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.

Efficacy and tolerability of chemosaturation in patients with hepatic metastases from uveal melanoma.

BACKGROUND: Patients with hepatic metastatic uveal melanoma still have a poor outcome. PURPOSE: To evaluate overall survival (OS), progression-free survival (PFS), and response predictors in these patients treated with chemosaturation by percutaneous hepatic perfusion with melphalan (CS-PHP). MATERIAL AND METHODS: Between June 2015 and March 2020, a total of 29 patients (median age 69.7 years; age range 30-81 years; 60% women; median BMI 25.7 kg/m2; range 18.7-35.3kg/m2; 1-6 procedures per patient) were treated with 53 CS-PHPs. All patients received cross-sectional imaging for initial and follow-up examinations. Baseline tumor load, extrahepatic tumor load, tumor response, PFS, and OS were assessed. Non-parametric statistics were used. RESULTS: After the initial CS-PHP, a partial response was observed in 11 patients (41%), stable disease in 12 patients (44%) and progressive disease in 4 patients (15%); two patients died before the response was evaluated. After initial CS-PHP, median OS was 12.9 ± 7.4 months and median PFS was 7.1 ± 7.4 months. OS after one year was 50%. After the second CS-PHP, median PFS was 7.9 ± 5.7 months. Seven patients had a liver tumor burden >25%, associated with a significantly shorter OS (6.0 ± 2.4 vs. 14.1 ± 12.7 months; P = 0.008). At the time of first CS-PHP, 41% (12/29) of the patients had extrahepatic metastases that did not affect OS (11.1 ± 8.4 months vs. 12.9 ± 13.6 months; P = 0.66). CONCLUSION: CS-PHP is a safe and effective treatment for the hepatic metastatic uveal melanoma, especially for patients with a hepatic tumor burden <25%.

Over 12 Years Single Institutional Experience Performing Percutaneous Hepatic Perfusion for Unresectable Liver Metastases.

Patients with unresectable hepatic metastases, from uveal or ocular melanoma, are challenging to treat with an overall poor prognosis. Although over the past decade significant advances in systemic therapies have been made, metastatic disease to the liver, especially from uveal melanoma, continues to be a poor prognosis. Percutaneous hepatic perfusion (PHP) is a safe, viable treatment option for these patients. PHP utilizes high dose chemotherapy delivered directly to the liver while minimizing systemic exposure and can be repeated up to 6 times. Isolation of the hepatic vasculature with a double-balloon catheter allows for high concentration cytotoxic therapy to be administered with minimal systemic adverse effects. A detailed description of the multidisciplinary treatment protocol used at an institution with over 12 years of experience is discussed and recommendations are given. A dedicated team of a surgical or medical oncology, interventional radiology, anesthesiology and a perfusionist allows PHP to be repeatedly performed as a safe treatment strategy for unresectable hepatic metastases.

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.

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively. RESULTS: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9). CONCLUSIONS: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

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.

[Anesthesiological and postinterventional management in percutaneous hepatic melphalan perfusion (chemosaturation)]. / Anästhesiologisches und postinterventionelles Management bei perkutaner hepatischer Melphalanperfusion (Chemosaturation).

Percutaneous hepatic melphalan perfusion (PHMP) is a last-line treatment of inoperable primary or secondary liver tumors. Selective perfusion and saturation (chemosaturation) of the liver with the chemotherapeutic agent melphalan is performed via catheterization of the hepatic artery without affecting the rest of the body with its cytotoxic properties. Using an extracorporeal circulation and balloon occlusion of the inferior vena cava, the venous hepatic blood is filtered and returned using a bypass procedure. During the procedure, considerable circulatory depression and coagulopathy are frequent. The purpose of this article is to review the anesthesiological and postprocedural management of patients undergoing PHMP with consideration of the pitfalls and special circumstances.

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.

Selective Internal Radiotherapy (SIRT) and Chemosaturation Percutaneous Hepatic Perfusion (CS-PHP) for Metastasized Uveal Melanoma: A Retrospective Comparative Study.

