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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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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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Buczek D, Zaucha R, Jassem J. Neurotoxicity-sparing radiotherapy for brain metastases in breast cancer: a narrative review. Front Oncol 2024; 13:1215426. [PMID: 38370347 PMCID: PMC10869626 DOI: 10.3389/fonc.2023.1215426] [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: 05/01/2023] [Accepted: 12/19/2023] [Indexed: 02/20/2024] Open
Abstract
Breast cancer brain metastasis (BCBM) has a devastating impact on patient survival, cognitive function and quality of life. Radiotherapy remains the standard management of BM but may result in considerable neurotoxicity. Herein, we describe the current knowledge on methods for reducing radiation-induced cognitive dysfunction in patients with BCBM. A better understanding of the biology and molecular underpinnings of BCBM, as well as more sophisticated prognostic models and individualized treatment approaches, have appeared to enable more effective neuroprotection. The therapeutic armamentarium has expanded from surgery and whole-brain radiotherapy to stereotactic radiosurgery, targeted therapies and immunotherapies, used sequentially or in combination. Advances in neuroimaging have allowed more accurate screening for intracranial metastases, precise targeting of intracranial lesions and the differentiation of the effects of treatment from disease progression. The availability of numerous treatment options for patients with BCBM and multidisciplinary approaches have led to personalized treatment and improved therapeutic outcomes. Ongoing studies may define the optimal sequencing of available and emerging treatment options for patients with BCBM.
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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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Wang H, Liu Q, Zhang M, Zhang J, Ran R, Ma Y, Yang J, Wang F, He S, Zhao X, Wang L, Zhang L, Dong D, Yang J. Real-world data of pyrotinib-based therapy for patients with brain metastases of HER2-positive advanced breast cancer: a single-center retrospective analysis and molecular portraits. Front Oncol 2023; 13:1105474. [PMID: 37397372 PMCID: PMC10313114 DOI: 10.3389/fonc.2023.1105474] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Introduction Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined. Methods and materials Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM. Results The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038). Conclusions Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.
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Affiliation(s)
- Hui Wang
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Qiaoyan Liu
- Department of Oncology, Xi’an Ninth Hospital, Xi’an, China
| | - Mi Zhang
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Juan Zhang
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ran Ran
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yingying Ma
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jiao Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Fan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shujuan He
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoai Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Le Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Lingxiao Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Danfeng Dong
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jin Yang
- Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Doshi K, James E. A Rare Case of Metastasis of Gastric Adenocarcinoma to the Leptomeninges. Cureus 2023; 15:e37120. [PMID: 37153327 PMCID: PMC10159219 DOI: 10.7759/cureus.37120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2023] [Indexed: 04/07/2023] Open
Abstract
Leptomeningeal carcinomatosis (LMC) is defined as the diffuse infiltration of malignant cells throughout the pia and arachnoid membrane. LMC is commonly observed in patients with leukemia, lymphoma, and breast and lung cancer. The prevalence of LMC spread in patients with primary gastric malignancy is very rare. Due to its devastating neurological complications and high mortality, it is difficult to assess the associated clinical features, treatment outcomes, and prognostic factors. Current treatment options include intra-thecal chemotherapy, radiotherapy, and supportive care with a median survival of three to four months. LMC is a rare manifestation of gastric cancer and is an extremely fatal disease. Therefore, it is difficult to distinguish LMC from other neurological etiologies. We present a unique case of an individual who presented with headaches and was found to have LMC.
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Sun H, Xu J, Dai S, Ma Y, Sun T. Breast cancer brain metastasis: Current evidence and future directions. Cancer Med 2023; 12:1007-1024. [PMID: 35822637 PMCID: PMC9883555 DOI: 10.1002/cam4.5021] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast cancer patients, affecting their survival and quality of life. Compared with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients, brain metastases are more likely to affect patients with triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.
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Affiliation(s)
- Hongna Sun
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Junnan Xu
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Shuang Dai
- Department of Medical Oncology, Lung cancer center, West China HospitalSichuan UniversityChengduChina
| | - Yiwen Ma
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Tao Sun
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
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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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Ebrahimi Z, Talaei S, Aghamiri S, Goradel NH, Jafarpour A, Negahdari B. Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours. IET Nanobiotechnol 2020; 14:441-448. [PMID: 32755952 PMCID: PMC8676526 DOI: 10.1049/iet-nbt.2019.0351] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/30/2020] [Accepted: 04/24/2020] [Indexed: 07/31/2023] Open
Abstract
Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide-based delivery, local delivery strategies, NP delivery, and cell-based delivery have been fully discussed.
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Affiliation(s)
- Zahra Ebrahimi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sam Talaei
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahin Aghamiri
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Jafarpour
- Students' Scientific Research Center, Virology Division, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zagouri F, Zoumpourlis P, Le Rhun E, Bartsch R, Zografos E, Apostolidou K, Dimopoulos MA, Preusser M. Intrathecal administration of anti-HER2 treatment for the treatment of meningeal carcinomatosis in breast cancer: A metanalysis with meta-regression. Cancer Treat Rev 2020; 88:102046. [PMID: 32599393 DOI: 10.1016/j.ctrv.2020.102046] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 05/29/2020] [Accepted: 05/29/2020] [Indexed: 12/31/2022]
Abstract
Leptomeningeal Metastases (LM) is a turning point in terms of prognosis and quality of life of patients with breast cancer (BC). Intrathecal therapy is largely used for the treatment of breast cancer LM. In this metanalysis with meta-regression, we gathered data on intrathecal (IT) trastuzumab administration in patients with HER2 positive breast cancer with LM. A total of 24 articles (58 patients) were included in the study and intrathecal trastuzumab was used in all patients. The mean age at IT administration was 50.7 years (SD 11.4, range 24-80) and the mean total dose of IT trastuzumab was 711.9 mg (SD 634.9, median 450). IT trastuzumab was used both alone (n = 20) and in combination with systemic pharmacotherapy (n = 37). No serious adverse events were reported in 87.9% of cases. In this selected population a significant clinical improvement was observed in 55.0% of cases while stabilization was reported in 14% of cases. CSF response was observed in 55.6% of the cases. MRI was improved or stable in 70.8% of the cases. Interestingly, the CNS-PFS was 5.2 months and the median OS was 13.2 months. A clinical improvement (HR 0.13, 95% CI 0.03-0.49) and CSF response (HR 0.13, 95% CI 0.03-0.58) were associated with a longer CNS-PFS. The association of longer CNS-PFS with radio- or neurosurgery prior to the administration of IT trastuzumab did not reach statistical significance. This metanalysis with meta-regression indicates that IT trastuzumab in patients with HER2 positive breast cancer LM might be a safe and effective treatment, but further prospective studies are needed to definitively prove such a point.
