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Wang X, Yao C, Quan L, Zhou J. A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors. Front Pharmacol 2025; 16:1472945. [PMID: 39981182 PMCID: PMC11841460 DOI: 10.3389/fphar.2025.1472945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/08/2025] [Indexed: 02/22/2025] Open
Abstract
Leptomeningeal disease (LMD) is a particular mode of central metastasis in malignant tumors. It occurs when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS). LMD is a rare but devastating complication of malignant tumors. It can occur in various types of cancers, with lung and breast cancer being the most frequently associated. The treatment approach for LMD includes a combination of supportive care, surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and intrathecal (IT) therapy, among other modalities. Despite the challenges in determining the optimal treatment for LMD, IT therapy remains one of the primary therapeutic strategies. This therapy can directly circumvent the blood-brain barrier. Moreover, a low-dose medication can achieve a higher drug concentration in the CSF, resulting in better cytotoxic effects. Chemotherapy drugs such as methotrexate, cytarabine, and thiotepa have been widely studied as traditional IT therapies. In recent years, the advent of novel anti-tumor drugs has led to a growing number of agents being employed for IT administration in the treatment of malignant tumors with LMD. This article presents a comprehensive review of the current advancements in IT administration of chemotherapy, targeted, and immunotherapy drugs for the treatment of LMD in solid tumors. In addition, we also discuss the safety issues associated with IT therapy, summarize the advantages of IT administration of different types of anti-tumor drugs, and put forward some suggestions for reducing adverse reactions. It is hoped that future research will focus on exploring more potentially effective anti-tumor drugs for IT treatment, conducting in-depth pharmacokinetic studies, and developing long-acting and low-toxic IT administration regimens for the treatment of meningeal metastases.
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Affiliation(s)
- Xuemei Wang
- Department of Clinical Pharmacy, Shifang People’s Hospital, North Sichuan Medical College, Deyang, China
| | - Chi Yao
- Department of Hepatobiliary Surgery, Shifang People’s Hospital, North Sichuan Medical College, Deyang, China
| | - Li Quan
- Department of Clinical Pharmacy, Shifang People’s Hospital, North Sichuan Medical College, Deyang, China
| | - Junxiang Zhou
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Afffliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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Garrone O, Ruatta F, Rea CG, Denaro N, Ghidini M, Cauchi C, Bareggi C, Galassi B, Merlano MC, Rosenfeld R. Current Evidence in the Systemic Treatment of Brain Metastases from Breast Cancer and Future Perspectives on New Drugs, Combinations and Administration Routes: A Narrative Review. Cancers (Basel) 2024; 16:4164. [PMID: 39766062 PMCID: PMC11675070 DOI: 10.3390/cancers16244164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/07/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15-30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody-drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches.
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Affiliation(s)
- Ornella Garrone
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Fiorella Ruatta
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Carmen Giusy Rea
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Nerina Denaro
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Michele Ghidini
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Carolina Cauchi
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Claudia Bareggi
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Barbara Galassi
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
| | - Marco C. Merlano
- Scientific Direction, Candiolo Cancer Institute, FPO-IRCCS Candiolo, 10060 Torino, Italy;
| | - Roberto Rosenfeld
- Department of Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (F.R.); (C.G.R.); (N.D.); (M.G.); (C.C.); (C.B.); (B.G.); (R.R.)
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Huppert LA, Fisch S, Tsopurashvili E, Somepalle SS, Salans M, Vasudevan HN, Jo Chien A, Majure M, Rugo HS, Balassanian R, Boreta L, Melisko ME. Demographic and clinical characteristics of patients with metastatic breast cancer and leptomeningeal disease: a single center retrospective cohort study. Breast Cancer Res Treat 2024; 206:625-636. [PMID: 38888796 PMCID: PMC11208257 DOI: 10.1007/s10549-024-07339-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/10/2024] [Indexed: 06/20/2024]
Abstract
PURPOSE Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). It is critical to better understand the risk factors, natural history, and treatment outcomes, including patients in a modern cohort. METHODS In this single center retrospective cohort study, we identified patients with MBC and LMD who received care from 2000 to 2024 and abstracted key clinical, treatment, and survival data. RESULTS We identified 111 patients with MBC and LMD, including patients with the following subtypes: HR+/HER2- (n = 53, 47.7%), HER2+ (n = 30, 27.0%), and triple negative breast cancer (TNBC; n = 28, 25.2%). Median time from the diagnosis of MBC to LMD was 16.4 months (range 0-101.3 months). After the diagnosis of LMD, most patients received systemic therapy (n = 66, 59.5%) and/or central nervous system (CNS)-directed therapy (n = 94, 84.7%) including intrathecal therapy (n = 42, 37.8%) and/or CNS-directed radiation therapy (n = 70, 63.1%). In all patients, median overall survival (OS) from the diagnosis of LMD to death was 4.1 months (range 0.1-78.1 months) and varied by subtype, with HR+/HER2- or HER2+ MBC patients living longer than those with TNBC (4.2 and 6.8 months respectively vs. 2.0 months, p < 0.01, HR 2.15, 95% CI 1.36-3.39). Patients who received CNS-directed therapy lived longer than those who did not (4.2 vs. 1.3, p = 0.02 HR 0.54, 0.32-0.91). Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014 (6.4 vs. 2.9 months, p = 0.04, HR 0.67, 95% CI 0.46-0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p = 0.004, HR 2.03, 95% CI 1.25-3.30). CONCLUSION This is one of the largest case series of patients with MBC and LMD. Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014, although median OS was short overall. Patients with TNBC and LMD had particularly short OS. Novel therapeutic strategies for LMD remain an area of unmet clinical need.
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Affiliation(s)
- Laura A Huppert
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
| | - Samantha Fisch
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Elene Tsopurashvili
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Sai Sahitha Somepalle
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Mia Salans
- Division of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Harish N Vasudevan
- Division of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - A Jo Chien
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Melanie Majure
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Hope S Rugo
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Ronald Balassanian
- Division of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Lauren Boreta
- Division of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
| | - Michelle E Melisko
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Jamison T, Haque E, Muhsen IN, Samarkandi H, Fakih RE, Aljurf M. Revisiting intrathecal thiotepa: Efficacy and safety in secondary CNS malignancies. Med Oncol 2024; 41:177. [PMID: 38884819 DOI: 10.1007/s12032-024-02401-w] [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: 02/23/2024] [Accepted: 04/28/2024] [Indexed: 06/18/2024]
Abstract
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
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Affiliation(s)
- Trevor Jamison
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Emaan Haque
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Ibrahim N Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Hadeel Samarkandi
- Oncology Pharmacy Services, Faisal Specialist Hospital and Research Center, Riyadh, King, Saudi Arabia
| | - Riad El Fakih
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Transplantation and Cellular Therapy Section, Oncology Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Mahmoud Aljurf
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
- Transplantation and Cellular Therapy Section, Oncology Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia.
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Bardhan M, Dey D, Suresh V, Javed B, Venur VA, Joe N, Kalidindi R, Ozair A, Khan M, Mahtani R, Lo S, Odia Y, Ahluwalia MS. An overview of the therapeutic strategies for neoplastic meningitis due to breast cancer: when and why? Expert Rev Neurother 2024; 24:77-103. [PMID: 38145503 DOI: 10.1080/14737175.2023.2293223] [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: 10/04/2023] [Accepted: 12/06/2023] [Indexed: 12/27/2023]
Abstract
INTRODUCTION Neoplastic meningitis (NM), also known as leptomeningeal carcinomatosis, is characterized by the infiltration of tumor cells into the meninges, and poses a significant therapeutic challenge owing to its aggressive nature and limited treatment options. Breast cancer is a common cause of NM among solid tumors, further highlighting the urgent need to explore effective therapeutic strategies. This review aims to provide insights into the evolving landscape of NM therapy in breast cancer by collating existing research, evaluating current treatments, and identifying potential emerging therapeutic options. AREAS COVERED This review explores the clinical features, therapeutic strategies, recent advances, and challenges of managing NM in patients with breast cancer. Its management includes multimodal strategies, including systemic and intrathecal chemotherapy, radiation therapy, and supportive care. This review also emphasizes targeted drug options and optimal drug concentrations, and discusses emerging therapies. Additionally, it highlights the variability in treatment outcomes and the potential of combination regimens to effectively manage NM in breast cancer. EXPERT OPINION Challenges in treating NM include debates over clinical trial end points and the management of adverse effects. Drug resistance and low response rates are significant hurdles, particularly inHER2-negative breast cancer. The development of more precise and cost-effective medications with improved selectivity is crucial. Additionally, global efforts are needed for infrastructure development and cancer control considering the diverse nature of the disease.
