03-10-29 Oplysninger om svulster-anaplastisk oligodendroglio · histologic features of the tumor, and use of adjuvant therapies. Overall, as many as three fourths of patients with

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INGE BØRVEN

ANAPLASTISK ORIGODENDROGLIOM • Litteraturoversigt fra Medscape, Medline, Medpub

• 1½ sides sammendrag

• Tre helt nye opsummeringsartikler fra internationale

tidsskrifter • Oversigt over eksperimentel behandling • Abstracts af artikler fra 2003 • En cd med 92 siders sammendrag med oversigt over

litteratur, links, henvisning til hjemmesider mv. • Oversigt over retningslinjer til at indhente second opinion

ved The Cleveland Clinics og Sloan-Kettinger Memorial i N.Y.

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29.10.2003 Oligodendrogliomer: Diagnosticering, behandling, prognose - uddrag fra litteratur fundet i Medline, Medscape og Medpub og hvordan man kan søge second opinion, også i udlandet.

C:\Documents and Settings\Administrator\Dokumenter\03-10-16 Oplysninger om svulster-anaplastisk oligodendrogliom.doc

Dokumentet fylder 91 sider. Du kan læse et sammendrag på side 4 og 5, eller kikke på side 2 og 3 som er en indholdsfortegnelse hvor du hurtigt kan navidere til det der interesserer dig ved at klikke på det relevante stikord. Næsten alt material er på engelsk.

Fra: Helge Børven Til: Intresserede Formål: Orientere mig selv og andre omkring oplysninger/ressourcer der er tilgængelige på internettet vedrørende min hustru, Inges, kræftlidelse. Dette er et udpluk af informationer fremkommet ved at jeg søgte på www.google.com med stikordet ”anaplastic oligodendroglioma”. Det er litteratur fra Medline, www.pubmed.com og www.medscape.com . Det er oplysninger fra hjemmesider for pårørende og patienter, og fra hjemmesider for læger og behandlere. Jeg har klippet-klistret oplysningerne ind i dette dokument. Foran de flæste bidrag er der et link. Hvis du er koblet på nettet kan du klikke på linket, og så er du på den hjemmeside hvor oplysningerne er fundet. Nemmere kan det ikke gøres, vel??

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Indholdfortegnelse med stikord og links FOR PATIENTER/PÅRØRENDE • Forskellige typer primær hjernetumor- for patienter og pårørende - fra National Cancer

Institute i USA. • Beskrivelse af oligodendrogliomer – fra engelsk hjemmeside for pårørende og patienter • Orientering fra Cedar-Sinai- et stort amerikans hospital orienterer om oligodendrogliomer –

for patienter og pårørende. • Et interessant dyreforsøg - kan genterapi/virus eliminere svulster? Fra University of Texas,

MD Anderson Hospital. • Kræftens Bekæmpelse – www.cancer.dk • Kræftens Bekæmpelse –

o Anbefalinger for second opinion o Retningslinjer for eksperimentelle behandlinger i udlandet

• Second opinion ved The Cleveland Clinic i USA o Hvordan får man “remote second opinion” Fra The Cleveland Clinics, procedurer,

pris (565 $) og formalia. o Hvorfor bruge The Cleveland Clinics til second opinion-“first choice of second

opinion” o Hvordan anmode om second opinion fra The Cleveland Clinic via internettet o Eksempel på en second opinion modtaget fra The Cleveland Clinic

• Second opinion hos Sloan-Kettering i N.Y. o For internationale patienter: Beskrivelse, procedurer og pris o Sloan-Kettering i N.Y.: Behandling for internationale patienter, procedurer og pris

FOR LÆGER/BEHANDLERE Kliniske forsøg:

o Klinisk forsøg for voksne med hjernesvulster generelt – National Cancer Institut og www.cancer.gov

o Kliniske forsøg for patienter med oligodendrogliomer – fra www.neuro-oncology.org

o Kliniske forsøg med hurtigvoksende oligodendroglomer (”Oligodendroglioma high grade”) fra www.virtualtrials.com

Diagnostisering og behandling

o Diagnoticering af oligodendrogliomer kan være svært o Diagnostisering/undergruppering ved hjælp af genetiske markører-meget nyttigt for

behandling og overlevelse o Oligodendrogliomer som ”low-grade gliomer” fra

http://www.ncbi.nlm.nih.gov/books ” o Diskussion og placering i WHO´s klassificeringssystem o Strålebehandling af oligodendriomer er kontroversiel – fra Cancer 1987 o Retningslinjer for diagnosticering, behandling af oligodendrogliomer – 8 sider fra

www.eDoctor.com

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o Diagnostisering og behandling af oligodendrogliom – fra www.medscape.org – for læger – mange litteraturreferencer. Artikel fra: Neurosurg Focus 12(2), 2002. © 2002 American Association of Neurological Surgeons

• Strålebehandling er godt for delvis fjernede svulster og for personer over 50 år • Anaplastisk oligodendroglomer – modtagelige for kemoterapi-God response til

TMZ-fra European Organization for Research and Treatment of Cancer Brain Tumor Group

• Modtagelige for kemo- Curr Neurol Neurosci Rep. 2003 May;3(3):223-8 • Modtagelige for kemo- European Orgniazation for Research and Treatment of

Cancer Brain Tumor Group Study 26971 • Radioterapi kombineret med kemo giver bedre overlevelse for anaplastisk

oligodendrogliomer. Prognose

• Prognose ifølge www.emedicine.com o Forskelligartede svulster med meget forskellig prognose

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Sammendrag:

• Incidense – cirka 5 % af alle primære hjernesvulster- tilpasset danske forhold vil det gæt være at der er cirka 5-6 tilfælde på årsbasis i hele Danmark.

• 50 % har epileptiske anfald før diagnosticering, 80 % har det i hele forløbet • Medianlevetid for patienter med diagnoceret anaplastisk oligodendrogliom er 3-4 år • Diagnostisering med biopsi er næsten altid nødvendig • Kemosensitiv – genetiske markører er effektiv ved dianosticering og behandling • Operation er at foretrække, supperet med stråling og kemo ved svulster der ikke kan fjernes

helt • Strålebehandling sikrer længer overlevelse for patienter over 50 år med delvis fjernet svulst.

Oligodendrogliomas may be diagnosed at any age but occur most commonly in young and middle-aged adults, with a median age at diagnosis of 40-50 years. In children, only 6% of gliomas are diagnosed as oligodendrogliomas Oligodendrogliomas occur in both sexes, with a slight male-to-female predominance of 2:1. Oligodendrogliomas are rare primary glial brain tumors that are chemosensitive. Typically, they have an indolent course, and patients may survive for many years after symptom onset. Their good prognosis relative to other parenchymal tumors probably stems from inherently less aggressive biological behavior and a favorable response to chemotherapy, a recently discovered finding based on genetic characteristics. No causes or risk factors are known. Occasional clustering occurs in some families, although the mode of inheritance is unknown. Patients with anaplastic oligodendrogliomas who have loss of heterozygosity (LOH) on 1p or combined LOH on 1p and 19q survive substantially longer (mean, 10 y) than patients whose tumors lack these genetic changes (mean, 2 y). A number of variables determine the prognosis for an individual patient, including age of the patient at diagnosis, location and extent of surgical resection, postoperative performance status, histologic features of the tumor, and use of adjuvant therapies. Overall, as many as three fourths of patients with nonanaplastic tumors can be expected to survive 5 years from the time of diagnosis, with a median reported survival duration of 6-10 years. For those with anaplastic oligodendrogliomas, median survival is more likely to be 3-4 years. Late progression of disease is common, so the usual 5-year survival time used to indicate "cure" in other cancers is not relevant for oligodendrogliomas.

The morbidity and mortality profile for oligodendrogliomas is much better than for astrocytic tumors. However, it also depends on tumor location and pressure effects, as with any other intracranial lesion. The median survival from initial diagnosis of all low-grade oligodendrogliomas (LGOs) is 4-10 years, but it is only 3-4 years for anaplastic oligodendrogliomas.

Historically, surgery has been the mainstay of treatment for oligodendrogliomas. The extent of resection depends in large part on the location of the tumor and its proximity to "eloquent” brain areas. If possible, the goal is total resection of the tumor. In patients who undergo total gross resection, no further treatment may be necessary, but the patient must be followed up for clinical or radiologic recurrence.

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Individualize treatment of an oligodendroglioma depending on the presence or absence of symptoms, location and biological aggressiveness of the tumor, extent of possible surgical resection, and histopathology and degree of anaplasia. Treatment options vary from conservative treatment of some patients with serial imaging studies and no intervention to aggressive multimodal treatment including surgical resection, radiotherapy, and chemotherapy in others. Because most patients either develop or present with seizures, anticonvulsive therapy is recommended once the patient is diagnosed with oligodendroglioma.

Recently, the role of chemotherapy for the treatment of oligodendroglioma was well established by several studies using nitrosurea-based therapy. Most used procarbazine, lomustine (CCNU), and vincristine, a combination chemotherapy regimen (ie, PCV) developed by Levin and coworkers. Patients with pure and mixed oligoastrocytic tumors, newly diagnosed, and recurrent mixed tumors responded to this therapy before receiving radiotherapy. Despite prolonged responses, most patients experience disease relapse and ultimately die of progressive disease. The median time for recurrence was at least 16 months in partial responders and at least 25 months in complete responders. Recurrent tumors are not cured by PCV, and the intensity of treatment may be limited by the bone marrow reserve.

The optimal use of radiotherapy in the treatment of oligodendroglioma is not entirely clear. Although differences of opinion exist regarding the efficacy of radiotherapy for oligodendrogliomas, radiation is used routinely at diagnosis in patients who have undergone incomplete removal of nonanaplastic oligodendrogliomas and generally is recommended for patients with anaplastic oligodendrogliomas regardless of the extent of resection. Radiotherapy also is used at recurrence in previously untreated patients. As systemic therapies are becoming available and more effective, delaying radiotherapy in many patients may be prudent to avoid the toxic side effects of radiation to the nervous system.

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Primære hjernesvulster Fra: http://www.nci.nih.gov/cancerinfo/wyntk/brain#6

Tumor Grade Doctors sometimes group brain tumors by grade—from low grade (grade I) to high grade (grade IV). The grade of a tumor refers to the way the cells look under a microscope. Cells from high-grade tumors look more abnormal and generally grow faster than cells from low-grade tumors.

Primary Brain Tumors Tumors that begin in brain tissue are known as primary tumors of the brain. (Information about secondary brain tumors appears in the following section.) Primary brain tumors are named according to the type of cells or the part of the brain in which they begin.

The most common primary brain tumors are gliomas. They begin in glial cells. There are many types of gliomas:

• Astrocytoma—The tumor arises from star-shaped glial cells called astrocytes. In adults, astrocytomas most often arise in the cerebrum. In children, they occur in the brain stem, the cerebrum, and the cerebellum. A grade III astrocytoma is sometimes called an anaplastic astrocytoma. A grade IV astrocytoma is usually called a glioblastoma multiforme.

• Brain stem glioma—The tumor occurs in the lowest part of the brain. Brain stem gliomas most often are diagnosed in young children and middle-aged adults.

• Ependymoma—The tumor arises from cells that line the ventricles or the central canal of the spinal cord. They are most commonly found in children and young adults.

• Oligodendroglioma—This rare tumor arises from cells that make the fatty substance that covers and protects nerves. These tumors usually occur in the cerebrum. They grow slowly and usually do not spread into surrounding brain tissue. They are most common in middle-aged adults.

Some types of brain tumors do not begin in glial cells. The most common of these are:

• Medulloblastoma—This tumor usually arises in the cerebellum. It is the most common brain tumor in children. It is sometimes called a primitive neuroectodermal tumor.

• Meningioma—This tumor arises in the meninges. It usually grows slowly. • Schwannoma—A tumor that arises from a Schwann cell. These cells line the nerve that controls

balance and hearing. This nerve is in the inner ear. The tumor is also called an acoustic neuroma. It occurs most often in adults.

• Craniopharyngioma—The tumor grows at the base of the brain, near the pituitary gland. This type of tumor most often occurs in children.

• Germ cell tumor of the brain—The tumor arises from a germ cell. Most germ cell tumors that arise in the brain occur in people younger than 30. The most common type of germ cell tumor of the brain is a germinoma.

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Engelsk hjemmeside for patienter og pårørende http://www.cancerbacup.org.uk/info/oligodendroglioma.htm This factsheet gives information about a specific type of brain tumour called an oligodendrioglioma.

It should ideally be read with CancerBACUP's booklet Understanding brain tumours, which gives more information and puts the factsheet into context.

You may also want to discuss it with a nurse or doctor involved in your treatment.

What is an oligodendroglioma?

Cells within the brain normally grow in an orderly and controlled way, but if for some reason this order is disrupted, the cells continue to divide and form a lump or tumour.

This may be benign, where the cells do not spread from the original site, or malignant (cancerous), where the cells invade and destroy surrounding tissue and may spread to other parts of the brain.

Most brain tumours are named after the cells from which they develop. Within the brain are nerve cells and also cells that support and protect the nerve cells. The supporting cells are called glial cells. A tumour of these cells is known as a glioma.

Oligodendroglioma is a type of glioma and develops from cells called oligodendrocytes that produce the fatty covering of nerve cells. This type of tumour is normally found in the cerebrum, particularly in the frontal or temporal lobes. Oligodendrogliomas may be divided into two types, the well differentiated tumour, which grows slowly, and the faster growing anaplastic oligodendroglioma.

Grading Like other gliomas, oligodendrogliomas may be graded between 1 and 4 depending on how abnormal the cells are and how quickly they are growing. Grade 1 is the least malignant and grade 4 the most. Grade 1 and 2 oligodendrogliomas may be referred to as low grade tumours and grade 3 and 4 as high grade.

Who gets an oligodendroglioma? Although this type of tumour is more common in adults it can occur in children. For unknown reasons it is more common in men than women.

What causes oligodendroglioma? Like most brain tumours the cause of oligodendroglioma is unknown. Research is being carried out into possible causes.

Signs and symptoms People with slowly growing oligodendrogliomas may have symptoms for several years before the tumour is discovered.

The first symptoms of any type of brain tumour are usually due to increased pressure within the skull (raised intracranial pressure). This may be caused by a blockage in the ventricles (fluid-filled spaces of the brain) which leads to a build-up of cerebrospinal fluid (CSF) or by swelling around the tumour itself. CSF is the fluid that surrounds the brain and the spinal

Related CancerQs

Questions and answers on brain tumours

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cord.

Raised intracranial pressure can cause headaches, sickness (vomiting) and visual problems. Fits (seizures) and changes in behaviour and personality can also be general signs of a brain tumour.

Oligodendrogliomas can grow in different parts of the brain, and symptoms may relate to the area of the brain which is affected. They are usually found in the frontal or temporal lobes of the cerebrum. A tumour of the frontal lobe of the brain may cause gradual changes in mood and personality. There may also be paralysis on one side of the body (known as hemiparesis). A tumour in the temporal lobe of the brain may cause problems with co-ordination and speech and may affect your memory.

Tests and investigations In order to plan your treatment it is important to find out as much as possible about the type, position and size of the tumour. This is done by having a number of tests and investigations.

You will usually have a neurological examination to assess any effect the tumour has had on your nervous system.

A CAT scan or MRI scan will be done to find the exact position and size of the tumour.

CT scan (CAT scan) A CT scan takes a series of x-rays, which are fed into a computer to build up a detailed picture of your brain. The test itself is completely painless, but it will mean that you have to lie still for about 10 to 30 minutes.

Magnetic resonance imaging (MRI or NMR scan) This test is similar to a CT scan, but uses magnetism instead of x-rays to build up cross-sectional pictures of your brain. During the test you will be asked to lie very still on a couch inside a large metal cylinder that is open at both ends. The whole test may take up to an hour. It can be slightly uncomfortable and some people feel a bit claustrophobic during the scan, which is also very noisy. You will be given earplugs or headphones and you can usually take someone with you into the room to keep you company.

Biopsy To give an exact diagnosis, a biopsy (sample of cells from the tumour) is sometimes taken, which is then looked at under a microscope. The biopsy involves an operation. Your doctor will discuss with you whether this is necessary in your case, and what the operation involves.

Treatment The treatment for oligodendroglioma, like all brain tumours, depends on a number of things including your general health, the size and position of the tumour and whether it has spread to surrounding areas. The results of your tests will enable your doctor to discuss your treatment plan with you.

There are some risks associated with treatment to the brain and your doctor will also discuss these with you.

Before any treatment is given for a brain tumour it is important to reduce the pressure within the skull if it is raised. Steroid drugs may be used to reduce swelling around the tumour. If raised intracranial pressure is due to a build-up of CSF a shunt (tube) may have to be

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inserted to drain off the excess fluid.

Surgery Where possible, surgery is the main treatment for oligodendroglioma. The aim of surgery is to remove as much of the tumour as possible without damaging the surrounding brain tissue. Depending on the size and position of the tumour it may not be possible to remove it completely and further treatment may be given after the surgery.

Some tumours cannot be reached by surgery, or the risk of damage to the rest of the brain is too high. If surgery is not possible your doctor will discuss other types of treatment with you.

Radiotherapy Radiotherapy treatment is the use of high-energy rays to destroy cancer cells and is often used after surgery. The aim of the radiotherapy is to destroy any remaining malignant cells. It may be used on its own to treat oligodendroglioma if surgery is not possible.

Radiotherapy is usually given as an external treatment but occasionally it may be given in the form of radioactive implants (small radioactive metal objects which are inserted into the tumour during an operation).

Chemotherapy Chemotherapy is the use of anti-cancer drugs that destroy cancer cells. It may be given alone or together with surgery and/or radiotherapy to treat oligodendroglioma.

Other CancerBACUP booklets which you may find helpful are Understanding brain tumours, Understanding radiotherapy, Understanding chemotherapy, Coping with hair loss, Diet and the cancer patient and A parent's guide to children's cancers.

Your feelings

The idea of a tumour affecting the brain is extremely frightening. The brain controls the body, and not being in control is something everyone worries about. You may experience many different emotions including anxiety and fear. These are all normal reactions and are part of the process many people go through in trying to come to terms with their condition. Many people find it helpful to talk things over with their doctor or nurse. Close friends and family members can also offer support.

CancerBACUP can send you a booklet on the emotional effects of cancer and how to deal with them.

For more information call CancerBACUP's Cancer Support Service on 020 7739 2280 or Freephone 0808 800 1234 to speak to a cancer specialist nurse. Lines are open Monday-Friday, 9am-7pm.

Last reviewed: November 2002

This factsheet has been compiled using information from a number of reliable sources including the Oxford Textbook of Oncology, Cancer and its management and The Textbook of Uncommon Cancers. Each CancerBACUP factsheet is regularly reviewed and updated by cancer doctors, specialist nurses, other relevant health professionals and people with cancer.

© CANCERBACUP 2002, OLIGODENDROGLIOMA. All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from CancerBACUP. British Association of Cancer United

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Patients, 3 Bath Place, Rivington Street, London EC2A 3JR. Charity Registration No. 1019719. A company limited by guarantee. Registered in England and Wales. Company No. 2803321. Registered office as above.

Homepage: http://www.cancerbacup.org.uk

Copyright CancerBACUP © All rights reserved.

Although every effort has been made to ensure accuracy,

CancerBACUP and its advisors cannot accept any liability in relation to this information.

Readers are strongly advised todiscuss the information with thei

doctor. CancerBACUP

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Kan genterapi/virus dræbe kræftceller? http://www3.mdanderson.org/~oncolog/gliomasep01.html

New Replication-Competent Adenovirus Shows Promise against Gliomas in Preclinical Studies

By Kerry L. Wright

In gene therapy, viruses are often utilized as vectors for carrying healthy genes into genetically deficient cells, but in some new strategies, the viruses themselves are weapons--designed to seek out, infiltrate, and destroy cancer cells. When pitted against the most vigorous animal model for human gliomas, one of the most powerful new oncolytic viruses, a replication-competent adenovirus called Delta24, completely eliminates tumors.

Based on these striking preclinical results, clinical trials of Delta24 are being planned, and investigators hope they will eventually lead to a more effective treatment for patients with some of the most devastating brain tumors.

