Leiomyosarcoma & Brain Metastases



Written/Compiled by doctordee       August 2002 - March 2003

Introduction 
Symptoms
Diagnosis
Management
Clinical Trials
Brain Metastases and Sarcoma
Neurosurgery
Irradiation
	Whole Brain
	Focused: Gamma knife, Stereotactic
	Intraoperative
	Radioisotope
	Proton Beam
	High Energy Neutrons -- Fermilab
Chemotherapy and the Blood Brain Barrier
Radio Frequency Ablation
Hyperthermia
Immunotherapy and Gene Therapy

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INTRODUCTION

How to Use This Page 

This page deals with Brain Metastases.  There is a general discussion, followed by treatment techniques with illustrative annotated medical journal articles, dealing with LMS or sarcoma if possible.  [For further discussion of some of the treatment techniques like Chemotherapy or Radiation, see another section of this website.] 

Should you be interested in a specific technique, abstracts can be highlighted and copied, and then printed out and taken with you to your doctor for further discussion.   Furthermore searches on Pubmed or on ASCO [www.asco.org] may provide further information on the technique, and places where it is done, for you and your doctor.   
[ ] will indicate editorial comment by the compiler. Some sentences are highlighted in bold, again done by the compiler.

***

Leiomyosarcoma & Brain Metastases

Metastasis is the spread of cancer. Cancer that begins in other parts of the body may spread to the brain and cause secondary tumors. These tumors are not the same as primary brain tumors. Cancer that spreads to the brain is the same disease and has the same name as the original (primary) cancer. For example, if lung cancer spreads to the brain, the disease is called metastatic lung cancer because the cells in the secondary tumor resemble abnormal lung cells, not abnormal brain cells.
Treatment for secondary brain tumors depends on where the cancer started and the extent of the spread as well as other factors, including the patient's age, general health, and response to previous treatment.
While brain metastases were an unusual development in leiomyosarcoma, there is now an increased incidence of cerebral metastases in sarcoma patients with prolonged survival from chemotherapy. Brain metastases from sarcoma usually occur with or after lung metastasis. Long-term survival is possible with treatment in some patients. [1,2,7,8, 9]

***

Letter posted to the L-M-Sarcoma Mailing List at ACOR [www.acor.org].
August 2002
Freda,

I am so sorry to hear of your symptoms.  By now, you most likely know the outcome of your MRI.  I just wanted you to know that I had brain mets and had them removed in Dec. 1999.  I lived a full life afterwards and then found last summer that more had returned.  Once again I had brain surgery back in July last year.  Unfortunately, my latest scan showed two more, but this time they are small and I am receiving stereotactic radiosurgery, which is a kind of radiation.  If I have slowed down my activities a bit lately, it is more due to painful tumors in my foot rather than the brain tumors.
I just wanted you to know that I am still out here and fighting.  My heart goes out to you, and hopefully this will not be your diagnosis.  If it is, you can do this.  One step at a time.

Hugs, Maria (New Jersey)

Uterine LMS 29 year survivor.  Surgery, radiation.
Next occurrence 21 years later, 1994.  Lung VAT procedure.
Next occurrence 5 years later, 1999, brain.  3 chemos.
Many mets, several surgeries.  Radiation presently.

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Read:  What You Need To Know About(tm) Brain Tumors from the cancer.gov site of the National Cancer Institute [NCI]:
http://www.cancer.gov/templates/page_print.aspx?viewid=b5500bd0-3da6-496a-8080-3052a630ba57

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Symptoms of Brain Tumors 
The symptoms of brain tumors depend mainly on their size and their location in the brain. Symptoms are caused by damage to vital tissue and by pressure on the brain as the tumor grows within the limited space in the skull. They also may be caused by swelling and a buildup of fluid around the tumor, a condition called edema. Symptoms may also be due to hydrocephalus, which occurs when the tumor blocks the flow of cerebrospinal fluid and causes it to build up in the ventricles. If a brain tumor grows very slowly, its symptoms may appear so gradually that they are overlooked for a long time.
The most frequent symptoms of brain tumors include:
Headaches that tend to be worse in the morning and ease during the day,
Seizures (convulsions or fits),
Nausea or vomiting,
Weakness or loss of feeling in the arms or legs,
Stumbling or lack of coordination in walking (ataxic gait),
Abnormal eye movements or changes in vision,
Drowsiness,
Changes in personality or memory, and
Changes in speech.
These symptoms may be caused by brain tumors or by other problems. Only a doctor can make a diagnosis.
Diagnosis 
To find the cause of a person's symptoms, the doctor asks about the patient's personal and family medical history and performs a complete physical examination. In addition to checking general signs of health, the doctor does a neurologic exam. This includes checks for alertness, muscle strength, coordination, reflexes, and response to pain. The doctor also examines the eyes to look for swelling caused by a tumor pressing on the nerve that connects the eye and the brain.
Depending on the results of the physical and neurologic examinations, the doctor may request one or both of the following:
A CT (or CAT) scan is a series of detailed pictures of the brain. The pictures are created by a computer linked to an x-ray machine. In some cases, a special dye is injected into a vein before the scan. The dye helps to show differences in the tissues of the brain.
MRI (magnetic resonance imaging) gives pictures of the brain, using a powerful magnet linked to a computer. MRI is especially useful in diagnosing brain tumors because it can "see" through the bones of the skull to the tissue underneath. A special dye may be used to enhance the likelihood of detecting a brain tumor.
The doctor may also request other tests such as:
A skull x-ray can show changes in the bones of the skull caused by a tumor. It can also show calcium deposits, which are present in some types of brain tumors.
A brain scan reveals areas of abnormal growth in the brain and records them on special film. A small amount of a radioactive material is injected into a vein. This dye is absorbed by the tumor, and the growth shows up on the film. (The radiation leaves the body within 6 hours and is not dangerous.)
An angiogram, or arteriogram, is a series of x-rays taken after a special dye is injected into an artery (usually in the area where the abdomen joins the top of the leg). The dye, which flows through the blood vessels of the brain, can be seen on the x-rays. These x-rays can show the tumor and blood vessels that lead to it.
A myelogram is an x-ray of the spine. A special dye is injected into the cerebrospinal fluid in the spine, and the patient is tilted to allow the dye to mix with the fluid. This test may be done when the doctor suspects a tumor in the spinal cord.

Discussion of Management 

Brain tumors are usually treated with surgery, radiation therapy, and/or chemotherapy. Depending on the patient's needs, several methods may be used. The patient may be referred to doctors who specialize in different kinds of treatment and work together as a team. This medical team often includes a neurosurgeon, a medical oncologist, a radiation oncologist, a nurse, a dietitian, and a social worker. The patient may also work with a physical therapist, an occupational therapist, and a speech therapist.
Before treatment begins, most patients are given steroids, which are drugs that relieve swelling (edema). They may also be given anticonvulsant medicine to prevent or control seizures. If hydrocephalus is present, the patient may need a shunt to drain the cerebrospinal fluid. 
As always with leiomyosarcoma, surgical resection is the treatment of choice.  Direct neurosurgical excision, with or without other treatments, is usually recommended if it is possible.  Surgery is the usual treatment for most brain tumors. To remove a brain tumor, a neurosurgeon makes an opening in the skull. This operation is called a craniotomy. Whenever possible, the surgeon attempts to remove the entire tumor. However, if the tumor cannot be completely removed without damaging vital brain tissue, the doctor removes as much of the tumor as possible. Partial removal (debulking) helps to relieve symptoms by reducing pressure on the brain and reduces the amount of tumor to be treated by radiation therapy or chemotherapy.

Radiation in some form  [intraoperative, whole brain irradiation, stereotactic or gamma knife, proton or other particle beam, or radioisotope insertion] is often used alone or in conjunction with surgery or possibly other treatments.  Cognitive defects may occur after whole brain irradiation, and possibly with other treatments.  Radionecrosis of the brain-the development of multiple and increasing areas of dead and dying brain tissue-is a serious complication of radiation treatment. 
Radiation therapy (also called radiotherapy) is the use of high-powered rays to damage cancer cells and stop them from growing. It is often used to destroy tumor tissue that cannot be removed with surgery or to kill cancer cells that may remain after surgery. Radiation therapy is also used when surgery is not possible.
Radiation therapy may be given in two ways. External radiation comes from a large machine. Generally, external radiation treatments are given 5 days a week for several weeks. The treatment schedule depends on the type and size of the tumor and the age of the patient. Giving the total dose of radiation over an extended period helps to protect healthy tissue in the area of the tumor.
Radiation can also come from radioactive material placed directly in the tumor (implant radiation therapy). Depending on the material used, the implant may be left in the brain for a short time or permanently. Implants lose a little radioactivity each day. The patient stays in the hospital for several days while the radiation is most active.
External radiation may be directed just to the tumor and the tissue close to it or, less often, to the entire brain. (Sometimes the radiation is also directed to the spinal cord.) When the whole brain is treated, the patient often receives an extra dose of radiation to the area of the tumor. This boost can come from external radiation or from an implant.
Stereotactic radiosurgery is another way to treat brain tumors. Doctors use the techniques described in the Surgery section to pinpoint the exact location of the tumor. Treatment is given in just one session; high-energy rays are aimed at the tumor from many angles. In this way, a high dose of radiation reaches the tumor without damaging other brain tissue. (This use of radiation therapy is sometimes called the gamma knife.)
Chemotherapy is the use of drugs to kill cancer cells. The doctor may use just one drug or a combination, usually giving the drugs by mouth or by injection into a blood vessel or muscle. Intrathecal chemotherapy involves injecting the drugs into the cerebrospinal fluid.
Chemotherapy is usually given in cycles: a treatment period followed by a recovery period, then another treatment period, and so on. Patients often do not need to stay in the hospital for treatment. Most drugs can be given in the doctor's office or the outpatient clinic of a hospital. However, depending on the drugs used, the way they are given, and the patient's general health, a short hospital stay may be necessary.


Chemotherapy is not very successful in treating brain tumors, because of something called the "blood brain barrier" [BBB], which prevents chemotherapy agents, present in the blood, from migrating into or penetrating brain tissue.  There are substances and conditions that do break down the BBB, and allow permeation of the brain, but these are in experimental use at this time.  We do know that trauma and radiation and certain substances can cause disruption of the BBB.  [3,4,6] Were chemotherapy agents able to pass the blood brain barrier, would their neurotoxicity become the limiting factor for treatment? [5]

Radio frequency ablation has also been used to treat brain metastases.  As has hyperthermia.

Generally, aggressive treatment of treatable brain metastases is indicated where conditions are favorable, with failures coming from local recurrence of the treated brain metastases, emergence of new brain metastases, or progression of other systemic disease. [2]

Aggressive treatment of brain metastases is recommended if a person's functioning is good. [1,2] In a sense, this depends upon the location [whether near vital centers] and the size of the tumor, so it is worthwhile being alert to the possibility of brain metastasis, and being scanned if there is a suspicion, to diagnose them early.  MRI scans are more accurate for this purpose than CT scans.

