Micro-invasive pancreaticoduodenectomy will be a promising treatment option for distal cholangiocarcinoma

Cholangiocarcinoma is a malignancy derived from biliary epithelial cells, a relatively rare but highly malignant type of malignancy. Cholangiocarcinoma located below the convergence of gallbladder duct and common hepatic duct is defined as distal cholangiocarcinoma (dCCA), accounting for 20–30% of total cholangiocarcinoma. In spite of the highly developed adjuvant therapy, surgical treatment remains the core in dCCA treatment, and radical pancreaticoduodenectomy is still the only potential cure for dCCA. However, the overall prognosis of dCCA after radical surgery is still unsatisfying, with a post-operative 5-year survival rate less than 40%. How to improve the effect of surgical treatment in dCCA patients has always been the hotspot of clinical research. With the continuous progress in laparoscopic and robotic surgery technique, the application of minimally invasive surgery in dCCA treatment attracted the attention from researchers in recent years. Currently, minimally invasive pancreaticoduodenectomy (MIPD), such as laparoscopic pancreaticoduodenectomy (LPD) or robotic pancreaticoduodenectomy (RPD), is technically barrier-free and has been widely applied in high-volume medical centers, effectively reducing operative trauma and accelerating post-operative recovery. However, the oncologic benefits of MIPD for dCCA patients remain controversial. Lymph node metastasis is an important factor affecting the prognosis of dCCA, the appropriate extent of lymph node dissection and counts of intra-operative retrieved lymph nodes are of great value in correctly evaluating the clinical stage of dCCA and improving long-term post-operative prognosis. However, there is still a lack of high-quality evidence on whether MIPD can achieve the same extent of lymph node dissection and long-term prognosis as open pancreaticoduodenectomy (OPD), restricting the clinical application of MIPD in dCCA treatment. In this research, Uijterwijk et al. launched a multicenter research including 478 patients from 8 high-volume medical center from 5 countries and compared peri-operative safety and post-operative prognosis of MIPD and OPD for the first time. The conclusion is highly reliable and has important clinical value (1).

In this research, data from multiple centers were included for analysis, patient screening was rigorous, study was well-designed, and results were highly reliable. By comparing OPD and MIPD, researchers confirmed that MIPD could achieve comparable extent of lymph node dissection and number of intra-operative retrieved lymph nodes as OPD, meeting the requirements of lymph node dissection in treatment guidelines for dCCA. Also the overall survival rate and disease-free survival rate were not statistically different between dCCA patients undergoing MIPD and OPD, affirming that the survival benefit of MIPD for dCCA patients is not inferior to that of OPD, consistent with the results of previous researches reported by Kim et al. and Xu et al. (2,3). It is worth noting that the median overall and disease-free survival time of patients in MIPD group were 8.9 and 14.5 months longer than those in OPD group, respectively. Although this difference is not statistically significant at present, considering that 97 enrolled patients receiving MIPD included early cases of performing MIPD in various centers, the overall and disease-free survival of dCCA patients receiving MIPD may exceed that of OPD in the future as the increase in number of cases and the accumulation of MIPD experience. Meanwhile, research also found that the proportion of post-operative chemotherapy in MIPD group was 12.9% higher than that in OPD group, indicating that MIPD enabled dCCA patients a higher chance to receive follow-up anti-tumor treatment and may benefit dCCA patients. This research also found that MIPD did not increase the incidence of post-operative complications and peri-operative mortality, and can effectively reduced intra-operative blood loss and the incidence of post-operative surgical site infection, fully elucidating the safety of MIPD in treating dCCA. Interestingly, previous studies suggested that MIPD could accelerate post-operative recovery. But contrary to previous researches, the median surgical duration of MIPD increased by 123 minutes compared with OPD in current research, and the median length of hospital stay was not statistically different within groups. Considering the differences in surgical techniques and peri-operative management in different centers, this result does not negate the benefit of MIPD in accelerating post-operative recovery. With the extensive application of MIPD, the difference in surgical duration between MIPD and OPD may gradually disappear, and the benefit of MIPD in accelerating recovery will show.