"The virus in these particular animal experiments is more powerful than anything we have seen before," said Juan Fueyo, M.D., an assistant professor in the Department of Neuro-Oncology at The University of Texas M. D. Anderson Cancer Center. Dr. Fueyo and Candelaria Gomez-Manzano, M.D., an instructor in the Department of Neuro-Oncology, are the minds behind the development of Delta24.

While many gene therapy strategies target cells with defects in their p53 pathway, Delta24 targets cells disrupted in the pathway of another master regulator of cell growth, the retinoblastoma (Rb) protein. The new virus contains a 24-base pair deletion in the adenovirus E1A gene, which is essential for viral replication in normal cells but not in cells deficient in their Rb pathways, such as many cancer cells.

In a healthy cell infected with a normal adenovirus, Rb interacts with the virus to prevent its replication--until the virus expresses E1A, which binds to Rb and easily counteracts its inhibitory effects. In contrast, when Delta24 (which has a mutation in E1A) infects a normal cell, E1A cannot overcome Rb's protective mechanism, so the virus cannot replicate. When the same virus infects a cancer cell that is defective in Rb, however, the virus replicates uncontrollably.

Gliomas, which comprise astrocytomas, oligodendrogliomas, and ependymomas, appear to be particularly well suited for treatment with Delta24. According to Dr. Fueyo and Dr. Gomez-Manzano, more than 90% of the cells in the brain are already quiescent, meaning that the mutant virus should not be able to propagate. At the same time, nearly all glioma cells have disruptions in their Rb pathways, providing the perfect environment for attack by Delta24.

For more than 20 years, patients receiving the conventional treatment for gliomas--aggressive systemic therapy consisting of surgery, chemotherapy, and radiation therapy--have survived an average of only six to eight years with low-grade astrocytomas or oligodendrogliomas, three years with anaplastic astrocytomas, and no more than a year and a half with glioblastomas, the highest-grade astrocytoma. Finding strategies to prolong patients' lives depends on the development of new agents, and successful animal experiments are the first step toward this goal.

When Delta24 was intracranially injected into nude mice containing U-87 human glioma cell-derived tumors, it did exactly what it was designed to do--avoid normal cells while targeting and killing cancer cells. As a consequence, it essentially cured the mice.

"What you could see was just a cavity where the tumor had been and then just these dystrophic calcifications and cystic structures, which is what the body's cleanup actions would leave," said Charles

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Conrad, M.D., an associate professor in the Department of Neuro-Oncology and the clinical medical director of the Neuro and Supportive Care Center at M. D. Anderson.

In mice that were killed midway through the experiment, pathologic assessment of tumor sections by Gregory Fuller, M.D., Ph.D., an associate professor in the Department of Pathology, showed immunohistochemical staining in a three-zone pattern that proved that Delta24 was replicating and spreading through the tumors. Staining of E1A to show viral replication and of the protein hexon to show particle formation identified a central region of necrosis, a middle area of highly infected cells, and an outer area of minimally infected cells. The normal tissues outside the tumor remained untouched by the virus.

Delta24 is not the first replication-competent adenovirus that has been developed to specifically target cancer cells. The prostate-specific attenuated adenovirus CN706, first developed at Johns Hopkins University Oncology Center, fared well against a human-xenograft mouse model for prostate cancer and is currently in clinical trials. In addition, Dr. Frank McCormick (currently at the University of California at San Francisco) recently developed the ONYX-015 adenovirus, designed to specifically infect cells with mutated p53. Although ONYX-015 showed no toxicity in phase I clinical trials (which is good news for those working on Delta24), it replicated in some cells that were already expressing wild-type p53, partly because it did not function the way its creators had predicted. Concerns that Delta24 may also behave unpredictably are being addressed to increase Delta24's potential for targeted activity in humans.

To increase selectivity, the Delta24 virus contains an extra arginine-glycine-aspartic acid-containing peptide that has a high affinity for alpha(v) integrins, receptors that are expressed much more frequently on the surfaces of glioma cells than on those of normal cells and some other types of cancer cells. Although the virus showed no toxic effects in preclinical studies, no toxicity in mice does not necessarily mean no toxicity in humans, warned Dr. Fueyo. Because adenoviruses almost exclusively infect human cells, many of the toxicity issues could not be directly addressed in the preclinical studies.

"Any time we use some of these viral agents, the immune system can react to them, and they can cause a lot of inflammation and swelling. That is one of the things we are going to be very careful about in the clinical trials," said Dr. Conrad.

A phase I gene therapy trial for malignant gliomas utilizing replication-deficient adenovirus-mediated p53 gene delivery was recently completed at M. D. Anderson. Despite the many differences between the adenovirus used in that trial and Delta24, the surgical procedures used during the trial serve as a paradigm for the Delta24 trial and subsequent gene therapy trials for brain cancer.

"The p53 trial was valuable because it provided us with a novel method for studying tissues," said Frederick Lang, Jr., M.D., an associate professor in the Department of Neurosurgery, who was the trial's principal investigator. Rather than excising a tumor from the inside out using suction, as most neurosurgeons do, Dr. Lang and his team actually cut around the entire tumor to remove it. This way, the virus could be injected through a catheter that remained in the tumor during excision, and the exact point of injection and the precise pattern of propagation of the virus could be determined.

In many ways, the p53 study was a successful gene therapy trial. According to Dr. Lang, the adenovirus vector had minimal toxic effects and produced no viral shedding when injected into the brains of 15 trial participants. In addition, the p53 gene was effectively delivered into glioma cells, where it produced a functional protein. Researchers found, however, that p53 was only delivered within a 5- to 7-mm radius from the point of viral injection.

As is the case in many gene therapy trials, the vector itself may have been effective, but the key to success will be improving delivery. Dr. Lang is currently collaborating with investigators at the National Institutes of Health on a new method called convection-enhanced delivery in which the gene therapy agent is infused (rather than injected) into the brain over several hours to create an electrical wave that will carry the vector farther through the tumor.

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For viruses like Delta24, which are already capable of infecting a large area of cells, enhancing selectivity may instead be the key. While Dr. Conrad and Dr. Lang are developing clinical studies of Delta24, Dr. Fueyo and his colleagues continue their preclinical investigations, working on ways to ensure that the virus targets only cells with defective Rb pathways.

"The main thing here is to prove that the Rb pathway in gliomas is a great target for new strategies," said Dr. Fueyo. "Replication-competent adenoviruses like Delta24 are just one way."

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Oversigt over kliniske forsøg for voksne med hjernetumor (National Cancer Institut – USA) http://www.cancer.gov/search/clinical_trials/results_clinicaltrials.aspx http://www.cancer.gov/search/clinicaltrials/ Search for Clinical Trials

Type of Cancer: Brain tumor, adult

Type of Trial: (check 1 or more)

All Treatment Screening Genetics

Location of Trial: ZIP Code: search within 0 miles

(look up ZIP Code)

Need to specify additional search criteria? Try the advanced search form.

Results: 1 - 99 of 99 Show 100 results per page Title of Trial Protocol IDs

Phase I Pilot Study of Topotecan and Thalidomide in Patients With Recurrent or Refractory Malignant Glioma

RUSH-G101, NCI-

V01-1651

Phase I Study of Atrasentan in Patients With Progressive or Recurrent Malignant Glioma

NABTT-2008,

JHOC-NABTT-2008

Phase I Study of Boron Neutron Capture Therapy and Borocaptate Sodium Following Craniotomy with Gross Total Resection in Patients With Glioblastoma Multiforme

EORTC-11961

Phase I Study of Bortezomib in Patients With Recurrent Glioma

NABTT-9910,

JHOC-NABTT-9910

Phase I Study of Brachytherapy Using An Intracavitary Applicator and Liquid Iodine I 125 in Patients With Recurrent Malignant Glioma

NABTT-2106,

JHOC-NABTT-2106

Phase I Study of Brachytherapy Via GliaSite RTS™ Applicator and External Beam Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme

NABTT-2105,

JHOC-NABTT-2105

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Phase I Study of Carboxyamidotriazole Plus Paclitaxel in Patients With Advanced Solid Tumors or Refractory Lymphomas

NCI-95-C-0015F, NCI-CPB-334, NCI-

T94-0006N

Phase I Study of CC-5013 in Patients With Recurrent High-Grade Gliomas

NCI-02-C-0145

Phase I Study of Continuous Intracerebral Infusion of Interleukin-13 PE38QQR Immunotoxin Before and After Second Resection in Patients With Recurrent Resectable Supratentorial Malignant Glioma

MSKCC-01141, NCI-G02-2066, NEOPHARM-

IL13PEI-002-R01

Phase I Study of EGFRvIII Peptide Vaccine With Sargramostim (GM-CSF) Versus Keyhole Limpet Hemocyanin as Adjuvant in Patients With EGFRvIII-Expressing Cancer

SWOG-S0114, NCI-V01-1664, UW-106

Phase I Study of Erlotinib in Patients With Solid Tumors and Hepatic or Renal Dysfunction

CLB-60101

Phase I Study of Gefitinib and Temozolomide in Patients With Malignant Primary Glioma

NABTC-0102

Phase I Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction

CWRU-1Y01, NCI-02-C-0073, NCI-

5340

Phase I Study of Immunization With Autologous Tumor Lysate-Pulsed Dendritic Cells in Patients With Malignant Gliomas

UCLA-0304053

Phase I Study of Interstitial Colloidal Phosphorus P32 in Patients With Recurrent or Poor Prognosis Grade 4 Astrocytoma

CMM-2, NCI-V99-

1575

Phase I Study of Intrathecal Iodine I 131 Monoclonal Antibody 3F8 in Patients With GD2 Positive Leptomeningeal Neoplasms

MSKCC-97021, NCI-G97-1267

Phase I Study of Intratumor BG00001 (Adenoviral Vector Encoding Human Interferon beta) in Patients With Recurrent or Progressive Glioblastoma Multiforme

BIOGEN-C-1502, NCI-V02-1696,

UARIZ-HSC-01197

Phase I Study of Irinotecan Plus Temozolomide in Patients With Recurrent Primary Malignant Glioma

DUMC-1087-02-

6R3, DUMC-001087-006R1,

DUMC-001087-01-6R2, DUMC-1067-99-6, NCI-G00-

1795

Phase I Study of Karenitecin in Patients With Recurrent Malignant Glioma

NABTT-2006,

JHOC-NABTT-2006

17

Phase I Study of Motexafin Gadolinium as a Radiosensitizer in Patients With Glioblastoma Multiforme Receiving Cranial Radiotherapy

NABTT-2116,

JHOC-NABTT-2116

Phase I Study of Mutant MGMT Gene Transfer into Human Hematopoietic Progenitors to Protect Hematopoiesis During O6-Benzylguanine and Carmustine Therapy in Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

CWRU-2Y97, NCI-

T97-0060

Phase I Study of Photodynamic Therapy With Benzoporphyrin Derivative Monoacid Ring A in Patients With Refractory Brain Tumors

MCW-7594, MCW-CHW-511, MCW-CHW-9411, NCI-

V95-0652

Phase I Study of Telomerase: 540-548 Peptide Vaccine and Sargramostim (GM-CSF) in Patients With Sarcoma or Brain Tumor

DFCI-02100

Phase I Study of Temozolomide, Thiotepa, and Carboplatin Followed By Autologous Peripheral Blood Stem Cell or Bone Marrow Transplantation in Patients With Malignant Brain Tumors

NYU-0006H, NCI-

G01-2022

Phase I Study of Thalidomide and Docetaxel in Patients With Advanced Malignancies

CWRU-4Y01, NCI-

G02-2123

Phase I Study of Tipifarnib and Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

NABTC-0202, NCI-

03-C-0189

Phase I/II Randomized Study of Intratumoral Radiolabeled Antitenascin Monoclonal Antibody 81C6 in Patients With Newly Diagnosed or Recurrent Malignant Primary Brain Tumors

DUMC-1529-01-8R4, DUMC-1363-97-9, DUMC-1409-

98-9R1, DUMC-1529-00-8R3,

DUMC-1630-99-9R2, DUMC-97112, NCI-5950NS20023,

NCI-G98-1471

Phase I/II Study of Astatine At 211 Antitenascin Human/Mouse Chimeric Monoclonal Antibody 81C6 Via Surgically Created Cystic Resection Cavity in Patients With Primary or Metastatic Brain Tumors

DUMC-2237-01-

12R4, DUMC-0013-00-1R2, DUMC-0036-99-1R1,

DUMC-060-98-1, DUMC-2237-00-12R3, DUMC-98007, NCI-

5P50NS20023, NCI-G98-1462

Phase I/II Study of BMS-247550 in Patients With Recurrent High-Grade Glioma

NABTT-2111,

JHOC-NABTT-2111

18

Phase I/II Study of Boron Neutron Capture Therapy Using Boronophenylalanine-Fructose Complex in Patients With Glioblastoma Multiforme or Intracranial Melanoma

BIDMC-E-010284FB, NCI-

V02-1702, NEDH-E-010284FB

Phase I/II Study of CCI-779 in Patients With Malignant Glioma

NABTC-0101

Phase I/II Study of Efaproxiral and Carmustine in Patients With Progressive or Recurrent High-Grade Gliomas

NABTT-9806,

JHOC-NABTT-9806

Phase I/II Study of Erlotinib and Radiotherapy in Patients With Glioblastoma Multiforme

NCCTG-N0177

Phase I/II Study of Erlotinib in Patients With Recurrent Malignant Glioma

NABTC-0103, NCI-

03-C-0114

Phase I/II Study of Gefitinib and Radiotherapy in Patients With Glioblastoma Multiforme

RTOG-0211,

RTOG-BR-0211, RTOG-DEV-1007

Phase I/II Study of Gefitinib in Patients With Recurrent or Progressive Supratentorial Malignant Gliomas or Brain or Spinal Meningiomas

NABTC-0001

Phase I/II Study of Imatinib Mesylate in Patients With Recurrent Malignant Glioma or Meningioma

NABTC-9908, NCI-01-C-0243, UCLA-

0101024

Phase I/II Study of Interstitial Interleukin-13 PE38QQR Immunotoxin in Patients With Malignant Glioma

NABTT-9903,

JHOC-NABTT-9903, NEOPHARM-

IL13PEI-001-R03, NEOPHARM-TS-G1-

TI4

Phase I/II Study of Irinotecan and Temozolomide in Patients With Recurrent Malignant Glioma

NABTC-9907, UCLA-0006095

Phase I/II Study of Oxaliplatin Followed By Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme

NABTT-9902,

JHOC-NABTT-9902

Phase I/II Study of Pyrazoloacridine and Radiotherapy in Adults With Newly Diagnosed, Supratentorial Glioblastoma Multiforme

NABTT-9804,

JHOC-NABTT-9804

Phase I/II Study of Sirolimus in Patients With Glioblastoma Multiforme

UCLA-0203078,

NCI-G02-2114

Phase Ib/II Study of Intracerebral G207 in Patients With Recurrent Malignant Glioma

MGENE-NG1-003,

NCI-V02-1695, NIH-OBA-0107-481

19

Phase II Pilot Study of Cyclophosphamide and Active Intralymphatic Immunotherapy With a Vaccine Containing Interferon alfa or Interferon gamma-Treated Tumor Cells Followed by Sargramostim (GM-CSF) in Patients With Advanced Cancers

SVMC-ONC-222,

NCI-V91-0075

Phase II Pilot Study of Post-Operative Intrathecal Radioimmunotherapy, Reduced-Dose Craniospinal Radiotherapy With Intensity-Modulated Radiotherapy Boost, and Chemotherapy in Patients With Standard-Risk Medulloblastoma

MSKCC-02088

Phase II Randomized Study of PEG-Interferon alfa-2b With or Without Thalidomide in Adults With Recurrent High Grade Gliomas

NCI-03-C-0002,

NABTC-0201

Phase II Study of Adjuvant Dose-Intensive Induction Chemotherapy With Cisplatin, Vincristine, Cyclophosphamide, and Etoposide With or Without Methotrexate Followed By Radiotherapy in Patients With Surgically Resected, Newly Diagnosed High-Stage Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor or Incompletely Resected Ependymoma

NYU-0002H, NCI-G00-1852, NYU-

0027H

Phase II Study of Adjuvant Temozolomide, Thalidomide, and Celecoxib After Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme

DFCI-00302,

CELGENE-2000-P-002521/1, NCI-

G02-2118

Phase II Study of Antineoplastons A10 and AS2-1 in Adults with Mixed Gliomas

BRI-BT-18

Phase II Study of Antineoplastons A10 and AS2-1 in Adults With Primary Malignant Brain Tumors

BRI-BT-21

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Anaplastic Astrocytoma

BRI-BT-15

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Anaplastic Astrocytoma

BRI-BT-8

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Brain Stem Glioma

BRI-BT-11

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Choroid Plexus Neoplasm

BRI-BT-26

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Craniopharyngioma

BRI-BT-25

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Ependymoma

BRI-BT-24

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Germ Cell Tumors of the Brain

BRI-BT-27

20

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Glioblastoma Multiforme

BRI-BT-7

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Incurable Glioblastoma Multiforme

BRI-BT-20

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Low-Grade Astrocytoma

BRI-BT-16

Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Meningioma

BRI-BT-28

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Recurrent or Refractory Oligodendroglioma

BRI-BT-17

Phase II Study of Antineoplastons A10 and AS2-1 in Patients With Severe Brain Tumors

BRI-BT-9

Phase II Study of Autologous Cancer Antigen Specific Immunotherapy in Patients With Malignant Glioma

WSU-C-1403-BT,

NCI-G99-1567

Phase II Study of BMS-247550 in Patients With Advanced Cisplatin-Refractory Germ Cell Tumors

MSKCC-03041,

NCI-6022

Phase II Study of CCI-779 in Patients With Recurrent Glioblastoma Multiforme

NCCTG-N997B

Phase II Study of Celecoxib in Patients With Newly Diagnosed Glioblastoma Multiforme Receiving Hepatic Enzyme-Inducing Drugs and Undergoing Radiotherapy

NABTT-2100,

JHOC-NABTT-2100

Phase II Study of Chemotherapy, Surgery, Radiotherapy, and High-Dose Chemotherapy With Autologous Bone Marrow or Peripheral Blood Stem Cell Rescue in Patients With Primary CNS Germ Cell Tumors

NYU-0007H, NCI-

G01-2019

Phase II Study of Cisplatin, Doxorubicin, and Tamoxifen (CAT) in Patients With Incurable Soft Tissue Sarcoma, Glioma, Mesothelioma, Hepatoma, Thyroid Cancer, or Adrenal Cancer

CAN-OTT-9401,

NCI-V94-0566

Phase II Study of Dalteparin and Conventional Radiotherapy in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme

E-E1F01

Phase II Study of Erlotinib in Patients With Recurrent or Progressive Glioblastoma Multiforme

CCF-IRB-5478

Phase II Study of High-Dose Thiotepa Followed By Autologous Peripheral Blood Stem Cell Transplantation in Patients With Malignant Glioma

CPMC-IRB-8017, CPMC-CAMP-013,

NCI-G00-1883

21

Phase II Study of Hydroxyurea in Patients With Recurrent and/or Nonresectable Meningioma

FRE-FNCLCC-98009, EU-20018

Phase II Study of Hydroxyurea in Patients With Unresectable Benign Meningioma

SWOG-S9811

Phase II Study of Imatinib Mesylate in Patients With Gliomas

EORTC-16011, EORTC-26013

Phase II Study of Imatinib Mesylate in Patients With Recurrent Meningioma

NABTC-0108

Phase II Study of Imatinib Mesylate in Patients With Recurrent Oligodendroglioma or Mixed Oligoastrocytoma

NCCTG-N0272

Phase II Study of Intensive Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation in Patients With Central Nervous System Malignancies

CPMC-IRB-8445,

CPMC-CAMP-004A, NCI-G00-1881

Phase II Study of Intracavitary Interleukin-2 (IL-2) and Lymphokine-Activated Killer (LAK) Cell Therapy in Patients with Primary, Recurrent, or Refractory Malignant Gliomas

SIUH-RP-96-004,

NCI-V97-1326

Phase II Study of LY317615 in Patients With Recurrent High-Grade Gliomas

NCI-03-C-0018

Phase II Study of Neoadjuvant and Concurrent Temozolomide With Radiotherapy in Patients With Newly Diagnosed Anaplastic Oligodendrogliomas or Mixed Anaplastic Oligoastrocytomas


