Excellent clinical outcomes can be achieved with neoadjuvant chemoradiation and orthotopic liver transplantation for unresectable cholangiocarcinoma: support for the need of an international transplant protocol.
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SUBMITTER: Laughlin BS
PROVIDER: S-EPMC9660035 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Excellent clinical outcomes can be achieved with neoadjuvant chemoradiation and orthotopic liver transplantation for unresectable cholangiocarcinoma: support for the need of an international transplant protocol.
Laughlin Brady S BS Ashman Jonathan B JB Rule William G WG Yu Nathan Y NY Sio Terence T TT
Journal of gastrointestinal oncology 20221001 5
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Project description:Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluorouracil-based chemotherapy. Our center recently embarked on a protocol using stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node-negative patients until liver transplantation. We, therefore, retrospectively determined the tolerability and pathological response in this pilot study. During a 3-year period, 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50-60 Gy in 3-5 fractions over the course of 2 weeks). After 1 week of rest, capecitabine was initiated at 1330 mg/m(2) /day, and it was continued until liver transplantation. During neoadjuvant therapy, there were 35 adverse events in all, with cholangitis and palmar-plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplantation, and 6 patients received a liver transplant. The explant pathology of hilar tumors showed at least a partial treatment response in 5 patients, with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic indices and low proliferative indices were measured during histological examinations. Eleven transplant-related complications occurred, and the 1-year survival rate after transplantation was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.
| S-EPMC4185427 | biostudies-literature
Project description:Background & aimsExcellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception.MethodsWe collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site.ResultsThe patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy.ConclusionsPatients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.
| S-EPMC3846443 | biostudies-literature
Project description:BackgroundThe Mayo protocol for liver transplantation in patients with unresectable perihilar cholangiocarcinoma is based on strict selection and neoadjuvant chemoradiotherapy. The role of neoadjuvant chemoradiotherapy in this scenario remains unclear. The aim of this study was to compare outcomes after transplantation for perihilar cholangiocarcinoma using strict selection criteria, either with or without neoadjuvant chemoradiotherapy.MethodsThis was an international, multicentre, retrospective cohort study of patients who underwent transplantation between 2011 and 2020 for unresectable perihilar cholangiocarcinoma using the Mayo selection criteria and receiving neoadjuvant chemoradiotherapy or not receiving neoadjuvant chemoradiotherapy. Endpoints were post-transplant survival, post-transplant morbidity rate, and time to recurrence.ResultsOf 49 patients who underwent liver transplantation for perihilar cholangiocarcinoma, 27 received neoadjuvant chemoradiotherapy and 22 did not. Overall 1-, 3-, and 5-year post-transplantation survival rates were 65 per cent, 51 per cent and 41 per cent respectively in the group receiving neoadjuvant chemoradiotherapy and 91 per cent, 68 per cent and 53 per cent respectively in the group not receiving neoadjuvant chemoradiotherapy (1-year hazards ratio (HR) 4.55 (95 per cent c.i. 0.98 to 21.13), P = 0.053; 3-year HR 2.07 (95 per cent c.i. 0.78 to 5.54), P = 0.146; 5-year HR 1.71 (95 per cent c.i. 0.71 to 4.09), P = 0.229). Hepatic vascular complications were more frequent in the group receiving neoadjuvant chemoradiotherapy compared with the group not receiving neoadjuvant chemoradiotherapy (nine of 27 versus two of 22, P = 0.045). In multivariable analysis, tumour recurrence occurred less frequently in the group receiving neoadjuvant chemoradiotherapy (HR 0.30 (95 per cent c.i. 0.09 to 0.97), P = 0.044).ConclusionIn selected patients undergoing liver transplantation for perihilar cholangiocarcinoma, neoadjuvant chemoradiotherapy resulted in a lower risk of tumour recurrence, but was associated with a higher rate of early hepatic vascular complications. Adjustments in neoadjuvant chemoradiotherapy reducing the risk of hepatic vascular complications, such as omitting radiotherapy, may further improve the outcome in patients undergoing liver transplantation for perihilar cholangiocarcinoma.