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Affiliation(s)
- Flora Zagouri
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens 11528, Greece.
| | - Panagiotis Zoumpourlis
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens 11528, Greece
| | - Emilie Le Rhun
- Breast Cancer Department, Oscar Lambret Center, Lille, France; Department of Neurology & Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
| | - Rupert Bartsch
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria.
| | - Eleni Zografos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens 11528, Greece
| | - Kleoniki Apostolidou
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens 11528, Greece
| | | | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria.
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12
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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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13
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Nguyen TT, Angeli E, Darrouzain F, Nguyen QT, Desvignes C, Rigal M, Nevine O, Nicolas P, Le QV, Winterman S, Pailler MC, Zelek L, Paintaud G, Janin A, Bousquet G. A successful compartmental approach for the treatment of breast cancer brain metastases. Cancer Chemother Pharmacol 2019; 83:573-580. [PMID: 30610367 DOI: 10.1007/s00280-018-3752-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 12/04/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND Brain metastases are challenging daily practice in oncology and remain a compartmental problem since most anti-cancer drugs do not cross the blood-brain barrier at relevant pharmacological concentrations. METHODS In a young woman with HER2-overexpressing breast cancer resistant to standard treatments, at the time of brain metastases progression, a ventricular reservoir was implanted for intrathecal drug injections and detailed pharmacokinetic studies. RESULTS A first association of intrathecal trastuzumab with intravenous cisplatin was offered to the patient. For trastuzumab, the mean cerebrospinal fluid trough concentration of 53.4 mg/L reached relevant levels, enabling the stabilization of the metastases. Adding intravenous cisplatin was not beneficial, since the cerebrospinal fluid exposure was almost undetectable under 0.08 mg/L. We then offered the patient an intrathecal combination of trastuzumab and methotrexate, because of their in vitro synergic cytotoxicity. The cerebrospinal fluid peak of methotrexate was 1037 µmol/L at 2 h, and the concentrations remained above the theoretical therapeutic concentration. After 2 months of this drug combination, we obtained an excellent response on the brain metastases. CONCLUSION Our preliminary study supports the interest of a compartmental approach through a direct administration of drugs into the cerebrospinal fluid for the treatment of breast cancer brain metastases.
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Affiliation(s)
- Thuy T Nguyen
- U1165, Université Paris 7, INSERM, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France.,AP-HP Hôpital Avicenne, Service d'Oncologie Médicale, 93000, Bobigny, France.,Medical Oncology Department A, National Cancer Hospital, Ha Noi, Viet Nam
| | - Eurydice Angeli
- U1165, Université Paris 7, INSERM, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - François Darrouzain
- Université François-Rabelais de Tours, CNRS, GICC UMR 7292, 37000, Tours, France.,CHRU de Tours, Pharmacologie-Toxicologie, 37000, Tours, France
| | - Quang T Nguyen
- Medical Oncology Department A, National Cancer Hospital, Ha Noi, Viet Nam
| | | | - Marthe Rigal
- AP-HP Hôpital Avicenne, Pharmacie, 93000, Bobigny, France
| | - Osman Nevine
- AP-HP Hôpital Avicenne, Pharmacie, 93000, Bobigny, France
| | - Patrick Nicolas
- AP-HP Hôpital Avicenne, Service de Biochimie, 93000, Bobigny, France
| | - Quang V Le
- Surgery Department A, National Cancer Hospital, Ha Noi, Viet Nam
| | - Sabine Winterman
- AP-HP Hôpital Avicenne, Service d'Oncologie Médicale, 93000, Bobigny, France
| | | | - Laurent Zelek
- AP-HP Hôpital Avicenne, Service d'Oncologie Médicale, 93000, Bobigny, France.,Université Paris 13, 93430, Villetaneuse, France
| | - Gilles Paintaud
- Université François-Rabelais de Tours, CNRS, GICC UMR 7292, 37000, Tours, France.,CHRU de Tours, Pharmacologie-Toxicologie, 37000, Tours, France
| | - Anne Janin
- U1165, Université Paris 7, INSERM, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France. .,AP-HP Hôpital Saint-Louis, Laboratoire de Pathologie, 75010, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1165, 75010, Paris, France.
| | - Guilhem Bousquet
- U1165, Université Paris 7, INSERM, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France. .,AP-HP Hôpital Avicenne, Service d'Oncologie Médicale, 93000, Bobigny, France. .,Université Paris 13, 93430, Villetaneuse, France. .,Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1165, 75010, Paris, France.