Phase II Study of Neoadjuvant Chemotherapy With Cisplatin and Etoposide Followed by Radiotherapy in Patients With CNS Germ Cell Malignancies

MAYO-891351, NCI-T92-0208D

Phase II Study of Poly ICLC in Patients With Recurrent or Progressive Anaplastic Glioma

NABTC-0106

Phase II Study of Poly-ICLC and Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme

NABTC-0105

Phase II Study of Preradiation Combination Chemotherapy in Adults with Poor-Risk Medulloblastoma, Peripheral Primitive Neuroectodermal Tumor, or Disseminated Ependymoma

E-4397, SWOG-

E4397

Phase II Study of Pyrazoloacridine Plus Carboplatin in Patients With Recurrent Glioma

NCCTG-987254

Phase II Study of Radiotherapy Followed By Sustained Release Intratumoral Bleomycin in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme


Phase II Study of Talampanel in Patients With Recurrent High-Grade Gliomas

NCI-03-C-0207

22

Phase II Study of Temozolomide in Patients With Progressive Low-Grade Gliomas

DUMC-1703-02-

9R5, DUMC-000693-01-3R1,

DUMC-1502-97-10, DUMC-1569-98-

10R1, DUMC-1703-01-94R, DUMC-

97125, NCI-G98-1469

Phase II Study of Thalidomide and Irinotecan After Radiotherapy in Patients With Glioblastoma Multiforme

DMS-0134, DMS-15615, NCI-G02-

2078

Phase II Study of Thalidomide, Celecoxib, Etoposide, and Cyclophosphamide in Patients With Relapsed or Refractory Malignant Glioma

DFCI-01278,

CELGENE-2001-P-001757/3, NCI-

G02-2117

Phase II Study of Tipifarnib and Radiotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme

NABTT-2200,

JHOC-NABTT-2200

Phase II Study of Tipifarnib in Patients With Recurrent or Progressive Malignant Glioma

NABTC-9901

Phase III Randomized Study of d-Methylphenidate to Improve Quality of Life in Patients Receiving Radiotherapy for Primary or Metastatic Brain Tumors

CCCWFU-97600,

NCI-P02-0211

Phase III Randomized Study of High or Low Light Dose Photodynamic Therapy Using Porfimer Sodium (Photofrin) in Patients with Recurrent Malignant Supratentorial Gliomas

RPCI-DS-9802, HEALTHONE-

43892, NCI-G98-1484

Phase III Randomized Study of Radiotherapy and Carmustine With or Without O6-Benzylguanine in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

SWOG-S0001

Phase III Randomized Study of Radiotherapy Combined With Temozolomide Versus Carmustine in Patients With Anaplastic Astrocytoma

RTOG-9813, E-R9813, NCCTG-

RTOG-9813

Phase III Randomized Study of Temozolomide Versus Procarbazine, Lomustine, and Vincristine in Patients With Recurrent Malignant Glioma

MRC-BR12, EU-20114, ISRCTN-

83176944

Randomized Study of Adjuvant Distance Healing Intention in Patients With Glioblastoma Multiforme

CALPMC-ROC026, CALPMC-00000921, CALPMC-20039EXP,

NCCAM

23

24

Kliniske forsøg i behandling af Oligodendroglioma http://www.neuro-oncology.org/oligotrials1.htm

Clinical Trials - Oligodendroglioma

Clinical Trials Links: Anaplastic Astrocytoma

Glioblastoma

Oligodendroglioma

CNS Lymphoma

Meningioma

Brain Metastases

Thalidomide

Practice Information:

Fox Chase Cancer Center

Temple University

Philadelphia Office

The following trials are open to patients with newly diagnosed and recurrent oligodendroglioma:

Recurrent Glioma

Compassionate Use Trial of Temodal in Recurrent Malignant Glioma.

Eligibility: Recurrent Malignant Glioma.

Protocol: Temodal, an oral agent, is taken five days out of each 4 week period.

Newly Diagnosed Anaplastic Oligodendroglioma and Oligoastrocytoma

Phase II study of High-Dose Carboplatin Prior to Radiation Therapy

Eligibility: Newly diagnosed anaplastic astrocytoma, glioblastoma multiforme

Protocol: up to four cycles of Carboplatin are given prior to the administration of local field radiation therapy. Follow-up chemotherapy is then given.

Newly Diagnosed Anaplastic Oligodendroglioma or Oligoastrocytoma

Phase III Intergroup Randomized Comparison of Radiation Alone vs Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas (RTOG 9402)

Eligibility: Patients with previously untreated anaplastic oligodendroglioma or mixed oligodendroglioma-astrocytoma 18 years or older are eligible.

Protocol: This is a randomized study. Half of the patients will receive chemotherapy prior to radiation, the other half will receive radiation as the initial therapy.

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Recurrent Anaplastic Oligodendroglioma and Oligoastrocytoma

Phase I/II dose escalation study of Carboplatin and Thalidomide in recurrent high grade glioma

Eligibility: Recurrent high grade glial neoplasm, no prior carboplatin or cisplatinum based chemotherapy.

Protocol: Carboplatin is administered monthly and Thalidomide is administered daily. Up to six courses of therapy may be given.

Newly Diagnosed or Anaplastic Oligodendroglioma and Oligoastrocytoma

Phase II study of high-dose Carboplatin/Thiotepa with autologous stem-cell support in newly diagnosed or recurrent high grade glioma

Eligibility: Newly diagnosed or recurrent high grade glial neoplasm, No prior Thiotepa, Carboplatin, or Cisplatinum based chemotherapy.

Protocol: Following stem-cell harvest, high-dose Carboplatin and Thiotepa are administered followed by stem cell re-infusion. Two cycles of therapy are given.

Recurrent Anaplastic Oligodendroglioma and Oligoastrocytoma Phase II study of high-dose Cyclophosphamide/Etoposide with gCSF

support in recurrent high grade glioma

Eligibility: Recurrent high grade glial neoplasm, No prior Cyclophosphamide or Etoposide, and failure of radiation therapy and carboplatin-based

chemotherapy.

Protocol: high-dose Cyclophosphamide and Etoposide are followed by gCSF support. Treatment is repeated as tolerated.

26

Diagnostisering og behandling af oligodendrogliomer – fra eMedicine http://www.emedicine.com/NEURO/topic281.htm

Back to: eMedicine Specialties > Neurology > Neuro-oncology

Subramanian Hariharan, MD, is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and American Medical Association Editor(s): Amy

Oligodendroglioma Last Updated: April 28, 2002

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Synonyms and related keywords: LGO, anaplastic oligodendroglioma

AUTHOR INFORMATION Section 1 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Author: Subramanian Hariharan, MD, Director, Associate Professor, Department of Neuro-oncology, Neuroscience Institute, Kennedy Medical Center, Seton Hall University

Coauthor(s): ABM Salah Uddin, MD, Director, Clinical Neurophysiology and Intraoperative Monitoring, Assistant Professor, Department of Neurology, Epilepsy and Clinical Neurophysiology, New Jersey Neuroscience Institute, JFK Medical Center A Pruitt, MD, Program Director, Assistant Professor, Department of Neurology, University of Pennsylvania; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Jorge Kattah, MD, Head, Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria; Selim R Benbadis, MD, Director of Comprehensive Epilepsy Program, Associate Professor, Departments of Neurology and Neurosurgery, University of South Florida, Tampa General Hospital; and Nicholas Lorenzo, MD, eMedicine Chief Publishing Officer, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

INTRODUCTION Section 2 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Oligodendrogliomas are rare primary glial brain tumors that are chemosensitive. Typically, they have an indolent course, and patients may survive for many years after symptom onset. Their good prognosis relative to other parenchymal tumors probably stems from inherently less aggressive biological behavior and a favorable response to chemotherapy, a recently discovered finding based on genetic characteristics.

Pathophysiology: Oligodendrogliomas arise in the cerebral hemispheres and are

Quick Find Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Click for related images.

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Arteriovenous Malformations Brainstem Gliomas CNS Melanoma Frontal Lobe Syndromes Glioblastoma Multiforme HIV-1 Associated Opportunistic Infections: CNS Toxoplasmosis HIV-1 Associated Opportunistic Neoplasms: CNS Lymphoma Low-Grade Astrocytoma Meningioma Metastatic Disease to the Brain

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classified as low grade or anaplastic. They usually occur in the cerebral white matter and are very cellular, with uniform nuclei. They react with glial fibrillary acidic protein on immunostaining.

Frequency:

• In the US: Oligodendrogliomas are uncommon tumors that account for less than 5% of primary brain tumors.

• Internationally: No difference in the incidence of oligodendroglioma exists worldwide.

Mortality/Morbidity: The morbidity and mortality profile for oligodendrogliomas is much better than for astrocytic tumors. However, it also depends on tumor location and pressure effects, as with any other intracranial lesion. The median survival from initial diagnosis of all low-grade oligodendrogliomas (LGOs) is 4-10 years, but it is only 3-4 years for anaplastic oligodendrogliomas.

Race: No difference exists among the races.

Sex: Oligodendrogliomas occur in both sexes, with a slight male-to-female predominance of 2:1.

Age: Oligodendrogliomas may be diagnosed at any age but occur most commonly in young and middle-aged adults, with a median age at diagnosis of 40-50 years. In children, only 6% of gliomas are diagnosed as oligodendrogliomas.

CLINICAL Section 3 of 10


History:

• In prior years, a long delay occurred between symptom onset and diagnosis (as long as 29 y in some series). Because of earlier and better imaging availability, oligodendrogliomas have been diagnosed much earlier in recent years.

• Like other intracranial space-occupying lesions, oligodendrogliomas present with focal cerebral dysfunction, depending on location, and rarely as increased intracranial pressure.

o Most oligodendrogliomas present as a single lesion in the cerebral hemispheres.

o Typically they are cortical or subcortical; they rarely are found in deep gray structures, and occasionally they may be primarily intraventricular.

o In 50% of patients, they are located in the frontal lobe, followed in frequency by the temporal and parietal lobes.

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o Rarely, they can occur infratentorially or in the spinal cord.

o Occasionally they may be multifocal, like other gliomas.

• The most common presenting symptom is a seizure, observed at diagnosis in as many as half of patients. As many as 80% of patients have seizures at some time during their illness.

o Depending on the location of the tumor, the seizure can be simple partial, complex partial, or generalized.

o Previously undiagnosed oligodendrogliomas may be identified with medically refractory epilepsy.

• Occasionally patients with oligodendrogliomas are brought to medical attention for headache, symptoms of increased intracranial pressure, or focal neurological deficits.

• Tumors that arise within the ventricles may cause obstructive hydrocephalus and are more likely to disseminate through the cerebrospinal fluid (CSF). Rarely, they can metastasize outside the nervous system.

• Occasional patients present with strokelike transient ischemic attacks or with intracerebral hemorrhage.

Physical: Physical findings depend on the location of the tumor.

• Frontal, parietal, and temporal lobe tumors most commonly present with seizures. Seizures may be simple, complex partial, and even generalized.

o Frontoparietal tumors may present with hemiparesis and sensory neglect.

o Sensory neglect is pronounced in right hemispheric lesions.

o Temporal lobe tumors rarely may present with visual field defects, although patients may be unaware of hemianopsia.

• Rare intraventricular oligodendroglioma may present with signs and symptoms of increased intracranial pressure such as headache, visual disturbance, and papilledema.

• Posterior fossa oligodendrogliomas are uncommon. However, well-documented cases are described in children and may present with cerebellar ataxia and increased intracranial pressure.

Causes: No causes or risk factors are known. Occasional clustering occurs in some families, although the mode of inheritance is unknown. Patients with anaplastic oligodendrogliomas who have loss of heterozygosity (LOH) on 1p or combined LOH on 1p and 19q survive substantially longer (mean, 10 y) than patients whose tumors lack these genetic changes (mean, 2 y).

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DIFFERENTIALS Section 4 of 10


Arteriovenous Malformations Brainstem Gliomas CNS Melanoma Frontal Lobe Syndromes Glioblastoma Multiforme HIV-1 Associated Opportunistic Infections: CNS Toxoplasmosis HIV-1 Associated Opportunistic Neoplasms: CNS Lymphoma Low-Grade Astrocytoma Meningioma Metastatic Disease to the Brain Primary CNS Lymphoma

Other Problems to be Considered:

Other CNS tumors (eg, meningioma, metastasis, astrocytoma, glioblastoma) Brain abscess CNS toxoplasmosis Lymphoma Vascular malformations

WORKUP Section 5 of 10


Lab Studies:

• Routine laboratory workup is not helpful. If seizures are noted, include EEG, serum electrolyte studies, and if necessary a lumbar puncture in the metabolic workup for seizure, after excluding intracranial pathology with an imaging study. These routine tests help exclude other causes of seizure (eg, electrolyte imbalance, metabolic abnormalities).

Imaging Studies:

• Diagnostic imaging studies are the most important part of the workup.

o MRI (with and without gadolinium) is the preferred modality. T1 images generally demonstrate a hypointense or mixed hypointense and

hyperintense mass. T2 images reveal a hyperintense mass with or without surrounding edema. With contrast administration, the LGO generally does not enhance, while an

anaplastic oligodendroglioma does enhance. These tumors also tend toward calcification.

o CT scans reveal a hypodense, reasonably well-demarcated mass with moderate surrounding edema.

Intratumoral calcification is common, and hemorrhage is noted occasionally.

30

As with contrast MRI, the tumor does not enhance unless it is behaving unusually aggressively or has an anaplastic astrocytic component.

Other Tests:

• Definite diagnosis in confirmed by stereotactic or open biopsy of the lesion. Currently, MR spectroscopy is performed regularly in some centers to differentiate the tumor from other benign lesions and to define the aggressiveness of the tumor, although this is in the investigational phase. In the future, it may offer another noninvasive modality of investigation.

Histologic Findings:

Macroscopic

Grossly, oligodendrogliomas appear as well defined, solid, and pinkish grey, frequently with areas of calcification and sometimes with areas of necrosis and cystic degeneration. Intratumoral hemorrhage may be present and in some patients may be massive and responsible for sudden death.

Microscopic

Oligodendrogliomas are distinctive, consisting of homogeneous, compact, rounded cells with distinct borders and clear cytoplasm surrounding a dense central nucleus, giving them a "fried egg" appearance. Oligodendrogliomas usually arise in the subcortical location but infiltrate diffusely into cortex around normal neuronal elements and, in superficially located lesions, may extend to the leptomeninges. Within the tumor, branching blood vessels are highly characteristic and divide the cells into discrete clusters. Many oligodendrogliomas have some component of astrocytoma within them; however, distinguishing neoplastic astrocytes from reactive astrocytes may be very difficult. Clearly some tumors are truly mixed oligoastrocytic tumors; both cell types are believed to arise from a common oligodendrocyte precursor termed the oligodendrocyte type-2 astrocyte.

To call a tumor a mixed oligoastrocytoma, the minimum proportion of astrocyte is variable but ranges from 10-25%. In most instances, the diagnosis of oligodendroglioma is apparent. Confusion can arise with intraventricular oligodendrogliomas, which can appear similar to central neurocytoma. Under light microscopy, neuronal differentiation (eg, Homer Wright rosette formation) can indicate a diagnosis of central neurocytoma, but immunohistochemical markers such as synaptophysin may be necessary to confirm the diagnosis.

Most oligodendrogliomas are slow-growing indolent tumors; however, they occasionally behave in a more malignant manner when initially diagnosed, or an indolent tumor may evolve into an aggressive one. Malignant tumors demonstrate increased cellularity, nuclear pleomorphism, endothelial proliferation, mitotic activity, and necrosis. Different grading systems are available for malignant tumors, but most pathologists use a simple two-tier grading system, diagnosing as "oligodendroglioma" tumors without anaplastic features and as "anaplastic oligodendroglioma" if several of the malignant features are present.

Staging: No other staging workup is required.

TREATMENT Section 6 of 10


Medical Care: Individualize treatment of an oligodendroglioma depending on the presence or absence of symptoms, location and biological aggressiveness of the tumor, extent of possible surgical resection, and

31

patients with serial imaging studies and no intervention to aggressive multimodal treatment including surgical resection, radiotherapy, and chemotherapy in others. Because most patients either develop or present with seizures, anticonvulsive therapy is recommended once the patient is diagnosed with oligodendroglioma.

• Recently, the role of chemotherapy for the treatment of oligodendroglioma was well established by several studies using nitrosurea-based therapy. Most used procarbazine, lomustine (CCNU), and vincristine, a combination chemotherapy regimen (ie, PCV) developed by Levin and coworkers. Patients with pure and mixed oligoastrocytic tumors, newly diagnosed, and recurrent mixed tumors responded to this therapy before receiving radiotherapy. Despite prolonged responses, most patients experience disease relapse and ultimately die of progressive disease. The median time for recurrence was at least 16 months in partial responders and at least 25 months in complete responders. Recurrent tumors are not cured by PCV, and the intensity of treatment may be limited by the bone marrow reserve.

Surgical Care:

• Historically, surgery has been the mainstay of treatment for oligodendrogliomas. The extent of resection depends in large part on the location of the tumor and its proximity to "eloquent " brain areas. If possible, the goal is total resection of the tumor. In patients who undergo total gross resection, no further treatment may be necessary, but the patient must be followed up for clinical or radiologic recurrence.

• The optimal use of radiotherapy in the treatment of oligodendroglioma is not entirely clear. Although differences of opinion exist regarding the efficacy of radiotherapy for oligodendrogliomas, radiation is used routinely at diagnosis in patients who have undergone incomplete removal of nonanaplastic oligodendrogliomas and generally is recommended for patients with anaplastic oligodendrogliomas regardless of the extent of resection. Radiotherapy also is used at recurrence in previously untreated patients. As systemic therapies are becoming available and more effective, delaying radiotherapy in many patients may be prudent to avoid the toxic side effects of radiation to the nervous system.

MEDICATION Section 7 of 10


The standard chemotherapeutic treatment for oligodendrogliomas is combination chemotherapy with PCV. While modifications of the timing and dosage of this regimen (increasing dose, decreasing time interval to every 6 wk), are beyond the scope of this article, interested readers can review the references cited in Bibliography. Physicians prescribing chemotherapy should be aware of the treatment regimens and monitoring required. PCV chemotherapy is administered every 6 weeks or 8 weeks for a total of 6 cycles. If the treatment should fail, radiation therapy, other clinical trials for recurrent gliomas, or other drugs may be considered.

Drug Category: PCV chemotherapy -- This combination of agents inhibits cell growth and differentiation.

Drug Name Procarbazine, lomustine (CCNU), vincristine -- Oral chemotherapy drugs administered in combination (PCV) on a specific chemotherapeutic schedule.

Adult Dose Procarbazine: 60 mg/m2/d PO for 14 d Vincristine: 2 mg IV twice per cycle CCNU: 110 mg/m2 PO on first d of each cycle Administer combination of 3 drugs on a specific

32

chemotherapeutic schedule every 6 or 8 wk Pediatric Dose Not established

Contraindications Documented hypersensitivity; preexisting bone marrow aplasia

Interactions

Sympathomimetic amines, barbiturates, phenothiazines, alcohol, and other CNS depressants can increase toxicity; foods containing high amounts of tyramine can increase toxicity owing to weak monoamine oxidase properties; concurrent mitomycin-C may cause acute pulmonary reaction

Pregnancy X - Contraindicated in pregnancy

Precautions

Only a physician trained in the appropriate use of chemotherapy should administer these drugs; for details please refer to standard oncology textbooks Caution in preexisting renal or hepatic disease (reduce dose); caution in patients diagnosed with severe cardiopulmonary or hepatic impairment and patients with pre-existing neuromuscular disease

FOLLOW-UP Section 8 of 10


Further Inpatient Care:

• After the initial surgical resection and rehabilitation, the patient may require further inpatient care depending on the development of complications from either therapy or tumor recurrence. Appropriate intervention also depends on the nature of complications (eg, surgery for recurrence, steroid therapy for increased vasogenic edema).

Further Outpatient Care:

• After initial appropriate management, closely monitor the patient with the family for tumor recurrence or chemotherapy-induced adverse effects. Monitor with regular follow-up care and MRI scans every 3 months initially and then every 6 months to 1 year.

In/Out Patient Meds:

• Patients with seizures require appropriate seizure medications even after surgery. Over time the dose of the medications can be reduced, depending on the frequency of seizures.

