使用於非小細胞肺癌的標靶治療

Title: Target Therapy in Non-Small-Cell Lung Cancer

陳育民(Yuh-Min Chen) ； 彭瑞鵬(Reury-Perng Perng)

《中華民國癌症醫學會雜誌》 22卷3期 (2006/09) Pp. 1-34

https://doi.org/10.6588/JCOS.2006.22.3.1

摘要

肺癌是全世界癌症死因的第一位。因70%的非小細胞肺癌在初次診斷時已是局部擴展期或發生遠端轉移，這類病患的傳統治療原則為化學藥物治療或化學藥物治療合併放射治療。在千禧年後，我們有了標靶治療。目前標靶治療使用於非小細胞肺癌治療的的藥品包括epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI；上皮細胞生長因素接收器－酪胺酸酶抑制劑）與抗血管增生劑(anti-angiogenesis)。目前可以使用的EGFR-TKI包括有gefitinib（Iressa，艾瑞莎）與erlotinib（Tarceva，得舒緩）。目前可以使用的抗血管增生劑的藥品包括bevacizumab（Avastin，癌思停）。艾瑞莎與安慰劑比較的雙盲試驗顯示有吃艾瑞莎的病患中值生存期為5.6個月，而安慰劑是5.1個月。但是就亞洲黃種人的病患而言，有吃艾瑞莎是中值生存期9.5個月，而安慰劑是5.5個月。得舒緩與安慰劑比較的雙盲試驗顯示有吃得舒緩的病患中值生存期為6.7個月，安慰劑是4.7個月，而且亞洲黃種人的病患吃得舒緩的中值生存期超過一年。臨床上對EGFR-TKI較有效的特點為女性、腺癌、不吸菸、亞洲黃種人。EGFR的kinase domain exon18-21有突變的病患對EGFR-TKI的反應較好，有反應的機率約60%到85%。EGFR有較高的表現或放大者（overexpression或amplification），有效的機率也比較高。而有T790M突變，k-ras突變，或MET活化的癌細胞對EGFR-TKI有效的機率極低。目前有很多前瞻性研究開始使用艾瑞莎或得舒緩於未曾接受化療的特定非小細胞肺癌病患。抗血管增生劑目前以Avastin(anti-VEGF antibody)為主。Avastin在第三期隨機臨床試驗時，只收錄未曾接受化療的非鱗狀上皮癌病患，而且沒有咳血病史，或每次發生咳血的咳血量不到半湯匙的病患才可以加入臨床試驗。Avastin有兩個第三期隨機臨床試驗。第一個第三期臨床試驗隨機分成控制組(paclitaxel+carboplatin)與試驗組(paclitaxel+carboplatin+Avastin 15mg/kg)二組。結果顯示反應率，無疾病惡化期，與中值生存期在有加Avastin那一組均明顯變好。這個臨床隨機試驗是目前為止唯一的大型隨機臨床試驗的中值生存期超過一年的臨床試驗。在第一代的標靶治療藥品(EGFR-TKI, anti-VEGF antibody)成功的使用於非小細胞肺癌治療以後，學者與藥廠又致力於研發第二代的標靶治療藥品。這些新藥品可以作用在二處或更多的靶上面，故而稱為多標靶治療。總結：標靶治療是當今與未來的趨勢。目前主要在找那些人比較合適使用，那些期別適合使用，如何與現有治療互相配合，與到底須用多久?新一代的多標靶治療也提供我們更多的標靶治療可以選擇的項目。

並列摘要

Lung cancer is the leading cause of cancer death in the world. Seventy percentage of non-small-cell lung cancer (NSCLC) was diagnosed with advanced or metastatic disease. The standard or conventional treatment for these patients is chemotherapy alone or with radiotherapy. Target therapy was available after millennium. Target therapy that is available for the treatment of NSCLC includes epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anti-angiogenesis. Available drugs that had been approved for use in NSCLC in Taiwan included gefitinib and erlotinib as EGFR-TKIs, and bevacizumab as anti-angiogenesis. Median survival was 5.6 months in patients received gefitinib comparing 5.1 months in those who received placebo treatment in a randomized phase Ⅲ study. However, it was 9.5 months and 5.5 months, respectively, in subgroup analysis of Asian patients. In contrast, median survival was 6.7 months in those who received erlotinib treatment comparing 4.7 months in those who received placebo treatment in another phase Ⅲ randomized trial. In addition, median survival was longer than one year in Asian patients who received erlotinib treatment in this study. Female, adenocarcinoma, non-smoker, and East Asian patients had a better response to EGFR-TKI. Those with EGFR mutation, over expression or amplification also had a better response to EGFR-TKI treatment. Those with T790M mutation, k-ras mutation, or MET activation had poorest response. Regarding anti-angiogenesis, combine Avastin with paclitaxel and carboplatin had significantly better survival than paclitaxel and carboplatin treatment in non-squamous, chemo-naïve, advanced NSCLC. Multi-targeted therapy is second generation targeted therapy and whether or not they are more effective in the treatment of lung cancer is still undetermined and we have to wait until more matured data available. In conclusion, targeted therapy is the main treatment modality of NSCLC right now and in the future. Who, when, and how to incorporate targeted therapy with other treatment modalities is the main issue we need to resolve.