The Treatment & Management of Brain Cancer

Cancer Connect - Treatment & Management of Brain Cancer

The Treatment & Management of Brain Cancer

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 8/2018

Surgery For Brain Cancer

Surgery is the primary treatment for brain tumors that can be removed without causing severe damage. Many benign (non-cancerous) tumors are treated only by surgery. Most malignant (cancerous) tumors, however, require treatment in addition to the surgery, such as radiation therapy and/or chemotherapy. Radiation therapy may be used alone for cancers that cannot be surgically removed or in combination with surgery and/or chemotherapy and precision cancer medicines.

The goals of surgical treatment for brain tumors are multiple and may include one or more of the following:

  • Confirm diagnosis by obtaining tissue that is examined under a microscope.
  • Remove all or as much of the tumor as possible.
  • Reduce symptoms and improve quality of life by relieving intracranial pressure caused by the cancer.
  • Provide access for implantation of internal chemotherapy or radiation.
  • Provide access for delivering intra-surgical treatments, including hypertherapy or laser surgery.

The following is a general overview of surgical treatment for brain tumors. There are different types of surgeries and techniques available, particularly in institutions that conduct many similar procedures. Circumstances unique to each patient’s situation may influence which approach is applied. The potential benefits of specific procedures must be carefully balanced with potential risks. The information on this web site is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their cancer physician.

Choosing a Surgeon and/or Institution: Experience and Volume are Important

Surgical procedures for the treatment of brain tumors can be complicated and may involve significant risk. Research indicates that patients who require complex surgical procedures have better outcomes (fewer surgery-related deaths and complications) if they are treated in high-volume institutions (hospitals that perform a high number of such procedures).[1],[2],[3],[4],[5] It is thought that the more favorable outcomes at high-volume institutions are due to more skilled surgeons as well as a more skilled and dedicated team.

These findings highlight the importance of choosing an experienced surgeon. Outcomes may vary between large and small institutions. However, researchers agree that it is important to select a surgeon with a great deal of experience conducting the specific procedure in question. Often these doctors work at large, specialized institutions.

Types of Surgery for Brain Tumors

Biopsy: A biopsy is a surgical procedure to remove a small piece of tumor in order to confirm the diagnosis. The sample is examined under the microscope by a pathologist who determines the type of the tumor. A biopsy can be performed as part of the surgery to remove the tumor or as a separate procedure.

There are two different approaches for performing a biopsy for brain tumors. An open biopsy involves exposing the tumor and then removing a small portion of it. A needle biopsy is performed by making an incision in the skin, drilling a small hole into the skull, inserting a narrow, hollow needle through the hole and into the tumor, and drawing up a small amount of tumor into the needle.

A needle biopsy may also be conducted with the assistance of computers and scanning equipment, including MRI or CT, in order to increase the precision of the procedure. This procedure is called stereotactic needle biopsy and is useful for patients with deep or multiple tumors. Stereotactic techniques are discussed further in the Surgical Techniques section.

Craniotomy: The most commonly performed surgery for removal of a brain tumor is called a craniotomy. “Crani” means skull, “otomy” means cutting into. In preparation for a craniotomy, a portion of the scalp is usually shaved, and an incision is made through the skin. Using specialized equipment, a surgeon removes a piece of bone to expose the area of brain over the tumor. The dura mater (the outermost layer of the brain tissue) is opened, the tumor is located and then removed (resected). After the tumor is removed, the bone is usually replaced and the scalp stitched shut.

In a conventional craniotomy, surgeons guide themselves by what they see, their knowledge of anatomy, and their interpretation of the pre-operative scans. During stereotactic surgery, surgeons may rely on a computer to help direct the craniotomy. This approach is discussed further in the Surgical Techniques section below.

Shunt: Some patients with brain tumors develop increased intracranial pressure. To relieve the pressure, a procedure is conducted to drain excess or blocked fluid. A shunt is a narrow piece of flexible tubing (called a catheter) that is inserted into a ventricle in the brain. The other end of the tubing is threaded under the scalp toward the neck, then, still under the skin, threaded to another body cavity where the fluid is drained and absorbed. The body cavities used for drainage are the right atrium of the heart and, more commonly, the abdominal cavity. Compared to other surgical treatments for brain tumors, the procedure to implant a shunt is relatively minor. A small hole is drilled in the skull through which the catheter is threaded into a ventricle. A small incision is made in the abdomen or the chest, depending on which cavity is used for drainage. The other end of the catheter is threaded under the skin to the cavity and then fastened. Some shunts can be temporary and are removed after treatment is completed. Other shunts are left in place after surgery. Following shunt insertion, many patients, particularly children, show dramatic improvement within days. In others, symptoms of intracranial pressure, such as headaches, might remain for a period of several weeks.

Imaging and Monitoring Techniques (Brain Mapping)

Doctors use a variety of techniques to determine what a brain tumor looks like both before and during surgery. Specialized images can be generated that shows what functions the brain tissue near the cancer is responsible for. Generating images both before and during surgery can increase the likelihood that extensive tumor removal can be achieved while avoiding these critical areas.

Before surgery, the location of the brain tumor in relation to other structures and blood vessels must be determined as precisely as possible. To achieve this, a variety of tests are performed. These may include:

  • Computerized tomography (CT)
  • Magnetic resonance imaging (MRI)
  • Positron emission tomography (PET)
  • Angiography (to map blood vessels)

Using the information obtained from these tests, the surgeon can plan and even rehearse the operation in order to obtain optimal results. Evaluation of outcomes in elderly patients who had undergone surgery for brain tumors indicates that those who underwent preoperative MRI experienced better outcomes than those patients who were not evaluated with MRI before surgery.[6]

The scans taken before surgery yield a great deal of information, but they don’t always provide the precision needed to avoid critical areas of the brain during the operation. Sophisticated mapping techniques can improve the safety and effectiveness of surgery by locating the exact areas of the brain responsible for speech, comprehension, sensation, or movement. Brain mapping is also used to help identify the margin of the tumor and to differentiate between tumor, swelling (edema), and normal tissue.