Transfer:

• Transfer depends on the residual neurological deficit. The patient may be fully ambulatory or may need appropriate transfer arrangements (eg, cane, wheelchair).

Complications:

• Closely observe the patient for any complications resulting from continuing treatment, such as radiation necrosis from radiation therapy or neuropathy from chemotherapy.

33

Prognosis:

• A number of variables determine the prognosis for an individual patient, including age of the patient at diagnosis, location and extent of surgical resection, postoperative performance status, histologic features of the tumor, and use of adjuvant therapies. Overall, as many as three fourths of patients with nonanaplastic tumors can be expected to survive 5 years from the time of diagnosis, with a median reported survival duration of 6-10 years. For those with anaplastic oligodendrogliomas, median survival is more likely to be 3-4 years. Late progression of disease is common, so the usual 5-year survival time used to indicate "cure" in other cancers is not relevant for oligodendrogliomas.

Patient Education:

• Throughout the entire process, educate the patient and family through regular follow-up care and involvement of support groups to cope with physical, emotional, and spiritual stress. With proper education, the patient and family can develop good insight into the course and prognosis of the tumor.

MISCELLANEOUS Section 9 of 10


Medical/Legal Pitfalls:

• Intraventricular oligodendrogliomas must be differentiated from the histologically very similar appearing central neurocytoma and dysembryoplastic neuroepithelial tumor. These tumors have a better prognosis. By considering and recognizing these tumors, inappropriate treatment by chemotherapy and radiotherapy and their medicolegal consequences can be avoided.

• As oligodendrogliomas commonly present with a long history of seizure, every patient with a history of intractable seizure and middle-aged patients with new onset of seizure should be evaluated aggressively by MRI scans. This will avoid unnecessary delay in diagnosis and ensure appropriate treatment for better quality of life and prolonged survival.

BIBLIOGRAPHY Section 10 of 10


• Bello MJ, Vaquero J, de Campos JM, et al: Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors. Int J Cancer 1994 Apr 15; 57(2): 172-5[Medline].

• Burger PC, Rawlings CE, Cox EB, et al: Clinicopathologic correlations in the oligodendroglioma. Cancer 1987 Apr 1; 59(7): 1345-52[Medline].

• Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1994 Oct; 12(10): 2013-21[Medline].

• Celli P, Nofrone I, Palma L, et al: Cerebral oligodendroglioma: prognostic factors and life history. Neurosurgery 1994 Dec; 35(6): 1018-34; discussion 1034-5[Medline].

• Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, et al: Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery 1988 Nov; 23(5): 545-56[Medline].

• Kaye AH, Laws ER Jr, eds: Brain Tumors. Churchill Livingstone; 1995:479-491. • Kleihus P, Cavenee WK: Pathology and Genetics of Tumours of the Nervous System. Oxford

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University Press; 2000:56-64. • Mason WP, DeAngelis LM: Procarbazine, CCNU, vincristine (PCV) chemotherapy for benign

oligodendroglioma. Neurology 1994; 44(Suppl 2): A262-A263. • Packer RJ, Sutton LN, Rorke LB, et al: Oligodendroglioma of the posterior fossa in childhood.

Cancer 1985 Jul 1; 56(1): 195-9[Medline]. • Paleologos NA, Vick NA, Kachoris JP: Chemotherapy for low grade oligodendrogliomas. Ann Neurol

1994; 36: 294-295. • Pitt MA, Jones AW, Reeve RS, Cowie RA: Oligodendroglioma of the fourth ventricle with intracranial

and spinal oligodendrogliomatosis: a case report. Br J Neurosurg 1992; 6(4): 371-4[Medline]. • Sarkar C, Roy S, Tandon PN: Oligodendroglial tumors. An immunohistochemical and electron

microscopic study. Cancer 1988 May 1; 61(9): 1862-6[Medline]. • Schold SC, Burger PC, Minna JD, et al: Primary Tumors of the Brain and Spinal Cord. Butterworth-

Heinemann; 1997:71-82. • Wen PY, Black PM: Brain Tumors in Adults. Neurol Clin 1995; 13: 861-873. • Yuen ST, Fung CF, Ng TH, Leung SY: Central neurocytoma: its differentiation from intraventricular

oligodendroglioma. Childs Nerv Syst 1992 Oct; 8(7): 383-8[Medline].

NOTE: Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

Oligodendroglioma excerpt

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Oligodendrogliomer-orientering til patienter og pårørende http://www.cedars-sinai.edu/5300.html Oligodendroglioma

Oligodendrogliomas are more slow growing tumors that usually occur in young adults. They are frequently located within the frontal, temporal or parietal lobes and cause seizures in a relatively high percentage of patients. Many oligodendrogliomas contain little specks of calcium (bone) and can easily bleed.

Diagnosis A neurologist -- a doctor who has received special additional training in the diagnosis and treatment of disorders of the brain, spinal cord and nerves -- will do a complete examination.

He or she may also request that a magnetic resonance imaging (MRI) scan be done or a computed tomography (CT or CAT) scan be done as well as chest X-rays to check whether the tumor has spread from another part of the body. An MRI usually finds low-grade astrocytomas earlier than CT. Cerebral angiography is rarely used to diagnose a brain tumor, but may be done before surgery.

Depending on the patient's symptoms, specialized tests may be done. These include tests of the field of vision, the sharpness of vision and hearing.

If the results of other tests aren't conclusive, an examination of the fluid that surrounds the brain and spinal cord may be done. This is usually unnecessary.

Treatment

These tumors require surgery to make an accurate diagnosis, control seizures or to remove a blood clot inside the tumor. The surgery can be more beneficial for this type of tumor than other gliomas, as there is less likelihood of the tumor spreading into normal brain tissues may be less.

There are several clinical trials in the USA and Europe that are studying newer chemotherapy treatments for this tumor type.

Resources at Cedars-Sinai

• Cedars-Sinai Comprehensive Cancer Center • Department of Neurology • Maxine Dunitz Neurosurgical Institute • S. Mark Taper Foundation Imaging Center

36

Diagnostisering af og behandling af oligodendrogliomer – type to – ikke oligoastrocytoma – fra Medscape Artikel fra Neurosurg Focus 12(2), 2002 To Print: Click your browser's PRINT button. NOTE: To view the article with Web enhancements, go to: http://www.medscape.com/viewarticle/429338

Billeder af skanningerne som teksten refererer til kan ses ved at klikke på linket til medscape (ovenfor).

Current Diagnosis and Treatment of Oligodendroglioma Herbert H. Engelhard, M.D., Ph.D.

Neurosurg Focus 12(2), 2002. © 2002 American Association of Neurological Surgeons

Abstract and Introduction

Abstract Object. The strategies used to diagnose and treat oligodendroglial tumors have changed significantly over the past decade. The purpose of this paper is to review the topic of oligodendroglioma, emphasizing the new developments. Methods. Information was obtained by conducting a Medline search in which the term oligodendroglioma was used. Recent editions of standard textbooks were also studied. Because of tools such as magnetic resonance imaging, oligodendrogliomas are being diagnosed earlier, and they are being recognized more frequently histologically than in the past. Seizures are common in these patients. Functional mapping and image-guided surgery may now allow for a safer and more complete resection, especially when tumors are located in difficult areas. Genetic analysis and positron emission tomography may provide data that supplement the standard diagnostic tools. Unlike other low-grade gliomas, patients in whom residual or recurrent oligodendroglioma (World Health Organization Grade II) is present may respond to chemotherapy. Although postoperative radiotherapy prolongs survival of the patient, increasingly this therapeutic modality is being delayed until tumor recurrence, especially if a gross-total tumor resection has been achieved. Oligodendrogliomas are the first type of brain tumor for which "molecular" characterization gives important information. The most significant finding is that allelic losses on chromosomes 1p and 19q indicate a favorable response to chemotherapy. Conclusions. Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted, primarily because of the lesion's relative chemosensitivity. Molecular characterization of oligodendrogliomas may become a standard practice in the near future.

Introduction New information has recently become available concerning oligodendroglioma, especially in terms

37

of diagnosis and response to chemotherapy. Oligodendroglial tumors may be more common than previously appreciated, possibly representing as much as 25 to 33% of gliomas.[18,33,86] The classic or "garden variety" oligodendroglioma is a lower-grade or well-differentiated tumor, considered to be a Grade II glioma by the WHO classification system. The term anaplastic oligodendroglioma is used for the more malignant phenotype, which is a Grade III glioma. Nuclear atypia and occasional mitosis can be seen in a WHO Grade II oligodendroglioma, but marked mitotic activity, noticeable microvascular proliferation, and/or conspicuous necrosis are hallmarks of an anaplastic oligodendroglioma.[32,64] A mixed glioma (oligoastrocytoma) contains both neoplastic astrocytes and neoplastic oligodendroglia. In this paper, the clinical features and current treatment of WHO Grade II oligodendroglioma (not including oligoastrocytoma) will be reviewed.

Clinical Presentation

Oligodendroglial tumors may occur in patients of any age but the initial diagnosis in the United States has two incidence peaks: between the ages of 6 and 12 years in children and between the approximate ages of 35 and 44 years in adults.[31,93] There is a slight male predominance, with the male/female ratio reported to range from 1.1 to 2.[56] Although familial clusterings of oligodendrogliomas have been reported, there are no recognizable patterns of inheritance nor known genetic risk factors.[60] Oligodendrogliomas are believed to arise from a neoplastic transformation of an oligodendrocyte; accordingly, they develop in any location throughout the neuraxis in relative proportion to the volume of white matter.[60,64,76] More than 90% arise in the supratentorial white matter, most commonly in the frontal and temporal lobes. Fewer than 10% occur in the posterior fossa and spinal cord.[31] Unusual primary locations have been mentioned in the literature, including the thalamus, brainstem, cerebellopontine angle, septum pellucidum, ventricles, optic nerve, and retina.[31] Multiple oligodendrogliomas have also been reported.[21] Oligodendrogliomas typically demonstrate slow, infiltrative growth and have a tendency to invade the leptomeninges.[32,64,86] Cerebrospinal fluid metastases in patients with oligodendroglioma (either drop metastases or leptomeningeal gliomatosis) have been reported to occur in up to 14% of cases.[19,56,72,85] Oligodendrogliomas may metastasize outside the brain more frequently than other gliomas, possibly because of the longer periods of survival in these patients.[56]

Symptoms related to oligodendroglial tumors are nonspecific -- that is, they do not reliably distinguish this type of brain tumor from other types.[31] Symptoms are caused by involvement of the central nervous system in general and/or because of the specific anatomical location of the tumor. In most series, seizure has been the most commonly reported presenting symptom, ranging in incidence from 35 to 85% of patients.[12,31,36,57,82,92] Daumas-Duport, et al.,[23] have reported that 91% of their patients presented with seizures at some point in their clinical course. The seizures may be simple partial, complex partial, generalized, or a combination of these.[60] Other reported presenting symptoms have included headache, mental status change, visual complaint, vertigo/nausea, and/or focal weakness.[31] The duration of symptoms prior to diagnosis is highly variable; and a diagnosis may be reached after a new seizure, headache, or (rarely) hemorrhage, as well as after a decade of epilepsy.[31,36]

Diagnostic Imaging

Findings on diagnostic imaging are often characteristic, but not pathognomonic.[82,90] Usually oligodendrogliomas are mass lesions with fairly well-defined margins, located in the cortex and subcortical white matter.[47] On CT scans, oligodendrogliomas appear hypodense or isodense and enhance poorly, if at all.[51] On MR images, oligodendrogliomas are usually hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences.[23,46,47,51] Calcification is common; CT scanning demonstrates the calcium deposits better than plain radiography or MR imaging.[47,60]

38

Statistically, because of the higher incidence of astrocytomas, a glioma with calcium deposits is more likely to be an astrocytoma.[31,46] Cystic changes and hemorrhage may be seen; peritumoral edema is usually mild or absent.[47] Like astrocytomas, oligodendrogliomas may spread through the corpus callosum, the leptomeninges, and/or the ependyma.[51,64] Magnetic resonance imaging is more sensitive than CT scanning in demonstrating contrast enhancement, which may be patchy or homogeneous. Contrast enhancement may indicate a more aggressive tumor.[23,47,51,60,62] The appearance of ring enhancement has been associated with a poor prognosis.[11] In children and adolescents with oligodendrogliomas, calcifications, enhancement, and edema are demonstrated less frequently than in adults.[82] An example of a CT scan depicting of an unusual oligodendroglioma is shown in Fig. 1; an example of an MR image is given in Fig. 2.

Figure 1. Unenhanced CT scan revealing a high density lesion extending from the midbrain to middle pons. Although this was believed likely to represent a cavernous hemangioma with hemorrhage, its appearance did not change over time, and examination of a biopsy sample later showed it to be an oligodendroglioma (WHO Grade II). Oligodendrogliomas may have a variable appearance and may occur in unusual locations.

39

Figure 2. A T2-weighted MR image of a Grade II oligodendroglioma,demonstrating the tumor as a bright signal in the anterior and medial temporal lobe. In this type of tumor T2-weighted sequences may be more sensitive than T1-weighted sequences.

The authors of recent studies have indicated that PET scanning may provide useful information in patients with gliomas, including oligodendroglioma and anaplastic oligodendroglioma. Positron emission tomography can be performed to give quantitative information regarding the blood flow, glucose metabolism, and amino acid metabolism of the brain as well as brain tumors.[26,27,55,81] Based on this information, PET has been used as a tool in distinguishing scar or gliotic tissue from tumor.[88] With respect to gliomas, PET has been reported to be able to differentiate between low-grade astrocytoma and oligodendroglioma.[27] In a study of 22 patients, Derlon, et al.,[27] have found that both of these tumor types exhibit glucose hypometabolism (slightly more pronounced in astrocytoma) but markedly different patterns of uptake of the labeled amino acid, MET. The uptake of MET was high in the oligodendrogliomas and decreased, normal, or only moderately increased in the astrocytomas.[27] The authors speculated that this difference might be related to different cell densities in the tumor tissue. Determining MET uptake may also be more helpful than studying glucose metabolism in patients with oligodendroglioma who are being followed for residual or recurrent tumor.[27]

Positron emission tomography might also prove to be useful for grading oligodendrogliomas noninvasively. In a different study by Derlon, et al.,[26] MET uptake and [18]F-fluorodeoxyglucose uptake were used to determine amino acid metabolism and glycolysis in comparison of low-and high-grade oligodendrogliomas. The authors found that anaplastic oligodendrogliomas exhibited a higher [18]F-fluorodeoxyglucose uptake than did the oligodendrogliomas but that the difference in MET uptake was even more pronounced. Positron emission tomography scans can be coregistered (that is, displayed together) with MR images to combine the metabolic data provided by PET with the superior anatomical resolution achieving using MR imaging.[8,81] Positron emission tomography has been used to guide target selection for stereotactic biopsy sampling and to guide resection.[8,81] Therefore, although confirmatory studies with large numbers of patients still need to be conducted, PET seems to hold promise for future use in the management of patients with oligodendroglioma.

Surgical Intervention

Surgery continues to be the primary treatment modality for most patients with gliomas, including oligodendroglioma.[1,31,60,70,75] Until highly accurate noninvasive histological assessment becomes a

40

reality, surgery (biopsy sampling or resection) will continue to be essential for establishing an accurate diagnosis.[33,60] Tumor resection (when feasible) is also useful for reducing mass effect, which may be the cause of symptoms and/or neurological deficit. Tumor resection may also decrease the need for steroid therapy, allow a decrease of radiotherapeutic portal size, increase the effect of chemotherapy, and limit sampling error that may occur in cases in which a biopsy sample alone is obtained.[33] A large cranial opening is typically made to facilitate optimum exposure and the use of multiple trajectories, as well as to aid in decompression of the brain. At the time of surgery, it may not be possible to distinguish reliably between oligodendroglial lesions and other intraaxial tumors. Establishing an intraoperative diagnosis of oligodendroglioma can be difficult based on the frozen section histological specimen.[32]

The rate of surgery-related morbidity should be low but is dependent on the location of the tumor. Although these lesions are usually infiltrative and blend into normal brain, at times there may be an abrupt tumor-adjacent white matter interface.[20] Staying within the confines of the tumor, as indicated by preoperative imaging studies, does not guarantee that a deficit will not occur. Functional MR imaging, functional cortical mapping, awake surgery, image-guided surgery (stereotactic craniotomy), and/or intraoperative MR imaging are modalities that may be used to increase the amount of tumor that can be safely resected.[6,8,20,29,60] The value of radiosurgery, for instance in a patient in whom an oligodendroglioma has locally recurred, remains undetermined.

Resection and Survival

Concerning extent of resection and survival, there are very little data available from the post-MR imaging era.[68] In some clinical series addressing this issue the authors have not been able to confirm that a more complete resection is beneficial.[58,80] In most reports, however, the authors have concluded that more complete resection is associated with increased patient survival.[6,12,24,34,38,45,48,58,71,74] Interestingly, in a recent series reported by Giannini, etal.,[35] gross-total resection or a biopsy procedure was associated with longer survival than subtotal resection. Most authors believe that the surgery-related goal for oligodendroglioma should be gross-total removal if the tumor can be safely resected.[6,20,70,79] Aggressive resection in regions engendering significant risk of neurological damage should probably be avoided, because these tumors are likely to respond to other therapies.[33]

Pathological Examination

Oligodendrogliomas appear macroscopically to be soft masses of fleshy to pinkish-gray color, but they may be gelatinous due to mucoid degeneration. They may contain areas of firm, gritty calcifications and/or areas of soft cystic degeneration, and intratumoral hemorrhages can be present.[10,32,64] Histological examination shows moderate cellularity, with tumor cells containing uniformly round, homogeneous nuclei and a swollen clear cytoplasm. This typical "honeycomb" or "fried-egg" appearance is actually an artifact of fixation but is a useful diagnostic feature if present.[32] Additionally, oligodendrogliomas can display a dense network of branching capillaries in what has been termed a "chicken-wire" vascular pattern.[32] Oligodendrogliomas may contain varying percentages of astrocytic cells. These are hypothesized to represent reactive astrocytes trapped by the invasive tumor, transitional forms of oligodendroglial cells, or differentiated neoplastic astrocytic cells. There is no specific immunocytochemical marker that allows for the recognition of human oligodendroglial tumor cells. Electron microscopy can help to discriminate oligodendrogliomas from other types of tumors.[13,32] A photomicrograph of a hematoxylin and eosin stained oligodendroglioma specimen is shown in Fig. 3.

41

Figure 3. Photomicrograph showing the histological features of a low-grade oligodendroglioma. Note the round to oval-shaped nuclei, with delicate chromatin and small nucleoli. The classic "fried egg" appearance, which is an artifact of fixation, may not always be present. H & E, original magnification x 400.

Postoperative Treatment

Because oligodendrogliomas, like other gliomas, have an infiltrative growth pattern, and the true extent of tumor cells cannot be determined using current imaging modalities,[30,31] an oligodendroglioma is very rarely completely resected, or cured.[34] Recurrences are usually seen locally at the previous operative site.[50] Patients with oligodendroglioma usually do succumb to progressive disease or to the effects of conversion of their tumor to a higher grade.[79] Because of this, postoperative limited-field radiotherapy has been performed in the past as a treatment option in adults with low-grade oligodendrogliomas. The majority of the available literature does indicate that radiotherapy prolongs patient survival, especially if the tumor has been partially resected.[2,34,40,71,73-75] In children, radiation is withheld whenever possible.[2,50]

Even in adults, because these patients experience a relatively long survival, the probability of encountering radiotherapy-induced adverse effects is high. Detrimental effects in long-term survivors have included personality change, memory loss, dementia, hypopituitarism, gait abnormality, coordination and/or balance difficulty, and radiation necrosis with mass effect.[33,48,58] In the study reported by Olson, et al.,[58] which included 77 patients with oligodendroglioma, 21% developed radiotherapy-induced cognitive changes and 15% developed necrosis. Reducing the total radiation dose, daily fraction size (hyperfractionation), and/or size of the fields -- or the use of three-dimensional conformal therapy -- may help reduce the incidence of complications.[31,40] Because radiotherapy helps but has serious side effects, the critical issue is whether it should be administered postoperatively, or reserved for later, either after chemotherapy or at the time of tumor progression.[31] The authors of recent studies (including a randomized trial) have indicated that delayed radiotherapy is as effective as postoperative therapy in treating patients with low-grade oligodendrogliomas, provided that minimum residual tumor is present.[38,48] Until this issue is settled by sound evidence, the decision to perform radiotherapy is made on a case-by-case basis, considering factors such as the extent of resection, tumor location, and the patient's age and occupation.

