Local and systemic therapy in breast cancer patients with central nervous system metastases

Purpose

As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases.

Methods

Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes.

Results

We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P?<?0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P?<?0.001). No significant difference in OS was observed between different systemic treatment regimens.

Conclusion

Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

     

Editor's choice: Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials

Purpose

To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM).

Methods

A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM.

Results

A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis.

Conclusion

Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.The term “leptomeningeal metastasis” (LM), also known as neoplastic meningitis, refers to involvement of the cerebrospinal fluid (CSF) and leptomeninges (pia and arachnoid) by any solid tumor or hematologic malignancy. When caused by systemic cancer, LM is often called carcinomatous meningitis or meningeal carcinomatosis and is reported in 4%–15% of patients with cancer.^1–13 Lymphomatous or leukemic meningitis occurs in 5%–15% of patients with lymphoma or leukemia.^1–13 LM is the third most common metastatic complication affecting the central nervous system (CNS) after brain metastases and epidural spinal cord compression, with 7000–9000 new cases diagnosed annually in the United States.^1–13 In decreasing order, the most common sources of systemic cancer metastatic to the leptomeninges are breast, lung, melanoma, aggressive non-Hodgkin'' lymphoma, and acute lymphocytic leukemia.Leptomeningeal metastasis usually (>70%) presents in the setting of active systemic disease but can present after a disease-free interval (20%) and even be the first manifestation of cancer (5%).^1–13 A diagnosis of LM must be considered in patients with cancer and neurologic symptoms.^1–13 Neurologic dysfunction most commonly involves one or more segments of the neuraxis, including cerebral hemispheres, cranial nerves, spinal cord, or spinal roots. Because any site in the CNS may be involved, clinical manifestations of LM overlap significantly with those of parenchymal brain metastases, treatment-related toxicities, metabolic disturbances, and, rarely, neurologic paraneoplastic syndromes.Clinical manifestations that strongly suggest the diagnosis of LM include cauda equina symptoms or signs, communicating hydrocephalus, and cranial neuropathies. Early in the disease, neurologic involvement can be subtle, such as an isolated diplopia or radicular pain.^1–13 In some patients, cerebral hemisphere symptoms such as altered mental status or seizures may predominate. Neuroimaging (ie, MRI of brain or spine) may suggest LM based upon focal or diffuse enhancement of the leptomeninges, nerve roots, or ependymal surface and, in the context of a patient with cancer and low likelihood of infectious meningitis, may be diagnostic of LM. Brain parenchymal metastases from nonhematologic cancers coexist in 38%–83% of LM patients.^14–18 The reported rates of negative CNS imaging in patients with LM range from 30% to 70%, thus normal CNS imaging does not exclude a diagnosis of LM. CSF analysis is crucial to diagnosing LM, as in nearly all patients some abnormality of CSF opening pressure, protein, glucose, or cell count will be apparent.^5,9,19 The finding of tumor cells in CSF establishes a definitive diagnosis of LM (excluding patients within 2 wk of a CNS tumor resection), but a single CSF analysis has a high false negative rate (nearly 50%) for positive cytology even when multiple large volume (>10 mL) samples are sent for cytologic examination and prompt processing methods are utilized.⁵ Repeated CSF analysis when initially negative increases the chances of finding malignant cells to 80% or more. CSF tumor marker concentrations are of unproven value, with the exception of nonseminomatous germ cell tumors.^20,21 In patients with hematologic cancers, CSF flow cytometry is more sensitive than CSF cytology and additionally requires a comparatively smaller volume of CSF (<2 mL) for analysis. The most specific ancillary study results (ie, positive cytology, abnormal flow cytometry [in hematologic cancers], and abnormal neuroimaging) can be negative or inconclusive in LM. The diagnosis of probable LM is made in patients with cancer when neurologic symptoms are suggestive for LM, associated with nonspecific CSF abnormalities and negative or inconclusive MRI studies.Two particular challenges arise in the treatment of LM: (i) deciding whether to treat and (ii) if LM-directed treatment is considered, deciding how to treat (radiotherapy, surgical intervention, systemic or intra-CSF chemotherapy).^{1–13,22–27} The optimal patients for treatment include those with low tumor burden as reflected by functional independence and lack of major neurologic deficits, no evidence of bulky CNS disease by neuroimaging, absence of CSF flow block by radioisotope imaging, expected survival >3 months, and limited extraneural metastatic disease.^28,29 CNS imaging studies commonly recommended prior to treatment are neuraxis MRI and, in patients considered for treatment with intra-CSF chemotherapy, a radioisotope CSF flow study; the latter is recommended in guidelines but infrequently utilized.^30,31 Flow studies assist in determining whether intra-CSF chemotherapy will distribute homogeneously throughout the CSF. If CSF is compartmentalized or flow impaired, therapeutic concentrations of chemotherapy may not reach all sites of disease and may be associated with increased risk of treatment-related neurotoxicity.^30,31 If intra-CSF chemotherapy treatment is believed warranted, a decision is made whether to treat by lumbar administration (intrathecal) or via a surgically implanted subgaleal reservoir and intraventricular catheter (ie, an Ommaya, Sophysa, or Rickham reservoir system).³²The role of surgical intervention in LM is largely limited to placement of a ventriculoperitoneal shunt in patients with symptomatic hydrocephalus, implantation of an intraventricular catheter and subgaleal reservoir for administration of cytotoxic drugs, or, very occasionally, obtaining a meningeal biopsy for pathological confirmation of LM.^1–13,22 Radiotherapy is used in the treatment of LM^1–14 to palliate symptoms, such as cauda equine syndrome and cranial neuropathies, to decrease coexistent bulky disease and correct regional areas of impaired CSF flow when patients are treated with intra-CSF chemotherapy. Common regimens are 20–30 Gy in 5–10 fractions to whole brain or to a partial spine field. Whole-neuraxis irradiation is often avoided in the treatment of LM from solid tumors, because it is associated with significant bone marrow toxicity and has not been shown to offer a therapeutic advantage.High-dose systemic chemotherapy with methotrexate (MTX) and cytarabine may result in cytotoxic CSF concentrations, theoretically obviating the need for intra-CSF chemotherapy.^25–27 However, the majority of systemic chemotherapy and many targeted chemotherapies, such as imatinib, lapatinib, rituximab, and trastuzumab, do not penetrate the intact blood–brain barrier in adequate concentrations—thus, the CNS including CSF may become a “sanctuary site” with such treatments. However, systemic chemotherapy has a role in the treatment of LM as an adjunct treatment of extraneural disease and possibly bulky subarachnoid disease.^{1–13,25–27} Importantly, intra-CSF chemotherapy commonly used in the treatment of LM is based upon limited studies with small numbers of patients and it has never been clearly established as an effective treatment for LM in a prospective randomized trial.^32–38     

Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab

Journal of Neurology -     

Prevention of disability in leprosy: the different levels

Prevention of disability in people affected by leprosy is primarily seen as prevention and management of impairments secondary to nerve function impairment. This article describes four different levels at which appropriate interventions may lead to the overall prevention of disability. These are--prevention of disease, timely diagnosis and adequate treatment of the disease, early recognition and adequate treatment of nerve function impairment and finally, prevention and treatment of secondary impairments due to nerve function loss.     

Immature delivery after intrauterine Candida albicans infection

The case is presented of a patient who delivered an immature infant after an intrauterine candidial infection in the presen ce of an intrauterine contraceptive device (IUD). 8 other cases of intrauterine Candida infection leading to immature deliveries were gathered from the literature. On the basis of the pathologic findings, the medium of infection is thought to be the amniotic fluid.     

EMDR Minus Eye Movements Equals Good Psychotherapy

Eye Movement Desensitization and Reprocessing (EMDR) is a therapy roughly equal in efficacy to others currently available. It is argued that this treatment method is efficacious independent of the value of its component parts (e.g., eye movements) and is successful because it applies common and generally accepted principles of psychotherapy. Ten curative principles of this procedure are discussed as reflective of sound psychotherapy practice. It is hoped mat an understanding of this therapy from the perspective of the practice and theory of psychotherapy will assist in its study.     

Accumulation of Aluminium in Rat Liver: Association with Constituents of the Cytosol

Abstract: Aluminium (A1) accumulation occurs in the liver of renal patients and in patients on parenteral nutrition. Human hepatotoxicity is not proven. The role of the liver in storage and biotransformation of A1 and in development of osteo- and neurotoxicity is not clarified as yet. The aim of the present investigation was to study the storage of A1 in total liver and in subcellular liver fractions, and its association with soluble cytosolic molecular species. Therefore, rats were loaded with A1 prior to liver fractionation by ultracentrifugation, and equilibrium gel filtration chromatography of the cytosol, using a previously described method for A1 speciation in serum. A1 accumulated dose-dependently in liver and subcellular liver fractions, the lowest levels occurring in the cytosol. A dose-dependent elevation of A1 in the blood was also observed. Gelfiltration of the cytosol indicated that A1 was associated with a low molecular weight form which was not a citrate complex, and a high molecular weight form, which was larger than transferrin. No induction of and association with metallothionein occurred.