| 摘要: | 研究背景及目的
過去十年，抗肝炎病毒藥、干擾素、肝臟移植、微創射頻燒灼技術、及BCLC準則的推出，預期對肝癌治療方式之選擇，以及相對應的肝癌病人存活率有所影響改變。然而，以往並無全國性大型研究針對上述主題作出相關探討，因此，第一步，我們想先釐清此問題。
再者，肝臟切除手術是目前肝癌的治癒性療法中的主流，但因其為高風險手術，因此，針對原本擁有嚴重共病病患，例如慢性腎臟衰竭須要洗腎，病患常心有顧忌而不選擇肝臟切除手術。然而，是否原本的嚴重共病，真會影響肝癌治療的風險及術後長期預後，甚少被討論。因此，第二步，我們想研究比較洗腎及非洗腎病患，接受肝癌切除手術後，術後併發症率及長期存活率的差異。
除了手術風險之外，術後居高不下的肝癌復發率，是另一項重要臨床議題，早期肝癌復發率約2年40﹪，明顯影響切肝手術成效。以往研究發現，原發性肝癌COX-2表現量愈高，則切除後復發率愈高。在癌症細胞株試驗，也可看到癌細胞受COX-2抑制劑調控，可減少癌細胞局部侵犯及誘發血管新生的能力。然而在臨床治療上，非類固醇類消炎止痛藥是否有第三級化學預防效果，降低肝癌切除後，腫瘤復發的風險，目前無任何研究探討這議題。所以，第三步，我們希望釐清此疑問。
研究方式
我們使用台灣健保資料庫作回溯性世代研究。它是台灣民眾使用健保資源時，所有的就醫記錄的整合。資料庫內容主要包含門診，住院期間用藥記錄，是否接受治療或檢查的記錄，住院天數，住院費用。另外健保資料庫中的重大傷病記錄子檔，囊括所有領有重大傷病的病患資料。我們研究的台灣肝癌族群資料，皆由重大傷病檔取得。
研究結果
首先，在過去十年，初次肝癌治療的首選為治癒型療法的人數比例顯著增加，而相對應存活預後，無論是個別治療分組，或是全體肝癌族群，也有顯著進步。
再者，我們發現，尿毒洗腎肝癌病患，相較於一般肝癌病患的存活預後，並無顯著差異，惟獨手術後感染相關和心臟相關併發症風險，在尿毒洗腎肝癌病患身上顯著較高。
最後，我們發現術後使用非類固醇類消炎止痛藥病患，有顯著較低的早期肝癌復發風險，而且此現象存在大部分不同的次族群當中。
結論
肝癌治療的進步，足以證明過去十年的醫界努力方向的正確性並值得再努力的。尿毒洗腎應該不是肝癌切肝手術的禁忌症。惟獨要注意的是，術後較高的併發症風險。非類固醇類消炎止痛藥，可能有第三級化學預防的效果。惟獨若要確認兩者間是否有因果關係，須有賴實驗室，甚至大型隨機臨床人體試驗加以證實才行。
Thesis 1: Improved overall and disease-free survival for hepatocellular carcinoma patients: a 12-year nationwide cohort study
Background and Aim:
Although many therapies have been developed to treat hepatocellular carcinoma (HCC), its survival remains unsatisfied. In this nationwide cohort-study we aimed to investigate whether the overall and disease-free survival of HCC in nationwide perspective had been improved in the past decade.
Material and Methods:
Using Taiwan’s National Health Insurance Research Database (NHIRD), we conducted a retrospective cohort study to examine the survival amongst HCC patients who had received curative (liver resection, liver transplant, radiofrequency ablation, percutaneous ethanol injection), palliative (trans-arterial chemoembolization), and symptomatic therapies over three continuous time periods (period 1: 1998-2001; 2: 2002-2005; 3: 2006-2009). Kaplan-Meir survival analyses and log-rank analyses were used to determine the cumulative incidences and their respective survival differences.
