Topotecan
IT administration of the topoisomerase I poison topotecan was studied in a recent phase I trial in children.123 Arachnoiditis was the dose-limiting toxicity, and the maximum tolerated dose was 0.4 mg. Several patients with leptomeningeal spread of solid tumors demonstrated responses or prolonged stable disease. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress in the Children's Oncology Group as is a Phase 1 trial in adults with carcinomatous meningitis.
Introduction Lgc
Despite over 50 years of clinical experience in treating neoplastic meningitis, few effective therapies have been identified. Although one reason for this failure is the lack of effective agents, there are many additional obstacles. Many intrathecal IT chemotherapeutic agents currently in use are cell-cycle specific, which potentially limits their efficacy in this particular disease setting. Prior studies have reported that cycling of cerebrospinal fluid CSF tumor cells is relatively slow, with...
Info Xek
The low initial sensitivity of cytologic examination may be attributed to the fact that tumor cells adhere to the meninges with few free-floating cells resulting in negative cytology. Increasing the CSF volume 10-20 cc , examining the specimen as soon as possible, and performing serial lumbar punctures LP may increase the diagnostic yield. If the specimen is delivered within minutes it may be examined without fixation, but routinely it is fixed in an equal volume of fixate. A recent review...
Radiation Therapy For Leptomeningeal Cancer
Minesh Mehta, M.D. and Kristin Bradley, M.D. University of Wisconsin Medical School, Madison, WI. 53792 Abstract Radiotherapy has multiple roles in the treatment of leptomeningeal cancer. While it is uncommon for patients to experience regression of neurologic deficits due to leptomeningeal cancer, focal radiotherapy often provides significant palliation of pain, increased intracranial pressure and other focal symptoms. Focal radiotherapy may also be used to eliminate blockages of cerebrospinal...
Thiotepa 1
IT administration of thiotepa, in contrast to systemic administration of the same agent, is well tolerated although it may be associated with myelosuppression.31 The active metabolite TEPA, however, is not detected in CSF after IT administration. In addition, because the drug is highly lipid soluble unlike most other intrathecally administered agents, thiotepa diffuses rapidly out of the CSF.121 Thus, the usual pharmacokinetic advantages of IT drug administration may be less prominent for...
Pnet
Central neurocytoma Dermoid epidermoid Primary CNS lymphoma Meningeal hemangiopericytoma Primary diffuse leptomeningeal gliomatosis For adults, review of the literature reveals reports of LM from both low and high grade primary CNS tumors of varying cell lineages.5'46'49'5068 While the adult list is similar to that for children, the predominant histologies responsible for LM in adults are generally of higher grade, a reflection of the more frequent occurrence of these types of tumors in adults....
References Boq
1. DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998 38 245-52. 2. Kaplan JG, DeSouza TG, Farkash A, et al. Leptomeningeal metastases Comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol 1990 9 225-9. 3. van Oostenbrugge RJ, Twijnstra A. Presenting features and value of diagnostic procedures in leptomeningeal metastases. Neurology 1999 53 382-5. 4. Freedman A, Nadler LM. Non-Hodgkin's Lymphomas. In...
Intrathecal Therapy
Intrathecal chemotherapy is a form of regional therapy directed specifically against leptomeningeal cancer. IT administration of relatively small drug doses produces very high CSF drug concentration usually with minimal systemic toxicity. 86 This pharmacokinetic advantage, however, is counterbalanced by limitations that must also be considered. For example, diffusion of drug from the CSF into the brain parenchyma or tumor nodules is limited to within a few millimeters of the CSF space.87 Thus,...
Melanoma
Melanoma is one of the most common leptomeningeal cancers in adults however, it is infrequently observed in children since melanoma comprises less than 1 of childhood cancers.88'99 Leptomeningeal dissemination of melanoma most commonly occurs in children who have advanced systemic disease, especially underlying CNS parenchymal metastases. Children who have large congenital nevi rarely present with primary leptomeningeal melanoma.88'99 Both primary leptomeningeal melanoma and metastatic...
Cancer Treatment and Research
Steven T. Rosen, M.D., Series Editor Sugarbaker, P. ed Peritoneal Carcinomatosis Principles of Management. 1995. ISBN 0-7923-3727-1. Dickson, R.B., Lippman, M.E. eds. Mammary Tumor Cell Cycle, Differentiation and Metastasis. 1995. ISBN 0-7923-3905-3. Freireich, EJ, Kantarjian, H. eds y.Molecular Genetics and Therapy of Leukemia. 1995. ISBN 0-7923-3912-6. Cabanillas, F., Rodriguez, M.A. eds Advances in Lymphoma Research. 1996. ISBN 0-7923-3929-0. Miller, A.B. ed. Advances in Cancer Screening....