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Affiliation(s)
- Mainak Bardhan
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | | | - Vinay Suresh
- King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Binish Javed
- Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Vyshak Alva Venur
- Seattle Cancer Care Alliance, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | - Neha Joe
- St John's Medical College Hospital, Bengaluru, India
| | | | - Ahmad Ozair
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | - Reshma Mahtani
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Simon Lo
- Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA, USA
| | - Yazmin Odia
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Manmeet S Ahluwalia
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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Jafari F, Nodeh MM, Hosseinjani H, Baharara H, Azad S, Arasteh O, Johnston TP, Sahebkar A. A Review on the Efficacy and Safety of Intrathecal Administration of Novel Medications for Leptomeningeal Metastases in Solid Cancers. Curr Med Chem 2024; 31:2732-2750. [PMID: 37157199 DOI: 10.2174/0929867330666230508142657] [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: 10/30/2022] [Revised: 02/27/2023] [Accepted: 03/31/2023] [Indexed: 05/10/2023]
Abstract
Leptomeningeal disease (LMD) is a rare and lethal manifestation that may occur in the advanced stages of solid tumors and hematological malignancies. With advances in diagnostic techniques, the detection and confirmation of the presence of LMD have increased. Although its optimal treatment remains a challenge, the use of the intrathecal route for the delivery of novel therapeutics is now considered a promising drug delivery strategy to complement radiation and systemic-based therapies. Although methotrexate, cytarabine, and thiotepa have a long history in the treatment of LMD, other medications have also been shown to be beneficial. In this article, we have reviewed the effects of novel medications administered via the intrathecal route for the treatment of solid tumors. We have searched PubMed, Scopus, and Google Scholar databases till the end of September 2021 using the following keywords: "leptomeningeal disease", "leptomeningeal carcinomatosis", "leptomeningeal metastases", "solid tumors", "solid cancers", and "intrathecal". Our literature findings have uncovered that most studies on LMD, which occurs secondary to solid cancers, are available as 'case reports', and few clinical trials have been conducted to date. Single-drug (monotherapy) or combination drug therapy, administered via the intrathecal route, especially in metastatic breast and lung cancer, has been shown to improve patients' symptoms and overall lifespan, while exhibiting a low and acceptable prevalence of side effects. However, judgments/conclusions about the effectiveness and safety of these drugs still require further clinical evaluation.
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Affiliation(s)
- Fatemeh Jafari
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Moeini Nodeh
- Division of Hematology and Oncology, Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hesamoddin Hosseinjani
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Baharara
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Azad
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Omid Arasteh
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Loison R, Abbar B, Drouin L, Bonnet-Bensimon C, Cuvier C, Giacchetti S, Espie M, Teixeira L, De Castelbajac V. Vinorelbine thiotepa in metastatic breast cancer: a large real-life retrospective study. Acta Oncol 2023; 62:1961-1966. [PMID: 37750392 DOI: 10.1080/0284186x.2023.2260943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/14/2023] [Indexed: 09/27/2023]
Affiliation(s)
- Rebecca Loison
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Baptiste Abbar
- Sorbonne Université, INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié Salpêtrière Hospital, Department of Medical Oncology, Institut Universitaire de Cancérologie, CLIP² Galilée, Paris, France
| | - Leonor Drouin
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Charlotte Bonnet-Bensimon
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Caroline Cuvier
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Sylvie Giacchetti
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Marc Espie
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Luis Teixeira
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
| | - Victoire De Castelbajac
- Université de Paris Cité, INSERM U976, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Breast Disease Unit (Sénopole), Paris, France
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Kumthekar P, Le Rhun E. Brain Metastases and Leptomeningeal Disease. Continuum (Minneap Minn) 2023; 29:1727-1751. [PMID: 38085896 DOI: 10.1212/con.0000000000001354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
OBJECTIVE Central nervous system (CNS) metastases include brain parenchymal, spinal cord, and leptomeningeal metastases. This article discusses the diagnostic and therapeutic advances of the last decade that have improved outcomes for patients with these CNS metastases. LATEST DEVELOPMENTS The diagnostic tools for CNS metastases, particularly leptomeningeal disease, have evolved over the past decade with respect to advancements in CSF analysis. Multiple medical therapies are now available for brain metastasis treatment that have shown CNS efficacy, including targeted therapies and antibody-drug conjugates. Molecular testing for CNS metastases has become more common and the repertoire of molecularly targeted therapies continues to expand. Advancements in radiation therapy, including improvements in stereotactic radiation techniques, whole-brain radiation with hippocampal avoidance, and proton beam radiation, have changed the radiation management of patients with CNS metastases. New intrathecal agents are currently being tested for the management of leptomeningeal metastases. ESSENTIAL POINTS CNS metastases are far more common than primary brain tumors and are increasing in prevalence in the setting of improved treatments and prolonged survival in patients with systemic cancers. There have been many changes in the diagnostics and treatment of CNS metastases, yielding subsequent improvements in patient outcomes with further advancements on the horizon.
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Chaurasia M, Singh R, Sur S, Flora SJS. A review of FDA approved drugs and their formulations for the treatment of breast cancer. Front Pharmacol 2023; 14:1184472. [PMID: 37576816 PMCID: PMC10416257 DOI: 10.3389/fphar.2023.1184472] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 06/23/2023] [Indexed: 08/15/2023] Open
Abstract
Breast cancer is one of the most diagnosed solid cancers globally. Extensive research has been going on for decades to meet the challenges of treating solid tumors with selective compounds. This article aims to summarize the therapeutic agents which are either being used or are currently under approval for use in the treatment or mitigation of breast cancer by the US FDA, to date. A structured search of bibliographic databases for previously published peer-reviewed research papers on registered molecules was explored and data was sorted in terms of various categories of drugs used in first line/adjuvant therapy for different stages of breast cancer. We included more than 300 peer-reviewed papers, including both research and reviews articles, in order to provide readers an useful comprehensive information. A list of 39 drugs are discussed along with their current status, dose protocols, mechanism of action, pharmacokinetics, possible side effects, and marketed formulations. Another interesting aspect of the article included focusing on novel formulations of these drugs which are currently in clinical trials or in the process of approval. This exhaustive review thus shall be a one-stop solution for researchers who are working in the areas of formulation development for these drugs.
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Affiliation(s)
| | | | | | - S. J. S. Flora
- Era College of Pharmacy, Era University, Lucknow, Uttar Pradesh, India
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10
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Warrior S, Cohen-Nowak A, Kumthekar P. Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis. Cancers (Basel) 2023; 15:cancers15112908. [PMID: 37296873 DOI: 10.3390/cancers15112908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/09/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors' review outlines the most current data in HER2-positive brain and leptomeningeal metastases and discuss the current treatment paradigm in this disease. Up to 55% of HER2-positive breast cancer patients go on to experience CNS metastases. They may present with a variety of focal neurologic symptoms, such as speech changes or weakness, and may also have more diffuse symptoms related to high intracranial pressure, such as headaches, nausea, or vomiting. Treatment can include focal treatments, such as surgical resection or radiation (focal or whole-brain radiation), as well as systemic therapy options or even intrathecal therapy in the case of leptomeningeal disease. There have been multiple advancements in systemic therapy for these patients over the past few years, including the availability of tucatinib and trastuzumab-deruxtecan. Hope remains high as clinical trials for CNS metastases receive greater attention and as other HER2-directed methods are being studied in clinical trials with the goal of better outcomes for these patients.
