Radiation Therapy

Radiation Therapy

Overview

The objective of radiation therapy is to kill cancer cells for a maximum probability of cure with a minimum of side effects. Radiation is usually delivered in the form of high-energy beams that deposit the radiation dose directly to the location of cancer cells in the body. Radiation therapy, unlike chemotherapy, is considered a local treatment. Cancer cells can only be killed where the actual radiation is delivered to the body. If cancer exists outside the radiation field, the cancer cells are not destroyed by the radiation.

Radiation therapy is commonly used to treat brain cancers. Modern radiation techniques have led to increased remission rates and improved local-regional control of cancer growth. However, radiation kills normal as well as cancer cells, often causing severe and debilitating side effects. The management of radiation-induced side effects often focuses on treating the symptoms as they manifest; however, preventing complications of radiation therapy is clearly more desirable than treating them.

Radiation therapy alone can be the treatment of choice for some primary or metastatic brain cancer, while combined radiation therapy, surgery and chemotherapy is used for others. Therefore, it is essential for patients with brain cancer to be treated at medical centers where radiation oncology, medical oncology and surgical specialists are available for a team approach to treatment. Stereotactic radiation therapy involves sophisticated scanning equipment and is now considered standard therapy for brain cancer. Thus, the chosen medical facility should be capable of performing this procedure. For specific information concerning outcomes of radiation therapy for each type of cancer, refer to the specific treatment sections.

Radiation can be delivered in several different ways. External beam radiation therapy (EBRT) is delivered via an external machine. Brachytherapy refers to radiation that is delivered by ìseedsî, which are needles or tubes containing a radioactive isotope. These radioactive ìseedsî are placed into the area of the cancer and removed when the appropriate dose is administered. Radiation can also be linked to elements such as iodine or monoclonal antibodies and injected into a vein. Monoclonal antibodies home to specific cancer cells, allowing delivery of radiation to a specific target area.

Delivery of Radiation Therapy

External Beam Radiation Therapy (EBRT): EBRT is delivered via machines called linear accelerators, which produce high-energy external radiation beams that penetrate the tissues and deliver the radiation dose deep into the areas 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.

EBRT is typically delivered on an outpatient basis for approximately 6 to 8 weeks. EBRT begins with a planning session, or simulation, during which the radiation oncologists 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 is treated with radiation from multiple directions. The actual area receiving radiation treatment may be large or small, depending on the features of the cancer.

Cobalt machines use cobalt isotopes as the radiation source. A nuclear reactor manufactures the isotopes. EBRT does not make a person radioactive. Once the waves or particles collide with a target (ideally a tumor cell), the energy is lost and is no longer a threat to the patient or anyone else.

Simulation: After an initial consultation with a radiation oncologist, the next session is usually a planning session which is called a "simulation". During this session, the radiation treatment fields and most of the treatment planning are determined. Of all the visits to the radiation oncology facility, the simulation session may actually take the most time. During simulation, the patient lies on a table somewhat similar to that used for a CT scan. The table can be raised and lowered and rotated around a central axis. The "simulator" machine is a machine whose dimensions and movements closely match that of an actual linear accelerator. Rather than delivering radiation treatment, the simulator lets the radiation oncologist and technologists see the area to be treated. The room is periodically darkened while the treatment fields are being set, and temporary marks may be made on the patient's skin with magic markers. The radiation oncologist is aided by one or more radiation technologists and often a dosimetrist, who performs calculations necessary in the treatment planning. The simulation may last anywhere from fifteen minutes to an hour or more, depending on the complexity of what is being planned.

Once the aspects of the treatment fields are satisfactorily set, x-rays representing the treatment fields are taken. In most centers, the patient is given multiple "tattoos" which mark the treatment fields, and replace the marks previously made with magic markers. These tattoos are not elaborate and consist of no more than pinpricks followed by ink, appearing like a small freckle. Tattoos enable the radiation technologists to set up the treatment fields each day with precision, while also allowing the patient to wash and bathe without worrying about obscuring the treatment fields. Radiation treatment is usually delivered in another room separate from the simulation room. The treatment plans and treatment fields resulting from the simulation session are transferred over to the treatment room, which contains a linear accelerator focused on a patient table similar to the one in the simulation room. The treatment plan is verified and treatment is started only after the radiation oncologist and technologists have rechecked the treatment field and calculations, and are thoroughly satisfied with the setup.

