暴露肺部疾病(氣喘、慢性阻塞性肺病、肺結核)與肺癌及心血管疾病的發生及預後的影響-使用全國性健康登記資料之研究

Exploring the effect of preexisting pulmonary diseases (asthma, chronic obstructive pulmonary disease (COPD) and Mycobacterium tuberculosis (TB)) on lung cancer and cardiovascular disease development / prognosis– using national health registry and insurance data

黃景揚(Jing-Yang Huang)

指導教授 ： 廖勇柏

中山醫學大學/健康管理學院/公共衛生學系博士班/博士(2016年)

摘要

前言:
不論肺癌或心血管疾病皆為全球重要的健康負擔及主要死因。至今，許多研究指出慢性肺病的局部性或全身性發炎反應可能與肺癌或心血管疾病有關。慢性肺病如氣喘、慢性阻塞性肺病(COPD)及肺結核(TB)是全球盛行率很高的疾病，且彼此之間共病狀況十分常見。因此，建立慢性肺病與肺癌或心血管疾病的發生及存活的相關性分析，對於全球公共衛生是非常重要的。
材料方法:
本研究主要資料來源是衛生福利資料科學中心提供的次級資料檔。共使用3大政府收集的健康資料集，包含(1) 2001-2012年全民健保資料檔、(2) 1979-2011年癌症登記檔(包含:短表、長表及TCDB)、(3) 2001-2012年全國死因登記檔。本研究針對肺癌進行4項研究，包含2篇回溯性世代研究法、1篇巢疊式病例對照研究以及1篇準臨床試驗研究設計，探討的主題為: (1) 評估2001-2003年罹患的慢性肺病對於2004-2008不同組織病理型態肺癌發生之危險性、(2) 比較氣喘或慢性阻塞性肺病者使用類固醇是否會提高肺鱗狀細胞癌的罹患風險、(3) 比較罹癌2年前慢性肺病罹患組合是否會影響罹癌後的存活率、(4) 比較經過傾向分數(Propensity score)配對後的不同肺癌治療手術組別是否有不同的術後存活率。針對心血管疾病進行2項研究，皆為回溯性世代研究，探討的主題為: (5) 探討2001-2003年慢性肺病的罹患情形對2004年後缺血性心臟病發生的風險、(6) 探討缺血性心臟病患手術介入與肺病共病死亡率效應之交互作用。
結果:
(第一篇) 探討肺部疾病(如氣喘、慢性阻塞性肺病(COPD)及肺結核病(TB)與肺癌發生的危險性研究指出，肺鱗狀細胞癌的風險經調整後，HR分別為男性TB 1.37 (95 % confidence interval [CI], 1.21–1.54)、氣喘1.52 (95 % CI, 1.42–1.64)、COPD 1.66 (95 % CI, 1.56–1.76)；女性TB 2.10 (95 % CI, 1.36–3.23)、氣喘1.50 (95 % CI, 1.21–1.85)、COPD 1.44 (95 % CI, 1.19–1.74)。肺腺癌男女分層的TB HR為1.33 (95 % CI, 1.19–1.50)及1.86 (95 % CI, 1.57–2.19)，氣喘的HR為1.13 (95 % CI, 1.05–1.21)及1.18 (95 % CI, 1.09–1.28)，COPD的HR為1.50 (95 % CI, 1.42–1.59)及1.33 (95 % CI, 1.25–1.42)。小細胞癌的男女分層TB HR為1.24 (95 % CI, 1.01–1.52)及2.23 (95 % CI, 1.17–4.25)，氣喘的HR為1.51 (95 % CI, 1.35–1.69)及1.63 (95 % CI, 1.16–2.27)，COPD的HR為1.39 (95 % CI, 1.26–1.53)及1.78 (95 % CI, 1.33–2.39)。
(第二篇) 比較氣喘或慢性阻塞性肺病者使用類固醇是否會提高肺鱗狀細胞癌(SqCC)的罹患風險研究指出，男性使用高劑量及低劑量吸入性類固醇( ICS)的勝算比(Odds Ratio ,OR)分別是2.18 (95 %CI, 1.56–3.04)及1.77 (1.22–2.57)。男性使用高劑量及低劑量口服性類固醇( OCS)的OR分別是1.46 (95 %CI, 1.16–1.84) 及1.55 (95 %CI, 1.22–1.98)。女性ICS或OCS的累積使用劑量與SqCC無顯著相關。近3個月ICS + OCS使用量突然增加者SqCC的OR值為8.08 (95 %CI, 3.22–20.30)，近3個月ICS突然增加者OR為4.49 (95 % CI, 2.05–9.85)，近3個月OCS突然增加者OR為3.54 (95 % CI, 2.50–5.01)。但女性僅發現近3個月OCS突然增加者有顯著的SqCC風險，OR為6.72 (95 %CI, 2.69–16.81)。
(第三篇) 罹癌2年前慢性肺病罹患組合與罹癌後存活率研究指出，罹患氣喘、COPD或TB的HRs分別是1.08 [95 % CI, 0.99–1.18]、1.04 (95% CI, 0.97–1.12)及1.14 (95% CI, 1.00–1.31)。男性的肺部共病狀態的HRs分別是氣喘+COPD+TB的1.56 (95% CI, 1.23–1.97)及氣喘+COPD,的1.11 (95% CI, 1.00–1.24)。男性第3期SqCC個案HRs分別是氣喘+TB的3.41(95%CI, 1.27–9.17)及氣喘+COPD+TB的1.65 (95%CI, 1.10–2.47)。男性第4期SqCC個案HRs分別是氣喘+COPD+TB的1.40 (95%CI, 1.00–1.97)及氣喘的1.25 (95%CI, 1.03–1.52)。女性第1、2期的患者，氣喘的HR為0.19 (95%CI, 005–0.77)。
(第四篇) 經傾向分數配對後開胸肺葉切除術的病人1年、3年及5年長期存活率(OS)分別為93.4%、79.3%及65.5%；另外胸腔鏡肺葉切除術的病人1年、3年及5年OS分別為94.1%、80.9%及68.7%。兩組的OS並沒有統計上顯著差異。在多變項分析中，手術切除的類別(開胸 v.s. 胸腔鏡)並不是獨立的預後影響因子。
(第五篇) COPD個案有較高的缺血性心臟病(IHD)發生率2.64(95% CI, 2.60-2.69) 每103人月，相較於無COPD個案的發生率1.05(95% CI, 1.05-1.06) 每103人月。經過多變項競爭風險Cox 迴歸模式調整後COPD患者發生IHD的風險比為1.23 (95% CI, 1.21-1.25)。
(6) 探討缺血性心臟病病人手術與肺病之共病的死亡率相關性研究指出，透過手術介入治療的病患有顯著較高的死亡率2.74 (95% CI, 2.53-2.97) 每103月，未進行手術的病人有較低的死亡率1.97(95% CI, 1.88-2.06)每103月。當檢定COPD與手術的交互作用項時，未達統計顯著，p值為0.2062。限制分析進行手術治療的病人時，COPD共病的HR為1.17(0.97-1.41)。當以手術的血管別作為分層分析時，3條PTCA的COPD患者有最高的死亡風險。
結論:
肺部共病會影響肺癌的發生及死亡率，其中女性TB與肺癌的發生特別有關，罹癌前近3個月的類固醇使用是癌症病患的重要指標，男性的肺部共病則會增加死亡率。肺癌手術的比較則發現，新穎的胸腔鏡手術雖然有較好的預後表現，但與傳統開胸手術無顯著差異。心血管疾病的風險分析呈現COPD會增加IHD的發生率，但心血管疾病與COPD的共病並不會影響手術介入治療帶來的存活效益。