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Affiliation(s)
- Surbhi Warrior
- Department of Hematology, Oncology Northwestern Memorial Hospital, Chicago, IL 60611, USA
| | - Adam Cohen-Nowak
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, USA
| | - Priya Kumthekar
- Department of Neuro-Oncology, Northwestern Memorial Hospital, Chicago, IL 60611, USA
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Huang W, Li Z, Kang Y, Ye X, Feng W. Drug Repositioning Based on the Enhanced Message Passing and Hypergraph Convolutional Networks. Biomolecules 2022; 12:1666. [PMID: 36359016 PMCID: PMC9687543 DOI: 10.3390/biom12111666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 10/17/2023] Open
Abstract
Drug repositioning, an important method of drug development, is utilized to discover investigational drugs beyond the originally approved indications, expand the application scope of drugs, and reduce the cost of drug development. With the emergence of increasingly drug-disease-related biological networks, the challenge still remains to effectively fuse biological entity data and accurately achieve drug-disease repositioning. This paper proposes a new drug repositioning method named EMPHCN based on enhanced message passing and hypergraph convolutional networks (HGCN). It firstly constructs the homogeneous multi-view information with multiple drug similarity features and then extracts the intra-domain embedding of drugs through the combination of HGCN and channel attention mechanism. Secondly, inter-domain information of known drug-disease associations is extracted by graph convolutional networks combining node and edge embedding (NEEGCN), and a heterogeneous network composed of drugs, proteins and diseases is built as an important auxiliary to enhance the inter-domain message passing of drugs and diseases. Besides, the intra-domain embedding of diseases is also extracted through HGCN. Ultimately, intra-domain and inter-domain embeddings of drugs and diseases are integrated as the final embedding for calculating the drug-disease correlation matrix. Through 10-fold cross-validation on some benchmark datasets, we find that the AUPR of EMPHCN reaches 0.593 (T1) and 0.526 (T2), respectively, and the AUC achieves 0.887 (T1) and 0.961 (T2) respectively, which shows that EMPHCN has an advantage over other state-of-the-art prediction methods. Concerning the new disease association prediction, the AUC of EMPHCN through the five-fold cross-validation reaches 0.806 (T1) and 0.845 (T2), which are 4.3% (T1) and 4.0% (T2) higher than the second best existing methods, respectively. In the case study, EMPHCN also achieves satisfactory results in real drug repositioning for breast carcinoma and Parkinson's disease.
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Affiliation(s)
- Weihong Huang
- School of Informatics Science and Technology, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Zhong Li
- School of Informatics Science and Technology, Zhejiang Sci-Tech University, Hangzhou 310018, China
- Zhejiang Province Key Laboratory of Smart Management & Application of Modern Agricultural Resources, School of Information Engineering, Huzhou University, Huzhou 313000, China
| | - Yanlei Kang
- Zhejiang Province Key Laboratory of Smart Management & Application of Modern Agricultural Resources, School of Information Engineering, Huzhou University, Huzhou 313000, China
| | - Xinghuo Ye
- Zhejiang Province Key Laboratory of Smart Management & Application of Modern Agricultural Resources, School of Information Engineering, Huzhou University, Huzhou 313000, China
| | - Wenming Feng
- Department of General Surgery, The First Affiliated Hospital of Huzhou University, Huzhou 313000, China
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12
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Palmisciano P, Watanabe G, Conching A, Ogasawara C, Vojnic M, D'Amico RS. Intrathecal therapy for the management of leptomeningeal metastatic disease: a scoping review of the current literature and ongoing clinical trials. J Neurooncol 2022; 160:79-100. [PMID: 35999434 DOI: 10.1007/s11060-022-04118-0] [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: 07/29/2022] [Accepted: 08/16/2022] [Indexed: 02/01/2023]
Abstract
PURPOSE Leptomeningeal metastatic disease (LMD) from advanced malignancies has poor prognoses and limited treatments. Intrathecal therapy (ITT) protocols are available, showing variable outcomes. We reviewed the therapeutic and toxicity profiles of ITT in LMD. METHODS PubMed, EMBASE, Web-of-Science, and Scopus were searched following the PRISMA-ScR guidelines to include studies reporting ITT for LMD. CLINICALTRIAL gov and Cochrane were searched to identify ongoing clinical trials. RESULTS We included 27 published studies encompassing 2161 patients and 4 ongoing trials. LMD originated from brain metastases (85.5%), lymphomas (5.4%), high-grade gliomas (4.6%), medulloblastomas (2.3%), and leukemias (2.1%). LMD was mostly diagnosed with the co-presence of neurological-related symptoms and positive imaging and/or cerebrospinal fluid cytology (60.8%). The most common ITT agents were methotrexate (35.9%), cytarabine (21.9%), and thiotepa (8.2%), standalone or combined. Patients received a median of 6.5 ITT cycles (range, 1.0-71.0) via intraventricular (58.8%) or lumbar intrathecal (41.2%) routes. The Ommaya reservoir was implanted in 38.5% cases. Concurrent systemic chemotherapy (45.2%) and/or radiotherapy (30.6%) were used. After 1-3 cycles, 44.7% patients had improved clinical status and 29.9% converted into negative cerebrospinal fluid cytology. The most common ITT-related severe adverse events were neutropenia (6.5%), meningitis (5.2%) and encephalopathy (4.5%). Median freedom from progression was 2.4 months (range, 0.1-59.5) and median overall survival 5.5 months (range, 0.1-148.0). CONCLUSION Current ITT protocols are variable but effective and well-tolerated in LMD. Ongoing trials are investigating dose-limiting toxicity profiles and long-term overall survival. Future studies should analyze the therapeutic and safety profiles of ITT compared to newer systemic therapies.
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Affiliation(s)
- Paolo Palmisciano
- Department of Neurosurgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45229, USA.
| | - Gina Watanabe
- John A. Burns School of Medicine, University Oh Hawai'i, Honolulu, HI, USA
| | - Andie Conching
- John A. Burns School of Medicine, University Oh Hawai'i, Honolulu, HI, USA
| | - Christian Ogasawara
- Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Morana Vojnic
- Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health Cancer Institute, Lenox Hill Hospital, New York, NY, USA
| | - Randy S D'Amico
- Department of Neurological Surgery, Donald and Barbara Zucker School of Medicine at Hofstra, Lenox Hill Hospital, New York, NY, USA
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13
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Yuan M, Chen D, Sun H, Wang X, Wan D. Primary neuroendocrine carcinoma of the breast with leptomeninges metastasis: A case report and literature review. J Int Med Res 2022; 50:3000605221118505. [PMID: 36069002 PMCID: PMC9459456 DOI: 10.1177/03000605221118505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Primary neuroendocrine carcinoma of the breast (NECB) is a rare tumour with an incident rate of 0.3-0.5%. The most common metastatic sites of NECB are liver, bones, lung, pancreas, soft tissues and brain, while leptomeninges metastasis (LM) is reported rarely. This current case report describes a 50-year-old female patient with NECB and LM whose overall survival was 2 months. The report also presents the current literature regarding the knowledge of this unusual tumour and metastatic type. The current patient was diagnosed with NECB with right cerebellar metastasis, followed by LM. She underwent modified radical mastectomy of the left breast, left whole breast radiation therapy and incomplete adjuvant chemotherapy until the metastasis occurred. Whole-brain radiation therapy and a first-line salvage regimen of etoposide and cis-platinum were then undertaken. The patient died 2 months after their LM diagnosis. Primary NECB with LM is sporadic, devoid of effective treatment and associated with a poor prognosis. Consequently, it is vitally important to identify LM in order to achieve longer patient survival.