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14
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Abstract
Leptomeningeal metastasis (LM) results from dissemination of cancer cells to both the leptomeninges (pia and arachnoid) and cerebrospinal fluid (CSF) compartment. Breast cancer, lung cancer, and melanoma are the most common solid tumors that cause LM. Recent approval of more active anticancer therapies has resulted in improvement in survival that is partly responsible for an increased incidence of LM. Neurologic deficits, once manifest, are mostly irreversible, and often have a significant impact on patient quality of life. LM-directed therapy is based on symptom palliation, circumscribed use of neurosurgery, limited field radiotherapy, intra-CSF and systemic therapies. Novel methods of detecting LM include detection of CSF circulating tumor cells and tumor cell-free DNA. A recent international guideline for a standardization of response assessment in LM may improve cross-trial comparisons as well as within-trial evaluation of treatment. An increasing number of retrospective studies suggest that molecular-targeted therapy, such as EGFR and ALK inhibitors in lung cancer, trastuzumab in HER2+ breast cancer, and BRAF inhibitors in melanoma, may be effective as part of the multidisciplinary management of LM. Prospective randomized trials with standardized response assessment are needed to further validate these preliminary findings.
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15
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Sahebjam S, Forsyth PA, Smalley KS, Tran ND. Experimental Treatments for Leptomeningeal Metastases From Solid Malignancies. Cancer Control 2017; 24:42-46. [PMID: 28178711 DOI: 10.1177/107327481702400106] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Leptomeningeal metastasis is a consequence of advanced solid malignancies and has limited treatment options. It is possible that it is becoming more common as the leptomeninges act as a sanctuary site for recurrence from systemic cancer. METHODS Potential targeted and immunotherapy agents for the most common types of solid-tumor leptomeningeal metastasis are reviewed, as are their dosing/delivery strategies and novel, immunological approaches. RESULTS Historically, patients with leptomeningeal metastasis have been excluded from clinical trials, and data on the management of leptomeningeal metastasis come from single case reports and retrospective analyses. CONCLUSION For the first time ever, published reports suggest the tide may be turning in this challenging disease.
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Affiliation(s)
- Solmaz Sahebjam
- Department of Neuro-Oncology, Moffitt Cancer Center and Department of Oncologic, University of South Florida Morsani College of Medicine, Tampa, FL.
| | - Peter A Forsyth
- Department of Neuro-Oncology, Moffitt Cancer Center and Department of Oncologic, University of South Florida Morsani College of Medicine, Tampa, FL, and the Tom Baker Cancer Center and University of Calgary, Alberta, Canada
| | - Keiran S Smalley
- Departments of Tumor Biology and Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL
| | - Nam D Tran
- Department of Neuro-Oncology, Moffitt Cancer Center and Department of Oncologic, University of South Florida Morsani College of Medicine, Tampa, FL
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16
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Maximiano S, Magalhães P, Guerreiro MP, Morgado M. Trastuzumab in the Treatment of Breast Cancer. BioDrugs 2016; 30:75-86. [PMID: 26892619 DOI: 10.1007/s40259-016-0162-9] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Breast cancer (BC) is the most common cancer in women worldwide, and has an undeniable negative impact on public health. The advent of molecular biology and immunotherapy has made targeted therapeutic interventions possible, providing treatments tailored to the individual characteristics of the patient and the disease. The over-expression of human epidermal growth factor receptor (HER) 2 is implicated in the pathophysiology of BC and represents a clinically relevant biomarker for its treatment. Trastuzumab, a recombinant antibody targeting HER2, was the first biological drug approved for the treatment of HER2-positive BC. Although there are currently other anti-HER2 agents available (e.g. pertuzumab and lapatinib), trastuzumab remains the gold standard for treatment of this disease subtype. Nonetheless, concerns have been raised regarding potential cardiotoxicity and treatment resistance. Moreover, several other therapeutic issues remain unclear and have been addressed in an inconsistent way. The current literature lacks a comprehensive review of trastuzumab providing useful information for clinical practice, including pharmacokinetic and pharmacodynamic aspects, its clinical use, existing controversies and future advances. This detailed review of trastuzumab in the pharmacotherapy of BC attempts to fill this gap.
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Affiliation(s)
- Sofia Maximiano
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, Covilhã, Portugal
| | - Paulo Magalhães
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, Covilhã, Portugal.,Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, Portugal.,CNC, Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz, Spain
| | - Mara Pereira Guerreiro
- Lisbon Nursing School (ESEL), Lisbon, Portugal.,CiiEM, Institute of Health Sciences Egas Moniz (ISCSEM), Monte de Caparica, Portugal
| | - Manuel Morgado
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, Covilhã, Portugal. .,Cova da Beira Hospital Centre, E.P.E., Quinta do Alvito, 6200-251, Covilhã, Portugal.
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17
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Hersh DS, Wadajkar AS, Roberts NB, Perez JG, Connolly NP, Frenkel V, Winkles JA, Woodworth GF, Kim AJ. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr Pharm Des 2016; 22:1177-1193. [PMID: 26685681 PMCID: PMC4900538 DOI: 10.2174/1381612822666151221150733] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 12/18/2015] [Indexed: 01/10/2023]
Abstract
The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.
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Affiliation(s)
| | | | | | | | | | | | | | - Graeme F. Woodworth
- Address correspondence to these authors at the Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201; E-mail: , Departments of Neurosurgery and Pharmaceutical Sciences, University of Maryland, Baltimore, 655 W. Baltimore Street, Baltimore, MD 21201;, E-mail:
| | - Anthony J. Kim
- Address correspondence to these authors at the Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201; E-mail: , Departments of Neurosurgery and Pharmaceutical Sciences, University of Maryland, Baltimore, 655 W. Baltimore Street, Baltimore, MD 21201;, E-mail:
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18
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Lu NT, Raizer J, Gabor EP, Liu NM, Vu JQ, Slamon DJ, Barstis JL. Intrathecal trastuzumab: immunotherapy improves the prognosis of leptomeningeal metastases in HER-2+ breast cancer patient. J Immunother Cancer 2015; 3:41. [PMID: 26380087 PMCID: PMC4570757 DOI: 10.1186/s40425-015-0084-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 08/04/2015] [Indexed: 11/10/2022] Open
Abstract
We describe the clinical and therapeutic course of a 51-year-old woman with HER-2+ breast cancer who developed leptomeningeal (LM) and spinal cord metastases after 8 years of stable disease on combination therapy with intravenous (IV) trastuzumab. Due to progressive CNS disease, intrathecal (IT) trastuzumab was introduced to enhance HER-2+ therapy into the CSF space. A combination HER-2+ targeted approach achieved clinical remission with stable disease in our patient 46 months after she was diagnosed with LM metastases. However, spinal cord C-1 metastasis was not fully controlled with IT trastuzumab, ultimately leading to the patient’s respiratory compromise. In our patient, IT trastuzumab immunotherapy improved prognosis and was an effective strategy to manage HER-2+ LM disease. Given alone or alongside other anti-HER-2+ therapeutics with sufficient CNS penetration, IT trastuzumab could extend the lifespan of patients with leptomeningeal and CNS metastases.