Leptomeningeal Cancer In The Pediatric Patient
Kathleen A. Neville, M.D, and Susan M. Blaney, M.D Texas Children's Cancer Center, Baylor College of Medicine Houston, TX 77030 Abstract The treatment and prophylaxis of leptomeningeal leukemia and lymphoma in children has dramatically improved disease control and long-term survival. However, the treatment of other leptomeningeal cancers has been less successful and the neurologic morbidity associated with central nervous system-directed therapy has a significant long-term impact on quality of...
References Cvl
1. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors experience with 90 patients. Cancer 1982 49 759-772. 2. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999 25 103-119. 3. Seeldrayers P, Hildebrand J. Treatment of neoplastic meningitis. Euro J Cancer Clin Oncol 1984 20 449-456. 4. Iaconetta G, Lamaida E, Rossi A, Signorelli F, Manto A, Giamundo, A. Leptomeningeal carcinomatosis review of the literature. Acta...
Introduction Ptw
Chemotherapy and radiation are the standard treatments for leptomeningeal disease. Intrathecal IT chemotherapy alone, or in combination with systemic chemotherapy1 including methotrexate, cytarabine2 Ara-C , and thiotepa3, are used to treat patients with lymphoma, leukemia, and metastatic solid tumors, such as breast carcinoma. More recently, IT, targeted radioimmunotherapy, such as 131I-3F84, has been explored for leptomeningeal tumors that are GD2-positive. Leptomeningeal disease, by...
Sustainedrelease and infusional intrathecal chemotherapy
As mentioned previously, most available intrathecal agents have short pharmacologic half-lives T Vi , which limit their efficacy. Prolonged drug exposure has been forwarded as a method to increase the cytotoxicity of such agents in CSF. It has been shown that some cell lines may be resistant in short exposure conditions, but demonstrate sensitivity with prolonged exposure. For example, in the human SO-M19 melanoma line, there was no inhibition of tritiated thymidine incorporation with short 2...
Agents
Contemporary immunotoxins are a group of cell-type specific cytotoxic agents that are made up of a monoclonal antibody linked to a protein toxin. The current immunotherapeutic approaches for the treatment of LC include the intrathecal administration of 1. Immunomodulating cytokines such as interleukin-2 IL-2 and interferon-a IFN-a . 2. Immune effector cells such as lymphokine-activated killer cells LAK cells . Both of these are referred to as active immunotherapeutic approaches as opposed to...
Corticosteroids
Prednisone the orally administered prodrug of prednisolone and dexamethasone, agents commonly used in the treatment of acute lymphoblastic leukemia, both penetrate into the CNS producing CSF concentrations that are equal to the plasma concentrations of free drug. However, dexamethasone is less protein bound than prednisone at equipotent doses. Therefore, dexamethasone can be considered to penetrate better into the CSF.78 Patients receiving dexamethasone rather than prednisone for CNS preventive...
Neuroimaging studies
Neuroimaging studies are extremely useful in defining the extent of leptomeningeal disease in children who have underlying primary CNS or solid tumors. Neuroimaging studies also facilitate the identification of areas of bulky disease and the assessment of CSF flow dynamics. In children with CNS leukemia, neuroimaging studies of the brain and or spinal cord are sometimes obtained if there are focal neurological symptoms e.g. cranial nerve palsies, visual problems, or localized pain ....
Methotrexate 1
Methotrexate has been the mainstay of IT chemotherapy for over 40 years.1619'23'27'29'30'32'43 It is used for CNS preventive therapy in nearly all patients with acute leukemia.112. In addition, it is the drug most commonly used for CNS reinduction therapy in meningeal relapse of leukemia.112114 Because it is successful against leukemia, and there is a large body of experience with its IT administration, methotrexate is sometimes also used as standard therapy for the treatment of meningeal...
Tumors
Leptomeningeal dissemination of primary CNS tumors is relatively rare, but is clinically relevant for patients with medulloblastoma, primary CNS lymphomas and germ cell tumors. Twenty-five 50 of patients with medulloblastoma will have evidence of LM dissemination at diagnosis this is a critical factor in determining appropriate therapy and overall prognosis.57,58'59 Approximately 25-30 of patients with primary central nervous system lymphoma PCNSL have LM dissemination at diagnosis. This should...
Introduction Hle
As discussed in previous chapters, many types of malignant tumors originating outside the central nervous system CNS are known to metastasize to the leptomeninges, including lymphomas, leukemias, and carcinomas from various primary sites. The spread of primary CNS neoplasms through the leptomeningeal space may be a fairly frequent occurrence, but has not been thoroughly studied, especially in adults. In 1837, Ollivier reported the autopsy findings of a patient with a cerebellar tumor that had...