Techniques for brain mapping include:

  • Direct cortical stimulation
  • Evoked potentials
  • Functional MRI
  • Intraoperative ultrasound imaging
  • Microsurgery

Direct cortical stimulation: In direct cortical stimulation, a probe passes a tiny electrical current into the brain and delicately stimulates a specific area. The result is a response from the body, such as a visible movement of the corresponding body part. This technique may be employed during surgery to help identify important functional areas. For example, direct cortical stimulation has been used during surgery for gliomas to successfully identify and preserve cortical areas responsible for language and minimize damage to motor function.

In a group of 30 patients who underwent direct cortical stimulation, surgeons were able to effectively identify and preserve language centers. Additionally, the brain tumor was completely removed in 14 of the patients.[7] Of 294 patients with gliomas near motor centers of the brain, 60 patients (20%) experienced deficits in motor ability after surgery and cortical stimulation. Of these 60 patients, 76.7% regained their baseline function within the first 90 days after surgery.[8]

Evoked potentials: The electrical response of the brain can be measured by stimulating the brain and measuring the resulting activity, or evoked potentials, on brain scanning equipment. Evoked potentials may be used to map and continuously monitor areas of the brain during surgery.

Research indicates that the use of evoked potentials can help doctors identify potential damage to motor function in time for repairs to be made. Researchers evaluated the use of motor evoked potentials (MEPs) in 51 patients who underwent surgery for gliomas. Using corrective measures, all intraoperative changes in MEPs were reversed in time to prevent an irreversible, complete injury to the motor system. None of the patients involved in this clinical trial lost motor function at the end of the operation.[9]

Researchers have also reported that evoked potentials are useful for accurately identifying the part of the brain that controls sensation in the lower lip, which can be damaged during surgery to remove tumors in patient with gliomas in that region of the brain.[10]

Functional MRI: MRI is a high-speed imaging device that generates images of the tumor’s use of oxygen. This helps distinguish between active, normal brain, and non-active tumor or dead tissue (necrosis). Functional MRI can be an alternative to direct cortical stimulation. Research indicates that motor and sensory areas identified with functional MRI are very similar to locations identified with direct cortical stimulation.[11] This technique is reliable but requires sophisticated and expensive equipment.

Intraoperative ultrasound imaging: The use of ultrasound during surgery can help determine the depth of the tumor and its diameter. Ultrasound works by sending ultrasonic wave pulses into the brain, which then reflect back to a device. A computer measures the amount of time it takes for the “echoes” to return, and the results are displayed as a TV image. Surgeons can monitor their movements to verify positioning and results during surgery. The waves can also reflect motion such as blood flow. Ultrasound can make it easier for the surgeon to locate the margins of the tumor so that more extensive tumor removal can be achieved. It helps distinguish between tumor, necrosis (dead tumor cells), cysts, edema, and normal brain. Because ultrasound does not readily penetrate bone, it cannot be used preoperatively.

Researchers from Germany who have used intraoperative ultrasound imaging routinely since 1987 have reported that it is a reliable method for determining the size, shape, and location of lesions, and can differentiate between solid tumor, cyst, and necrosis (dead tissue).[12]

Microsurgery: Microsurgery involves the use of a high-powered microscope during surgery, which allows the surgeon to obtain a magnified view of the surgical field. Microsurgery is widely used for brain tumor surgery.

Surgical Techniques

Many different surgical techniques are utilized in the treatment of brain tumors, particularly in large medical centers that treat a significant number of patients. The technique utilized for a particular patient depends on the type of tumor and its location as well as the preference of the surgeon. The surgical techniques most commonly employed in the treatment of brain tumors include:

  • Stereotactic surgery,
  • Embolization,
  • Endoscopy,
  • Laser surgery,
  • Photodynamic laser surgery, and
  • Ultrasonic aspiration.

Stereotactic surgery: The use of computers to create a three-dimensional image is called stereotaxy. The purpose of this technique is to provide precise information about the location of a tumor and its position relative to the many structures in the brain. Stereotaxy can be used by the surgeon to map out the surgical procedure beforehand so that the neurosurgeon can “rehearse” the procedure or to allow the radiation specialist to plan radiation therapy.

While conventional X-ray pictures depict tumors in two dimensions, stereotaxy provides the third dimension—depth—by obtaining readings in both left to right and front to rear directions, and then using a computer to analyze the information. It is the third dimension that allows the surgeon to accurately insert the needle for biopsy, the laser beam for vaporization, the scalpel for cutting, or the suction device for aspiration.

Stereotactic surgical techniques are used to perform biopsies, remove tumors, implant radiation pellets or other local treatments, or to provide a navigational system during surgery (frameless stereotaxy). These techniques are particularly useful for reaching a tumor located deep within the brain, such as the brain stem or thalamus. Stereotaxy can also help limit the extent of surgery. Some stereotactic systems can project images of the surgery as it is being performed (“real-time” imaging). Stereotaxy is performed either with or without a head frame.

  • Steriotaxy with a head frame involves placing the patient’s head in a rigid frame so the attached scanning devices can accurately pinpoint the tumor location in three-dimensional space. The rigid frame holds the patient’s head in place during the pre-surgical scans and the surgery itself. The information from the CT and/or MRI scans, along with coordinate information from the headframe, is entered into a computer system. The images produced, with their relational coordinates, are used to plan the surgery and guide the surgeon’s tools during the procedure.
  • Frameless steriotaxy utilizes an imaging hand-held device rather than CT or MRI. With this approach, the head must be stabilized in a frame. The surgeon touches structures in the patient’s brain with an imaging “wand” that superimposes that location in the brain on a computer monitor showing a recent scan or three-dimensional image of the brain. This tool is used to orient the surgeon as to the exact location of the tumor as compared to a specific point on the exterior of the brain. The wand provides quick and continuous “real-time” information about its location during surgery. This tool is particularly useful during skull base surgery, which is an especially complicated area. It is also of value when multiple tumors are to be removed. The viewing wand can shorten the surgical time by quickly identifying parts of the brain and localizing the tumor.

Researchers anticipate that, in the not too distant future, a significant portion of neurosurgical procedures, as well as many general surgical procedures will involve stereotaxy.[13]

Embolization: Embolization is used to reduce the amount of blood supply to a tumor by blocking the flow of blood in selected arteries. This procedure is conducted prior to surgery. Results from an arteriography, which is an X-ray taken after radiolabeled dye has been injected into the circulatory system, help determine whether embolization is necessary and which blood vessel or vessels may need to be blocked. Surgery follows as soon as possible to avoid re-growth of blood vessels. This technique might be used with vascular tumors such as meningiomas, meningeal hemangiopericytomas, and glomus jugulare tumors.

