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Actual 10-Year Survival after Resection of Perihilar Cholangiocarcinoma: What Factors Preclude a Chance for Cure?

ABSTRACT: Complete resection of perihilar cholangiocarcinoma (pCCA) is the only potentially curative treatment. Long-term survival data is rare and prognostic analyses are hindered by the rarity of the disease. This study aimed to determine the cure rate and to identify clinicopathological factors that may preclude cure. All consecutive resections for pathologically confirmed pCCA between 2000 and 2009 in 22 centers worldwide were included in a retrospective cohort study. Each center included its retrospective data series. A total of 460 patients were included with a median follow-up of 10 years for patients alive at last follow-up. Median overall survival (OS) was 29.9 months and 10-year OS was 12.8%. Twenty-nine (6%) patients reached 10-year OS. The observed cure rate was 5%. Factors that virtually precluded cure (i.e., below 1%) according to the mixture cure model included age above 70, Bismuth-Corlette type IV tumors, hepatic artery reconstruction, and positive resection margins. Cure was unlikely (i.e., below 3%) in patients with positive lymph nodes or poor tumor differentiation. These factors need to be considered in patient counseling and long-term follow-up after surgery.

SUBMITTER: van Keulen AM

PROVIDER: S-EPMC8699376 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the effect of vascular resection (VR), including portal vein resection (PVR) and hepatic artery resection (HAR), on short- and long-term outcomes in patients with perihilar cholangiocarcinoma (PHC).BackgroundResection surgery and transplantation are the main treatment methods for PHC that provide a chance of long-term survival. However, the efficacy and safety of VR, including PVR and HAR, for treating PHC remain controversial.MethodsThis study was registered at the International Prospective Register of Systematic Reviews (CRD42020223330). The EMBASE, PubMed, and Cochrane Library databases were used to search for eligible studies published through November 28, 2020. Studies comparing short- and long-term outcomes between patients who underwent hepatectomy with or without PVR and/or HAR were included. Random- and fixed-effects models were applied to assess the outcomes, including morbidity, mortality, and R0 resection rate, as well as the impact of PVR and HAR on long-term survival.ResultsTwenty-two studies including 4,091 patients were deemed eligible and included in this study. The meta-analysis showed that PVR did not increase the postoperative morbidity rate (odds ratio (OR): 1.03, 95% confidenceinterval (CI): [0.74-1.42], P = 0.88) and slightly increased the postoperative mortality rate (OR: 1.61, 95% CI [1.02-2.54], P = 0.04). HAR did not increase the postoperative morbidity rate (OR: 1.32, 95% CI [0.83-2.11], P = 0.24) and significantly increased the postoperative mortality rate (OR: 4.20, 95% CI [1.88-9.39], P = 0.0005). Neither PVR nor HAR improved the R0 resection rate (OR: 0.70, 95% CI [0.47-1.03], P = 0.07; OR: 0.77, 95% CI [0.37-1.61], P = 0.49, respectively) or long-term survival (OR: 0.52, 95% CI [0.35-0.76], P = 0.0008; OR: 0.43, 95% CI [0.32-0.57], P < 0.00001, respectively).ConclusionsPVR is relatively safe and might benefit certain patients with advanced PHC in terms of long-term survival, but it is not routinely recommended. HAR results in a higher mortality rate and lower overall survival rate, with no proven benefit.

Project description:Photodynamic therapy (PDT) of solid cancers comprises the administration of a photosensitizer followed by illumination of the photosensitizer-replete tumor with laser light. This induces a state of local oxidative stress, culminating in the destruction of tumor tissue and microvasculature and induction of an anti-tumor immune response. However, some tumor types, including perihilar cholangiocarcinoma, are relatively refractory to PDT, which may be attributable to the activation of survival pathways in tumor cells following PDT (i.e., activator protein 1 (AP-1)-, nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-?B)-, hypoxia-inducible factor 1-alpha (HIF-1?)-, nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)-, and unfolded protein response-mediated pathways).To assess the activation of survival pathways after PDT, human perihilar cholangiocarcinoma (SK-ChA-1) cells were subjected to PDT with zinc phthalocyanine (ZnPC)-encapsulating liposomes. Following 30-minute incubation with liposomes, the cells were either left untreated or treated at low (50 mW) or high (500 mW) laser power (cumulative light dose of 15 J/cm(2)). Cells were harvested 90 min post-PDT and whole genome expression analysis was performed using Illumina HumanHT-12 v4 expression beadchips. The data were interpreted in the context of the survival pathways. In addition, the safety of ZnPC-encapsulating liposomes was tested both in vitro and in vivo.PDT-treated SK-ChA-1 cells exhibited activation of the hypoxia-induced stress response via HIF-1? and initiation of the pro-inflammatory response via NF-?B. PDT at low laser power in particular caused extensive survival signaling, as evidenced by the significant upregulation of HIF-1- (P?<?0.001) and NF-?B-related (P?<?0.001) genes. Low-power PDT was less lethal to SK-ChA-1 cells 90 min post-PDT, confirmed by annexin V/propidium iodide staining. In vitro toxicogenomics and toxicological testing in chicken embryos and mice revealed that the ZnPC-encapsulating liposomes are non-toxic.PDT-treated perihilar cholangiocarcinoma cells exhibit extensive survival signaling that may translate to a suboptimal therapeutic response and possibly tumor recurrence. These findings encourage the development of photosensitizer delivery systems with co-encapsulated inhibitors of survival pathways.

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Actual 10-Year Survival after Resection of Perihilar Cholangiocarcinoma: What Factors Preclude a Chance for Cure?

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