To the Editor:
We read the recent article in Annals of Surgery (July 2022) by Breuer et al with great interest.1 A great study concerns a controversial problem regarding the application of neoadjuvant therapy combining chemotherapy and radiotherapy associated with liver transplantation (LT) in selected patients with unresectable perihilar cholangiocarcinoma (PHC). A total of 213 patients who were considered for LT after the Mayo-like protocol in 17 reference centers on 2 continents were identified. For selected patients, credible benchmark values and strong evidence are provided for surgeons to take more LT strategies into consideration. We congratulate the authors for their efforts because we know the difficulties of conducting such a trial. However, we would like to raise the following comments about some details.
In the methods section, we note that the authors state the indication for LT is PHC patients with negative lymph nodes at least. We wonder how LN-negative is determined, especially in the LT subgroup in this article. For the judgment of lymph nodes in PHC, researchers have also proposed some preoperative diagnosis methods, such as endoscopic ultrasound-guided fine-needle aspiration, computed tomography, and/or magnetic resonance imaging, which have certain defects. Unfortunately, pathological diagnosis is still the gold standard for judgment, and most staging operations are close to liver transplant surgery and can even be performed at the same time.2 For selected patients in this study, lymph node pathology examination during the operation, if positive, is disastrous for both patients waiting for transplantation and the doctors who perform the procedure. LN positivity is not in line with the cohort and LT requirements. Once undesirable results occur during surgery, patients will no longer meet the requirements of cohort and LT, facing a waste of organ resources and waiting times and a worse prognosis.
In addition, there is another concern that makes us slightly confused. That is about the comparison between the LT group and resection group. As the article describes, for patients in the LT subgroup, neoadjuvant therapy is applied according to the Mayo criteria before the transplant, while this measure is not taken in the resection subgroup. As mentioned in this article, a significantly better 5-year disease-free survival was observed in the LT subgroup (50.2% vs 17.4%, P < 0.001), with the absence of significant differences between the 2 subgroups of overall survival. We wonder how the authors make sure whether it was mainly due to the use of grafts or neoadjuvant therapy carried out in the early stage. Furthermore, a critically important question appears: can the neoadjuvant therapy combination alone similarly improve outcomes in patients undergoing surgical resection? For this result, some studies have revealed the potential benefits of neoadjuvant therapy for PHC patients, including the R0 rate and complete response.3 Additionally, based on the long-term survival results obtained in this paper, further research is needed.
1. Breuer E, Mueller M, Doyle MB, et al. Liver transplantation as a new standard of care in patients with perihilar cholangiocarcinoma? Results from an International Benchmark Study. Ann Surg. 2022. doi: 10.1097/SLA.0000000000005641
2. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143:88–98.e3; quiz e14.
3. Lauterio A, De Carlis R, Centonze L, et al. Current surgical management of peri-hilar and intra-hepatic cholangiocarcinoma. Cancers (Basel). 2021;13:3657.