Even with liver-targeted therapies, uveal melanoma with hepatic metastasis remains a challenge. The aim of this study was to compare the outcome of patients treated with either SIRT or CS-PHP. We included 62 patients with hepatic metastasized uveal melanoma (n = 34 with SIRT, receiving 41 cycles; n = 28 with CS-PHP, receiving 56 cycles) that received their treatments between 12/2013 and 02/2020 at a single center. We evaluated their response according to the RECIST 1.1, as well as progression-free survival (PFS) and overall survival (OS), after the initiation of the first cycle of the liver-directed treatment using Cox regression, adjusted via propensity score analysis for confounders, including the amount of hepatic involvement. The disease control rate was 18% for SIRT and 30% for CS-PHP. The median (range) of PFS was 127.5 (19-1912) days for SIRT and 408.5 (3-1809) days for CS-PHP; adjusted Cox regression showed no significant difference (p = 0.090). The median (range) of OS was 300.5 (19-1912) days for SIRT and 516 (5-1836) days for CS-PHP; adjusted Cox regression showed a significant difference (p = 0.006). In our patient cohort, patients treated with CS-PHP showed a significantly longer OS than patients treated with SIRT. CS-PHP might therefore be preferable for patients with liver-dominant metastatic uveal melanoma.

Vascular Interventions in Oncology.

Vascular interventions are an important and established tool in the management of the oncology patient. The goal of these procedures may be curative, palliative or adjunctive in nature. Some of the common vascular interventions used in oncology include transarterial embolisation or chemoembolisation, selective internal radiation therapy, chemosaturation, venous access lines, superior vena cava stenting and portal vein embolisation. We provide an overview of the principles, technology and approach of vascular techniques for tumour therapy in both the arterial and venous systems. Arterial interventions are currently mainly used in the management of hepatocellular carcinoma. Transarterial embolisation, chemoembolisation and selective internal radiation therapy deliver targeted catheter-delivered treatments with the aim of reducing tumour burden, controlling tumour growth or increasing survival in patients not eligible for transplantation. Chemosaturation is a regional chemotherapy technique that delivers high doses of chemotherapy directly to the liver via the hepatic artery, while reducing the risks of systemic effects. Venous interventions are more adjunctive in nature. Venous access lines are used to provide a means of delivering chemotherapy and other medications directly into the bloodstream. Superior vena cava stenting is a palliative procedure that is used to relieve symptoms of superior vena cava obstruction. Portal vein embolisation is a procedure that allows hypertrophy of a healthy portion of the liver in preparation for liver resection. Interventional radiology-led vascular interventions play an essential part of cancer management. These procedures are minimally invasive and provide a safe and effective adjunct to traditional cancer treatment methods. Appropriate work-up and discussion of each patient-specific problem in a multidisciplinary setting with interventional radiology is essential to provide optimum patient-centred care.

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.

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.

Radial Artery Access for Hepatic Chemosaturation: The First Description of Technical Feasibility.

Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System, Delcath Systems Inc, Wilmington, Delaware) is an interventional radiology procedure that delivers high doses of melphalan, a chemotherapeutic agent, directly to the liver in patients with unresectable primary and secondary liver tumours. Traditionally, CS-PHP is delivered by arterial access via the femoral artery. However, there can be many risks and adverse effects associated with femoral artery punctures, such as retroperitoneal haemorrhage and haematoma formation. The monitoring and bed rest required following the removal of a femoral arterial catheter may also cause significant distress to patients as they remain immobile, potentially prolonging their stay in hospital. The radial artery is an alternative access point, with fewer reported adverse events and increased patient tolerance when compared with femoral access. This case report details the first reported use of Hepatic CHEMOSAT® therapy being delivered via the radial artery. Two patients received hepatic chemosaturation with no reported complications. This report demonstrates that access via the radial artery is a feasible alternative for the delivery of chemotherapy, which may reduce morbidity and the risks usually associated with femoral access.