Treatment Schedules: Conventional EBRT for brain cancer consists of external beams of energy aimed at the cancer or at the whole brain, which is called whole-brain radiation therapy. Some cancers that spread rapidly are treated with whole-brain radiation therapy plus highly focused stereotactic radiation delivered only to the cancer. This is discussed below under the section on stereotactic radiation therapy.

Radiation therapy often begins a week or two after surgery, or as soon as the surgical wound heals. Whole-brain radiation therapy is usually recommended for a large or spreading brain cancer. Conventional radiation is delivered in divided doses, called fractions, over a long period of time. The usual fraction of standard, conventional, external radiation for primary brain tumors is 180-200 cGy. It is given over a six-week period, five days a week. The total dose is usually 5400-6000 cGy for adults.

A typical course of radiation for brain cancer would involve daily radiation treatments Monday through Friday for 5 to 6 weeks. However, other treatment schedules are also used. Each session consists of a few minutes to aim the machine, and then a few more minutes to deliver the rays. Patients must remain perfectly still during the treatment. The actual radiation treatment generally lasts no more than a few minutes, during which time the patient is unlikely to feel any discomfort. Anesthesia is not needed for radiation treatment, and patients generally have few restrictions on activities during radiation therapy. Many patients continue to work during the weeks of treatment. Patients are encouraged, however, to carefully gauge how they feel and to not overexert themselves.

Prevention of Radiation Side Effects

Several techniques help to prevent radiation side effects. Effective strategies include altering the manner in which radiation is delivered and administering drugs that protect normal cells from radiation damage. Another early technique involved physical shielding with lead blocks to prevent radiation from penetrating parts of the body adjacent to the cancer.

Dose Fractionation and Hyperfractionation of Radiation Dose: Originally, radiation therapy was delivered in one large dose; however, it is now understood that does fractionation, or splitting up the total dose of radiation therapy, is less toxic and more effective. Dose fractionation allows radiologists to administer radiation on a daily basis, thereby facilitating the delivery of a larger total dose of radiation to the cancer than would have been possible as a single dose. Currently, most radiation treatments are based on daily administration for 5 days a week. This schedule is strictly for the convenience of maintaining a normal workweek. However, the 24-hour interval and the two-day interval between doses allows for recovery of normal tissues between doses while cancer cells, in general, have less capability of recovery in this 24-hour period. There is no doubt that using fractionation has reduced radiation-induced side effects compared with side effects caused by delivery as a single dose. However, the relatively long intervals between doses of radiation may allow cancer cells to recover as well as normal cells. More recently, it has been found that some cancers are best treated by reducing the 24-hour interval between doses to 6-8 hours, in order to enhance the toxic effects on cancer cells, while still preserving an adequate time interval for the recovery of normal cells. This technique, called hyperfractionation, is being widely used to treat a variety of cancers. It is important for patients with cancer to be treated at medical centers that have sophisticated equipment and the personnel to perform hyperfractionated radiation when it is indicated.

Stereotactic Radiation: Stereotactic radiation therapy is a promising approach for the treatment of some cancers with decreased toxicity to normal tissues. This approach to the treatment of cancer by radiation therapy decreases the amount of normal tissues exposed to radiation. Using computerized tomography (CT) scans and other scans, radiation oncologists have developed methods for determining the cancer size and shape in 3 dimensions. This allows high-dose external beam radiation therapy to be delivered primarily to the cancer with less damage to normal cells. It is important for patients with cancer to be treated at centers with sophisticated equipment to carry out conformal radiation.

Surgery

In some instances, there is increased intra-cranial pressure because the tumor blocks the flow of cerebrospinal fluid. When this is the case, an operation is necessary for decompression. In some patients, surgical placement of a temporary or permanent shunt (tube) is required to drain excess cerebrospinal fluid.

Stereotactic surgery uses computers to create a three-dimensional image in order to provide precise information about a tumor's location and its position relative to the many structures in the brain. Stereotactic techniques can be used by the surgeon to map out the surgical procedure and "rehearse," or by the radiation specialist to plan radiation therapy.

The development of new surgical techniques over the past twenty years has led to a reduction in operative morbidity and mortality. Surgery followed by whole-brain radiation therapy is still considered the method of choice for the treatment of metastases to the brain.

Complications of Radiation

Radiation therapy is painless. Patients will not feel, see, or hear anything, but a few people notice an unusual smell. Patients are not radioactive during or after conventional radiation therapy, so there is no need to take any special precautions for the safety of others. Although patients do not feel anything during a radiation treatment, the effects of radiation gradually build up over time. Most patients have very few side effects; however, many patients experience fatigue as treatment continues.