Currently, many clinicians are administering chemotherapy before radiotherapy to postpone radiation-

42

related adverse effects.[15,52] Responses have definitely been seen in patients with low-grade oligodendrogliomas, in whom PCV chemotherapy is administered before or after radiotherapy.[49,52,78,79,83,85] Patients undergoing both treatments have been reported to experience a longer survival than those treated with either modality alone.[2,79] As with radiotherapy, chemotherapy is associated with significant adverse effects. Side effects of PCV chemotherapy have been reported to include nausea, vomiting, anorexia, fatigue, rash, numbness or paresthesias, weakness, abdominal pain, constipation, neuropathy, hepatotoxicity, encephalopathy, seizures, intracranial hemorrhage, pneumonia and other infections, neutropenia, and thrombocytopenia.[31] In the series published by Olson, et al.,[58] 46% of patients treated with PCV chemotherapy developed significant myelosuppression. Given the potential benefit of chemotherapy, however, until new data become available, PCV chemotherapy continues to be an option for the treatment of patients with low-grade oligodendroglioma, either before or after radiotherapy, particularly if residual or recurrent tumor is present.[49,52,78] Temozolomide is being tested

A recurrent oligodendroglioma is often an anaplastic oligodendroglioma or glioblastoma multiforme.[74,79] In patients with recurrent oligodendroglioma, either radiotherapy and/or PCV chemotherapy is undertaken, depending on which treatment has already been used.[84] Patients in whom radiotherapy has been previously performed seem to be as likely to respond to PCV therapy as those who have not undergone irradiation therapy.[31] Other salvage chemotherapy regimens have also been attempted.[14,31,61,72]Veninga, et al.,[87] concluded that repeated radiotherapy can be considered as a treatment option in good-condition patients with recurrent gliomas, including oligodendrogliomas.

Clinical Prognostic Factors and Survival

In addition to the aforementioned resection-and histology-related aspects, other prognostic factors have been reported for oligodendroglial tumors. Age has been found to be one of the strongest independent predictors of survival.[35,71,74,92] Older age is associated with more aggressive tumor behavior and a worse prognosis, whereas in patients younger than age 40 to 45 years a significantly longer survival time has been documented.[9,12,45,58,63,71,74,93] The presence of a neurological deficit at the time of diagnosis has also been reported to predict a poor outcome.[9,12,22,91,92] In patients with low-grade oligodendrogliomas who present clinically with seizures and have no neurological deficits, a significantly better outcome has been reported than in those with raised intracranial pressure or neurological deficits.[9,12,34]

Other favorable features include location in the frontal lobe (which may relate to the extent of resection possible) and higher initial or postoperative functional performance status.[1,22,45,71] Additional studies are currently underway in which the authors may be able to confirm the validity of these clinical prognostic factors (H Engelhard, et al., unpublished data).

The survival times reported in recent studies are already significantly longer than those cited only a few years ago. In 2001 Henderson and Shaw[38] reported 5- and 10-year survival rates of 73% and 49%, respectively, for patients with Grade II oligodendroglioma. In 2000 Olson, et al.,[58] reported a median survival time of 16.7 years in their series of patients with oligodendroglioma and mixed glioma. The authors of other studies have published similar results.[2,34,48,63,68] Despite the information available, it is difficult to predict survival for the individual oligodendroglioma patient on clinical grounds, given the following factors: 1) earlier diagnosis and improved surveillance provided by MR imaging; 2) rapid evolution in treatment taking place; and 3) possibility of conversion to an anaplastic tumor that is refractory to all treatments.[31,50]

Molecular Biology and Tumor Markers. Significant advances have recently been made in our understanding the molecular genetics of oligodendroglioma. Oligodendrogliomas generally demonstrate distinct genetic alterations that distinguish them from other types of gliomas. Their most frequent genetic alteration is the LOH on the long arm (designated "q") of chromosome 19. In published studies, the incidence of LOH on 19q has varied from 50 to more than 80% of cases.[4,41,65,77,89] The second most

43

frequent genetic alteration is LOH on the short arm (designated "p") of chromosome 1. The incidence of LOH on 1p has been reported to range from 40 to 92%.[5,65,77] Such molecular markers have now been shown to have prognostic value in cases of oligodendrogliomas. Specifically, LOH on chromosome arm 1p (especially if accompanied by loss on 19q) appears to be strongly associated with the oligodendroglial phenotype and also an independent predictor of response to chemotherapy (with or without radiotherapy) and survival, in cases of high-and low-grade oligodendrogliomas.[3,11,39,77,83] Ino, et al.,[39] however, have recently reported that the loss of 1p does not identify all the chemosensitive tumors, nor was long survival demonstrated in all the patients with 1p loss. Therefore, further clarification of these findings is needed.

Cell proliferation markers such as Ki-67 and proliferative cell nuclear antigen have been studied in oligodendrogliomas to provide additional information regarding tumor behavior.[63] The Ki-67 antigen is recognized by the MIB-1 antibody. Typically, in WHO Grade II oligodendrogliomas, because mitotic activity is absent, labeling indices for proliferation markers such as Ki-67 are quite low. In some studies, Ki-67 staining has been reported to have prognostic significance (with higher staining implying poorer prognosis) and also to be higher in recurrent tumors than in the original tumors.[17,44,63,66] Increased proliferative activity assessed by flow cytometry (as indicated by a higher percentage of cells in the S phase) has also been strongly associated with decreased survival time.[16]

Enzyme markers have also been studied in oligodendroglioma. In a recent study, in which topoisomerase II- (a molecular target for cytotoxic drugs) was evaluated, the authors found that it is associated with a higher proliferation rate and a poorer prognosis in patients with oligodendrogliomas. Topoisomerase was therefore suggested to be a useful marker for the selection of oligodendroglioma patients in whom a poorer prognosis exists and who would therefore be candidates for earlier adjuvant therapy.[53] In another new immunohistochemical study, investigators evaluated the COX isoenzymes, COX-1 and COX-2.[25] The COX-1 enzyme is expressed in macrophages/microglial cells. Patients with low COX-1 labeling scores were found to have a better survival than those with high scores. Because COX-2-expressing astrocytes were found to be present around areas of tumor necrosis, its expression was found to be significantly lower in the more benign oligodendrogliomas than in higher-grade oligodendrogliomas.

Uncommonly in oligodendrogliomas, there is decreased expression of the cell-cycle regulatory protein p16, which is encoded by a gene designated CDKN2A. If a CDKN2A deletion (or a decrease in p16 expression) does occur, it may be an important negative prognostic indicator.[7,11,54,69]

The p53 protein, nicknamed "the guardian of the genome," has also been studied in oligodendrogliomas. Oligodendrogliomas have demonstrated p53 gene mutations in a small subset of cases.[43,59] Growth factors that have been studied include vascular endothelial growth factor, the epidermal growth factor receptor, and platelet-derived growth factor. The expression of vascular endothelial growth factor in oligodendroglioma has been evaluated as a possible prognostic factor, and results have been mixed.[42] Epidermal growth factor receptor does seem to be expressed in these tumors regardless of prognosis.[66,76] Platelet-derived growth factors A and B and their receptors have also been found to be consistently expressed.[28,67] Loss of the p18 tumor suppressor gene, which is located on chromosome 1p, may be involved in the progression of oligodendrogliomas.[37]

Conclusions

Recent improvements in diagnostic imaging, surgical technique, histological diagnosis, and chemotherapy have significantly improved the prognosis for patients with oligodendroglioma.[31] The observation that oligodendrogliomas (whether WHO Grade II or III) respond to PCV chemotherapy has been one of the more significant developments in medical neurooncology in recent years. Oligodendrogliomas seem to represent the first type of brain tumor for which genetic alterations and immunohistochemical findings may have significant prognostic value. Given the clear differences in biological features and response to treatment, investigators should no longer group oligodendrogliomas with other types of gliomas. With further advances in neuroimaging, molecular diagnostics, and chemotherapy, the treatment of patients with this tumor should be even

44

more successful in the future.

Abbreviations used in this paper: COX = cyclooxygenase; CT = computerized tomography; LOH = loss of heterozygosity; MET = 11C-methionine; MR = magnetic resonance; PCV = procarbazine, lomustine, and vinctristine; PET = positron emission tomography; WHO = World Health Organization.

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Reprint Address Herb Engelhard, M.D., Ph.D., Department of Neurosurgery (M/C 799), The University of Illinois at Chicago, 912 South Wood Street, Chicago, Illinois 60612. email: [email protected]. Herbert H. Engelhard, M.D., Ph.D. Departments of Neurosurgery, Bioengineering, and Molecular Genetics, The University of Illinois at Chicago, Illinois

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Forsøgsbehandling af hurtigvoksende oligodendrogliomer-”high grade oligodendroglioma” Fra www.virtualtrials.com

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Winship Cancer Institute, Emory University is part of NCI-Sponsored clinical trial NABTT Consortium. See www.nabtt.org for a list of protocols and eligibility

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Malignant Astrocytoma or Glioblastoma and Recurrent or Progressive Meningioma: A Phase II Study with a Phase I Component for Patients Receiving EIAEDs

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Adoptive IL-2 activated LAK cell intratumoral immunotherapy implant with adjuvant radiosurgery boost and naturopathic/nutritional immune enhancement. This is for newly diagnosed patients only.

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Details Phase 1,2 study of Continuous Infusion vincristine (CIV) for Adults and selected Pediatric patients with brain tumors.


Details

Phase II Study of Temozolomide (Temodar) Prior to PCV Chemotherapy in Adults with Newly Diagnosed, Recurrent/ Progressive Oligodendroglial/Mixed Glioma Tumors of the Central Nervous System


Details NABTT Study: A phase I/II Trial of Oral Procarbazine in the Treatment of Reucrrent High Grade Astrocytomas

Boston, MA USA 02/04/2002

Details NABTT 9911 A Phase I/II Trial of EMD 121974 for Treatment of Patients with Recurrent Malignant Gliomas


Details NABTT9809 A Phase I/II Study of Col-3 Administered on a Continurous Daily Oral Schedule in Patients with Recurrent High-Grade Astrocytoma


Details CPT-11 and Temozolomide (Temodar) in Patients with Recurrent Malignant Glioma


Details

A Phase I/II Study to Evaluate the Safety and Tolerance of Escalating Doses of RSR13 Administered with a Fixed Dose of BCNU Every Six Weeks in Patients with Recurrent Malignant Glioma


Details A Phase I/II Study of Oral Procarbazine in the Treatment of Recurrent High Grade Astrocytomas


Details A Phase I/II Trial of EMD 121974 for Treatment of Recurrent Malignant Gliomas


Details A Phase I/II Study Of Col-3 Administered on a Continuous Daily Oral Schedule in Patients with High Grade Astrocytoma


Details A Phase I Evaluation of the Safety of PS 341 in the Baltimore, MD 09/05/2001

56

Treatment of Recurrent Gliomas USA

Details A Phase I/II Trial of MGI 114 for Treatment of Patients with Recurrent Malignant Gliomas


Details

A Phase I, Open Label, Dose Escalation Trial of Intratumoral Injectin with E1B-Attenuated Adenovirus (Active an UV-Inactivated), Onyx-015, into Recurrent Malignant Gliomas


Details A Phase I Gliadel and Escalating Doses of Intravenous O6-Benzylguanine Trial in Patients with Recurrent Malignant Glioma


Details Interstitial Infusion of IL13-PER38QQR Cytotoxin in Recurrent Malignant Glioma: Phase I/II Study


Details

Computer assisted minimally invasive image guided surgery for improved resection of malignant brain tumors and frameless stereotactic brain biopsies For Deep Brain Tumors.

Smithtown, NY USA 08/30/2001

Details

Gene Therapy: Open-Label Dose Escalation to with an E1B-attenuated Adenovirus, Onyx-015 into Recurrent Malignant Brain Tumors Undergoing Surgical Resection.


Details

Intratumoral Immunotherapy: IL-13 pseudomonas exotoxin: Phase I, Escalating Doses of Intratumoral IL-13 pseudomonas exotoxin in People with Recurrent Malignant Glioma


Details Phase I, Gliadel® & Escalating Doses of Intravenous O6-Benzylguanine in People with Recurrent Malignant Glioma


Details Phase I/II Trial of STI571 (Gleevec) (NSC 716051) in Patients with Recurrent Malignant Gliomas


Details Gliadel Wafer for the treatment of primary brain tumor.

Chapel Hill, NC USA 04/05/2001

Details Pilot study of combination Temozolomide (Temodal) and 6-Thioguanine chemotherapy for patients with recurrent malignant gliomas

Hartford, CT USA 11/13/2000

Details RTOG 94-02: Phase 3 Intergroup Randomized Comparison Of radiation Alone Vs. Pre-Radiation


57

Chemotherapy For Pure And Mixed Anaplastic Oligodendrogliomas

Details

A Phase I dose escalation trial of Temodar that will attempt to determine the maximum tolerated dose of Temodar (Temozolomide) when given by prolonged oral exposure to children with recurrent or progressive brain tumors.


Details

Headstart II A Phase II study of two alternative intensive induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous stem cell rescue with or without subsequent radiation therapy for children less than 10 yrs of age newly diagnosed with malignant brain tumors


Details A Phase I/II study of oral procarbazine in treatment of recurrent high grade astrocytoma


Details

The Effect of Methylphenidate on Neurobehavioral Slowing and Quality of Life in Patients with Metastatic or Primary Brain Tumors Recieving Radiation Therapy


Details Reliable Imaging Diagnosis of Recurrent Brain Tumor


Details

Temozolomide for treatment of glioblastoma multiforme, anaplastic astrocytoma or other malignant glial tumors which have responded poorly to conventional therapy.

Philadelphia, PA USA 05/14/1999

Details A phase 2 trial of Irinotecon (CPT-11) in recurrent glioma

Grand Rapids, MI USA 05/02/1999

Details Phase 2 open label study of SU-101 for recurrent glioblastoma and oligodendroglioma.

Chicago, IL USA 04/22/1999

Details Phase 2 study of antineoplastons A10 and AS2-1 in children with brain tumors


Details Phase 2 study of Antineoplastons A10 and AS2-1 in patients with brain tumors


Details Corticotropin-Releasing Factor (CRF) in the treatment of worsening neurologic symptoms from edema associated with any malignant brain tumor,


58

primary or metastatic.

Details Multiple light fiber interstitial photodynamic therapy for brain tumors

Hershey, PA USA 01/27/1999

Details High dose chemo for resistant or recurrent brain tumors in children and young adults up to age 25

Denver, CO USA 01/27/1999

Details Feasibility of using oral Etoposide combined with escalating doses of Tamoxifen for children with recurrent gliomas


Details Phase 1/2 trial of carboplatin with Thalidomide in recurrent high-grade glioma


Details Phase 2 study of pre-irradiation high dose Carboplatin in malignant glioma


Details Intra-arterial chemotherapy for primary and metastatic brain tumors

Columbus, OH USA 01/27/1999

Details Phase 3 randomized placebo controlled trial of Gliadel wafers implantation at primary surgery for malignant gliomas.

Gainesville, FL USA 01/24/1999

Details Double sequential high dose Thiotepa with autologous stem cell rescue for patients age <60 years with recurrent malignant brain cancer.


Details Regulus Navigator for use with a three point pinion -frameless stereotactic surgery


Details Intraoperative MRI for brain tumors Boston, MA USA 01/22/1999

Details Intracranial application of GM3 for high grade gliomas.


Details Intraoperative navigation in neurosurgical patients Boston, MA USA 01/22/1999

Details L-Alanosine Therapy For MTAP-Deficient Brain Tumors Tulsa, OK USA 11/03/1998

Details Familial Brain Tumor Registry - An Epidemiological Study


Details Intra-arterial Chemotherapy Given In Conjunction Jerusalem, 02/09/1998

59

With Hyperosmotic Blood-Brain Barrier Disruption For Primary Brain Tumors And For Some Categories Of Metasatic Brain Tumors

ISRAEL

Details Phase I/II Study of Multiple Light Fiber Interstitial Photodynamic Therapy for Primary and Metastatic Supratentorial Brain Tumors

Hershey, PA USA 12/21/1997

Details Phase II Study of Interstitial Thermoradiotherapy for Newly Diagnosed and Recurrent Malignant Intracranial Tumors

Saint Louis, MO USA 12/21/1997

Details Phase 3 Trial of Chemotherapy + Radiation Therapy VS. Radiation Therapy Alone For Pure Or Mixed Oligodendroglioma.


Details Utilization Of Iodine-125 Monoclonal Antibody In The Treatment Of Primary Glioblastoma Multiforme And Anaplastic Astrocytoma

Philadelphia, PA USA 11/14/1997

Details Combination Chemotherapy with Carboplatin and Etoposide with BBBD in Patients with Brain Malignancies

Portland, OR USA 11/01/1997

Details Phase 3 Randomized Trial Of Standard Vs. Dose Intensified Chemotherapy Followed By Radiation For Pediatric Brain Tumors


Details Comprehensive Genetic Analysis Of Brain Tumors In Children. (A Non-Therapeutic Study)


Details

Phase 1 Trial of Inter-Arterial Chemotherapy with Blood Brain Barrier Disruption and IV Radiolabeled mAbs Administered with Osmotic BBBD in Patients with Brain Tumors.

Portland, OR USA 09/20/1997

Details Phase 1b Study Of Stereotactic Radiosurgery And Etanidazole For The Treatment Of Recurrent Primary Brain Tumors Or CNS Mets


Details Phase 2 Study Of Suramin In The Treatment Of Recurrent Or Progressive Malignant Glioma


Details Intergroup Randomized Comparison Of Radiation Therapy Alone Vs. Pre-Radiation Therapy Chemo For Pure And Mixed Anaplastic Oligodendrogliomas


Details Risk Adapted, Multimodal Therapy In Newly Kreischa 05/25/1997

60

Diagnosed Supratentorial Malignant Glioma, Stratified To KPS.

Dresden, GERMANY

Details Phase 2 Trial Of Recombinant Human Interferon Beta In The Treatment Of Patients With Recurrent Glioma


Details Phase I/II Evaluation Of CI-980 For The Treatment Of Recurrent Or Progressive Malignant Gliomas


Details Volumetric Stereotactic Procedures New York, NY USA 02/04/1997

Details Phase 1/2 Study of Monoclonal Antibody (OKT-3) And Cyclophosphamide in Patients With Advanced Brain Tumors.


Details Phase 1 Study of Adoptive Cellular Immunotherapy Plus IL-2 in Patients With Recurrent High Grade Gliomas or Metastases to the Brain.

Kansas City, KS USA 09/22/1995

Details Phase 1 Study of Small Field Stereotactic External Beam Irradiation in Patients with Recurrent Primary Brain Tumors or CNS Metastases.