Percutaneous isolated hepatic perfusion (chemosaturation) with melphalan following right hemihepatectomy in patients with cholangiocarcinoma and metastatic uveal melanoma: peri- and post-interventional adverse events and therapy response compared to a matched group without prior liver surgery.

To evaluate feasibility, frequency and severity of peri-procedural complications and post-procedural adverse events (AEs) in patients with advanced cholangiocarcinoma or liver metastasis of uveal melanoma and prior hemihepatectomy undergoing chemosaturation percutaneous hepatic perfusion (CS-PHP) and to analyze therapy response and overall survival compared to a matched group without prior surgery. CS-PHP performed between 10/2014 and 02/2018 were retrospectively assessed. To determine peri-procedural safety and post-procedural adverse events, hospital records and hematological, hepatic and biliary function were categorized using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (1-5; mild-death). Significance was tested using Wilcoxon signed-rank and Mann-Whitney U test. Kaplan-Meier estimation and log-rank test assessed survival. Overall 21 CS-PHP in seven patients (4/7 males; 52 ± 10 years) with hemihepatectomy (grouphemihep) and 22 CS-PHP in seven patients (3/7 males; 63 ± 12 years) without prior surgery (groupnoresection) were included. No complications occurred during the CS-PHP procedures. Transient changes (CTCAE grade 1-2) of liver enzymes and blood cells followed all procedures. In comparison, grouphemihep presented slightly more AEs grade 3-4 (e.g. thrombocytopenia in 57% (12/21) vs. 41% (9/22; p = 0.37)) 5-7 days after CS-PHP. These AEs were self-limiting or responsive to treatment (insignificant difference of pre-interventional to 21-45 days post-interventional values (p > 0.05)). One patient in grouphemihep with high tumor burden died eight days following CS-PHP. No deaths occurred in groupnoresection. In comparison, overall survival after first diagnosis was insignificantly shorter in groupnoresection (44.7(32-56.1) months) than in grouphemihep (48.3(34.6-72.8) months; p = 0.48). The severity of adverse events following CS-PHP in patients after hemihepatectomy was comparable to a matched group without prior liver surgery. Thus, the performance of CS-PHP is not substantially compromised by a prior hemihepatectomy.

Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience.

OBJECTIVE: To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma. MATERIAL AND METHODS: This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed. CONCLUSION: CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.

Safety of Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Liver Metastases from Ocular Melanoma Using the Delcath Systems' Second-Generation Hemofiltration System: A Prospective Non-randomized Phase II Trial.

PURPOSE: To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems' second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter. MATERIALS AND METHODS: A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03. RESULTS: A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4-21.7). CONCLUSIONS: M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Chemosaturation Percutaneous Hepatic Perfusion (CS-PHP) with Melphalan: Evaluation of 2D-Perfusion Angiography (2D-PA) for Leakage Detection of the Venous Double-Balloon Catheter.

PURPOSE: To evaluate the feasibility of 2D-perfusion angiography (2D-PA) for detecting leakage of the double-balloon catheter used for chemosaturation percutaneous hepatic perfusion (CS-PHP). MATERIALS AND METHODS: Overall, 112 CS-PHP (09/2015-09/2018) in 52 patients were retrospectively screened for leakage alongside the double-balloon catheter on standard venograms. Finally, 18 procedures with visually detected leakage were included. Fifteen consecutive procedures without leakage served as control. To evaluate 2D-PA for leakage detection, the acquired digital subtraction venograms were post-processed. For each balloon, two different target ROIs were evaluated to assess a possible impact of localization and shape of the ROIs. Time to peak (TTP), peak density (PD), area under the curve (AUC), and ratios of target ROI/reference ROIs (PDtROI/PDREF; AUCtROI/AUCREF; and TTPtROI/TTPREF) were calculated. RESULTS: Leakages were located as follows: 15/18 cranial and 3/18 caudal. At the cranial balloon both ROIs showed a significant decrease in PDtROI/PDREF and AUCtROI/AUCREF (ROI1: p < 0.0001; p < 0.0001; ROI2: p < 0.0001; p < 0.0001) and a significant increase in TTPtROI/TTPREF (ROI1: p = 0.0009; ROI2: p = 0.0003) after double-balloon correction. Following balloon adjustment, the 2D-PA ratios (PD and AUC) of the tested ROIs differed significantly (p < 0.05). The inter-individual comparison of the 2D-PA parameters of the group with leakage before balloon correction and the non-leakage group showed significantly different 2D-PA values for the cranial balloon in both ROIs (p < 0.05). No significant differences were found for the caudal balloon. CONCLUSION: 2D-PA provides a feasible tool for detecting leakages alongside the cranial portion of the double-balloon catheter used in CS-PHP. The shape and position of the ROIs used to assess perfusion and flow have an impact on the measurements.