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Affiliation(s)
- Nu T Lu
- Division of Hematology/Oncology, UCLA School of Medicine, 11-934 Factor Building, Los Angeles, 90025 CA USA ; Department of Pathology & Laboratory Medicine, UCLA, Los Angeles, 90095 CA USA
| | - Jeffrey Raizer
- Department of Neurology and Division of Hematology and Oncology Northwestern University, Chicago, 60611 IL USA
| | - Erwin P Gabor
- David Geffen School of Medicine, UCLA, Los Angeles, 90095 CA USA
| | - Natalie M Liu
- Department of Pathology & Laboratory Medicine, UCLA, Los Angeles, 90095 CA USA
| | - James Q Vu
- Department of Pathology & Laboratory Medicine, UCLA, Los Angeles, 90095 CA USA
| | - Dennis J Slamon
- Division of Hematology/Oncology, UCLA School of Medicine, 11-934 Factor Building, Los Angeles, 90025 CA USA ; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, 90095 CA USA
| | - John L Barstis
- Division of Hematology/Oncology, UCLA School of Medicine, 11-934 Factor Building, Los Angeles, 90025 CA USA ; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, 90095 CA USA
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19
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Orlandi E, Mordenti P, Zangrandi A, Cavanna L. Intrapleural Trastuzumab Therapy for Malignant Pleural Effusion from HER2 Overexpression in Metastatic Gastric Cancer. Chemotherapy 2015; 60:321-4. [PMID: 26279275 DOI: 10.1159/000437136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 06/23/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Malignant pleural effusion (MPE) is an extremely common problem affecting cancer patients with advanced disease. The current therapy for MPE is local treatment, such as thoracentesis, chemical pleurodesis, intracavitary administration of anticancer drugs and systemic therapy. However, the management of MPE is still unsatisfactory. CASE We report a case of MPE secondary to human epidermal growth factor receptor 2 (HER2)-positive gastric cancer that was successfully treated with intrapleural trastuzumab. A 52-year-old male with metastatic HER2-positive gastric cancer received chemotherapy (FOLFOX4 regimen) plus trastuzumab; after 11 courses of chemotherapy, he developed right MPE refractory to systemic treatment and pleurodesis. A pleural biopsy performed during thoracoscopy showed pleural metastasis from HER2-positive gastric cancer. The patient received 2 courses of intrapleuric trastuzumab. After the second course, the MPE disappeared, and he continued systemic therapy with trastuzumab and docetaxel. CONCLUSION The safety was good, no local or systemic complications occurred, and the dyspnea secondary to MPE improved and subsequently disappeared. To our knowledge, this case is the first report on intrapleuric trastuzumab use to treat refractory MPE secondary to metastasis from HER2-positive gastric cancer. The treatment was well-tolerated and efficacious.
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Affiliation(s)
- Elena Orlandi
- Department of Oncology-Hematology, Ospedale Guglielmo da Saliceto, Piacenza, Italy
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20
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Arslan C, Dizdar O, Altundag K. Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. Expert Opin Pharmacother 2014; 15:1643-58. [PMID: 25032884 DOI: 10.1517/14656566.2014.929664] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. AREAS COVERED Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. EXPERT OPINION Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.
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Affiliation(s)
- Cagatay Arslan
- Izmir University Medical Park Hospital, Department of Medical Oncology , Izmir , Turkey
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21
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Woodworth GF, Dunn GP, Nance EA, Hanes J, Brem H. Emerging insights into barriers to effective brain tumor therapeutics. Front Oncol 2014; 4:126. [PMID: 25101239 PMCID: PMC4104487 DOI: 10.3389/fonc.2014.00126] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/13/2014] [Indexed: 12/27/2022] Open
Abstract
There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.
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Affiliation(s)
- Graeme F Woodworth
- Department of Neurosurgery, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Anatomy and Neurobiology, University of Maryland School of Medicine , Baltimore, MD , USA
| | - Gavin P Dunn
- Department of Neurosurgery, Pathology and Immunology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine , St. Louis, MO , USA
| | - Elizabeth A Nance
- Center for Nanomedicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Justin Hanes
- Center for Nanomedicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA ; Department of Ophthalmology, Johns Hopkins University School of Medicine , Baltimore, MD , USA ; Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Henry Brem
- Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, MD , USA
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22
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Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res 2014; 19:6404-18. [PMID: 24298071 DOI: 10.1158/1078-0432.ccr-13-0790] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities.
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Affiliation(s)
- Nancy U Lin
- Authors' Affiliations: Dana-Farber Cancer Institute, Boston, Massachusetts; Medical Oncology Branch, Center for Cancer Research, National Cancer Institute; Women's Cancers Section, Laboratory of Molecular Pharmacology; and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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23
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Kim CH, Shin JE, Roh HG, Lee JS, Yoon SY. Sudden hearing loss due to internal auditory canal metastasis of Her2-positive gastric cancer: A case report. Oncol Lett 2014; 8:394-396. [PMID: 24959283 PMCID: PMC4063633 DOI: 10.3892/ol.2014.2058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 03/20/2014] [Indexed: 11/06/2022] Open
Abstract
Internal auditory canal (IAC) metastasis due to leptomeningeal carcinomatosis (LMC) from gastric cancer (GC) has rarely been reported. Early manifestation of symptoms, such as hearing loss, vertigo and facial paralysis, in cases of IAC metastasis due to LMC may facilitate the early detection of brain metastasis. To the best of our knowledge, the present study is the first to report IAC metastasis due to LMC in human epidermal growth factor receptor 2 (Her2)-positive GC. This study reports a case of an Her2-positive GC patient with LMC including IAC metastasis, who presented with acute sensorineural hearing loss, ipsilateral facial paralysis and vertigo during trastuzumab containing chemotherapy. The current study also discusses the early diagnosis and management of this complicated condition, demonstrating that clinical suspicion is key for a prompt diagnosis and proper management of LMC including IAC metastasis in Her2-positive GC.