Endoscopy: Endoscopes are long, narrow, flexible lighted tubes that are inserted into the surgical area. They provide the surgeon with light and visual access. Preoperative scans help determine the location of tumors and enable the surgeon to plan surgery using relatively small openings. These small openings (sometimes called keyhole approaches) make it difficult for the surgeon to see. The endoscope helps solve that problem. The neuro-endoscope is particularly useful for surgery that involves correcting a malfunctioning shunt, removing scar tissue blocking a shunt, or removing intra-ventricular tumors. It can also be useful for removing brain cysts.

Laser surgery: Using a laser during brain surgery is a relatively routine practice. The aim of laser surgery is to direct the laser beams at the cancer and destroy it with heat. Because the light beams cannot penetrate bone, the laser can be used only during surgery. Lasers are used in addition to, or in place of, a scalpel. Lasers are capable of immense heat and power when focused at close range. Lasers destroy tumor cells by vaporizing them. Stereotactic, or computer-assisted techniques, are frequently used to direct the laser. Lasers are chiefly used in the treatment of tumors that have invaded the skull base or are deep within the brain, with hard tumors that cannot be removed by suction, or with tumors that break apart easily.

Photodynamic laser surgery: A laser is also used in photodynamic therapy. Photodynamic therapy combines a drug that increases a tissue’s sensitivity to light and laser surgery. Prior to surgery, the photosensitizing drug is injected into a vein or artery. It travels through the blood system to the tumor, accumulating in the cells of the tumor. The patient is then taken to surgery for removal of the tumor. During the operation, the treated tumor cells appear fluorescent. The physician aims a laser at the tumor cells, activating the drug. The activated drug then kills the tumor cells. Only operable tumors can be treated with this procedure. Tumor cells not seen by the surgeon or not sensitive to the drug are not affected by this treatment. This is a local form of therapy because some parts of the tumor might not be exposed to the light. Because of the danger of swelling, tumors near the brain stem cannot be treated with this technique.

Ultrasonic aspiration: Ultrasonic aspiration uses ultrasonic sound waves to fragment and break the tumor into small pieces, which are then aspirated, or suctioned out. This technique causes fewer disturbances to adjacent tissue than other types of suction devices because it causes less heat and destruction of normal tissue. This is particularly helpful with tumors that would be difficult to remove with cautery and suction because of their firmness and location. As with the laser, the use of ultrasound has permitted the removal of tumors that would otherwise have been inoperable.

Radiation Therapy For Brain Cancer

The three primary ways that radiation therapy is administered in the treatment of brain tumors are with:

  • External Beam Radiation Therapy (EBRT): a machine that directs radioactive beams from outside the body;
  • Stereotactic Radiation Therapy (Gamma Knife): a computer and image guided technique that directs radiation only at the tumor; and
  • Brachytherapy: a radioactive implant that is placed in or near the tumor.

EBRT is the conventional technique for administering radiation therapy to the brain, but stereotactic radiosurgery has also become a standard treatment. The most recent advance in the radiation treatment of brain tumors is the brachytherapy technique called GliaSite radiotherapy system, which involves placing a balloon in or near the tumor during surgery and then passing a radioactive material into the balloon for treatment.

The following is a general overview of radiation therapy for brain tumors. Radiation therapy may be delivered as EBRT, brachytherapy, stereotactic radiation therapy, or through another, innovative technique. Combining two or more of these treatment techniques has become an important approach for increasing a patient’s chance of cure and prolonging survival.

In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. The information on this Web site is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

  • Procedures for Delivering Radiation Therapy to Brain Tumors
    • Treatment Schedules
    • Follow-up
    • Retreatment with radiation
  • Techniques for Delivering Radiation Therapy to Brain Tumors
    • External beam radiation therapy (EBRT)
    • Stereotactic radiosurgery
    • Internal radiation therapy (brachytherapy)
  • Side Effects and Complications of Radiation Therapy

Procedures for Delivering Radiation Therapy to Brain Tumors

Treatment schedules: Radiation therapy often begins a week or two after surgery, or as soon as the surgical wound heals. Conventional EBRT is usually given in 30–40 doses over a six-week period, five days a week. Brachytherapy may be administered for only a few days, followed by removal of the radioactive “seed”, and stereotactic radiation therapy is typically conducted in one single session

Follow-up examinations: Results of therapy might not be obvious for several months or longer. Tumor cells that have been damaged by radiation cannot reproduce normally and gradually die. The brain clears away the dead tumor cells, but this is a lengthy process. Scans taken immediately following therapy can be confusing because swelling and dead cells often appear larger than the original tumor, and can cause symptoms similar to the tumor. It takes a few months before scans show the full benefit of the radiation.

Re-treatment with radiation: Radiation kills normal cells as well as tumor cells. Since brain tissue cannot replace itself, the effects of radiation are cumulative, causing severe side effects beyond a certain degree of exposure to radiation. For this reason, re-treatment with conventional fractionated radiation is not often recommended. However, additional radiation is possible in selected circumstances, including:

  • Location of the tumor and its relation to critical brain tissue,
  • When the previous radiation was given,
  • The amount of radiation originally given, and
  • The type of tumor and the age of the patient.

Brachytherapy and stereotactic radiation therapy are frequently used for selected patients who may benefit from retreatment with radiation therapy. These patients typically have recurrent malignant gliomas or metastatic brain tumors and have previously undergone conventional EBRT.

For more information about radiation therapy procedures, go to What to Expect During Radiation Therapy.

Techniques for Delivering Radiation Therapy to Brain Tumors

The three primary techniques for delivering radiation therapy—external, internal, and stereotactic—have each been evaluated in the treatment of patients with brain tumors and may be utilized in different circumstances. While EBRT is the conventional treatment for brain tumors, SRS has also become a standard procedure. SRS has been used in the treatment of many types of brain tumors and been proven effective in the treatment of brain metastases. A recent advance in brachytherapy includes the FDA-approved GliaSite® radiation therapy system that involves passing a radioactive material into an implanted balloon.