Results:
During 1998-2009, we identified a total of 79,202 HCC patients. The number of HCC patients increased from 21,475 in period 1 to 30,350 in period 3. Higher percentage of patients received curative treatment as their initial therapy in recent years (19.4%, 22.5% and 28.9% in period 1, 2 and 3, respectively, P<0.001). For all HCC patients, the 5-year overall survival increased from 14.5% (period 1) to 25.0% (period 3) (P<0.001). For those receiving curative therapy, the 5-year overall survival increased from 42.5% (period 1) to 56.8% (period 3) (P<0.001); the 5-year disease-free survival increased from 30.5% (period 1) to 36.3% (period 3) (P<0.001). For those receiving palliative therapy, the 5-year overall survival increased from 13.7% (period 1) to 21.0% (period 3) (P<0.001).
Conclusions:
In the past decade, more percentage of HCC patients had received curative therapies. Both overall and disease-free survival for all HCC patients among different therapy groups improved significantly.
Thesis 2: Hepatic resection for hepatocellular carcinoma patients on hemodialysis for uremia: a nationwide cohort study
Background and Aim:
The association between uremia and survival outcomes of patients receiving hepatic resection for hepatocellular carcinoma (HCC) has not been well investigated, particularly for perioperative complications. This nationwide cohort study was aimed to compare survival outcomes as well as perioperative mortality and complication between uremia-HCC and non-uremia HCC patients who received hepatic resection.
Material and Methods:
Using Taiwan’s National Health Institute Research Database, 149 uremia-HCC patients who underwent hepatic resection between 1996 and 2008 were enrolled. The control group comprised 596 HCC patients who also received hepatic resection during the same time period. The two groups were matched for age, gender, viral hepatitis status, and underlying liver cirrhosis. Disease-free survival, overall survival and perioperative complications were compared between both groups.
Results:
For uremia-HCC cohort, the 1-, 5-, and 10-year overall and disease free survival rates were 86%, 52% and 38%, as well as 77%, 27% and 18%, respectively. The survival outcomes were comparable between uremia-HCC and HCC cohort, regardless of extent of hepatic resection. As for perioperative complications, uremia-HCC cohort had a higher risk of postoperative infections requiring invasive interventions as well as increased risk of life-threatening heart-associated complications, compared to non-uremia HCC cohort.
Conclusions:
Uremia did not influence survival outcomes between uremia-HCC and non-uremia HCC cohorts, irrespective of extent of hepatic resection. This study urges a better perioperative care strategy to avoid potential cardiac and infectious complications in uremia-HCC patients.
Thesis 3: Non-steroid Anti-inflammatory Drugs are Associated with Reduced Risk of Early Hepatocellular Carcinoma Recurrence after Curative Liver Resection: A Nationwide Cohort Study
Background and Aim:
The efficacy of non-steroid anti-inflammatory drugs (NSAIDs) to reduce risk of various de novo cancers had been reported; however, its role in reducing hepatocellular carcinoma (HCC) recurrence after liver resection is still unknown.
Material and Methods:
We conducted a nationwide cohort study by recruiting all newly diagnosed HCC patients who received curative liver resection as initial treatment. The use of NSAIDs and the risk of early HCC recurrence have been examined by multivariate analysis and stratified analysis. To avoid immortal time bias, use of NSAIDs was treated as time dependent variable in COX proportional hazard ratio models.
Results：
Between January 1997 and December 2010, 15,574 HCC patients who received liver resection were enrolled into this study. The 1-, 3-, 5-year overall survival rates were 90.4%, 73.2%, and 59.8%, respectively. The 1-, 3-, 5-year disease-free survival rates were 80.5%, 59.4%, and 50.2%, respectively. NSAIDs use (HR 0.81, 95%CI 0.73-0.90) and minor liver resection (HR, 0.83; 95% CI, 0.78-0.89) were independently associated with reduced risk of early HCC recurrence after liver resection. In the stratified analyses, NSAIDs was universally associated with reduced risks in most subgroups, particularly for those aged less than 65 years, male, with underlying diabetes mellitus, and receiving major liver resection.
Conclusion：
Use of NSAIDs is associated with a reduced risk of early HCC recurrence within 2 years after curative liver resection, irrespective of patients’ age, extent of liver resection, viral hepatitis status, underlying diabetes, and liver cirrhosis. |
