用外科手術方式的不可逆電流穿孔對無法切除的胰臟膽道癌症進行局部控制

Abstract

背景：胰臟癌與膽道癌仍是肝胰膽外科領域中最具挑戰性的惡性腫瘤。由於腫瘤常侵犯主要血管或膽管，大多數病人在確診時即無法進行根治性切除。對於局部晚期胰臟癌（locally advanced pancreatic cancer, LAPC）或不可切除的肝門膽管癌（perihilar cholangiocarcinoma, PHCC），傳統化學治療或放射治療在局部腫瘤控制與整體存活上的效果有限。近年來，不可逆電流穿孔（irreversible electroporation, IRE）作為一種非熱能消融技術，能選擇性破壞腫瘤細胞，並保留血管及膽管等重要結構，逐漸被視為潛在的新興治療選項。與傳統熱能消融(thermal ablation)不同，IRE 透過短暫高電壓脈衝造成細胞膜永久性穿孔，使腫瘤細胞凋亡而非凝固性壞死。這項技術特別適合應用於靠近大血管、膽管或十二指腸等高風險區域的腫瘤，可避免熱損傷所造成的併發症。過去臨床研究顯示，IRE 能在胰臟與膽道惡性腫瘤中達成較佳的局部控制率與延長存活時間，但其適應症、安全性與長期療效仍有待進一步驗證。以手術途徑執行 IRE，可在直視下精準放置電極，對於胰頭或肝門區等複雜解剖位置的病灶，能提高手術安全性與完整性。本研究旨在評估以手術方式進行 IRE 治療在不可切除胰臟和膽道惡性腫瘤之安全性、治療成效及其於多重治療策略中的角色。

研究方法：本研究回溯性分析臨床診斷為 T4 期且無遠端轉移之胰臟癌（LAPC）及不可切除之 PHCC 病患。所有 LAPC 病人皆先接受誘導性化學治療（induction chemotherapy），僅於影像學確認無遠端轉移或局部惡化後進行 IRE。除了在 IRE 治療組內的比較外，亦將存活結果與同期間僅接受化學治療之 LAPC 病人進行分析，並進一步透過傾向分數配對(propensity score matching)分析，以降低治療選擇偏差。PHCC 病人皆為無法手術切除者，原因包括腫瘤侵犯或包繞肝動脈或門靜脈主幹，或侵犯雙側第二級肝內膽管分支，以及預期手術後殘肝功能不足，無法安全進行根治性切除。這些病人於手術中同時進行 IRE 與膽道內支架置換，以維持膽道通暢。術後以電腦斷層或磁振造影於一個月內及後續定期追蹤，評估腫瘤完全消融率，以及病患是否需要膽道引流管的情況，並且分析復發和存活時間。

研究結果：在 74 位接受誘導性化療後進行 IRE 的 LAPC 病人中，中位無病惡化存活期（PFS）為 38.1 個月（IQR: 10.8–45.0），明顯長於僅接受化療之對照組 83 位病人（10.67 個月，IQR: 6.87–17.5，p < 0.001）。中位整體存活期（OS）為 46.9 個月（IQR: 30.8–63.0），亦顯著優於化療組（19.0 個月，IQR: 13.0–23.5，p < 0.001）。在 IRE 組內，局部復發率為 12.2%，而 40.5% 出現遠端轉移。多變項分析顯示，化療藥物（TS-1 vs. gemcitabine-based；HR = 1.676, 95% CI 1.093–2.571, p = 0.018）及是否接受 IRE（HR = 3.250, 95% CI 2.105–5.018, p < 0.001）為 PFS 的獨立預後因子；在 OS 的分析中，化療藥物（HR = 1.562, 95% CI 1.019–2.396, p = 0.041）與 IRE 治療（HR = 4.673, 95% CI 2.976–7.340, p < 0.001）亦具顯著相關。在經傾向分數配對後(n= 74 vs 74)，IRE合併化療相較於僅接受化學治療，在PFS與OS上呈現一致且較佳的存活趨勢。 在 PHCC 組中，手術 IRE 合併膽道支架置換之完全消融率達 94.1%，中位 PFS 為 21.5 個月（95% CI: 10.8–32.2），中位 OS 為 27.9 個月（95% CI: 25.3–30.5），一年整體存活率為 94.1%。大多數病人在術後一年內皆不需外引流管。手術後總膽紅素（T-bil）與 CA19-9 水準明顯下降，顯示膽道通暢恢復與良好局部控制。