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Affiliation(s)
- Mengqi Yuan
- Department of Oncology, China-Japan Friendship Hospital, Beijing, China.,Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Dongmei Chen
- Department of Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Hongliang Sun
- Department of Radiology, China-Japan Friendship Hospital, Beijing, China
| | - Xiuhong Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Donggui Wan
- Department of Oncology, China-Japan Friendship Hospital, Beijing, China
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14
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Chi Y, Shang M, Xu L, Gong H, Tao R, Song L, Zhang B, Yin S, Cong B, Li H. Durable Effect of Pyrotinib and Metronomic Vinorelbine in HER2-Positive Breast Cancer With Leptomeningeal Disease: A Case Report and Literature Review. Front Oncol 2022; 12:811919. [PMID: 35251981 PMCID: PMC8888838 DOI: 10.3389/fonc.2022.811919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/25/2022] [Indexed: 12/26/2022] Open
Abstract
Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor. There is no high-quality evidence of treatment regimens in HER2-positive BC with LM yet. Here, we present a case of LM in a 50-year-old woman with HER2-positive BC. Immunohistochemistry revealed invasive ductal carcinoma, estrogen receptor negative, progesterone receptor negative, HER2 3+, P53 positive 80%, and Ki-67 positive 35%. Reported for the first time, the patient was given pyrotinib-targeted therapy (400 mg, oral, every day), metronomic vinorelbine (40 mg, oral, three times a week), and intrathecal methotrexate (10 mg, infrequent and irregular use due to poor compliance) synchronously. The patient received and benefited from the treatment regimen for 16 months. And the quality of life, as self-reported, improved significantly. We also comprehensively summarized all the case reports, observational studies, and clinical trials related to HER2-positive BC with LM in the PubMed database and ClinicalTrials.gov. Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa), intrathecal trastuzumab, whole-brain radiotherapy, and systemic therapy are commonly used treatment options according to a review of the literature and research. Pembrolizumab and trastuzumab deruxtecan (DS-8201) as novel drugs are promising in LM. Furthermore, trastuzumab emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs) such as tucatinib and neratinib have exhibited good efficacy in HER2-positive BC with central nervous system (CNS) metastases and deserve further exploration. In our report, combining pyrotinib-targeted therapy with metronomic chemotherapy is a potential regimen, which has presented satisfactory therapeutic efficacy and also warrants additional investigation in HER2-positive BC with LM.
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Affiliation(s)
- Yajing Chi
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- School of Medicine, Nankai University, Tianjin, China
| | - Mao Shang
- Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liang Xu
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Heyi Gong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Rongjie Tao
- Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Lihua Song
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Baoxuan Zhang
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Sha Yin
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Binbin Cong
- Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Huihui Li
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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15
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Colorectal signet ring cell carcinoma with leptomeningeal carcinomatosis: A case report and review of literature. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2021. [DOI: 10.1016/j.cpccr.2021.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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16
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Leptomeningeal Disease. Hematol Oncol Clin North Am 2021; 36:189-215. [PMID: 34756800 DOI: 10.1016/j.hoc.2021.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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17
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Mollica L, Leli C, Puglisi S, Sardi S, Sottotetti F. Leptomeningeal carcinomatosis and breast cancer: a systematic review of current evidence on diagnosis, treatment and prognosis. Drugs Context 2021; 10:dic-2021-6-6. [PMID: 34745272 PMCID: PMC8552906 DOI: 10.7573/dic.2021-6-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/14/2021] [Indexed: 02/02/2023] Open
Abstract
Leptomeningeal carcinomatosis (LC) is a rare but challenging manifestation of advanced breast cancer with a severe impact on morbidity and mortality. We performed a systematic review of the evidence published over the last two decades, focusing on recent advances in the diagnostic and therapeutic options of LC. Lobular histology and a triple-negative intrinsic subtype are well-known risk factors for LC. Clinical manifestations are diverse and often aspecific. There is no gold standard for LC diagnosis: MRI and cerebrospinal fluid cytology are the most frequently used modalities despite the low accuracy. Current standard of care involves a multimodal strategy including systemic and intrathecal chemotherapy in combination with brain radiotherapy. Intrathecal chemotherapy has been widely used through the years despite the lack of data from randomized controlled trials and conflicting evidence on patient outcomes. No specific chemotherapeutic agent has shown superiority over others for both intrathecal and systemic treatment. Although endocrine therapy was heuristically considered unable to exert significant control on central nervous system metastatic disease, retrospective data suggest a favourable toxicity profile and even a possible positive impact on survival. In recent years, encouraging data on the use of targeted agents has emerged but further research in this field is required. Palliative treatment in the form of whole brain or stereotactic radiotherapy is associated with improvement in clinical manifestations and quality of life, with no proven impact on survival. The most investigated prognostic factors include performance status, non-triple-negative disease and multimodal treatment. Validation of prognostic scores is necessary to aid clinicians in the identification of patient subgroups that are most likely to benefit from an intensive therapeutic approach.
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Affiliation(s)
| | - Claudia Leli
- Division of Medical Oncology, IRCCS-ICS Maugeri, Pavia, Italy
| | - Silvia Puglisi
- Division of Medical Oncology, Ospedale Policlinico San Martino, Genova, Italy
| | - Silvia Sardi
- Department of Anaesthesia and Intensive Care Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Federico Sottotetti
- Division of Medical Oncology, IRCCS-ICS Maugeri, Pavia, Italy.,Department of Molecular Medicine, University of Pavia, Pavia, Italy
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18
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Pennisi G, Burattini B, Gessi M, Montano N, Perna A, Silvestri G, Papacci F. Unusual case of long survival patient with leptomeningeal carcinomatosis from breast cancer. Br J Neurosurg 2021; 37:1-4. [PMID: 34137319 DOI: 10.1080/02688697.2021.1940860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 06/07/2021] [Indexed: 10/21/2022]
Abstract
Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma and often represents the end stage of cancer disease. In breast cancer, LC is associated with a median survival of approximately 6-8 weeks without specific treatment. It could increase by only few months with personalized treatment plans. Usually, the median time of onset of leptomeningeal spread is 18 months and it is diagnosed in up to 70% of patients with active and progressive systemic disease. We present an uncommon case of LC in a patient with history of breast cancer with a 10 year-disease-free condition and an overall survival after LC diagnosis of 10 months. Central Nervous System (CNS) Magnetic Resonance Imaging (MRI) showed contrast enhancement of medullary cone and cauda. Despite the negativity of cytological analysis of Cerebral-Spinal Fluid (CSF), the patient underwent meningeal and radicular biopsy in November 2019. The neuropathological examination confirmed the diagnosis of LC. The patient was started on the aromatase inhibitor anastrozole. A whole body contrast Computed Tomography (CT) scan at three months follow-up was negative for further disease dissemination. The patient is currently under oncological and radiological follow-up after more than 10 months from diagnosis. Although nowadays diagnosis of LC is prompted by cytological examination of CSF, its negativity should not halt the diagnostic process. In the presence of a high clinical suspicion of LC, we suggest the biopsy of lesion.
