ABSTRACT
BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). METHODS/DESIGN: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. DISCUSSION: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01785316 (registered 1 February 2013). EudraCT registration number: 2013-000564-29.
Subject(s)
Chemotherapy, Cancer, Regional Perfusion , Clinical Protocols , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Melanoma/pathology , Uveal Neoplasms/pathology , Chemotherapy, Cancer, Regional Perfusion/adverse effects , Female , Humans , Liver Neoplasms/mortality , Male , Prospective StudiesABSTRACT
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
Subject(s)
DNA Repair Enzymes/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/metabolism , Nucleotides/metabolism , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Animals , Catalytic Domain , Cell Death/drug effects , Cell Survival/drug effects , Crystallization , DNA Damage , DNA Repair Enzymes/chemistry , DNA Repair Enzymes/metabolism , Deoxyguanine Nucleotides/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Molecular Targeted Therapy , Neoplasms/pathology , Oxidation-Reduction/drug effects , Phosphoric Monoester Hydrolases/chemistry , Phosphoric Monoester Hydrolases/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Pyrophosphatases/antagonists & inhibitors , Reproducibility of Results , Xenograft Model Antitumor Assays , Nudix HydrolasesABSTRACT
PURPOSE: The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity. MATERIALS AND METHODS: A retrospective follow-up of all patients (n = 163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register. RESULTS: Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II-III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity. CONCLUSION: We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.
Subject(s)
Chemotherapy, Cancer, Regional Perfusion , Hyperthermia, Induced , Melanoma/therapy , Skin Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/administration & dosage , Combined Modality Therapy , Extremities , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Melanoma/pathology , Melphalan/administration & dosage , Middle Aged , Perfusion , Skin Neoplasms/pathology , Tumor Necrosis Factor-alpha/administration & dosage , Young AdultABSTRACT
PURPOSE: Isolated limb perfusion (ILP) with hyperthermia is an effective treatment for in-transit metastases of malignant melanoma in the extremities. Preclinical studies have shown that hyperthermia may induce an immunogenic death of tumour cells. We therefore decided to study whether ILP may induce tumour-specific immune responses in the clinical setting. METHOD: The number of Melan-A/Mart-1 specific CD8+ T cells, as well as other phenotypically different immune cells, was recorded in peripheral blood in 12 HLA-A2+ patients with in-transit metastases undergoing hyperthermic ILP with melphalan. RESULTS: All patients underwent ILP without any complication and with an overall response rate of 83%. No substantial changes in the number of circulating T-cells, B-cells, NK-cells or monocytes were observed during follow-up. Four out of 12 patients showed an elevation of Melan-A+ CD8+ T-cells 4 weeks after ILP. CONCLUSION: We here report our preliminary observations that a small increase in tumour-specific T-cells could be seen in a subpopulation of patients after ILP. However, much more work is necessary to fully delineate the systemic immune response to hyperthermic ILP.
