of detecting the cardiotoxicity of breast cancer patients during chemotherapy. |
