講者: 周益聖 醫師

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少數幾個發生率在往下的腫瘤:子宮頸癌、肝癌

發生率明顯在往上爬升的腫瘤:乳癌、大腸癌

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1.癌症治療的難處:它會跑來跑去!

2.Ex:1cm的癌細胞內有1011個細胞

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1.環境因素:簡單來說就是西化飲食

2.遺傳基因-> ex:FAP、FNP-C、HNPCC

3.Inflammatory bowel disease

4.近幾年因為大腸鏡健檢的普及乃至大腸息肉的切除,有效降低了大腸癌的機率

 

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1.家族性腺瘤性瘜肉症 Familial adenomatous polyposis(FAP)->通常都會在40歲以前罹患colon cancer,在20~30歲之前需做全結腸切除術(但台灣的FAP病人非常非常少!)

2.遺傳性非瘜肉結直腸癌綜合症 Hereditary NonPolyposis Colorectal Cancer (HNPCC)或稱Lynch syndrome-> 在台灣其實也滿少的

 

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年輕患者越來越高,早期發現的患者比率也越來越高

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1.周醫師小提醒:anemia一定要survey呀!特別是女生,不要太快以為一定就是經期出血的緣故!

2.相對左側colon cancer的症狀,右側colon cancer的症狀較不明顯,是故發現時常常較為晚期,預後通常也因此較差

3.左側colon cancer大概可以佔到全部colon cancer的六成左右

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Large intestine – major sites of cancer

Several recent reports have analysed the incidence of cancer in subsites of the colon and rectum.

 In a study of 1,959 patients between 1964 and 1990 Sariego et al1 showed:

 that tumours of the colon are more common on the left-side (descending and sigmoid) than on the right-side (ascending).

 a relative increase in the incidence of tumours on the right-side of the colon compared to the left-side occurred during the period 1975 to 1990.

 Devesa and Chow reported a similar rightward shift . a trend towards earlier stage at the time of diagnosis.

A study in the Netherlands in 1995 reported that between 1975 and 1989 the incidence of tumours of the ascending colon, sigmoid colon and rectosigmoid colon in men had increased whereas the incidence of tumours of the rectum had decreased.3

The Eurocare study suggests that cancers of the left colon have a slightly better prognosis than those in the right colon, however, the survival advantage of left-sided tumours appears to be limited to the first 4 -5 years after diagnosis.4

1 Sariego J, et al. Am Surg. 1992; 58: 686-691.

2 Devesa SS, Chow W-H Cancer 1993; 71: 3819-3826.

3 Damhuis RAM, et al. Eur J Cancer 1995; 31A: 2116-2117.

4 Berrino F, et al. (eds). The Eurocare Study IARC 1995; 132: 1-1463.

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Change of AJCC-7

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1.只要有lymph node metastasis,至少都是第三期!

2.開刀時有拿大於12顆以上的淋巴結->預後比較好!

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Colon cancer最常見metastasis的地方:Liver!!

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接續前一次上課,lymph node在手術過程中希望取超過12顆,只要有invasion to lymph node都至少stage III,就需要adjuvant chemotherapy來降低 recurrence rate

目前大腸癌術後的adjuvant chemotherapy以6個月的FOLFOX為主

FOLFOX: leucovorin (FOLinic acid) =>  oxaliplatin =>bolus 5FU  => cotinuous infusion 5FU

在stage III 目前”不建議”使用標靶藥物,target therapy在stage III都被證實無效

(重要!!!)

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MSI高代表prognosis好

Stage 2的病人約有30%是屬於MSI high

但stage 3病人, MSI high的比率就比較少

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以下開始介紹 Target therapy 著重在常用的

VEGF: vascular endothelial growth factor ,  因為腫瘤生長都會與血管新生有關

常聽到的 Avastin (Bevacizumab)

EGFR: Epidermal growth factor receptor

腫瘤名字有 carcinoma 的都代表是 epithelium 由來的,EGFR 就是 positive

EGFR 的 monoclonal antibody 常用的是 cetuximab (erbitux)

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RAS, RAF 都是 protein + transcription factor

只要有 RAS mutation 都會影響到 EFGR target therapy 的效果

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Hazard ratio for overall survival:  HR 越低表示 survival 越好

基本上大部分的標靶藥物都降低約 2 成的 HR

若三線的藥物都有使用到的話可改善存活率,hazard ratio 就會變成 0.8 * 0.8 * 0.8 = 0.512

然而第一線的標靶藥物可以改善的平均存活月數較長, 平均增加 3-4 months

Colon CA stage 4 的平均餘命 由 12 個月( 1950 年代以前) 改善到目前約 30 個月

 

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藍色線為 progression free survival   第一線的治療藥物的 progression free survival 從 2004 年到 2014 年都沒有明顯改變,progression free survival 約 10個月