Rochester, MN USA 09/20/1995

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62

1: Cancer. 1987 Nov 1;60(9):2179-88. Related Articles, Links

Oligodendroglioma. An analysis of the value of radiation therapy. Bullard DE, Rawlings CE 3rd, Phillips B, Cox EB, Schold SC Jr, Burger P, Halperin EC. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710. The role of radiation therapy in the treatment of supratentorial oligodendrogliomas is controversial. To evaluate the role of radiation therapy, the Duke University Medical Center series was retrospectively analyzed. Clinical history, radiation dosages, and pathologic materials were reviewed. Seventy-one patients were identified as having histologically proven oligodendroglioma. Analysis of the patient population demonstrated it to be similar in all major parameters to other populations previously reported in the literature. Multivariate statistical analysis of the demographic, clinical and radiographic variables of these patients showed that a poorer prognosis was associated with persons of increased age (P = 0.052) and black persons (P = 0.014), and in those with papilledema (P = 0.07), hemiparesis (P = 0.001), intellectual deficits (P = 0.0002), and necrosis (P = 0.041). All patients had a surgical procedure as first treatment while 18 and three patients, respectively, underwent a second and third surgical procedure. Thirty-seven patients had a subsequent course of radiotherapy. Univariate and multivariate statistical analysis comparing the patients treated with surgery alone those treated with surgery plus radiotherapy revealed no significant population or prognostic differences between the groups. The median times until clinical deterioration were 39 versus 27 months, the median times until documented tumor recurrence were 27 versus 28 months and the median survival times were 4.5 versus 5.2 years, for nonirradiated versus irradiated patients. These data, from a large and rigidly evaluated population, demonstrated no statistically significant difference in the symptom-free interval, time until tumor recurrence, or survival between the groups nor did radiation appear beneficial to any subgroup evaluated. The results suggest the need for a prospective clinical trial to evaluate the true role of radiation therapy in the treatment of this tumor. PMID: 3440228 [PubMed - indexed for MEDLINE]

63

J Clin Oncol. 2003 Jul 1;21(13):2525-8. Related Articles, Links

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group. Department of Neuro-Oncology, University Hospital Rotterdam/Rotterdam Cancer Center, the Netherlands. [email protected] PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted. Publication Types:

• Clinical Trial • Clinical Trial, Phase II • Multicenter Study

PMID: 12829671 [PubMed - indexed for MEDLINE]

64

1: Curr Neurol Neurosci Rep. 2003 May;3(3):223-8. Related Articles, Links

Oligodendrogliomas: an update on basic and clinical research. Sanson M, Aguirre-Cruz L, Cartalat-Carel S, Hoang-Xuan K. Inserm U495 and Federation de Neurologie Mazarin, Hopital de la Salpetriere, 47 Boulevard de l'Hopital, 75013 Paris, France. [email protected] Oligodendrogliomas have been the focus of considerable interest over the past decade, ever since they were recognized as chemosensitive tumors. They were once believed to represent less than 5% of gliomas, but by using expanded criteria, they may well represent up to one third. In fact, morphologic criteria are vague and highly subjective and the histologic diagnosis, therefore, remains highly controversial and unsatisfactory. New oligodendrocytic lineage markers, such as OLIG1/2 gene, will probably help to define the real spectrum of oligodendroglial tumors, which may include a wide variety of tumors with very different prognoses. Recently, genetic markers, and particularly loss of 1p and 19q chromosomes, have been shown to predict both prognosis and response to treatment. There is little doubt that these emerging techniques will be very helpful in clinical practice for refining both classification and therapeutic indications of oligodendroglial tumors. Publication Types:

• Review • Review, Tutorial

PMID: 12691627 [PubMed - indexed for MEDLINE

65

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About this book

Section 24. Neoplasms of the Central Nervous System

80. Neoplasms of the Central Nervous System

Epidemiology and Risk Factors

Molecular Genetics

Familial Syndromes

Pathology Grading Systems


Diagnostic Neuroimaging

Surgical Diagnosis and Resection

Cortical Mapping and Interactive Image-Guided Resections

Postoperative Imaging

Clinical Trials

Glioblastoma Multiforme and Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Cancer Medicine e.5 Section 24. Neoplasms of the Central Nervous System 80. Neoplasms of the Central Nervous System Anaplastic Oligodendroglioma

Patients with anaplastic oligodendrogliomas (AOs) have shown exceptional chemosensitivity and frequently will show a complete response following chemotherapy using PCV.92 The reason for this unusual response is unknown, but an observation has been made that molecular alterations seen in some of these patients is linked to chemotherapy response and survival. The allelic loss of chromosomes 1p and 19q are a molecular signature of these tumors and occur in 50 to 70% of cases.39 There has been an association shown between this molecular marker and response to chemotherapy. In a recent study, 100% of the patients with loss of 1p or combined 1p and 19q had an objective response to chemotherapy (24 of 24 and 22 of 22, respectively).39 In contrast, only 25% and 31% of the patients that retained these alleles had a response. The 5-year survival rate for patients with loss of heterozygosity at both 1p and 19q is 95% as opposed to a 5-year survival rate of 25% in patients with AOs who retained these alleles. This observation is important and suggests that molecular markers may be useful to identify patients who have a greater likelihood of a response to chemotherapy. A phase III trial is ongoing that randomizes newly diagnosed AO patients to radiation only or radiation preceded by chemotherapy using the PCV regimen.

66

Low-Grade Gliomas

Ependymoma Brainstem Glioma

Spinal Cord Tumors

Medulloblastoma and Primitive Neuroectodermal Tumors

Other Primary Tumors of the Central Nervous System

Disease Metastatic to the Central Nervous System

Spinal Metastases

Neoplastic Meningitis

Future Directions References

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About this book Section 24.

Cancer Medicine e.5 Section 24. Neoplasms of the Central Nervous System 80. Neoplasms of the Central Nervous System Low-Grade Gliomas

67

Neoplasms of the Central Nervous System

80. Neoplasms of the Central Nervous System

Epidemiology and Risk Factors

Molecular Genetics

Familial Syndromes

Pathology Grading Systems



Surgical Diagnosis and Resection

Cortical Mapping and Interactive Image-Guided Resections

Postoperative Imaging

Clinical Trials

Glioblastoma Multiforme and Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Low-Grade Gliomas

Ependymoma Brainstem Glioma

Spinal Cord Tumors

Medulloblastoma and Primitive

Low-grade gliomas include astrocytoma, oligodendroglioma, mixed tumors, such as oligoastrocytoma, and a variety of other more unusual lesions, such as ganglioglioma and neurocytoma, to name a few. Astrocytomas may be further classified as pilocytic, protoplasmic, or fibrillary, on the basis of their histologic appearance. The term low grade suggests slow biologic growth that would account for the appearance of a lesion in a patient with a seizure disorder that remains unchanged for many years or a lesion that may be surgically cured with total resection. The childhood cerebellar juvenile pilocytic astrocytoma (JPA) is one of the most common of these lesions and is unique and somewhat distinct from the other low-grade lesions. It has a characteristic appearance on MRI and is often curable with surgery alone. However, when it arises from the hypothalamus, complete surgical resection is not usually possible, and other forms of therapy are often needed. On the other hand, dysembryoplastic neuroepithelial tumors (DNET) are rarely treated even with minimal resection. The histologic diversity and biologic behavior of these diseases make generalizations difficult. However, many such tumors are biologically very slow growing, and may not require intervention for many years. Accurate classification must be based on pathologic assessment. Neuroimaging is not sufficient to make a diagnosis or to predict behavior in many of these tumors. Because of the rarity of the tumors other than astrocytoma, oligodendroglioma, and mixed oligoastrocytoma, those tumors will not be discussed further. Table 80.8 lists the low-grade gliomas included in the current WHO classification system.

Etiology and Epidemiology

Low-grade gliomas may occur in any of many areas of the brain, including the optic nerve, cerebellum, hypothalamus, cerebral hemispheres, or brainstem. The mean age at diagnosis for patients with low-grade astrocytoma other than JPA is 35 years, and for those with JPA 14 years. In children, the incidence of glial neoplasms is 2 to 5 cases in each 100,000 population per year, and approximately 70% of those neoplasms are low-grade gliomas. Patients with NF-1 or NF-2 are at increased risk for these lesions, especially for low-grade astrocytomas of the optic pathways. Constituting less than 5% of the total number of gliomas, oligodendroglioma most often occur in young and middle-aged adults and account for only 5 to 6% of CNS tumors in children. Oligodendroglioma most often arise in hemispheric white matter but may be located wherever oligodendroglial cells occur in the CNS. Frequent locations are the frontal lobe (over 40%), parietal lobe (30%), and temporal lobe (20%). They may be pure tumors, or mixed tumors, with elements of astrocytoma.

Pathology

Pathologically, low-grade astrocytomas are infiltrative lesions with a population of regular, uniform cells, a slight increase in cellularity, and minimal pleomorphism.37 Most often, there is no clear border between the tumor and surrounding normal brain parenchyma. The astrocytes may show a fibrillary or protoplasmic morphology, or they may be mixed with abnormal oligodendrocytes or ependymal cells. Cerebellar JPA consist of spongy tissue and microcysts interlaced with bundles of neoplastic cells, and they may have vascular endothelial proliferation. Lesions in the hypothalamus and optic pathways may appear identical. Biologic growth is slow, both in the infiltrative fibrillary astrocytomas and juvenile pilocytic astrocytomas.

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Neuroectodermal Tumors

Other Primary Tumors of the Central Nervous System

Disease Metastatic to the Central Nervous System

Spinal Metastases

Neoplastic Meningitis

Future Directions References

Figures

Figure 80.6. Typical MRI appearance of a...

Tables

Table 80.8. Low-Grade Gliomas as Classified by...

Table 80.9. Management Algorithm for the Adult...

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Oligodendrogliomas appear as small, round cells in a monotonous pattern. The cytoplasm has distinct borders, the nuclei are dark and round, and an artifact of fixation often causes individual cells to look like fried eggs. The histologic appearance is that of a low-grade lesion with minimal anaplasia or pleomorphism; however, some oligodendrogliomas have anaplastic features with pleomorphism, in the extreme case even resembling GBM. Others have intermediate features. One of the more perplexing problems in contemporary neuropathology is the designation of a lesion as oligodendroglioma or mixed oligoastrocytoma. A consensus has yet to be reached as to the criteria that should be used to make these diagnoses. Because of this fact, interpretation of clinical outcomes of patients may be difficult to compare between various institutions and groups.


Patients with astrocytoma often present with seizures that may have been present for many years before the diagnosis. In most series, seizures are the most common presenting symptom, followed by headache and, finally, focal neurologic findings. The interval from the onset of symptoms to diagnosis may be as long as 10 years. Cerebellar JPA in children presents with symptoms of clumsiness, ataxia, head tilt, and intermittent headaches and vomiting. Pilocytic astrocytomas of the optic nerve, chiasm, tract, and hypothalamus may present with eye movement disorders, visual field defects, and, in older children, precocious puberty. Cerebral lesions show signs and symptoms associated with the specific location of the lesion. Most patients with oligodendroglioma also have a history of symptoms extending over many years. Seizures are common, occurring in as many as 50% of patients before diagnosis and eventually during the course of the disease in over 80%. Other focal findings depend on the location and rate of growth of the lesion. Occasionally, sudden onset of symptoms manifests as a consequence of hemorrhage into the tumor.


Neuroimaging studies include CT and MRI, the latter being a more sensitive technique. In general, CT often shows a cystic or solid tumor of low density and variable amounts of contrast enhancement. Pilocytic astrocytomas reveal a cystic mass with intense contrast enhancement. Classically, the cerebellar JPA appears as a large, smooth-walled cyst with a small enhancing mural nodule. In adults, astrocytoma in the cerebrum will often appear diffusely infiltrative or solid and hypodense. These lesions may or may not enhance. Often the lesion involves an entire lobe but has indistinct margins and causes minimal mass effect. MRI reveals either a hypointense or isointense lesion on T1-weighted images, with a larger area of T2 shortening being hyperintense in appearance. Gd enhancement is variably present. The CT appearance of oligodendroglioma is a hypodense or isodense lesion that may or may not enhance. Many oligodendrogliomas have calcifications scattered within the lesion, reflecting the mineralization seen histologically within blood vessel walls. There is little peritumoral edema. MRI reflects the CT lesion, with a hypointense or isointense lesion on T1-weighted images, a hyperintense lesion on T2-weighted images, and areas of signal void where calcifications arise. Enhancement with Gd is variable. Figure 80.6depicts a typical pilocytic astrocytoma arising from the hypothalamus and extending into the optic radiations in both the axial (see Fig. 80.6A) and coronal (see Fig. 80.6B) plane. A lesion in this location could not be completely resected and would require additional treatment.

69

Treatment Options

The treatment of low-grade gliomas depends on the location of the tumor, the age of the patient, the extent of resection possible, and evaluations based on an understanding of the biology of these lesions. Options include observation alone, biopsy and/or resection, surgery plus irradiation, chemotherapy alone, or some combination of all three modalities of surgery, irradiation, and chemotherapy. Childhood cerebellar JPAs, for instance, are manageable in most cases with surgical resection alone. Only in very unusual cases do JPAs recur following gross total resection, and even the rare patient with recurrence may still enjoy a good outcome with repeat surgical interventions, with or without adjuvant radiation therapy. In contrast, infiltrative astrocytomas in adults often are not amenable to gross total surgical resection and usually require additional therapy, such as irradiation.

Surgery will be necessary in almost all cases to accurately establish the pathologic diagnosis. There are a few instances where neuroimaging alone will support a diagnosis. For instance, children with neurofibromatosis and a lesion in the optic nerve or hypothalamus will occasionally be treated on the basis of imaging criteria alone. In almost all cases where surgery is done, only incomplete resections are possible, and the pathology of these tumors is invariably a low-grade astrocytoma, often a JPA. Beyond this situation, most lesions of the brain should be biopsied. A more extensive resection may also be appropriate, assuming that the procedure can be done safely. In one series by Berger and colleagues, the pre- and postoperative tumor volume was measured and used to analyze the probability of recurrence in patients with low-grade tumors.93 When the authors reviewed the postoperative volume, they noted that 15% of patients had recurrences with a median time to tumor progression of 50 months, if the volume was < 10 cm3. However, in cases with a postoperative tumor volume of > 10 cm3, 40% of patients had recurrences at a median of 30 months. Other series tend to support the notion that reduction of tumor burden by surgery will lengthen the time to tumor progression.94 97 Not all series are positive, however, and as suggested earlier, there are no prospective randomized studies that have addressed this question. Institutional bias, subsequent treatment beyond surgery, inadequate tissue sampling when biopsy alone is used to make a diagnosis, and the retrospective nature of these reviews need to be considered when one interprets the data concerning surgery in low-grade glioma. Other factors may influence the decision to attempt an extensive resection in these lesions, including patient age, the potential need for subsequent irradiation and long-term risks associated with that therapy, and patient preference. At least in the setting of a lesion that can be safely removed, one potential benefit would be the option to defer any additional treatment for many years and, in the case of JPA, perhaps cure the disease with surgery alone.

The next question that usually arises in this group of diseases is the need for and timing of radiation therapy. A number of retrospective reviews have been published describing the outcome of patients who are treated initially with surgery alone, or surgery plus radiation therapy. Some reports suggest a survival benefit to immediate adjuvant radiation therapy. Shaw and colleagues reported on the outcome of patients treated at Mayo Clinic.98 The 5-year and 10-year survival rates were 32% and 11%, respectively, for patients treated with surgery, versus 47% and 21%, respectively, in those receiving postoperative irradiation. Other reports suggest that there may not be a survival advantage to immediate treatment with radiation

70

therapy.96,99,100 The European Organization for the Research and Treatment of Cancer (EORTC) has recently reported on a phase III study in adult patients with low-grade glioma, randomizing to either observation or initial treatment with radiation.101 The overall 5-year survival rate was similar between the two groups (63% and 66%), with a reduction noted in the 5-year progression-free survival rate in those patients who received radiation initially, compared with those who did not (44% and 37%). At the time of this preliminary report, up to two-thirds of cases randomized to the observation arm ultimately received radiation. Thus, the strategy may be considered to be one that justifies deferral of radiation to a later date without a negative impact on overall survival. There remains controversy about this approach, and it is probable that certain subsets of patients will benefit from an observation approach and others from an immediate treatment approach. For instance, it is known that a negative prognostic factor for survival is older age. Philippon and colleagues reviewed data from a group of patients with low-grade tumors and concluded that radiation did not improve survival outcome when all patients were considered, except in the subset of patients age 50 years and older who had a subtotal resection or biopsy. In that subset, the 5-year survival with radiation was 70% versus 25% in older patients who were not irradiated immediately following surgery. The series by Shaw from the Mayo Clinic also supported this notion of prognostic subgroups.103 Patients older than 35 years had longer 5-year survivals, if they had postoperative irradiation to a dose larger than 53 Gy.

The dose used for radiation has been partially addressed in two prospective randomized studies.104,105 The EORTC randomized 379 patients to receive low-dose (45 Gy) or high-dose (59.4 Gy) radiation given to a local field and reported no difference in outcome. The 5-year survival rate was 58% with 45 Gy and 59% with 59.4 Gy. The second study compared doses of 50.4 Gy and 64.8 Gy, and a preliminary report also shows no 5-year survival advantage to the higher dose (73% and 68%, respectively). A recently opened trial of the RTOG now uses 54 Gy in the treatment of these patients. In practice, when radiation therapy is used, the most common dose is between 50 and 60 Gy, given to a focal field. The large EORTC study reported a lower level of functioning, higher fatigue, malaise, and insomnia in patients treated at the higher doses of radiation, suggesting that a negative impact on quality of life is a potential risk over time when higher doses of radiation are used.

Chemotherapy currently is being investigated in the initial management of adults with newly diagnosed low-grade glioma. The role of chemotherapy appears well established in younger children (discussed below), with the hopes of deferral of radiation for as long as possible. However, as of this time, there is no proof that chemotherapy, used either prior to or following radiation, will improve survival in adults. One phase III trial is ongoing in the RTOG that randomizes patients to radiation therapy alone or radiation therapy plus the combination of procarbazine, CCNU, and vincristine (PCV). The results of this study will not be known for many years. Table 80.9 depicts a common management algorithm for adults with low-grade glioma.

Treatment of Young Children.

Ideally, children with low-grade glioma will be treated with surgery alone, or surgery with chemotherapy. There is a risk to neurocognitive and growth development, if radiation is used too early in the neurologic development of

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delay, endocrine dysfunction, and the long-term risk of secondary malignancy. If surgery is feasible, it should be considered particularly in cases where an extensive resection is possible. In some cases, surgery alone will be sufficient to manage a low-grade lesion for many years. In the setting of JPA, surgery can be curative. If additional treatment is needed, chemotherapy may be considered. Several trials have documented the benefit of chemotherapy as primary therapy following partial surgical resection for low-grade gliomas in children, especially in the group with JPA.107 109 Among the regimens investigated are the use of carboplatin and vincristine according to a protocol developed at Children's Hospital in Philadelphia, and a multi-agent nitrosourea-based regimen used at UCSF that includes lomustine, procarbazine, 6-thioguanine, dibromodulcitol, and vincristine. The significance of these studies is that each has shown up to a 75% response or stabilization rate with chemotherapy alone, in some cases with years of disease-free survival. Ultimately, up to about one-third or one-half of patients require irradiation for tumor regrowth. In children under the age of 5 years, the use of chemotherapy remains a viable option for incompletely resected or symptomatic progressive low-grade tumors. A phase III trial is ongoing within the Children's Cancer Group (CCG) that randomizes children with newly diagnosed symptomatic low-grade tumors to treatment with one of two chemotherapy regimens on the basis of the results previously discussed above. Radiation is reserved for patients who progress. In some cases, sequential chemotherapy may be considered rather than immediate initiation of radiation. This strategy would be particularly helpful in children under the age of 3 years whose disease is progressing.

Recurrence

If it is determined that a tumor has progressed, various strategies are available, including further surgery, chemotherapy, radiation therapy, or some combination of those modalities. Many patients will be candidates for repeat resection and should be considered for those procedures. Symptom control may be one reason to consider surgery, but there is also the benefit of tumor reduction and a more accurate diagnosis of the disease at that moment in time. Many low-grade tumors will progress to a more malignant phenotype, often with histologic features that are consistent with anaplastic glioma or GBM. In the series reported by Leighton and colleagues, malignant transformation occurred in approximately 50% of patients.110 Malignant transformation would influence the subsequent treatment strategies, and surgery should be considered as part of the overall management of these patients. If prior radiation has been used, reirradiation may be possible, either using radiosurgery techniques or interstitial brachytherapy. Chemotherapy is also an option, with encouraging objective response rates in the subset of oligodendroglioma patients who transform to a more anaplastic histology.92

Recommendation

Low-grade astrocytomas that can be removed totally may be managed with surgery alone. If the decision is made for surgery, the goal should be maximal, safe resection. Incompletely resected tumors may be managed with surgery and irradiation or by observation alone. In infants and young children, primary chemotherapy may be useful in controlling symptomatic

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treated with radiation typically receive 54 Gy in single daily-dose fractions to the tumor volume and a small margin surrounding it. Despite the optimism associated with the treatment of lower-grade lesions, many patients still die of this disease. New approaches are needed in the management of these tumors, with clinical research trials designed to answer questions concerning the optimal extent of resection, the timing and dose of radiation therapy, and the use of chemotherapy.

