台灣女性肺癌發生趨勢分析及其相關因子及重要預後因子探討

Related Factors and Important prognostic Factors Analysis for Women Lung Cancer Occurrence in Taiwan

吳佩芬(Pei-Fen Wu)

指導教授 ： 葛應欽 ； 黃明賢

高雄醫學大學/醫學院/醫學研究所/博士(2005年)

摘要

肺癌為世界各國常見的癌症之一，但其發生的主因卻有所差異。台灣婦女肺癌的主要病理組織型態為肺腺癌，更有低吸菸率卻有高肺癌發生率的特性，且根據先前的眾多研究指出，肺腺癌與吸菸只呈現微弱的相關性。這些現象說明台灣女性肺癌更應著重於非吸菸之危害因子進行探討。目前台灣婦女肺癌發生率持續增加，而曾被學者專家所重視的肺癌危險因子包括：環境危險因子、基因遺傳因子等。本研究的目的在於藉由觀察及分析罹患肺癌之高危險群的人口學資料、環境因子等特性，探討危險因子及其他相關因子(related factors)與疾病致病機轉的關係，並提供預防疾病發生或早期發現疾病等策略，以協助醫療保健政策的規劃、執行及評估。
本論文運用流行病學甚或是遺傳流行病學的優勢，來探討與台灣婦女肺癌發生有關的人口學因素、環境因素、遺傳因素及其所存在的交互效應以及與台灣女性肺癌存活有關的重要預後因子，是本論文的研究重點。本論文由下列三個獨立的研究所組成：(1).第一篇研究為病例對照研究法，蒐集經病理証實之108位不吸菸婦女肺癌患者的資料為病例組，並以1：1年齡配對方式，蒐集同醫院其他非呼吸道疾病個案的資料為對照組，包括其配偶、一級血親共2760人，以邏輯迴歸分析(multiple logistic regression methods)探討共變量效應及以孟德爾複雜分離分析(complex segregation analysis)探討不吸菸婦女肺癌家族聚集之主因。(2).第二篇研究為收集從1981年到1998年間台灣女性肺癌發生檔中的資料，使用出生世代分析法探討出生世代對肺癌發生率的影響，使用年齡-年代-世代分析法(APC)探討年齡、年代、世代對肺癌發生率的效應，並觀察女性肺癌發生率的變化及其他相關因子，藉以了解驅動女性肺癌發生率改變的主要因素。(3).第三篇研究是收集1987-1994年間由衛生署登記的癌症發生檔及死亡檔為分析資料，其肺癌個案共26605人，並追蹤其存活狀態直到2000年的12月31日，進入分析的個案數共24910人，利用存活分析來探討女性肺癌存活率的相關因子。根據這一系列的研究結果，來探討女性肺癌的發生因素中，環境因子與遺傳因子所扮演的角色及可提高女性肺癌患者存活率的重要預後因子。
本系列研究結果如下：(1).控制proband及其一級血親的環境危險因子，女性親屬的肺癌家族史(adjusted OR=14.4, 95%CI=2.7-75.5)，特別是母親(adjusted OR=12.3, 95%CI=2.2-68.7)，對於肺癌的發生是一項很強的預測因子，亦即女性肺癌具有很強的家族聚集性。(2).肺癌早期發病者(<60歲)的家族聚集性(adjusted OR=11.2, 95%CI=2.2-56.9)證明了肺癌發生的遺傳因素(孟德爾共顯性遺傳模式為最佳模式，AIC值(Akaikes Information Criteria)=1081.2為所有模式中最小)。基因對於環境毒物的易感受性自雙親遺傳給子女，進而引發肺癌，通常此種遺傳性癌症都會比散發型病例更易早期發病。(3).台灣婦女肺癌的發生率仍持續在增加(線性相關係數r=0.96, P<0.05)，且主要病理組織型態為肺腺癌(分率(proportion rate)=38.98%-46.88%)。年輕世代的女性肺癌發生率呈現下降的趨勢，尤其是在1956年後的出生世代，肺腺癌及鱗狀上皮癌的發生率皆呈現下降的趨勢。(4).年輕世代的女性肺癌發生率呈現下降的趨勢，可能意味著增加抽油煙機的使用對年輕世代具有保護效果(因先前研究資料顯示：在1960年代，其裝設抽油煙機的比率低於62%，而在1980年代已達到82%，且到了2000年代更高達95%以上)。(5).女性肺癌患者之肺癌死因五年存活率(23.6%)顯著高於男性(21.3%)，而全死因五年存活率(15.6%)也顯著高於男性(14.6%)。在女性肺癌患者中，以罹患鱗狀上皮惡性腫瘤者有較佳的預後(其涉險比值(HR)最小，五年存活率最高)，而以小細胞惡性腫瘤患者預後最差(五年存活率最低)，大細胞惡性腫瘤患者其涉險比值(HR)最大，但都未達到統計顯著性差異。(6).治療方式以僅單獨接受手術治療者有最佳的五年存活率(42.3%)及最低的涉險比值(HR=0.49)，且與其他治療方法比較，都達到統計顯著性差異。但女性肺癌存活率的影響因素除考慮其治療方式外，患者的癌症分期也可能是重要關鍵，但也是本研究的限制。
本論文的研究結果發現，台灣女性肺癌發生的主因與環境因素及遺傳因素皆有關聯，且呈現交互作用效應。其中，早期發病者，其發病原因以遺傳因素為主，而環境因素中，又以烹飪油煙為掌控肺癌發生率趨勢的主因。除了預防疾病發生之外，對於疾病患者，必須盡力提高其存活率。因此，對於一級血親(尤其是母親)具有肺癌家族史者，應推行肺癌每年定期篩檢，期能早期發現疾病，早期治療，以提高肺癌患者的存活率，並且改變烹飪的習慣、正確裝設排油煙機且確實使用。

