|
1
|
Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, Kazeminejad A. VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives. Life Sci 2024; 345:122563. [PMID: 38508233 DOI: 10.1016/j.lfs.2024.122563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.
Collapse
Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Armaghan Kazeminejad
- Department of Dermatology, Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences,Sari, Iran
| |
Collapse
|
|
2
|
Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era? J Neurooncol 2022; 158:471-480. [PMID: 35665462 DOI: 10.1007/s11060-022-04036-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/12/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS Mean age was 63 ± 15 years, 39% were female and 29% had BRAF-mutated tumors. Median overall survival after radiosurgery was 15.7 months (95% Confidence Interval 11.4-27.7) and 25 months in patients managed since 2015. Thirty-two patients survived [Formula: see text] 5 years from their initial SRS. BRAF mutation-targeted therapies showed a survival advantage in comparison to chemotherapy (p = 0.009), but not to immunotherapy (p = 0.09). In a multivariable analysis, both immunotherapy and the number of metastases at 1st SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
Collapse
|
|
3
|
Glitza IC, Smalley KSM, Brastianos PK, Davies MA, McCutcheon I, Liu JKC, Ahmed KA, Arrington JA, Evernden BR, Smalley I, Eroglu Z, Khushalani N, Margolin K, Kluger H, Atkins MB, Tawbi H, Boire A, Forsyth P. Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions. Pigment Cell Melanoma Res 2020; 33:527-541. [PMID: 31916400 PMCID: PMC10126834 DOI: 10.1111/pcmr.12861] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/26/2019] [Accepted: 01/03/2020] [Indexed: 01/31/2023]
Abstract
In February 2018, the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System Metastases in Tampa, Florida. The meeting included investigators from multiple academic centers and disciplines. A consensus summary of the progress and challenges in melanoma parenchymal brain metastases was published (Eroglu et al., Pigment Cell & Melanoma Research, 2019, 32, 458). Here, we will describe the current state of basic, translational, clinical research, and therapeutic management, for melanoma patients with leptomeningeal disease. We also outline key challenges and barriers to be overcome to make progress in this deadly disease.
Collapse
Affiliation(s)
- Isabella C. Glitza
- Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Keiran S. M. Smalley
- Melanoma Research Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | | | - Michael A. Davies
- Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Ian McCutcheon
- Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, TX, USA
| | - James K. C. Liu
- Department of Neuro-Oncology & Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Kamran A. Ahmed
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - John A. Arrington
- Head of Neuroradiology Section, Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Brittany R. Evernden
- Department of Neuro-Oncology & Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Inna Smalley
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Zeynep Eroglu
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Nikhil Khushalani
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Kim Margolin
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Harriet Kluger
- Department of Medical Oncology, Yale Cancer Center, New Haven, CT, USA
| | - Michael B. Atkins
- Department of Medical Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Hussein Tawbi
- Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Adrienne Boire
- Department of Neuro-Oncology, Memorial Sloan Kettering, New York, NY, USA
| | - Peter Forsyth
- Department of Neuro-Oncology & Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| |
Collapse
|
|
4
|
Becco P, Gallo S, Poletto S, Frascione MPM, Crotto L, Zaccagna A, Paruzzo L, Caravelli D, Carnevale-Schianca F, Aglietta M. Melanoma Brain Metastases in the Era of Target Therapies: An Overview. Cancers (Basel) 2020; 12:cancers12061640. [PMID: 32575838 PMCID: PMC7352598 DOI: 10.3390/cancers12061640] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/18/2022] Open
Abstract
Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.
Collapse
Affiliation(s)
- Paolo Becco
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
| | - Susanna Gallo
- Ospedale Mauriziano Umberto I-Largo Turati 62, 10128 Torino, Italy
- Correspondence:
| | - Stefano Poletto
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| | - Mirko Pio Manlio Frascione
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| | - Luca Crotto
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
| | - Alessandro Zaccagna
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
| | - Luca Paruzzo
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| | - Daniela Caravelli
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
| | - Fabrizio Carnevale-Schianca
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
| | - Massimo Aglietta
- Istituto di Candiolo, FPO - IRCCS - Str. Prov.le 142, km 3,95, 10060 Candiolo, Italy; (P.B.); (S.P.); (M.P.M.F.); (L.C.); (A.Z.); (L.P.); (D.C.); (F.C.-S.); (M.A.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| |
Collapse
|
|
5
|
Jung YJ, Tweedie D, Scerba MT, Greig NH. Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments. Front Cell Dev Biol 2019; 7:313. [PMID: 31867326 PMCID: PMC6904283 DOI: 10.3389/fcell.2019.00313] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/18/2019] [Indexed: 12/14/2022] Open
Abstract
Neuroinflammation is initiated when glial cells, mainly microglia, are activated by threats to the neural environment, such as pathogen infiltration or neuronal injury. Although neuroinflammation serves to combat these threats and reinstate brain homeostasis, chronic inflammation can result in excessive cytokine production and cell death if the cause of inflammation remains. Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that target the 3'-untranslated region (3'-UTR) of TNF-α mRNA, inhibiting TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs such as 3,6'-dithiothalidomide and adamantyl thalidomide derivatives, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression. In this review, we evaluate the role of neuroinflammation in neurodegenerative diseases, focusing specifically on the role of TNF-α in neuroinflammation, as well as appraise current research on the potential of IMiDs as treatments for neurological disorders.
Collapse
Affiliation(s)
- Yoo Jin Jung
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | | | | | - Nigel H. Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| |
Collapse
|
|
6
|
Nassif EF, Arsène-Henry A, Kirova YM. Brain metastases and treatment: multiplying cognitive toxicities. Expert Rev Anticancer Ther 2019; 19:327-341. [PMID: 30755047 DOI: 10.1080/14737140.2019.1582336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Thirty per cent of cancer patients develop brain metastases, with multiple combination or sequential treatment modalities available, to treat systemic or central nervous system (CNS) disease. Most patients experience toxicities as a result of these treatments, of which cognitive impairment is one of the adverse events most commonly reported, causing major impairment of the patient's quality of life. Areas covered: This article reviews the role of cancer treatments in cognitive decline of patients with brain metastases: surgery, radiotherapy, chemotherapy, targeted therapies, immunotherapies and hormone therapy. Pathological and molecular mechanisms, as well as future directions for limiting cognitive toxicities are also presented. Other causes of cognitive impairment in this population are discussed in order to refine the benefit-risk balance of each treatment modality. Expert opinion: Cumulative cognitive toxicity should be taken into account, and tailored to the patient's cognitive risk in the light of the expected survival benefit. Standardization of cognitive assessment in this context is needed in order to better appreciate each treatment's responsibility in cognitive impairment, keeping in mind disease itself impacts cognition in this context.