External Beam Radiation Therapy (EBRT)

EBRT involves directing radiation beams from outside the body into the tumor. Machines called linear accelerators produce the high-energy radiation beams that penetrate the tissues and deliver the radiation dose deep in the body where the cancer resides. These modern machines and other state-of-the-art techniques have enabled radiation oncologists to significantly reduce side effects while improving the ability to deliver radiation directly to the tumor.

EBRT is typically delivered as an outpatient procedure for approximately six to eight weeks. EBRT begins with a planning session, or simulation, during which the radiation oncologist places marks on the body and takes measurements in order to line up the radiation beam in the correct position for each treatment. During treatment, the patient lies on a table and the radiation is delivered from multiple directions. The actual area receiving radiation treatment may be large or small, depending on the features of the cancer. Radiation can be delivered to one specific area or encompass the surrounding tissues, including the lymph nodes.

EBRT may be used to deliver radiation therapy to a part of the brain or the whole-brain. Whole-brain radiation therapy is usually recommended for a large or spreading brain tumor.

Proton radiation therapy: Proton radiation therapy is a form of EBRT that utilizes a beam of protons as the source of radiation rather than X-rays or gamma rays. Protons are released from atoms using technology similar to that employed in nuclear reactors. Computer-programmed blocks are precisely placed to direct the proton beam toward the tumor and match it to the shape of the tumor.

As a source of radiation, proton beams offer advantages over X-rays. In particular, a proton beam delivers a high dose of radiation to the tumor, but very little radiation affects normal tissue in front of and beside the tumor, and no radiation is deposited in the normal tissue behind the tumor. In this way, healthy brain tissue is spared from radiation damage. X-ray beams may deposit most of their dose in tissues in front of the tumor, causing damage to normal tissue and associated side effects.

Proton radiation therapy may have a role in the treatment of unusually shaped tumors and small tumors that are located deep in the skull, such as skull base tumors or pituitary tumors. Proton radiation therapy has been evaluated in the treatment of meningiomas and appears to be effective. In a clinical trial involving 16 patients with intracranial meningiomas, over 90% survived free of cancer progression for three years or longer.[1]

Stereotactic Radiation Therapy (Gamma Knife Therapy)

Stereotactic radiation therapy (SRT) is a noninvasive approach to the treatment of brain tumors that uses pencil-thin beams of radiation to treat only the tumor. SRT uses imaging techniques—including CT scans or MRI—and special computerized planning to precisely focus a high dose of radiation on the brain tumor, while sparing normal tissue. This focused technique allows radiation to be delivered in an area of the brain or spinal cord that might be considered inoperable, and can be delivered to tumors that are one and one-half inches in diameter or smaller. Another advantage to SRT is that radiation treatment is delivered in a single session.

SRT has become a standard treatment for primary and metastatic brain tumors and may be delivered as:

  • An addition to conventional EBRT, called local “boost” radiation, when the patient has already received the maximum safe dose of conventional radiation therapy,
  • The only technique used to deliver radiation therapy to some brain tumors, or
  • A substitute for surgery for a metastatic brain tumor or a benign tumor (such as a pituitary, pineal region, or acoustic tumor).

Prior to SRT, the patient is fitted with a head frame. CT and/or MRI scans are performed with the head frame in place to locate the tumor and obtain information necessary for computerized treatment planning. Treatment is totally non-invasive and painless. Patients maintain their normal function and are completely awake and alert throughout the entire procedure.

Possible side effects of SRT include edema (swelling), occasional neurological problems, and radiation necrosis (an accumulation of dead cells). A second surgery to remove the build-up of dead tumor cells may be required.

Types of Stereotactic Radiosurgery Equipment

Two types of machines are used routinely to deliver stereotactic radiation therapy: Gamma Knife® and linear accelerators (LINAC).

Gamma Knife: The Gamma Knife is an instrument that was developed by researchers in Sweden nearly three decades ago. It delivers 201 beams of radiation that are focused by a computer so that they intersect at the precise location of the cancer. The patient is placed on a couch and then a large helmet is attached to the head frame. Holes in the helmet allow the beams to match the calculated shape of the tumor.

The most frequent use of the Gamma Knife has been for small, benign tumors, particularly acoustic neuromas, meningiomas, and pituitary tumors. For larger tumors, partial surgical removal might be required first. The Gamma Knife is also used to treat solitary metastases and small malignant tumors with well-defined borders.

LINAC: An adapted linear accelerator can deliver a single, high-energy beam that is computer-shaped to the tumor. The patient is positioned on a sliding bed around which the linear accelerator circles. The linear accelerator directs arcs of radioactive photon beams at the tumor. The pattern of the arc is computer-matched to the tumor’s shape. This reduces the dose delivered to surrounding normal tissue.

LINAC radiation therapy may be used in the treatment of metastatic cancer or some benign brain tumors.

Stereotactic Radiation Therapy in the Treatment of Specific Types of Brain Tumors

Brain metastases: The addition of SRT to whole-brain radiation therapy (WBRT) appears to benefit patients thought to have only a single brain metastasis. A clinical study involving patients with one to three brain metastases was conducted to directly compare WBRT with or without SRS boost. Overall, the SRT boost appeared to improve survival only among patients who had a single metastasis (see table 1).[2]

Table 1 Outcomes with the addition of SRT to whole-brain radiation in the treatment of a single brain metastasis

Research also indicates that SRT may be as effective as surgery for the treatment of some patients with brain metastases. A review of outcomes from patients with a single brain metastasis treated at the Mayo Clinic indicates that 56% of patients who received SRT and 62% patients treated with surgery lived one year or more after treatment, a difference that was not statistically significant. Furthermore, tumor control was better for the patients treated with SRT. None of the patients who received SRT had local recurrence of cancer, compared to 58% patients treated with surgery.[3]

Glioblastoma multiforme: Researchers from the Radiation Therapy Oncology Group have reported that the addition of SRT to conventional EBRT and chemotherapy does not appear to improve outcomes in patients with glioblastoma multiforme. There were 203 patients with brain tumors greater than or equal to 44 mm in diameter involved in this clinical trial. Patients were randomly assigned to receive conventional EBRT, chemotherapy, and SRT, or conventional EBRT and chemotherapy alone. Patients in both groups survived slightly more than a year: 13.6 months for patients who received the additional SRT and 13.5 months for patients who received only EBRT and chemotherapy. SRT did not appear to improve quality of life or mental functioning.[4]

While these results from SRT as “boost” therapy did not show an improvement over conventional treatment, research is ongoing to determine if SRT may benefit patients with glioblastoma multiforme.