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Affiliation(s)
- Chang-Hee Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
| | - Jung Eun Shin
- Department of Otorhinolaryngology-Head and Neck Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
| | - Hong Gee Roh
- Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
| | - Jong Sik Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
| | - So Young Yoon
- Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
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Calias P, Banks WA, Begley D, Scarpa M, Dickson P. Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. Pharmacol Ther 2014; 144:114-22. [PMID: 24854599 DOI: 10.1016/j.pharmthera.2014.05.009] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 05/12/2014] [Indexed: 12/25/2022]
Abstract
Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world's leading causes of disability. Delivery of drugs to the CNS is complicated by the blood-brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood-brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally.
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Affiliation(s)
| | - William A Banks
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care Center, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - David Begley
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Maurizio Scarpa
- Department of Paediatrics, University of Padova, Padova, Italy
| | - Patricia Dickson
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA
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Freyer CW, Yaghmour G, Jennings K, Dhanapal V. Drug-Induced Aseptic Meningitis Associated With Intrathecal Trastuzumab. J Pharm Technol 2014; 30:43-47. [PMID: 34860873 PMCID: PMC5990126 DOI: 10.1177/8755122513500918] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2024] Open
Abstract
Objective: To report a case of drug-induced aseptic meningitis (DIAM) in a patient receiving intrathecal trastuzumab (ITT) for leptomeningeal carcinomatosis (LC) secondary to HER-2/neu positive breast cancer. Case Summary: A 43-year-old female with stage IV breast cancer presented with headache, parasthesias, and aphasia. Brain imaging suggested leptomeningeal enhancement. Adenocarcinoma cells were found on cerebrospinal fluid analysis, and infectious etiologies were excluded. The patient received 30 mg of ITT via Ommaya reservoir and suffered sudden neurologic deterioration within 2 hours. Given the sudden onset of clinical deterioration after ITT administration, it was determined that the patient had suffered from DIAM. The patient suffered progressive neurologic decline and was unable to care for herself any further. Discussion: Treatment for LC remains challenging due to limited clinical experience and the challenging location of the disease. ITT has been used in multiple reports without adverse events. A temporal relationship existed between ITT administration and significant neurologic deterioration, possibly related to DIAM. Our patient was not exposed to any more common causative agents of DIAM. Reasons for her lack of recovery are likely multifactorial. Symptoms of DIAM may have in part been exacerbated by progressive LC; however, prior to ITT, symptoms had shown slow but persistent progression rather than significant, acute changes in severity. Retrial of the offending agent was not attempted due to patient risk; thus, a cause-and-effect relationship cannot be established. This event is a "possible" drug-induced adverse event scoring 2 on the Naranjo algorithm. Conclusions: Use of ITT for LC has been frequently reported in recent literature with substantial efficacy and lack of adverse events. This is the first published report of any significant adverse event associated with ITT. Clinicians need to be aware of the possibility of DIAM with ITT and explore options to prevent or manage this severe complication.
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Peddi PF, Hurvitz SA. PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. J Neurooncol 2014; 117:7-13. [PMID: 24469856 DOI: 10.1007/s11060-014-1369-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 01/15/2014] [Indexed: 11/27/2022]
Abstract
The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood-blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs.
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Affiliation(s)
- Parvin F Peddi
- Division of Hematology Oncology, University of California, Los Angeles, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA
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Kaplan MA, Ertugrul H, Firat U, Kucukoner M, İnal A, Urakci Z, Pekkolay Z, Isikdogan A. Brain metastases in HER2-positive metastatic breast cancer patients who received chemotherapy with or without trastuzumab. Breast Cancer 2014; 22:503-9. [PMID: 24385387 DOI: 10.1007/s12282-013-0513-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 12/18/2013] [Indexed: 01/01/2023]
Abstract
OBJECTIVE The aim of this study was to assess whether trastuzumab usage is a risk factor for the development of brain metastasis (BM) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and factors affecting survival after development of BM. MATERIALS AND METHODS One hundred thirty-two patients treated with (treatment group) or without trastuzumab (control group) with brain metastasis were retrospectively analyzed. RESULTS Ninety of the 132 HER2-positive MBC patients were in the treatment group and 42 were in the control group. BM was significantly increased in patients who were treated with trastuzumab in two or more lines (58.5 vs 24.1 %, p < 0.001). Trastuzumab and lapatinib usage after BM and age were independent prognostic factors for overall survival in univariate and multivariate analysis. CONCLUSION The risk for BM was increased in patients who were treated with trastuzumab in two or more lines. Using trastuzumab and lapatinib after BM and age were independent prognostic factors for time to death from BM.
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Affiliation(s)
- Muhammet Ali Kaplan
- Department of Medical Oncology, Dicle University School of Medicine, Diyarbakir, Turkey,
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Dawood S, Gonzalez-Angulo AM. Progress in the biological understanding and management of breast cancer-associated central nervous system metastases. Oncologist 2013; 18:675-84. [PMID: 23740934 DOI: 10.1634/theoncologist.2012-0438] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.