Chemosaturation Percutaneous Hepatic Perfusion: A Systematic Review.

The Hepatic CHEMOSAT® Delivery System is an innovative medical device for the treatment of patients with unresectable primary liver tumors or unresectable hepatic metastases from solid organ malignancies. This system is used to perform chemosaturation percutaneous hepatic perfusion (CS-PHP), a procedure in which a high dose of the chemotherapeutic agent melphalan is delivered directly to the liver while limiting systemic exposure. In a clinical trial program, CS-PHP with melphalan significantly improved hepatic progression-free survival in patients with unresectable hepatic metastases from ocular or cutaneous melanoma. Clinically meaningful hepatic responses were also observed in patients with hepatocellular carcinoma or neuroendocrine tumors. Furthermore, the results of published studies and case reports demonstrated that CS-PHP with melphalan resulted in favorable tumor response rates in a range of tumor histologies (ocular or cutaneous melanoma, colorectal cancer, and hepatobiliary tumors). Analyses of the safety profile of CS-PHP revealed that the most common adverse effects were hematologic events (thrombocytopenia, anemia, and neutropenia), which were clinically manageable. Taken together, these findings indicate that CS-PHP is a promising locoregional therapy for patients with primary and secondary liver tumors and has a acceptable safety profile. FUNDING: Delcath Systems Inc., New York, NY, USA.

Percutaneous Isolated Hepatic Perfusion as a Treatment for Isolated Hepatic Metastases of Uveal Melanoma: Patient Outcome and Safety in a Multi-centre Study.

PURPOSE: Percutaneous isolated hepatic perfusion (PIHP) with Melphalan has been developed as a treatment for patients with isolated hepatic metastases of uveal melanoma. We discuss patient outcome and safety in a retrospective multi-centre study. MATERIALS AND METHODS: Between 2012 and 2016 18 patients with un-resectable isolated hepatic metastases of uveal melanoma received single or repeated PIHP with Melphalan (n = 35) at seven sites. Progression-free time, overall survival time (OS) and tumour response by means of RECIST 1.1 criteria were evaluated. Peri- and post-procedural adverse events (AE) were registered. Patients' life quality was assessed using four-point scale questionnaires. RESULTS: Of 18 patients, initial PIHP treatment resulted in partial response (PR) in eight, stable disease (SD) in seven and progressive disease (PD) in three cases. Nine patients underwent second PIHP with PR in eight cases and PD in one case. Six patients were evaluated after third PIHP with PR in five patients and SD in one patient. Two patients received fourth PIHP with PD in both cases. Median OS was 9.6 months (range 1.6-41.0 months). Median progression-free survival time was 12.4 months (range 0.9-41.0 months) with 1-year survival of 44%. Most common post-procedural AE grade 3 and 4 were temporary leukopenia (n = 11) and thrombocytopenia (n = 8). Patients' self-assessments showed good ratings for overall health and quality of life with only slight changes after PIHP, and a high degree of satisfaction with PIHP treatment. CONCLUSION: PIHP with Melphalan proved to be a relatively safe, minimal-invasive and repeatable treatment for patients with non-resectable hepatic metastases of uveal melanoma.