Pituitary tumors: The pituitary gland is a bean-sized organ that produces many hormones that affect other parts of the body. Cancer in the pituitary gland is typically treated with surgical removal and radiation therapy. However pituitary tumors may result in the over-production of one or several important hormones, and SRT may decrease dangerously high hormonal levels faster than conventional radiation. A review of 34 published studies including 1,567 patients with pituitary cancers that were treated with SRT indicated that tumor growth can be controlled in approximately 90% of cases.[5]

Meningiomas: Meningiomas arise from the layers of tissue that cover the brain and spinal cord, called meninges. Most meningiomas are benign, or non-cancerous, and slow-growing. When the tumor cannot be completely removed with surgery, it may be possible to control the size and growth with radiation therapy, allowing patients to live many years with residual tumor tissue. However, meningiomas that are not controlled may cause pressure on the brain or spinal cord and associated symptoms, such as pain and impaired function. Long-term (10-year) results of Gamma Knife radiation therapy conducted at the University of Pittsburgh indicate that tumor size was reduced in more than half of patients with meningiomas.[6]

Results of SRT for meningiomas cannot be detected on radiographic imaging immediately after treatment. Therefore, the effect of treatment may not be known for many years. Researchers are evaluating new techniques to more quickly determine the outcomes of treatment.

Internal Radiation Therapy (Brachytherapy)

Brachytherapy is the delivery of radiation therapy by placing radioactive material directly into or near the brain tumor. The radioactive material may also be called “implants” or “seeds.” While standard radiation aims rays at the tumor from outside the body, brachytherapy attacks the tumor from the inside. The advantages to internal delivery of radiation are:

  • Reduced damage to normal tissue, and therefore, reduced side effects,
  • More concentrated delivery of radiation to the area where the cancer is mostly likely to recur, and
  • Reduced risk of damage to normal brain tissue makes brachytherapy an option for patients with recurrent tumors who have undergone radiation treatment for recurrent brain tumors and may not be able to tolerate additional EBRT.

Brachytherapy is used in the treatment of newly diagnosed or recurrent brain tumors. It may be administered as the primary radiation therapy or as a “boost” of additional radiation delivered before or following standard external beam radiation. For boost therapy to be effective, the brain tumor must be no more than 2 inches in diameter and accessible by surgery. Larger tumors may require surgery to reduce the size of the tumor before the radiation sources are implanted. Brachytherapy is a local therapy; it is not commonly used for widely spread or multiple tumors.

Implantation procedure: To implant radiation energy in the tumor, catheters (tubes) are placed into the tumor bed using surgical techniques that are directed by CT and MRI. The sources of radiation, usually in pellet form, are placed in the catheters. Depending on the isotopes used, the implant is removed either after a few days, after several months or is left in place permanently. Steroids are commonly used with this therapy to decrease brain swelling. In rare instances, implantation might be repeated. Brachytherapy implants are typically temporary and are removed once treatment is completed. In some cases, an implant may be permanent.

A possible complication associated with brachytherapy is the build-up of dead tissue. The radiation being emitted from the implant kills the cancer cells, and in some cases, this may cause dead cells to build up faster than the body can remove them. Large amounts of dead tumor cells can cause complications. Some patients will require follow-up surgery to remove the dead tissue.

GliaSite® radiation therapy system (RTS): The GliaSite RTS involves placing an inflatable balloon in the area of the brain tumor at the time of surgery. Low-dose-rate radiation is delivered through a catheter (tube) into the balloon. The GliaSite RTS offers the advantage of a shorter stay in the hospital; most patients who undergo traditional external beam radiation therapy remain hospitalized for six weeks, whereas patients who receive their radiation treatment with GliaSite may return home within a week. GliaSite is approved by the U.S. Food and Drug Administration (FDA) for the treatment of malignant brain tumors.

Three published clinical trials indicate that GliaSite is a safe treatment for high-grade gliomas[7] and brain metastases[8] and may increase survival in the treatment of recurrent gliomas compared to surgery alone or surgery plus internal chemotherapy.

Results from a clinical trial of GliaSite that was carried out in nine institutions in the U.S. and involved 81 patients indicate that this procedure improves survival and does not appear to reduce patients’ quality of life. The patients in this trial lived, on average, more than three months (38 weeks) after implantation and they were free from cancer progression for approximately 19 weeks. The researchers estimated that approximately one-third of patients lived one year or more. These patients lived nearly twice as long as a similar groups of patients from another trial who only underwent surgery. Also, approximately one-third of the patients treated with GliaSite lived longer than a group that underwent surgery and the placement of internal Gliadel wafer chemotherapy.[9]

Permanent low-intensity brachytherapy: Two studies have failed to show a significant improvement in outcomes with high-intensity, temporary brachytherapy implants. However, researchers have investigated the use of low-intensity, permanent implants comprised of iodine 125 and found them to be safe. Results from a clinical trial involving 22 patients with astrocytomas treated with surgical placement of a permanent implant showed that patients lived an average of 64 weeks and 57% of patients lived one year or more.[10]

Side Effects and Complications of Radiation Therapy for Brain Tumors

Radiation therapy is commonly associated with some side effects. However, patients experience side effects at different rates and to different degrees. A dose that causes some discomfort in one patient may cause no side effects in another, and may be disabling to a third. Side effects of radiation therapy can be grouped into general and those pertaining to neurological, or brain function. General side effects may include:

  • Hair loss,
  • Skin irritation,
  • Hearing problems,
  • Nausea/Vomiting,
  • Appetite changes, and
  • Fatigue.

Neurological side effects

The major side effect of radiation for brain tumors is damage to normal brain tissues, which can lead to mild, moderate, or severe brain damage. Newer radiation therapy techniques can limit these effects, but may not always eliminate them. Neurological side effects may occur immediately after treatment, a few weeks to a few months after the completion of treatment, or they may occur months or years after treatment and persist as long-term effects.

