Radiofrequency ablation for cholangiocarcinoma: it works, but how?Referring to Yang J et al. p. 751–760
26 July 2018 (online)
In this issue of Endoscopy, Yang et al. present the first randomized trial showing that radiofrequency ablation (RFA) combined with plastic stent placement leads to longer survival than plastic stents alone in patients with unresectable extrahepatic cholangiocarcinoma . Several features of this study are unique and not comparable to previous, nonrandomized studies: the majority of the patients had cholangiocarcinoma distal to the bifurcation, no chemotherapy had been received, no long-term antibiotics were used, and only a single 8.5 Fr plastic drain was inserted after RFA.
“How can RFA in the bile duct lead to a systemic effect slowing down metastatic growth? One could speculate that by reducing tumor volume and change of tumor microenvironment the speed of tumor progression could be influenced.”
RFA for cholangiocarcinoma has been described previously in several studies; however, most of the patients in these studies had hilar cholangiocarcinoma. These earlier studies also led to the impression of prolonged survival in RFA-treated patients  . However, the studies did not include a control group and are therefore likely to be biased.
In the Yang et al. study, RFA improved bilirubin levels, and increased duration of stent patency and overall survival time significantly. However, the number of endoscopic retrograde cholangiopancreatography (ERCP) procedures performed was the same in both groups, most likely because ERCP for intraductal endosonography was scheduled for every 3 months. In addition, there was no difference in cholangitis between the two groups. Overall, 12 out of 65 patients died of sepsis due to cholangitis. The majority of patients died from metastases due to tumor progression. The 5-month difference in survival time (8 vs. 13 months) between the two groups is explained by the slower tumor growth and the later occurrence of metastasis in patients in the RFA group. The latter effect is difficult to explain. How can RFA in the bile duct lead to a systemic effect slowing down metastatic growth? One could speculate that by reducing tumor volume and change of tumor microenvironment, the speed of tumor progression could be influenced.
The only alternative local treatment is photodynamic therapy (PDT). Specific outcome measures for both methods, besides overall survival, are quality of life, stent patency, improvement in cholestasis, cholangitis, and number of ERCP procedures. In prospective uncontrolled nonrandomized studies, four controlled nonrandomized trials, and two randomized studies  , PDT has proven its efficacy in hilar cholangiocarcinoma Bismuth type III and IV. Cholestasis was treated successfully in patients without successful endoscopic drainage, survival time was prolonged, tumor mass and growth were reduced, small intrahepatic bile ducts were reopened, and stent patency was prolonged. In the first trial , quality of life was poor at study entry and improved after PDT; in the second trial , patient’s performance status was normal at the beginning and did not improve further.
In contrast to RFA, the mechanism of action of PDT is well defined. Tumor necrosis is due to three mechanisms: direct cytotoxic effects on tumor cells (apoptosis), ischemic necrosis because of the sensitivity of tumor microvasculature to PDT, and induction of an inflammatory reaction that leads to the development of systemic immunity, as shown in experimental models.
The improvement of cholestasis, and control of sepsis and cholangitis are probably more important as survival factors in Bismuth Type III and IV cholangiocarcinoma than in distal cholangiocarcinoma. Survival time is particularly short in Bismuth type III and IV tumors , possibly due to unsuccessful endoscopic drainage . In contrast, distal cholangiocarcinoma can usually be treated easily and successfully with metal stents.
In an Austrian multicenter study, plastic stents and metal stents were used together with RFA . Although patients were not randomized, patients with metal stents showed longer survival than those with plastic stents. Comparing the results for the RFA/metal stent group with studies of metal stents alone, the authors claimed that the combination of both methods is superior to stenting alone. In addition, survival of the patient was determined mainly by tumor progression and not by sepsis or cholangitis.
Without RFA, metal stents have not been shown to be superior to plastic stents with respect to survival, with the exception of some patients in particular patient subgroups . The extent to which RFA can further improve the outcome of metal stents alone is unknown. In patients with malignant distal bile duct stenosis, it is possible that placement of a metal stent results in survival durations that are similar to the combination of RFA with a plastic drain.
Whether RFA or PDT should be used primarily is also open to debate. In an open study, both methods were compared in patients with mainly hilar cholangiocarcinoma . RFA appeared to be superior, but a randomized trial would be necessary to confirm these findings. In contrast to PDT, RFA does not require additional drugs or dosimetry, making it slightly easier for endoscopists to use. However, the type of RFA probe, type of generator, and settings of the generators are not standardized, leaving the operator in some uncertainty. Furthermore, the RFA catheter is more rigid than the PDT catheter. This could cause problems when introducing the RFA catheter into proximal bile ducts with serious stenosis.
As there appears to be relatively consistent evidence for the benefit of RFA and few adverse events, the use of RFA for malignant bile duct stenosis will increase, even though the systemic antineoplastic effect is unexplained. Most importantly, a randomized trial in Bismuth type III and IV tumors should be performed.
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