Analysis of patient's X-ray exposure in hepatic chemosaturation procedures: a single center experience.

BACKGROUND: Hepatic chemosaturation is a technique in which a high dose of the chemotherapeutic agent melphalan is administered directly into the liver while limiting systemic side effects. We reviewed our institutional experience regarding patient's X-ray exposure caused by the procedure. METHODS: Fifty-five procedures, performed between 2016 and 2020 in 18 patients by three interventional radiologists (radiologist), were analyzed regarding the patient's exposure to radiation. Dose-area-product (DAP) and fluoroscopy time (FT) were correlated with the experience of the radiologist and whether the preprocedural evaluation (CS-EVA) and the procedure were performed by the same radiologist. Additionally, the impact of previous liver surgery on DAP/FT was analyzed. RESULTS: Experienced radiologist require less DAP/FT (50 ± 18 Gy*cm2/13.2 ± 3.84 min vs. 69 ± 20 Gy*cm2/15.77 ± 7.82 min; p < 0.001). Chemosaturations performed by the same radiologist who performed CS-EVA required less DAP/FT (41 ± 12 Gy*cm2/11.46 ± 4.41 min vs. 62 ± 11 Gy*cm2/15.55 ± 7.91 min; p < 0.001). Chemosaturations in patients with prior liver surgery with involvement of the inferior cava vein required significantly higher DAP/FT (153 ± 27 Gy*cm2/25.43 ± 4.57 min vs. 56 ± 25 Gy*cm2/14.44 ± 7.55 min; p < 0.001). CONCLUSION: There is a significant learning curve regarding the procedure of hepatic chemosaturation. Due to dose reduction the evaluation and chemosaturation therapy should be performed by the same radiologist. Procedures in patients with previous liver surgery require higher DAP/FT.

Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival.

OBJECTIVES: Cholangiocarcinoma is the second most common primary liver tumour with a poor overall prognosis. Percutaneous hepatic perfusion (PHP) is a directed therapy for primary and secondary liver malignancies, and its efficacy and safety have been shown in different entities. The purpose of this study was to prove the safety and efficacy of PHP in patients with unresectable intrahepatic cholangiocarcinoma (iCCA). PATIENTS AND METHODS: We retrospectively reviewed data from 15 patients with unresectable iCCA treated with PHP in nine different hospitals throughout Europe. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Adverse events (AEs) and toxicity were evaluated. RESULTS: Fifteen patients were treated with 26 PHPs. ORR was 20%, disease control was achieved in 53% after the first PHP. Median OS was 26.9 months from initial diagnosis and 7.6 months from first PHP. Median PFS and hPFS were 122 and 131 days, respectively. Patients with liver-only disease had a significantly longer median OS compared to patients with locoregional lymph node metastases (12.9 vs. 4.8 months, respectively; p < 0.01). Haematological toxicity was common, but manageable. No AEs of grade 3 or 4 occurred during the procedures. DISCUSSION: PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with iCCA, especially in non-metastatic disease. KEY POINTS: • Percutaneous hepatic perfusion (PHP) offers an additional locoregional therapy strategy for the treatment of unresectable primary or secondary intrahepatic malignancies. • PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with intrahepatic cholangiocarcinoma (iCCA), especially in non-metastatic disease. • Side effects seem to be tolerable and comparable to other systemic or local treatment strategies.

Chemosaturation with percutaneous hepatic perfusion for unresectable metastatic melanoma or sarcoma to the liver: a single institution experience.