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Affiliation(s)
- Shaheenah Dawood
- Departments of Breast Medical Oncology and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
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29
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Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 2013; 4:S265-88. [PMID: 23717798 PMCID: PMC3656567 DOI: 10.4103/2152-7806.111304] [Citation(s) in RCA: 190] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 04/11/2013] [Indexed: 11/04/2022] Open
Abstract
Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.
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Affiliation(s)
- Emilie Le Rhun
- Breast Unit, Department of Medical Oncology, Centre Oscar Lambret and Department of Neuro Oncology, Roger Salengro Hospital, University Hospital, Lille, France
| | - Sophie Taillibert
- Neurology, Mazarin and Radiation Oncology, Pitié Salpétrière Hospital, University Pierre et Marie Curie, Paris VI, Paris, France
| | - Marc C. Chamberlain
- Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Research Cancer Center, Seattle, WA, USA
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Lin NU. Breast cancer brain metastases: new directions in systemic therapy. Ecancermedicalscience 2013; 7:307. [PMID: 23662165 PMCID: PMC3646423 DOI: 10.3332/ecancer.2013.307] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Indexed: 11/06/2022] Open
Abstract
The management of patients with brain metastases from breast cancer continues to be a major clinical challenge. The standard initial therapeutic approach depends upon the size, location, and number of metastatic lesions and includes consideration of surgical resection, whole-brain radiotherapy, and stereotactic radiosurgery. As systemic therapies for control of extracranial disease improve, patients are surviving long enough to experience subsequent progression events in the brain. Therefore, there is an increasing need to identify both more effective initial treatments as well as to develop multiple lines of salvage treatments for patients with breast cancer brain metastases. This review summarises the clinical experience to date with respect to cytotoxic and targeted systemic therapies for the treatment of brain metastases, highlights ongoing and planned trials of novel approaches and identifies potential targets for future investigation.
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Affiliation(s)
- Nancy U Lin
- Dana-Farber Cancer Institute, Boston, MA, USA
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31
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Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat 2013; 139:13-22. [DOI: 10.1007/s10549-013-2525-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Accepted: 04/04/2013] [Indexed: 02/04/2023]
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Abstract
The incidence of brain metastases (BM) in breast cancer patients has increased over the last decade, presumably due to advances in systemic treatment. Today, breast cancer is the second most common cause of BM among all solid malignancies, second only to lung cancer; furthermore, it is the most common cause of leptomeningeal carcinomatosis. The HER2-positive subtype was consistently shown to have a higher risk for BM as compared with HER2-negative disease. More recently, however, it was shown that a similar incidence exists in triple-negative tumours. Local treatment options, radiotherapy and neurosurgical resection, remain the mainstay of therapy for BM. While some studies have suggested a direct effect of conventional chemotherapy on BM, the main beneficial aspect of systemic treatment is rather due to control of non-CNS systemic disease. Importantly, in patients with HER2-positive breast cancer receiving HER2-targeted therapy after local treatment for BM, superior survival outcomes were reported. Leptomeningeal carcinomatosis has a dismal prognosis. Survival with whole brain radiotherapy alone remains short and the potential additional benefit of intrathecal chemotherapy is still disputed. According to case reports, intrathecal administration of trastuzumab appears to be a promising strategy in patients with HER2-positive leptomeningeal carcinomatosis. In conclusion, while the outcome of breast cancer patients with BM has improved especially in the HER2-positive subtype, the prognosis for the majority of patients remains poor. Therefore, development of novel systemic treatment options offering activity within the brain is urgently warranted. Novel insights into the pathobiology of BM formation may offer the possibility for targeted drug prophylaxis of CNS involvement in high-risk patients.
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Hollebecque A, Levy A, Broutin S, Lemare F, Gazzah A, Desmaris R, Chenailler C, Elbaum M, Besse B, Paci A, Soria JC. First case report of intrathecal panitumumab for treatment of meningeal carcinomatousis in an EGFR mutant lung adenocarcinoma patient. Lung Cancer 2013; 80:113-4. [PMID: 23352031 DOI: 10.1016/j.lungcan.2012.12.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 12/16/2012] [Indexed: 10/27/2022]
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Intrathecal Trastuzumab Treatment of the Neoplastic Meningitis due to Breast Cancer: A Case Report and Review of the Literature. Case Rep Oncol Med 2013; 2013:154674. [PMID: 23424693 PMCID: PMC3568912 DOI: 10.1155/2013/154674] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 12/30/2012] [Indexed: 11/21/2022] Open
Abstract
We report the case of a 65-year-old woman, diagnosed with a breast cancer human epidermal growth factor receptor (HER2) previously negative, who developed leptomeningeal carcinomatosis and was treated with intrathecal (IT) trastuzumab (TST). After five doses of IT trastuzumab, at escalading doses, once weekly, the patient's neurological status stabilised, and that result was maintained for two months. There is evidence in the literature that breast cancer receptor status may change over time, and when it occurs, it may modify the therapeutical approach. We reviewed the pertinent literature and concluded that IT trastuzumab might be a promising treatment for patients with HER2-positive breast cancer leptomeningeal carcinomatosis.
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35
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[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies]. Bull Cancer 2013; 100:7-14. [PMID: 23305997 DOI: 10.1684/bdc.2012.1676] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases.