The vast majority of patients are able to complete radiation therapy without significant difficulty. Side effects and potential complications of radiation therapy are infrequent and, when they do occur, are typically limited to the areas that are receiving treatment with radiation. The chance of a patient experiencing side effects, however, is highly variable. Side effects of radiation therapy affect each person differently. Some patients experience few or none of them and are able to continue working and performing normal activities. Patients who experience side effects should inform the technologists and radiation oncologist, because treatment is almost always available and effective.

Perhaps the most common side effects from radiation therapy are mucositis and xerostomia. Mucositis sometimes occurs when radiation that is administered directly to or near the head and neck region causes damage to the mucosal lining of the entire gastrointestinal tract. This results in inflammation and sloughing of the mucosal cells, causing pain and increasing the risk of infection. Xerostomia is a chronic dry-mouth condition, which results from radiation therapy that damages the salivary glands. Xerostomia can greatly impair a patientís ability to speak, chew, swallow and taste and therefore, can have a negative effect on a patientís quality of life.

Sometimes, radiation therapy affects blood counts, but this is not usually the case in patients with brain tumors. However, many radiation therapy institutions make it a policy to check the blood counts at least once during radiation treatments.

It is common for some patients to note changes in sleep or rest patterns during the time they are receiving radiation therapy and some patients will describe a sense of tiredness and fatigue.

The major side effect of radiation for brain cancer is neurologic damage to normal tissues. This can lead to mild, moderate, or severe brain damage. This can be limited by newer techniques of radiation therapy.

One of the major side effects of radiation therapy is the development of a second cancer. This often takes years to develop, but is a frequent cause of second cancers in the head and neck area

Brachytherapy

Brachytherapy is also called interstitial radiation, intracavitary radiation, radiation implants, radiation seeding or radioactive pellets. Brachytherapy involves of implanting sources of radiation energy directly into a brain cancer. While standard radiation aims rays at the cancer from outside the body, interstitial radiation attacks the cancer from the inside. The advantage to interstitial radiation is that the effect on normal brain tissue may be greatly reduced. For this type of therapy to be effective, the cancer must be no more than 2 inches in diameter and surgically accessible. Larger tumors may require surgery to reduce the size of the tumor before the radiation sources are implanted. Interstitial radiation is a local therapy. It is not commonly used for widely spread or multiple tumors. This type of therapy can be used for newly diagnosed or recurrent tumors, as a boost before or following standard EBRT for newly diagnosed or recurrent cancers.

Interstitial radiation requires placement of catheters (tubes) into or near the cancer using CT or MRI-directed stereotactic surgical techniques. The sources of radiation, usually in pellet form, are then placed into the catheters. Depending on the isotopes used, the implant is removed either after a few days or several months, or left in place permanently. Steroids are commonly used with this therapy to decrease brain swelling. Different radioactive isotopes are currently being used as implants and others are being developed. Follow-up surgery to remove dead cancer cells is required in about 30% - 40% of the patients receiving this therapy. Unlike external radiation, with interstitial radiation the patient is radioactive and precautions are needed until the implant is removed or until a predetermined amount of time has elapsed.

Stereotactic Radiation Therapy (Radiosurgery, Gamma Knife Therapy

Stereotactic radiation therapy is now a standard form of treatment for primary and metastatic brain cancer. The use of CT scans and MRI allows precisely focused, high-dose radiation beams to be delivered to a small brain cancer (usually 1› inches or less in diameter) in a single or multiple treatment sessions. The cancer can be located in an area of the brain or spinal cord that might be considered inoperable. Using special computer planning, this treatment minimizes the amount of radiation received by normal brain tissue. Prior to stereotactic radiation therapy, the patient is fitted with a head frame. CT and/or MRI scans are performed with the head frame in place to obtain information necessary for treatment planning. Once the planning is completed, treatment can begin. Because treatment is totally non-invasive, patients maintain their normal function throughout this process. Patients are completely awake and alert throughout the entire painless procedure. Stereotactic radiation therapy can be delivered as a single dose or in daily doses (fractionated) or more than one fraction per day (hyperfractionated).

Stereotactic radiation therapy is also used as a local "boost" following conventional radiation therapy, for a recurrent tumor when the patient has already received the maximum safe dose of conventional radiation therapy, as a substitute for surgery for a benign tumor (such as a pituitary, pineal region or acoustic tumor) or for a metastatic brain tumor

Possible side effects of stereotactic radiation therapy 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.