BACKGROUND: Patients with unresectable melanoma or sarcoma hepatic metastasis have a poor prognosis with few therapeutic options. Percutaneous hepatic perfusion (PHP), isolating and perfusing the liver with chemotherapy, provides a promising minimally invasive management option. We reviewed our institutional experience with PHP. METHODS: We retrospectively reviewed patients with unresectable melanoma or sarcoma hepatic metastasis treated with PHP from 2008 to 2013 and evaluated therapeutic response, morbidity, hepatic progression free survival (hPFS), and overall survival (OS). RESULTS: Ten patients were treated with 27 PHPs (median 3). Diagnoses were ocular melanoma (n = 5), cutaneous melanoma (n = 3), unknown primary melanoma (n = 1), and sarcoma (n = 1). Median hPFS was 240 days, 9 of 10 patients (90%) demonstrated stable disease or partial response to treatment. At a median follow up of 11.5 months, 4 of 10 (40%) remain alive. There were no perioperative mortalities. Myelosuppresion was the most common morbidity, managed on an outpatient basis with growth factors. The median hospital stay was 3 days. CONCLUSIONS: Patients with metastatic melanoma and sarcoma to the liver have limited treatment options. Our experience with PHP demonstrates promising results with minimal morbidity and should be considered (pending FDA approval) as a management option for unresectable melanoma or sarcoma hepatic metastasis.

Isolated hepatic perfusion for metastatic melanoma.

Unresectable hepatic metastases from melanoma present a challenge to the physician. Although there have been advances in systemic therapies for patients with metastatic cutaneous melanoma to the liver, the overall prognosis is poor and is worse in patients with metastatic ocular melanoma. Isolated hepatic perfusion, open or percutaneous, allows high doses of cytotoxic chemotherapy to be delivered directly to the liver while minimizing systemic exposure, and has emerged as a viable treatment options for these complex patients.

Use of partial venovenous cardiopulmonary bypass in percutaneous hepatic perfusion for patients with diffuse, isolated liver metastases: a case series.

OBJECTIVES: Diffuse isolated liver metastases are the dominant mode of tumor progression in a number of cancers and present a major treatment challenge for oncologists. An experimental treatment, percutaneous hepatic perfusion (PHP), utilizes partial venovenous cardiopulmonary bypass to allow administration of high-dose chemotherapy directly and solely to the liver with filtration of chemotherapeutic agents from the blood prior to its return to the systemic circulation, thereby minimizing toxic systemic effects. The following case series describes the management of 5 patients with metastatic melanoma undergoing serial PHPs. DESIGN: A single-center experience from a national multi-center random-assignment trial comparing PHP to best alternative care (BAC) in patients with diffuse melanoma liver metastases. SETTING: A tertiary care hospital. PARTICIPANTS: Five patients with metastatic melanoma to the liver. INTERVENTION: Five patients underwent a total of fifteen PHPs using a venovenous bypass circuit with hemofiltration, receiving hepatic intra-arterial melphalan, 3 mg/kg of ideal body weight, for 30 minutes with a total of 60 minutes of hemofiltration. MEASUREMENTS AND MAIN RESULTS: Five patients tolerated the procedure well with transient hemodynamic and metabolic changes. CONCLUSIONS: In patients with diffuse isolated liver metastases, PHP is a safe and well-tolerated procedure that can be performed more than once and is associated with marked anti-tumor activity in some patients.

Quality of Life Analysis of Patients Treated with Percutaneous Hepatic Perfusion for Uveal Melanoma Liver Metastases.

PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP. MATERIALS AND METHODS: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0. RESULTS: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia. CONCLUSION: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.

Successful application of chemosaturation with percutaneous hepatic perfusion in metastatic uveal melanoma patient progressing after systemic treatment options: a case report.

Uveal melanoma (UM) is a rare subtype of melanoma, accounting for less than 5% of all melanoma cases. Metastatic UM differs notably from cutaneous melanoma, exhibiting variations in etiology, prognosis, driver mutations, metastatic patterns, and poor responses to immune checkpoint inhibitors (ICI). Beyond local treatment options, such as resection, radiation therapy, and enucleation, and systemic treatments, such as ICIs, the approval of tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T-cell engager, marks a breakthrough in treating HLA-A*02:01 metastatic UM. Despite the advancements in treatment options, the long-term survival rates remain inadequate. We report a patient with metastatic UM who previously received ICI and progressed on tebentafusp treatment but subsequently exhibited a remarkable response to local treatment targeting liver metastasis. Such observations highlight the significance of exploring sequential therapeutic strategies for advanced UM, offering potential avenues to enhance treatment efficacy and patient prognosis.