關鍵字

肺癌 ； 氣喘 ； 慢性阻塞性疾病 ； 肺結核 ； 心血管疾病 ； 缺血性心臟病 ； 健保資料

並列摘要

Introduction
Regardless of lung cancer or cardiovascular disease are leading causes of death in the world and impair the global public health. Chronic pulmonary disease such as asthma, chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) is the high prevalence disease, and the coexisting situation is very common among pulmonary diseases. Therefore, it is very important to explore the relationship between coexisting chronic pulmonary disease with lung cancer or cardiovascular disease and analysis the survival of them under specific treatment.

Material and methods
This study used the secondary datasets collected from Health and Welfare Data Science Center, Taiwan including 2001-2012 National Health Insurance Research Database (NHIRD), 1979-2011 Taiwan Cancer Registry Database (TCRD), 2001-2012 National Death Registry Database (NDRD). This study conducted 6 researches which were 4 lung cancer studies and 2 ischemic heart disease studies, for lung cancer study there were 2 retrospective cohort study, 1 nested case control study and 1 semi-randomization clinical trial: (1) incidence risk of pulmonary disease on different histological type lung cancer, (2) association between corticosteroids use and incidence of lung cancer in patients with COPD or asthma, (3) mortality risk of pulmonary disease in squamous cell carcinoma patients, (4) compare long term survival between different lobectomy produces; for ischemic heart disease, there are 2 retrospective cohort study, including (5) incidence risk of COPD on ischemic heart disease, (6) survival analysis of patients underwent percutaneous coronary intervention or coronary artery bypass graft surgery interacted with COPD.