Collapse
Affiliation(s)
- Elise F Nassif
- a Department of Radiotherapy , Institut Curie , Paris , France
| | | | - Youlia M Kirova
- a Department of Radiotherapy , Institut Curie , Paris , France
| |
Collapse
|
|
7
|
Franchino F, Rudà R, Soffietti R. Mechanisms and Therapy for Cancer Metastasis to the Brain. Front Oncol 2018; 8:161. [PMID: 29881714 PMCID: PMC5976742 DOI: 10.3389/fonc.2018.00161] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/30/2018] [Indexed: 12/12/2022] Open
Abstract
Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60–70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a “piecemeal” resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other “druggable” alterations seen in up to 5% of NSCLC patients are the rearrangements of the “anaplastic lymphoma kinase” gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).
Collapse
Affiliation(s)
- Federica Franchino
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy
| | - Roberta Rudà
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy
| | - Riccardo Soffietti
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy
| |
Collapse
|
|
8
|
Nolan C, Deangelis LM. Overview of metastatic disease of the central nervous system. HANDBOOK OF CLINICAL NEUROLOGY 2018; 149:3-23. [PMID: 29307359 DOI: 10.1016/b978-0-12-811161-1.00001-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
In 2016, the American Society of Clinical Oncology reported that 1.7 million Americans were diagnosed with cancer; this number will rise to 2.3 million in the United States and 22 million worldwide in 2030. This rising need is being met by an explosion of new cancer therapies, including: immune checkpoint inhibitors, T-cell therapies, tumor vaccines, antiangiogenic therapies, and various targeted therapies. This armamentarium of targeted therapies has led to better systemic control of disease and longer patient overall survival (OS). The incidence of metastatic disease to the central nervous system (CNS) is rising as patients are living longer with these more effective systemic therapies. Prolonged OS allows increased time to develop CNS metastases. The CNS is also a sanctuary for metastatic tumor cells that are protected from full exposure to therapeutic concentrations of most anticancer agents by the blood-brain barrier, the tumor microenvironment, and immune system. In addition, CNS metastases often develop late in the course of the disease, so patients are frequently heavily pretreated, resulting in drug resistance. Although genomic profiling has led to more effective therapies for systemic disease, the same therapy may not be effective in treating CNS disease, not only due to failure of blood-brain barrier penetration, but from discordance between the molecular profile in systemic and CNS tumor.
Collapse
Affiliation(s)
- Craig Nolan
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
| | - Lisa M Deangelis
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| |
Collapse
|
|
9
|
Hargadon KM. Strategies to Improve the Efficacy of Dendritic Cell-Based Immunotherapy for Melanoma. Front Immunol 2017; 8:1594. [PMID: 29209327 PMCID: PMC5702020 DOI: 10.3389/fimmu.2017.01594] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 11/06/2017] [Indexed: 12/20/2022] Open
Abstract
Melanoma is a highly aggressive form of skin cancer that frequently metastasizes to vital organs, where it is often difficult to treat with traditional therapies such as surgery and radiation. In such cases of metastatic disease, immunotherapy has emerged in recent years as an exciting treatment option for melanoma patients. Despite unprecedented successes with immune therapy in the clinic, many patients still experience disease relapse, and others fail to respond at all, thus highlighting the need to better understand factors that influence the efficacy of antitumor immune responses. At the heart of antitumor immunity are dendritic cells (DCs), an innate population of cells that function as critical regulators of immune tolerance and activation. As such, DCs have the potential to serve as important targets and delivery agents of cancer immunotherapies. Even immunotherapies that do not directly target or employ DCs, such as checkpoint blockade therapy and adoptive cell transfer therapy, are likely to rely on DCs that shape the quality of therapy-associated antitumor immunity. Therefore, understanding factors that regulate the function of tumor-associated DCs is critical for optimizing both current and future immunotherapeutic strategies for treating melanoma. To this end, this review focuses on advances in our understanding of DC function in the context of melanoma, with particular emphasis on (1) the role of immunogenic cell death in eliciting tumor-associated DC activation, (2) immunosuppression of DC function by melanoma-associated factors in the tumor microenvironment, (3) metabolic constraints on the activation of tumor-associated DCs, and (4) the role of the microbiome in shaping the immunogenicity of DCs and the overall quality of anti-melanoma immune responses they mediate. Additionally, this review highlights novel DC-based immunotherapies for melanoma that are emerging from recent progress in each of these areas of investigation, and it discusses current issues and questions that will need to be addressed in future studies aimed at optimizing the function of melanoma-associated DCs and the antitumor immune responses they direct against this cancer.
Collapse
Affiliation(s)
- Kristian M. Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, United States
| |
Collapse
|
|
10
|
Gupta A, Roberts C, Tysoe F, Goff M, Nobes J, Lester J, Marshall E, Corner C, Wolstenholme V, Kelly C, Wise A, Collins L, Love S, Woodward M, Salisbury A, Middleton MR. RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt. Br J Cancer 2016; 115:1193-1200. [PMID: 27711083 PMCID: PMC5104891 DOI: 10.1038/bjc.2016.318] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 08/13/2016] [Accepted: 09/13/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases. METHODS In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials. RESULTS Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments. CONCLUSIONS The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.
Collapse
Affiliation(s)
- Avinash Gupta
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
| | - Corran Roberts
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK
| | - Finn Tysoe
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
| | - Matthew Goff
- Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Jenny Nobes
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich NR4 7UY, UK
| | - James Lester
- Sheffield Teaching Hospitals NHS Foundation Trust, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK
| | - Ernie Marshall
- Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Wirral CH63 4JY, UK
| | - Carie Corner
- Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK
| | - Virginia Wolstenholme
- Barts Health NHS Trust, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
| | - Charles Kelly
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne NE7 7DN, UK
| | - Adelyn Wise
- Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Linda Collins
- Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Sharon Love
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK
| | - Martha Woodward
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
| | - Amanda Salisbury
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
| | - Mark R Middleton
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
- Department of Oncology, NIHR Oxford Biomedical Research Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK
| |
Collapse
|
|
11
|
Kim MM, Parmar H, Cao Y, Pramanik P, Schipper M, Hayman J, Junck L, Mammoser A, Heth J, Carter CA, Oronsky A, Knox SJ, Caroen S, Oronsky B, Scicinski J, Lawrence TS, Lao CD. Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial: A TITE-CRM Phase I/II Clinical Trial. Transl Oncol 2016; 9:108-113. [PMID: 27084426 PMCID: PMC4833892 DOI: 10.1016/j.tranon.2015.12.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 12/22/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial.
