Ocular melanoma and colorectal carcinoma are two malignancies with a predilection for metastasizing to the liver. Patients with liver-only or liver-dominant metastatic disease might be eligible for... Show moreOcular melanoma and colorectal carcinoma are two malignancies with a predilection for metastasizing to the liver. Patients with liver-only or liver-dominant metastatic disease might be eligible for locoregional or so-called liver-directed therapy. Liver-directed therapies include surgery and thermal ablation, as well as various arterial therapies such as percutaneous hepatic perfusion with melphalan (M-PHP). Although M-PHP is well-tolerated by most patients, hematologic events due to bone marrow suppression were quite common in M-PHP using the first-generation filter. In an attempt to reduce bone marrow suppression by increasing the filter extraction rate, a new second-generation filter (GEN 2 filter) was developed and became commercially available in 2012. In this thesis, it was demonstrated that M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile and it seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. This thesis contributes to the scientific evidence showing that M-PHP using the GEN 2 filter is an effective treatment for liver metastases from ocular melanoma. In contrast, M-PHP seems to have no additional value in the current treatment of unresectable liver metastases from colorectal carcinoma. Show less
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 ... Show morePurpose 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. Show less
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... Show morePurpose 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 ( >= 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liverdominant 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. Show less
Tong, T.M.L.; Kooij, M.K. van der; Speetjens, F.M.; Erkel, A.R. van; Meer, R.W. van der; Lutjeboer, J.; ... ; Kapiteijn, E. 2022
Background: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal... Show moreBackground: 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. Show less
Meijer, T.S.; Burgmans, M.C.; Fiocco, M.; Geus-Oei, L.F. de; Kapiteijn, E.; Leede, E.M. de; ... ; Vahrmeijer, A.L. 2019
This thesis is a contribution to the fight against cancer. It focuses on patients with hepatic malignancies. Interventional oncology (IO) is a rapidly evolving sub-speciality of interventional... Show moreThis thesis is a contribution to the fight against cancer. It focuses on patients with hepatic malignancies. Interventional oncology (IO) is a rapidly evolving sub-speciality of interventional radiology with an increasing role in the management of cancer patients. Over the past two decades interventional radiologists together with scientists have ridding the tidal wave of technological innovation to introduce multiple novel cancer treatments. IO procedures are minimally invasive, targeted therapies that are associated with low complication rates and short hospital admissions. Such therapies offer clear advantages over surgical procedures and intense chemotherapeutic regimes that put a larger burden on both the health care budget and patients. In this thesis several novel minimally invasive therapies are investigated. PART I focuses on image-guided percutaneous RFA. PART II discusses transarterial liver therapies, such as transarterial chemoembolisation, radioembolisation and percutaneous hepatic perfusion. PART III investigates ways to improve the management of patients that undergo IO procedures. Show less
Liver malignancies are a major burden of disease worldwide. The long-term prognosis for patients with unresectable tumors remains poor, despite advances in systemic chemotherapy, targeted agents,... Show moreLiver malignancies are a major burden of disease worldwide. The long-term prognosis for patients with unresectable tumors remains poor, despite advances in systemic chemotherapy, targeted agents, and minimally invasive therapies such as ablation, chemoembolization, and radioembolization. Thus, the demand for new and better treatments for malignant liver tumors remains high. Surgical isolated hepatic perfusion (IHP) has been shown to be effective in patients with various hepatic malignancies, but is complex, associated with high complication rates and not repeatable. Percutaneous isolated liver perfusion (PHP) is a novel minimally invasive, repeatable, and safer alternative to IHP. PHP is rapidly gaining interest and the number of procedures performed in Europe now exceeds 200. This review discusses the indications, technique and patient management of PHP and provides an overview of the available data. Show less