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Affiliation(s)
- Giovanni Pennisi
- Facoltà di Medicina e Chirurgia, Neurosurgery, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Benedetta Burattini
- Facoltà di Medicina e Chirurgia, Neurosurgery, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Marco Gessi
- Institute of Pathology, Policlinico Universitario Agostino Gemelli, Roma, Italy
| | - Nicola Montano
- Facoltà di Medicina e Chirurgia, Neurosurgery, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alessia Perna
- Facoltà di Medicina e Chirurgia, Institute of Neurology, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Gabriella Silvestri
- Facoltà di Medicina e Chirurgia, Institute of Neurology, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Fabio Papacci
- Facoltà di Medicina e Chirurgia, Neurosurgery, Università Cattolica del Sacro Cuore, Roma, Italy
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19
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Apostolidis L, Schrader J, Jann H, Rinke A, Krug S. Leptomeningeal Carcinomatosis: A Clinical Dilemma in Neuroendocrine Neoplasms. BIOLOGY 2021; 10:biology10040277. [PMID: 33800581 PMCID: PMC8066280 DOI: 10.3390/biology10040277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/26/2021] [Indexed: 11/16/2022]
Abstract
Central nervous system (CNS) involvement by paraneoplastic syndromes, brain metastases, or leptomeningeal carcinomatosis (LC) in patients with neuroendocrine neoplasms (NEN) has only been described in individual case reports. We evaluated patients with LC in four neuroendocrine tumor (NET) centers (Halle/Saale, Hamburg, Heidelberg, and Marburg) and characterized them clinically. In the study, 17 patients with a LC were defined with respect to diagnosis, clinic, and therapy. The prognosis of a LC is very poor, with 10 months in median overall survival (mOS). This is reflected by an even worse course in neuroendocrine carcinoma (NEC) G3 Ki-67 >55%, with a mOS of 2 months. Motor and sensory deficits together with vigilance abnormalities were common symptoms. In most cases, targeted radiation or temozolomide therapy was used against the LC. LC appears to be similarly devastating to brain metastases in NEN patients. Therefore, the indication for CNS imaging should be discussed in certain cases.
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Affiliation(s)
- Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Jörg Schrader
- I. Medical Department—Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Charité—University Medical Center Berlin, Campus Virchow Klinikum and Charité Mitte, Augustenburger Platz 1, 13353 Berlin, Germany;
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, University Hospital Marburg, Baldinger Strasse, 35043 Marburg, Germany
- Correspondence: (A.R.); (S.K.); Tel.: +49-0345-557-2661 (S.K.); Fax: +49-0345-557-2253 (S.K.)
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Correspondence: (A.R.); (S.K.); Tel.: +49-0345-557-2661 (S.K.); Fax: +49-0345-557-2253 (S.K.)
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20
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Claudel A, Talbot A, Harel S, Royer B, Naelle L, Zagdanski AM, Madelaine I, Lemaire P, Arnulf B. Thiotepa intrathecal injections for myelomatous central nervous system involvement. Br J Haematol 2021; 193:e9-e12. [PMID: 33686665 DOI: 10.1111/bjh.17343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Alexis Claudel
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Alexis Talbot
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Stéphanie Harel
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Bruno Royer
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Lombion Naelle
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Anne-Marie Zagdanski
- Department of Radiology, Saint-Louis Hospital (AP-HP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Isabelle Madelaine
- Pharmacy Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Pierre Lemaire
- Hematology Laboratory, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
| | - Bertrand Arnulf
- Immuno-Hematology Department, Saint-Louis Hospital (APHP), University of Paris Diderot-Paris VII (Sorbonne Paris Cité), Paris, France
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21
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Hyun JW, Shin HS, Kim SH, Kong SY, Yoo H, Gwak HS, Kim HJ. CYFRA 21-1 levels in cerebrospinal fluid as a putative therapeutic monitoring biomarker for patients with leptomeningeal carcinomatosis: A pilot study. Cancer Biomark 2021; 28:81-89. [PMID: 32176621 DOI: 10.3233/cbm-190187] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND To investigate the feasibility of cerebrospinal fluid (CSF) CYFRA 21-1 levels as a therapeutic monitoring biomarker in leptomeningeal carcinomatosis (LMC) patients undergoing ventriculo-lumbar perfusion (VLP) chemotherapy. METHODS The levels of CYFRA 21-1 in 42 CSF samples from 15 LMC patients were analyzed using an electrochemiluminescence immunoassay. Samples were collected at individual time points during VLP chemotherapy. Therapeutic outcomes were measured as improvements in the Karnofsky Performance Status (KPS) score and decreasing intracranial pressure (ICP) as the main endpoint of VLP chemotherapy. Changes in CSF CYFRA 21-1 levels, protein levels, and cytology results were also investigated. We subsequently evaluated whether these changes were correlated with KPS score and ICP. RESULTS The CSF CYFRA 21-1 levels at individual time points were associated with KPS score and ICP. The KPS scores (p= 0.007) and ICP (p= 0.018) of patients with high CSF CYFRA 21-1 levels were significantly different from those of patients with low CSF CYFRA 21-1 levels. By contrast, CSF protein levels and cytological responses were not significantly associated with KPS scores and ICP. CONCLUSIONS CSF CYFRA 21-1 may have utility as a therapeutic monitoring biomarker to design personalized therapeutic strategies in LMC patients undergoing VLP chemotherapy.
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Affiliation(s)
- Jae-Won Hyun
- Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Hyung Shik Shin
- Department of Laboratory Medicine, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Su-Hyun Kim
- Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Sun-Young Kong
- Department of Laboratory Medicine, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Heon Yoo
- Department of Neurosurgery, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Ho-Shin Gwak
- Department of Neurosurgery, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Ho Jin Kim
- Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea
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22
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Fernandes L, de Matos LV, Cardoso D, Saraiva M, Medeiros-Mirra R, Coelho A, Miranda H, Martins A. Endocrine therapy for the treatment of leptomeningeal carcinomatosis in luminal breast cancer: a comprehensive review. CNS Oncol 2020; 9:CNS65. [PMID: 33078616 PMCID: PMC7737195 DOI: 10.2217/cns-2020-0023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Leptomeningeal disease (LMD) represents a devastating complication of advanced breast cancer (ABC), with survival of <5 months with multimodal treatment. The role of endocrine therapy (ET), due to its favorable toxicity profile and first-line indication in luminal ABC, appears promising in the setting of LMD, where symptom stabilization and quality-of-life preservation are the main goals; however, evidenced-based data are lacking. We conducted a thorough review of published evidence, aiming to investigate the role of ET in LMD treatment in luminal ABC. Twenty-one of 342 articles, evaluating 1302 patients, met inclusion criteria. ET use was rarely reported. New targeted agents show CNS activity. Research is lacking on the role of ET and targeted agents in BC-LMD treatment.
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Affiliation(s)
- Leonor Fernandes
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
| | - Leonor Vasconcelos de Matos
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
| | - Débora Cardoso
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
| | - Marlene Saraiva
- Department of Neurology, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental, 1349-019 Lisboa, Portugal
| | - Renata Medeiros-Mirra
- Cardiff School of Dentistry, College of Biomedical & Life Sciences, Cardiff University, Cardiff CF10 3AT, Wales, UK
| | - Andreia Coelho
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
| | - Helena Miranda
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
| | - Ana Martins
- Department of Medical Oncology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, 1449-005 Lisboa, Portugal
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Smalley I, Law V, Wyatt C, Evernden B, Fang B, Koomen JM, Welsh EA, Macaulay RJB, Forsyth PA, Smalley KSM. Proteomic Analysis of CSF from Patients with Leptomeningeal Melanoma Metastases Identifies Signatures Associated with Disease Progression and Therapeutic Resistance. Clin Cancer Res 2020; 26:2163-2175. [PMID: 31924735 PMCID: PMC7196498 DOI: 10.1158/1078-0432.ccr-19-2840] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/24/2019] [Accepted: 01/08/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the cerebrospinal fluid (CSF) from patients with LMM to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells. EXPERIMENTAL DESIGN A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells that were subjected to RNA sequencing (RNA-seq) analysis. Functional assays were performed to validate the pathways identified. RESULTS Mass spectrometry analyses showed the CSF of most patients with LMM to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anticorrelated in the extraordinary responder. RNA-seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGFβ, and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGFβ expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays. CONCLUSIONS These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from patients with LMM has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.See related commentary by Glitza Oliva and Tawbi, p. 2083.