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36
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Martens J, Venuturumilli P, Corbets L, Bestul D. Rapid clinical and radiographic improvement after intrathecal trastuzumab and methotrexate in a patient with HER-2 positive leptomeningeal metastases. Acta Oncol 2013; 52:175-8. [PMID: 22655969 DOI: 10.3109/0284186x.2012.689857] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
MESH Headings
- Adult
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Agents/therapeutic use
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/drug therapy
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/secondary
- Female
- Humans
- Injections, Spinal
- Magnetic Resonance Imaging
- Meningeal Carcinomatosis/drug therapy
- Meningeal Carcinomatosis/pathology
- Meningeal Carcinomatosis/secondary
- Methotrexate/therapeutic use
- Receptor, ErbB-2/metabolism
- Trastuzumab
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37
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Chien AJ, Rugo HS. Emerging treatment options for the management of brain metastases in patients with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 2013; 137:1-12. [PMID: 23143215 PMCID: PMC3528960 DOI: 10.1007/s10549-012-2328-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 10/30/2012] [Indexed: 11/10/2022]
Abstract
The widespread use of trastuzumab in the past decade has led to a significant and measureable improvement in the survival of patients with human epidermal growth factor receptor-2 (HER2) overexpressing breast cancer, and in many ways has redefined the natural history of this aggressive breast cancer subtype. Historically, survival in patients with HER2-positive disease was dictated by the systemic disease course, and what appears to be the central nervous system (CNS) tropism associated with HER2-amplified tumors was not clinically evident. With improved systemic control and prolonged survival, the incidence of brain metastases has increased, and CNS disease, often in the setting of well-controlled extracranial disease, is proving to be an increasingly important and clinically challenging cause of morbidity and mortality in patients with HER2-positive advanced breast cancer. This review summarizes the known clinical data for the systemic treatment of HER2-positive CNS metastases and includes information about ongoing clinical trials of novel therapies as well as emerging strategies for early detection and prevention.
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Affiliation(s)
- A. Jo Chien
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisidero Street, Box 1710, San Francisco, CA 94143-1710 USA
| | - Hope S. Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisidero Street, Box 1710, San Francisco, CA 94143-1710 USA
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38
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39
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Intra-CSF administration of chemotherapy medications. Cancer Chemother Pharmacol 2012; 70:1-15. [DOI: 10.1007/s00280-012-1893-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 05/11/2012] [Indexed: 10/28/2022]
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40
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Abu Hejleh T, Deyoung BR, Engelman E, Deutsch JM, Zimmerman B, Halfdanarson TR, Berg DJ, Parekh KR, Lynch WR, Iannettoni MD, Bhatia S, Clamon G. Relationship between HER-2 overexpression and brain metastasis in esophageal cancer patients. World J Gastrointest Oncol 2012; 4:103-8. [PMID: 22645633 PMCID: PMC3360103 DOI: 10.4251/wjgo.v4.i5.103] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 01/19/2012] [Accepted: 03/10/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To study if HER-2 overexpression by locally advanced esophageal cancers increase the chance of brain metastasis following esophagectomy.
METHODS: We retrospectively reviewed the medical records of esophageal cancer patients who underwent esophagectomy at University of Iowa Hospitals and Clinics between 2000 and 2010. Data analyzed consisted of demographic and clinical variables. The brain metastasis tissue was assayed for HER-2 overexpression utilizing the FDA approved DAKO Hercept Test®.
RESULTS: One hundred and forty two patients were reviewed. Median age was 64 years (36-86 years). Eighty eight patients (62%) received neoadjuvant chemoradiotherapy. Pathological complete and partial responses were achieved in 17 (19%) and 71 (81%) patients. Cancer relapsed in 43/142 (30%) patients. The brain was the first site of relapse in 9/43 patients (21%, 95% CI: 10%-36%). HER-2 immunohistochemistry testing of the brain metastasis tissue showed that 5/9 (56%) cases overexpressed HER-2 (3+ staining).
CONCLUSION: HER-2 overexpression might be associated with increased risk of brain metastasis in esophageal cancer patients following esophagectomy. Further studies will be required to validate this observation.
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Affiliation(s)
- Taher Abu Hejleh
- Taher Abu Hejleh, Eric Engelman, Jeremy M Deutsch, Thorvardur R Halfdanarson, Daniel J Berg, Gerald Clamon, Division of Hematology, Oncology and Marrow Transplantation, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, C32 GH, Iowa City, IA 52242-1081, United States
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Wauters CAP, Poelen J, Mulder I, Venderink D, Strobbe LJA, Wesseling P. Contribution of CSF cytology in the diagnostic work-up of breast cancer patients with neurological symptoms: a retrospective analysis over two decades. J Neurooncol 2012; 107:581-9. [PMID: 22215233 DOI: 10.1007/s11060-011-0782-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Accepted: 12/19/2011] [Indexed: 11/29/2022]
Abstract
The aim of this study was to evaluate the contribution of cytological analysis of cerebrospinal fluid (CSF) in the diagnostic work-up of breast cancer patients who present with neurological symptoms suspected for central nervous system (CNS) metastases. In the period 1989-2009, a total of 81 patients with breast cancer underwent CSF cytological examination. Relevant tumour characteristics, clinical presentation and radiological findings were scored. The CSF cytological diagnosis was classified according to the 1996 NCI-sponsored conference approach as malignant, suspicious for malignancy, atypical, benign or inadequate. During the course of 20 years, 145 CSF cytological examinations were performed. Relatively common neurological symptoms resulting in cytological CSF examination were headache (n = 25), nausea and vomiting (n = 19), sensory disturbances (n = 16), and cranial nerve dysfunction (n = 16). Of these, headache and nausea/vomiting were most often associated with malignant cells in the CSF (CSF(+)) (in 48 and 53% of the cases, respectively). The 4 patients with both headache and confusion/altered mental status all had CSF(+). In 10 patients, CSF(+) was found despite the absence of radiological evidence for metastasis in/around the CNS. In our series, repeated CSF analysis appeared to have limited additional value, and CSF(+) was strongly correlated with shorter survival. A substantial number of patients with neurological symptoms but without radiological abnormalities can have CSF(+). In our series, the additional value of repeated cytological examination of CSF was limited. Our study underscores the value of CSF cytology as a tool for the unequivocal diagnosis of metastatic spread of breast cancer to the CNS, and confirms that CSF(+) is a strong predictor of poor survival.
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Affiliation(s)
- C A P Wauters
- Department of Pathology, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands.