但 overall survival 有從 20 個月改善到 30 個月

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從四個方面決定治療的選擇

#Tumor:  看腫瘤的特性及是否可切除,在大腸癌中手術切除遠端轉移部分仍有20%可以改善survival

#Molecular: RAS, BRAF, 及前面提到的MSI都可以當作參考

   RAS: 分K-RAS及N-RAS, 會影響EGFR的表現

   BRAF mutation: 預後最差, 有BRAF mutation則針對EGFR receptor的藥物都無效,因此會在第一線治療就盡量投入能使用的治療方法

#Patient characteristic: 年輕病人不一定adverse event少,但是young age 對於副作用的tolerance會較高,從嚴重的副作用造成的critical condition 回復的機會也比較大,  因此young age的病人較能用較intense的治療

  Age不是唯一參考要素,performance status( ECOG)也是常用的參考指標

 

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AVEX: Bevacizumab + capecitabine superior PFS to capecitabine alone

AGITG MAX: PFS significantly longer with bevacizumab treatment (capecitabine + bevacizumab ± mitomycin C vs capecitabine)

ARTIST: bevacizumab + mIFL superior PFS to mIFL (Chinese patients) :[irinotecan (125 mg/m(2)), leucovorin (20 mg/m(2)) bolus, and 5-fluorouracil intravenous infusion (500 mg/m(2)) weekly for four weeks every six weeks

AVF2107g: Bevacizumab + IFL superior OS & PFS to placebo + IFL

NO16966: Bevacizumab + CAPOX/FOLFOX4 superior PFS to placebo + CAPOX/FOLFOX4

CAIRO3: bevacizumab + capecitabine maintenance superior PFS2 to observation only

CRYSTAL: cetux + FOLFIRI superior PFS to FOLFIRI alone

FIRE-3: superior OS with cetux vs bev

PRIME: superior PFS with panitumumab + FOLFOX4 vs FOLFOX4

CALGB: no difference with bevacizumab + FOLFOX vs cetuximab + FOLFOX

COIN: no PFS or OS benefit with Cetuximab + CAPOX/FOLFOX4 vs no cetux

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NCCN GL Dept. Review: <Changed FP to fluoropyrimidine. Add “ziv-.”> (DFC, 2/18/15)

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原先使用 IFL

I: irinotecan

F: bolus 5-FU

L: leucoforin, 葉酸抑制劑, 減少5-FU代謝, 會讓5-FU濃度增加毒性上升,有使用則可以減少5-FU使用dose

單打chemotherapy:  15.6 months, 加上Bevacizumab後延長到 20.3 months,  

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有使用 Bevacizumab 後 HR 0.54 降低接近一半的死亡率

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FOLFOX使用 Bevacizumab後可以延長2個月的progression free survival

XELOX好處是可以門診口服,針劑只要打一天

FOLFOX要打兩天, 需要住院,但在center會用攜帶式輸液器(奶瓶)

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NCCN GL Dept. Review: <Added “Ziv-” and “FP = fluoropyrimidine.” Changed Ctx to chemo.> (DFC, 2/18/15)

 

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目前PI3K及Akt 也有相對應的藥物(inihibitor) 但目前仍在臨床試驗中
EGFR inhibitor 常見adverse effect為acne

當target therapy 專一性越高(即越針對tumor cell) ,副作用就可以越小

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在使用EGFR inhibitor前需要確定KRAS, NRAS都要是wild type才可以使用( 才會有效)

BRAF mutation 與 RAS mutation 屬於 exclusive mutation,只有其中一種會有mutation

另外在lung CA 裡面EGFR 與 ALK 也是屬於 exclusive mutation

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The design of this trial is similar to the Hurwitz trial: 5-FU/LV/irino +/- a targeted agent, but the PFS curves look very different, in particular, when the KRAS mut CRC are included.

此組數據為沒有特別挑出K-RAS的病人,因此可以看到8個月前兩組效果接近,8個月後才分開,後來才知道是與K-RAS mutation 有關係

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RAS, BRAF mutation 佔約60%

=>所以約有40%的病人沒有RAS 或BRAF mutation 可以使用 anti –EGFR的標靶藥物

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NCCN GL Dept. Review: <Fixed number at risk at bottom and added labels for the 2 rows. Shrunk and moved reference.> (DFC, 2/18/15)

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NCCN GL Dept. Review: <Fixed number at risk at bottom and added labels for the 2 rows. Shrunk and moved reference.> (DFC, 2/18/15)

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NCCN GL Dept. Review: <Moved reference so full text was on slide.> (DFC, 2/18/15)

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基本上Bevcizumab 及 cetuximab 效果相近,但也有研究發現左側的大腸癌用Bevcizumab,  右側的大腸癌用cetuximab 會有較好的overall survival

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Predicting factor: 預測藥物是否對於tumor是有效的

Prognostic factor: 看疾病的預後狀況

腫瘤長在哪一側同時是predicting factor 也是prognostic factor

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