Collapse
Affiliation(s)
- Michelle M Kim
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA.
| | - Hemant Parmar
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Yue Cao
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Priyanka Pramanik
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Matthew Schipper
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - James Hayman
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Larry Junck
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Aaron Mammoser
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Jason Heth
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Corey A Carter
- Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD, 20889, USA
| | - Arnold Oronsky
- InterWest Partners, 2710 Sand Hill Rd #200, Menlo Park, CA, 94025, USA
| | - Susan J Knox
- Stanford University School of Medicine, Radiation Oncology, 875 Blake Wilbur Dr Clinic D, Stanford, CA, 94305, USA
| | - Scott Caroen
- EpicentRx Inc., 800W El Camino Real, Suite 180, Mountain View, CA, 94040, USA
| | - Bryan Oronsky
- EpicentRx Inc., 800W El Camino Real, Suite 180, Mountain View, CA, 94040, USA
| | - Jan Scicinski
- EpicentRx Inc., 800W El Camino Real, Suite 180, Mountain View, CA, 94040, USA
| | - Theodore S Lawrence
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Christopher D Lao
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA
| |
Collapse
|
|
12
|
|
|
13
|
Abstract
The discovery of the BRAFV600 mutation and the development of targeted therapies directed against this mutation as well as effective immunotherapies with durable benefits have revolutionized the treatment of patients with melanoma. Nonetheless, the frequent occurrence of brain metastases in patients with advanced melanoma represents a significant obstacle to long-term, high quality survival. The application of stereotactic radiation therapy has provided an opportunity to control brain metastases in the majority of patients with metastatic melanoma reducing the impact of these lesions on morbidity and mortality and enabling patients to receive and potentially benefit from these novel systemic treatments. Encouragingly, several of these novel new therapies have shown antitumor activity against CNS metastases that approach that seen against extracranial disease. As a consequence, several effective treatment options are now available for patients with melanoma brain metastases. With these tools in hand, it is anticipated that further investigation into the optimal sequence and/or combination of systemic therapies and local therapies along with multidisciplinary team practice will continue to improve the outcome of patients with this previously life-limiting disease complication.
Collapse
Affiliation(s)
- Sekwon Jang
- Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA
| | - Michael B Atkins
- Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA.
| |
Collapse
|
|
14
|
Long GV, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma: the emerging role of systemic therapies. Am Soc Clin Oncol Educ Book 2015:393-8. [PMID: 23714558 DOI: 10.14694/edbook_am.2013.33.393] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Melanoma brain metastases are common, difficult to treat, and carry a poor prognosis. Until recently, systemic therapy was ineffective. Local therapy (including surgery, stereotactic radiotherapy, and whole brain radiotherapy) was considered the only option for a chance of disease control in the brain, and was highly dependent on the patient's performance status and age, number and size of brain metastases, and the presence of extracranial metastases. Since 2010, three drugs have demonstrated activity in progressing or "active" brain metastases including the anti-CTLA4 antibody ipilimumab (phase II study of 72 patients), and the BRAF inhibitors dabrafenib (phase II study of 172 patients, both previously treated and untreated brain metastases) and vemurafenib (a pilot study of 24 patients with heavily pretreated brain metastases). The challenge and unanswered question for clinicians is how to sequence all the available therapies, both local and systemic, to optimize the patient's quality of life and survival. This is an area of intense clinical research. The treatment of patients with melanoma brain metastases should be discussed by a multidisciplinary team of melanoma experts including a neurosurgeon, medical oncologist, and radiation oncologist. Important clinical features that help determine appropriate first line therapy include single compared with solitary brain metastasis, resectablity, BRAF mutation status of melanoma, rate of progression/performance status, and the presence of extracranial disease.
Collapse
Affiliation(s)
- Georgina V Long
- From the Melanoma Institute Australia, The University of Sydney, Sydney, Australia; University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
| | | |
Collapse
|
|
15
|
Goyal S, Silk AW, Tian S, Mehnert J, Danish S, Ranjan S, Kaufman HL. Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review. JAMA Oncol 2015; 1:668-76. [PMID: 26181286 PMCID: PMC5726801 DOI: 10.1001/jamaoncol.2015.1206] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
IMPORTANCE The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. OBJECTIVE To review the current evidence regarding the treatment of MBM from melanoma. EVIDENCE REVIEW The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included. FINDINGS Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. CONCLUSIONS AND RELEVANCE At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.
Collapse
Affiliation(s)
- Sharad Goyal
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Ann W. Silk
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Sibo Tian
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Janice Mehnert
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Shabbar Danish
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Sinthu Ranjan
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| | - Howard L. Kaufman
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School
| |
Collapse
|
|
16
|
|
|
17
|
Gibney GT, Gauthier G, Ayas C, Galebach P, Wu EQ, Abhyankar S, Reyes C, Guérin A, Yim YM. Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting. Cancer Med 2015; 4:1205-13. [PMID: 25991583 PMCID: PMC4559032 DOI: 10.1002/cam4.475] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 04/15/2015] [Accepted: 04/21/2015] [Indexed: 01/22/2023] Open
Abstract
Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0–1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan–Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5–10 mm vs. <5 mm) and number of brain metastases (≥5 vs. <2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. <2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥2 extracranial disease sites, progressive extracranial disease, and ≥5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.