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Affiliation(s)
- Inna Smalley
- The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Vincent Law
- The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Neurooncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Clayton Wyatt
- The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Brittany Evernden
- Department of Neurooncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Bin Fang
- Proteomics and Metabolomics Core, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - John M Koomen
- Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Eric A Welsh
- Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Robert J B Macaulay
- Department of Neurooncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Peter A Forsyth
- Department of Neurooncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
| | - Keiran S M Smalley
- The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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25
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Franzoi MA, Hortobagyi GN. Leptomeningeal carcinomatosis in patients with breast cancer. Crit Rev Oncol Hematol 2019; 135:85-94. [PMID: 30819451 DOI: 10.1016/j.critrevonc.2019.01.020] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 01/26/2019] [Accepted: 01/26/2019] [Indexed: 12/11/2022] Open
Abstract
Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma, a relatively uncommon but devastating complication of many malignancies. Although only 5% of patients with breast cancer develop leptomeningeal involvement, it remains the most common etiology of LC. It can occur as a late-stage complication of systemic progression or present as the first sign of metastatic disease, with or without parenchymal brain metastases. Lobular carcinomas have a higher propensity to metastasize into the meninges when compared to ductal carcinoma, especially the triple-negative subtype, which usually is associated with a shorter interval between metastatic breast cancer diagnosis and the development of LC. Prognosis remains poor, with median survival of 4 months for patients receiving state-of-the-art treatment. The main factors associated with survival are performance status at diagnosis, CSF protein level and triple-negative subtype. Headache is commonly the first clinical presentation of LC, and the diagnostic workup usually requires CSF-cytological analysis and or/MRI. The current management of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiotherapy and/or best-supportive care. The standard intra-CSF chemotherapy regimen is methotrexate. Radiotherapy is used for relieving obstruction points on CSF-outflow channels due to ependymal nodules, tumor deposits or bulky disease. Objective responses have been reported with intrathecal administration of trastuzumab for HER2-positive disease, yet this strategy is still under investigation. Further prospective trials are needed to better address the impact of these treatment modalities on overall survival and quality of life.
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Affiliation(s)
| | - Gabriel N Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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26
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Assi HI, Mahmoud T, Saadeh FS, El Darsa H. Management of leptomeningeal metastasis in breast cancer. Clin Neurol Neurosurg 2018; 172:151-159. [PMID: 30015053 DOI: 10.1016/j.clineuro.2018.07.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/22/2018] [Accepted: 07/01/2018] [Indexed: 10/28/2022]
Abstract
Leptomeningeal metastasis (LM), which occurs when malignant cells spread to the central nervous system, is becoming an increasingly common complication in patients with breast cancer. Diagnosis and treatment of LM is challenging. Moreover, prognosis of patients with LM is poor, with a median survival of 6 months after diagnosis. This review highlights the strengths and limitations of currently available diagnostic tools and therapies for LM. The current treatments for LM, including radiotherapy, systemic therapy, and intrathecal treatment, aim to maintain the quality of life of patients by correcting neurological deficits and arresting neurological degeneration. However, there is no standardized therapy for LM because of a lack of randomized trials on this condition.
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Affiliation(s)
- Hazem I Assi
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Lebanon.
| | - Tala Mahmoud
- Faculty of Medicine, University of Balamand, Lebanon.
| | - Fadi S Saadeh
- Faculty of Medicine, American University of Beirut, Lebanon.
| | - Haidar El Darsa
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Lebanon.
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Le Rhun E, Taillibert S, Chamberlain MC. Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases. Cancer Control 2018; 24:22-32. [DOI: 10.1177/107327481702400104] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Emilie Le Rhun
- Division of Neuro-Oncology, Departments of Neurology and
Neurological Surgery, University of Washington School of Medicine, Seattle,
Washington
- Department of Neurosurgery, University Hospital, the Breast
Unit, Departments of Neurology and Neurological Surgery, University of Washington School of
Medicine, Seattle, Washington
| | - Sophie Taillibert
- Department of Medical Oncology, Oscar Lambret Center, Lille
Cedex, France, the Division of Neuro-Oncology, Departments of Neurology and Neurological
Surgery, University of Washington School of Medicine, Seattle, Washington
| | - Marc C. Chamberlain
- Departments of Neurology, and Radiation Oncology,
Pitié-Salpétrière Hospital, Assistance Publique des Hôpitaux de Paris, Université Pierre et
Marie Curie, Paris, France, and the Department of Neurology, Fred Hutchinson Cancer Research
Center, Seattle Cancer Care Alliance, and Division of Neuro-Oncology, Departments of
Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle,
Washington
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The necessity of intrathecal chemotherapy for the treatment of breast cancer patients with leptomeningeal metastasis: A systematic review and pooled analysis. Curr Probl Cancer 2017; 41:355-370. [DOI: 10.1016/j.currproblcancer.2017.07.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 06/23/2017] [Accepted: 07/07/2017] [Indexed: 11/19/2022]
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Diagnostic and prognostic values of cerebrospinal fluid CYFRA 21-1 in patients with leptomeningeal carcinomatosis. Oncotarget 2017; 8:53326-53335. [PMID: 28881814 PMCID: PMC5581113 DOI: 10.18632/oncotarget.18405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 05/18/2017] [Indexed: 11/25/2022] Open
Abstract
Objectives To investigate the diagnostic and prognostic values of cerebrospinal fluid (CSF) CYFRA 21-1 in patients with leptomeningeal carcinomatosis (LMC). Methods Concentration of CSF CYFRA 21-1 was detected using electro-chemiluminescent immunoassay. The difference in level of CYFRA 21-1 between 61 patients with LMC and 200 patients with other neurological disease was evaluated, and diagnostic performance of CSF CYFRA 21-1 was investigated. In LMC patients treated with ventriculo-lumbar perfusion (VLP) chemotherapy, prognostic performance of CSF CYFRA 21-1 was evaluated. Results The CSF CYFRA 21-1 was significantly higher in LMC patients than that in patients with other neurological diseases (p<0.001). The sensitivity, specificity, accuracy, and positive and negative predictive values were 80.3%, 95.0%, 91.6%, 83.1%, and 94.1% for CSF CYFRA 21-1, and 65.6%, 100%, 92.0%, 100%, and 90.5% for CSF cytology, respectively. The use of high CSF CYFRA 21-1 and/or positive CSF cytology findings resulted in an increased sensitivity of 85.3%, without compromising specificity. LMC patients with high CSF CYFRA 21-1 were more frequently accompanied by positive CSF cytology results than those with low CSF CYFRA 21-1. The median overall survival was longer in LMC patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1 (p=0.031). During VLP chemotherapy, the clinical responses were found to be correlated with the biological responses, including the level of CSF CYFRA 21-1 and intracranial pressure. Conclusions CSF CYFRA 21-1 might be regarded as an additional diagnostic tool for LMC and a potential significant prognostic biomarker in LMC patients treated with VLP chemotherapy.