結論：以手術方式施行的不可逆電流穿孔（IRE）為不可切除胰臟與膽道惡性腫瘤提供了一種安全且具效益的局部治療選擇。此技術能維持關鍵結構完整，達成穩定的局部腫瘤控制，並帶來有意義的存活延長。結合全身性治療後，IRE 可作為多重治療策略中的重要環節。未來仍需更大規模及前瞻性研究，以釐清其與全身性治療的最佳時序及長期效果，為原先無法接受根治性治療的病人帶來新的治療契機。

Background: Pancreatic and biliary tract cancers remain among the most challenging diseases in hepatopancreatobiliary surgery. Because of frequent involvement of major vessels or bile ducts, curative resection is often unachievable at diagnosis. For patients with locally advanced pancreatic cancer (LAPC) or unresectable perihilar cholangiocarcinoma (PHCC), conventional chemotherapy or radiotherapy rarely achieves durable local control or long-term survival. Irreversible electroporation (IRE), a nonthermal ablation technique that destroys tumor cells while preserving vital structures, has emerged as a promising local therapy. When performed through a surgical approach, IRE allows direct visualization and precise electrode placement, enabling safe ablation in anatomically complex regions. This study evaluated the safety and oncological outcomes of surgical IRE for unresectable pancreaticobiliary malignancies and its potential role within multidisciplinary treatment strategies.

Methods: Patients diagnosed with LAPC, defined as clinical T4 stage pancreatic adenocarcinoma without evidence of distant metastasis, and those with unresectable PHCC were retrospectively analyzed. All LAPC patients underwent induction chemotherapy, and IRE was performed only when follow-up imaging confirmed no disease progression or new metastases. In addition to comparisons within the IRE-treated cohort, survival outcomes were also compared with those of LAPC patients who received chemotherapy alone during the same period. To reduce selection bias between treatments, propensity score matching was additionally performed to create comparable LAPC cohorts for outcome comparison. Demographic data, operative findings, and postoperative outcomes were reviewed. For PHCC, IRE was performed along with intraoperative replacement of intrabiliary stents to maintain ductal patency. Radiological evaluation using contrast-enhanced CT or MRI was conducted one month after surgery and periodically thereafter to assess ablation completeness and recurrence.

Results: Among 74 patients with LAPC who received IRE following induction chemotherapy, the median progression-free survival (PFS) was 38.1 months (IQR: 10.8–45.0), compared with 10.67 months (IQR: 6.87–17.5) in the chemotherapy-alone group (n=83) (p < 0.001). The median overall survival (OS) was 46.9 months (IQR: 30.8–63.0) versus 19.0 months (IQR: 13.0–23.5) (p < 0.001). Within the IRE group, local recurrence occurred in 12.2% of patients, while 40.5% developed distant metastases. In multivariate analysis comparing the IRE and chemotherapy-alone groups, the chemotherapy regimen (TS-1 vs. gemcitabine-based; HR = 1.676, 95% CI 1.093–2.571, p = 0.018) and IRE treatment (HR = 3.250, 95% CI 2.105–5.018, p < 0.001) were significant independent predictors of improved PFS. Similarly, for OS, the chemotherapy regimen (HR = 1.562, 95% CI 1.019–2.396, p = 0.041) and IRE (HR = 4.673, 95% CI 2.976–7.340, p < 0.001) remained significant prognostic factors. In the propensity score-matched LAPC cohort (n=148; 74 vs 74), the survival advantage of IRE plus chemotherapy remained evident, with persistent differences in PFS and OS between the two groups. In the PHCC cohort, surgical IRE with intraoperative biliary stent replacement achieved a complete ablation rate of 94.1%, with a median PFS of 21.5 months (95% CI: 10.8–32.2) and median OS of 27.9 months (95% CI: 25.3–30.5). The one-year OS rate was 94.1%, and nearly all patients maintained satisfactory biliary drainage without external tubes during the first postoperative year. Serum total bilirubin and CA19-9 levels improved markedly after surgery, reflecting restored biliary flow and local disease control.

Conclusion: Surgical IRE is a safe and effective local treatment for unresectable pancreatic and biliary malignancies. It achieves durable local control, preserves vital structures, and provides meaningful survival benefits. When integrated with systemic therapy, IRE serves as a valuable part of multidisciplinary management, offering new treatment opportunities for patients who previously had no chance for curative therapy.