Collapse
Affiliation(s)
| | | | | | | | - Eric Q Wu
- Analysis Group Inc., Boston, Massachusetts
| | | | | | | | - Yeun Mi Yim
- Genentech Inc., South San Francisco, California
| |
Collapse
|
|
18
|
OSTHEIMER CHRISTIAN, BORMANN CAROLINE, FIEDLER ECKHARD, MARSCH WOLFGANG, VORDERMARK DIRK. Malignant melanoma brain metastases: Treatment results and prognostic factors - a single-center retrospective study. Int J Oncol 2015; 46:2439-48. [DOI: 10.3892/ijo.2015.2970] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/27/2015] [Indexed: 11/06/2022] Open
|
|
19
|
Abstract
The worldwide incidence of melanoma continues to rise. It is a leading cause of cancer death and the second leading cause of loss of productive years of life. Although the diagnosis of melanoma is straightforward, there remain many controversies regarding treatment and surveillance. This chapter addresses important questions in melanoma treatment such as sentinel lymph node biopsy, what to do with a positive sentinel lymph node, margins of resection for melanoma, radiation for primary, nodal and metastatic melanoma, and routine use imaging. Through this chapter, the evidence for these controversial subjects and the barriers to resolution will be elucidated.
Collapse
Affiliation(s)
- Maria C Russel
- Department of Surgery, Emory University, Atlanta, GA, USA,
| | | |
Collapse
|
|
20
|
Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: An overview of the literature. Cancer Treat Rev 2014; 40:951-9. [DOI: 10.1016/j.ctrv.2014.05.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 05/16/2014] [Accepted: 05/19/2014] [Indexed: 11/24/2022]
|
|
21
|
Pan E, Yu D, Zhao X, Neuger A, Smith P, Chinnaiyan P, Yu HHM. Phase I study of bendamustine with concurrent whole brain radiation therapy in patients with brain metastases from solid tumors. J Neurooncol 2014; 119:413-20. [PMID: 24965340 DOI: 10.1007/s11060-014-1510-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 06/16/2014] [Indexed: 12/25/2022]
Abstract
A phase I study was conducted to evaluate the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD)/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at three dose levels (60, 80, and 100 mg/m(2)) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (six with non-small cell lung cancer, four with melanoma, one with breast cancer, and one with neuroendocrine carcinoma). The first two dose levels had three patients each, and the third dose level had six total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m(2). The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. The efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.
Collapse
Affiliation(s)
- Edward Pan
- Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, 5323 Harry Hines Blvd. ND3.300A, Dallas, TX, 75390-9186, USA,
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Kenchappa RS, Tran N, Rao NG, Smalley KS, Gibney GT, Sondak VK, Forsyth PA. Novel treatments for melanoma brain metastases. Cancer Control 2014; 20:298-306. [PMID: 24077406 DOI: 10.1177/107327481302000407] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The development of brain metastases is common in patients with melanoma and is associated with a poor prognosis. Treating patients with melanoma brain metastases (MBMs) is a major therapeutic challenge. Standard approaches with conventional chemotherapy are disappointing, while surgery and radiotherapy have improved outcomes. METHODS In this article, we discuss the biology of MBMs, briefly outline current treatment approaches, and emphasize novel and emerging therapies for MBMs. RESULTS The mechanisms that underlie the metastases of melanoma to the brain are unknown; therefore, it is necessary to identify pathways to target MBMs. Most patients with MBMs have short survival times. Recent use of immune-based and targeted therapies has changed the natural history of metastatic melanoma and may be effective for the treatment of patients with MBMs. CONCLUSIONS Developing a better understanding of the factors responsible for MBMs will lead to improved management of this disease. In addition, determining the optimal treatments for MBMs and how they can be optimized or combined with other therapies, along with appropriate patient selection, are challenges for the management of this disease.
Collapse
|
|
23
|
Owonikoko TK, Arbiser J, Zelnak A, Shu HKG, Shim H, Robin AM, Kalkanis SN, Whitsett TG, Salhia B, Tran NL, Ryken T, Moore MK, Egan KM, Olson JJ. Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol 2014; 11:203-22. [PMID: 24569448 DOI: 10.1038/nrclinonc.2014.25] [Citation(s) in RCA: 206] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.
Collapse
Affiliation(s)
- Taofeek K Owonikoko
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA
| | - Jack Arbiser
- Department of Dermatology, Atlanta Veterans Administration Medical Center, Emory University, Atlanta, GA 30322, USA
| | - Amelia Zelnak
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA
| | - Hui-Kuo G Shu
- Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA
| | - Hyunsuk Shim
- Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA
| | - Adam M Robin
- Department of Neurosurgery, Henry Ford Health System, 2799 West Grand Boulevard, K-11, Detroit, MI 48202, USA
| | - Steven N Kalkanis
- Department of Neurosurgery, Henry Ford Health System, 2799 West Grand Boulevard, K-11, Detroit, MI 48202, USA
| | - Timothy G Whitsett
- Division of Cancer and Cell Biology, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA
| | - Bodour Salhia
- Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA
| | - Nhan L Tran
- Division of Cancer and Cell Biology, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA
| | - Timothy Ryken
- Iowa Spine and Brain Institute, 2710 St Francis Drive, Suite 110, Waterloo, IA 50702, USA
| | - Michael K Moore
- Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA
| | - Kathleen M Egan
- H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Jeffrey J Olson
- Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA
| |
Collapse
|
|
24
|
Zhu W, Zhou L, Qian JQ, Qiu TZ, Shu YQ, Liu P. Temozolomide for treatment of brain metastases: A review of 21 clinical trials. World J Clin Oncol 2014; 5:19-27. [PMID: 24527399 PMCID: PMC3920177 DOI: 10.5306/wjco.v5.i1.19] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Revised: 11/02/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.
Collapse
|
|
25
|
Puzanov I, Wolchok JD, Ascierto PA, Hamid O, Margolin K. Anti-CTLA-4 and BRAF inhibition in patients with metastatic melanoma and brain metastases. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17469872.2013.835922] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
|
|
26
|
Vemurafenib and radiation therapy in melanoma brain metastases. J Neurooncol 2013; 113:411-6. [DOI: 10.1007/s11060-013-1127-1] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 03/31/2013] [Indexed: 01/07/2023]
|
|
27
|
Fonkem E, Uhlmann EJ, Floyd SR, Mahadevan A, Kasper E, Eton O, Wong ET. Melanoma brain metastasis: overview of current management and emerging targeted therapies. Expert Rev Neurother 2013; 12:1207-15. [PMID: 23082737 DOI: 10.1586/ern.12.111] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The high rate of brain metastasis in patients with advanced melanoma has been a clinical challenge for oncologists. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive. This is due to the high incidence of CNS metastases, which progress relentlessly and which are only anecdotally responsive to systemic therapies. Surgery, stereotactic radiosurgery and whole-brain radiotherapy with or without cytotoxic chemotherapy remain the mainstay of treatment. However, new drugs have been developed based on our improved understanding of the molecular signaling mechanisms responsible for host immune tolerance and for melanoma growth. In 2011, the US FDA approved two agents, one antagonizing each of these processes, for the treatment of advanced melanoma. The first is ipilimumab, an anti-CTLA-4 monoclonal antibody that enhances cellular immunity and reduces tolerance to tumor-associated antigens. The second is vemurafenib, an inhibitor that blocks the abnormal signaling for melanoma cellular growth in tumors that carry the BRAF(V600E) mutation. Both drugs have anecdotal clinical activity for brain metastasis and are being evaluated in clinical trial settings. Additional clinical trials of newer agents involving these pathways are also showing promise. Therefore, targeted therapies must be incorporated into the multimodality management of melanoma brain metastasis.