Meanwhile, this research compared the therapeutic effect of LPD and RPD for the first time, and found that RPD group had shorter operation time, more intra-operative retrieved lymph node count and lower incidence of major complications than LPD group, indicating that RPD may have more advantages over LPD in dCCA treatment. This is also a highlight of this research, providing reference for the selection of MIPD procedure in clinical practice. However, due to limited sample size of RPD and LPD, further researches are necessary to fully verify these findings.

However, this research also has certain limitations. Firstly, a total of 16 patients categorized as stage IIIB and 6 patients categorized as stage IV who were not suitable for surgeries according to current guidelines were included, causing negative effect on results of survival analysis. Secondly, current risk factor analysis did not include several indexes that have been reported as independent risk factors for poor prognosis in dCCA patients, such as lymph node metastasis and vascular invasion, making the result of risk factor analysis less reliable. Vascular invasion has been reported as a risk factor for poor prognosis in dCCA patients. According to Yamamoto et al., the 5-year survival rate of dCCA patients with portal vein or hepatic artery invasion was only 16.7%, significantly lower than those without vascular invasion (4). Researches reported by Maeta et al., Miura et al., and Lyu et al., also identified portal vein system invasion as one of the independent risk factors for poor disease-free survival and overall survival in dCCA patients (5-7). In current research, a total of 53 patients were suspected of vascular invasion and received intra-operative vascular resection and reconstruction and the overall incidence of vascular invasion exceed 10%, indicating the necessity to include vascular invasion in risk factor analysis. Although authors included TNM stage and tumor diameter in risk factor analysis, considering that current TNM stage of dCCA does not include portal vein system invasion, and the diameter cannot reflect the depth of tumor invasion and the existence of vascular invasion due to its growth characters of infiltrating growth along bile duct wall, it will be better to include vascular invasion as a potential risk factor in univariate and multivariate analysis. Besides, the incidence of lymph node metastasis reached 41.5% to 44.4% in dCCA patients. Murakami et al. and Kiriyama et al. reported that the occurrence of lymph node metastasis and number of positive lymph nodes were independent risk factors for poor prognosis after dCCA surgery and Union for International Cancer Control (UICC) also included positive lymph nodes counts in the TNM staging of dCCA, indicating the predictive effect of lymph node metastasis on the prognosis of dCCA (8,9). In recent years, lymph node indexes like retrieved lymph node count and positive lymph node rate were also reported to have correlations with the prognosis of dCCA, further elucidating the predictive value of lymph node metastasis for prognosis (10,11). Indeed, researchers paid attention to the involvement of lymph nodes and included lymph-vascular invasion in risk factors analysis. However, lymph-vascular invasion is only a precursor condition of lymph node metastasis and cannot directly indicate occurrence of lymph node metastasis, so the impact of lymph node metastasis on prognosis may be underestimated (12). In addition, carbohydrate antigen 19-9 (CA19-9) also has a significant impact on prognosis of dCCA patients. Tella et al. reported that elevated CA19-9 was observed in 70.2% of all extrahepatic cholangiocarcinoma patients, and the median survival time of those patients was only 8.5 months, much lower than that of patients with normal CA19-9. They also confirmed CA19-9 as an independent risk factor for poor long-term survival (13). As the rapid development of deep machine learning, CA19-9 also serve as an important risk factor in various prediction models in predicting post-operative prognosis of dCCA, further demonstrating the prognostic value of CA19-9 (14). However, CA19-9 was neither included in inter-group comparison and corrected in propensity score matching, nor was it included in risk factor analysis, limiting the reliability of results of risk factor analysis. Therefore, results of risk factors analysis for post-operative overall and disease-free survival is less persuasive and requires further research. However, in spite of these limitation, the results of multivariate analysis fully illustrated that the selection of MIPD and OPD has little effect on the prognosis of dCCA patients, confirming the value of MIPD in treating dCCA. The above deficiencies do not affect the reliability of the overall conclusion of the research.

Generally, this research has important clinical value. In the era of minimally invasive surgery, this multi-center large-sample research affirmed that MIPD are not inferior to OPD in effectiveness and safety, even more advantageous in reducing intra-operative blood loss and post-operative surgical site infection, providing a theoretical basis for the application of MIPD in dCCA treatment. With the progress in comprehensive anti-tumor treatment of dCCA like targeted therapy and immunotherapy, the advantages of MIPD may further emerge in the future, bringing further survival benefits to dCCA patients (15).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-331/coif). The authors have no conflicts of interest to declare.

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