關鍵字

涉險比值 ； 存活分析 ； 年齡-年代-世代分析法 ； 分離分析 ； 家族聚集性 ； 肺癌

並列摘要

Lung cancer is one of the most common carcinomas in the world. In Taiwan, the causal factors of women lung cancer are very different from other countries. According to annual reports of the National Cancer Registry in Taiwan, adenocarcinoma is the most common type of lung cancer in women, affecting 54-63% of women with lung cancer. Taiwanese women, like Chinese women in other countries, have a relatively high lung cancer incidence despite the fact that very few smoke cigarettes. While cigarette smoking is strongly associated with squamous cell and small cell carcinoma, it is less of a factor for adenocarcinoma. The present finding that the incidence of lung cancer among Taiwanese women has remained fairly stable in the last two decades. Factors that have been correlated with an elevated risk of lung cancer include specific environmental exposure and genetic susceptibility. In this study series, the authors observe the characteristics of the higher risk population of women lung cancer and further explore the relationship between the related factors and women lung cancer occurrence in Taiwan.
In this study series, the authors make use of epidemiology to control for as many potential confounders as possible and to explore demography, environmental factors, genetic factors and their interaction effects. The authors used three types of study designs to explore the study purposes, these methods were follows: (1). To determine the familial aggregation and if evidence exists for a major gene controlling susceptibility to female non-smoking lung cancer, multiple logistic regression methods for estimating covariate effect and maximum likelihood segregation analyses were performed on 108 female non-smoking lung cancer probands (2760 individuals) in a population-based case-control study. (2). To investigate the birth cohort effect on lung cancer incidence in Taiwanese women between 1981 and 1998, an age-period cohort (APC) model analysis is employed to study the effects of age, time periods, birth cohorts and histological types of lung cancer. (3). The purpose of this study was to identify the gender differences and clinical factors associated with lung cancer survival rates in Taiwan. We analyzed the 5-year survival rates of 24910 subjects diagnosed with lung cancer between 1987 and 1994. The Cox proportional hazards model identified clinical characteristics for gender according to lung cancer death and all-cause death outcomes.
In these studies, we have the following findings: (1). Having a history of lung cancer in a female relative (adjusted OR=14.4, 95%CI =2.7-75.5) was much more strongly associated with lung cancer risk than was having a male relative with lung cancer. The prevalence of lung cancer was particularly high in the mothers of cases for controls (P<0.05). The cases that were diagnosed before the age of 60 were more likely to have a family history of lung cancer than were those diagnosed after age 60 and this difference was statistically significant (P=0.014). All of the Mendelian models fit the data significantly better than the sporadic (no major type) model or the environmental model. (2). Linear correlation coefficients (r) demonstrated an increasing trend (r=0.96, P<0.05) in the incidence rate of women lung cancer in Taiwan. Adenocarcinoma was the highest proportion out of all histological types between 1981-1983 (43.17%) and 1996-1998 (46.88%). The birth cohort from 1917-1926 suffers the highest risk of lung cancer. However, in recent cohorts, particularly those born after 1956, the incidence has fallen. The declining incidence in younger cohorts may be accredited to increased fume extractor usage and reduced exposures to carcinogenic cooking-oil fumes. (3). 5-year survival rates were significantly higher for females than males (P<0.0001). The adjusted hazard ratio of females versus males was 0.94 (95%CI=0.91-0.99) for lung cancer death and 0.96 (95%CI=0.93-0.99) for all-cause death. Gender and other clinical characteristics (i.e. diagnostic age, histological type, and treatment modality) play important roles in lung cancer survival.
In these studies, we have found evidence for a major gene influencing earlier age of onset of women lung cancer, and would seem to provide support for a genetic hypothesis. The major factor represents an unmeasured environmental factor such as cacinogensof cooking oil fume that increases cancer risk and is passed from parent to offspring. Thus, we must change cooking practices, increase fume extractor usage and implement early screen of lung cancer for higher risk population.

並列關鍵字

segregation analysis ； survival analysis ； age-period-cohort model ； family aggression ； Cox proportional hazard model ； lung cancer

參考文獻

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