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Abstract
Leptomeningeal metastasis (LMD) is a lethal complication caused by a variety of cancers, typically developing late in the disease course. It is associated with major neurologic disabilities and short survival. The incidence of LMD may increase because of longer survival of patients who have cancer, and because of the use of newer large-molecule therapies with poor central nervous system penetration. To achieve improved outcomes for patients who have LMD, new treatments need to reach the meninges and cerebrospinal fluid and interact with relevant molecular targets. Some of the agents currently in testing may contribute to this goal. To allow for better outcomes through earlier treatment, advances in diagnosis are needed. By using agents with higher therapeutic indices, in patients with a lower burden of disease (identified earlier with clinical or molecular markers) it should be possible to achieve gradual improvements in outcomes for patients suffering from this devastating disease.
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Affiliation(s)
- Morris D Groves
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe, Unit 431, Houston, TX 77030, USA.
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Leal T, Chang JE, Mehta M, Robins HI. Leptomeningeal Metastasis: Challenges in Diagnosis and Treatment. CURRENT CANCER THERAPY REVIEWS 2011; 7:319-327. [PMID: 23251128 DOI: 10.2174/157339411797642597] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
As therapeutic options and supportive care for the treatment of neoplastic disease have improved, there has been an associated increase in the incidence of leptomeningeal disease. In this review, the clinical presentation, natural history, diagnostic evaluation, and treatment options for this often devastating sequela of solid tumors, lymphoma, and leukemia will be summarized. The therapeutic efficacy of ionizing radiation, systemic agents, and intrathecal drugs will be examined from the existing literature. Additionally the pathophysiology, which in part defines the therapeutic limitations in approaching this patient population, will be discussed in order to assist in individualized clinical decision making.
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Affiliation(s)
- Ticiana Leal
- University of Wisconsin Paul P Carbone Comprehensive Cancer Center 600 Highland Ave Madison WI, 537192
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Lombardi G, Zustovich F, Farina P, Della Puppa A, Manara R, Cecchin D, Brunello A, Cappetta A, Zagonel V. Neoplastic meningitis from solid tumors: new diagnostic and therapeutic approaches. Oncologist 2011; 16:1175-88. [PMID: 21795431 PMCID: PMC3228160 DOI: 10.1634/theoncologist.2011-0101] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Accepted: 05/17/2011] [Indexed: 01/19/2023] Open
Abstract
Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%-15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography-computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.
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Affiliation(s)
- Giuseppe Lombardi
- Medical Oncology 1 Unit, Istituto Oncologico Veneto–IRCCS, Padova, Italy.
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Papadatos-Pastos D, Banerji U. Revisiting the role of molecular targeted therapies in patients with brain metastases. J Neurooncol 2011; 105:467-74. [DOI: 10.1007/s11060-011-0661-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 07/02/2011] [Indexed: 12/20/2022]
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[Leptomeningeal meningitis related to breast cancer overexpressing HER2: is there a place for a more specific treatment?]. Bull Cancer 2011; 98:417-24. [PMID: 21540147 DOI: 10.1684/bdc.2011.1341] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment. However overall results are disappointing. Despite specific and symptomatic treatment, improvement in survival and quality of life remains very modest, highlighting the importance for ongoing research for developing new molecules or on improving the use a better use of those available today. The incidence of leptomeningeal metastases is particularly marked in cases of overexpression of HER2. The main hypothesis is there may be a better control of extra-cerebral localisations with trastuzumab therefore intra-cerebral recurrences may be encountered preferentially as they are not reached by this high molecular weight monoclonal antibody (148 kD). Analyses performed in the cerebrospinal fluid following intravenous trastuzumab showed extremely low levels of the antibody and support the hypothesis that leptomeningeal metastasis of HER2-overexpressing breast carcinoma remain potentially sensitive to HER2-type receptor inhibition by a target agent under the condition of by-passing the meningeal blood brain barrier. Intra-ventricular or IT administered with trastuzumab would reach high loco-regional therapeutic concentrations in the cerebro-meningeal without risk for normal non-expressing HER2 leptomeningeal tissue. This strategy has been successfully tested on several animal models. A limited number of administrations in humans have been described in the literature, with weekly doses up to 100 mg. No specific toxicity has been described and some data suggest a potential benefit in survival despite the real difficulties for adequate interpretations. Furthermore, a multicentric phase I-II clinical trial, of which the Curie institute is the sponsor and investigating the intra-thecal administration and the efficacy of the trastuzumab will begin very soon. More studies are needed to measure the exact impact of small molecule inhibitors of tyrosine kinase on the leptomeningeal localizations.
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Yin W, Jiang Y, Shen Z, Shao Z, Lu J. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One 2011; 6:e21030. [PMID: 21695277 PMCID: PMC3111470 DOI: 10.1371/journal.pone.0021030] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 05/17/2011] [Indexed: 11/23/2022] Open
Abstract
Background Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. Methods Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. Findings With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms. Conclusion This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.
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Affiliation(s)
- Wenjin Yin
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Cavanna L, Rocchi A, Gorgni S, Ambroggi M, Foroni RP, Ubbiali A, Civardi G. Cerebrospinal Fluid Cytology Diagnosis of HER2-Positive Leptomeningeal Carcinomatosis From HER2-Positive Metastatic Gastric Cancer: Case Report. J Clin Oncol 2011; 29:e367-8. [DOI: 10.1200/jco.2010.33.2577] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Association concomitante d’une irradiation encéphalique en totalité avec trastuzumab concomitant pour des métastases cérébrales d’un cancer du sein : questions et réponses Expérience de l’Institut Curie et revue de la littérature. Bull Cancer 2011; 98:425-32. [DOI: 10.1684/bdc.2011.1342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Oliveira M, Braga S, Passos-Coelho JL, Fonseca R, Oliveira J. Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat 2011; 127:841-4. [PMID: 21369716 DOI: 10.1007/s10549-011-1417-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 02/16/2011] [Indexed: 01/26/2023]
Abstract
Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.
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Affiliation(s)
- Mafalda Oliveira
- Medical Oncology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal.
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