Two types of machines are used routinely to deliver stereotactic radiation therapy, Gamma Knife and Linac (adapted linear accelerators). Cyclotrons, which generate proton beam radiosurgery, are also being investigated for stereotactic treatment of brain tumors.

Gamma Knife: The Gamma Knife contains 201 radioactive cobalt sources, which can all be computer-focused onto a single area. 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 cancer. The couch is then pushed into a globe that contains radioactive cobalt. 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 Radiosurgery: An adapted linear accelerator delivers a single, high-energy beam that is computer-matched to the cancer. 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.

Re-irradiation

Radiation kills normal cells as well as cancer cells. Since brain tissue cannot replace itself, the effects of radiation are cumulative. Only so many normal cells can be killed before severe side effects occur. For this reason, re-treatment with conventional fractionated radiation is not often recommended. However, re-irradiation is possible in selected circumstances. It depends on the location of the tumor and its relation to critical brain tissue, when the previous radiation was delivered, the amount of radiation originally delivered, the type of tumor and the age of the patient. Interstitial radiation therapy and stereotactic radiation therapy are frequently used for re-irradiation of selected patients with recurrent malignant gliomas and metastatic brain tumors after previous conventional fractionated external radiation.

Strategies to Improve Radiation Treatment of Brain Cancer

The progress that has been made in the treatment of brain cancers with radiation therapy has resulted from doctor and patient participation in clinical studies. Future progress in the therapy of brain cancer will result from continued participation in appropriate studies designed to refine radiation techniques and effectively combine radiation with other treatment modalities. There are several areas of active exploration aimed at improving the radiation treatment of brain tumors.

Radiosensitizers: Cancers with low levels of oxygen are less responsive to radiation than cancers with normal or high levels. Increased oxygen makes cancers more sensitive to the deadly effects of radiation therapy. Radiosensitizers are drugs which increase the oxygen content in tumors. Currently, there are no FDA-approved radiosensitizer drugs on the market. However, radiosensitizers are being tested in clinical trials. One such drug is RSR13, which creates its effects by binding to hemoglobin and changing its shape. Hemoglobin is a molecule in the blood that is responsible for carrying and delivering oxygen to cells throughout the body. Normally, oxygen binds to hemoglobin and travels through the blood, where it is released and delivered to cells. The change in shape of hemoglobin caused by RSR13 creates the formation of a loose bond between oxygen and hemoglobin. This allows oxygen to be released from hemoglobin easily, forcing its delivery to hypoxic cells.
The first phase of clinical trials evaluating RSR13 in patients with glioblastoma multiforme suggested a significant improvement in survival. Results of the second phase of clinical trials involved 50 patients with newly diagnosed glioblastoma multiforme. These patients received 6 weeks of RSR13 plus cranial radiation. The average duration of survival following treatment for these patients was one year, compared to 9 months for patients who did not received RSR13. The significant improvement in survival of patients plus tolerability of treatment had lead to the initiation of the last phase of clinical trials evaluating RSR13 plus cranial radiation for treatment of newly diagnosed glioblastoma multiforme.
Radiation Protectors: Over the past 50 years, many drugs called radiation protectors have been tested in the laboratory for prevention of radiation damage to normal cells and tissues. For such drugs to work effectively, they have to protect the normal cells, but not the cancer cells, from radiation damage. EthyolÆ is a radiation protector and the only drug that has been approved by the FDA for use in patients receiving radiation therapy for cancers of the head and neck. Clinical trials have demonstrated that Ethyol can reduce both acute and late radiation-induced side effects of treatment for head and neck tumors. However, this drug has not been FDA approved for use with radiation for brain tumors.

Boron Neutron Capture Therapy: Treatment with Boron Neutron Capture Therapy (BNCT) involves the use of a non-toxic Boron compound and external radiation. First, the patient is given the Boron compound through a vein. This compound selectively collects in glioblastoma cells. Next, radiation in the form of fast or slow moving neutrons, depending upon the depth of the tumor, is aimed directly at the glioblastoma cells. This type of radiation is not harmful to normal cells. However, when the neutrons from the radiation reach the Boron compound, a reaction occurs in which lethal radiation is given off. This radiation kills the cell with a penetration depth of only one cell. This allows radiation to kill cancer cells while sparing healthy cells from detrimental effects.