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Clinical Trials 
Researchers are looking for treatment methods that are more effective against brain tumors and have fewer side effects. When laboratory research shows that a new method has promise, doctors use it to treat cancer patients in clinical trials. These trials are designed to answer scientific questions and to find out whether the new approach is both safe and effective. Patients who take part in clinical trials make an important contribution to medical science and may have the first chance to benefit from improved treatment methods.
Many clinical trials of new treatments for brain tumors are under way. Doctors are studying new types and schedules of radiation therapy, new anticancer drugs, new drug combinations, and combinations of chemotherapy and radiation.
Scientists are trying to increase the effectiveness of radiation therapy by giving treatments twice a day instead of once. Also, they are studying drugs called radiosensitizers. These drugs make the cancer cells more sensitive to radiation. Another method under study is hyperthermia, in which the tumor is heated to increase the effect of radiation therapy.
Many drugs cannot reach brain cells because of the blood-brain barrier, a network of blood vessels and cells that filters blood going to the brain. Researchers continue to look for new drugs that will pass through the blood-brain barrier. Studies are under way using different techniques to temporarily disrupt the barrier so that drugs can reach the tumor.
In other studies, scientists are exploring new ways to give the drugs. Drugs may be injected into an artery leading to the brain or may be put directly into the ventricles. Doctors are also studying the effectiveness of placing tiny wafers containing anticancer drugs directly into the tumor. (The wafers dissolve over time.)
Biological therapy is a new way of treating brain tumors that is currently under study. This type of treatment is an attempt to improve the way the body's immune system fights disease.
Patients interested in taking part in a clinical trial should discuss this option with their doctor. They may want to read Taking Part in Clinical Trials: What Cancer Patients Need To Know  an NCI booklet that explains some of the possible benefits and risks of treatment studies.
One way to learn about clinical trials is through PDQ(r), computerized resource developed by the National Cancer Institute. This resource contains information about cancer treatment and about clinical trials in progress all over the country. The Cancer Information Service can provide PDQ information to patients and the public. 
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PUBMED SEARCH
Brain metastases and treatment
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=brain%20metastases%20AND%20treatment

Brain Metastasis Information



RADIATION

Staten Island, NY University Hospital.
www.radiosurgury@siuh.edu/conindex5.html

Fermi National Accelerator Laboratory - This is neutron beam radiation.
http://www-bd.fnal.gov/ntf/ntf_home.html
 
Massachusetts General Hospital, Harvard Medical School, affiliated with Dana Farber Cancer Center.
They have proton beam radiation. This is a link to the brain tumor information. http://brain.mgh.harvard.edu/

Loma Linda, CA, University Medical Center. 
They use Proton Beam radiotherapy. http://www.llu.edu/proton/



Gamma Knife Radiosurgery

www.midwestgammaknife.com

http://www.sdgkc.com/faqs/faqs.htm

www.midwestgammaknife.com/contact.htm
 
http://gammaknife.uams.edu/about.htm

http://www.oncolink.com/library/article.cfm?c=2&s=20&id=34



Brain Anatomy

Brain Anatomy
www.vh.org/Providers/Textbooks/BrainAnatomy/TOC.html

More Brain Anatomy
http://www.waiting.com/brainanatomy.html

Brain Functions and Map
http://www.neuroskills.com/index.html


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Annotated References for this section:

1. Surg Neurol 2000 Aug;54(2):160-4 
Brain metastasis in patients with sarcoma: an analysis of histological subtypes, clinical characteristics, and outcomes. 
Yoshida S, Morii K, Watanabe M, Saito T. Department of Neurosurgery, Niigata Cancer Center Hospital, Niigata, Japan. 

"... All sarcoma patients treated at our institution from 1975 to 1998 were reviewed for brain metastasis. Diagnosis of the primary tumor was confirmed histologically, and brain metastasis was confirmed using computed tomographic (CT) brain scan." 
"... Brain metastasis was found in 27 (5.6%) of 480 patients with systemic sarcoma (7.2% soft part sarcoma, 3.5% bone sarcoma, 15.1% distant metastasis). Of these 27 sarcoma patients with brain metastases, lung metastasis occurred in 16 patients (59.3%). Out of 10 patients surgically treated, 8 patients survived more than 16 months. Median survival period after craniotomy was 25.4 months." 
"...We recommend aggressive treatment for those patients with brain metastases whose performance scores are over 70." PMID: 11077098 

2. Neurochirurgie 1999 Dec;45(5):382-92 
[Cerebral metastases: radiotherapy and chemotherapy]. [Article in French] 
Helfre S, Pierga J. Institut Curie, 26, rue d'Ulm, 75005 Paris, France. 

"Brain metastases are common events in adult patients with solid tumors. The choice of the optimal therapy is still challenging and controversial. Whole brain radiotherapy (WBRT) is a standard practice in most patients with an excellent palliative effect. Boost to gross disease has also been advocated without a clear benefit. Moreover following extended irradiation, a substantial proportion of the long term survivors (>6 months), will present documented cognitive impairments. Patients with favorable prognostic factors can benefit from more aggressive therapy: local resection, mono or multifractionated irradiation with or without radiosensitizing agents, stereotactic radiotherapy, brachytherapy. Although brain metastases of solid tumors occur in the presence of progressive widespread disease, chemotherapy has played a limited role in their treatment. Poor drug penetration across the normal blood-brain barrier of chemotherapy agents is not a limiting factor because of the neovascularization in the tumor. [?] The few prospective studies that have addressed this issue, especially in lung and breast tumors, are reviewed." 
PMID: 10717587 



3.  Neuro-oncol 2001 Jan;3(1):46-54  
Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Meeting of the Blood-Brain Barrier Disruption Consortium.
Doolittle ND, Anderson CP, Bleyer WA, Cairncross JG, Cloughesy T, Eck 
SL, Guastadisegni P, Hall WA, Muldoon LL, Patel SJ, Peereboom D, Siegal 
T, Neuwelt EA.
Dept of Neurology, Oregon Health Sciences University, Portland  97201-3098, USA.

 " Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain 
Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened ...This meeting...brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. "
"Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of ... metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies ... are discussed."   
Publication Types: Congresses  PMID: 11305417 


4.  Curr Oncol Rep 2000 Sep;2(5):445-53 
Cytotoxic chemotherapy: advances in delivery, pharmacology, and testing.
Ciordia R, Supko J, Gatineau M, Batchelor T.
Brain Tumor Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Cox 315, 100 Blossom Street, Boston, MA 02114, USA.

"... A major factor in the failure of iv chemotherapy [for treatment of brain tumors] is the blood-brain barrier (BBB), a physiologic impediment to the delivery of cytotoxic chemotherapeutic drugs to the central nervous system (CNS). Intra-arterial and intrathecal infusion, blood-brain barrier disruption, high-dose chemotherapy, intratumoral administration, and convection-enhanced delivery are methods developed to overcome the BBB. Although some of these methods may increase the local concentration-time profile, improvement in clinical outcomes has yet to be definitively established. New methods for assessment of drug delivery to the brain tumor will assume increasing importance in the study of new cytotoxic chemotherapeutic drugs for these types of cancer. Pharmacokinetic studies are critical components of these clinical trials and allow         assessment of drug delivery to the CNS and brain tumor. Additionally, pharmacokinetic studies will remain an important component of early clinical trials, particularly for identifying significant drug interactions involving the various supporting medications that are typically used in this patient population."
PMID: 11122877 



5.  Neurosurgery 2000 Jul;47(1):199-207         
        Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model.

Fortin D, McCormick CI, Remsen LG, Nixon R, Neuwelt EA.
Dept of Neurology, Oregon Health Sciences University, and Veterans Administration Medical Center, Portland, USA.

"... Osmotic blood-brain barrier disruption (BBBD) increases brain and brain tumor delivery of chemotherapeutic agents, which results in increased efficacy against brain tumors. We previously noted that the use of propofol anesthesia for BBBD increased the percentage of successful disruptions, resulting in delivery of increased amounts of chemotherapeutic drugs. This study evaluated the neurotoxicity of combination chemotherapeutic administration with this enhanced delivery system."...
"Neurotoxicity was significantly increased for etoposide phosphate combination groups, particularly when both drugs were administered IA after BBBD. This increase in neurotoxicity may reflect on increase in         drug delivery observed with propofol anesthesia. ..."
        PMID: 10917363 



6. Clin Pharmacol Ther 2000 Jun;67(6):631-41 

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

Zylber-Katz E, Gomori JM, Schwartz A, Lossos A, Bokstein F, Siegal T.
Division of Medicine, the Neuro-Oncology Center, Hadassah University Hospital, Jerusalem, Israel. esterzk@hadassah.org.il

        "... Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration." 
PMID: 10872645 



7. Cancer 1988 Feb 1;61(3):593-601 
        Sarcoma metastatic to the brain.

        Lewis AJ.
        Department of Pathology, University of Toronto, Ontario, Canada.

        "...Reportedly, most types of sarcomas are able to metastasize to the brain, and are represented in these 94 patients.  ... There may be a group of tumors, including ...perhaps leiomyosarcoma ... in which the incidence of brain metastases has increased with improved sarcoma chemotherapy ... In this group particularly... the presence of lung metastases may increase the probability of brain metastasis occurring subsequently.        PMID: 3276383 


8. Med Pediatr Oncol 1985;13(5):280-92 
        Sarcoma metastatic to the central nervous system parenchyma: a review of 
        the literature.
        Sarno JB, Wiener L, Waxman M, Kwee J.

Sarcoma metastatic to cerebral parenchyma, although rare, occurs more frequently than generally recognized. With increased duration of survival due to multi-modal therapy, more CNS metastases are being 
found. A literature search occasioned by a patient with metastatic sarcoma has produced some interesting results.  PMID: 3897818 



9. Cancer 1975 Nov;36(5):1843-51 
        Increased incidence of cerebral metastases in sarcoma patients with 
        prolonged survival from chemotherapy. Report of cases of leiomyosarcoma 
        and chondrosarcoma.
        Gercovich FG, Luna MA, Gottlieb JA.

        Soft tissue and bony sarcomas rarely metastasize to the central nervous system, particularly to the cerebral hemispheres. In 456 patients with metastatic sarcoma, only 6 (1.3%) had cerebral metastases documented by brain scan at the time of referral for chemotherapy. Adriamycin-containing combination chemotherapeutic regimens have led to a significant increase in the median survival of patients from the start of chemotherapy (18 + months for responders compared, to 7 months in nonresponders). Of 14 patients relapsing after a response or stabilization of disease of 6 months or greater, the cause of relapse was the development of cerebral metastases in 5 (36%). Two of these cases, one a patient with leiomyosarcoma and one with chondrosarcoma, were documented by autopsy and are reported in detail because of their rarity in the medical literature. Although the numbers are small, the increased incidence of cerebral metastases in the group relapsing after a lengthy response suggests that improved chemotherapy for sarcomas resulting in improved survival may be changing the pattern of metastatic disease, and may require new therapeutic approaches. PMID: 1192369 




Brain Metastases and Sarcoma and Leiomyosarcoma


"The autopsy findings of 73 patients with uterine sarcoma were studied to determine the sites and possible modes of metastasis. [26% of the tumor types were LMS] The peritoneal cavity and omentum were the most frequently involved sites (59%), followed by the lung (52%), pelvic lymph nodes (41%), paraaortic lymph nodes (38%), and liver parenchyma (34%). The presence of lung metastasis was not associated with pelvic or paraaortic node metastasis or intraperitoneal disease. Metastasis to other distant sites including the brain, heart, kidney, and bone were independent of pelvic and paraaortic nodal metastasis or intraperitoneal disease. Metastatic sites were not different among various histologic types. Distant metastatic sites were statistically associated with lung metastasis. Hematogenous metastasis best explains this metastatic pattern..."[12]

Soft tissue and bony sarcomas rarely metastasize to the brain.  [1,2,5,6,8,9,18] Data concerning the treatment and results of therapy are sparse [5]  Sarcoma and leiomyosarcoma metastatic to the brain is uncommon and rarely occurs as the initial manifestation of tumor.  Central nervous system metastases are an unusual sequela of leiomyosarcoma. The incidence of brain metastases from systemic sarcoma has been reported as 7% or less.  [2]

If sarcoma does metastasize to the brain, it is often after lung metastases [approximately 60% of those with brain metastases will have had or have lung metastases. [1,5]  Although the numbers are small, the increased incidence of cerebral metastases in the group relapsing after a lengthy response suggests that improved chemotherapy for sarcomas resulting in improved survival may be changing the pattern of metastatic disease, and may require new therapeutic approaches.[18]

"Treatment allowing longer survival may be allowing brain metastases to become noticeable.  With increased duration of survival due to multi-modal therapy, more CNS metastases are being found. A literature search occasioned by a patient with metastatic sarcoma has produced some interesting results"  [14]