| S-EPMC10083139 | biostudies-literature
Project description:The majority of patients who present with hilar cholangiocarcinoma will have incurable disease and require only palliation. Efficient relief of disabling symptoms is required with minimal morbidity and mortality and can be achieved by either surgical or non-operative options. A review of the indications, anatomical considerations and surgical techniques is presented. Segment III cholangio-jejunostomy is the most frequently used surgical bypass procedure and in those patients with an expected survival of more than 6 months, surgical palliation offers good quality and long-lasting palliation. There is a need for randomized controlled data to define the optimal role of surgical palliation in this difficult disease.
| S-EPMC2043105 | biostudies-other
Project description:Patients undergoing pancreatic resection at William Beaumont Hospital (Royal Oak, MI) were consented prior to surgery with local IRB oversight. Samples were collected at time of surgery and stored at -80°C according to CAP (College of American Pathologist)-accredited standard operating procedures. Disease pathology of frozen samples was validated with hematoxylin and eosin stained tissue sections from adjacently collected formalin fixed paraffin embedded tissue. The objective of this study was to examine the gene expression patterns of pancreatic adenocarcinoma treated with neoadjuvant chemoradiotherapy compared to pancreatic adenocarcinoma that had not under gone neoadjuvant treatment. The results of this study demonstrate that neoadjuvant therapy alters the gene expression of pancreatic adenocarcinoma
2015-10-01 | GSE60646 | GEO
Project description:BACKGROUND: Hilar cholangiocarcinoma is a rare tumour which is best managed by an aggressive surgical approach. The role of adjuvant or neoadjuvant radiation therapy, chemotherapy or chemoradiation remains controversial, as no prospective randomized studies have been performed. METHODS: This review summarizes the recent literature regarding the role of radiation, chemotherapy and chemoradiation in hilar cholangiocarcinoma. The results of a biliary cancer questionnaire regarding current treatment strategies are also reported. RESULTS: A number of retrospective studies have shown that patients treated with adjuvant radiation therapy have prolonged survival compared with untreated patients. However, most of these reports did not control for tumour stage or performance status. A carefully controlled trial from the Johns Hopkins Hospital did not demonstrate any benefit for adjuvant radiation therapy. A number of phase II trials of chemotherapy have demonstrated modest response rates (20-40%). The best responses have been reported with 5-fluorouracil (5-FU) in combination with interferon-alpha or with leucovorin and mitomycin C. Recent non-randomized reports of chemoradiation with 5-FU with or without gemcitabine as the radiosensitizer suggest, but do not prove, improved survival. Adjuvant chemoradiation is currently being employed at specialized centres most often in the Americas (71%) and the Asia/Pacific region (55%) and to a lesser degree in Europe (29%). DISCUSSION: The only chance for long-term survival in patients with hilar cholangiocarcinoma is complete resection with negative margins. Neither radiation therapy nor chemotherapy alone has been proven to prolong survival in completely or partially resected patients or in unresected patients. Recent uncontrolled data suggest that chemoradiation may improve survival in resected and locally unresectable patients. However, prospective, randomized multicentre trials need to be performed to confirm efficacy.
| S-EPMC2043100 | biostudies-other
Project description:PURPOSE:To evaluate the effect of escalated dose radiation therapy (EDR, defined as doses >50.4 Gy in 28 fractions [59.5 Gy BED]) on overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) of patients with unresectable extrahepatic cholangiocarcinoma (EHCC). METHODS:A consecutive cohort of 80 patients who underwent radiotherapy for unresectable EHCC from 2001 to 2015 was identified. Demographic, tumor, treatment, toxicity, and laboratory variables were collected. The maximal RT doses ranged from 30 to 75 Gy (median 50.4 Gy, at 1.8-4.5 Gy/fraction). Gross tumor volume (GTV) coverage by maximal dose in EDR group ranged from 38% to 100%. Kaplan-Meier method was used to estimate OS, FFLP, and FFDP. Univariate and multivariate Cox regression models were analyzed. RESULTS:After radiotherapy, median OS, FFLP, and FFDP were 18.7, 22.6, and 24.3 months, respectively. There was no significant difference in OS or FFLP between patients who received EDR to portions of the GTV and patients who did not. On multivariate analysis, bigger GTV, age, and ECOG performance status were independently associated with shorter OS. Local progression on chemotherapy prior to RT was independently associated with shorter FFLP. High baseline neutrophil/lymphocyte ratio (>5.3) was independently associated with shorter FFDP. Toxicity grades were similar in EDR and lower doses except lymphopenia which was higher in EDR (P = 0.053). CONCLUSIONS:EDR to selective portions of the GTV may not benefit patients with unresectable EHCC despite having acceptable toxicity. New methods to improve local control and survival for unresectable EHCC are needed.