Results
1st research noted the risk of chronic pulmonary disease such as asthma, COPD and TB on lung cancer by gender. In men and women, the adjusted HR estimates of squamous cell carcinoma were respectively 1.37 (95 % confidence interval [CI], 1.21–1.54) and 2.10 (95 % CI, 1.36–3.23) for TB, 1.52 (95 % CI, 1.42–1.64) and 1.50 (95 % CI, 1.21–1.85) for asthma, and 1.66 (95 % CI, 1.56–1.76) and 1.44 (95 % CI, 1.19–1.74) for COPD. Similarly, the adjusted HR estimates of adenocarcinoma were respectively 1.33 (95 % CI, 1.19–1.50) and 1.86 (95 % CI, 1.57–2.19) for TB, 1.13 (95 % CI, 1.05–1.21) and 1.18 (95 % CI, 1.09–1.28) for asthma, and 1.50 (95 % CI, 1.42–1.59) and 1.33 (95 % CI, 1.25–1.42) for COPD. The HRs of small cell carcinoma were respectively 1.24 (95 % CI, 1.01–1.52) and 2.23 (95 % CI, 1.17–4.25) for TB, 1.51 (95 % CI, 1.35–1.69) and 1.63 (95 % CI, 1.16–2.27) for asthma, and 1.39 (95 % CI, 1.26–1.53) and 1.78 (95 % CI, 1.33–2.39) for COPD.
2nd research mentioned the odds ratios (ORs) of lung squamous cell carcinoma (SqCC) in men who received high and low-dose inhaled corticosteroid (ICS) were 2.18 (95 %CI, 1.56–3.04) and 1.77 (1.22–2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16–1.84) and 1.55 (95 %CI, 1.22–1.98) for men who were placed on low and high dose oral corticosteroid (OCS). However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteriod was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22–20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05–9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50–5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69–16.81).
3rd research presented for all cause-mortality, HRs were 1.08 [95% confidence interval (CI), 0.99–1.18], 1.04 (95% CI, 0.97–1.12), and 1.14 (95% CI, 1.00–1.31) for individuals with asthma, COPD, and TB, respectively. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.56 (95% CI, 1.23–1.97) and 1.11 (95% CI, 1.00–1.24) for individuals with asthma+COPD+TB and asthma+COPD, respectively. Among male patients with stage III SqCC, HRs were 3.41 (95%CI, 1.27–9.17) and 1.65 (95%CI, 1.10–2.47) for individuals with asthma+TB and asthma+COPD+TB, respectively. Among male patients with stage IV SqCC, HRs were 1.40 (95%CI, 1.00–1.97) and 1.25 (95%CI, 1.03–1.52) for individuals with asthma+ COPD +TB and asthma. Among female patients with stage I and II, HR was 0.19 (95%CI, 005–0.77) for individuals with asthma.
4th research provided the results. The 1-year, 3-year, and 5-year OS rates for propensity-matched patients treated with open lobectomy were 93.4%, 79.3%, and 65.5%, respectively. The 1-year, 3-year, and 5-year OS rates for propensity-matched patients treated with thoracoscopic lobectomy were 94.1%, 80.9%, and 68.7%, respectively. The difference was not statistically significant. In multivariate analysis, surgical resection (open versus thoracoscopic) was not an independent prognostic factor.
5th research mentioned that patients with COPD had higher incidence rate of ischemic heart disease, the incidence rate is 2.64 (95% CI, 2.60-2.69) per 103 person-month in COPD patients and 1.05 (95% CI, 1.05-1.06) in non-COPD group, respectively. The hazard ratio (HR) of COPD was 1.23 (95% CI, 1.21-1.25).
6th research explored the interaction between heart surgical intervention with COPD on postoperative survival in patients with ischemic heart disease. Patients treated by surgical intervention had significantly higher mortality 2.74 (95% CI, 2.53-2.97) per 103 months than patients without surgery (mortality: 1.97, 95% CI, 1.88-2.06). When we tested the interaction of [surgical intervention]*[COPD], the p value was not significant (p=0.2062). We conducted the result by limited the patients underwent the surgery, the HR of COPD was 1.17 (0.97-1.41). The interaction may be existing, when COPD patients treated 3 coronary arteries narrowed by percutaneous coronary intervention.

Conclusion
The chronic pulmonary diseases associated with the lung cancer development, especially the female patients with TB. Recent dose increase in corticosteroids was associated with SqCC. Coexisting pulmonary diseases increased the risk of mortality from SqCC in male patients. For female patients with early stage SqCC, pre-existing asthma decreased mortality. Open and thoracoscopic lobectomy are associated with similar long-term survival in the setting of lung cancer. Analysis presented COPD may increase the risk of ischemic heart disease. The coexisting with COPD and ischemic did not moderate the benefit of coronary intervention sugery.

並列關鍵字

Lung cancer ； asthma ； chronic obstructive pulmonary disease ； tuberculosis ； cardiovascular disease ； ischemic heart disease ； national health insurance research

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