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Cordone I, Masi S, Summa V, Carosi M, Vidiri A, Fabi A, Pasquale A, Conti L, Rosito I, Carapella CM, Villani V, Pace A. Overexpression of syndecan-1, MUC-1, and putative stem cell markers in breast cancer leptomeningeal metastasis: a cerebrospinal fluid flow cytometry study. Breast Cancer Res 2017; 19:46. [PMID: 28399903 PMCID: PMC5387324 DOI: 10.1186/s13058-017-0827-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 03/03/2017] [Indexed: 01/09/2023] Open
Abstract
Background Cancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness. We focused on one of the most aggressive circulating tumor cells (CTCs) which, from the primitive tumor, spreads to the central nervous system (CNS), evaluating the expression of prognostic and putative cancer stem cell markers in breast cancer (BC) leptomeningeal metastasis (LM). Methods Flow cytometry immunophenotypic analysis of cerebrospinal fluid (CSF) samples (4.5 ml) was performed in 13 consecutive cases of BCLM. Syndecan-1 (CD138), MUC-1 (CD227) CD45, CD34, and the putative cancer stem cell markers CD15, CD24, CD44, and CD133 surface expression were evaluated on CSF floating tumor cells. The tumor-associated leukocyte population was also characterized. Results Despite a low absolute cell number (8 cell/μl, range 1–86), the flow cytometry characterization was successfully conducted in all the samples. Syndecan-1 and MUC-1 overexpression was documented on BC cells in all the samples analyzed; CD44, CD24, CD15, and CD133 in 77%, 75%, 70%, and 45% of cases, respectively. A strong syndecan-1 and MUC-1 expression was also documented by immunohistochemistry on primary breast cancer tissues, performed in four patients. The CSF tumor population was flanked by T lymphocytes, with a different immunophenotype between the CSF and peripheral blood samples (P ≤ 0.02). Conclusions Flow cytometry can be successfully employed for solid tumor LM characterization even in CSF samples with low cell count. This in vivo study documents that CSF floating BC cells overexpress prognostic and putative cancer stem cell biomarkers related to tumor invasiveness, potentially representing a molecular target for circulating tumor cell detection and LM treatment monitoring, as well as a primary target for innovative treatment strategies. The T lymphocyte infiltration, documented in all CSF samples, suggests a possible involvement of the CNS lymphatic system in both lymphoid and cancer cell migration into and out of the meninges, supporting the extension of a new form of cellular immunotherapy to LM. Due to the small number of cases, validation on large cohorts of patients are warranted to confirm these findings and to evaluate the impact and value of these results for diagnosis and management of LM. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0827-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Iole Cordone
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy.
| | - Serena Masi
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Valentina Summa
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Mariantonia Carosi
- Regina Elena National Cancer Institute, Histopathology Department, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Antonello Vidiri
- Regina Elena National Cancer Institute, Radiology Department, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Alessandra Fabi
- Regina Elena National Cancer Institute, Medical Oncology Department, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Alessia Pasquale
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Laura Conti
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Immacolata Rosito
- Regina Elena National Cancer Institute, Clinical Pathology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Carmine Maria Carapella
- Regina Elena National Cancer Institute, Neuro-Surgery Department, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Veronica Villani
- Regina Elena National Cancer Institute, Neuro-Oncology Division, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Andrea Pace
- Regina Elena National Cancer Institute, Neuro-Oncology Division, Via Elio Chianesi 53, 00144, Rome, Italy
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31
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Liu H, Tariq R, Liu GL, Yan H, Kaye AD. Inadvertent intrathecal injections and best practice management. Acta Anaesthesiol Scand 2017; 61:11-22. [PMID: 27766633 DOI: 10.1111/aas.12821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 09/20/2016] [Accepted: 09/25/2016] [Indexed: 12/25/2022]
Abstract
The intrathecal space has become an important anatomic site for medical intervention not only in anesthesia practice, but also in many other medical specialties. Undesired/inadvertent intrathecal injections (UII) are generally rare. There is tremendous variation in reported inadvertent administrations via an intrathecal route in the literature, mainly as individual cases and very small case-series reports. This review aims to identify potential sources of UII, its clinical presentations, and appropriate management. The inadvertent injectants are classified as anesthetic agents and pain medicines, chemotherapeutics, radiological contrast agents, antibiotics and corticosteroids, and miscellaneous chemical agents such as tranexamic acid. The clinical effects of UII are dependent upon inadvertent injectant(s) and dose being administered intrathecally, and can range from no adverse effect to profound neurological consequences and/or death. Prompt cerebrospinal fluid (CSF) lavage and cardiopulmonary support seem to be the mainstay of treatment. If serious consequences are anticipated, CSF lavage could be lifesaving. This review additionally provides some options for comprehensive management and preventing strategies.
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Affiliation(s)
- H. Liu
- Department of Anesthesiology & Perioperative Medicine; Drexel University College of Medicine; Hahnemann University Hospital; Philadelphia PA USA
| | - R. Tariq
- Department of Anesthesiology & Perioperative Medicine; Drexel University College of Medicine; Hahnemann University Hospital; Philadelphia PA USA
| | - G. L. Liu
- Department of Anesthesiology & Perioperative Medicine; Drexel University College of Medicine; Hahnemann University Hospital; Philadelphia PA USA
| | - H. Yan
- Department of Anesthesiology; Wuhan Central Hospital; Wuhan Hubei China
| | - A. D. Kaye
- Department of Anesthesiology; LSUHSC-New Orleans; New Orleans LA USA
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32
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Meissner M, Addeo A. Intrathecal Methotrexate and Craniospinal Radiotherapy Can Be an Effective Treatment of Carcinomatous Meningitis in Patients with Breast Cancer: Case Reports. Case Rep Oncol 2016; 9:586-592. [PMID: 27920689 PMCID: PMC5118826 DOI: 10.1159/000449448] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 08/28/2016] [Indexed: 11/19/2022] Open
Abstract
Introduction Carcinomatous meningitis in breast cancer occurs as a complication in up to 5% of all cases. It is a very devastating diagnosis, with a median patient survival of about 3 months. Treatment is very controversial, and different modalities of treatment have been used but none of them show significant benefit for overall survival. Case Reports We report 2 cases of carcinomatous meningitis in breast cancer patients. They received a similar treatment of a combination of intrathecal (IT) methotrexate followed by craniospinal radiotherapy. Both patients survived for many years after treatment and are in complete clinical and radiological remission. Conclusion Meningeal metastasis from breast cancer can be very effectively treated with IT and/or systemic chemotherapy followed by craniospinal radiotherapy. Further studies are needed to determine the effectiveness of this sequential combination of chemotherapy with radiotherapy.
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Affiliation(s)
| | - Alfredo Addeo
- Bristol Cancer Institute, University Hospitals Bristol Foundation NHS Trust, Bristol, UK
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33
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Dudani S, Mazzarello S, Hilton J, Hutton B, Vandermeer L, Fernandes R, Ibrahim MFK, Smith S, Majeed H, Al-Baimani K, Caudrelier JM, Shorr R, Clemons M. Optimal Management of Leptomeningeal Carcinomatosis in Breast Cancer Patients-A Systematic Review. Clin Breast Cancer 2016; 16:456-470. [PMID: 27553811 DOI: 10.1016/j.clbc.2016.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 06/22/2016] [Accepted: 07/20/2016] [Indexed: 11/19/2022]
Abstract
The incidence of leptomeningeal carcinomatosis in breast cancer patients (LC-BC) is increasing. Despite significantly affecting patient quality of life (QoL) and overall survival (OS), little is known about its optimal management. A systematic review of treatment strategies for LC-BC was performed. EMBASE, Ovid Medline, Pubmed, and the Cochrane Central Register of Controlled Trials were searched from 1946 to 2015 for trials reporting on treatments for LC-BC. All treatment modalities and study types were considered. The outcome measures of interest included OS, time to neurologic progression (TTNP), QoL, and treatment toxicity. Of 718 unique citations, 173 studies met the prespecified eligibility criteria. Most were not specific to LC-BC patients. Of 4 identified randomized controlled trials (RCTs), 1 was specific to LC-BC patients and compared systemic therapy and involved-field radiotherapy with or without intrathecal (IT) methotrexate (35 patients), and the remaining 3 had compared different IT chemotherapy regimens (58 of 157 with LC-BC). Of the remaining studies, 19 were nonrandomized interventional studies (225 LC-BC patients), 148 were observational studies (3230 LC-BC patients), and 2 systematic reviews. Minimal prospective data were available on OS, TTNP, QoL, and toxicity. Owing to study heterogeneity, meta-analyses of the endpoint data could not be performed. Limited high-quality evidence exists regarding optimal treatment of LC-BC. The identified studies were heterogeneous and often methodologically poor. The only RCT that specifically assessed the role of IT chemotherapy showed no benefit, and, if anything, harm. Further prospective, tumor-specific trials with improved interstudy methodologic consistency and transparently reported data on OS, TTNP, QoL, and toxicity are urgently needed.