Neuroectodermal Tumors
Medulloblastoma has a great propensity for leptomeningeal dissemination relative to other pediatric CNS tumors. Leptomeningeal metastases are present at diagnosis in up to 27-43 of infants and young children with medulloblastoma, compared with an incidence of less than 20-25 in older children with similar histologic diagnosis.15 The reported incidence of leptomeningeal spread is greater than 90 in patients with medulloblastoma who come to autopsy.15-39'40 Because of the predilection for...
Herbert H Engelhard Md Phd
Departments of Neurosurgery, Bioengineering and Molecular Genetics University of Illinois at Chicago Chicago, Illinois Memorial Sloan-Kettering Cancer Center Herbert H. Engelhard, MD, PhD Departments of Neurosurgery, Bioengineering amp Molecular Genetics University of Illinois at Chicago Chicago, IL 60612 Norris Comprehensive Cancer Center and Hospital Library of Congress Cataloging-in-Publication Data A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN...
Clinical presentation and diagnosis
The clinical presentation of LM in patients with NHL is similar to that seen in patients with LM from solid tumors. However, patients with hematologic malignancies present with a higher frequency of cranial nerve signs as initial manifestations of LM.3 Since LM involve the entire neuroaxis, their clinical symptoms and signs are typically divided into three general groups 1 cerebral hemispheres, 2 cranial nerves and, 3 spinal cord and nerve roots. The most frequent presenting symptoms signs are...
Choroid plexus tumors
Choroid plexus tumors, including choroid plexus carcinoma and choroid plexus papilloma, account for 1-3 of all pediatric brain tumors generally present during the first two years life.6971 Extensive disease, including leptomeningeal metastases, has been reported in up to 70 of infants with choroid plexus carcinoma. Multi-modality therapy with surgery, chemotherapy, and radiation has been effective for some patients. The efficacy of adjuvant therapy in terms of both chemotherapy and radiotherapy...
References Aal
1. Kuo AH, Yataganas X, Galicich JH, Fried J, Clarkson BD Proliferative kinetics of central nervous system CNS leukemia. Cancer 1975 36 232-239. 2. Blasberg RG, Patlak CS, Shapiro WR. Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration. Cancer Treat Rep 1977 61 633-41. 3. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal Chemotherapy Brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975 195 73-83. 4....
Clinical studies
A phase I trial involving 23 patients treated with intraventricular topotecan via Ommaya reservoir recommended a Phase II dose of .4 mg in patients gt 3 years of age. Arachnoiditis characterized by fever, nausea or vomiting, headache, and back pain was the dose limiting side effect 6 23 assessable patients had prolonged disease stabilization or response.23'24 A phase II study in 27 adults with neoplastic meningitis treated with topotecan 0.4 mg intrathecally twice weekly for six weeks, followed...
Prognosis
The prognosis of LM from solid tumor remains poor. The median survival is four to six weeks without treatment. Treatment can stabilize the neurological symptoms and prolong survival for a few months but less than 10 of patients are alive after one year. Breast cancer has the best prognosis about 15 of patients survive more than a year.120'75 Prognosis remains poor in patients with lung cancer and melanoma.26 In these patients, some clinicians question the usefulness of vigorous treatment and...
Hydrocephalus
At Memorial Sloan-Kettering Cancer Center MSKCC , approximately 10 of patients referred for placement of Ommaya reservoirs have or develop hydrocephalus.6 This is typically communicating hydrocephalus, resulting from occlusion of the arachnoid granulations necessary for CSF resorption into the venous system or from basilar carcinomatous meningitis. On rare occasions patients will develop a non-communicating hydrocephalus secondary to an obstructing lesion at the foramen of Monro, Sylvian...
Cns Tumor Types Leading To Lm Children And Adults
The high tendency for several types of childhood brain tumors to metastasize to the leptomeninges has long been recognized. In addition to medulloblastoma, these tumors include ependymoma, germinoma, pineoblastoma and other primitive neuroectodermal tumors PNETs . '' ' ' ' ' The leptomeningeal spread of pediatric posterior fossa tumors has been especially well-documented The known propensity of these tumors to lead to drop metastases, i.e. metastases to the spinal subarachnoid space, has...
Anatomy And Physiology Of The Leptomeninges And Csf Space
Neil Barshes, MD,1 Alexis Demopoulos, MD,2 Herbert H. Engelhard, MD, PhD1 1The University of Illinois at Chicago, Chicago, IL 60612 2Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Abstract The arachnoid membrane and pia mater are the two membranous layers that comprise the leptomeninges. Cerebrospinal fluid is made within the ventricular system by cells of the choroid plexus and ependyma. This chapter describes in detail the normal anatomic structure and...