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSectionquery_key=12&db=books&dopt=&page=0&dispmax=20&WebEnv=066KlMnh6dftlVhpiM-tFAjPs0hCYidtfx4EuiJGoRvstFgPQflu5L&WebEnvRq=1&rid=cmed.section.18076 Pathology Grading Systems

The World Health Organization (WHO) has classified CNS tumors into nine categories in its most recent revision.37 Tumors of neuroepithelial tissue comprise a large number of the tumors often thought of as "primary brain tumors." Neuroepithelial tumors are further subclassified into tumor types described in Table 80.5. In general, children present most frequently with low-grade astrocytomas, primitive neuroectodermal tumors (PNET), and ependymomas. Of interest, these tumors also have a predilection toward midline locations. Adults, on the other hand, more frequently present with higher-grade astrocytomas, such as glioblastoma and anaplastic gliomas, have fewer PNETs or ependymomas, and their tumors tend to occur in nonmidline locations. For the astrocytic tumors, there is a trend toward using one of two systems for grading the malignant gliomas, the WHO definition and the Daumas-Duport grading system.38 The WHO definition of astrocytic tumors emphasizes degrees of cellularity, nuclear and cellular pleomorphism, mitoses, endothelial proliferation, and necrosis. Glioblastoma is a highly cellular tumor with nuclear and cellular pleomorphism, endothelial proliferation, mitotic figures, and often necrosis. Although necrosis is a hallmark of this tumor and is frequently present, the presence of necrosis is not mandated to designate a tumor as GBM in the WHO classification. Anaplastic astrocytomas (AAs) are less cellular, with less pleomorphism, mitoses, and no necrosis. Finally, astrocytomas are glial tumors other than GBM and AA, with little cellularity and minimal pleomorphic changes. Daumas-Duport uses a different method of grading based on the presence or absence of four criteria: (1) nuclear atypia, (2) mitoses, (3) endothelial proliferation, and (4) necrosis. Grade 1 neoplasms have none of these features, grade 2 have one, grade 3 have two, and grade 4 have at least three criteria present. This system of numerical grading is used by many neuropathologists who do not use the WHO criteria to describe astrocytic tumors. In clinical practice, there are rarely any tumors that are classified as grade 1 by the Daumas-Duport system, and thus even this system, for all practical purposes, is a three-tiered system like that of the WHO. Of all the tumor types above, perhaps the lower-grade tumors represent the most challenging for the pathologists to classify. Numerous subtypes of low-grade glioma exist, including ganglioglioma, mixed tumors, pleomorphic xanthoastrocytoma, dysembryoplastic neuroectodermal tumor (also called DNET), neurocytoma, pineocytoma, and others. These are uncommon tumors, and treatment differs with each. Unfortunately, it is also not uncommon that expert neuropathologists disagree with each other in the identification of these tumors.

Another set of tumors that tends to cause some discordance among pathologists is oligodendrogliomas. Oligodendroglioma and mixed oligoastrocytoma correspond to WHO grade 2 tumors; anaplastic oligodendroglioma and anaplastic oligoastrocytoma correspond to WHO grade 3 tumors. Occasionally, some oligodendroglial tumors show sufficient anaplasia, pleomorphism, mitoses, and necrosis that they would fulfill the criteria of a WHO grade 4 tumor. These unique tumors tend to have a better outcome following therapy than their pure astrocytoma counterparts. A uniform consensus does not exist to help classify these tumors as either pure oligodendroglioma or mixed tumors, and what degree of anaplasia constitutes the criterion to call them grade 2 or grade 3. Unfortunately, specific tumor markers do not currently exist to assist in the classification of these lesions. One common molecular alteration noted in these tumors include losses of genetic information

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on chromosomes 1p and 19q.39 Increased sensitivity to chemotherapy is common when those chromosomal patterns are present. However, not all oligodendroglial tumors have these losses, and they cannot be relied on to make a specific diagnosis.

Of the childhood tumors, PNETs most frequently occur in the cerebellum and are traditionally called medulloblastoma. When they occur in other locations, they are referred to as PNETs of the pineal region (or pineoblastoma), or the cerebral hemispheres (or supratentorial PNET). These tumors are characteristically fast-growing tumors and have a high propensity toward dissemination along the cerebrospinal fluid (CSF) pathways. Astrocytic tumors in childhood tend to occur along the midline axis, including the cerebellum and optic nerve and chiasm or hypothalamic regions. Most are low-grade tumors, such as juvenile pilocytic astrocytoma (JPA) or fibrillary astrocytoma, and may occur in association with NF-1 or NF-2. Ependymomas in children commonly occur in the posterior fossa, may disseminate to other areas of the brain and spine, and tend to have a worse outcome than in adults, particularly in the younger age group (age < 3 years).

As molecular markers become more fully understood and prognosticate more efficiently than light microscopy in making a diagnosis of a particular tumor, greater emphasis will be given for those markers in the future.

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1: Curr Opin Neurol. 2001 Dec;14(6):705-10. Related Articles, Links

Oligodendrogliomas: clinical and genetic correlations. Perry JR. Division of Neurology, Department of Medicine, University of Toronto, Sunnybrook and Women's College Health Science Centre, Room A-442, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. [email protected] Oligodendrogliomas, once obscure, are now recognized as a relatively common form of primary brain tumour, and are among the most chemosensitive of all solid human malignancies. New histopathological, molecular, and genetic information has, for the first time, allowed the distinction of several subtypes of human glioma with predictable biological and clinical behaviour. Genetic markers are emerging as useful not only for the diagnosis of oligodendroglioma, but also as specific predictors of both the response to treatment and prolonged survival. This review will focus upon the past year of advances in the area of clinical-molecular genetic predictors of glioma behaviour and highlight the importance of these advances in everyday clinical practice.

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Hvordan anmode om second opinion fra The Cleveland Clinics via internettet???

To request a second opinion via the Internet from The Cleveland Clinic, you will first need to register to use the site. Once you have established a user name and password, you can access the e-Cleveland Clinic second opinion service from any computer with Internet access and a browser capable of 128-bit encryption (either Netscape 4.0 or higher or Internet Explorer 4.0 or higher). If this service is being provided by your employer, you may contact your human resources department for additional information or instruction. Upon log in, you will be in a secure Web environment -- any information you send can be read by only you and The Cleveland Clinic. (See our privacy policy for more information.) There are seven steps in the request opinion process, which will take about 30-45 minutes to complete. It will be helpful to have a copy of the patient's medical records with you as you complete the medical history questions. You will be notified by e-mail when your opinion is ready and an e-Cleveland Clinic nurse will follow up by phone to ensure all of your questions are answered. Each step of the Request Opinion process is outlined in more detail below: Step 1—Requestor Information In this section we ask for basic registration information about you. This section takes about 5 minutes to complete. Step 2—Patient Information In this section we ask for basic registration information about the patient. You may make a request on behalf of someone else if you have the patient's permission. The patient should complete a proxy form and it should be included in the package that you send to The Cleveland Clinic. This section takes about 5 minutes to complete. Step 3—Diagnosis or Problem In this step, tell us the diagnosis the patient was given on his or her first opinion. If you aren't sure, type in a general term and then choose from the list given. This step takes 1-5 minutes to complete. We will let you know if we have a specialist available who can render an opinion about your condition. Step 4—Payment Process Your credit card information is required to process this request for a second opinion. If you are receiving this service as a benefit from your employer you will not be required to enter your credit card information. This step takes about a minute to complete. Step 5—Medical History In this section, we ask for specific information about the patient's diagnosis and medical history, such as history of symptoms, any treatment received to date, medications, prior illnesses, etc. It may be helpful to have the patient's medical record with you as you complete this section. See "How do I obtain my medical record," if necessary. This information is submitted online and will take about 30 minutes to complete. Step 6—Information Checklists In this section, we provide lists and forms for you to print out to assist in completing your second opinion request. We ask for actual films or studies that are necessary for our physicians to perform a thorough assessment. You may print this checklist and take it to the doctor or hospital where the patient's tests were performed. We also ask that you provide consent and/or proxy for a Cleveland Clinic physician to render your second opinion. This takes 5-7 minutes to read and complete. Finally, we provide specific mailing instructions for those items on your information checklist. You will then mail these items to us. Once we receive your information we will usually render a second opinion within 3-5 business days, although it may take longer if radiology and/or pathology review is required. Step 7—Review and Authorization

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This section allows you to review and change any of the information you have provided. If you are charging the service to your credit card, this step also authorizes us to charge your card. The charge will be posted when you receive the second opinion. Once you have submitted your opinion request, you may check on the status of your opinion by logging on to the secure Web site. The opinion status will be displayed on the home page. In addition, we will notify you by e-mail when your opinion is ready. If at any time you have questions or concerns about your second opinion request, please contact the e-Cleveland Clinic nurse at 800/223-2273, ext. 43223. The e-Cleveland Clinic nurse is available Monday through Friday, 8 a.m. to 5 p.m., eastern time. You may leave a voice mail any time, which we will return on the next business day. Fax: 216/445-6911 E-mail: [email protected] Appointment Information If you would rather come to The Cleveland Clinic in Cleveland, Ohio, to be seen by one of our specialists, call us toll-free 800/223-2273. Or, you may request an appointment via the Cleveland Clinic Web site. For an appointment at Cleveland Clinic Florida in Weston, call toll-free 866/293-7866. For an appointment at Cleveland Clinic Florida in Naples, call toll-free 866/627-1533.

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Eksempel på en second opiniom medtaget fra The Cleveland Clinic

12/10/2001 Dear Mr. Doe, Thank you for your recent request for a second opinion consultation from The Cleveland Clinic Foundation. Please find below the second opinion consultation written by Dr. Gene Barnett, Department of Neurological Surgery. A registered nurse from the e-Cleveland Clinic office will call you within the next 1-2 days to ensure that you have received your second opinion and that any questions you may have are answered.

Feel free to contact the e-Cleveland Clinic nurse at 800/223-2273, ext. 43223, 8 a.m.- 5 p.m., EST, Monday through Friday, should you have additional questions or concerns.

e-Cleveland Clinic 9500 Euclid Avenue, Desk QQb2-28 Cleveland, Ohio 44195 USA Tel: 1-216/444-eCCF (3223) or 1-800/223-2273, ext.43223 Fax: 1-216/445-6911 E-mail: [email protected]

Second Opinion Consultation

Summary:

Date: 12/10/2001 Patient Name: John Doe Physician's name: Gene H. Barnett, M.D. Department: Neurological Surgery CCF#: (MRN) 0-111-222-3 Date of Birth: 10/01/1949 Patient Address: 123 Main Street Phoenix, Arizona 85012

Diagnosis / Reason for Consultation:

Meningioma

Mr. Doe was evaluated for headache and an intracranial mass was found. He has sought the opinion of a Cleveland Clinic specialist through e-Cleveland Clinic in order to determine his "next step" and, in particular, the role of noninvasive treatment of the tumor.

Diagnostic Summary:

Review of his medical records, which he has forwarded to e-Cleveland Clinic, demonstrates a right sphenoid wing meningioma 2.0 x 2.5 x 3.0 cm (as well as small vessel disease and sinusitis). His past medical history is notable for hypertension, history of colonic polyps, diverticulosis, lumbar spinal stenosis, and a remote history of atrial fibrillation. His present medications include Allegra 60 mg

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bid, Maxzide 75-50 Qd, Celebrex 200 mg Qd, Clonazepam 1 mg Qhs and methylprednisolone 4 mg Qd. According to a history by his PCP from 9/00 he is manager in technology company, he does not use cigarettes and drinks wine occasionally. There is no family history of brain tumor or cancer.

Treatment Summary:

This 52 year-old man was treated for sinusitis in May/June of this year with resolution of that headache, but a persistent right-sided dull pain. It was not exacerbated by light or sound and he distinguished it as being something other than migraine headache. They were improved by reclining.The headaches worsened, and his wife noted a change in behavior such that he would come home from work at lunch and not return to work thereafter. An MRI of the brain was performed on 11/12/01 showing a right sphenoid wing meningioma 2.0 x 2.5 x 3.0 cm (as well as small vessel disease and sinusitis). When seen by his primary care physician, his weight was 250 pounds, BP 148/70, pulse 72 and respirations 16. Some right lateral deviation and puffiness were observed of the right eye. He was begun on a tapering schedule of low dose Medrol. Use of this steroid is associated with improved symptoms and a return to more normal behavior.

An opinion from a neurosurgeon in Phoenix was reportedly that his options were to monitor the tumor, surgically remove it, get a second opinion, or treat with radiosurgery / radiotherapy.

I personally reviewed his MRI scan. This shows a durally based, avidly enhancing lesion in the region of the medial right sphenoid wing. There is hyperostosis of the underlying bone. There is surrounding brain edema and mild shift of the midline. The tumor is adjacent to the middle cerebralartery and right optic nerve. It is most consistent with meningioma. There are also small vessel changes in the brain and brainstem.

Second Opinion Recommendations:

Mr. Doe has various options. These include observation, surgical resection, radiosurgery, fractionated radiosurgery and radiotherapy. I do not believe that medical therapy would be effective or indicated at this time other than symptomatic treatment with steroids - these should betapered off as soon as symptoms allow.

Of these options, I believe that conformal radiosurgery (where the delivered radiation conforms to the shape of the tumor -- such as delivered with the Gamma Knife) or fractionated conformal radiosurgery (such as delivered with the CyberKnife) are the best management options. Although observation is clearly an option, his headaches are likely to worsen and chronic steroid treatment is not a good alternative. Surgery on this lesion is certainly feasible, but its proximity to the middle cerebral artery and nerves to and from the right orbit (eye) mean there is real risk of disabling stroke or visual impairment in the right eye (it is unclear if he has any vision problems at this time - this should be assessed with formal visual testing and peripheral vision testing). Also, surgery of this lesion is not likely to be curative.

The extended control rate from radiosurgery of meningioma is upwards of 80%. The principal risk in this case would be a small risk of visual loss in the right eye or delayed brain edema (swelling). The risk of visual loss could be further lessened by fractionating the radiation (delivering lower doses in several sessions) but would require about two weeks of treatment. The Gamma Knife requires one day for treatment. There is no convincing evidence that Proton Beam radiosurgery is superior to Gamma Knife radiosurgery for meningioma - in fact, results of the Gamma Knife are generally held as the "gold standard" for radiosurgery. The Lexar system may also be able to provide single or multiple fraction conformal radiosurgery although there is much less published information on it than for Gamma Knife or CyberKnife.

In short, my recommendations are: 1) Get visual acuity and field testing, 2) taper off steroid

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(Medrol) as soon as symptoms allow, 3) Treat with either conformal radiosurgery or fractionated conformal radiosurgery in the near future.

References:

I am forwarding with this consultation written literature on the Gamma Knife. In addition, should the patient have additional questions regarding these recommendations as he prepares to make his decision regarding future care, he should not hesitate to contact the nursing staff at e-Cleveland Clinic, who are in contact with my clinical nurse specialist.

Physician Signature: Gene H. Barnett, M.D./sp

D: 12/10/01 T: 12/10/01

e-Cleveland Clinic Disclaimer

By using this Second Opinion service, you agree to abide by the Terms and Conditions posted at our Second Opinion Web Site, including particularly the Terms and Conditions described below:

Diagnostic Service

The service provided through our Web site is different from the diagnostic services typically provided by a physician. The Cleveland Clinic Foundation (CCF) physicians providing this service will not have the benefit of information that would be obtained by examining you in person and observing your physical condition. Therefore, the physician may not be aware of facts or information that would affect his or her opinion of your diagnosis. TO REDUCE THE RISK TO YOU OF THIS LIMITATION, CCF STRONGLY ENCOURAGES YOU TO SHARE THE SECOND OPINION WITH YOUR PHYSICIAN. BY DECIDING TO ENGAGE THIS SERVICE, YOU ACKNOWLEDGE AND AGREE THAT YOU ARE AWARE OF THIS LIMITATION AND AGREE TO ASSUME THE RISK OF THIS LIMITATION.

BY REQUESTING A SECOND OPINION PURSUANT TO THIS WEB SITE, YOU ACKNOWLEDGE AND AGREE THAT:

* THE DIAGNOSIS THAT YOU WILL RECEIVE IS LIMITED AND PROVISIONAL; * THE SECOND OPINION IS NOT INTENDED TO REPLACE A FULL MEDICAL EVALUATION OR A FACE-TO-FACE VISIT WITH A PHYSICIAN; * THE PHYSICIAN DOES NOT HAVE IMPORTANT INFORMATION THAT IS USUALLY OBTAINED THROUGH APHYSICAL EXAMINATION; * THE ABSENCE OF A PHYSICAL EXAMINATION MAY AFFECT THE PHYSICIAN'S ABILITY TO DIAGNOSIS YOUR CONDITION, DISEASE OR INJURY;

BY ENGAGING OUR SERVICES, YOU ACKNOWLEDGE AND AGREE TO ASSUME THE RISK OF THESE LIMITATIONS. YOU FURTHER UNDERSTAND THAT NO WARRANTY OR GUARANTEE HAS BEEN MADE TO ME CONCERNING ANY PARTICULAR RESULT OR CURE OF MY CONDITION.

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KRÆFTENS BEKÆMPELSES ÆNDRINGSFORSLAG TIL SECOND OPINION ORDNINGEN

26. juni 2003

Det er vigtigt at holde sig for øje, at ordningen er etableret for at tilgodese en gruppe patienter, der er i en meget alvorlig situation. Det er patienter, der har fået at vide, at der ikke er yderligere behandlingsmuligheder, og som nu har brug for at få sikkerhed for, at alle muligheder er blevet afsøgt. Det gælder i forhold til dokumenteret behandling, forsøgsbehandling og den eksperimentelle behandling, den ny bekendtgørelse giver mulighed for.

Det er derfor afgørende, at patienterne og deres pårørende kan have tillid til, at second opinion ordningen opfylder dette behov for en afklaring af, at alle muligheder er taget i betragtning.

1. Indgangen til lægepanelet Der skal ske en kvalitetssikring af samtalen om behandlingsmuligheder, når sygehuslægen ikke kan tilbyde yderligere behandling. Der bør udarbejdes en checkliste over, hvad denne samtale skal indeholde, herunder at sygehuslægen lytter til patientens ønsker og oplyser patienten om muligheden for, at disse behandlingsønsker indsendes til lægepanelet. En helt nødvendig forudsætning for denne samtale er naturligvis, at sygehuslægen kender til ordningen, hvorfor kendskab til ordningen skal udbredes til alle relevante sygehusafdelinger.

I de tilfælde, hvor det ikke lykkes at etablere en tilfredsstillende dialog mellem sygehuslæge og patient i forhold til at søge rådgivning hos lægepanelet, bør det være muligt for patientens egen læge at søge rådgivning hos panelet på patientens vegne.

Hvis en patient er i den situation, at han/hun hverken har kunnet opnå en tilfredsstillende samtale om rådgivning fra lægepanelet med sygehuslægen eller egen læge, skal det være muligt for patienten selv at kontakte panelet.

2. Tidsfrist og ventetid Som udgangspunkt skal tidsfristen på 4 uger overholdes. Hvis der opstår problemer i forhold til, at panelet kan overholde fristen, skal patienten informeres herom.

Patienten skal adviseres, når sygehuslægen indsender en ansøgning om rådgivning til lægepanelet.

Patienten skal adviseres, når panelet sender deres anbefaling til sygehuslægen.

3. Panelet Det er vigtigt at der skabes en balance mellem patienters ønske om en eksperimentel behandling, hvis effekt ikke er tilstrækkeligt dokumenteret og den lægefaglige vurdering af risikoen for at skade patienten. I de sager, hvor der er indsendt et patientønske om en bestemt eksperimentel behandling, bør panelet derfor - for at imødekomme både et fagligt hensyn og et patienthensyn - suppleres med ikke lægefaglige repræsentanter. Det kan f.eks. være repræsentanter fra Kræftens Bekæmpelse og PAKU.

4. Sagsbehandling I den nuværende ordning sker sagsbehandlingen alene på papir. Det kan betyde urealistiske

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behandlingsforslag, idet lægepanelet læger ikke har tilstrækkelige oplysninger om patientens tilstand. Der bør indbygges en dialog mellem den behandlingsansvarlige sygehuslæge og panelets læger, så panelet får tilstrækkelige oplysninger om patienten.

Det er endvidere vigtigt, at panelets læger får kendskab til, hvilke behandlinger der har været overvejet i sygehusregi men som ikke er blevet vurderet realistiske.