Combining Melphalan Percutaneous Hepatic Perfusion with Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma: First Safety and Efficacy Data from the Phase Ib Part of the Chopin Trial.

PURPOSE: To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS. MATERIALS AND METHODS: Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs. RESULTS: Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months). CONCLUSION: Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg.

New perspectives in unresectable cholangiocarcinoma? Evaluation of chemosaturation with percutaneous hepatic perfusion as a palliative treatment option.

Cholangiocarcinoma (CCA) are the second most common primary liver tumors and carry a dismal prognosis. Chemosaturation with percutaneous hepatic perfusion (PHP) is a palliative, intra-arterial therapeutic approach that provides a high dose chemotherapy of the liver with reduced systemic exposure. Aim of this retrospective, monocentric study was to analyze PHP as a palliative treatment for unresectable CCA. Toxicity, adverse events and complications were classified using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1). Median overall survival (mOS), median progression-free survival (mPFS) and hepatic mPFS (mhPFS) were computed using Kaplan-Meier estimation. In total 17 patients were treated with 42 PHP between 10/2014 and 09/2020. No significant complications occurred during the interventions. mOS was 27.6 (interquartile range (IQR) 16.5-37) months from first diagnosis and 9.9 (IQR 3.8-21) months from first PHP. mPFS was 4 (IQR 2-7) and mhPFS was 4 (IQR 3-10) months. ORR was 25% and DCR 75%. Significant, but transient hematotoxicity was frequent with grade 3/4 thrombopenia after 50%, leukopenia after 26% and anaemia after 21% of the interventions. An increase of transaminases (AST increase after 21% and ALT increase after 14% of the PHP) developed more often than a deterioration of the liver synthesis capacity. Salvage treatment with PHP has the potential to prolong life in selected patients with unresectable, refractory cholangiocarcinoma. The interventional procedure is safe. Post-interventional toxicity is frequent but manageable.

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PURPOSE: Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP. MATERIALS AND METHODS: All patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0). RESULTS: Thromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine. CONCLUSION: Our retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Prognostic Factors for Postoperative Bleeding Complications and Prolonged Intensive Care after Percutaneous Hepatic Chemosaturation Procedures with Melphalan.

Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.

Isolated hyperthermic perfusions for cutaneous melanoma in-transit metastasis of the limb and uveal melanoma metastasis to the liver.

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy.

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial.

BACKGROUND: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease. METHODS: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves. DISCUSSION: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT04283890 . Registered as per February 2020 - Retrospectively registered. EudraCT registration number: 2018-004248-49. Local MREC registration number: NL60508.058.19.

Predictive Parameters in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan for Unresectable Liver Metastases from Uveal Melanoma: A Retrospective Pooled Analysis.

PURPOSE: The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively pooling data from three centers. MATERIALS AND METHODS: Retrospective analysis including patients ([Formula: see text] 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liver-dominant or liver-only metastases from UM. Predictors for OS were assessed using uni- and multivariate analyses. Other study outcome measures were response rate, progression-free survival (PFS), liver progression-free survival (LPFS), overall survival (OS) and complications according to CTCAEv5.0. RESULTS: In total, 101 patients (47.5% males; median age 59.0 years) completed a minimum of one M-PHP. At a median follow-up time of 15.0 months, complete response (CR), partial response (PR), stable disease (SD) and progressive disease were seen in five (5.0%), 55 (54.5%), 30 (29.7%) and 11 (10.9%) patients, respectively, leading to a 89.1% disease control rate. Median PFS, LPFS and OS were 9.0, 11.0 and 20.0 months, respectively. Survival analyses stratified for radiological response demonstrated significant improved survival in patients with CR or PR and SD category. Treatment of the primary tumor with radiotherapy, ≥ 2 M-PHP and lactate dehydrogenase (LDH) < 248 U/L were correlated with improved OS. Thirty-day mortality was 1.1% (n = 2). Most common complication was hematological toxicity (self-limiting in most cases). CONCLUSION: M-PHP is safe and effective in patients with UM liver metastases. Achieving CR, PR or SD is associated with improved survival. Primary tumor treatment with radiotherapy, normal baseline LDH and > 1 M-PHP cycles are associated with improved OS.