Pediatric acute lymphoblastic leukemia
With modern therapy, the event-free survival of pediatric patients with ALL is approximately 80 .34 Prior to the inclusion of prophylactic therapy for CNS disease in the treatment of children with ALL, the major obstacle to cure was relapse of disease in the CNS. Meningeal relapse is a poor prognostic indicator of survival because it is typically followed by bone marrow relapse.35 With new advances in the treatment of children with ALL, including CNS prophylaxis, the incidence of CNS relapse is...
Mechanisms Of Metastasis
In the literature, three different pathways have been suggested through which cells from a CNS tumor might gain access to the leptomeningeal space.1215 First, a tumor might be in direct contact with the CSF pathways, as in the case of a medulloblastoma or intraventricular tumor. In this situation, tumor cells could be shed directly into the CSF. Second, tumor cells might invade the leptomeningeal space by moving through and or displacing normal brain parenchyma, then eroding through the pia...
Introduction Evb
While leptomeningeal metastases LM are estimated to occur in approximately 5 of all patients with cancer, the incidence of LM from leukemias and lymphomas may be underestimated in most series.1 This may be due to the greater prevalence of solid tumors compared to hematologic malignancies. Also, in contrast to patients with solid tumors, those with LM from leukemias and lymphomas often present without evidence of systemic disease or during periods of remission. In a review of 63 cases, Kaplan et...
Leptomeningeal Spread Sclc
The incidence of LM in patients with small cell lung cancer is between 9-25 . 3,5's'99 The incidence appears to increase with length of survival from 0.5 at cancer diagnosis to 25 after three years.99 Aroney et al reported that 42 of patients who relapsed after initial treatment did so in the leptomeninges this being the only site of relapse in 27 .5 For patients with small cell lung cancer and limited stage disease, prophylactic cranial radiotherapy RT is recommended to prevent brain...
Ependymomas
The reported incidence of leptomeningeal dissemination in children with ependymomas ranges from 3 - 22 .15'52 Until recently, there was ongoing debate about the need for prophylactic CSI in the absence of leptomeningeal dissemination. At the present time, most investigators limit the use of CSI in ependymoma to children with objective evidence of leptomeningeal spread.52 In a recent retrospective series neither evidence for dissemination at presentation nor the detection of anaplastic...
Pathophysiology
There are multiple mechanisms by which tumor cells can disseminate into the subarachnoid spaces. Once the tumor cells gain access to the CSF, there is direct communication with the entire subarachnoid space. Tumor cells are carried by bulk flow, with most deposits occurring at the base of the skull or spine. Tumor cells can hematogenously spread to involve the brain parenchyma or choroid plexus. Once implanted they may rupture seeding the leptomeninges with micrometastases. However, not all...
Craniospinal Radiation
This technique treats the entire craniospinal axis and frequently is utilized with a high rate of success in other malignant diseases of the craniospinal axis, such as medulloblastoma and central nervous system CNS germinoma. Because of the compartmental nature of leptomeningeal carcinomatosis, craniospinal irradiation is occasionally used in the treatment of this disease process. It involves a technically complex set-up of two opposed lateral brain fields and one or two posterior spine fields...
Leptomeningeal Carcinomatosis
1. Eberth CJ. Zur Entwicklung des Epitheliomas Cholesteatomas dur Pia under der Lungs. Virchow's Arch 1870 49 51-63. 2. Posner, JB. Leptomeningeal Metastases. In Neurological complication of cancer, Posner JB, Philadelphia, PA F.A. Davis Co., 1995. 3. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999 25 103-1979. 4. DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998 38 245-52. 5. Freilich RJ, Seidman AD, DeAngelis LM. Central...
The cerebral spinal fluid space
The CSF circulates between the ventricles within the brain and a series of cisterns and spaces outside the brain and spinal cord. While the ventricles are lined with ependymal cells, the cisterns and spaces outside the brain are lined with arachnoid and pial cells. The paired lateral ventricles are often divided into five sections. From anterior to posterior these sections are 1 the anterior frontal horn, 2 the body, 3 the atrium trigone , 4 the posterior occipital horn, and 5 the inferior...
Incidence
The incidence of NHL has risen over the past several decades and currently accounts for approximately 50 of all cases of leukemias and lymphomas.4 The incidence of CNS involvement in NHL, as reported in the literature, is variable and closely associated with certain clinical risk factors for the disease see below . Patients with NHL are not at uniform risk of developing CNS disease. CNS disease from NHL more often involves the leptomeninges than the parenchyma. In a review of a multiple series...