" In 456 patients with metastatic sarcoma, only 6 (1.3%) had cerebral metastases documented by brain scan at the time of referral for chemotherapy. Adriamycin-containing combination chemotherapeutic regimens have led to a significant increase in the median survival of patients from the start of chemotherapy (18 + months for responders compared, to 7 months in nonresponders). Of 14 patients relapsing after a response or stabilization of disease of 6 months or greater, the cause of relapse was the development of cerebral metastases in 5 (36%). Two of these cases, one a patient with leiomyosarcoma and one with chondrosarcoma, were documented by autopsy and are reported in detail because of their rarity in the medical literature." [18]

"Eleven cases of brain metastases that developed in 114 sarcoma patients are presented. Two of 11 patients presented with brain metastasis at the time of diagnosis and the other nine developed them later. The high incidence of brain metastases in patients with rhabdomyosarcoma (26%) and malignant fibrous histiocytoma (27%), two types of tumor which supposedly metastasize rarely to the brain, is remarkable. The increased incidence of brain metastases may be related to longer survival of sarcoma patients and to the inability of AMN and other drugs used in the treatment of sarcomas to cross the blood-brain barrier. Preventive treatment of brain metastases with drugs active in the CNS or with radiotherapy following the diagnosis of pulmonary metastases, could be useful, especially in patients with rhabdomyosarcoma and malignant fibrous histiocytoma" [17]

"There may be a group of tumors, including malignant fibrous histiocytoma, rhabdomyosarcoma, and perhaps leiomyosarcoma and osteosarcoma, in which the incidence of brain metastases has increased with improved sarcoma chemotherapy (CT). In this group particularly, but also in alveolar soft-part sarcoma and others, the presence of lung metastases may increase the probability of brain metastasis occurring subsequently." [13]



"Since brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible". [5]

"In one series where sarcoma was surgically resected, one-year survival was 36% and 2-year survival was 18%. Three patients (12%) survived over 5 years. "[5]

"Out of 10 patients surgically treated, 8 patients survived more than 16 months. Median survival period after craniotomy was 25.4 months. ... We recommend aggressive treatment for those patients with brain metastases whose performance scores are over 70."[1]

"We report on 21 patients surgically treated for intraparenchymal brain metastasis from sarcoma, including ... four leiomyosarcomas, .... Median survival after craniotomy was 11.8 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 15.7 versus 6.6 months for those with a Karnofsky performance score < or = 70. Patients undergoing complete resection survived 14.0 versus 6.2 months for patients undergoing incomplete resection. Patients with evidence of lung metastases at the time of surgery survived 11.8 months, which was similar to the 10.5-month survival for patients with disease limited to the brain. .... We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from alveolar soft-part sarcoma may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis, whereas the presence of concurrent lung metastases is not a contraindication to surgery."[7]

"Of 480 sarcoma patients, 179 had distant metastases, including 20 patients with brain metastases (4.2%). ,,, Three patients underwent surgical treatment and two of them survived over 1 year. Mean survival after diagnosis of brain metastasis was 5.1 months".[2]

In a series of sarcoma brain metastases: "Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). ,,,". [3]
"...We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain ,,,. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery.[3]


Brain Metastases and Sarcoma

Annotated Citations



1. Surg Neurol 2000 Aug;54(2):160-4 
Brain metastasis in patients with sarcoma: an analysis of histological subtypes, clinical characteristics, and outcomes. 
Yoshida S, Morii K, Watanabe M, Saito T. Department of Neurosurgery, Niigata Cancer Center Hospital, Niigata, Japan. 

... We examined the incidence and the characteristics of brain metastasis in patients with sarcomas.  ...  All sarcoma patients treated at our institution from 1975 to 1998 were reviewed for brain metastasis.  ...   Brain metastasis was found in 27 (5.6%) of 480 patients with systemic sarcoma (7.2% soft part sarcoma, 3.5% bone sarcoma, 15.1% distant metastasis). Of these 27 sarcoma patients with brain metastases, lung metastasis occurred in 16 patients (59.3%). Out of 10 patients surgically treated, 8 patients survived more than 16 months. Median survival period after craniotomy was 25.4 months. ... We recommend aggressive treatment for those patients with brain metastases whose performance scores are over 70. PMID: 11077098  


2. Jpn J Clin Oncol 1999 May;29(5):245-7 
Brain metastases in musculoskeletal sarcomas. 
Ogose A, Morita T, Hotta T, Kobayashi H, Otsuka H, Hirata Y, Yoshida S. 
Department of Orthopaedic Surgery, Niigata Cancer Center Hospital, Japan. 

...In musculoskeletal sarcomas, brain metastases are rare, but severely affect quality of life. ... All patients with musculoskeletal sarcomas who were treated at our institutions from 1975 to 1997 were reviewed for examples of brain metastasis. 
...Of 480 sarcoma patients, 179 had distant metastases, including 20 patients with brain metastases (4.2%). Alveolar soft part sarcoma (3/4), extraskeletal Ewing's sarcoma (2/8), rhabdomyosarcoma (2/13) and bone Ewing's sarcoma (2/18) tended to metastasize to the brain. All 20 patients had distant or local relapses and 16 of the 20 patients had pulmonary metastases. Three patients underwent surgical treatment and two of them survived over 1 year. Mean survival after diagnosis of brain metastasis was 5.1 months...: Patients with alveolar soft part sarcoma, Ewing's sarcoma, rhabdomyosarcoma and pulmonary metastases have a high risk of brain metastasis. PMID: 10379335  



3. Surg Neurol 1998 Apr;49(4):441-4 
Sarcoma metastatic to the brain: a series of 15 cases. 
Salvati M, Cervoni L, Caruso R, Gagliardi FM, Delfini R. Department of Neurosurgery, Neurological Mediterranean Neuromed Institute, IRCCS, Pozzilli (IS), Italy. 

We report on 15 patients surgically treated for intraparenchymal brain metastases from sarcoma, including six osteosarcomas, five leiomyosarcomas, two malignant fibrous histiocytomas, and two alveolar soft-part sarcomas (ASPS). 
...Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). The two patients with alveolar soft-part sarcomas are alive at 15 and 20 months after surgery. 
...We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from ASPS may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery. PMID: 9537665 



4.Am J Clin Oncol 1996 Aug;19(4):351-5 
Late onset of isolated central nervous system metastasis of liposarcoma--a case report. 
Arepally G, Kenyon LC, Lavi E. 
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104, USA. 

Metastatic soft-tissue sarcoma of the central nervous system (CNS) is exceedingly rare,,,
 PMID: 8677903 


5. Chir Narzadow Ruchu Ortop Pol 1995;60(1):55-60 
[Surgical treatment of brain metastases from sarcoma]. [Article in Polish] 
Wronski M. Oddzialu Neurochirurgii Centrum Onkologii im. Sloana-Ketteringa w Nowym Jorku. 

Brain metastases from sarcoma are rare, and data concerning the treatment and results of therapy are sparse. ,,, Median time from primary diagnosis to diagnosis of brain metastasis was 26.7 months. Lung metastases were present in 21 patients (76%) (8 synchronous with the brain lesion). Pulmonary metastases were resected in 14 patients (50%). The overall median survival time from diagnosis of primary sarcoma was 38.8 months, and from craniotomy was 6.6 months. The presence or absence of lung lesion did not change the median survival calculated from diagnosis of brain metastasis (7 mos and 4.5 mos, respectively, p < 0.48, log-rank test). ,,,. One-year survival was 36% and 2-year survival was 18%. Three patients (12%) survived over 5 years. Since brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Brain metastases from sarcoma are uncommon and usually occur in association with or following lung metastasis. Long term survival is possible in a small percentage of patients. PMID: 7736836 


6.Gynecol Oncol 1994 Aug;54(2):237-41 
Leiomyosarcoma of the uterus metastatic to brain: a case report and a review of the literature. 
Wronski M, de Palma P, Arbit E. Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021. 

Central nervous system metastases are an unusual sequela of uterine sarcomas. ,,, Only seven other cases of uterus leiomyosarcoma metastatic to the brain have been published. Review of reported cases PMID: 8063254 


7. Neurosurgery 1994 Aug;35(2):185-90; discussion 190-1 
Sarcoma metastatic to the brain: results of surgical treatment. 
Bindal RK, Sawaya RE, Leavens ME, Taylor SH, Guinee VF. 
Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston. 

We report on 21 patients surgically treated for intraparenchymal brain metastasis from sarcoma, including ... four leiomyosarcomas, .... Median survival after craniotomy was 11.8 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 15.7 versus 6.6 months for those with a Karnofsky performance score < or = 70. Patients undergoing complete resection survived 14.0 versus 6.2 months for patients undergoing incomplete resection. Patients with evidence of lung metastases at the time of surgery survived 11.8 months, which was similar to the 10.5-month survival for patients with disease limited to the brain. The two patients with alveolar soft-part sarcoma are alive at 16 and 25 months after surgery. We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from alveolar soft-part sarcoma may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis, whereas the presence of concurrent lung metastases is not a contraindication to surgery. PMID: 7969824 


8. Neurosurgery 1994 Jan;34(1):168-70 
Metastatic alveolar soft part sarcoma presenting as a dural-based cerebral mass. 
Perry JR, Bilbao JM. 
Division of Neurology, St. Michael's Hospital, Toronto, Ontario, Canada. 

Sarcoma metastatic to the brain is uncommon and rarely occurs as the initial manifestation of tumor. ....   PMID: 8121554 




9. Br J Radiol 1993 Nov;66(791):1009-15 
Survival, patterns of spread and prognostic factors in uterine sarcoma: a study of 76 patients. 
Moskovic E, MacSweeney E, Law M, Price A. 
Department of Radiology, Royal Marsden Hospital, London, UK. 

We have analysed the medical records and diagnostic imaging of 76 patients presenting to this hospital for treatment of uterine sarcoma between 1970 and 1990. ,,, Bone and brain metastases were uncommon (< 10%). Following diagnosis of relapse, the median survival was 9 months, with the outcome significantly worse if multiple metastatic sites were involved (p < 0.001). No survival benefit was demonstrated from either local radiotherapy or combination chemotherapy once relapse had occurred. Prognostic factors and current policies for the diagnosis and management of uterine sarcomas are discussed. PMID: 8281375 



10.  J Heart Lung Transplant 1993 May-Jun;12(3):527-30 
Heart transplantation for cardiac angiosarcoma: should its indication be questioned? 
Crespo MG, Pulpon LA, Pradas G, Serrano S, Segovia J, Vegazo I, Salas C, Espana P, Silva L, Burgos R, et al. 
Heart Transplant Unit, Clinica Puerta de Hierro, Madrid, Spain. 
Two men, aged 31 and 32 years, respectively, underwent orthotopic heart transplantation, in both cases to treat primary cardiac angiosarcoma of the right atrium. Total removal of the tumor was performed, and no evidence was found of distant dissemination at the time of surgery. Their postoperative progress was good; however, the patients died 8 and 9 months after transplantation, respectively, of multiple brain metastases. We do not consider heart transplantation to be indicated in the management of malignant cardiac tumors. PMID: 8329433 


11. Thorac Cardiovasc Surg 1992 Feb;40(1):48-51 
Leiomyosarcoma of the pulmonary hilar vessels. 
Berney CR, Roche B, Kurt AM, Spiliopoulos A, Megevand R. 
Institute of Pathology, University Hospital, Geneva, Switzerland. 
PMID: 1631867 


12. Cancer 1989 Mar 1;63(5):935-8 
Patterns of metastasis in uterine sarcoma. An autopsy study. 
Rose PG, Piver MS, Tsukada Y, Lau T. 
Department of Gynecologic Oncology, Roswell Park Memorial Institute, Buffalo, NY 14263. 
The autopsy findings of 73 patients with uterine sarcoma were studied to determine the sites and possible modes of metastasis. Homologous mixed mesodermal tumors were the most frequent (41%) followed by leiomyosarcoma (26%), heterologous mixed mesodermal tumor (18.3%), stromal sarcoma (12%), and endolymphatic stromal myosis (3%). The peritoneal cavity and omentum were the most frequently involved sites (59%), followed by the lung (52%), pelvic lymph nodes (41%), paraaortic lymph nodes (38%), and liver parenchyma (34%). The presence of lung metastasis was not associated with pelvic or paraaortic node metastasis or intraperitoneal disease. Metastasis to other distant sites including the brain, heart, kidney, and bone were independent of pelvic and paraaortic nodal metastasis or intraperitoneal disease. Metastatic sites were not different among various histologic types. Distant metastatic sites were statistically associated with lung metastasis. Hematogenous metastasis best explains this metastatic pattern and adjuvant systemic therapy seems indicated. PMID: 2914299 


13. Cancer 1988 Feb 1;61(3):593-601 
Sarcoma metastatic to the brain. Lewis AJ. 
Department of Pathology, University of Toronto, Ontario, Canada. 