Initiation of Chemosaturation With Percutaneous Hepatic Perfusion Program in Interventional Radiology Department.

Objectives Chemosaturation with percutaneous hepatic perfusion (PHP) is a relatively new minimally-invasive liver-directed therapy, which aims to deliver high-dose chemotherapy into the liver with low systemic side effects. Initial studies showed promising results, especially in the treatment of metastatic uveal melanoma. But unfamiliarity of the interventional radiologists prevents its widespread implantation in clinical routine. This study aimed to outline how to initiate a PHP program and report initial results. Methods We retrospectively reviewed all patients who underwent chemosaturation with PHP in our institution between March 2016 and February 2017 and their follow-up results till October 2018. Patient demographics, procedural characteristics, clinical and imaging results, and complications were evaluated. Additionally, modifications regarding infrastructure and procedure techniques were described. Results A total of three patients (two females and one male) with a mean age of 59 underwent six PHP procedures. The primary disease was colorectal carcinoma in one patient and uveal melanoma in two patients. The technical success rate was 100% and the mean melphalan dose was 190.8 mg. No procedural death was observed. Patients were hospitalized for a mean of 3.3 days after procedures. Grade 3 and 4 complications were seen after 50% and 33.3% of procedures, respectively. Two patients showed partial response and the other patient showed stable disease after procedures. Mean hepatic progression-free survival was 10.8 months. Overall survival from the first procedure was 14.8 months in our cohort. Conclusion Our results show that chemosaturation with PHP offers a promising minimally invasive treatment option in patients with unresectable liver metastases. The technical challenges of PHP can be easily handled by an experienced interventional radiology (IR) team. It is a relatively safe procedure and its toxicities are usually hematological and can be manageable with close surveillance and appropriate medical therapies.

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.

A New Option for the Treatment of Intrahepatic Cholangiocarcinoma: Percutaneous Hepatic Perfusion with CHEMOSAT Delivery System.

Liver metastases are a major management problem; since they occur in tumors of different origin, they are often multiple, difficult to visualize and can lie dormant for many years. Patients with liver metastases usually die of their disease, mostly due to liver failure, since systemic treatments are unable to eradicate micro-metastasis, and interventional loco-regional procedures cannot treat all existing ones. Cholangiocarcinoma (CCA) is the second most common primary liver tumor, showing a poor overall prognosis. When resection is not possible, treatment options include tumor-focused or local ablative therapy, organ-focused or regional therapy and systemic therapy. We reviewed available loco-regional therapeutic options, with particular focus on the CHEMOSAT® Melphalan/Hepatic Delivery System (CS-HDS), which is uniquely positioned to perform a percutaneous hepatic perfusion (PHP), in order to treat the entire liver as a standalone or as complementary therapy. This system isolates the liver circulation, delivers a high concentration of chemotherapy (melphalan), filters most chemotherapy out of the blood and is a repeatable procedure. Most CS-HDS benefits are demonstrated in liver-predominant diseases, like liver metastasis from uveal melanoma (UM), hepatocarcinoma (HCC) and CCA. More than 650 procedures have been performed in Europe to date, mostly to treat liver metastases from UM. In CCA, experience is still limited, but retrospective analyses have been reported, while phase II and III studies are closed, waiting for results or ongoing.

Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases.

Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.

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.

Locoregional Therapies for the Treatment of Uveal Melanoma Hepatic Metastases.

Uveal melanoma is the most common primary intraocular malignant tumor in adults. Approximately 50% of patients develop metastatic disease of which greater than 90% of patients develop hepatic metastases. Following the development of liver tumors, overall survival is dismal with hepatic failure being the cause of death in nearly all cases. To prolong survival for patients with metastatic uveal melanoma, controlling the growth of hepatic tumors is essential. This article will discuss imaging surveillance following the diagnosis of primary uveal melanoma; locoregional therapies used to control the growth of hepatic metastases including chemoembolization, immunoembolization, radioembolization, percutaneous hepatic perfusion, and thermal ablation; as well as currently available systemic treatment options for metastatic uveal melanoma.