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Affiliation(s)
- Shaan Dudani
- Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | | | - John Hilton
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Division of Medical Oncology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | - Brian Hutton
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | | | - Ricardo Fernandes
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | - Mohammed F K Ibrahim
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | | | - Habeeb Majeed
- Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | - Khalid Al-Baimani
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada
| | - Jean-Michel Caudrelier
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Radiation Medicine, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada
| | | | - Mark Clemons
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Division of Medical Oncology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada.
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Smalley KSM, Fedorenko IV, Kenchappa RS, Sahebjam S, Forsyth PA. Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer 2016; 139:1195-201. [PMID: 27084046 DOI: 10.1002/ijc.30147] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/24/2016] [Accepted: 04/08/2016] [Indexed: 12/11/2022]
Abstract
Melanoma frequently metastasizes to the brain, with CNS involvement being clinically evident in ∼30% of patients (as high as 75% at autopsy). In ∼5% cases melanoma cells also metastasize to the leptomeninges, the sub-arachnoid space and cerebrospinal fluid (CSF). Patients with leptomeningeal melanoma metastases (LMM) have the worst prognosis and are characterized by rapid disease progression (mean survival 8-10 weeks) and a death from neurological causes. The recent years have seen tremendous progress in the development of targeted and immune therapies for melanoma that has translated into an increased survival benefit. Despite these gains, the majority of patients fail therapy and there is a suspicion that the brain and the leptomeninges are a "sanctuary" sites for melanoma cells that escape both targeted therapy and immunologic therapies. Emerging evidence suggests that (1) Cancer cells migrating to the CNS may have unique molecular properties and (2) the CNS/leptomeningeal microenvironment represents a pro-survival niche that influences therapeutic response. In this Mini-Review, we will outline the clinical course of LMM development and will describe how the intracranial immune and cellular microenvironments offer both opportunities and challenges for the successful management of this disease. We will further discuss the latest data demonstrating the potential use of BRAF inhibitors and immune therapy in the management of LMM, and will review future potential therapeutic strategies for the management of this most devastating complication of advanced melanoma.
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Affiliation(s)
- Keiran S M Smalley
- The Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL.,Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Inna V Fedorenko
- The Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Rajappa S Kenchappa
- The Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL.,Department of NeuroOncology, Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Solmaz Sahebjam
- Department of NeuroOncology, Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Peter A Forsyth
- The Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL.,Department of NeuroOncology, Moffitt Cancer Center & Research Institute, Tampa, FL.,Department of Oncology, Tom Baker Cancer Center & University of Calgary, Calgary, AB, Canada
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Nair A. Implications of Intrathecal Chemotherapy for Anaesthesiologists: A Brief Review. SCIENTIFICA 2016; 2016:3759845. [PMID: 27123363 PMCID: PMC4830729 DOI: 10.1155/2016/3759845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 03/14/2016] [Indexed: 06/02/2023]
Abstract
Intrathecal chemotherapy is routinely prescribed in medical oncology practice, either for prophylaxis or for treatment of leptomeningeal disease due to a primary haematological disease or a metastatic disease due to any other malignancy. As these groups of patients are coagulopathic either because of the disease per se or due to systemic chemotherapy, lumbar puncture in them is considered challenging and is expected to be performed by an anaesthesiologist because of their expertise in this procedure. However, the challenge is not only in performing the lumbar puncture safely but also in dealing with other issues like explaining and handling complications that can happen either due to the drug injected intrathecally or due to a neurodeficit occurring either due to the underlying coagulopathy or due to the progression of leptomeningeal disease.
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Affiliation(s)
- Abhijit Nair
- Department of Anaesthesiology, Basavatarakam Indo-American Cancer Institute and Research Centre, Hyderabad 500034, India
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36
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Cochereau D, Da Costa S, Le Maignan C, Gauthier H, Cochereau J, Espié M, Giacchetti S, Teixeira L. [Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule]. Bull Cancer 2016; 103:444-54. [PMID: 26987841 DOI: 10.1016/j.bulcan.2016.02.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 02/06/2016] [Accepted: 02/08/2016] [Indexed: 12/30/2022]
Abstract
Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression.
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Affiliation(s)
- Delphine Cochereau
- AP-HP, hôpital Saint-Louis, centre des maladies du sein, 1, avenue Claude-Vellefaux, 75010 Paris, France.
| | - Sabrina Da Costa
- AP-HP, hôpital Saint-Louis, centre des maladies du sein, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Christine Le Maignan
- AP-HP, hôpital Saint-Louis, service d'oncologie médicale, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Hélène Gauthier
- AP-HP, hôpital Saint-Louis, service d'oncologie médicale, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Jérôme Cochereau
- CHRU, hôpital Gui-de-Chauliac, service de neurochirurgie, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France
| | - Marc Espié
- AP-HP, hôpital Saint-Louis, centre des maladies du sein, 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris-Diderot, UFR de médecine, 75890 Paris cedex 18, France
| | - Sylvie Giacchetti
- AP-HP, hôpital Saint-Louis, centre des maladies du sein, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Luis Teixeira
- AP-HP, hôpital Saint-Louis, centre des maladies du sein, 1, avenue Claude-Vellefaux, 75010 Paris, France; AP-HP, hôpital Saint-Louis, service d'oncologie médicale, 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris-Diderot, UFR de médecine, 75890 Paris cedex 18, France
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Park MJ. Durable Response of Leptomeningeal Metastasis of Breast Cancer to Salvage Intrathecal Etoposide After Methotrexate: A Case Report and Literature Review. AMERICAN JOURNAL OF CASE REPORTS 2015; 16:524-7. [PMID: 26258900 PMCID: PMC4535194 DOI: 10.12659/ajcr.894007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Patient: Female, 42 Final Diagnosis: Breast cancer with leptomeningeal metastasis Symptoms: Headache Medication: Etoposide Clinical Procedure: Intrathecal chemotherapy Specialty: Oncology
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Affiliation(s)
- Min Jae Park
- Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea, South
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Intravenous thiotepa for treatment of breast cancer-related leptomeningeal carcinomatosis: case series. Neurol Sci 2015; 36:1691-3. [PMID: 25990104 DOI: 10.1007/s10072-015-2259-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 05/15/2015] [Indexed: 12/22/2022]
Abstract
Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.
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Gallagher SM, Selman SH. From the battlefield to the bladder: The development of thioTEPA. World J Clin Urol 2014; 3:195-200. [DOI: 10.5410/wjcu.v3.i3.195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 06/01/2014] [Accepted: 08/29/2014] [Indexed: 02/06/2023] Open
Abstract
Effective medications for the treatment of cancer were nonexistent in the early twentieth century. Ironically the widespread use of toxic chemical weapons, chlorine and sulfur mustard gas, during the “Great War” led to the first successful chemotherapeutic treatment of cancer patients. Soon after the introduction of poisonous gas on the battlefield, reports of the resulting pancytopenia in exposed combatants appeared in the medical literature. The biologic effect of chemical weaponry on rapidly dividing cells eventually was recognized for its salutary potential in the treatment of cancer. Once this potential was appreciated, hundreds of similar compounds were synthesized and evaluated as chemotherapeutic agents. One such compound, thioTEPA, would eventually open the era of intravesical treatment of urothelial cancer.
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