Hyperfractionated and/or Accelerated Radiation Therapy: Conventional fractionation of radiation therapy is defined as one fraction daily of 180 to 200 cGy, five times a week, for six weeks, for a total dose of 5400 to 6000 cGy. Researchers are attempting to determine if two to three fractions of radiation per day (hyperfractionated radiation) is more effective than a single daily dose. The rationale for this approach is that tumor cells repair less rapidly than normal tissues. By administering two to three fractions of radiation per day the cancer cells will not repair and normal cells will. It is currently not clear whether hyperfractionated radiation regimens are superior to conventional fractions for the treatment of glioblastoma. Two randomized trials in patients with glioblastoma have failed to show superior outcomes using hyperfractionated radiation therapy compared to conventional fractions.

Hyperthermia and Radiation Therapy: Heating tumors (hyperthermia) makes them more sensitive, and therefore responsive, to the lethal effects of radiation therapy. In one clinical study, adults with newly diagnosed surgically removed glioblastomas less than two inches in diameter were treated with radiotherapy with or without hyperthermia (heat). The time to tumor progression and the duration of overall survival were significantly longer for patients who received hyperthermia than for those who did not. The average survival for the hyperthermia group was 85 weeks, compared to 76 weeks for the radiotherapy only group. The 2-year survival for the hyperthermia group was 31%, compared to 15% for the brachytherapy only group. The researchers concluded that adjuvant interstitial brain hyperthermia given before and after brachytherapy boost, following conventional radiotherapy, significantly improved survival of patients with focal glioblastoma, with acceptable toxicity.

Intra-operative Radiation Therapy: Intra-operative radiotherapy is a technique for delivering radiation directly to the tumor at the time of the operation. A radiation boost delivered with high-energy electron beams can intensify the anti-tumor therapy in patients undergoing cancer surgery. Intra-operative radiotherapy can improve the precision of radiation, thus decreasing the damage to normal tissue.
A recent study was conducted involving 17 patients with primary or recurrent high-grade malignant gliomas, including glioblastoma multiform, who were treated after surgical resection with a single dose of intra-operative radiation therapy. For glioma patients, the 18-month survival rate was 56%. For patients with recurrent gliomas, the 18-month survival rate was 47% and the average survival time was 13 months. The researchers concluded that intra-operative radiation therapy is an attractive, tolerable and feasible treatment modality. Researchers will continue to evaluate what role, if any, intra-operative radiation therapy has for the treatment of glioblastoma multiforme.
Monoclonal Antibodies: Monoclonal antibodies are proteins that can be made in the laboratory and are designed to recognize and bind to very specific cells such as cancer cells. This binding action stimulates the immune system to attack and kill the cancerous cells. Monoclonal antibodies can also be fused with a toxin or radioactive substance which is delivered to the cancer cell upon binding with the antibody. A significant benefit of this approach is that monoclonal antibodies only target cancer cells, sparing healthy cells from destruction. This is in contrast to chemotherapy or radiation, which do not differentiate between cancer cells and healthy cells in the body, leading to potentially destructive side effects.
Researchers have conducted an early phase clinical trial involving the surgical removal of the cancer followed by an injection of a radioactive isotope linked to a monoclonal antibody called Iodine-131 Antitenascin 81C6 (I-labeled 81C6). Antitenascin 81C6 identifies cancerous glioma cells by recognizing small proteins displayed on the surface of the cancer cells, called tenascin. When antitenascin binds to the cancerous glioma cells, the immune system is stimulated to attack the cancer cells. I-131 is a radioactive isotope substance that is attached to antitenascin 81C6. Radioactive isotopes kill cancer cells by spontaneously emitting forms of radiation. When antitenascin binds to cancer cells, the attached I-131 destroys these cells by emission of its radiation. I-labeled 81C6 not only provides two separate treatment strategies, but also allows the delivery of greater amounts of radiation directly to the cancer cells, while minimizing radiation exposure to normal cells. In this study, I-labeled 81C6 was injected directly into the cavity of the brain from which the cancer was removed in 42 patients with malignant gliomas who had not received prior treatment. The average duration of survival for patients was extended over standard treatment to one and half years. Some patients experienced neurological complications from the procedure, including seizures, memory loss, an inability to coordinate muscle movement and slight weakness on one side of their body. Future clinical trials evaluating this treatment approach will be conducted to further refine the overall strategy and confirm these encouraging results.

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