第六章、膽道癌之追蹤與支持性療法

6.1 膽道癌之追蹤

6.1.1 膽道癌復發概況與追蹤要點^[8]

• 復發高峰期：高達60-70%之復發集中於術後2年內 (中位復發時間約9.5個月)，且以遠端轉移較常見。[61]

• 追蹤原則：目前國際尚無單一標準時程，臨床建議參考Capecitabine的BILCAP試驗追蹤模式，並由多專科團隊個別化評估。

6.1.2 手術後追蹤建議^[8]

• 可參考之追蹤時程：建議患者於術後2年內需每3-6個月安排一次影像檢查，第2-5年每6-12個月安排一次，或依臨床需求調整。

• 影像追蹤建議：胸部CT (±顯影劑) + 腹部及骨盆CT (建議含顯影劑)或MRI。

• 腫瘤標記追蹤建議：可考慮追蹤CEA與CA 19-9兩種標記作為檢測復發之部分參考。

6.2 膽道與壺腹癌併發症之照護

6.2.1 阻塞性黃疸與急性膽管炎^[62]

• 病生理機制：膽管癌腫瘤直接壓迫管腔導致膽汁排出受阻，滯留之膽汁極易續發腸道細菌逆行性感染，演變為致命的急性膽管炎與敗血症。

• 臨床表現：

  • 阻塞性黃疸：皮膚與鞏膜黃染、皮膚搔癢、茶色尿、灰白便 (陶土便)

  • 急性膽管炎：典型表現為Charcot's triad (發燒、右上腹痛、黃疸)。病情惡化時可出現Reynolds' pentad (再加上意識改變與休克)，表示嚴重敗血症之可能。

• 處置原則：

  • 初步穩定與抗生素：輸液復甦、盡早給予廣效抗生素、監測生命徵象

  • 急迫性膽道引流：中度膽管炎建議儘早接受內視鏡或經皮穿肝膽道引流。較嚴重之患者則待生命徵象與血液動力學穩定後，儘速進行膽道引流。

  • 膽道引流方式：可選擇內視鏡ERCP或經皮PTBD，將滯留之感染性膽汁引流以達到感染源控制。需綜合考量腫瘤位置 (腫瘤擴散風險)、病人凝血功能與技術可近性。

6.2.2 膽道支架 (Biliary Stent) 之併發症：支架阻塞/移位^[63]

• 膽道支架適應症：對於無法切除患者之緩解性引流方式。較適合使用於遠端膽管癌或是壺腹癌；對於肝門部膽管癌則較困難 (需評估單側或雙側引流與對肝臟影響)。

• 支架阻塞/移位成因：腫瘤經支架網眼向內生長、腫瘤上下端邊緣的黏膜增生反應、膽泥 (sludge) 與細菌生物膜堆積於支架管腔。移位則與腫瘤物理性壓迫較相關。

• 臨床表現：

  • 支架阻塞：膽紅素回升、搔癢或黃疸復發，嚴重時會併發膽管炎。

  • 支架移位：部分患者無症狀，並由影像追蹤時意外發現。少部分患者可能有腸胃穿孔併發症。

• 預防與處置：

  • 支架種類選用：建議使用具有覆膜的自膨式金屬支架 (Covered self-expandable metal stent)，因其通暢期間長，且具有可移除性。

  • 影像學追蹤：建議常規以超音波、CT評估支架位置與膽道擴張程度。

  • 阻塞之處置：經超音波或CT確認後，以內視鏡療法進行舊支架移除與置換新支架。部分情況下無法移除舊支架，則可能於支架內置放新支架。

6.3 膽道癌用藥副作用之管理

6.3.1 膽道癌化療藥物相關副作用

• 膽道癌症最常使用的化療藥物包括晚期與轉移性全身性療法首選的Gemcitabine與白金類藥物；其次為輔助療法使用的Capecitabine。其餘為二線療法可能用的5-FU、Oxaliplatin與Irinotecan。詳細之注意事項與預防照護如下表：

表6.3.1 膽道癌化療藥物常見副作用之預防與處置

6.3.2 免疫相關副作用 (Immune-Related Adverse Events, irAEs)^[64]

• 免疫檢查點抑制劑 (ICIs) 為目前轉移性膽道癌首選療法組成之一，免疫相關副作用(irAEs) 之預防與照護相當重要。

• 免疫檢查點抑制劑之相對禁忌症 (非絕對但irAE風險更高)：

  • 自體免疫疾病：高達四至五成具有自體免疫疾病背景的患者，在免疫檢查點抑制劑治療期間曾發生自體免疫疾病惡化 (flare) 之情形。僅控制良好且自體免疫疾病嚴重度低之患者可能考慮使用ICI。