,,, Reportedly, most types of sarcomas are able to metastasize to the brain, and are represented in these 94 patients. ,,, There may be a group of tumors, including malignant fibrous histiocytoma, rhabdomyosarcoma, and perhaps leiomyosarcoma and osteosarcoma, in which the incidence of brain metastases has increased with improved sarcoma chemotherapy (CT). In this group particularly  ,,, the presence of lung metastases may increase the probability of brain metastasis occurring subsequently. Review, multicase PMID: 3276383 



14. Med Pediatr Oncol 1985;13(5):280-92 
Sarcoma metastatic to the central nervous system parenchyma: a review of the literature. 
Sarno JB, Wiener L, Waxman M, Kwee J. 
Sarcoma metastatic to cerebral parenchyma, although rare, occurs more frequently than generally recognized. With increased duration of survival due to multi-modal therapy, more CNS metastases are being found. ,,,. Publication Types: Bibliography PMID: 3897818 

15. Cancer 1985 Mar 15;55(6):1382-8 
Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. 
Sundaresan N, Galicich JH. 
PMID: 3971308 


16. Arch Surg 1983 Aug;118(8):915-8 
Metastatic patterns in soft-tissue sarcomas. 
Vezeridis MP, Moore R, Karakousis CP. 

In 242 patients with recurrent soft-tissue sarcomas, the most common sites of initial recurrence were the primary site in 47.5% of patients and the lungs in 38% of patients. Further recurrences in the course of the disease concerned the lungs, bones, liver, and brain. Total survival and survival after recurrence were influenced by the histologic type, which also affected the site of recurrence. In the management of local recurrence, a five-year disease-free survival rate of 38% was achieved with surgical treatment, while radiation or chemotherapy alone was ineffective. Local recurrences resulted in significantly higher survival rates than those involving other organs. The disease-free interval was a significant prognostic indicator of subsequent survival in the whole group of patients and among those with local recurrence. PMID: 6307217 

17. Cancer 1980 Jan 15;45(2):377-80 
Increased incidence of brain metastases in sarcoma patients. 
Espana P, Chang P, Wiernik PH. 

Eleven cases of brain metastases that developed in 114 sarcoma patients are presented. Two of 11 patients presented with brain metastasis at the time of diagnosis and the other nine developed them later. The high incidence of brain metastases in patients with rhabdomyosarcoma (26%) and malignant fibrous histiocytoma (27%), two types of tumor which supposedly metastasize rarely to the brain, is remarkable. The increased incidence of brain metastases may be related to longer survival of sarcoma patients and to the inability of AMN and other drugs used in the treatment of sarcomas to cross the blood-brain barrier,,, PMID: 6243247 



18. Cancer 1975 Nov;36(5):1843-51 
Increased incidence of cerebral metastases in sarcoma patients with prolonged survival from chemotherapy. Report of cases of leiomyosarcoma and chondrosarcoma. 
Gercovich FG, Luna MA, Gottlieb JA.
 
Soft tissue and bony sarcomas rarely metastasize to the central nervous system, particularly to the cerebral hemispheres. In 456 patients with metastatic sarcoma, only 6 (1.3%) had cerebral metastases documented by brain scan at the time of referral for chemotherapy. Adriamycin-containing combination chemotherapeutic regimens have led to a significant increase in the median survival of patients from the start of chemotherapy (18 + months for responders compared, to 7 months in nonresponders). Of 14 patients relapsing after a response or stabilization of disease of 6 months or greater, the cause of relapse was the development of cerebral metastases in 5 (36%). ,,,. Although the numbers are small, the increased incidence of cerebral metastases in the group relapsing after a lengthy response suggests that improved chemotherapy for sarcomas resulting in improved survival may be changing the pattern of metastatic disease, and may require new therapeutic approaches. PMID: 1192369 


~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~`


Neurosurgery


Brain metastases from sarcoma are uncommon, usually occurring with or after lung metastasis.
Because brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Surgery is effective in treating selected patients with sarcoma metastatic to the brain. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery. Long-term survival is possible in some patients. [1,2, 3, 4]

~~~~~~~~~~~~~~~~~~~~~~~~
For the latest studies, do the searches:

Pubmed Search for Surgery and Leiomyosarcoma Brain Metastases
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=surgery%20AND%20brain%20metastases%20AND%20leiomyosarcoma

Pubmed Search for Surgery and Sarcoma Brain Metastases
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=surgery%20brain%20metastases%20sarcoma 


~~~~~~~~~~~~~~~~~~~~~~~

References for Neurosurgery

1. Surg Neurol 1998 Apr;49(4):441-4 
Sarcoma metastatic to the brain: a series of 15 cases. 
Salvati M, Cervoni L, Caruso R, Gagliardi FM, Delfini R. Department of Neurosurgery, Neurological Mediterranean Neuromed Institute, IRCCS, Pozzilli (IS), Italy. 

"...We report on 15 patients surgically treated for intraparenchymal brain metastases from sarcoma, including six osteosarcomas, five leiomyosarcomas, two malignant fibrous histiocytomas, and two alveolar soft-part sarcomas (ASPS)."
"...Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). The two patients with alveolar soft-part sarcomas are alive at 15 and 20 months after surgery."
"...We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from ASPS may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery."  PMID: 9537665 


2. Ann Surg Oncol 1995 Sep;2(5):392-9 
Resection of brain metastases from sarcoma. 
Wronski M, Arbit E, Burt M, Perino G, Galicich JH, Brennan MF. 
Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 

"... Brain metastases from sarcoma are rare, and data concerning the treatment and results of therapy are sparse. ... We retrospectively reviewed 25 patients with brain metastases from sarcoma of skeletal or soft-tissue origin, surgically treated in a single institution during 20 years." "... In 18 patients the brain lesion was located supratentorially, and in 7 patients infratentorially. Median age at brain metastasis diagnosis was 25 years. Median time from primary diagnosis to diagnosis of brain metastasis was 26.7 months. Lung metastases were present in 19 patients and in 8 patients they were synchronous with the brain lesion. Pulmonary metastases were resected in 12 patients (48% of total, and 63% of those with pulmonary lesions). The overall median survival from diagnosis of the primary sarcoma was 38 months and from craniotomy was 7 months. The presence or absence of lung lesions did not alter the median survival as calculated from diagnosis of brain metastasis. Overall percent survival was 40% at 1 year and 16% at 2 years." 
"...Because brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Brain metastases from sarcoma are uncommon, usually occurring with or after lung metastasis. Long-term survival is possible in some patients." PMID: 7496833 


3. Gynecol Oncol 1994 Aug;54(2):237-41 
Leiomyosarcoma of the uterus metastatic to brain: a case report and a review of the literature. 
Wronski M, de Palma P, Arbit E. Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021. 

Central nervous system metastases are an unusual sequela of uterine sarcomas. A single brain metastasis from a leiomyosarcoma occurred in a 60-year-old woman, 6.5 years after hysterectomy and more than 2 years following the diagnosis of bilateral lung metastases, treated by combination chemotherapy. 
After resection of the cerebral metastasis, she was treated with brain radiation therapy and survived 2.5 years. Only seven other cases of uterus leiomyosarcoma metastatic to the brain have been published. Review of reported cases PMID: 8063254 




4. Neurosurgery 1994 Aug;35(2):185-90; discussion 190-1 
Sarcoma metastatic to the brain: results of surgical treatment. 
Bindal RK, Sawaya RE, Leavens ME, Taylor SH, Guinee VF. 
Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston. 

We report on 21 patients surgically treated for intraparenchymal brain metastasis from sarcoma, including six osteosarcomas, four leiomyosarcomas, three malignant fibrous histiocytomas, two alveolar soft-part sarcomas, two Ewing's bone sarcomas, one extraskeletal osteosarcoma, one extraskeletal Ewing's sarcoma, and two unclassified sarcomas. Median survival after craniotomy was 11.8 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 15.7 versus 6.6 months for those with a Karnofsky performance score < or = 70. Patients undergoing complete resection survived 14.0 versus 6.2 months for patients undergoing incomplete resection. Patients with evidence of lung metastases at the time of surgery survived 11.8 months, which was similar to the 10.5-month survival for patients with disease limited to the brain. The two patients with alveolar soft-part sarcoma are alive at 16 and 25 months after surgery. We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from alveolar soft-part sarcoma may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis, whereas the presence of concurrent lung metastases is not a contraindication to surgery. PMID: 7969824 

5. Cancer 1985 Mar 15;55(6):1382-8 
Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. 
Sundaresan N, Galicich JH. 

The results of treatment of brain metastases in a series of 125 patients who underwent surgery with or without postoperative radiation from 1978 through 1982 were analyzed. The major sites of primary tumor included the lung (40%), melanoma-skin (11%), kidney (11%), colon (8%), soft tissue sarcoma (8%), breast (6%), and a variety of others (15%). At the time of craniotomy, disease was considered limited to the central nervous system in 63 patients (50%). After surgery, 83 patients (66%) were neurologically improved, and 26 (21%) had their deficits stabilized. The overall median survival was 12 months, and 25% lived 2 years. Eight patients (12%) are alive 5 years or more following surgery. Survival varied with site of primary tumor, location of brain metastasis, extent of systemic disease, and neurologic deficit at time of craniotomy. Over a follow-up period ranging from 18 months to 6 years, 42 patients (34%) developed either local recurrences or other sites of brain metastases. These data suggest that although craniotomy followed by radiation is highly effective in the initial treatment of selected patients with brain metastases, alternate therapies require investigation in view of the high central nervous system relapse rate in long-term survivors. PMID: 3971308 



Irradiation

Brain metastases are often irradiated with focused beams, as in the gamma knife or cyber knife or radiosurgery, and sometimes the whole brain is irradiated with a diffuse beam to prophylactically prevent further metastases from growing.

One of the toxic and late effects of brain irradiation is Cerebral Radiation Necrosis.

With radiation necrosis of the brain, MRI scans show the progressive deterioration of white matter.  Late delayed effects, occurring several months to many years later, are classified into diffuse white-matter injury, radiation-induced arteriopathy & stroke, with associated death of brain tissue. These reactions are due to death of brain tissue caused by radiation-damaged blood vessels. 
Cerebral Radiation Necrosis generally occurs a few months to years after radiation therapy. Symptoms include decreased intellect, memory impairment, confusion, personality changes and alteration of the normal function of the area irradiated.  

Memory impairment, fine motor coordination, and other difficulties in thinking and functioning are not unusual after irradiation.  These symptoms were related to the total dose of the radiation delivered.
: 


Cerebral Radiation Necrosis

Annotated References

J Radiol 2002 Nov;83(11):1749-57
    
        [CT and MRI aspects of 28 patients with cerebral radiation necrosis 
        irradiated for ORL tumors: correlation with the radiation technique] 
        [Article in French]

         ...To describe and correlate with radiation therapy the occurrence 
        of cerebral radiation necrosis in patients irradiated for nasopharyngeal 
        or ethmoidal tumor. ... From 1986 to 1998, 1 201 patients... 
        were treated by radiotherapy. Twenty-eight developed cerebral necrosis. 
         ... The incidence of cerebral radionecrosis was 2.33%. The time interval 
        between treatment and necrosis ranged from 2 months to 9 years. ...
      . Lesions were localized ... The doses related to the areas of necrosis ranged from 13 to 
        135Gy. In 2 cases necrosis was situated at the boundaries of the 
        radiation field. Imaging follow-up showed complete (n=3) or incomplete 
        remission (n=1), lesion progression (n=11), cerebral atrophy (n=5) and 
        stability (n=7). ...New technologies may reduce the incidence of this complication.
        PMID: 12469012   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12469012&dopt=Abstract



Ann Dermatol Venereol 2002 Jan;129(1 Pt 1):41-5
                        
        [Delayed cerebral radionecrosis following radiation therapy of cutaneous 
        squamous cell carcinomas of the head]         [Article in French]

         ... Little is known of cerebral radionecrosis following radiotherapy. 
        This may be related to their rare 
        occurrence and/or to the difficulties in establishing diagnosis. The 
        delay of occurrence after radiotherapy can vary between a few months and 
        several years, and the lesions are directly correlated with the doses 
        and the fractioning of the X-rays. Intracerebral localization of the 
        tumour is the main differential diagnosis. Localized and cystic forms of 
        cerebral radionecrosis can be treated by surgery. Treatment otherwise 
        relies on systemic steroids.
        PMID: 11937928  
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11937928&dopt=Abstract


 Eur J Radiol 2001 Sep;39(3):133-8
       
        Late temporal lobe necrosis in patients with nasopharyngeal carcinoma: 
        evaluation with combined multi-section diffusion weighted and perfusion 
        weighted MR imaging.