Collapse
Affiliation(s)
- Ekokobe Fonkem
- Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Caffo M, Barresi V, Caruso G, Cutugno M, La Fata G, Venza M, Alafaci C, Tomasello F. Innovative therapeutic strategies in the treatment of brain metastases. Int J Mol Sci 2013; 14:2135-74. [PMID: 23340652 PMCID: PMC3565370 DOI: 10.3390/ijms14012135] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Revised: 01/08/2013] [Accepted: 01/09/2013] [Indexed: 12/29/2022] Open
Abstract
Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood-brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.
Collapse
Affiliation(s)
- Maria Caffo
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| | - Valeria Barresi
- Department of Human Pathology, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mail:
| | - Gerardo Caruso
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-090-2217167; Fax: +39-090-693714
| | - Mariano Cutugno
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| | - Giuseppe La Fata
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| | - Mario Venza
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| | - Concetta Alafaci
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| | - Francesco Tomasello
- Department of Neurosciences, School of Medicine, University of Messina, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy; E-Mails: (M.C.); (M.C.); (G.L.F.); (M.V.); (C.A.); (F.T.)
| |
Collapse
|
|
29
|
Ramakrishna N, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma; local therapies for central nervous system metastases. Am Soc Clin Oncol Educ Book 2013:399-403. [PMID: 23714560 DOI: 10.14694/edbook_am.2013.33.399] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The overall treatment paradigm for melanoma brain metastases continues to evolve and reflects the relative radioresistance of this histology, as well as the effect of emerging systemic therapies with central nervous system (CNS) activity. Local therapies, including surgery, whole brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS), play an important role in the multidisciplinary management of melanoma brain metastases. Treatment selection for local therapies must consider many factors: (1) size, number, and location of lesions, (2) presence or absence of neurological symptoms, (3) extracranial disease status, expected survival, age, and performance status, (4) prior treatment history, (5) expected treatment toxicities, and (6) predicted response to systemic therapies. The choice of treatment modalities for brain metastases is among the most controversial areas in oncology. There has been a trend toward reduced use of WBRT and increased reliance on SRS and surgery for melanoma brain metastases. Although no prospective randomized data exist comparing local therapies for melanoma brain metastases, several large retrospective studies suggest aggressive local treatment with modalities including surgery and SRS are associated with favorable outcomes in select patients. Multidisciplinary collaboration is required to facilitate a treatment plan that balances reduction in risk of neurological death and symptomatic progression against the risk of treatment-related toxicity.
Collapse
Affiliation(s)
- Naren Ramakrishna
- From the MD Anderson Cancer Center Orlando, University of Central Florida College of Medicine, Orlando FL; University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA
| | | |
Collapse
|
|
30
|
Chemosensitized radiosurgery for recurrent brain metastases. J Neurooncol 2012; 110:265-70. [DOI: 10.1007/s11060-012-0965-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 08/10/2012] [Indexed: 12/30/2022]
|
|
31
|
Kleibeuker EA, Griffioen AW, Verheul HM, Slotman BJ, Thijssen VL. Combining angiogenesis inhibition and radiotherapy: A double-edged sword. Drug Resist Updat 2012; 15:173-82. [DOI: 10.1016/j.drup.2012.04.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 03/20/2012] [Accepted: 04/11/2012] [Indexed: 01/01/2023]
|
|
32
|
|
|
33
|
The role of radiation therapy in the management of metastatic melanoma in the brain. Int J Surg Oncol 2012; 2012:294735. [PMID: 22577532 PMCID: PMC3332202 DOI: 10.1155/2012/294735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 10/18/2011] [Accepted: 01/18/2012] [Indexed: 01/14/2023] Open
Abstract
Brain metastasis is common in patients with melanoma and represents a significant cause of morbidity and mortality. There have been no specific randomized trials for patients with melanoma brain metastasis, so treatment is based on management of brain metastasis in general and requires multidisciplinary expertise including radiation oncology, neurosurgery, medical oncology, and palliative care. In this paper, we summarize the prognosis, general management, and the role of radiation therapy in the management of metastatic melanoma in the brain.
Collapse
|
|
34
|
Niyazi M, Maihoefer C, Krause M, Rödel C, Budach W, Belka C. Radiotherapy and "new" drugs-new side effects? Radiat Oncol 2011; 6:177. [PMID: 22188921 PMCID: PMC3266653 DOI: 10.1186/1748-717x-6-177] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 12/21/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. MATERIALS AND METHODS Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. RESULTS Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. CONCLUSIONS The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.