  • 慢性病毒感染：如曾感染HCV、HBV、HIV。給藥前需仔細確認感染之控制狀況。

  • 固體器官移植：使用ICI可能大幅增加排斥移植物之可能，一般來說不建議使用ICI。

  • 血液幹細胞移植：曾移植過患者，使用免疫檢查點抑制劑可能會大幅提升GvHD風險，一般來說不建議使用ICI。

• 免疫療法相關副作用機制：免疫檢查點抑制劑透過活化T細胞攻擊腫瘤，同時也可能導致正常組織被攻擊。irAEs可發生在任何器官，發作時間不可預測。

irAEs常見部位：

• 皮膚：皮疹、搔癢(最常見，通常早期出現)。

• 腸胃道：腹瀉、結腸炎 (Colitis) 。需監測排便次數，排除感染。

• 內分泌：甲狀腺功能低下/亢進 (需定期監測TSH, fT4)、腦下垂體炎、第一型糖尿病。內分泌副作用通常是永久性的，需長期荷爾蒙補充。

• 肺部：間質性肺炎 (Pneumonitis)。這是最嚴重且可能致死的副作用。症狀包括咳嗽、呼吸困難、血氧下降。

• 肝臟：肝指數 (AST/ALT) 升高。

irAEs分級處置原則：

• Grade 1 (輕微)：維持ICI治療，給予症狀治療並密切追蹤。

• Grade 2 (中度)：暫停免疫治療，直到副作用緩解至Grade 1或消失。若持續不退，考慮開始使用中等劑量全身性類固醇 (Prednisone或Methylprednisolone IV 0.5-1 mg/kg/day)，待緩解後慢慢減量 (taper)。

  • 若為皮膚毒性則可使用強效外用類固醇。

  • 腸胃毒性則可考慮使用口服不吸收性類固醇。

  • 若為二級之間質性肺炎，經排除其他原因應儘早給予高劑量全身性類固醇 (Prednisone或Methylprednisolone IV 1-2 mg/kg/day)。

• Grade 3 (嚴重)：暫停免疫治療。立即開始高劑量全身性皮質性類固醇 (Prednisone 1-2 mg/kg/day 或IV methylprednisolone)。類固醇需在4-6週內緩慢減量。若48-72小時內嚴重程度未能有效降低，需考慮其他免疫抑制劑 (如Infliximab，但肝毒性病患禁用)。

• Grade 4 (危及生命)：通常永久停止ICI治療 (內分泌副作用除外)。需住院並給予高劑量類固醇並加上更強的免疫抑制療法。

6.3.3 標靶藥物相關副作用

膽道癌症使用標靶之患者佔少數，須按照特定標靶藥物之副作用進行預防與處置。

• 選擇性FGFR2抑制劑 (如Pemigatinib、Futibatinib、Erdafitinib)：常見副作用為皮膚毒性 (皮疹、甲溝炎)、乾眼症、高血磷與味覺障礙。需預防性給予人工淚液，並持續追蹤血磷數值，必要時行低磷飲食甚至服用磷結合劑。

• HER2單株抗體/雙特異性抗體：共通之副作用為心臟毒性、腹瀉與皮疹。T-DXd則需特別注意間質性肺炎 (ILD) 之嚴重副作用；Tucatinib造成之腹瀉非常常見，仿單建議開始用藥前必須使用loperamide預防；而Zanidatamab與Zenocutuzumab等BsAb則需特別注意輸注相關不良反應較高。

• IDH抑制劑 (如：Ivosidenib)：常見副作用為腹瀉與QTc間隔延長。治療前需測基準ECG，並定期監測ECG與排便情況。

• BRAF抑制劑 + MEK抑制劑：副作用包括噁心、腹瀉與皮疹，罕見但嚴重則為惡性高熱。

• NTRK抑制劑：須注意其獨特的中樞神經毒性，包括頭暈、運動失調、感覺異常與記憶障礙。

• RET抑制劑：常見副作用為高血壓、肝毒性與QTc間隔延長。治療前需測基準ECG，並定期監測血壓、ECG、腸胃毒性與肝指數

• 選擇性KRAS G12C抑制劑 (如：Adagrasib)：常見副作用為腹瀉、噁心嘔吐、肝毒性與QTc間隔延長。治療前需測基準ECG，並定期監測ECG、腸胃毒性與肝指數。

表6.3.3 膽道與壺腹癌相關標靶藥物副作用之預防處置

ECG: electrocardiography; LVEF: left ventricular ejection fraction; ILD: interstitial lung disease. *本表格資訊整理自各藥物美國FDA仿單，詳細劑量調整與完整警語請參閱各藥物最新版仿單。

結語

1. 膽道癌依解剖位置分為肝內、肝門、遠端膽道癌與膽囊癌四大類，慢性膽道發炎為推動膽道上皮癌化之危險因子。而壺腹癌則為另一種癌症。

2. 初期影像評估依賴多相位CT搭配MRCP進行分期，診斷則以以ERCP直視膽道鏡切片為主要方式。

3. 進行根治性手術以達成R0切緣為唯一治癒方式，遠端膽管/壺腹癌採Whipple術式、膽囊癌採擴大膽囊切除、肝門膽管癌則採取半肝併尾狀葉切除。

4. 由於膽道癌術後復發率仍高，且以遠端復發為主，術後患者建議進行6個月的口服 Capecitabine輔助療法。

5. 轉移性/不可切除之膽道癌，第一線標準療法為Durvalumab/Pembrolizumab加上雙藥化療GEMCIS，二線療法首選FOLFOX。

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