肝门部胆管癌：新辅助治疗+肝移植有效

《胃肠病学》杂志(Gastroenterology)7月刊发的一项多中心回顾性研究显示，新辅助化放疗序贯肝移植治疗不可切除性肝门部胆管癌有效且合理(Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008])。

2006年，基于化放疗/移植方案的优异单中心预后报告，联合器官共享网络(UNOS)建立了标准化的肝门部胆管癌终末期肝病模型(MELD)例外标准(Liver Transpl. 2006;12:S95-7)。

在这项研究中，梅奥医院的Sarwa Darwish Murad博士及其同事分析了1993~2010年美国12家采用新辅助疗法和肝移植治疗≥3例肝门部胆管癌患者的大手术量移植中心的数据。

共有287例患者达到研究标准。分别有99%、75%、98%和65%的患者完成外照射、近距离放射治疗、放射增敏治疗和维持化疗。71例(24.7%)患者在中位4.6个月后至肝移植前这段时间内退出。在治疗的最初3.5个月内，11.5%的患者退出，证实了MELD例外标准的合理性。

从被列入移植名单起的中位随访时间为2.5年。在此期间，122例患者在发病1.2年(中位数)后死亡。在这些死亡中，60例(49%)是在移植前发生，死亡原因为肿瘤进展(52)、肝衰竭(3)、心血管原因(2)、多器官衰竭(2)和脓毒症(1)。移植后，43例(20%)患者出现复发，62例(22%)死亡，死亡原因为复发(40)、脓毒症(8)、多器官衰竭(3)、肝衰竭(3)、移植后淋巴增生性疾病(2)和其他原因(6)。

移植后2年、5年和10年无复发生存率分别为78%、65%和59%，表明这种治疗非常有效。接受死体供肝移植的患者与接受活体供肝移植的患者的无复发生存率无显著差异。患有基础原发性硬化性胆管炎的患者与未患该病者的无复发生存率亦无显著差异。

但是，未达到UNOS标准的患者的生存时间显著减少，这些患者包括肿瘤＞3 cm的患者、经腹腔肿瘤活检的患者或转移性肿瘤患者。具体而言，与在目前MELD例外标准以内移植的患者相比，在该标准以外移植的患者的危险比(HR)为2.98。肿瘤大小引起的差异最大，肿瘤＞3 cm者和＜3 cm者的5年无复发生存率分别为32%和69%。

进行手术分期的患者与未进行手术分期的患者之间无显著差异。分期时间点与生存之间也无显著关联。同样，接受近距离放射治疗的患者的无复发生存率与未接受该治疗的患者无差异。

一项评价移植中心效应的分析显示，各中心的无复发生存率无显著差异。在多变量Cox回归模型中，患者选择仍然是无复发生存的唯一显著决定因素。事实上，患者选择不仅是唯一的预后的独立、可控预测因素，而且单独通过校正这一变量，可使5年无复发生存率最大增至72%。

未校正的5年无病生存率为65%，不仅与既往单中心研究的结果相似，而且与其他恶性和非恶性适应证的肝移植预后相似。此外，3个月退出率为11.5%，与根据标准化MELD例外评分当量预期的10%相似，因此支持采用肝移植来治疗这种致命性疾病的做法。

该研究的局限性在于其回顾性设计及从一家移植中心入选了较多患者(193)。此外，由于不同移植中心实施的维持化疗的时间、类型和剂量不同，因此该研究无法明确维持化疗的独立影响。

尽管研究结果证实新辅助化放疗序贯肝移植可使肝门部胆管癌患者获得优异预后，但未来还需进一步了解肝门部胆管癌的生物学特性，并通过优化患者选择或更有效的化放疗来减少等候移植患者的退出率和移植后复发率。

研究者声明无经济利益冲突。

爱思唯尔  版权所有

By: DIANA MAHONEY,  Oncology Report Digital Network

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.