        Late temporal lobe necrosis is a well-known and serious complication in 
        patients with nasopharyngeal carcinoma (NPC) following radiotherapy. 
        Owing to the close proximity to the skull base, the medial temporal 
        lobes are inevitably included in the target volume of irradiation. 
        ...Since late temporal lobe necrosis is probably caused by 
        damage of the endothelium of vessels and ischemia, perfusion and 
        diffusion mismatch might imply injured tissue but potentially 
        salvageable brain tissue. ...
        PMID: 11566238 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11566238&dopt=Abstract 



J Neurooncol 2001 Jan;51(2):143-50

        Acute hemorrhage in late radiation necrosis of the temporal lobe: report 
        of five cases and review of the literature.

        Hemorrhage in late cerebral radiation necrosis is a rare complication 
        after radiotherapy ...
        In a review of the literature, the authors identified a total of 27 such 
        cases. The interval period between the onset of hemorrhage and cranial 
        irradiation is long (mean = 7.8 years). The most prominent histological 
        feature was the proliferation of large, dilated and thin-walled new 
        blood vessels in a background of gliosis and fibrinoid necrosis of 
        vessels. Rupture of these thin-walled new blood vessels is the proposed 
        mechanism of hemorrhage in this condition.
        PMID: 11386411 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11386411dopt=Abstract 
     

Int J Radiat Oncol Biol Phys 2000 Jan 1;46(1):51-5 

        Neurocognitive effects of therapeutic irradiation for base of skull 
        tumors.

         ... Nineteen patients who received paranasal sinus irradiation at 
        least 20 months and up to 20 years before assessment were given a 
        battery of neuropsychologic tests of cognitive function,,,
      . The median radiation dose was 60 Gy (range 50-68 Gy) in 
        fractions of 1.8 to 2 Gy. 
        
        ... Memory impairment was found in 80% of the patients, and 
        one-third manifested difficulty with visual-motor speed, frontal lobe 
        executive functions, and fine motor coordination. Two of the patients 
        had frank brain necrosis with resultant dementia and blindness, and 
        three had evidence of brain atrophy. Three of the fourteen patients 
        without documented cerebral atrophy or necrosis were disabled from their 
        normal activities. Three patients also developed pituitary dysfunction. 
        Neurocognitive symptoms were related to the total dose of radiation 
        delivered but not to the volume of brain irradiated, side of radiation 
        boost, or chemotherapy treatment. The pattern of test findings was 
        consistent with radiation injury to subcortical white matter. 

        ... Radiation therapy for paranasal sinus cancer may cause 
        delayed neurocognitive side effects. Currently, however, the development 
        of severe adverse effects appears to be decreasing because of 
        improvements in the techniques used to deliver radiation. Lowering the 
        total dose and improving dose distributions should further decrease the 
        incidence of delayed brain injury due to radiation. 
        PMID: 10656372 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10656372&dopt=Abstract





Whole Brain Irradiation for Treatment of Brain Mets


Whole brain irradiation is meant to decrease growth of more metastases, prophylactically.
It can increase survival time.

However, there are symptoms from its use. "Early toxicity consisted of headache, nausea, fatigue, concentration problems and alopecia. These symptoms and signs were mild and usually reversible within a few months. Late toxicity was studied in patients whose survival exceeded two years." Seven of the prophylactically irradiated survived for more than two years, while no control patients survived for more than two years. "Memory problems were seen in six of the seven patients. These problems were non-disabling and, once established, remained stable for months to years. The most prominent radiologic abnormalities were cortical atrophy and leukoencephalopathy, found in four of the five patients who underwent radiologic follow-up examination. "J Neurooncol 1997 Nov;35(2):153-60

"In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection ,,,"  Acta Neurochir (Wien) 1994;131(1-2):91-6

~~~~~~~~~~~~~~~

Whole Brain Irradiation

Annotated Citations


Radiology 1999 Sep;212(3):755-9 
Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging: preliminary results in brain metastases. 

Viala J, Vanel D, Meingan P, Lartigau E, Carde P, Renschler M. Department of Radiology, Institut Gustave-Roussy, Villejuif, France. 

PURPOSE: ,,,, , and to determine an appropriate intravenous dose of gadolinium texaphyrin [a tumor-selective radiation sensitizer that is detectable at MR imaging ],,, and the response to treatment. 

MATERIALS AND METHODS: Ten daily intravenous injections of gadolinium texaphyrin, each followed by whole-brain radiation therapy (total of 10 fractions, 30 Gy), were administered to patients with brain metastases in a multicenter study. ,,, 

RESULTS: MR imaging revealed selective drug uptake in metastases, without enhancement of normal brain tissue. In 10 patients, tumor uptake was higher after the 10th injection than after the first injection, which indicated accumulation of gadolinium texaphyrin in metastases. One lesion was visible only after the 10th injection ,,,. Response to treatment was defined as a reduction in the size of the metastases ,,,; seven patients achieved partial remission with tumor regression exceeding 50% of the initial size, and four achieved a minor response with less than 50% tumor regression. CONCLUSION: These preliminary results indicate that gadolinium texaphyrin is tumor selective and that brain metastases can be depicted at MR imaging long after the administration of gadolinium texaphyrin. Publication Types: Clinical trial Clinical trial, phase i Clinical trial, phase ii Multicenter study PMID: 10478243 


Radiother Oncol 1998 Jan;46(1):29-32 
Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study. 
Postmus PE, Haaxma-Reiche H, Gregor A, Groen HJ, Lewinski T, Scolard T, Kirkpatrick A, Curran D, Sahmoud T, Giaccone G. Free University Hospital Amsterdam, The Netherlands. 
BACKGROUND AND PURPOSE: To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer. 
PATIENTS AND METHODS: The patients had brain metastases of small cell lung cancer without any sign of tumour outside the brain and were treated with 10 x 3.0 Gy WBRT. ,,,. 
RESULTS: Twenty ,,, patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% ,,,. Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function. 
CONCLUSION: WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short. Publication Types: Clinical trial, phase ii Multicenter study PMID: 9488124 


Radiother Oncol 1997 Oct;45(1):17-22 
Accelerated radiotherapy for brain metastases. 

Nieder C, Nestle U, Niewald M, Schnabel K. Department of Radiotherapy, University Hospital, Homburg/Saar, Germany. 

BACKGROUND AND PURPOSE: Two novel fractionation schedules for whole-brain irradiation were applied to patients with brain metastases. Both schedules were aimed at reduction of treatment time, whereby tumour control should be increasing with the application of a higher total dose (schedule 2). 
MATERIALS AND METHODS: We applied 2 x 2.5 Gy/day to a total dose of 30 Gy (schedule 1) or 2 x 1.8 Gy/day to a total dose of 50.4 Gy (schedule 2) ,,,The 30 Gy schedule was also used in adjuvant treatment for resected brain metastases. We compared the results of 15 patients who underwent the 50.4 Gy schedule and 47 patients who were treated up to 30 Gy with those of a historical patient group, treated with one daily fraction of 3 Gy up to 30 Gy (n = 283). 

RESULTS: Local result, clinical course and survival were similar for the 30 Gy groups, whereby prognostic factors were equally distributed. Despite a favourable patient selection no therapeutic gain was seen for the 50.4 Gy group. Patients treated with the accelerated 30 Gy schedule had a significantly worse progression-free survival and a higher rate of late radiation toxicity than the historical group. In contrast, no severe acute toxicity was observed. 
CONCLUSIONS: Considering progression-free survival and late toxicity, the accelerated 30 Gy schedule cannot be recommended ,,,. Radiotherapy with a higher total dose (50.4 Gy) showed no advantage. Publication Types: Clinical trial Controlled clinical trial 
PMID: 9364627 


J Neurooncol 1997 Nov;35(2):153-60 
Efficacy and safety of prophylactic cranial irradiation in patients with small cell lung cancer. 

van de Pol M, ten Velde GP, Wilmink JT, Volovics A, Twijnstra A. Department of Neurology, University Hospital Maastricht, The Netherlands. 

BACKGROUND: Prophylactic cranial irradiation (PCI) as part of the treatment regimen for patients with limited stage small cell lung cancer (SCLC) remains controversial. ,,,
PATIENTS AND METHODS: Between 1983 and 1993, thirty-nine patients with limited stage SCLC who had shown complete remission after chemotherapy were enrolled prospectively into the non-randomized study. Eighteen of them received PCI (PCI+), while 21 did not (PCI-). Pretreatment CT or MRI of the brain was performed in all patients. Patients were prospectively evaluated by a neurologist at regular intervals. 
RESULTS: ,,, The frequencies of brain metastases were not significantly different between the groups (Fisher's exact test, p = 0.207), but brain metastases in PCI+ patients tended to occur later (log rank, p = 0.008). Overall survival was significantly longer in PCI+ patients (log rank, p &lt; 0.001). Early toxicity consisted of headache, nausea, fatigue, concentration problems and alopecia. These symptoms and signs were mild and usually reversible within a few months. Late toxicity was studied in patients whose survival exceeded two years. Seven PCI+ patients survived for more than two years, while no PCI- patients survived for more than two years. Memory problems were seen in six of the seven patients. These problems were non-disabling and, once established, remained stable for months to years. The most prominent radiologic abnormalities were cortical atrophy and leukoencephalopathy, found in four of the five patients who underwent radiologic follow-up examination. 
CONCLUSIONS: This non-randomized study suggests that PCI may be effective by decreasing the frequency of brain metastases and by increasing the brain metastasis-free survival and overall survival, with a minor risk of clinical and radiologic neurotoxicity. Publication Types: Clinical trial PMID: 9266453  




Am J Clin Oncol 1997 Apr;20(2):158-60 
The role of hyperfractionated re-irradiation in metastatic brain disease: a single institutional trial. 

Abdel-Wahab MM, Wolfson AH, Raub W, Landy H, Feun L, Sridhar K, Brandon AH, Mahmood S, Markoe AM. Department of Radiation Oncology, University of Miami School of Medicine, Florida 33136, U.S.A. 

Progression of brain metastases after brain irradiation has prompted several studies on retreatment of the brain. Increased durations of survival and improved quality of life have been reported. 
Fifteen patients with previously treated brain metastases were entered into this pilot study between May 1990 and January 1994. All patients had neurologic and/or radiologic evidence of progression of brain metastases. ,,, The median interval between the first treatment and retreatment was 10 months. All patients received whole-brain irradiation with or without a boost for their initial treatment course. Doses ranged from 3,000 to 5,500 cGy for initial treatments (median, 3,000). Retreatment consisted of limited fields with a median side equivalent square of 8.8 cm. Patients were retreated with a median dose of 3,000 cGy (range, 600-3,000 cGy). A median cumulative dose of 6,000 cGy was achieved. 

,,, Retreatment was tolerated without serious complications. Of the 15 patients treated, nine (60%) experienced improvement, and five (27%) had stabilization of neurologic function and/or radiographic parameters. Median survival was 3.2 months; two of the reirradiated patients survived >or = 9 months.

In conclusion, reirradiation is a viable option in patients with recurrent metastatic lesions of the brain, and the use of a limited retreatment volume makes this a well-tolerated, low-morbidity treatment that leads to clinical benefits and, in some instances, enhanced survival. The influence of hyperfractionation on the outcome needs to be investigated further in large series. Publication Types: Clinical trial PMID: 9124191 

~~~~~

Acta Neurochir (Wien) 1994;131(1-2):91-6 
New treatment protocol by intra-operative radiation therapy for metastatic brain tumours. 
Nakamura O, Matsutani M, Shitara N, Okamoto K, Kaneko M, Nakamura H, Asai A, Ueki K, Shimizu T, Tanaka Y, et al. Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Japan. 