Collapse
Affiliation(s)
- Maximilian Niyazi
- Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 München, Germany
| | - Cornelius Maihoefer
- Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 München, Germany
| | - Mechthild Krause
- Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Claus Rödel
- Klinik für Strahlentherapie und Onkologie, Johann Wolfgang Goethe Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Wilfried Budach
- Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Heinrich Heine Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Claus Belka
- Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 München, Germany
| |
Collapse
|
|
35
|
Kyritsis AP, Markoula S, Levin VA. A systematic approach to the management of patients with brain metastases of known or unknown primary site. Cancer Chemother Pharmacol 2011; 69:1-13. [DOI: 10.1007/s00280-011-1775-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 10/20/2011] [Indexed: 12/13/2022]
|
|
36
|
Single brain metastases from melanoma: remarks on a series of 84 patients. Neurosurg Rev 2011; 35:211-7; discussion 217-8. [PMID: 21915621 DOI: 10.1007/s10143-011-0348-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Revised: 05/04/2011] [Accepted: 05/15/2011] [Indexed: 10/17/2022]
Abstract
The authors report on 84 patients with single melanoma brain metastasis surgically treated from 1997 to 2007. There were 46 males and 38 females; mean age was 41 years (range 24-58 years). All patients were surgically treated, and 52 of them received postoperative adjuvant therapy consisting of whole-brain radiation therapy (36), radiosurgery (9), or a combination of these two techniques (7). Brain recurrences were observed in 44 cases, of which 9 were local. Of the latter, seven were re-operated while the remaining two were treated by radiosurgery. At 1-year follow-up, the survival rate was 52% (32 patients) whereas only 12 patients (14%) were still alive after 2 years. None of the patients in which removal was subtotal survived for more than 6 months after surgical treatment. Three years after the onset of the brain metastasis, five patients (6%) were still alive. Survival was significantly influenced by treatment with regard to overall survival reported in other series. A review of literature, together with our own series, suggests that radical surgical treatment of the lesion possibly employing the internal no-touch technique has significantly increased survival in our patients (p < 0.05) and that the association of postoperative radiotherapy and re-operation in the event of recurrent metastatic lesions is advisable even though statistical significance was not reached (p > 0.05).
Collapse
|
|
37
|
Addeo R, Caraglia M. Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: an unending quest or chasing a chimera? Expert Opin Investig Drugs 2011; 20:881-95. [PMID: 21529310 DOI: 10.1517/13543784.2011.580736] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Medical treatment of brain metastases (BM) is still a controversial issue in cancer therapy being mainly limited by the existence of the BBB. Temozolomide (TMZ) can cross BBB and several clinical trials have been performed attempting to demonstrate the activity of TMZ in combination with whole brain radiotherapy (WBRT) in the treatment of BM. AREAS COVERED This review summarizes TMZ-WBRT combination trials highlighting the confounding factors that limit the interpretation of the achieved results and describes the main clinical trials using TMZ in combination with other cytotoxic or biological agents. The main limitations of these trials are: i) patient selection for heterogenous primitive neoplasms and for heterogeneous neuro-functional score; ii) poor penetration across BBB of the other drugs; iii) cumulative toxicity and iv) poor control of extracranial tumor sites. EXPERT OPINION Biotechnological, biological and biochemical advances in the management of BM could allow in short time the definition of new schedules based on the rational use of new anticancer weapons. The latter could be cytotoxic agents encapsulated in nanotechnological tools able to cross BBB, lipophilic small kinase inhibitors (lapatinib, sunitinib), mTOR inhibitors and PARP inhibitors combined with old drugs such as TMZ.
Collapse
Affiliation(s)
- Raffaele Addeo
- S.Giovanni di Dio Hospital, Oncology Department, Frattamaggiore, Naples, Italy.
| | | |
Collapse
|
|
38
|
The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma. Eur J Cancer 2011; 47:1219-30. [DOI: 10.1016/j.ejca.2010.12.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Revised: 12/01/2010] [Accepted: 12/14/2010] [Indexed: 11/23/2022]
|
|
39
|
Khan N, Khan MK, Almasan A, Singh AD, Macklis R. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 2011; 80:645-54. [PMID: 21489712 DOI: 10.1016/j.ijrobp.2010.12.071] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 12/19/2010] [Accepted: 12/26/2010] [Indexed: 02/01/2023]
Abstract
The incidence of melanoma is rising in the United States, leading to an estimated 68,720 new diagnoses and 8,650 deaths annually. The natural history involves metastases to lymph nodes, lung, liver, brain, and often to other sites. Primary treatment for melanoma is surgical excision of the primary tumor and affected lymph nodes. The role of adjuvant or definitive radiation therapy in the treatment of melanoma remains controversial, because melanoma has traditionally been viewed as a prototypical radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, there may be a significant role for radiation therapy in melanoma treatment. Stereotactic radiosurgery for brain metastases has shown effective local control. High dose per fraction radiation therapy has been associated with a lower rate of locoregional recurrence of sinonasal melanoma. Plaque brachytherapy has evolved into a promising alternative to enucleation at the expense of moderate reduction in visual acuity. Adjuvant radiation therapy following lymphadenectomy in node-positive melanoma prevents local and regional recurrence. The newer clinical data along with emerging radiobiological data indicate that radiotherapy is likely to play a greater role in melanoma management and should be considered as a treatment option.
Collapse
Affiliation(s)
- Niloufer Khan
- Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
| | | | | | | | | |
Collapse
|
|
40
|
A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels. Br J Cancer 2011; 104:1106-15. [PMID: 21386847 PMCID: PMC3068510 DOI: 10.1038/bjc.2011.78] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background: The possibility of eradicating cancer by selective destruction of tumour blood vessels may represent an attractive therapeutic avenue, but most pharmaceutical agents investigated so far did not achieve complete cures and are not completely specific. Antibody conjugates now allow us to evaluate the impact of selective vascular shutdown on tumour viability and to study mechanisms of action. Methods: We synthesised a novel porphyrin-based photosensitiser suitable for conjugation to antibodies and assessed anticancer properties of its conjugate with L19, a clinical-stage human monoclonal antibody specific to the alternatively spliced EDB domain of fibronectin, a marker of tumour angiogenesis. Results: Here we show in two mouse model of cancer (F9 and A431) that L19 is capable of highly selective in vivo localisation around tumour blood vessels and that its conjugate with a photosensitiser allows selective disruption of tumour vasculature upon irradiation, leading to complete and long-lasting cancer eradication. Furthermore, depletion experiments revealed that natural killer cells are essential for the induction of long-lasting complete responses. Conclusions: These results reinforce the concept that vascular shutdown can induce a curative avalanche of tumour cell death. Immuno-photodynamic therapy may be particularly indicated for squamous cell carcinoma of the skin, which we show to be strongly positive for markers of angiogenesis.
Collapse
|
|
41
|
Sheehan JP, Yen CP, Nguyen J, Rainey JA, Dassoulas K, Schlesinger DJ. Timing and risk factors for new brain metastasis formation in patients initially treated only with Gamma Knife surgery. J Neurosurg 2011; 114:763-8. [DOI: 10.3171/2010.2.jns091539] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Stereotactic radiosurgery has been shown to afford a reasonable chance of local tumor control. However, new brain metastasis can arise following successful local tumor control from radiosurgery. This study evaluates the timing, number, and risk factors for development of subsequent new brain metastasis in a group of patients treated with stereotactic radiosurgery alone.
