Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer

Purpose Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM. Materials and methods Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. Results A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable. Conclusion M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.

Percutaneous Hepatic Perfusion (PHP) with Melphalan in Liver-Dominant Metastatic Uveal Melanoma: The German Experience

Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection.

Immediate results of treatment of patients with metastatic uveal melanoma using isolated liver chemoperfusion. The first domestic experience

Introduction. Uveal melanoma is the most common primary intraocular tumor in adults. Despite some achievements in primary tumor treatment, 50% of patients develop distant metastases in various times (3 years to decades). Hematogenous spread is typical for uveal melanoma, and in 90% of the cases liver is the target. Median survival of patients with liver metastases is 4 to 9 months according to various researchers. And the result of treatment is extremely poor, unlike the results of skin melanoma treatment.The aim is to evaluate the immediate results of treatment of patients with uveal melanoma metastatic to the liver using isolated hepatic perfusion technique.Materials and methods. Considering a high risk of developing a metastatic liver disease in patients with uveal melanoma, local therapy is particularly interesting. This article describes the results of 10 metastatic uveal melanoma patients’ Isolated Hepatic Perfusion (IHP) Treatment. IHP was conducted using the standard methods with 100 mg of Melphalan for 60 min.Results and discussion. IHP treatment shows low complication rate. The data for response assessment is available on 9 out of 10 patients, because 10th patient received this treatment less than a month ago. Follow-ups a month after 9 patients underwent IHP showed an objective response to treatment in 6 patients (complete response in 1, partial response in 5 patients).Conclusion. The use of isolated liver chemoperfusion in a small group of patients according to the standard procedure allowed achieving an immediate response in 67% of cases.

Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function

Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.

Quantification of Liver Fat Content after Radiofrequency Ablation for Liver Cancer: Correlation with Hepatic Perfusion Disorders

Purpose: To quantitatively investigate the correlation between liver fat content and hepatic perfusion disorders (HPD) after radiofrequency ablation (RFA) for liver cancer using magnetic resonance imaging (MRI)-determined proton density fat fraction (PDFF). Materials and methods: A total of 150 liver cancer patients underwent liver MRI examination within one month after RFA and at four months after RFA. According to the liver fat content, they were divided into non-, mild, moderate, and severe fatty liver groups. The liver fat content and hepatic perfusion disorders were determined using PDFF images and dynamic contrast-enhanced MRI images. The relationship between the liver fat content and HPD was investigated. Results: At the first postoperative MRI examination, the proportion of patients in the nonfatty liver group with hyperperfused foci (11.11%) was significantly lower than that in the mild (30.00%), moderate (42.86%), and severe fatty liver (56.67%) groups (p < 0.05), whereas the proportions of patients with hypoperfused foci (6.67%, 7.5%, 5.71%, and 6.67%, respectively) were not significantly different among the four groups (p > 0.05). In the nonfatty liver group, the liver fat content was not correlated with hyperperfusion abnormalities or hypoperfusion abnormalities. By contrast, in the three fatty liver groups, the liver fat content was correlated with hyperperfusion abnormalities but was not correlated with hypoperfusion abnormalities. At the second postoperative MRI examination, six patients in the nonfatty liver group were diagnosed with fatty liver, including two patients with newly developed hyperperfusion abnormalities and one patient whose hypoperfusion abnormality remained the same as it was in the first postoperative MRI examination. Conclusion: There was a high correlation between the liver fat content and hyperperfusion abnormalities after RFA for liver cancer. The higher the liver fat content was, the higher the was risk of hyperperfusion abnormalities. However, there was little correlation between liver fat content and hypoperfusion abnormalities, and the increase in postoperative liver fat content did not induce or alter the presence of hypoperfused foci.

Repeated percutaneous hepatic perfusion with melphalan can maintain long-term response in patients with liver cancers

Chemosaturation (CS; CHEMOSAT®, Delcath Systems Inc.) temporarily administers melphalan into the liver by percutaneous hepatic perfusion (PHP). CS-PHP can effectively control growth in liver tumors, but efficacy and tolerability of sequential treatments are unclear. We analyzed outcomes of sequential CS-PHP treatment. Patients with either unresectable intrahepatic metastases of ocular melanoma (OM, n = 9), cholangiocarcinoma (CCA, n = 3), or hepatocellular carcinoma (HCC, n = 1) were recruited retrospectively. Response was assessed by tomography imaging. Ten patients (mean age 60 years) with more than one CS-PHP treatment were included. CS-PHP was administered 2–6 times in the OM patients, 3 times in the CCA, and the HCC patient received 6 treatments. Overall response rate (ORR) to CS-PHP was 80%, and stable disease was achieved in one patient. Median hepatic progression-free survival (hPFS) was 336 days (range 0–354) for OM, 251 days for the CCA patient, and 256 days for the HCC patient. At the end of observation (153–701 days after first CS-PHP), 6/10 patients were still alive (5/9 with OM, 0 with CCA, and 1 with HCC). Death cases were not related to CS-PHP. Adverse events were mostly hematologic, grade I-IV, and self-resolving. The liver function was not deteriorated by CS-PHP. We conclude that repeated CS-PHP treatments were effective and well tolerated in the long term.

Meta-Analysis of Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion as a Treatment for Uveal Melanoma Liver Metastases

Background: Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous hepatic perfusion (PHP), a minimally invasive technique, is available as well. PHP benefits from the fact that the procedure can be repeated and therefore possibly offers better survival. We conducted a systematic review and meta-analysis comparing both techniques. Methods: A systematic literature search was performed using the electronic databases of Scopus, MEDLINE, Web of Science, PubMed and Cochrane CENTRAL. A total of nine articles reporting on eight studies were included in the analysis. Individual survival data were extracted from each study. Results: The median overall survival (OS) was 17.1 months for IHP and 17.3 months for PHP. The median progression-free survival (PFS) was 7.2 months for IHP and 9.6 months for PHP. The median hepatic progression-free survival was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. Conclusion: There was no difference in OS or PFS between IHP and PHP for patients with uveal melanoma liver metastases, but patients have significantly less of a risk for complications and mortality following PHP.

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.