Immediately after treatment: Acute reactions occur immediately after treatment and are caused by radiation-induced brain swelling (edema). Symptoms can mimic the symptoms of your brain tumor, like speech problems or muscle weakness or those of increased intracranial pressure, such as headache, nausea, or double vision. Acute side effects are usually temporary and may be relieved by corticosteroids such as dexamethasone. Often, steroids are prescribed to be taken during the entire treatment so that acute side-effects are avoided or minimized. The steroid dose is gradually reduced and discontinued when treatment is completed.

Weeks or months after treatment: So-called “early delayed” or sub-acute reactions commonly occur between one and three months after treatment. Symptoms include loss of appetite, sleepiness, lack of energy, and an increase in pre-existing neurological symptoms. Sub-acute reactions are thought to be due to temporary disruption to the nerve coverings. These symptoms are usually temporary, lasting about six weeks, the length of time it takes for myelin to repair itself. In some cases, however, recovery may take several months.

Another reaction that can occur weeks or months after treatment is swelling as a result of the build-up of dead tumor cells. The brain lacks an effective lymph system, the clean-up system of the body. Therefore, dead tumor cells are cleared away very slowly and radiation-induced cell death may cause rapid build-up of dead cells. The swelling that occurs as a result of the dead cells may cause an increase in neurological symptoms similar to the symptoms of the brain tumor.

Months or years after treatment: Long-term effects occur as a result of changes in the white matter of the brain and death of brain tissue caused by radiation-damaged blood vessels. Symptoms can occur months to years after therapy is completed. These long-term effects are permanent and can be progressive. Symptoms vary from mild to severe and include: decreased intellect, memory impairment, confusion, personality changes, and alteration of the normal function of the area irradiated.

Long-term effects of radiation therapy are difficult to distinguish from new tumor growth. CT and MRI scans are not accurate and PET scanning might be helpful, but is not totally accurate either. It might be necessary to conduct a biopsy of the area to determine if a patient has new tumor growth.

One of the major, long-term side effects of radiation therapy is the development of a second cancer, frequently in the head and neck area. This often takes years to develop.

Strategies to Improve Radiation Therapy for Brain Tumors

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new treatment strategies. Future progress in radiation treatment for brain tumors will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the radiation treatment of brain tumors include the following:

  • Three-dimensional conformal radiation therapy (3D-CRT)
  • Intensity modulated radiation therapy (tomotherapy)
  • Radioactive monoclonal antibodies
  • Intraoperative radiation therapy
  • Radiosensitizers
  • Boron Neutron Capture Therapy (BNCT)
  • Hyperthermia

Three-dimensional conformal radiation therapy (3D-CRT): EBRT can be delivered more precisely with the help of a special scan and a computer. The scan is called computed tomography (CT scan) and is used to identify the cancer “target.” The computer is used to “conform” the radiation to the tumor shape. This technique is known as three-dimensional conformal radiation therapy, or 3D-CRT. The use of 3D-CRT appears to reduce the chance of injury to nearby normal tissues. Since 3D-CRT can better target the area of cancer, radiation oncologists are evaluating whether higher doses of radiation can be given safely and provide more chances for cure.

Researchers have evaluated 3D-CRT in the treatment of patients with high-grade gliomas. In a clinical trial involving 34 patients treated with 3D-CRT, patients lived an average of 11.7 months. Nearly half of the patients lived one year or more after treatment and approximately 13% lived two years or more.[11]

High-dose 3D-CRT has been shown to increase survival compared to conventional radiation therapy. Researchers from Japan have reported that high-dose conformal radiation therapy improves survival for patients with anaplastic astrocytoma and glioblastoma compared to standard doses without increasing disabilities associated with radiation to the brain. Among 184 patients who were treated with high-dose conformal radiation, more than half (51%) survived five years or more compared to 15% of patients who had been treated with conventional radiation therapy.[12]

Intensity modulated radiation therapy (IMRT): IMRT is an advanced form of 3-D conformal radiation therapy. IMRT, also called tomotherapy, delivers varying intensity of radiation with a rotating device. IMRT is similar to computed tomography (CT) scanning. In CT, a beam rotates around the patient, creating a sequence of cross-sectional images. IMRT also uses a rotating beam, except the beam delivers radiation. And like CT, IMRT delivers treatment one cross-section at a time.

The intensity of radiation that is delivered with IMRT is varied by the placement of “leaves” between the patient and the radiation delivery device, which either block or allow the passage of radiation. Rotating the radiation delivery around the patient allows for more specific targeting of the cancer. In conventional radiation therapy, the beam is usually delivered from several different directions, possibly five to 10. The greater the number of beam directions, the more the dose will be confined to the target cancer cells, sparing normal cells from exposure. IMRT delivers radiation from every point on a helix, or spiral, in contrast to only a few points.

Research indicates that IMRT is a viable treatment option for brain tumors, but preliminary results have not shown an increase in survival with this radiation therapy technique. In a clinical trial, 25 patients with glioblastoma multiforme were treated with surgery followed by IMRT. Patients survived an average of 9.5 months and were free from cancer progression for 5.2 months. Approximately 40% of patients lived one year or more.[13]

Radioactive monoclonal antibodies: Monoclonal antibodies are targeted therapies that can locate cancer in the body based on unique proteins (antigens) present on the surface of some cancer cell. A radioactive material, such as iodine 131, may be attached to the monoclonal antibody. The result is a treatment in which the antibody acts as the homing device to the cancer and the radioactive iodine 131 kills the cancer cells.

When used in the treatment of brain tumors, radioactive monoclonal antibodies are usually injected directly into the tumor tissue that remains after surgery or implanted into the tumor bed (the space left after the tumor is removed). Administration occurs over the course of several days. This procedure appears to be associated with fewer side effects than brachytherapy or stereotactic radiosurgery. Another important advantage to radioactive monoclonal antibodies is this treatment approach appears to produce substantially fewer dead cells, reducing the need for additional surgery to remove the dead tissue.

Researchers from the Duke University Medical Center have reported that a radioactive monoclonal antibody (131I-m81C6) that can locate a protein called tenascin shows promise in the treatment of recurrent brain cancers. Tenascin is present in large quantities on the surface of high-grade glioma cells but is not present on normal brain cells.