Methods
One hundred seventeen patients with histologically confirmed metastatic cancer underwent Gamma Knife surgery (GKS) to treat all brain metastases demonstrable on MR imaging. Patients were followed clinically and radiologically at approximately 3-month intervals for a median of 14.4 months (range 0.37–51.8 months). Follow-up MR images were evaluated for evidence of new brain metastasis formation. Statistical analyses were performed to determine the timing, number, and risk factors for development of new brain metastases.
Results
The median time to development of a new brain metastasis was 8.8 months. Patients with 3 or more metastases at the time of initial radiosurgery or those with cancer histologies other than non–small cell lung carcinoma were found to be at increased risk for early formation of new brain metastasis (p < 0.05). The mean number of new metastases per patient was 1.6 (range 0–11). Those with a higher Karnofsky Performance Scale score at the time of initial GKS were significantly more likely to develop a greater number of brain metastases by the last follow-up evaluation.
Conclusions
The timing and number of new brain metastases developing in patients treated with GKS alone is not inconsequential. Those with 3 or more metastases at the time of radiosurgery and those with cancer histology other than non–small cell lung carcinoma were at greater risk of early formation of new brain metastasis. Frequent follow-up evaluations, such as at 3-month intervals, appears appropriate in this patient population, particularly in high-risk patients. When detected early, salvage treatments including repeat radiosurgery can be used to treat new brain metastasis.
Collapse
|
|
42
|
|
|
43
|
Abstract
Melanoma metastasizes frequently to the brain, and brain metastases generally drive the prognosis of melanoma patients. Surgical and radiation therapy improve the outcome of selected melanoma patients with brain metastasis, while systemic treatment using cytotoxic agents still plays a limited role. Temozolomide and fotemustine are preferentially used in melanoma patients with brain metastases in the United States and in Europe, respectively, with modest clinical activity. However, the results obtained with either agent are still limited, and efforts are needed to improve the outcome of these patients who are generally excluded from clinical trials. Among therapeutic agents in development, antibodies that block the interaction of cytotoxic T-lymphocyte-associated antigen (CTLA-4) with its ligands B7.1 and B7.2 and thus enhance antitumor immune responses have shown clinical benefit in patients with metastatic melanoma, including durable control of brain metastases. This chapter reviews the current data and the rationale for ongoing and future trials of combination cytotoxic plus immunomodulatory therapy by US and Italian multicenter trial groups.
Collapse
Affiliation(s)
- Kim A Margolin
- Medical Oncology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA 98109-1023, USA.
| | | | | |
Collapse
|
|
44
|
Schild SE, Behl D, Markovic SN, Brown PD, Sande JR, Deming RL, Rowland KM, Bearden JD. Brain metastases from melanoma: is there a role for concurrent temozolomide in addition to whole brain radiation therapy? Am J Clin Oncol 2010; 33:633-6. [PMID: 20042969 PMCID: PMC5690555 DOI: 10.1097/coc.0b013e3181c4c54b] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES This study was performed to evaluate the addition of temozolomide (TMZ) to whole brain radiotherapy (WBRT) for brain metastases from melanoma. METHODS Seven patients with brain metastases from melanoma were treated on a North Central Cancer Treatment Group (NCCTG) trial (N0274) of TMZ plus WBRT. TMZ was given orally in doses of 200 mg/m² for 5 days every 4 weeks for up to 8 cycles. WBRT was started on the first day of TMZ and included the delivery of 3750 cGy in 15 fractions. In addition, separately analyzed was a cohort of 53 patients treated at the Mayo Clinic who received WBRT alone (39 patients) or WBRT plus TMZ (14 patients). RESULTS The median survival of the 7 patients treated on N0274 was 3.6 months with 2 of 7 (29%) failing in brain and 5 of 7 (71%) failing elsewhere. For the other cohort of 53 patients, the median survival was 3.8 months with WBRT alone compared 4.3 months for WBRT plus TMZ (P = 0.5). CONCLUSIONS Patients did not appear to benefit from the addition of TMZ to WBRT for the treatment of their brain metastases. Further improvements in outcome will require research to discover more effective systemic therapy and RT techniques.
Collapse
Affiliation(s)
- Steven E Schild
- Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, Hwu P, Bedikian A. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2010; 117:1687-96. [PMID: 20960525 DOI: 10.1002/cncr.25634] [Citation(s) in RCA: 401] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 08/19/2010] [Accepted: 08/24/2010] [Indexed: 11/11/2022]
Abstract
BACKGROUND One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS). METHODS An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS. RESULTS Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded. CONCLUSIONS The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials.
Collapse
Affiliation(s)
- Michael A Davies
- Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Angiogenesis and progression in human melanoma. Dermatol Res Pract 2010; 2010:185687. [PMID: 20631829 PMCID: PMC2901609 DOI: 10.1155/2010/185687] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 04/06/2010] [Indexed: 12/25/2022] Open
Abstract
In tumor growth, angiogenesis, the process of new-formation of blood vessels from pre-existing ones, is uncontrolled and unlimited in time. The vascular phase is characterized by the new-formation of vascular channels that enhances tumor cell proliferation, local invasion and hematogenous metastasis. Human malignant melanoma is a highly metastatic tumor with poor prognosis, and high resistance to treatment. Parallel with progression, melanoma acquires a rich vascular network, whereas an increasing number of tumor cells express the laminin receptor, which enables their adhesion to the vascular wall, favouring tumor cell extravasation and metastases. Melanoma neovascularization has been correlated with poor prognosis, overall survival, ulceration and increased rate of relapse. Secretion of various angiogenic cytokines, i.e. VEGF-A, FGF-2, PGF-1 and -2, IL-8, and TGF-1 by melanoma cells promote the angiogenic switch and has been correlated to transition from the radial to the vertical growth phase, and to the metastatic phase. Moreover, melanoma cells overexpress alphavbeta3, alphavbeta5, alpha2beta1 and alpha5beta1 integrins and release, together with stromal cells, higher amount of metalloproteases that increasing their invasive potential and angiogenesis. Basing on these observations, different molecular targets of antiangiogenic molecules has be recognized and various antiangiogenic agents are currently in preclinical and clinical trials for melanoma.