Ewings Sarcoma
Although leptomeningeal dissemination has been reported in children who have Ewing's sarcoma, it is uncommon occurring in less than 3 of patients.90 98 Leptomeningeal metastases are generally observed in children who have advanced systemic disease rather than as an isolated event. 91 gt 98 Prophylactic treatment of the CNS with cranial radiation and or intrathecal therapy is not warranted due to the low overall incidence of CNS spread historically, CNS prophylaxis has not prevented subsequent...
Intrathecal Isotope Therapy
The limitations of external beam radiotherapy, whether to the entire neuraxis, or localized, have prompted the investigation of intrathecal isotope delivery techniques which although promising, are in their infancy. In general, three approaches can be utilized 1 direct intrathecal administration of an isotope 2 delivery of the isotope to tumor cells using a homing molecule specific for cancer cells or 3 use of isotopes tagged to large microspheres that remain localized within the CSF space. The...
Techniques for catheter placement
The precise placement of intraventricular catheters is of paramount importance when considering the surgical nuances of implanting Ommaya reservoirs. Proper catheter placement is important to avoid damaging eloquent cortex or subcortical structures along the catheter's trajectory. In addition, proper targeting of the catheter so that its tip is within the ventricle is crucial to avoid administering toxic chemotherapy directly into brain parenchyma. Inadvertent administration of chemotherapy...
Leptomeningeal
The optimal treatment for tumors with a predilection for leptomeningeal metastases is preventative or presymptomatic therapy. This approach has been successfully employed for the vast majority of children with leukemias or lymphomas and, to a somewhat lesser extent, for medulloblastoma or supratentorial PNET through utilization of CNS-targeted treatment approaches with intrathecal chemotherapy or CSI. CNS-directed treatment approaches have also been increasingly successful in the treatment of...
Cytarabine 1
Like methotrexate, cytarabine can be administered intrathecally to produce high CSF cytarabine concentrations with minimal systemic toxicity. Cytarabine may be given by the intralumbar route or via an Ommaya reservoir on a C x T schedule that has the same advantages as C x T methotrexate administration.102107 In addition, cytarabine is often combined with methotrexate and or hydrocortisone for IT administration in children with leukemic meningitis this is the only standard regimen for...
Ommaya Reservoir
1. Pels H, Schmidt-Wolf IG, Glasmacher A, et al. Primary central nervous system lymphoma results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003 21 4489-95. 2. Esteva FJ, Soh, LT, Holmes FA, et al. Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 2000 46 382-6. 3. Witham TF, Fukui MB, Meltzer CC, et al. Survival of patients...
Leptomeningeal Metastases From Leukemias And Lymphomas
Craig P. Nolan, M.D., Lauren E. Abrey, M.D. Department of Neurology, Memorial Sloan-Kettering Cancer Center, 12745 York Avenue, New York, NY 10021 Abstract Leptomeningeal dissemination of lymphoma and leukemia differs from that of solid tumors in a number of clinically important aspects. Specific histologic variants of lymphoma and leukemia have such a high incidence of cerebrospinal fluid CSF dissemination that assessing CSF cytology at diagnosis is crucial and prophylactic therapy of the CSF...
Adult acute lymphoblastic leukemia
Approximately 80 of patients with adult acute lymphoblastic leukemia ALL can achieve remissions with current treatment regimens. However, the cure rate remains low at 20-30 .46'47 Extramedullar disease is common in adult patients with ALL and the CNS is a frequent location. At the time of diagnosis of ALL, LM are seen in 6 of adult patients with a range of 110 . The rate of relapse into the CNS is higher at approximately 30 .46'47 As in pediatric patients with ALL, CNS relapse is frequently...
Complications 1
Risks of Ommaya catheter placement include hemorrhage, poor positioning and the sequelae of intraparenchymal chemotherapy toxicity, malfunction and infection.9 The rate of intraventricular hemorrhage in published series is between 1 to 2.8 .2'4'5'6 Hemorrhages in the cancer population may be related to hematologic abnormalities, such as thrombocytopenia or disseminated intravascular coagulopathy related to the primary cancer or treatment related effects. These risks may be long-standing and...
Treatment and survival
Currently, the goal of treatment of LM is palliative which often improves or delays progression of neurologic symptoms and signs. The reported median survival after CNS recurrence in NHL ranges between two and six months. The treatment of LM from NHL includes craniospinal irradiation, traditional systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with hematopoietic stem cell rescue. The reported median patient survival after the development of LM, from both solid and...