Among 43 patients who were treated with the radioactive monoclonal antibodies, more than half (60%) survived one year or more after treatment. On average, patients with glioblastoma multiforme and gliosarcoma survived more than one year (64 weeks) and patients with anaplastic astrocytoma and anaplastic oligoastrocytoma survived nearly two years (99 weeks) after treatment.[14] Evaluation of this radioactive monoclonal antibody continues and a phase III trial has been planned.

A small clinical trial of another anti-tenascin monoclonal antibody that is labeled with radioactive yttrium 90 has also shown activity in the treatment of high-grade gliomas. There were 37 patients involved in this clinical trial who were disease-free after being treated with surgery and radiation. The patients with glioblastoma that were treated with the radioactive monoclonal antibody lived an average of 33.5 months and were disease-free for an average of 28 months. Twelve similar patients who did not receive the additional treatment lived an average of eight months.[15]

Intraoperative radiotherapy (IORT): Intraoperative radiotherapy is a technique for delivering a large, single dose of radiation directly to the tumor at the time of surgery. Conducting radiation therapy during surgery provides the advantage of decreasing the damage to normal brain tissue. While research has not shown IORT to improve survival over conventional external beam radiation therapy, outcomes are not worse with IORT. A clinical trial involving patients with malignant gliomas showed no significant difference in survival between the 32 patients who received IORT and a similar group of patients who underwent EBRT (see table 2).[16]

Table 2 Outcomes for patients undergoing intraoperative radiotherapy (IORT) and conventional EBRT

Radiosentizers: Radiosentizers are drugs that increase the effectiveness of radiation therapy. Cancers tend to have low levels of oxygen, making them less sensitive to radiation than cells with normal or high levels of oxygen. Radiosensitizers work by increasing the level of oxygen in cancer cells.

Researchers have reported that the addition of the radiosensitizer Efaproxyn™ (efaproxiral) prior to radiation therapy appears to reduce the risk of death by over half (54%) in the treatment of patients with brain metastases. There were 57 patients with brain metastases who received Efaproxyn™ prior to radiation therapy. The outcomes of these patients were compared to a group of patients with similar characteristics who were previously treated with only radiation therapy. Results indicate that the patients who received Efaproxyn™ lived longer on average, and a larger percentage of these patients lived one to two years or more (see table 3)[17]

Table 3 Survival with and without the radiosensitizer Efaproxyn™

Efaproxyn™ may also benefit patients with glioblastoma multiforme. The average survival was more than one year for a group of 50 patients with newly diagnosed glioblastoma multiforme who were treated with RSR13 immediately before radiation therapy.

Boron Neutron Capture Therapy (BNCT): BNCT combines a special form of radiation with a drug that concentrates in tumor cells. The drug, which is a compound of the element boron, “captures” radiation energy, becomes unstable, and disintegrates. In this process, cell-killing radiation is emitted. Normal tissue is spared because the drug accumulates in cancer cells to a greater degree than in normal brain tissue and the radiation is harmless unless it reacts with the boron.

Initial research with this form of treatment began more than 30 years ago, but it was not possible to administer it until advanced radiation beam technology was developed. Research with BNCT is aimed at finding suitable boron compounds that do not have harmful side effects and are capable of concentrating only in tumor cells. Currently, research is ongoing around the world, but findings are still in their early stages.

In Japan, 183 patients with different kinds of brain tumors have been treated with BNCT since 1968.[18] Initial results from clinical trials that are ongoing in Sweden indicate that BNCT is feasible in the treatment of glioblastoma multiforme. Seventeen patients have undergone treatment and researchers report that there have not been any BNCT-related side effects.[19] This study is ongoing and final results will indicate whether the treatment was effective.

BNCT was found to be safe in a clinical trial conducted at the Brookhaven National Laboratory in Upton , New York . In this trial, 53 patients with glioblastoma multiforme were treated with BNCT. Patients who received the highest doses of radiation to the brain experienced some side effects, especially somnolence, or an inclination to sleep. Radiation dose did not appear to affect survival; rather the aggressiveness of therapy for recurrence impacted survival to a greater degree than radiation dose.[20] Clinical trials of BCNU for glioblastomas are ongoing in a limited number of medical centers in the U.S.

Hyperthermia: Hyperthermia is heat therapy. The goal of this treatment technique is to heat the area where the cancer is to make the cancer cells more vulnerable to the effects of the cancer treatment. Cancer cells tend to be more sensitive to heat due to poor blood flow, decreased levels of oxygen, and an acidic environment. The procedure for hyperthermia involves careful and uniform administration of heat to the tumor while preventing contact with, and potential damage to, normal cells. Techniques used to heat the tissue involve directing different types of energy waves toward the cancer, such as radiofrequency waves, microwaves, and ultrasound. Researchers are working to determine the most effective way to deliver hyperthermia for the treatment of brain tumors.

A clinical trial that evaluated the addition of hyperthermia (“heat”) to brachytherapy found that the patients who received heat lived significantly longer and were free from cancer progression longer than patients who didn’t receive heat. All patients involved in this trial were initially treated with partial brain radiation therapy. Patients whose tumor was still implantable after the initial treatment were randomly assigned to receive brachytherapy boost with hyperthermia for 30 minutes immediately before and after brachytherapy (40 patients) or brachytherapy alone (39 patients). Of the patients who were randomized, outcomes were better for patients who were treated with hyperthermia (see table 4).[21]

Table 4 Outcomes for patients undergoing brachytherapy with or without hyperthermia

Surgery References

[1] Birkmeyer J, Siewers AE, Finlayson EVA, et al. Hospital Volume and Surgical Mortality in the United States . New EnglandJournal of Medicine. 2002;346:1128-37.

[2] Begg C, Elyn R. Riedel ER, et al. Variations in morbidity after radical prostatectomy. The New England Journal of Medicine. 2002;346:1138-1144.

[3] Hu J, Gold K, Pashos C, et al. Role of surgeon volume in radical prostatectomy outcomes. Journal of Clinical Oncology. 2003:21: 401-405.

[4] Hodgson DC , Zhang W, Zaslavsky AM. Relation of Hospital Volume to Colostomy Rates and Survival for Patients with Rectal Cancer. Journal of the National Cancer Institute. 2003;95:708-716.