Collapse
|
|
47
|
Liew DN, Kano H, Kondziolka D, Mathieu D, Niranjan A, Flickinger JC, Kirkwood JM, Tarhini A, Moschos S, Lunsford LD. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg 2010; 114:769-79. [PMID: 20524829 DOI: 10.3171/2010.5.jns1014] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT To evaluate the role of stereotactic radiosurgery (SRS) in the management of brain metastases from melanoma, the authors assessed clinical outcomes and prognostic factors for survival and tumor control. METHODS The authors reviewed 333 consecutive patients with melanoma who underwent SRS for 1570 brain metastases from cutaneous and mucosal/acral melanoma. The patient population consisted of 109 female and 224 male patients with a median age of 53 years. Two hundred eleven patients (63%) had multiple metastases. One hundred eighteen patients (35%) underwent whole-brain radiation therapy (WBRT). The target volume ranged from 0.1 cm(3) to 37.2 cm(3). The median marginal dose was 18 Gy. RESULTS Actuarial survival rates were 70% at 3 months, 47% at 6 months, 25% at 12 months, and 10% at 24 months after radiosurgery. Factors associated with longer survival included controlled extracranial disease, better Karnofsky Performance Scale score, fewer brain metastases, no prior WBRT, no prior chemotherapy, administration of immunotherapy, and no intratumoral hemorrhage before radiosurgery. The median survival for patients with a solitary brain metastasis, controlled extracranial disease, and administration of immunotherapy after radiosurgery was 22 months. Sustained local tumor control was achieved in 73% of the patients. Sixty-four (25%) of 259 patients who had follow-up imaging after SRS had evidence of delayed intratumoral hemorrhage. Sixteen patients underwent a craniotomy due to intratumoral hemorrhage. Seventeen patients (6%) had asymptomatic and 21 patients (7%) had symptomatic radiation effects. Patients with ≤ 8 brain metastases, no prior WBRT, and the recursive partitioning analysis Class I had extended survivals (median 54.3 months). CONCLUSIONS Stereotactic radiosurgery is an especially valuable option for patients with controlled systemic disease even if they have multiple metastatic brain tumors.
Collapse
Affiliation(s)
- Donald N Liew
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Siu TL, Huang S. Cerebral metastases from malignant melanoma: current treatment strategies, advances in novel therapeutics and future directions. Cancers (Basel) 2010; 2:364-75. [PMID: 24281074 PMCID: PMC3835082 DOI: 10.3390/cancers2020364] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 03/25/2010] [Accepted: 04/01/2010] [Indexed: 11/18/2022] Open
Abstract
Of all primary cancers in humans, melanoma has the highest propensity to metastasize to the brain. The prognosis of patients with this disease is extremely poor. Due to its radioresistance and poor response to existing chemotherapeutic regimes, no treatment options other than surgical extirpation, when feasible, have been shown to be effective. An understanding of the underlying tumor biology therefore remains the cornerstone of offering new hope in the treatment. In this review, we comment on the current treatment strategies for melanoma brain metastases and summarize some recent experimental findings from our laboratory with potential for the development of target specific antitumor therapies.
Collapse
Affiliation(s)
- Timothy L Siu
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | | |
Collapse
|
|
49
|
Kim CY, Kim SK, Phi JH, Lee MM, Kim IA, Kim IH, Wang KC, Jung HL, Lee MJ, Cho BK. A prospective study of temozolomide plus thalidomide during and after radiation therapy for pediatric diffuse pontine gliomas: preliminary results of the Korean Society for Pediatric Neuro-Oncology study. J Neurooncol 2010; 100:193-8. [PMID: 20309719 DOI: 10.1007/s11060-010-0157-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Accepted: 03/08/2010] [Indexed: 10/19/2022]
Abstract
This prospective study was performed to determine the efficacy and safety of temozolomide (TMZ) plus thalidomide during and after radiation therapy (RT) in pediatric patients with newly diagnosed diffuse pontine glioma (DPG). Seventeen patients with pediatric DPG were enrolled between November 2004 and March 2008. The median age was eight years (range, 3-16 years); seven patients were male and ten were female. With the exception of one glioblastoma case, which was diagnosed via open biopsy, all diagnoses were established using neuroradiological studies. The authors used the Korean Society for Pediatric Neuro-Oncology (KSPNO)-A053 protocol. The mean follow-up period was 12 months (range, 8.5-25 months). Five patients were withdrawn from the study. The rates of response to treatment and survival were analyzed in 12 patients. Ten out of the 12 patients showed a partial response (PR), whereas one patient exhibited stable disease (SD) and another patient had progressive disease (PD). The tumor control rate was 92% (11/12) and the response rate was 83% (10/12). The median progression-free survival (PFS) of the 12 patients was 7.2 months (95% confidence interval (CI), 3.6-10.7). Six-month and twelve-month PFS were 58.3 and 16.7%, respectively. Overall survival (OS) was 12.7 months (95% CI, 10.4-15.1). One and two-year survival were 58.3 and 25%, respectively. The main adverse effect was hematological toxicity, with four patients exhibiting grade 3 or 4 toxicity. All patients tolerated the regimen well enough to continue the adjuvant chemotherapy. No Pneumocystis jiroveci pneumonia was noted. The TMZ plus thalidomide regimen was safe and tolerated well enough to be administered on an outpatient basis. Larger studies are required to demonstrate the efficacy of this regimen.
Collapse
Affiliation(s)
- Chae-Yong Kim
- Department of Neurosurgery, Seoul National University Bundang Hospital, Gyeonggi-do, Korea.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Ribatti D, Annese T, Longo V. Angiogenesis and melanoma. Cancers (Basel) 2010; 2:114-32. [PMID: 24281035 PMCID: PMC3827594 DOI: 10.3390/cancers2010114] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 02/10/2010] [Accepted: 02/24/2010] [Indexed: 11/16/2022] Open
Abstract
Angiogenesis occurs in pathological conditions, such as tumors, where a specific critical point in tumor progression is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells, which are able to stimulate the growth of the host's blood vessels. This article summarizes the literature concerning the relationship between angiogenesis and human melanoma progression. The recent applications of antiangiogenic agents which interfere with melanoma progression are also described.
Collapse
Affiliation(s)
- Domenico Ribatti
- Department of Human Anatomy and Histology, University of Bari Medical School, Piazza G. Cesare, 11, Policlinico 70124, Bari, Italy.
| | | | | |
Collapse
|