In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection ,,, PMID: 7709790 

~~~~~~~~~~~~~~~~


Gamma Knife  & Stereotactic Radiosurgery 

These are all attempts to focus the beam so that the Xrays or Gamma rays are kept tightly to the contours of the tumor, and do less scattering through normal tissue.  It is impossible with this modality to completely spare normal tissue from any exposure to radiation, but it does help preserve tissue.


~~~~~~~~~~~~~~~~~~~~

Radiosurgery

Annotated Citations


Gamma Knife


Stereotact Funct Neurosurg 2000;74(1):37-51 

Gamma knife radiosurgery for the treatment of brain metastases. 

Sansur CA, Chin LS, Ames JW, Banegura AT, Aggarwal S, Ballesteros M, Amin P, Simard JM, Eisenberg H. 
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. 

One hundred and ninety-three patients with brain metastases from various primary sites received Gamma Knife radiosurgery (GKR) from July 1992 to August ,,, Survival follow-up was available on 173 patients. Whole-brain radiation therapy was also administered to 148 of these patients. The median survival was 13.1 months from initial detection of brain metastases, and 7.5 months from GKR. Univariate and multivariate analyses were performed to determine prognostic factors that influenced survival following GKR. Enhanced survival is observed in patients with radiosensitive tumor types, supratentorial tumor, history of brain tumor resection, controlled primary site, and absent extracranial metastases. Local lesion control was obtained in 82% of the patients according to their last follow-up MRI scan. GKR is an effective means of treating patients with brain metastases. Copyright 2000 S. Karger AG, Basel [permission to use abstract] PMID: 11124663  


Stereotactic Radiosurgery

J Clin Oncol 1990 Apr;8(4):576-82 Comment in: J Clin Oncol. 1990 Apr;8(4):571-3 
The treatment of recurrent brain metastases with stereotactic radiosurgery. 

Loeffler JS, Kooy HM, Wen PY, Fine HA, Cheng CW, Mannarino EG, Tsai JS, Alexander E 3rd. 
Neurosurgical Service, Brigham and Women's Hospital, Boston, MA. 

,,, To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. ,,, With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy. PMID: 2179476 



Neurochirurgie 1999 Dec;45(5):393-7 
[Radiosurgery for brain metastases]. [Article in French] 
Nataf F. Service de Neurochirurgie, CH Sainte-Anne, 1, rue Cabanis, 75674 Paris Cedex 14, France. 

This article presents the state of art in radiosurgery as a new therapeutic strategy of brain metastases. Radiosurgery of brain metastases is ten years old and we propose to make an update of the literature. X-rays and gamma-rays are commonly used for radiosurgery and does not make a difference for dosimetry and precision. Selected patients for this treatment have usually good Karnofsky status and the mean size of their metastases is about 20 mm. Mean number of metastases treated in the same procedure is 2. Most frequent primary sites are lung and breast, but also kidney and skin (malignant melanoma) which are supposed to be radioresistant and so often untreatable by other techniques. Usual dose administrated ranges between 15 and 25 Grays in center of target with a 80% isodose in peripheral. Results are quite good for local control (80% to 100%) but survival does not seem to be improved (11 months). Radiation complication rate is 4% and sometimes hemorrhagic complications occur (1 to 2%). For local control, quality of life and cost/benefit ratio, there are strong arguments in favor of radiosurgery, especially for radioresistant metastases in spite of the lack of improvement of survival duration. Moreover published studies do not allow any comparison with efficacy of surgery and radiosurgery, whole brain radiosurgery and radiosurgery of the present metastases. Evaluations are still going on in several centers. Their results will allow more precise indications of this technique. Publication Types: Review tutorial PMID: 10717588 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Intraoperative Radiation for Brain Mets


Acta Neurochir (Wien) 1994;131(1-2):91-6 
New treatment protocol by intra-operative radiation therapy for metastatic brain tumours. 

Nakamura O, Matsutani M, Shitara N, Okamoto K, Kaneko M, Nakamura H, Asai A, Ueki K, Shimizu T, Tanaka Y, et al. Department of Neurosurgery, Tokyo Metropolitan Komagome Hospital, Japan. 

In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection. 

Among 43 patients, 19 patients who had no metastases other than the brain metastases, were chosen as subjects for active treatment (surgical resection+IOR). Their 1-year survival rate was 75%. Fourteen out of 27 patients with brain metastases from lung cancer received active treatment and their 1-year survival rate was 74%. This result was not inferior to our result of 71 patients who received surgical resection and whole brain irradiation. 

When no preventive whole brain irradiation was performed, patients were observed every 8 weeks by CT scan in order to ascertain tumour recurrence limited to the treated site or appearance of any new metastatic lesion remote from the treated site. Among all 43 patients, local recurrence was recognized in 7 cases and remote recurrence was observed in 7 cases. Within 6 months, local and remote recurrence was found in 3 cases each. These results were almost the same as those for the usual therapy (surgery plus whole brain irradiation). If such a new lesion is detected, additional radiation can be performed with the possibility of achieving complete remission. PMID: 7709790  


~~~~~~~~~~~~


Radioisotope

16 MAY 2001 Wake Forest University Baptist Medical Center. 
Wake Forest first in world to perform new brain tumor treatment 
WINSTON-SALEM, N.C. - Physicians at Wake Forest University Baptist Medical Center are the first in the world to treat a brain tumor patient with the newly FDA-approved GliaSite" Radiation Therapy System (RTS). The GliaSite RTS delivers site-specific, internal radiation to malignant brain tumors, treating the target area while minimizing exposure to healthy tissue. 

Stephen B. Tatter, M.D., Ph.D., assistant professor of neurosurgery at Wake Forest University School of Medicine, said "GliaSite represents an important new treatment option for malignant brain tumors. Until now, treatment for patients with recurrent brain tumors has been extremely limited. Radiation combined with surgery is the single most effective treatment, and the GliaSite RTS will enable these patients to receive additional radiation, while minimizing the risks associated with external beam radiation." 

The device is a balloon catheter that is inserted into the cavity created by surgical removal of the malignant brain tumor and filled with liquid radiation. Over a course of three to seven days, GliaSite delivers radiation directly to the tissue surrounding the cavity, where tumors are most likely to recur. ,,,
Traditionally, patients are first treated with external beam radiation therapy, in which the radiation travels from outside the body to the tumor site, passing through healthy brain tissue. While this treatment is proven to delay tumor regrowth, a second course of external beam radiation is rarely an option due to the high risk of damage to healthy tissue. 

"It's a significant advancement to be able to offer an improved therapy that delivers radiation directly to the site of the cancer, while maintaining the quality of life for patients by completing the treatment in just one week," said Tatter. In addition, study results suggest that the survival rate of these patients is favorable in comparison to the next best secondary treatment, which is surgery plus chemotherapy wafers. 

Safety and performance of the device were demonstrated in a National Cancer Institute (NCI)-sponsored, multi-centered study. Tatter was the principal investigator for the national study, which involved patients with recurrent brain tumors. All of the patients had undergone previous surgery and radiation therapy, and more than half had received chemotherapy. The median survival rate of the patients is currently 14 months, with patients still being followed, a substantial improvement over the results historically seen with other treatments. 

Additionally, GliaSite has the potential to be used in combination with external beam radiation when treating newly diagnosed tumors, and there is substantial interest in using the device in combination with surgical removal of metastatic brain tumors. The GliaSite RTS was developed by Proxima Therapeutics Inc., a Georgia-based developer and marketer of site-specific cancer treatments. 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~


Proton Beam Therapy for Brain Tumors 


Sometimes proton beam irradiation works well. This is a focal radiation treatment. It is much more focused than other beamed radiation, so there is less damage and late effects to surrounding tissues. Proton radiotherapy is an alternative to conventional X-ray radiation therapy, both of which are used to kill cancer cells and other rogue tissue.
Unlike X-rays, however, proton radiation does not do significant damage to the healthy cells around a cancerous growth. 
Proton beam is an ideal way to deliver radiation to an LMS tumor.  The Braggs Peak of energy dispersed means there is an intense increase of radiation just about at the edge of the target...which is excellent for LMS as it fries the tendrils.

*********
Current Opinion in Orthopaedics 2002; 13(6):434-439
Proton beam therapy in the management of bone and soft tissue sarcomas
Thomas F. DeLaney, MD

For cancer treatment, protons, the nuclei of hydrogen atoms, can be
accelerated to high energies, extracted, and transported to treatment rooms
where the proton beam undergoes a series of modifications (spreading,
modulation, and shaping) that conform the dose in a particular patient to
the tumor target. Because of their charge and mass, there is no dose
delivered beyond the desired target. Proton beam therapy thus provides a
means to reduce both the volume of irradiated normal tissues and the
radiation dose they receive. This may permit higher doses to the tumor and
achieve a higher tumor control probability without increasing the frequency
or severity of treatment-related morbidity. Additionally, the more conformal
treatment volumes of proton therapy should result in a reduced frequency and
severity of comorbidity between radiation and chemotherapy, thus allowing
for improved tolerance of the patient to therapy, better treatment
compliance, and increased treatment intensity.

******************

For more information on this technique, see Proton Beam Therapy in the section Metastatic Disease -Techniques



Neutron Therapy 

~~~~~~~~~~~~~~

Boron Neutron Capture

Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):209-18
                       
        Boron neutron capture therapy of brain tumors: enhanced survival and 
        cure following blood-brain barrier disruption and intracarotid injection 
        of sodium borocaptate and boronophenylalanine.

        Barth RF, Yang W, Rotaru JH, Moeschberger ML, Boesel CP, Soloway AH, 
        Joel DD, Nawrocky MM, Ono K, Goodman JH.
        Department of Pathology, The Ohio State University, Columbus, OH, USA. 
        barth.1@osu.edu