| S-EPMC6198206 | biostudies-other
Project description:Owing to their nontoxicity, environmental friendliness, and high biocompatibility, physically cross-linked hydrogels have become popular research materials; however, their high water content and high free volume, along with the weak bonding interactions inherent to ordinary physically cross-linked hydrogels, limit their application in fields such as flexible devices, packaging materials, and substance transport regulation. Here, a structural barrier approach based on directional freezing-assisted salting out was proposed, and the directional structure significantly enhanced the barrier performance of the hydrogel. When the direction of substance diffusion was perpendicular to the pore channel structure of the directional freezing-PVA hydrogel (DFPVA), the Cl- transmission rate was 57.2% for the uniform freezing-PVA hydrogel (UFPVA). By adjusting the concentration of the salting-out solution and the salting-out time, the crystallinity and crystal domain size of the hydrogel could be further changed, optimizing and regulating the barrier performance of the hydrogel, with the best Cl- unit permeability being 36.02 mg mm per cm2 per day. Additionally, DFPVA had excellent mechanical properties (stress of 6.47 ± 1.04 MPa, strain of 625.85 ± 61.58%, toughness of 25.77 ± 3.72 MPa). Due to the barrier and mechanical properties of the direct structure, DFPVA is suitable as a drug carrier for slow drug release in vitro.
| S-EPMC11362914 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and is increasing in incidence. Long-term outcomes are optimized when patients undergo margin-negative resection followed by adjuvant chemotherapy. Unfortunately, a significant proportion of patients present with locally advanced, unresectable disease. Furthermore, recurrence rates are high even among patients who undergo surgical resection. The delivery of systemic and/or liver-directed therapies prior to surgery may increase the proportion of patients who are eligible for surgery and reduce recurrence rates by prioritizing early systemic therapy for this aggressive cancer. Nevertheless, the available evidence for neoadjuvant therapy in ICC is currently limited yet recent advances in liver directed therapies, chemotherapy regimens, and targeted therapies have generated increasing interest its role. In this article, we review the rationale for, current evidence for, and ongoing research efforts in the use of neoadjuvant therapy for ICC.
| S-EPMC7643214 | biostudies-literature
Project description:BackgroundThe ideal adjuvant therapy for resected cholangiocarcinoma remains controversial. National guidelines stratify recommendations based on margin status, though few studies are currently available for reference.MethodsData was abstracted on all patients with definitive resections of cholangiocarcinoma at our institution between 2000 and 2013. Adjuvant chemoradiation consisted of 45 Gy delivered to elective nodal regions and 50.4-54 Gy to the surgical bed with concurrent fluoropyrimidine-based chemotherapy. Subgroup analyses were performed delineated by margin status.ResultsCurative resection was performed on 95 patients followed by adjuvant chemoradiation in 23/95 (24%) and observation in 72/95 (76%) with a median follow-up of 21.7 months. For those receiving adjuvant chemoradiation the median overall survival was 30.2 months compared with 26.3 months for those observed (p = 0.0695). In a multivariable model controlling for other prognostic factors, adjuvant chemoradiation was associated with improved disease-free survival (HR 0.50, p = 0.03) and overall survival (HR 0.37, p = 0.004). In multivariable models stratified by margin status, adjuvant chemoradiation was associated with improved overall survival following both margin-negative (HR 0.34, p = 0.035) and margin-positive (HR 0.15, p = 0.003) resections.ConclusionsOverall survival was improved with adjuvant chemoradiation following either margin-negative or margin-positive resections, which is not currently reflected in national guidelines.
| S-EPMC5061024 | biostudies-literature