[5] Smith TJ, Hillner BE and Bear HD. Taking Action on the Volume-Quality Relationship: How Long Can We Hide Our Heads in the Colostomy Bag? Journal of the National Cancer Institute. 2003;95:695-697.

[6] Fujimura M, Kumabe T, Tominaga T, et al. Routine clinical adoption of magnetic resonance imaging was associated with a better outcome after surgery in elderly patients with a malignant astrocytic tumour: a retrospective review. Acta Neurochir. (Wien) 2004;146:251-255.

[7] Duffau H, Capelle L, Sichez N, et al. Intraoperative mapping of the subcortical language pathways using direct stimultations. An anato-functional study. Brain. 2002;125:1990214.

[8] Keles GE, Lundin DA, Lamborn KR, et al. Intraoperative subcortical mapping for hemispherical perirolandic gliomas located within or adjacent to the descending motor pathways: evaluation of morbidity and assessment of functional outcome in 294 patients. Journal of Neurosurgery. 2004;100:369-375.

[9] Sala F, Lanteri P. Brain surgery in motor areas: the invaluable assistance of intraoperative neurophysiological monitoring. Journal of Neurosurgical Sciences. 2003 Jun;47(2):79-88.

[10] Kumabe T, Nakasato N, Nagamatsu K, et al. Intraoperative localisation of the lip sensory area by somatosensory evoked potentials. Journal of Clinical Neuroscience. 2005 Jan;12(1):66-70.

[11] Majos A, Tybor K, Stefanczyk L, et al. Cortical mapping by functional magnetic resonance imaging in patients with brain tumors. European Radiology. 2004; December 31 (published online ahead of print).

[12] Reinacher PC, van Velthoven V. Intraoperative ultrasound imaging: practical applicability as a real-time navigation system. Acta Neurochir Suppl. 2003;85:89-93.

[13] Kelly PJ. Stereotactic surgery: what is past is progogue. Neurosurgery. 2000;46:16-27.

[14] Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-Guided Surgery with 5-Aminolevulinic Acid for Resection of Malignant Glioma: an Aandomised Controlled Multicentre Phase III Trial. *Lancet Oncology.*Early online publication April 13, 2006. DOI:10.1016/S1470-2045(06)70665-9.

Radiation References

[1] Weber DC, Lomax AJ, Rutz HP, et al. Spot-scanning proton radiation therapy for recurrent, residual and untreated intracranial meningiomas. Radiotherapy Oncology. 2004;71(3):247-9.

[2] Andrews DW, Scott CB, Sperduto PW, et al. Whoel brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665-1672.

[3] O’Neill BP, Iturria NJ, Link MJ, et al. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. International Journal of Radiation Oncology Biology Physics. 2003;55(5):1169-1176.

[4]) Souhami L, Seiferheld W, Brachman D, et al. Radomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group-93-05 protocol. International Journal of Radiation Oncology Biology Physics. 2004;60(3):853-60.

[5] Laws ER, Sheehan JP, Sheehan JM, et al. Stereotactic radiosurgery for pituitary adenomas: a review of the literature. Neurooncology. 2004;69(1-3):257-72

[6] Kondziolka D, Nathooo N, Flickinger JC, et al. Long-term results after radiosurgery for benign intracranial tumors. Journal of Neurosurgery. 2003; 53:815-821.

[7] Tatter SB, Shaw EG, Rosenblum ML, et al. An inflatable balloon catheter and liquid 125I radiation source (GliaSite Radiation Therapy System) for treatment of recurrent malignant glioma: multicenter safety and feasibility trial. Journal of Neurosurgery. 2003;99(2):297-303.

[8] Rogers L, Shaw E, Rock JP, et al. Interim Results of A Phase II Study of Resection and GliaSite Brachytherapy for a Single Brain metasesis. Proceedings from the 46th annual meeting of the American Society of Radiology and Oncology held in Atlanta GA , October 2004; Abstract #1005.

[9] Gabayan A, Sanan A, Bastin K, et al. Gliasite Radiotherapy System for Treatment of Recurrent Malignant Glioma: A Multi-Institutional Analysis. Proceedings from the 46th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, held in Atlanta GA , October 2004. Abstract #1002.

[10] Halligan JB, Selzer KJ, Rostomily RC, et al. Operation and permanent low activity 125I brachytherapy for recurrent high-grade astrocytomas. International Journal of Radiation Oncology, Biology, Physics. 1996;35:541-547.

[11] Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. Journal of Clinical Oncology. 2002;20(6):1635-42.

[12] Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T. High-dose Conformation Radiotherapy for Supratentorial Malignant Glioma: A Historical Comparison. Lancet Oncology. 2005; 6: 953-960.

[13] Sultanem K, Patrocinio H, Lambert C, et al. The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: preliminary results of a prospective trial. International Journal of Radiation Oncology Biology Physics. 2004;58(1):247-52.

[14] Reardon D, Akabani G, Coleman R, et al. Salvage Radioimmunotherapy With Murine Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 for Patients With Recurrent Primary and Metastatic Malignant Brain Tumors: Phase II Study Results. Journal of Clinical Oncology. 2005; 24: 115-122.

[15] C Grana, M Chinol, C Robertson, et al. Pretargeted adjuvant radioimmunotherapy with Yttrium-90-biotin in malignant glioma patients: A pilot study. British Journal of Cancer. 2002;86:207-212.

[16] Nemoto K, Ogawa Y, Matsushita, H, et al. Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas. BMC Cancer. 2002;2:1.

[17] Shaw E, Scott C, Suh J, et al. RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database. Journal of Clinical Oncology. 2003;21(12):2364-71.

[18] Nakgawa Y, Pooh K, Kobayashi T, et al. Clinical review of the Japanese experience with boron neutron capture therapy and a proposed strategy using epithermal neutron beams. *Journal of Neurooncology.*2003;62:87-99.

[19] Capala J, Stenstam BH, Skold K, et al. Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden . Journal of Neurooncology. 2003;62:135-144.

[20] Diaz AZ. Assessment of the results from the Phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician’s point of view. Journal of Neurooncology. 2003;62:101-109.

[21] Sneed PK , Stauffer PR, McDermott MW, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme. International Journal of Radiation Oncology, Biology, Physics. 1998;40(2):287-95.

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