        PURPOSE: Boronophenylalanine (BPA) and sodium borocaptate 
        (Na(2)B(12)H(11)SH or BSH) have been used clinically for boron neutron 
        capture therapy (BNCT) of high-grade gliomas. These drugs appear to 
        concentrate in tumors by different mechanisms and may target different 
        subpopulations of glioma cells. The purpose of the present study was to 
        determine if the efficacy of BNCT could be further improved in 
        F98-glioma-bearing rats by administering both boron compounds together 
        and by improving their delivery by means of intracarotid (i.c.) 
        injection with or without blood-brain barrier disruption (BBB-D). 
        ,,, CONCLUSIONS: The combination of BPA and BSH, administered 
        i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable 
        F98 rat glioma with minimal late radiation-induced brain damage. These 
        results demonstrate that using a combination of boron agents and 
        optimizing their delivery can dramatically improve the efficacy of BNCT 
        in glioma-bearing rats.         PMID: 10758326  


~~~~~~~~~~~

Treatment with Fast Neutrons at the Midwest Institute for Neutron Therapy at Fermilab  
For more information see the web page on High Energy Neutrons and Fermilab in the section on Metastatic Disease - Techniques.


http://www-bd.fnal.gov/ntf/what_is/brain.html
Neutron therapy is appropriate for patients with localized brain metastasis from primary sarcoma. 

"Clinical trials were conducted at Fermilab for ten years to determine which cancers could be well treated by fast neutron therapy. The types of cancer studied were those which are classified as "radioresistant," that is, tumors which resist treatment by low LET radiation such as photons, electrons or protons." ... "Soft tissue sarcomas well treated by fast neutrons include: ... leiomyosarcoma." ...
http://www-bd.fnal.gov/ntf/what_is/softtissue.html 
Midwest Institute for Neutron Therapy at Fermilab operated by Provena Saint Joseph Hospital, Elgin, Il 
For information about referral or for further information 
please call the Fermilab Neutron Therapy Facility staff at: (630)840-3865, Monday through Friday, 8:30 A.M. to 5:00 P.M. CDT. 
or E-Mail: Fermi suggests emailing neutrons@fnal.gov .
or write: Midwest Institute for Neutron Therapy at Fermilab P.O. Box 5004, MS 301 Batavia, Il 60510-0500 
or Phone: (630) 840-3865 Fax : (630) 840-8766 
http://www-bd.fnal.gov/ntf/ 



~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~  

Chemotherapy and Brain Tumors

"A major factor in the failure of iv chemotherapy is the blood-brain barrier (BBB), a physiologic impediment to the delivery of cytotoxic chemotherapeutic drugs to the central nervous system (CNS). " [2]

"Intra-arterial and intrathecal infusion, blood-brain barrier disruption, high-dose chemotherapy, intratumoral administration, and convection-enhanced delivery are methods developed to overcome the BBB.  Although some of these methods may increase the local concentration-time         profile, improvement in clinical outcomes has yet to be definitively established. New methods for assessment of drug delivery to the brain tumor will assume increasing importance in the study of new cytotoxic chemotherapeutic drugs for these types of cancer. Pharmacokinetic studies are critical components of these clinical trials and allow assessment of drug delivery to the CNS and brain tumor. Additionally, pharmacokinetic studies will remain an important component of early clinical trials, particularly for identifying significant drug interactions involving the various supporting medications that are typically used in this patient population." [2]


"Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium,,,, was convened in April 2000. ,,, It brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. " [1]

"Optimizing chemotherapy delivery to the CNS is crucial. ,,,   The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can         therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. "  [1]

Efforts are also being made to create "cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies."  [1]
 
[1] Doolittle ND, Anderson CP, et.al.  Neuro-oncol 2001 Jan;3(1):46-54 PMID: 11305417 
[2]Ciordia R, Supko J, Gatineau M, Batchelor T.  Curr Oncol Rep 2000 Sep;2(5):445-53 PMID: 11122877


Annotated Citations

~~~~~~~~~~~~~~

P-glycoprotein expression in brain tumors. 
Henson JW, Cordon-Cardo C, Posner JB. 
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY. 
Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. ,,,. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents. PMID: 1361524 [PubMed - indexed for MEDLINE] [NOTE: there has recently been developed oral P-gp treatment for tumors, entering trials, hopefully to deal with chemotherapy drug resistance. doctordee]


http://www.nature.com/cgi-taf/Gateway.taf?g=2&file=/cancer/resround/200212/n
rc961.html&filetype=&_UserReference= 

Therapeutics: Breaking down barriers
Kristine Novak

"One of the reasons that brain tumours are such a challenge to treat is
because of the difficulties in delivering anticancer drugs across the
blood-brain barrier. In fact, the brain is a sanctuary for metastases from
tumours that respond to cytostatic drugs, such as paclitaxel, in other parts
of the body. In the November issue of the Journal of Clinical Investigation,
Fellner et al. report an approach to overcome this barrier, allowing
paclitaxel to enter the brain and reduce the size of brain tumours."

'Paclitaxel is used to treat various tumours, but it is not always effective
because it is a substrate for the multidrug-resistance protein
P-glycoprotein (P-GP) - a transporter that pumps drugs out of cells. Fellner
et al. investigated whether P-GP was expressed in the brain, where it might
transport paclitaxel and other drugs away from central nervous system (CNS)
tumours. They found that P-GP is expressed at high levels in intact rat and
human brain capillaries at the luminal surface of the endothelium - a
location that could restrict permeation of drugs into the CNS. When human
glioblastomas were transplanted into the brains of mice, the blood vessels
that developed within the tumours also expressed high levels of P-GP.'

"Previous studies have shown that animals with reduced P-GP function
accumulate P-GP substrates in the brain, so the authors checked to see
whether blocking this transporter increased paclitaxel entry into the CNS.
They showed that intravenous administration of the P-GP blocker valspodar
increased the levels of fluorescently labelled paclitaxel in the brains of
mice. Furthermore, co-administration of valspodar with paclitaxel reduced
the growth of human glioblastomas by 90%, whereas treatment with paclitaxel
or valspodar alone had no effect on tumour size."  ,,,

,,,

Fellner, S. et al. Transport of paclitaxel (Taxol) across the blood brain
barrier in vitro and in vivo.
J. Clin. Invest. 110, 1309-1318 (2002)

FURTHER READING
Rellin, M. V. & Dervieux, T. Pharmacogenetics and cancer therapy.
Nature Rev. Cancer 1, 99-108 (2001)


~~~~~

Gan To Kagaku Ryoho 1998 Feb;25(3):385-90 
[Pilot study of relapsed osteosarcoma and brain tumor with ifosfamide, carboplatin and etoposide (ICE therapy)] 
[Article in Japanese] 
Hirota T, Takeuchi M, Iwata A, Kitagawa S, Sato T, Konno K, Sawada K, Kobayashi S, Hamaguchi N, Agata H, Katano N, Fujimoto T. 
Dept. of Pediatrics, Aichi Medical University. 
Ifosfamide, Carboplatin and Etoposide (ICE) therapy was used to treat 4 patients, 2 with refractory osteosarcoma, and one each with relapsed brain tumor and newly diagnosed brain tumor. ICE therapy was administered in doses of Ifosfamide 1,800 mg/m2 x 5, Carboplatin 400 mg/m2 x 2 and Etoposide 100 mg/m2 x 5. A total of 30 courses were administered. Two cases of osteosarcoma had a stable disease (range, 3-9 months) and 2 cases of brain tumor had a complete response by magnetic resonance imaging. Moderate or severe toxicity evaluated on a per course basis included: neutropenia 83%, thrombocytopenia 93%, fever 30%, hepatotoxicity 3%, and hemorrhagic cystitis 3%. The median time to hematologic recovery was 20 days. ICE therapy is highly effective for the treatment of refractory or recurrent solid tumors with acceptable toxicity. 
PMID: 9492832 

~~~~~

 Curr Neurol Neurosci Rep 2002 May;2(3):216-24

        Chemotherapeutic dose intensification for treatment of malignant brain 
        tumors: recent developments and future directions.

        Kraemer DF, Fortin D, Neuwelt EA.
        Departments of Neurology and Neurosurgery, Oregon Health & Science 
        University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201, USA. 
        neuwelte@ohsu.edu

        Despite a large amount of research on malignant brain tumors over the 
        past 70 years, the prognosis for most tumor types is poor. One current 
        focus of research is increasing dose intensity of chemotherapeutic 
        agents. Various ways to increase dose intensity include high-dose 
        chemotherapy followed by stem cell rescue (eg, bone marrow transplant), 
        blood-brain barrier disruption or use of RMP7 to increase transvascular 
        drug delivery, local delivery of chemotherapeutic agents (convection 
        enhancement or clysis, antibody conjugates, and biodegradable polymers), 
        chemoprotective agents, and tumor sensitizers. Improved identification 
        of patients likely to respond to a given regimen may also increase the 
        effectiveness of chemotherapy. We also discuss approaches to improve the 
        design of nonrandomized trials by identifying and controlling potential 
        confounding variables. This will improve the quality of individual 
        studies and perhaps the comparability across studies. PMID: 11937000  

~~~~~

Expert Opin Pharmacother 2002 Jan;3(1):39-49
                Pharmacotherapy of primary CNS lymphoma.

        Abrey LE, Park DM.
        Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 
        York Avenue, New York, NY 10021, USA. abreyl@mskcc.org

        Primary CNS lymphoma (PCNSL) is distinguished from other brain tumours 
        by its striking response to chemotherapy. Surgery has little role (if 
        any) in the treatment of PCNSL. Radiation therapy has been proven to 
        prolong survival but its use is complicated by delayed neurological 
        toxicity, particularly among the elderly. Progress in understanding the 
        physiology of the blood-brain barrier (BBB) and the pharmacology of 
        chemotherapeutic agents has substantially improved the treatment and 
        prognosis of this disease. The single most effective agent is 
        methotrexate (MTX). The goal of delivering an adequate dose of MTX to 
        the brain and the cerebrospinal fluid (CSF) has been achieved by a 
        variety of strategies, including systemic high dose, intra-arterial 
        injection following pharmacological disruption of the BBB and 
        intrathecal (it.) administration. MTX-based combination chemotherapy has 
        yielded the best results to date but the prognosis of patients with 
        PCNSL remains significantly worse than comparable patients with systemic 
        non-Hodgkin's lymphoma (NHL). Ongoing trials continue to test novel 
        combinations of agents, doses and improved routes of delivery with the 
        hope of improving disease control and diminishing treatment-related 
        neurotoxicity.          PMID: 11772332 

~~~~~

Neurosurgery 2001 May;48(5):1033-40; 
        
        Association of total dose intensity of chemotherapy in primary central 
        nervous system lymphoma (human non-acquired immunodeficiency syndrome) 
        and survival.

        Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA.
        Division of Medical Informatics and Outcomes Research, Oregon Health 
        Sciences University, Portland 97201-3098, USA.

        OBJECTIVE: The importance of enhanced drug delivery in patients with 
        central nervous system (CNS) malignancies has not yet been demonstrated 
        conclusively. Intra-arterial chemotherapy in combination with osmotic 
        bloodbrain barrier disruption (BBBD) increases drug delivery to tumor by 
        2- to 5-fold and to surrounding brain tissue by 10- to 100-fold as 
        compared with intravenous administration of chemotherapy. ,,,
        CONCLUSION: In patients with PCNSL, a chemotherapy-responsive tumor 
        type, survival time is highly associated with total drug dose delivered, 
        even in analyses designed to control for potential survival biases. 
        These results probably constitute the strongest evidence to date of the 
        importance of total dose intensity in treating CNS malignancies.
        PMID: 11334269  
~~~~~

Curr Opin Oncol 2000 May;12(3):187-93      
        Local drug delivery.

        Haroun RI, Brem H.
        Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, 
        MD, USA.

        Intensive research efforts are now focused on the development of new 
        strategies for more effective delivery of drugs to the central nervous 
        system. These strategies include chemical modification of drugs, 
        disruption of the blood-brain barrier, and utilization of alternative 
        routes for drug delivery. This paper focuses on local drug delivery for 
        the treatment of brain tumors. It reviews papers published in the past 
        year on local chemotherapy and immunotherapy. Other aspects of local 
        drug delivery are discussed, including convection-enhanced delivery and 
        drug delivery via a controlled-release microchip.  Publication Types: Review 
        PMID: 10841189 
~~~~~

J Neurosurg 2000 Apr;92(4):599-605
              
In vivo assessment of the window of barrier opening after osmotic 
        blood-brain barrier disruption in humans.