5. Håndtering af behandlingsforslag Der skal ske en kvalitetssikring af sygehuslægens samtale med patienten om lægepanelets anbefalinger. I de tilfælde, hvor denne kommunikation ikke lykkes, skal patienten have mulighed for at kontakte lægepanelet med henblik på en samtale.

6. Erfaringsopsamling Der bør ske en løbende opsamling på panelets anbefalinger, f.eks. om behandlingen er blevet tilbudt patienten og om patienten har sagt ja eller nej.

Der bør ske en evaluering af konkrete patientforløb, så patientperspektivet kan være i fokus. Hvordan går det disse patienter? Opfylder ordningen behovet for denne gruppe patienter, så de har tillid til, at alle muligheder er afsøgt?

Der bør ske en erfaringsopsamling fra de sager, hvor patienten har ønsket en eksperimentel behandling, og hvor det udvidede panel har taget stilling til ønsket.

7. Ressourcer Der bør afsættes tilstrækkelige ressourcer til at sikre en grundig sagsbehandling i panelet samt dialog mellem sygehuslæge og patient, second opinion-panel og sygehuslæge samt patient og second opinion-panel.

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FORMALIA OG PRIS VED SECOND OPINION FRA THE CLEVELAND CLINIC

Should I pursue an experimental treatment? Will the therapy recommended by my doctoraddress my problem fully? What are my treatment options? These and many other questionsare common if you or someone you love has a serious illness.

When faced with a difficult decision, it’s usually helpful to gather other points of view. Often,a second opinion can provide reassurance that a prescribed treatment is best, or it can be asafeguard against inappropriate or unnecessary treatment.

When it comes to your health and well being, confidently understanding your condition andoptions is a crucial first step in pursing what is best for you. Now, you can access secondopinions from some of the nation’s best physicians from the comfort of your home throughe-Cleveland Clinic.

What is e-Cleveland Clinic?e-Cleveland Clinic is a new Web-based extension of the Clinic’s 80-year role as one ofAmerica’s most respected referral institutions, providing specialist consultations and secondopinions using the Internet for patients with life-threatening and life-altering diagnoses. Youcan view the e-Cleveland Clinic Web site at http://www.eclevelandclinic.org/

Why was it established?Today patients, especially those in the high-stress situation of making decisions abouttreatment for a life-threatening health problem for themselves or a family member, areactively seeking reliable information and knowledgeable guidance.

The Cleveland Clinic historically has been a resource for physicians and patients seekingsecond opinions – and the Internet gives us a new channel to continue fulfilling that role. Patients are increasingly using the Internet and, by creating a Web-based service, weprovide convenient access to Cleveland Clinic physicians for even more patients.

What is the key benefit for patients who use the service?e-Cleveland Clinic provides patients with convenient access to The Cleveland Clinic’snationally recognized specialists for second opinions, without the time or expense of travel.

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How does the Cleveland Clinic’se-second opinion service work?Using a secure Web environment,the patient contacts e-ClevelandClinic and we determine if he/sheis an appropriate candidate for asecond opinion via the Internet. Ifyes, the patient submits medicalhistory information and answersquestions specific to the diagnosis.The patient then gathersinformation pertinent to thediagnosis from his/her local doctoror hospital, such as pathologyslides or X-rays, and mails them tothe Cleveland Clinic.

The Cleveland Clinic physician thoroughly reviews the online medical history and the originaltests before rendering a second opinion. The patient will be notified by e-mail that theopinion is ready and can be viewed online at our secure Web site. A Cleveland Clinicregistered nurse will follow up with every patient by phone to ensure that the patientunderstands the information that has been provided and that all of the patient’s questionshave been answered.>

How much does an e-Cleveland Clinic consult cost?An e-second opinion is $565, payable at the time of the request with a major credit card. Ifpathology reading there will be an additional charge. Check with your plan’s memberservices department to determine if this service is covered.

How will the patient’s privacy be protected?The Cleveland Clinic and e-Cleveland Clinic adhere to the highest standard of privacy. Torequest a second opinion, the patient/requestor must register using a user name andpassword. This establishes a secure connection between the patient and the ClevelandClinic. The patient’s information is encrypted using Secured Socket Layer (SSL) 128-bitencryption keys. Encrypted information is transferred privately between the patient’scomputer and the Cleveland Clinic. If our system detects that the user’s browser does notmeet this specification, we will instruct the user to upgrade the browser.

Why wouldn’t a patient be appropriate for an e-consultation?There are some diagnoses and conditions that are far too complex to handle through ourservice model. Additionally, there are some diagnoses (i.e, complex, multiple organdisease) that may require a more thorough physical examination from a specialist than theone that may have been provided. In these cases, the reasons for not doing the secondopinion will be fully explained to the patient and we will advise them on other alternative foraddressing their health concerns.

After obtaining a second opinion, what are typical next steps?Once a second opinion is obtained, the patient has many options. Patients may proceedwith the treatment that was originally recommended by their own physician, they may askthat physician to consult with The Cleveland Clinic physician or another specialist, or theymay decide that they want to seek another opinion or arrange care with another physician.

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What differentiates e-Cleveland Clinic from other sites and physicians offeringsecond opinions?The Cleveland Clinic’s program differs from other Internet second opinion portals in that theprogram goes beyond “reviewing slides or studies,” to provide the kind of detailedconsultation and second opinion patients receive in person at The Cleveland Clinic.

• Patients are not just “consults” – they are formally registered just as theywould be if they were physically at the Clinic and their records provide aformal medical record at TheCleveland Clinic.

• We have a nurse coordinator who is available to patients and she will contactevery patient who receives a second opinion to make sure that all thepatient’s questions are answered.

• Our physicians review the original materials, such as X-rays or MRI scans,pathology slides, etc. – rather than copies.

• When possible, our service provides the second opinion directly to the patient,which gives patients complete privacy and autonomy. Upon request, a copyof the second opinion is sent to the patient’s primary care provider.

• Our system matches the diagnosis the patient enters against our database ofclinical services to determine if he/she is an appropriate candidate for usinge-Cleveland Clinic. The patient is notified immediately if a remote secondopinion is not available. The patient does not complete the process and thenfind that the service is not available.

• Our physicians will meet all licensing requirements in every state in whichpatients who are using the service reside.

Is this service available to anyone?The e-Cleveland Clinic second opinion program is available in most locations. Patients mayaccess the e-Cleveland Clinic second opinion service directly by going tohttp://www.eclevelandclinic.org/. In some states, to comply with state licensing requirements,the patient’s physician will need to sign a “request for consultation“ form. This form ispresented online to the patient. Once the form is signed and returned to e-Cleveland Clinic,the patient will work directly with e-Cleveland Clinic staff to complete the second opinionrequest. The program is not available in a few states that do not allow for remoteconsultation. The patient will be notified if the service is not available.

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HVORFOR BRUGE “THE CLEVELAND CLINIC” TIL SECOND OPINION???

For 80 years, patients and families have looked to The Cleveland Clinic for medical advice and treatment. Now you may consult with our world-renowned physicians from the comfort of your home utilizing the customized second opinion service that is right for you:

• Full remote second medical opinion: Cleveland Clinic experts review your medical records and diagnostic tests and render an opinion that includes treatment options or alternatives and recommendations regarding future therapeutic considerations. • Comprehensive pre-adoption evaluation: Conducted by a board-certified pediatrician specializing in adoption services, this evaluation is designed to assist prospective parents preparing to meet the needs of children adopted locally, or internationally. Evaluations include reviews and analysis of medical information including: medical history; laboratory and radiology; video information; birth history; delivery; hospitalization; growth parameters; developmental milestones; illnesses and treatments; immunization history and other pertinent details when available. • Cardiac film review: For those cardiac patients who desire to have a second expert review of a cardiac catheterization, echocardiogram, or transesophageal echocardiogram imaging study, this specialized service provides a second expert review of these materials.

The Cleveland Clinic has a tradition of leadership in medical excellence, and has been named among the top 10 hospitals in America in each of the 13 years that U.S. News & World Report magazine has published its "best hospitals" ranking. Our physicians are consistently recognized as national and international leaders in their fields.

When it comes to your health and well-being, confidently understanding your condition and options is a crucial first step in pursuing what is best for you.

If you would like more information on the e-Cleveland Clinic program, please contact us at 800/223-2273, ext. 43223; e-mail [email protected].

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KRÆFTENS BEKÆMPELSE-EKSPERIMENTELL BEHANDLING I UDLANDET Eksperimentel behandling betalt af det offentlige

Kræftpatienter kan henvises til eksperimentel behandling i udlandet eller til private sygehuse herhjemme på det offentliges regning. Formålet er at sikre patienter en sidste chance for at få vurderet, om der findes yderligere muligheder for behandling.

De kræftpatienter, som kan henvises på det offentliges regning, er patienter, som det offentlige sygehusvæsen ikke længere har et behandlingstilbud til. De kan heller ikke tilbydes en højst specialiseret behandling eller forskningsmæssig behandling i udlandet.

Hvad er eksperimentel behandling? En eksperimentel behandling er: En ikke prøvet eller en ikke tilstrækkeligt dokumenteret behandling, der ikke gives i et protokolleret forsknings- eller forsøgsmæssigt regi. Behandlingen iværksættes i relation til en bestemt patient med det formål at yde patienten den bedst mulige behandling i den konkrete situation.

Læs mere nedenfor:

• Hvilke patienter kan komme i betragtning? • Det rådgivende panel • Hvor lang tid er panelet om at behandle en sag? • Hvad kan patienten gøre? • Hvad er den praktiserende læges rolle? • Hvad skal sygehuslægen gøre? • Hvad skal bopælsamtet gøre? • Hvem betaler? • Dækker patientforsikringen ved eksperimentel behandling i udlandet? • Her kan du se den nye regel i bekendtgørelsen

Hvilke patienter kan komme i betragtning? Reglerne dækker patienter, som har kræft eller anden livstruende sygdom, og som ikke kan tilbydes behandling på offentlige sygehuse her i landet, eller som ikke kan tilbydes videnskabelig forsøgsbehandlingi udlandet.

Det rådgivende panel Sundhedsstyrelsen har nedsat et panel, der skal rådgive sygehuslægen, om den enkelte patient skal sendestil eksperimentel behandling i udlandet på det offentliges regning. Panelet består af to danske kræfteksperter, og der suppleres med indenlandsk eller udenlandsk ekspertbistand i det omfang, det er nødvendigt.

Hvor lang tid er panelet om at behandle en sag? Med mindre helt særlige forhold gør sig gældende, vil der maksimalt gå fire uger fra sygehusafdelingen harforelagt en sag for Sundhedsstyrelsen, til der foreligger et råd fra panelet.

• Til top

Hvad kan patienten gøre?

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Patienter, som ønsker at blive henvist til eksperimentel behandling i udlandet eller på private sygehuse herhjemme, skal henvende sig til den sygehusafdeling, de er tilknyttet. Så kan sygehuslægen bede Sundhedsstyrelsen om råd i den konkrete sag. Hvis patienten selv har konkrete ønsker om behandling, skal han eller hun sige det til sygehusafdelingen, som står for kontakten til det rådgivende panel.

Patienten kan ikke selv henvende sig direkte til Sundhedsstyrelsens rådgivende panel.

Hvad er den praktiserende læges rolle? Patientens praktiserende læge kan hjælpe med information om de nye regler og kan (gen)henvise patienten til sygehuset.

De praktiserende læger kan ikke henvise patienten til Sundhedsstyrelsens rådgivende panel eller bede panelet om råd. Det skal foregå via sygehusafdelingen.

• Til top

Hvad skal sygehuslægen gøre? Sygehusafdelingen beslutter, om der skal søges råd om eksperimentel behandling.

Det er afdelingens opgave at informere patienten om det råd, der er givet og drøfte det videre forløb med patienten.

Hvis der henvises til eksperimentel behandling skal Sundhedsstyrelsens formelle godkendelse indhentes.

Hvad skal Sundhedsstyrelsen gøre? Sundhedsstyrelsen kan med dags varsel godkende en henvisning til eksperimentel behandling på baggrund af rådgivning fra panelet, hvis der kan være mulighed for, at en bestemt eksperimentel behandling på et privat sygehus her i landet eller et sygehus i udlandet kan helbrede patienten eller forlænge patientens liv.

Hvad skal bopælsamtet gøre? Når Sundhedsstyrelsen har godkendt en henvisning til eksperimentel behandling i udlandet, skal bopælsamtet sørge for de praktiske forhold vedrørende patientens behandling i udlandet (herunder fx transport, tolkebistand mv.)

Hvem betaler? Staten dækker alle udgifter til behandling, transport og ophold (inkl. eventuel ledsager).

Dækker patientforsikringen ved eksperimentel behandling i udlandet? Patientforsikringen dækker på samme vilkår som ved behandling på de offentlige sygehuse her i landet.

Der er afsat ti mio. kr. til eksperimentel behandling i finansloven for år 2002.

Her kan du se den nye regel i bekendtgørelsen:

• Bekendtgørelse om ret til sygehusbehandling og fødselshjælp m.v., § 26

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SECOND OPINION HOS MEMORIAL SLOAN-KETTERING FOR INTERATIONALE PATIENTER, PROCEDURER OG PRIS Patient Information > For International Patients > Practical Information > Requesting a Review of Records by Mail

How to Request a Review of Records by Mail

A review of records by mail can be a convenient way for an international patient to get an opinion from a cancer specialist Memorial Sloan-Kettering without having to travel to New York. Usually we can complete a "mail review" within 15 businesdays after we receive all the requested materials and payment.

Although a review of records by mail can be more convenient than an on-site consultation, there are important limitatioto bear in mind -- including the following:

• The mail review -- which is based on the extent, quality, and quantity of information we receive -- doesn't mean thaMemorial Sloan-Kettering physician is directing your care. Should you have questions about the recommendationsyou should first discuss those issues of concern with your physician at home. The opinion by mail does not providefor further opinions or other involvement of our physicians in your care.

• Mail reviews do not provide for direct interaction with a Memorial Sloan-Kettering physician. We recommend that apatient who desires interaction with one of our physicians consider an on-site consultation.

To ensure an appropriate referral to a Memorial Sloan-Kettering physician, we require a medical summary from the patient's physician.

For patients from visa waiver countries (click here for list), please use our Patient & Contact Information form.

For patients from countries that are required to obtain a visa for entry into the United States, we require a (2-3 page) medical summary from the patient's physician. This report must be in English. The physician medical summary cannotprepared a friend, family member, or the patient.

The physician medical summary must include the following information, as we will not be able to provide a referral recommendation if the information is not complete.

1. Country of which the patient is a citizen. 2. Patient's name (first name, then last name, as on the patient's passport), address, phone number, fax number, and

date of birth (Month/Day/Year). 3. Name, telephone number (and email address) of the one (1) individual with whom we will need to be in contact to

discuss/arrange a referral. 4. Diagnosis and date of diagnosis. 5. Type of treatment modalities received and corresponding dates. 6. Current treatment plan recommended by the physician at home. 7. The current state of health of the patient. 8. The physician must indicate if the patient would benefit from a review of records by mail.

All documents must be in English. Sending documents in any language other than English will cause a delay. We cannottranslate documents; however, we can provide a list of private translation services.

Do not send us any actual pathology slides/blocks, scans or images.

After we receive the physician's medical summary, an International Center guest services assistant will contact you abou

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other materials our physician will need to perform a review. Based on those materials, you will also be informed of the for a mail review.

The fee for a review of records by mail is $500.* (In the event additional materials are needed for the review such asScans, MRI or X-Rays – the fee will be higher).

Please fax all medical information (in English) to the attention of:

Guest Services Assistant, (patient's country or citizenship) Memorial Sloan-Kettering International Center Attention: Review of Records by Mail Fax: 212-639-4938

Please note that in certain instances (depending on the diagnosis) the review of records by mail option may not besuitable, as a physical examination may be more appropriate in order for an opinion to be rendered.

You may also call the International Center with questions regarding the process. From outside the United States, you cause AT&T Direct Access: first dial the access number for the country you are in, then 888-675-7722. From within the United States, call 212-639-4900 or toll-free 888-675-7722.

Because standard email is not a secure form of communication, we ask that you not send us any medical information orother confidential information by email.

Email this page

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BEHANDLING HOS SLOAN-KATTERING I N.Y. – PROCEDURER, INDHÆNTNING AF PRISTILBUD MV.

Patient Information > For International Patients > Practical Information > Requesting a Cost Estimate

How to Request a Cost Estimate

We can provide international patients with an estimate noting the possible cost of treatment at Memorial Sloan-KetteInternational Center charges no fee to arrange for a medical services cost estimate.

To ensure an appropriate referral to a Memorial Sloan-Kettering physician, we require a medical summary from tpatient's physician.

For patients from visa waiver countries (click here for list), please use our Patient & Contact Information form.

For patients from countries that are required to obtain a visa for entry into the United States, we require a (2-3 pmedical summary from the patient's physician. This report must be in English. The physician medical summary cprepared a friend, family member, or the patient.

The physician medical summary must include the following information, as we will not be able to provide a referrecommendation if the information is not complete.

1. Country of which the patient is a citizen. 2. Patient's name (first name, then last name, as on the patient's passport), address, phone number, fax numb

date of birth (Month/Day/Year). 3. Name, telephone number (and email address) of the one (1) individual with whom we will need to be in cont

discuss/arrange a referral. 4. Diagnosis and date of diagnosis. 5. Type of treatment modalities received and corresponding dates. 6. Current treatment plan recommended by the physician at home. 7. The current state of health of the patient. 8. The physician must indicate if the patient would benefit from a consultation or treatment at Memorial Sloan-

or have a review of records by mail.

All documents must be in English. Sending documents in any language other than English will cause a delay. Wetranslate documents; however, we can provide a list of private translation services.

The estimate is based on the extent, quality, and quantity of the information provided to us. This service does nothat a Memorial Sloan-Kettering physician is directing your care, nor does it provide for direct interaction with a Sloan-Kettering physician. We recommend that any patient who desires interaction with one of our physicians conon-site second-opinion consultation.

Please fax all medical information (in English) to the attention of:

Guest Services Assistant, (patient's country or citizenship) Memorial Sloan-Kettering International Center Fax: 212-639-4938

Obtaining an on-site second-opinion consultation does not obligate you to obtain treatment or services at MemoriKettering, nor does it obligate Memorial Sloan-Kettering to provide treatment or services.

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You may also call the International Center with questions regarding this process. From outside the United States,use AT&T Direct Access: first dial the access number for the country you are in, then 888-675-7722. From within United States, call 212-639-4900 or toll-free 888-675-7722.

Because standard email is not a secure form of communication, we ask that you not send us any medical informatother confidential information by email.

Email this page

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KOMBINERET BEHANDLING MED STRÅLING OG RADIOTERAPI GIVER BEDRE OVERLEVELSE FOR PERSONER UNDER 60 ÅR OG MED ANAPLASTISK OLIGODENDROGLIOMER

1: Gan To Kagaku Ryoho. 2002 May;29(5):669-76. Related Articles, Links

[Chemo-radiotherapy for malignant brain tumors] [Article in Japanese] Kochi M, Ushio Y. Dept. of Neurosurgery, Kumamoto University Medical School. I) Malignant gliomas: Randomized clinical trials conducted in the USA showed that radiotherapy plus chemotherapy with nitrosoureas offered a long-term survival advantage to patients younger than 60 years old with malignant gliomas. Combination chemotherapy, such as procarbazine/CCNU/vincristine (PCV) must be tested further, and intra-arterial chemotherapy with nitrosoureas offered no survival advantage. Combination chemotherapy with PCV showed efficacy for patients with anaplastic oligodendroglioma and anaplastic oligoastrocytoma. II) Medulloblastoma: The addition of chemotherapy to radiotherapy improved the survival of patients with poor risk medulloblastoma, and may reduce the required craniospinal radiation dose in patients with good risk medulloblastoma. III) Primary CNS lymphoma (PCNSL): Combination of chemotherapy with high-dose MTX and radiotherapy improved survival of patients with PCNSL; however, the neurotoxicity produced by this treatment modality is a serious problem in older patients. IV) Intracranial germ cell tumors: The addition of chemotherapy to radiotherapy may produce long term survival with good quality of life in patients with germinoma. Neoadjuvant therapy consisting of chemotherapy and radiotherapy followed by complete surgical excision improved survival of patients with intracranial nongerminomatous germ cell tumors. Publication Types:

• Review • Review, Tutorial