        Siegal T, Rubinstein R, Bokstein F, Schwartz A, Lossos A, Shalom E, 
        Chisin R, Gomori JM.
        Department of Nuclear Medicine, Hadassah Hebrew University Hospital, 
        Jerusalem, Israel. siegal@hadassah.org.il

        OBJECT: Osmotic blood-brain barrier (BBB) disruption induced by 
        intraarterial infusion of mannitol is used in conjunction with 
        chemotherapy to treat human brain tumors. The time course to barrier 
        closure, or the so-called therapeutic window, has been examined in 
        animals but little information is available in humans. The authors, 
        therefore assessed the time course to barrier closure after osmotic BBB 
        disruption in humans. METHODS: Disruption of the BBB was demonstrated 
        using 99mTc-glucoheptonate (TcGH) single-photon emission computerized 
        tomography (SPECT) scanning in 12 patients who were treated monthly with 
        combination chemotherapy in conjunction with BBB disruption. ,,,
        CONCLUSIONS: 
        Results of these in vivo human studies indicate that the time course to 
        closure of the disrupted BBB for low-molecular-weight complexes is 
        longer than previously estimated. The barrier is widely open during the 
        first 40 minutes after osmotic BBB disruption and returns to baseline 
        levels only after 6 to 8 hours following the induction of good or 
        excellent disruption. These findings have important clinical 
        implications for the design of therapeutic protocols.         PMID: 10761648 

~~~~~

Neurosurgery 2000 Mar;46(3):704-9
       
        Enhanced delivery improves the efficacy of a tumor-specific doxorubicin 
        immunoconjugate in a human brain tumor xenograft model.

        Remsen LG, Trail PA, Hellstrom I, Hellstrom KE, Neuwelt EA.
        Department of Neurology, Oregon Health Sciences University, Portland 
        97201, USA.

        OBJECTIVE: To evaluate dose intensification with osmotic blood-brain 
        barrier disruption (BBBD) and the potential use of drug targeting with 
        monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now 
        called SGN15) for treatment of intracerebral and subcutaneous human LX-1 
        small cell lung carcinoma xenografts in rats. ,,,
        RESULTS: Both BR96-DOX and MAb BR96 
        treatment resulted in significant regression of subcutaneous tumors, in 
        contrast to control groups including doxorubicin alone, saline, or 
        nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to 
        brain tumors with low antigen expression resulted in significantly (P < 
        0.001) increased rat survival time compared with animals that received 
        intravenous or intra-arterial BR96-DOX. 
        CONCLUSION: The combination of 
        an effective drug such as doxorubicin with a MAb to facilitate 
        tumor-selective localization and osmotic BBBD to increase tumor delivery 
        may have practical application in the clinic, because an increased 
        delivery of drug to tumor can be obtained without increasing the dose of 
        systemic drug.          PMID: 10719867  

~~~~~
Neuro-oncol 2000 Jan;2(1):45-59
              
        The blood-brain and blood-tumor barriers: a review of strategies for 
        increasing drug delivery.

        Groothuis DR.
        Evanston Northwestern Healthcare, Department of Neurology, Northwestern 
        University Medical School, IL 60201, USA.

        ,,,[Approaches to circumvent the BBB] can be divided into two 
        categories: those that attempt to increase drug delivery of 
        intravascularly administered drugs by manipulating either the drugs or 
        capillary permeability, and those that attempt to increase drug delivery 
        by local administration. Several strategies have been developed to 
        increase the fraction of intravascular drug reaching the tumor, 
        including intra-arterial administration, barrier disruption, new ways of 
        packaging drugs, and, most recently, inhibiting drug efflux from tumor. 
        When given intravascularly, all drugs have a common drawback: the body 
        acts as a sink, and, even in the best situations, only a small fraction 
        of administered drug actually reaches the tumor. A consequence is that 
        systemic toxicity is usually the dose-limiting factor. When given 
        locally, such as into the cerebrospinal fluid or directly into the 
        tumor, 100% of an administered dose is delivered to the target site. 
        However, local delivery is associated with variable and unpredictable 
        spatial distribution and variation in drug concentration. The major 
        dose-limiting factor of most local delivery methods will be 
        neurotoxicity. The relative advantages and disadvantages of the 
        different methods of circumventing the blood-brain barrier are presented 
        in this review, and special attention is given to convection-enhanced 
        delivery, which has particular promise for the local delivery of large 
        therapeutic agents such as monoclonal antibodies, antisense 
        oligonucleotides, or viral vectors.     PMID: 11302254 


~~~~~

Neurosurgery 2000 Jan;46(1):51-60;              
         
        Cognitive outcomes and long-term follow-up results after enhanced 
        chemotherapy delivery for primary central nervous system lymphoma.

        McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, 
        Crossen JR, Neuwelt EA.
        Department of Neurology, Oregon Health Sciences University, Portland 
        97201, USA.

        OBJECTIVE: Patients with non-acquired immunodeficiency syndrome-related 
        primary central nervous system lymphomas have the potential to achieve 
        durable complete responses without radiotherapy, with treatment using 
        enhanced chemotherapy delivery with blood-brain barrier disruption 
        (BBBD). Reported 5-year survival rates with combined chemotherapy and 
        radiotherapy were generally only 9 to 22% and were associated, in one 
        study, with an overall 32% incidence of overt dementia and ataxia, which 
        are dramatically increased among patients more than 60 years of age. 
        ,,,
        RESULTS: The estimated 5-year survival rate 
        for this group was 42%, and the median survival time was 40.7 months. 
        Overall, ,, 36 patients continued to exhibit complete responses after 1 year 
        of BBBD-enhanced chemotherapy ,,, [and] none demonstrated evidence of 
        cognitive loss in neuropsychological tests and/or clinical examinations. 
        
        CONCLUSION: BBBD-enhanced chemotherapy delivery, without subsequent 
        radiotherapy, resulted in favorable survival and cognitive outcomes for 
        patients with primary central nervous system lymphomas who had not 
        previously undergone irradiation. ,,,
          Clinical Trial      PMID: 10626935 

~~~~~
Drug Resist Updat 1999 Feb;2(1):30-37
       Causes of drug resistance and novel therapeutic opportunities for the 
        treatment of glioblastoma.

        Nagane M, Huang HJ, Cavenee WK.

        Ludwig Institute for Cancer Research, University of California at San 
        Diego, La Jolla, USA

        ,,,. Recent advances in the molecular biology and 
        genetics of human cancers provide a detailed understanding of cellular 
        and molecular responses to chemotherapy and how drug resistance may 
        develop. Several oncogenes and tumor suppressor genes have been shown to 
        confer resistance to tumor cells and should, therefore, provide novel 
        and defined targets for cancer treatment. In addition to overcoming 
        cellular resistance, special efforts to increase drug delivery to ,,,
        tumors need to be pursued because of the relatively unique problem of 
        the blood-brain barrier. Treatments aimed at these targets will likely 
        benefit from combined therapies including surgery, traditional 
        chemotherapy and targeted disruption of other physiological processes 
        such as angiogenesis. Copyright 1999 Harcourt Publishers Ltd.
        PMID: 11504467  

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Radio Frequency Ablation  [RFA] of Brain Tumors

For discussion of the method, see the RFA page in the Metastatic Disease Techniques Section.


AJNR Am J Neuroradiol 1995 Jan;16(1):39-48; discussion 49-52 
Preliminary experience with MR-guided thermal ablation of brain tumors. 

Anzai Y, Lufkin R, DeSalles A, Hamilton DR, Farahani K, Black KL. 
Department of Radiological Science, University of California, Los Angeles Medical Center 90024-1721. 

PURPOSE: To evaluate the feasibility of a technique of MR-guided stereotactic radio frequency ablation, which was developed as a minimally invasive treatment for brain tumors, and to determine MR characteristics and sequential evolution of radio frequency lesions created to ablate brain tumors. METHODS: Fourteen lesions in 12 patients with primary and metastatic brain tumors were treated with this technique and followed for up to 10 months. The stereotactic coordinates of the tumor and the angle of the radio frequency probe were calculated on MR imaging. The radio frequency lesion was generated in the awake patient by increasing the temperature to 80 degrees C within the tumor for 1 minute. This was repeated until the entire tumor volume was destroyed. MR imaging was performed before, during, and immediately after the radio frequency procedure, and sequential MR was obtained during clinical follow-up. 
RESULTS: MR imaging clearly showed well-defined radio frequency lesions and provided feedback for treatment planning. The radio frequency lesion boundary was well identified as a dark signal rim on T2-weighted images and showed ring enhancement on contrast-enhanced T1-weighted images. The sequential MR imaging showed the radio frequency lesions decreased in volume in all cases, suggesting focal control. CONCLUSION: Stereotactic MR-guided radio frequency brain tumor ablation is a feasible and promising technique that can be an attractive brain tumor treatment alternative. MR provided not only accurate tumor location but also visualization of feedback of thermal tissue changes that reflected therapeutic effect. 
PMID: 7900601 



~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~


Hyperthermia in Treating Brain Tumors



Anticancer Res 1995 Mar-Apr;15(2):597-601 
Hyperthermia in the treatment of brain metastases from lung cancer. Experience on 17 cases. 

Pontiggia P, Duppone Curto F, Rotella G, Sabato A, Rizzo S, Butti G. Service of Oncologic Hyperthermia, Casa di Cura Citta di Pavia, Italy. 

Medium or long-term survival in metastatic non oat cell lung tumors is seldom possible only if surgery can eradicate the lesion. Out of 17 patients treated with hyperthermia plus nitrosoureas 16 (94%) responded, with clinical improvement, radiological regression or disease stabilization. The survival time of the improved patients was 12.7 months. Hyperthermia in combination with nitrosoureas seems to allow clinically and radiologically satisfactory responses in lung tumors metastatic to the brain. Publication Types: Clinical trial PMID: 7763043 [PubMed - indexed for MEDLINE] 

~~~~~~~~~~~~~~~~~~~~~

Immunotherapy and Gene therapy of Brain Tumors

Acta Neuropathol 100: 101-5. 1995
Stockhammer G, Obwegeser A, Kostron H, Schumacher P, Muigg A, 
Felber S, Maier H, Slavc I, Gunsilius E, Gastl G (2000) 

Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and 
correlates with tumor progression. 


J Neurosurg 1990 Jan;72(1):102-9 
Adoptive immunotherapy of intracerebral metastases in mice. 
McCutcheon IE, Baranco RA, Katz DA, Saris SC. 
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. 

Lymphokine-activated killer (LAK) cells are a heterogeneous population of immune effector cells that nonspecifically destroy neoplastic cells but not normal cells. Although parenteral treatment with interleukin-2 (IL-2) alone or a combination of IL-2 and LAK cells reduces tumor load and prolongs survival in mice with pulmonary, peritoneal, or hepatic metastases, the effect of these treatments on brain metastases has not been studied. ,,, intracardiac and intravenous injections of 10(5) KHT sarcoma cells were performed in C3H mice to create brain and lung metastases, respectively. The mice were treated with adoptive immunotherapy to determine if efficacy seen in an extracerebral site could be reproduced in the brain, ,,, Animals were treated with either parenteral IL-2 ,,, or IL-2 plus LAK cells ,,,or IL-2 excipient ,,,

As compared to control animals, pulmonary metastases on Day 14 after tumor injection were reduced or eliminated in animals treated with either IL-2 or IL-2 plus LAK cells (p less than 0.01). In these same animals, there was no reduction in the number of intracerebral metastases and no evidence of lymphocytic infiltration or cytolytic activity in the brain. This is the first study that reveals an organ-specific resistance to the treatment of metastases with adoptive immunotherapy, and affirms the concern that due to inadequate trafficking of endogenous or exogenous-activated lymphocytes or due to inadequate activation of in situ brain lymphoid precursors, there is no rejection of tumors in the brain. This information suggests that brain metastases in patients with systemic malignancies will not respond to intravenous treatment with LAK cells and IL-2, and that alternative forms of treatment are needed. ,,, PMID: 2294169 



Proc Natl Acad Sci U S A 2000 Jun 20;97(13):7567-72 
         
        Noninvasive gene targeting to the brain.

        Shi N, Pardridge WM.
        Department of Medicine, University of California School of Medicine, Los 
        Angeles, CA 90095-1682, USA.

        Gene therapy of the brain is hindered by the presence of the blood-brain 
        barrier (BBB), which prevents the brain uptake of bloodborne gene 
        formulations. Exogenous genes have been expressed in the brain after 
        invasive routes of administration, such as craniotomy or intracarotid 
        arterial infusion of noxious agents causing BBB disruption. The present 
        studies describe the expression of an exogenous gene in brain after 
        noninvasive i.v. administration of a 6- to 7-kb expression plasmid 
        encoding either luciferase or beta-galactosidase packaged in the 
        interior of neutral pegylated immunoliposomes. ,,,
      . In conclusion, widespread gene expression in the 
        brain can be achieved by using a formulation that does not employ 
        viruses or cationic liposomes, but instead uses endogenous 
        receptor-mediated transport pathways at the BBB.
        PMID: 10840060  





